The researchers noted that this study alone does not allow conclusions to be drawn about the causes of the associations identified in the study. However, they argued that their results suggested that certain developmental and academic problems are common in children and teens with HIV, even well-controlled HIV.

They also noted that mental health and coping issues of children’s primary caregivers likely influence their parenting ability, regardless of the caregivers’ HIV status. This could potentially affect treatment adherence and viral outcomes in the children.

According to the study authors, it is important to understand the relationship between the severity of psychiatric symptoms in HIV-positive youth and HIV severity and type of highly active antiretroviral therapy (HAART). They argued that behavioral and cognitive problems are related to social and academic difficulties as well as risky sexual behavior and greater risk of HIV transmission.

The study authors also noted that in a previous study they conducted, HIV-positive children and teens were more likely to receive medication or other interventions for psychological problems than children who were exposed to HIV before birth but not infected. They speculated that their findings may be due to effects of HIV or HAART on behavioral problems in children with HIV.

In this two year-long study, researchers aimed to assess psychiatric symptoms and cognitive, social, and academic performance as well as quality of life in youth born with HIV. They also monitored the children’s disease severity and HAART regimens to find any link between these and psychiatric symptoms or other impairments.

The study included 319 children between the ages of six and 17 who were born in the United States or Puerto Rico. Just over half (51 percent) were male, and 62 percent were 12 years old or older at the time of the study.

Most children in the study (74 percent) had current CD4 percentages (a measure often used in children rather than CD4, or white blood cell, count) of 25 percent or greater at the beginning of the study. More than half (59 percent) had undetectable viral loads (amount of HIV in the blood), defined in this study as less than 400 copies per milliliter.

Most participants (81 percent) were on HAART at the start of the study. All participants had recent or past exposure to Sustiva (efavirenz) which is a non-nucleoside reverse transcriptase inhibitor that, according to the study authors, may be linked with psychiatric problems.

Half of the participants lived with their HIV-positive mother, and 70 percent had one or more additional HIV-positive people in the home.

Results showed that a third of teens born with HIV qualified as having at least one of four main categories of psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), depression, disruptive behavior disorder or conduct disorder, and anxiety.

Disruptive behavior disorders are characterized by behaviors like temper tantrums, physical aggression, excessive argumentativeness, stealing, and other forms of defiance or resistance to authority.

In addition, 54 percent of children whose primary caregivers had at least one psychiatric disorder also had at least one psychiatric disorder themselves. Thirty-one percent of children whose primary caregivers did not have a psychiatric disorder had at least one disorder.

Findings regarding measures of HIV severity and the severity of psychiatric symptoms were mixed. For instance, a lower initial CD4 percentage was linked with more severe conduct disorder symptoms but with less severe depression symptoms.

A higher initial viral load was associated with more severe depression symptoms but also with less severe ADHD symptoms. Greater HIV disease severity, such as a previous AIDS-related infection, was linked with less severe ADHD symptoms.

Older age at the nadir CD4 percentage (the lowest percentage of CD4 cells since HIV infection) was associated with more severe disruptive behavior disorder, and youth with a lower nadir CD4 percentage and younger age at peak HIV viral load had lower quality of life. According to the study authors, these findings suggest that poorer immune system performance or control of HIV virus at different ages affects different brain functions.

Youth with a lower nadir CD4 percentage had impaired social function, and those with higher peak viral load in addition to lower nadir CD4 percentage took longer to process information.

The researchers found little evidence for an association between specific HAART regimens and severity of psychiatric symptoms.

However, there was some evidence for an association between less severe ADHD symptoms and a HAART regimen containing a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor.

Exposure to Sustiva was associated with impaired working memory but with better academic performance. Five or more years of HAART was associated with better social functioning but lower information processing speeds; however, the exact effects differed slightly depending on HAART regimen. Youth with at least five years of protease inhibitor exposure had poorer social functioning and impaired working memory.

For more information, please see the study in the Archives of Pediatric and Adolescent Medicine (abstract).

Based on their results, the study authors recommended future studies to look for links between individual protease inhibitors and increased risk of death. However, they also noted that deaths are rare, which makes it difficult to find such links even if they exist.

According to the study authors, concerns have arisen recently that protease inhibitors may be linked to problems with the electrical conductivity of the heart. In particular, researchers have found that the drugs may affect heart rate and the timing of heartbeats.

The researchers noted that these heartbeat abnormalities, which can be measured on an electrocardiogram, are associated with congestive heart failure and risk of sudden death.

In this study, the authors evaluated whether people with HIV who are taking protease inhibitors are at increased risk for non-hemorrhagic stroke, a type of stroke caused by lack of oxygen in the brain rather than bleeding, or sudden death. Non-hemorrhagic strokes are a common complication of heart attacks.

The study included 49,737 HIV-positive adults, 64 percent of whom were exposed to protease inhibitors for a median of 1.5 years. The median participant age was 43 years old. About half were Caucasian, and 73 percent were male.

Results showed that less than 0.2 percent of participants suffered from sudden death during the study and about 0.3 percent suffered a non-hemorrhagic stroke.

Participants who experienced either sudden death or a stroke were more likely to be male, have a low body mass index (less than 18 kg/m²), smoke, take medications for high blood pressure, or have diabetes.

In addition, participants who suffered sudden death or a stroke had a longer median exposure to protease inhibitors, nucleoside reverse-transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors. They also had higher cholesterol and triglyceride levels and lower CD4 (white blood cell) counts.

After adjusting for other risk factors such as age and smoking, the researchers found that current protease inhibitor use was not associated with an increased risk of either outcome. However, cumulative protease inhibitor use was associated with a slightly higher risk of sudden death and stroke.

For more information, please see the study in the Journal of Infectious Diseases.

Based on the results, the study authors recommended implementing strategies to reduce smoking, and therefore lung cancer risk, in HIV-positive adults.

The study authors also speculated that links between lung cancer and HIV or immune deficiency in previous studies were caused by overrepresentation of people with advanced HIV infections in lung cancer studies or accidental inclusion of cancers known to be caused by infectious diseases, such as Kaposi’s sarcoma of the lung.

According to the study authors, previous research has shown that people with HIV are at about a two- to seven-fold increased risk for lung cancer compared to people without HIV (see related AIDS Beacon news). However, scientists are uncertain whether this higher risk arises from HIV or from lifestyle factors, such as a greater rate of smoking in people with HIV.

According to the study authors, while people with HIV are known to be more likely to smoke than people without HIV, some studies have shown that HIV-positive adults with lower CD4 (white blood cell) counts are more likely to develop lung cancer than adults with higher CD4 counts. This might suggest that weakened immune systems caused by HIV are also a factor in higher lung cancer rates among people with HIV.

The authors also noted that HIV can lead to a greater risk for lung infections such as pneumonia or tuberculosis, which could play role in increased lung cancer risk.

In this study, the researchers aimed to determine whether HIV infection is a factor in higher lung cancer risk in people with HIV or whether the increased risk is due solely to lifestyle factors, especially smoking.

The study included 68 HIV-positive Swiss adults who developed lung cancer between 1985 and 2010. The study also included 337 HIV-positive Swiss adults without lung cancer who were matched by age (within nine years), sex, treatment center in Switzerland, route of HIV infection (sexual, injection drug use, etc.), and date enrolled in the study.

The researchers collected information on each participant’s CD4 counts, viral loads (amount of HIV in the blood), nadir CD4 count (the lowest CD4 count measured after HIV infection), antiretroviral therapy regimen, and smoking habits. They also examined their medical records for any HIV-related lung infections.

Most of the participants (79 percent) were male, and 37 percent were intravenous drug users, who are known to be at higher risk of lung cancer. Participants who had cancer developed it at an average age of 50 years old; 86 percent died within two years of diagnosis.

Results showed that participants who currently smoked were over 14 times more likely to develop lung cancer than participants who had never smoked, with an increased risk in patients with heavier smoking habits. Participants who were former smokers were about three times more likely to develop lung cancer, although the study authors stated that the difference was not statistically significant.

Contrary to results from other studies, lung cancer risk was not associated with nadir CD4 count, CD4 count within a year of lung cancer diagnosis, or CD4 count one to two years before diagnosis. There was no difference in average CD4 counts between participants who developed lung cancer and those who did not, for up to 10 years prior to lung cancer diagnosis.

The researchers also found no link between lung cancer and viral load, taking or not taking antiretrovirals, or history of HIV-related lung infections.

For more information, please see the study in the British Journal of Cancer (abstract).

Based on their results, the study authors suggested that even lower cutoff levels for residual HIV in the blood may be necessary to avoid treatment failure.

The goal of antiretroviral therapy is to reduce viral loads (amount of HIV in the blood) to levels that are undetectable with most tests, usually less than 50 copies per milliliter. Achieving an undetectable viral load is known as attaining viral suppression.

According to the study authors, however, newer viral load tests are able to detect residual HIV levels at less than 50 copies per milliliter, even down to 5 copies to 10 copies per milliliter in some cases.

In this study, the researchers aimed to determine if having a viral load that is very low – less than 50 copies per milliliter, and thus considered suppressed under the usual definitions – but still detectable using these newer methods affects the risk of later treatment failure.

In particular, the study authors looked at the risk of having viral load increase to above 50 copies per milliliter and above 400 copies per milliliter, as a function of current viral load. According to current U.S. treatment guidelines, a viral load above 200 copies per milliliter is considered treatment failure (see related AIDS Beacon news).

The study included 1,247 HIV-positive adults with viral loads of 49 copies per milliliter or less. Just under half (45 percent) of study participants were Caucasian and over half (53 percent) were male.

Of 1,247 study participants, 19 percent had viral loads between 40 and 49 copies per milliliter, 41 percent had viral loads that were below 40 copies per milliliter but still detectable using the sensitive tests, and 40 percent had viral loads that were not detectable using the sensitive tests.

The researchers found that patients with undetectable viral loads had been on highly active antiretroviral therapy longer and had a longer period of viral suppression prior to starting the study. They also had slightly lower viral loads before starting therapy and higher CD4 (white blood cell) counts. They were more likely to be Caucasian and to be taking a non-nucleoside reverse transcriptase inhibitor-based therapy.

During the course of the study, 17 percent of study participants experienced viral load increases to above 50 copies per milliliter and 6 percent experienced increases to above 400 copies per milliliter.

The risk of having a viral load above 50 copies per milliliter was 34 percent for study participants with initial viral loads between 40 and 49 copies per milliliter, 11 percent for participants with low but detectable viral loads, and 4 percent for participants with undetectable viral loads.

The risk of having a viral load above 400 copies per milliliter was 13 percent for participants with initial viral loads between 40 and 49 copies per milliliter, 4 percent for participants with low but detectable viral loads, and 1 percent for participants with undetectable viral loads.

In addition, the risk of having a viral load increase was lower in participants who had a longer period of viral suppression before starting the study.

For more information, please see the study in Clinical Infectious Diseases (abstract).

The researchers also found that more than a third of study participants had stopped working five years after the start of the study.

Based on the results, the study authors concluded that people with HIV are still at a substantial risk of stopping employment after their diagnosis and recommended further investigation into strategies to help keep people with HIV who also have other health conditions employed.

Prior research has suggested that stigma and health problems related to being HIV-positive can have a significant impact on various aspects of an individual’s lifestyle, including employment.

However, newer treatment regimens, such as highly active antiretroviral therapy, offer people with HIV a more normal lifestyle and health status. As a result, more recent studies have suggested HIV now has a minimal impact on HIV-infected adults’ ability to work (see related AIDS Beacon news).

Nonetheless, according to the study authors, other diseases and conditions that people with HIV are more prone to – including heart disease, diabetes, cancer, and other problems – may affect a person’s ability to work.

In this study, researchers aimed to evaluate the impact of both HIV itself and other additional health conditions on the ability of people with HIV in France to work.

The study included 622 HIV-positive adults who were diagnosed with HIV between 2004 and 2008. At the start of the study, 60 percent of participants were employed. Thirty percent of study participants were women. Employed participants were slightly older than unemployed participants (median age of 36 years old versus 33 years old, respectively) and were better educated.

Participants were followed through 2010, for a median of about three years.

Approximately two-thirds of study participants (62 percent) were employed as clerks, associate professionals, or technicians, and most (72 percent) held permanent salaried positions.

Results showed that 18 percent of employed study participants became unemployed before age 60 during the study period. The median time between entering the study and stopping work was 20 months.

Overall, the probability of stopping work was 5 percent after a year, 14 percent after two years, 19 percent after three years, 23 percent after four years, and 35 percent after five years.

However, 36 percent of participants who stopped working subsequently returned to work, after a median time of 11 months. By the end of the study period, 88 percent of participants who were employed at the beginning of the study were still employed.

People with diabetes were more than five times more likely to stop working during the study period. Participants with high blood pressure were about three times more likely to stop working, and participants with depression about twice as likely.

However, HIV disease severity, antiretroviral drug regimen, and co-infection with hepatitis were not linked with a higher risk of stopping work. HIV-related discrimination, which was rarely reported by participants, was also not linked with a higher risk of work stoppage.

Younger participants (aged 30 to 39 years old) were about three times more likely to stop working than older participants (aged 40 to 49 years old). Participants with more education were less likely to stop working, while participants who were self-employed, had a temporary job contract, or worked in the private sector were more likely to stop working.

For more information, please see the study in the journal AIDS (abstract).

Based on the results, the study authors recommended that people with HIV who are taking Viread, Truvada, or Atripla (which both contain Viread) and have a low body weight be monitored for loss of kidney function at least twice per year, particularly during their first year of treatment.

The researchers also noted that further research should be carried out to examine possible kidney function loss in women and in non-Japanese patients with HIV who have low body weights.

Previous studies have shown that people with HIV are more prone to kidney disease. The increased risk is due to both the HIV virus, which can infect and kill kidney cells, and the effect of certain antiretrovirals on the kidneys (for more information on kidney disease in people with HIV, see related AIDS Beacon news).

The nucleoside reverse transcriptase inhibitor (NRTI) Viread (tenofovir), in particular, has been associated with kidney damage. According to the study authors, the loss of kidney function associated with Viread is usually considered to be mild and tolerable.

However, in severe cases, people taking Viread can develop Fanconi Syndrome (see related AIDS Beacon news). Fanconi syndrome is a disorder of the kidney tubes in which certain substances normally absorbed into the bloodstream, such as proteins and amino acids, are released into the urine by the kidneys instead. Symptoms include bone pain, weakness, and passing large amounts of urine.

In the current study, Japanese researchers investigated the effects of Viread on kidney function in people with low body weight. According to the researchers, people with low body weight may be more prone to kidney damage from Viread due to higher exposure levels per pound. They noted that there have been reports of kidney toxicity in smaller Japanese HIV-positive patients taking Viread.

The study included 503 Japanese HIV-positive adults who had not previously been treated for HIV. Almost all the study participants (98 percent) were male, with a median body weight of 141 pounds (64 kg).

Forty percent of study participants took a Viread-containing antiretroviral regimen; the rest received a Ziagen (abacavir)-containing regimen. Ziagen, which is also an NRTI, is widely used as part of antiretroviral therapy, though it is less widely used than Viread.

The researchers monitored participants’ kidney function by measuring the estimated glomerular filtration rate (eGFR), a measure of how well the kidneys are filtering toxins from the blood. Normal eGFR values are usually above 90 ml/min; values below 60 ml/min may indicate the presence of kidney damage.

Patients were followed for at least 24 weeks after starting antiretroviral therapy.

Results showed that participants taking Viread were significantly more likely to lose kidney function than participants taking Ziagen. By the end of the study period, 22 percent of patients in the Viread group had a more than 25 percent decline in eGFR, compared to 13 percent of patients in the Ziagen group. The median time to a greater than 25 percent decline in eGFR was 246 days after starting antiretroviral therapy in the Viread group, compared to 501 days in the Ziagen group.

Results also showed that older age, lower body weight, low CD4 (white blood cell) count, high viral load (amount of HIV in the blood), use of kidney-damaging drugs, infection with hepatitis B, and diabetes were associated with a greater likelihood of kidney function loss.

Study participants with a body weight of less than 132 pounds (60 kg) who were taking a Viread-containing therapy were nearly three times more likely to experience loss of kidney function than study participants who were taking a Ziagen-containing therapy. Participants with a body weight between 132 pounds and 150 pounds (68 kg) were about twice as likely to experience loss of kidney function. There was no increased risk above 150 pounds.

Use of Norvir (ritonavir)-boosted protease inhibitors as part of antiretroviral therapy was not associated with increased risk of kidney function loss.

For more information, please see the study in PLoS One.

“We are very pleased to provide an important new therapeutic option for younger HIV patients, and will work to make the pediatric formulations of Viread available as quickly as possible,” said Norbert Bischofberger, executive vice president of Research and Development and chief scientific officer of Gilead Sciences, in a press release.

Viread will be available as tablets in smaller doses of 150 mg, 200 mg, and 250 mg, and as a powder for children two to five years old. Regular Viread tablets, which are 300 mg, were approved for use in children above 12 years of age in 2010.

For children taking the smaller dose tablets or the powder, dosages are based on age and weight. Children should receive 8 mg of Viread per kilogram of body weight, up to a maximum dose of 300 mg once daily.

Viread (tenofovir) is a nucleoside reverse transcriptase inhibitor (NRTI) that is also a component of Truvada (emtricitabine/tenofovir) and Atripla (efavirenz/emtricitabine/tenofovir). In adults, it is one of the most commonly prescribed NRTIs.

However, until now Viread was not recommended for HIV-positive children under the age of 12 due to lack of data on safety and dosing for this population.

The approval was based on a study of Viread in 89 previously treated children with HIV, aged two to 12 years old. Results showed that Viread was as effective as the NRTIs zidovudine (Retrovir) and stavudine (Zerit) in children this age.

Gilead noted that the side effects in children were similar to those of adults. The most common side effects of Viread are rash, diarrhea, headache, pain, depression, weakness, and nausea. Four percent of study participants discontinued the drug early due to signs of kidney damage, which is also a known possible side effect of Viread.

Viread is still not recommended for children under two years of age, since its safety and efficacy have not been established for children that young.

The approval of Viread marks the second antiretroviral recently approved for younger children with HIV. The FDA approved Isentress (raltegravir) for children aged two to 18 years old in December (see related AIDS Beacon news).

For more information, please see the Gilead Sciences press release.

“Our results show that children exposed to HIV have more than twice the chance of having a language impairment than do children in the general population,” said Dr. George K. Siberry, of the Pediatric, Adolescent and Maternal AIDS Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, in a press release.

However, the study authors also pointed that the age of children in the study was fairly old – a median age of 12 years old – and that earlier antiretroviral therapy guidelines did not recommend initiation of antiretroviral therapy as early as current guidelines. As a result, they noted that younger children who started therapy at an earlier age may suffer from fewer language problems.

Based on their results, the study authors suggested that children exposed to HIV be screened for language impairments at an early age so that language therapy can be initiated if needed.

According to the study authors, previous studies have shown that prior to highly active antiretroviral therapy (HAART), children with HIV were more likely to suffer from a variety of learning and developmental problems, including language impairments.

Since the advent of HAART, however, the health of children with HIV has improved. In this study, researchers attempted to determine if children who were infected with HIV during pregnancy from their HIV-positive mothers and children exposed to HIV but who did not get infected are nonetheless at a higher risk of language impairments than HIV-negative, unexposed children.

The study included 468 children, 65 percent of whom were HIV positive and the rest of whom had been exposed to HIV but not infected. Children were assessed for language impairments and hearing problems, which can contribute to language delays. Just over half (52 percent) were male, 69 percent were African-American, and 29 percent were Hispanic.

Children with HIV were on average older and more likely to be female and African-American. They were also less likely to be from a low-income household and less likely to be raised by a biological parent.

Uninfected but HIV-exposed children were more likely to have been exposed to antiretrovirals before birth.

Results showed that 35 percent of the children scored abnormally low on a language assessment. According to the study authors, this compares to about 16 percent of children in the general population who suffer from language impairments. Scores for HIV-positive and HIV-negative but exposed children were similar.

Overall, 11 percent of the children had a primary language impairment, in which the language problem was the only learning difficulty, while 24 percent had a concurrent language impairment, in which the children also suffered from hearing problems or other developmental delays. The rates of primary versus concurrent language impairments were similar between the two groups.

Results also showed that, among HIV-positive children, those who had concurrent language impairments were more likely to have greater HIV disease progression, including low CD4 (white blood cell) percentages and detectable viral loads (amount of HIV in the blood). Male children and children whose biological parents were their primary caregivers were less likely to have concurrent language impairments.

Children who initiated antiretroviral therapy later were more likely to have primary language impairments, while children with concurrent impairments were more likely to have been on antiretroviral therapy by six months of age. However, the study authors suggested that in the latter case, this may be because children with signs of developmental problems were placed on therapy earlier.

For both HIV-positive and HIV-negative study participants, African-American children were about twice as likely to have primary language impairments and three times as likely to have concurrent language impairments. Hispanic children were also more likely to have concurrent language problems, as were children with less-educated caregivers or caregivers who were not their biological parents.

For more information, please see the study in the Journal of Development and Behavioral Pediatrics (pdf) or the press release from the National Institutes of Health.

The study authors suggested more research into the cause of low testosterone levels in men with HIV and any possible link to antiretroviral therapy. They also suggested that in some cases, weight loss might improve testosterone levels in men with deficiencies.

In addition, they noted that further study is necessary before prescribing testosterone supplements to men with HIV, since the supplements have side effects and it is currently unclear whether testosterone supplementation is needed or helpful.

Previous studies have shown that men infected with HIV, particularly men with advanced HIV, are more likely to have inflammation of the testicles and are more likely to produce insufficient testosterone levels.

In addition, men with HIV are more likely to experience decreased sex drive and an estimated 60 percent experience erectile or ejaculatory dysfunction (see related AIDS Beacon news).

According to the study authors, estimates of testosterone deficiency rates in men with HIV vary considerably, in part due to the difficulty in accurately measuring a person’s testosterone levels. They also noted that the cause of low testosterone levels in HIV-positive men has not been established.

In this study, the researchers aimed to determine the rate of testosterone deficiency in men with HIV and any factors that might be linked to low testosterone levels.

The study included 1,325 men with HIV. The median age of the men was 45 years old. All study participants were on antiretroviral therapy, and most (86 percent) had lipodystrophy, a condition that is a common side effect of certain antiretrovirals in which body fat is abnormally redistributed.

The researchers found that 16 percent of the men had testosterone deficiencies, including 11 percent of participants aged 30 to 39 years old, 15 percent of participants 40 to 49 years old, and 24 percent of participants 50 to 59 years old.

The authors noted that according to other studies, the rate of testosterone deficiency in HIV-negative men aged 40 to 59 years old is around 6 percent. In men under the age of 40 deficiency is rare, with a rate of less than 1 percent.

Further analysis of the men’s hormone levels showed that 30 percent of participants met the criteria for hypogonadism, a condition in which the sex glands produce insufficient amounts of sex hormones, including testosterone.

Results also showed that men with more body fat, particularly abdominal fat, and men who were older were more likely to have testosterone deficiencies. There was no link between testosterone levels and CD4 (white blood cell) count, viral load (amount of HIV in the blood), length of HIV infection, or type of antiretrovirals used.

Of 247 study participants who filled out an additional questionnaire on sexual function, more than half (53 percent) had erectile dysfunction and most were dissatisfied with their overall sex life. A higher percentage of men with testosterone deficiencies reported sexual dysfunction and dissatisfaction but the difference was not large enough to be statistically significant.

For more information, please see the study in PLoS One.

The researchers also found that the vast majority of patients receive regimens that conform to guideline recommendations.

The authors stated that their results validate the recommendations in current guidelines as well as the utility of the guides in helping clinicians decide on initial regimens to prescribe.

“Our results suggest that, in the context of constant increase in the number of therapeutic options and knowledge on specific drug-related side-effects and interactions, the release of updated treatment recommendations as well as the promotion of their use are important to guarantee the best possible care of HIV infected patients,” wrote the study authors.

The United States Department of Health and Human Services releases treatment guidelines on when to start antiretroviral therapy and which initial combination regimens to use for previously untreated (treatment-naïve) people with HIV.

The guidelines contain preferred treatment regimens as well as alternative and acceptable regimens. Preferred regimens are recommended as the best treatment regimens for most people starting antiretroviral therapy.

The guidelines are intended for use by HIV care practitioners when treating HIV-positive adults and adolescents in the U.S. The most recent set of guidelines were released in October 2011 (see related AIDS Beacon news).

According to the study authors, the U.S. guidelines are also used to determine initial treatment regimens for people with HIV in Switzerland, which no longer issues its own guidelines.

In this study, the researchers sought to determine how often the guidelines are followed by clinicians in Switzerland when prescribing antiretroviral regimens. They also attempted to determine whether following the guidelines led to better treatment outcomes, such as higher CD4 (white blood cell) counts or greater probability of successfully achieving an undetectable viral load (amount of virus in the blood).

The study included 4,189 previously untreated patients from seven different clinical sites in Switzerland. All patients began antiretroviral therapy between August 1998 and December 2007. Approximately two-thirds (68 percent) of the study participants were male, and three-quarters (75 percent) were Caucasian. About 42 percent of participants were between the ages of 31 and 40 when they started therapy.

Results showed that 73 percent of the study participants were prescribed one of the preferred first-line regimens as their initial antiretroviral therapy treatment. Five percent of participants were prescribed a regimen that violated the recommendations in the guideline. The definition of a violation regimen included regimens that consisted of fewer than three antiretroviral drugs or had three drugs but included a nucleoside reverse transcriptase inhibitor (NRTI) regimen base, or backbone, that was not recommended.

The most common type of regimen guideline violation was prescribing a non-recommended NRTI backbone (34 percent of violations).

Results also showed that participants who were prescribed a violation regimen were about half as likely to successfully achieve undetectable viral loads within a year after starting treatment. CD4 cell count increases were similar between the groups after one year, with an average increase of 185 cells per microliter in the group taking a recommended regimen, versus 152 cells per microliter in those on violation regimens.

Within the first year of treatment, 34 percent of patients on violation regimens switched to a different regimen, versus 25 percent of patients on recommended regimens.

Women and highly educated patients were more likely to receive violation regimens, as were participants who started the study with CD4 counts above 350 cells per microliter. The study authors speculated that these patients may negotiate more with their clinicians over which antiretrovirals to take.

Participants with high viral loads (between 10,000 and 100,000 copies per milliliter) were less likely to receive a violation regimen.

For more information, please see the study in PLoS One.

“We are delighted to be able to open these two important clinical studies ahead of schedule,” said Geoff Nichol, executive vice president of research and development at Sangamo, in a press release.

Both trials are testing gene therapy approaches to curing HIV. In the field of HIV/AIDs, gene therapy involves modifying a person’s DNA (the genetic information in cells) so that it becomes, for example, resistant to HIV infection (see related AIDS Beacon news).

In both trials, cells will be taken from the patient’s body, genetically modified in the laboratory, and then injected back into the patient.

Altogether, Sangamo anticipates recruiting around 29 people with HIV for both clinical trials.

Gene therapy as a cure for HIV is a somewhat controversial approach. Some researchers believe the technique is too risky and expensive for widespread use. Others, however, think that gene therapy may be the only way to cure HIV, and that the science behind it is developing rapidly enough to make it a viable treatment option (see related AIDS Beacon news).

The gene therapy approach being tested by Sangamo is an attempt to mimic the success of “The Berlin Patient,” a man who received a bone marrow transplant from a carefully selected donor with a mutated form of the CCR5 gene.

HIV requires the CCR5 protein, which is located on the surface of white blood cells, in order to attach to and infect the cell. People naturally born with an alternate form of the CCR5 gene are almost entirely immune to HIV. Since his transplant, no sign of HIV has been detected in The Berlin Patient.

In the Sangamo trials, investigators will genetically modify immune cells, called T-cells, to remove CCR5. The researchers hope that the genetically modified T-cells will be immune to the virus and thus able to block viral entry and replication. They also hope the cells will multiply to make other HIV-resistant T-cells. The goal is to eventually attain a “functional cure” for HIV: a remission state with long-term control of HIV, including low viral loads (amount of HIV in the blood) in the absence of antiretroviral therapy.

Results from a Phase 1 trial showed that the technique successfully reduced viral loads in patients with HIV. One study participant, who already naturally had one copy of the HIV-resistant CCR5 gene form, achieved undetectable viral loads with the treatment.

“Both of these new Phase 2 clinical trials are specifically designed to confirm and further investigate these findings,” said Nichol.

In the Phase 2 trials, Sangamo will test two approaches to improve the efficacy of their technique.

In the first trial, the researchers will further explore the gene therapy’s effects on people who naturally have one copy of the HIV-resistant CCR5 gene. Up to 20 HIV-positive adults on antiretroviral therapy who have the alternate gene will be enrolled.

Study participants will receive one course of the gene therapy treatment. After two months, they will then stop antiretroviral therapy for 16 weeks while the researchers monitor their CD4 (white blood cell) counts and viral loads.

Participants whose CD4 counts drop below 350 or whose viral loads rise above 100,000 copies per milliliter will restart therapy, as will participants with detectable viral loads after 16 weeks. However, participants who retain undetectable viral loads will remain off therapy until their viral loads become detectable or their CD4 counts drop below 350.

In the second trial, researchers will test whether an initial preparative regimen of cyclophosphamide (Cytoxan) prior to the gene therapy treatment improves its efficacy.

Cyclophosphamide is used in cancer patients to improve the outcome of stem cell transplants by killing a patient’s existing T-cells. The goal of the trial is to determine if depleting these cells will allow the gene therapy-modified T-cells to better take hold and multiply.

The trial will enroll at least nine participants and will test three different dosages of cyclophosphamide a day prior to the gene therapy treatment. After the gene therapy treatment, study participants will then undergo a 16 week antiretroviral treatment interruption with the same guidelines as in the first trial, but with a more stringent CD4 count cutoff of 500 cells per microliter.

For more information, please see the Sangamo BioSciences press release.

Based on their results, the authors concluded that adherence to antiretroviral regimens is most important in the period before and shortly after achieving undetectable viral loads (amount of HIV in the blood), known as viral suppression.

“Individuals may be more vulnerable to [treatment failure due to] suboptimal adherence shortly after achieving viral suppression but may be able to tolerate missed doses after long-term viral suppression,” wrote the study authors.

“It should be noted that the probability of remaining [virally] suppressed might also be related to inter-individual differences in immune response to HIV virus,” they added.

The researchers estimated that the minimal adherence level needed to maintain each regimen’s efficacy was 86 percent for Sustiva-based regimens and 93 percent for Kaletra-based regimens. They added that treatment failure was more likely with Kaletra if patients took it once daily rather than twice daily (with 80 percent versus 42 percent experiencing treatment failure, respectively).

The study authors also found, contrary to their initial hypothesis, that genes that are thought to influence how the body metabolizes antiretroviral drugs did not play a role in the antiretroviral regimens’ efficacy during non-adherent periods.

Poor adherence to highly active antiretroviral therapy can lead to higher viral loads (amount of HIV in the blood), decreased CD4 (white blood cell) counts, and increased resistance to antiretroviral medications.

Studies have shown that approximately 50 percent to 80 percent of people living with HIV have difficulty adhering to their antiretroviral regimens. Typically, clinicians recommend taking at least 95 percent of prescribed doses to avoid treatment failure.

According to the study authors, however, some people are able to successfully maintain low or undetectable viral loads even when they are not strictly adherent to their medications. The authors hypothesized that this may be because some people metabolize the drugs differently – resulting, for example, in higher drug concentrations or longer active periods in the blood, so that missed doses become less of a concern.

In this study, the researchers examined whether successfully retaining low viral loads during treatment non-adherence was related to genes known to affect drug metabolism. They also investigated other factors, such as how long patients were adherent to their regimens before they began to miss doses and how many doses they missed.

The study included 106 HIV-positive adults, 35 percent of whom took a Sustiva (efavirenz)-based antiretroviral regimen and 65 percent of whom took a Kaletra (lopinavir/ritonavir)-based regimen. All study participants reported on two or more successive clinic visits that they had missed medication doses daily, once per week, or more than once per week.

Participants taking Sustiva were slightly older (a median of 44 years old versus 42 years old for participants taking Kaletra) and more likely to be male (84 percent of participants versus 71 percent). Participants taking Sustiva had a median of two prior treatment regimens, versus four for participants taking Kaletra, and had been on antiretroviral therapy a median of four years, versus almost six years for patients taking Kaletra.

Results showed that 76 percent of study participants who took Sustiva and 55 percent of patients who took Kaletra successfully maintained low viral loads (less than 400 copies per milliliter) during their period of non-adherence. The median length of non-adherence was 32 weeks for both treatment groups, with 19 percent of Sustiva patients and 20 percent of Kaletra patients reporting daily missed doses.

Results also showed that the likelihood of maintaining low viral loads was not associated with any of the genetic variants the researchers tested. For patients taking either treatment regimen, missing more than one dose per week was associated with a higher risk of treatment failure than missing one dose per week, although for the Sustiva group the difference was not considered statistically significant.

In addition, previously achieving undetectable viral loads with the current regimen was associated with a lower risk of treatment failure due to non-adherence. Longer durations of viral suppression were linked to a decreased risk. Older age was also associated with a lower risk of failure.

For more information, please see the study in PLoS One.

Truvada For Prevention Of HIV Makes Time Magazine’s “Top 10 Medical Breakthroughs” For 2011 – Results from several studies showing that a daily dose of the antiretroviral Truvada (emtricitabine/tenofovir) can reduce the risk of HIV infection by 60 percent to 90 percent were declared one of the top 10 medical breakthroughs of 2011 by Time Magazine. The magazine noted that if the antiretrovirals were made widely available they could help curb the HIV/AIDS epidemic. The primary study, HPTN 052, was also chosen by Science Magazine as “2011 Breakthrough of the Year.” Gilead Sciences, which makes Truvada, applied for FDA approval to market the drug as an HIV prevention measure in December (see related AIDS Beacon news). However, Bloomberg noted that the drug costs $12,000 per year and has side effects, both of which may prevent widespread implementation. For more information, please see the articles in Time Magazine, Science Magazine, and Bloomberg.

Physicians Caution That Certain Anti-Seizure Drugs May Interfere With Antiretrovirals – New guidelines from American Academy of Neurology warn that certain anti-seizure medications, such as those taken to treat epilepsy, may interact with antiretroviral medications for HIV/AIDS. For example, the guidelines note that valproic acid (Depakote, Depakene) may increase the concentration of zidovudine (Retrovir) in the blood, increasing the risk of toxicity and side effects. Several anti-seizure medications also may interact with Norvir (ritonavir)-boosted Reyataz (atazanavir) and Kaletra (lopinavir/ritonavir). The guidelines recommend that people with HIV and seizure disorders share with their clinician what medications they are taking so that drug types and dosages can be adjusted if needed. For more information, please see the guidelines (pdf) or the patient information guide (pdf) at the American Academy of Neurology website.

FDA Accepts Gilead’s Application For Approval Of “Quad” Combination Antiretroviral – The U.S. Food and Drug Administration (FDA) has accepted Gilead Science’s application for approval of its investigational “Quad” combination antiretroviral pill. The Quad regimen is a fixed-dose, single tablet consisting of the investigational booster drug cobicistat, the investigational integrase inhibitor elvitegravir, and Truvada (emtricitabine/tenofovir). Gilead submitted its application to the FDA in October; the FDA has stated that it will make a decision on the drug by August 27, 2012. For more information, please see the Gilead Sciences press release.

Gilead Files For Approval Of “Quad” Combination Antiretroviral In Europe – Gilead Sciences has also applied for marketing approval of its investigational “Quad” combination antiretroviral pill from the European Medicines Agency (EMA). If approved, the Quad will be the third all-in-one combination antiretroviral pill approved in Europe; the first two, also marketed by Gilead Sciences, were Atripla (efavirenz/emtricitabine/tenofovir) and Eviplera (rilpivirine/emtricitabine/tenofovir), known as Complera in the U.S. Based on average approval times for the EMA, a decision would be expected mid to late next year. For more information, please see the Gilead Sciences press release.

Merck Agrees To Cut Price Of Isentress For ADAPs – U.S. pharmaceutical company Merck has agreed to lower its price for Isentress (raltegravir) for state AIDS Drug Assistance Programs (ADAPs), which provide free antiretrovirals to low-income people with HIV. The agreement follows pledges by Gilead Sciences and Janssen Therapeutics (a division of Johnson & Johnson) to also reduce the prices they charge ADAPs for their HIV drugs (see related AIDS Beacon news). Due to state budget crises and an increase in the number of people requesting assistance, many states have tightened eligibility requirements or implemented waiting lists for ADAPs. For more information, please see the Merck press release.

“Many young children and adolescents are living with HIV, and this approval provides an important additional option for their treatment,” said Dr. Edward Cox, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research, in a press release.

Isentress will be available as a chewable 100 mg scored tablet and a chewable 25 mg tablet for children. Regular Isentress tablets, which are 400 mg and not chewable, are also approved for use in older children.

For children two to less than six years old, dosing is based on weight with a maximum dose of 300 mg twice daily of the chewable tablets. For children six to 12 years of age and over 55 pounds (25 kilograms), the dosage is either one 400 mg regular Isentress tablet twice daily or chewable tablets with a dosage based on weight, up to 300 mg twice daily. For children above 12 years old, the dosage is one 400 mg regular Isentress tablet twice daily. Both the regular tablets and chewable tablets should be taken with food.

Isentress (raltegravir) is an integrase inhibitor, a relatively new class of antiretroviral. When combined with Truvada (emtricitabine/tenofovir), Isentress is listed as a preferred regimen for previously untreated adults in the Department of Health and Human Services treatment guidelines.

However, until now Isentress was not recommended for HIV-positive children due to lack of data on safety and dosing for this population.

The approval was based on a study of Isentress in 96 previously treated children with HIV, aged two to 18 years old with a median age of 13 years old. Just over half (51 percent) of the children were female; 34 percent were Caucasian and 59 percent were African-American.

Results showed that after 24 weeks, 54 percent of study participants successfully achieved undetectable viral loads (amount of HIV in the blood) and 72 percent achieved viral loads of less than 400 copies per milliliter.

Participants also experienced an average increase in CD4 (white blood cell) counts of 199 cells per microliter, which was an average 3.8 percent increase in CD4 percentage (a measure often used in children rather than CD4 count).

The most common severe side effects were insomnia and headache. The FDA also noted that Isentress should be discontinued if rash occurs. In addition, the chewable form of Isentress contains the amino acid phenylalanine, which can be harmful to children with phenylketonuria, a rare genetic disorder in which phenylalanine cannot be properly metabolized, leading to problems with brain development.

For more information, please see the FDA press release and Isentress pediatric dosing recommendations from the FDA.

Previously, Prezista was only approved for children six years old or older and came only in a tablet form. Prezista is still not approved for children under three years old due to possible toxicity in children this young.

The new liquid form of Prezista will come as a 100 mg/ml solution. Dosages for children will be based on weight; full information will be included in the new prescribing information, which is not yet available.

For adults who are previously untreated or who have no resistance to Prezista, the dosage is 8 ml once daily with food, plus 1.25 ml of Norvir. For adults with some resistance to Prezista, the dosage is 6 ml plus 1.25 ml of Norvir, both twice daily with food.

Prezista (darunavir) is a relatively new protease inhibitor that was approved by the FDA in 2006. Prezista must be taken with the boosting agent Norvir (ritonavir) and with other antiretrovirals as part of highly active antiretroviral therapy.

Prezista and Reyataz (atazanavir), another fairly new protease inhibitor approved in 2003, are often prescribed because they are more active than other, older protease inhibitors. When combined with Truvada (emtricitabine/tenofovir), both are listed as preferred regimens for adults and adolescents starting therapy for the first time.

However, Prezista is currently listed as an alternative regimen for children aged six years old or older in Department of Health and Human Services treatment guidelines.

The new liquid form of Prezista was approved for children based on results from a study that included 21 treatment-experienced children with a median age of 4.4 years old. About half the participants (48 percent) were male; 57 percent were African-American and 29 percent were Caucasian. Seventy-six percent had previously taken protease inhibitors.

Results showed that after 24 weeks of treatment, 57 percent of participants had viral loads (amount of HIV in the blood) of less than 50 copies per milliliter, and 81 percent had viral loads of less than 400 copies per milliliter.

Participants on average had a 4 percent increase in CD4 (white blood cell) counts compared to their CD4 counts at the beginning of the study.

The most common side effects were diarrhea (19 percent of participants), vomiting (14 percent), and rash (10 percent). One participant discontinued the study due to vomiting, which was attributed to Norvir rather than Prezista.

For more information, please see the FDA website.

People With HIV May Be At Higher Risk Of Migraines – Results from a recent study indicate that people with HIV may be at a higher risk of headaches, particularly migraines, than people without HIV. The researchers found that more than half of study participants reported headaches; more than 85 percent of these patients met the criteria for migraine headaches. According to the scientists, this represents a 13-fold higher risk of chronic migraines in people with HIV compared to the general population. The researchers also found that more advanced HIV infection was associated with more severe headaches. For more information, please see the press release from the University of Mississippi or the study in the journal Headache (abstract).

2012 Federal Spending Bill Bans Needle Exchange Programs For HIV Prevention – The 2012 federal spending bill, approved by Congress last week, contains a provision that prohibits federal money from being used for needle exchange programs for illegal drug users. The programs are meant to help prevent transmission of HIV and other blood-borne diseases by ensuring that users do not share needles. The AIDS Institute, a non-profit AIDS advocacy organization, expressed disappointment with the bill and also noted that funds remained flat for programs such as the Ryan White Program, which provides money to care for low-income people with HIV. For more information, please see the article in the Washington Post or the press release from The AIDS Institute.

Florida “Faces Of HIV” Project To Launch In Tallahassee, FL – Florida state will launch its traveling “Faces of HIV” exhibit January 13 at Florida State University in Tallahassee, FL. The project showcases the faces, experiences, and daily lives of people with HIV. The aim of the exhibit is to reduce stigma against people with HIV and to demonstrate that HIV infection strikes all sexes, ages, and races and cannot be deduced from a person’s appearance. The project will also stop in Orlando, Miami, Tampa, and Jacksonville, FL. For more information, please see the Faces of HIV website at the Florida Department of Health.

Gilead Sciences And Janssen Therapeutics Agree To Lower AIDS Drug Prices For ADAPs – Gilead Sciences and Janssen Therapeutics (a division of Johnson & Johnson) have reached agreements with the ADAP Crisis Task Force (ACTF) to further reduce the prices for antiretrovirals purchased by state AIDS Drug Assistance Programs (ADAPs), which provide free antiretrovirals to low-income people with HIV. Due to state budget crises and an increase in the number of people requesting assistance, many states have tightened eligibility requirements or implemented waiting lists for ADAPs. According to ACTF, there were 6,595 people on ADAP waiting lists nationwide as of November 17. For more information, please see the press releases from ACTF (pdf) and the AIDS Healthcare Foundation.

GeoVax Begins Phase 1/2 Trial Of Therapeutic AIDS Vaccine; Still Recruiting Participants – Biotechnology company GeoVax Labs announced today that the first patient has received a dose of its investigational therapeutic HIV vaccine as part of a Phase 1/2 trial. The company is testing the safety and efficacy of the vaccine in controlling HIV replication in people already infected with the virus; participants will stop taking antiretrovirals for 12 weeks as part of the trial. The company also noted that it is still recruiting participants for the trial. Eligible participants must be HIV-positive and have started antiretrovirals within 18 months of their last negative HIV test; or have had a negative HIV test within the past 18 months and not yet started antiretrovirals. For more information, please see the GeoVax press release (pdf) or the U.S. Clinical Trials Registry.

Governors Push For Legalization Of Medical Marijuana – The governors of Rhode Island and Washington states have petitioned the federal government to legalize use of marijuana for medicinal purposes. Both states have legalized medical marijuana, and the governors argue that the change in federal law is necessary so that state employees are not prosecuted for distributing the drug. The U.S. Justice Department had previously sent letters to state governments warning of prosecution if they continued to distribute medical marijuana (see related AIDS Beacon news). The federal Drug Enforcement Agency rejected a request to reclassify the drug as acceptable for medicinal use in June; however, the governors argued that the evidence used for that rejection is several years old and that the medical community has since changed its stance on marijuana. For more information, please see the article in the New York Times.

To be eligible, patients must have undetectable viral loads (amount of HIV in the blood) and CD4 (white blood cell) counts above 200 cells per microliter.

“With the utilization of highly active antiretroviral therapy (HAART) to control HIV disease, it is very clear that solid organ transplant is both feasible and successful [in people with HIV],” said Dr. Mary Prendergast, a kidney specialist at the Mayo Clinic, in a press release.

“We are very excited to be able to offer this service, which will provide end-stage kidney disease patients an alternative to years of difficult dialysis treatment,” she added. She also noted that the Mayo Clinic has been successfully performing liver transplants on people with HIV for several years.

However, patients with HIV, like other patients in need of transplants, will still need to wait until organs become available. According to the Mayo Clinic, there are currently 96,000 patients on the kidney transplant waiting list nationwide, and 1,300 patients on the waiting list for a pancreas. The median national waiting times for a kidney or pancreas are 1,219 days and 260 days, respectively.

Until recently people with HIV were not considered eligible for organ transplants. People with serious health problems that are unrelated to the reason for the transplant and that may affect short- or long-term survival are usually excluded from receiving organs.

In addition, clinicians have been concerned that immunosuppressants, which are used in transplant recipients to reduce the risk of organ rejection and failure, may further harm the immune systems of people with HIV, leading to a greater risk of illness or death.

More recently, however, transplant centers have begun to consider people with HIV as candidates for organ transplants. This is due to results from several studies showing that outcomes for people with HIV are similar to those of patients who are HIV negative.

For example, a large study of 150 HIV-positive kidney transplant patients, published in November 2010, showed that almost 95 percent of patients were alive one year after the transplant and 88 percent were alive three years after the transplant (see related AIDS Beacon news).

The survival percentages were lower than those reported for all kidney transplant recipients but higher than those reported for older recipients (above 65 years old). The researchers also found that patients’ HIV infections remained well controlled throughout the study, with stable CD4 counts and few HIV-associated complications.

The Mayo Clinic is not the only clinic that considers patients with HIV for organ transplantation. Several other centers nationwide offer kidney and liver transplants to people with HIV as part of a study on transplant outcomes in HIV-positive patients. Although this particular study is no longer accepting new participants, many of the treatment centers will still offer transplants to patients with HIV, including children.

For more information, please see the Mayo Clinic press release. For more information on organ transplants in HIV-positive patients, please see the HIV Transplant Study for People with HIV website.

Phase 3 Trial Results Show Gilead’s Investigational Booster Cobicistat Is Effective And Safe – Interim 48-week results from an ongoing Phase 3 clinical trial show that Gilead Science’s investigational boosting agent cobicistat is as effective as Norvir (ritonavir). Boosting agents are drugs that allow patients to take medications less often without losing efficacy. Results showed that 85 percent of previously untreated adults with HIV who took cobicistat-boosted Reyataz (atazanavir) plus Truvada (emtricitabine/tenofovir) successfully achieved undetectable viral loads (amount of HIV in the blood), compared to 87 percent of study participants taking Norvir-boosted Reyataz plus Truvada. Discontinuation rates due to side effects were similar between the two groups of participants. Based on the results, Gilead stated that it would apply for approval of cobicistat from the U.S. Food and Drug Administration in the second quarter of 2012. For more information, please see the Gilead Sciences press release.

Supreme Court To Decide On Government Liability For Breaches Of HIV Privacy – Justices for the U.S. Supreme Court will hear arguments this week on whether the federal government can be held liable for emotional distress when it illegally discloses a person’s HIV status. The government was sued by an HIV-positive pilot whose status was disclosed to officials at the Federal Aviation Administration by officials in the Social Security Administration, violating medical privacy laws. The government argues that it is only responsible for damages due to economic losses from such violations, not emotional distress. For more information, please see the article in the Los Angeles Times.

Merck Initiates Anti-Stigma Initiative For People With HIV And Their Clinicians – U.S. pharmaceutical company Merck has announced a new anti-stigma initiative to improve health care and communication between people with HIV and their clinicians. The program, called Clinic Activation to Lead and Implement Best Practices for Enhancing Response to HIV (CALIBER), includes a website with a discussion guide on dealing with and reducing stigma related to HIV and an expert panel of physicians to help answer stigma-related questions. For more information, please see the Merck press release (pdf) or the CALIBER website.

Thirty years after the start of the AIDS epidemic, scientists and researchers know more than ever about the elusive and difficult-to-treat HIV virus. And, with the first-ever example of a person cured of HIV – the so-called Berlin Patient – scientists are once again starting to look toward a cure.

One of those working toward a cure for HIV is the Foundation for AIDS Research (amfAR). Founded in 1985, the Foundation to date has awarded around $325 million to HIV and AIDS researchers.

“Historically, amfAR has looked to see where the gaps were in AIDS research – things that were promising but weren’t being funded by federal programs – and have stepped in. [AmfAR] also funds things that are just too offbeat,” said Dr. Jeffrey Laurence, senior scientific consultant at amfAR and a professor of medicine at New York Hospital-Cornell Medical Center in New York City.

In an interview with The AIDS Beacon, Dr. Laurence discussed some of the avenues toward a cure that he and amfAR think are most promising.

Gene Therapy

Like other research organizations, one focus of amfAR is on gene therapy, with the goal of replicating the success of the Berlin Patient, who was cured of HIV using a bone marrow stem cell transplant from a donor whose cells were resistant to HIV infection.

Gene therapy is an experimental approach that is currently in early stages of clinical testing. Gene therapy involves modifying a person’s DNA (the genetic information in cells) so that it becomes, for example, resistant to HIV.

According to Dr. Laurence, amfAR is working on methods to produce the same result as in the Berlin Patient using a person’s own cells rather than a donor’s.

“We’re interested in whether there is a way to use…a much more practical method based on gene therapy to cure HIV in someone’s own body, in a person’s own cells, so they don’t have to go through that complex donor transplant,” said Dr. Laurence.

For the most part, gene therapy efforts toward curing HIV are still fairly preliminary, and there are several barriers that must be overcome before it can become an effective cure. According to Dr. Laurence, one of amfAR’s goals is to help eliminate these barriers.

For example, one barrier is creating enough cells that have been modified by gene therapy to effectively grant HIV immunity. “We know how to take one cell out of your body and make it completely resistant to HIV and inject it back into you, but one cell injected back into you is not going to replenish your body,” said Dr. Laurence.

“So, one approach is, can we overcome the barrier of taking that one cell and growing it up in a test tube to the several million cells that we need, to repopulate your body?” This has been done with mouse cells, but not yet with human cells, said Dr. Laurence.

Another barrier involves making the gene therapy more efficient. “At the moment, we know how to knock out genes to make a cell resistant to the AIDS virus, but if we’re going to do it in a person’s own cells, we can [currently] knock [the gene] out in 70 percent of the cells, 80 percent of the cells. We need to knock it out in 100 percent of a person’s cells,” he said.

According to Dr. Laurence, ideas on how to address these issues were one focus of a gathering of scientists he hosted earlier this year. “We came up with some very interesting ideas as further targets for amfAR grants,” he said.

Elimination Of Latent HIV Reservoirs

Another approach amfAR is pursuing is eliminating latent HIV. Latent HIV is HIV that lies dormant and will start multiplying again if antiretroviral therapy is stopped. Current antiretrovirals cannot get rid of latent HIV.

“If the first two things [to improve gene therapy] I mentioned don’t work, and we can’t replace every cell in your body with your own cells that have been genetically modified, as we can in mice, then we’re going to have these barriers of latent cells,” said Dr. Laurence.

Eradicating latent HIV is a major focus of current amfAR efforts. Aside from trying to find drugs to activate latent HIV and make it susceptible to antiretrovirals, which is being pursued by several research groups, amfAR also has some more unusual strategies it is pursuing.

One of these is to try to find indicators that a cell might be infected with latent HIV so that the entire cell can be destroyed. “[The infected cells] may be Trojan horses, that is, for all the world they look like a normal horse or a normal cell, but there’s got to be some sort of signal on their surface that says they’re not completely normal, that’s there a virus lurking inside of them,” said Dr. Laurence. “If we can discover the signal, then we can wake it up and attack those cells specifically.”

There are also a variety of other questions amfAR would like to answer to help figure out how to eradicate latent HIV. For example, said Dr. Laurence, “How are we going to get every single latent cell? Do we need to get every latent cell, or will some just die by attrition if we can identify markers on their surface to kill most of them off?”

To help answer these questions, amfAR recently gave research grants to a group of scientists from top universities as part of its new amfAR Research Consortium on HIV Eradication. These scientists will work toward understanding latent HIV, how it persists, and how to eliminate it.

Moving Forward

Gene therapy and eradication of latent HIV are two areas of HIV cure research that amfAR is focusing on. However, Dr. Laurence admitted that scientists do not really know yet what will work and what will not. One benefit of amfAR grants, he said, is that they often fund unusual projects that fail to get funding elsewhere.

“There are certainly all sorts of ideas out there that we’re not smart enough to think of, that will be coming out of unusual laboratories. The methods of growing cells that have been genetically modified and cure a mouse came out of a chemistry lab in California, not a biology or an AIDS lab,” he said.

In the meantime, Dr. Laurence emphasized the enormous amount of progress that has already been made in understanding and treating HIV. “There’s been tremendous progress that’s happened in what is, in medical research, a relatively short period of time,” he said.

Dr. Laurence is also confident that a cure for HIV can and will be achieved.

“I think it’s going to be a lot easier to find a cure for AIDS than a cure for cancer,” he said. Unlike cancer, HIV has a known cause, and scientists are learning more about it every day.

“I think AIDS, being a single virus that we have a tremendous amount of information on, is going to be a lot, a lot easier technical challenge than many of the common kinds of cancer that we get,” he said.

For Dr. Laurence, the progress in HIV research in the past 30 years is a symbol of hope for where the field could be and for people who have HIV in this era.

“I think that this should be a message to go out and get yourself tested, tested regularly if you’re at risk, to use all of the prevention strategies, behavioral and mechanical that we have to prevent an infection,” he said.

“If you do get infection, get yourself tested so that you can get treated early,” he added.

For more information on HIV cure research, please see The AIDS Beacon’s series on Advances And Barriers To A Cure For HIV.

When it was founded in 1985 by actress Elizabeth Taylor and scientist Mathilde Krim, the purpose of the Foundation for AIDS Research, known by its initials amfAR, was to determine how the virus worked and how to treat it. Today, 26 years later and 30 years after the AIDS epidemic began, that focus has turned specifically toward research for a cure – a goal that the foundation and many scientists believe is closer than ever before.

“I’d be tremendously disappointed if within 10 years we didn’t have something that was in large-scale clinical trials that looked like something that could cure AIDS,” said Dr. Jeffrey Laurence, senior scientific consultant at amfAR and a professor of medicine at New York Hospital-Cornell Medical Center in New York City.

“Perhaps not by itself but in conjunction with other modalities, that is, drugs for latency and so forth,” he added.

Dr. Laurence admitted that this is pure speculation – “It’s based on work I know is going on in mice and monkeys,” he said – but he is not alone in thinking that an end to the AIDS epidemic is in sight.

“The goal of an AIDS-free generation may be ambitious, but it is possible with the knowledge and interventions we have right now. And that is something we’ve never been able to say without qualification before,” said Secretary of State Hillary Clinton in a speech November 8 at the National Institutes of Health in Bethesda, MD.

In an interview with The AIDS Beacon, Dr. Laurence shared amfAR’s perspective on why a cure is necessary, why the Foundation is optimistic that a cure for HIV is on the horizon, and how amfAR thinks a cure might be achieved.

The Need For A Cure For HIV

One thing Dr. Laurence and amfAR are clear on is that a cure for HIV is, indeed, necessary.

In her speech last month, Secretary Clinton promoted several methods for creating an AIDS-free generation, including treating people with HIV earlier – which scientists have shown can make people less likely to pass the virus on to others – encouraging adult male circumcision, and making sure pregnant women with HIV receive antiretrovirals to prevent transmission of the virus to their babies.

The problem, said Dr. Laurence, is that these measures alone will not be enough.

“It’s absolutely fine to do all the measures that Secretary Clinton suggested, and they’re important and they should be done, but they’re going to cost a tremendous amount of money, and it’s unclear that there’s the will, certainly right now, in federal governments and international governments, to pay for it,” he said.

According to amfAR’s estimates, antiretroviral therapy costs $600,000 or more over a person’s lifetime. In addition, said Dr. Laurence, two and a half people currently get infected for every one person who starts antiretroviral therapy.

Another factor working against eliminating HIV with the current treatment paradigm is that antiretroviral therapy requires strict adherence, or a person’s HIV will become resistant to the drugs. Many people have a difficult time committing to a lifetime of perfect adherence to a drug regimen, particularly when many of those drugs have long-term side effects, said Dr. Laurence.

“All of [these things] mean that if we could have a one-shot approach to a cure for HIV – we’re nowhere near that yet – it would be a tremendous step towards reaching that goal of Secretary Clinton, an AIDS-free world.”

A Cure For AIDS: Phantom Or Reality?

This is not the first time, however, that scientists have claimed to be close to a cure for HIV.

“For the longest while, certainly in the AIDS advocacy community, and perhaps in the federal government, cure was a four-letter word,” said Dr. Laurence.

“False hopes had been raised in the past, initial studies and some scientists saying that you can cure AIDS in two or three years with these highly potent antiviral drugs, and the rest of the virus-infected cells will just die off. It turned out not to be true,” he said.

Those early hopes that antiretroviral therapy might cure HIV turned out to be overly optimistic. Instead, scientists discovered that even when it is not detectable in the blood, HIV hides out in the cells it infects as a dormant form called latent HIV.

Since this HIV is not actively replicating, it is not affected by antiretrovirals, which means that they cannot cure the disease. As soon as antiretrovirals are stopped, the virus begins replicating again, multiplying from those hidden reservoirs of latent HIV.

Today, the approach to a cure is more realistic, because scientists acknowledge that curing HIV is more challenging than expected. In addition, scientists today have something they did not have when they first starting work on a cure – one patient who has, in fact, been cured.

“The good news is that since we have the one proof of concept from the Berlin patient, AIDS advocates have come around to the fact that this is now possible [to cure HIV], it’s not a pipe dream, it’s been done once. Let’s do it again, in a different way,” said Dr. Laurence.

The Berlin patient, Timothy Ray Brown, has been HIV-free since receiving a bone marrow stem cell transplant in 2007 to cure his leukemia. Sensing an opportunity, his doctors chose a stem cell donor with a genetic mutation – present in about 1.5 percent of the Caucasian population – that makes people resistant to HIV.

The transplant worked, and Brown has tested negative for HIV ever since. While the approach is not safe or practical for widespread use – “Upwards of 18 percent of people are going to die in the first 100 days from the transplant, you’d never do it for HIV itself,” said Dr. Laurence – the fact that it worked means that HIV can, in fact, be cured.

Such a feat, said Dr. Laurence, gives scientists hope. “I think there will be a cure in my lifetime. I just don’t know what that cure looks like yet,” he said.

For more information on HIV cure research, please see The AIDS Beacon’s series on Advances And Barriers To A Cure For HIV.

The results suggest that effects of early treatment on the size of the latent HIV reservoir, and therefore the viral setpoint, may only be temporary. They also suggest that reinitiating therapy in early treated patients should not be delayed too long.

“Early treatment during primary HIV infection may create a window of opportunity for (future) interventions aiming at eradicating HIV,” said Dr. Viktor von Wyl and Dr. Huldrych Günthard, from the Division of Infectious Diseases and Hospital Epidemiology at the University Hospital in Zürich, Switzerland, and lead authors of the study.

“It is plausible and likely that a smaller viral reservoir will increase chances for success of such (still experimental) interventions. However, it is conceivable that such therapeutic strategies might be much more successful if applied in patients with a viral reservoir of reduced size. Thus, to know that the viral reservoir can be lowered by early intervention is of great value,” said Dr. von Wyl and Dr. Günthard.

“Nevertheless, the limited and waning positive effect on the viral setpoint should also act as a warning signal to physicians when considering stopping therapy outside of study protocols,” they added.

During the early stages of HIV infection, HIV replicates rapidly and many immune cells are infected with the virus. This “acute” stage, also called primary infection, usually lasts several weeks to a few months. After that, the chronic stage of HIV infection begins, which can last years or even decades. At this point, the viral load (amount of HIV in the blood) naturally levels off; this level is called the setpoint.

When a person with HIV starts antiretroviral therapy – often during the chronic phase of HIV infection – the amount of HIV circulating in the blood usually drops to undetectable levels. However, some cells remain infected with latent HIV – HIV that lies dormant and will start multiplying again until the viral setpoint is reached if antiretroviral therapy is stopped. Current antiretrovirals cannot get rid of latent HIV.

Some previous research, including research by the same study authors, has suggested that antiretroviral therapy initiated in the acute phase of HIV infection may help limit the size of this latent reservoir (see related AIDS Beacon news) and lower the viral setpoint. However, results have been conflicting, and according to the study authors, little is known about the long-term effects of antiretroviral therapy on the viral load setpoint and the size of the latent HIV reservoir after early treatment is stopped.

In this study, the Swiss researchers examined viral load and HIV DNA levels, an indicator of the size of the latent HIV reservoir, before, during, and after treatment in people with HIV who started therapy within four months of initial HIV infection.

The study included 67 HIV-positive adults who started treatment early; 33 of these participants (49 percent) subsequently chose to stop therapy after one year of detectable viral loads. The study also included a comparison group of 79 untreated patients with chronic HIV.

Participants who started treatment early and then chose to stop were followed for a median of 37 months after stopping treatment. The comparison group of untreated participants was followed for a median of 34 months.

Results showed that HIV viral loads were very high in most patients before starting treatment. During antiretroviral therapy, viral loads decreased rapidly to undetectable levels but the drop in HIV DNA levels was significantly slower. In addition, HIV DNA levels remained constant after about 12 months of therapy, indicating that antiretroviral therapy was ineffective at eliminating residual latent HIV even when started early.

After stopping treatment, results showed that both viral loads and HIV DNA increased rapidly, then leveled off after about nine months. Participants who started treatment early had significantly lower viral loads than participants who were not treated.

However, three years after stopping treatment, participants in the early treatment group no longer had lower viral loads than participants who were not treated, indicating that the effects of early treatment on the viral setpoint were only temporary.

Results also showed that duration of antiretroviral therapy, pre-treatment HIV DNA levels, and CD4 (white blood cell) counts had no significant effect on post-treatment viral loads. Only the timing of treatment was significant: patients who began treatment 60 days or less after infection tended to have lower post-treatment viral loads than patients who started therapy between 61 and 120 days after infection.

For more information, please see the study in PLoS One.

Gilead Receives Approval For Eviplera In Europe – The European Medicines Agency (EMA) has approved Gilead Sciences’ new once-daily combination antiretroviral pill Eviplera (rilpivirine/emtricitabine/tenofovir) for the treatment of HIV in previously untreated adults with viral loads (amount of HIV in the blood) of 100,000 copies per milliliter or less. The approval means that Eviplera can be marketed in all 27 countries in the European Union. Eviplera, known as Complera in the U.S., was approved by the U.S. Food and Drug Administration in August. For more information, please see the Gilead Sciences press release.

AIDS Deaths Continue To Drop Worldwide – An annual report from the United Nations shows that the number of deaths worldwide due to AIDS has continued to drop for the third year in a row. The number of new HIV infections also fell 21 percent in 2010 compared to 1997; 70 percent of new infections were in sub-Saharan Africa. However, the number of people on antiretrovirals increased 20 percent in 2010 in sub-Saharan Africa, bringing the total to 50 percent of clinically eligible people with HIV in low- and middle-income countries. The report also notes that due to longer lifespans and greater survival rates, the number of people living with HIV now stands at an estimated 34 million, the highest ever. For more information, please see the United Nations report (pdf) or the article in the Washington Post.

Study Finds Viread Vaginal Gel Is Safe But Ineffective For HIV Prevention – Results from the Oral Interventions to Control the Epidemic (VOICE) study indicate that a vaginal gel containing 1 percent Viread (tenofovir) is safe but ineffective at preventing HIV infection in women. Based on the results, the National Institutes of Health, which is funding the study, has decided to drop the vaginal gel from the study. The trial, whose purpose is to provide women with methods to prevent HIV infection, will continue to evaluate the safety and efficacy of Truvada (emtricitabine/tenofovir) pills instead. The VOICE study was first modified in September after results showed that a Viread pill was also ineffective (see related AIDS Beacon news). For more information, please see the National Institutes of Health press release.

FDA Grants Priority Review For HIV Neuropathy Pain Relief Patch Qutenza – The U.S. Food and Drug Administration (FDA) has granted biopharmaceutical company NeurogesX a priority review for its capsaicin patch Qutenza, which is currently being evaluated for the treatment of pain from HIV-associated neuropathy. The decision means that the FDA will review the application for approval of Qutenza in six months rather than the usual 10 months. NeurogesX stated that it expects a decision from the FDA on March 7, 2012. Neuropathy is a condition that causes pain, numbness, burning, or tingling in the extremities. Qutenza is a capsaicin patch that is placed on the skin for 30 minutes. If approved, it would be the first product in the U.S. indicated for the treatment of pain from HIV-related neuropathy. It is currently approved for treatment of nerve pain due to shingles. For more information, please see the NeurogesX press release.

World AIDS Day Is December 1 – December 1 marks the 23rd World AIDS Day, a day set aside to remember those who have passed from the disease, acknowledge those who are living with HIV and AIDS, and spread awareness of its impact around the globe. The theme of this year’s AIDS day is “Getting to Zero,” which refers to zero new infections, zero new deaths from AIDS, and zero discrimination against people with HIV. Cities around the nation and the world will be holding events to mark World AIDS Day. For more information on participating or to register an event, please see the AIDS.gov website. For more information on World AIDS Day, please see the international World AIDS Day website.

Redesigned AIDSinfo Website To Debut On World AIDS Day – AIDSinfo, a website maintained by the U.S. Department of Health and Human Services, has been redesigned; the new design will debut on World AIDS Day, December 1. In addition, the Spanish version of the site, infoSIDA, will now have its own web address at www.infoSIDA.nih.gov. The AIDSinfo websites bring federal information regarding HIV and AIDS research, treatments, prevention, and medical practices to the public, with a specific focus on clinical research information and medical guidelines related to the care of people with HIV and AIDS. For more information, please see the AIDSinfo website.

GS 7340 is expected to be safer and more effective than the current version of Viread (tenofovir). Gilead has stated that GS 7340 will enter Phase 2 clinical trials early next year.

“This is the first time we are developing a protease inhibitor-containing single-tablet regimen, and we’re able to do that based on the small milligram size of GS 7340, which is less than one tenth of the amount of the 300 mg of tenofovir disoproxil fumarate contained in Viread and Truvada,” said Norbert Bischofberger, executive vice president of Research and Development and chief scientific officer of Gilead Sciences, in a press release.

Gilead will be responsible for developing and marketing the combination pill.

Prezista (darunavir), developed by Tibotec, a division of Janssen Therapeutics, is currently listed as a preferred protease inhibitor for first-line antiretroviral regimens for people with HIV. Emtriva (emtricitabine) is a nucleoside reverse transcriptase inhibitor that is often prescribed in combination with Viread in the form of Truvada (tenofovir/emtricitabine).

Cobicistat, which is not yet approved by the U.S. Food and Drug Administration (FDA), is under development by Gilead as a boosting agent similar to Norvir (ritonavir). Cobicistat is currently in Phase 3 clinical trials. Gilead expects to file a New Drug Application for cobicistat with the FDA in mid-2012.

The new Prezista-based regimen, if approved, will be the first once-daily combination antiretroviral pill that is protease inhibitor-based. Current combination regimens that are on the market, which include Atripla (efavirenz/emtricitabine/tenofovir) and Complera (rilpivirine/emtricitabine/tenofovir), are based on non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Gilead also recently submitted a New Drug Application for its investigational “Quad” pill, which is an integrase inhibitor-based combination regimen.

Tibotec and Gilead are in the process of developing another pill that combines just Prezista and cobicistat (see related AIDS Beacon news). The pill would be the second once-daily protease inhibitor pill that combines an antiretroviral with a boosting agent; the other is Abbott Laboratories’ Kaletra (lopinavir/ritonavir). All other protease inhibitors must currently be taken with Norvir as a separate pill.

For more information, please see the press release from Gilead Sciences.

Secretary Of State Clinton Calls For AIDS-Free Generation – Secretary of State Hillary Clinton called for the world to work toward an AIDS-free generation in a speech at the National Institutes of Health last week. Secretary Clinton advocated the use of antiretroviral drugs in combination with prevention measures such as male circumcision and promotion of condom use to cut the number of HIV infections. Secretary Clinton stated that the U.S. would grant $60 million toward these efforts in sub-Saharan Africa. Clinton also appointed talk show host Ellen DeGeneres as an international envoy for AIDS awareness. For more information, please see the article in the Washington Post.

Magic Johnson Marks 20 Years Of Living With HIV – Last week marked the 20th anniversary of basketball player ‘Magic’ Earvin Johnson’s announcement that he would retire from the Los Angeles Lakers due to HIV infection. At the time, in 1991, people with HIV were not expected to live very long. Last week, Johnson said that if he had known how well he would live with HIV he would not have retired. Since going public with his HIV infection, Johnson has been an active member of the HIV/AIDS community, including starting the Magic Johnson Foundation to help fight HIV and serving as a United Nations Ambassador of Peace. For more information, please see the Associated Press article.

AIDS Patients Sue Ohio Department Of Health Over New ADAP Regulations – Three HIV-positive patients and advocates have sued the Ohio Department of Health over new restrictions to the state’s AIDS Drug Assistance Program (ADAP), which provides free antiretrovirals to low-income people with HIV. According to the lawsuit, Department of Health officials failed to follow state laws on adopting new regulations, making them illegal. The plaintiffs also argue that the regulations would arbitrarily deny treatment to people with HIV. The new regulations would allow the Department to tighten restrictions on patient income for ADAP eligibility; they also include medical guidelines to determine waitlist priority if a waitlist is needed. A judge granted an injunction last week delaying implementation of the new regulations until the lawsuit has been resolved. For more information, please see the article on the New England Cable News website or the AIDS Healthcare Foundation press release.

Vertex Pharmaceuticals To Initiate Phase 3 Trial Of 12-Week Hepatitis C Regimen – Vertex Pharmaceuticals, the developer of Incivek (telaprevir), announced last week that it will initiate a Phase 3 trial of a 12-week hepatitis C treatment regimen consisting of Incivek, peginterferon-alfa, ribavirin, and its investigational hepatitis C virus polymerase inhibitor VX-222. The trial will test the regimen in both previously untreated and relapsed hepatitis C patients. The announcement of the new trial is based on results from a Phase 2 clinical trial that showed that 93 percent of patients treated with the four-drug regimen were cured of hepatitis C after 12 weeks. For more information, please see the Vertex Pharmaceuticals press release.

Bristol-Myers Squibb Investigates 12-Week, Interferon-Free Hepatitis C Treatment Regimen – Bristol-Myers Squibb is also independently investigating a 12-week, interferon-free treatment regimen for the treatment of hepatitis C. Bristol-Myers Squibb announced that it is adding the new 12-week treatment protocol to an existing Phase 2 clinical trial that is testing the same regimen as a 24-week treatment program. Patients will receive the investigational polymerase inhibitor PSI-7977 (developed by Pharmasett) plus Bristol-Myers Squibb’s investigational NS5A replication complex inhibitor daclatasvir (BMS-790052). Some patients will also receive ribavirin. The trial will test the regimens in both previously untreated patients and patients who have failed treatment with Incivek or Victrelis. For more information, please see the Bristol-Myers Squibb press release.

The response rate is similar to that reported last month for Victrelis (boceprevir) in a Phase 2 clinical trial in people with HIV (see related AIDS Beacon news).

“As HIV treatments have improved, liver disease associated with hepatitis C has become a leading cause of death among people who are co-infected, so offering patients a better chance at a cure for hepatitis C while maintaining their suppression of HIV would be a major advance in treatment,” said Dr. Kenneth Sherman, a professor of medicine at the University of Cincinnati College of Medicine and lead investigator of the trial, in a press release.

The results were presented today at the 62nd Annual Meeting of the American Association for the Study of Liver Diseases in San Francisco.

Based on the results, Vertex Pharmaceuticals, which developed Incivek (telaprevir), stated that it will initiate a Phase 3 trial of the drug in people with HIV by the end of the year. The trial will evaluate both a 24-week and 48-week treatment course for hepatitis C.

“As we prepare for our new Phase 3 study to evaluate Incivek combination therapy in a much larger group of people who are co-infected, data from this study give us hope that in the future we’ll be able to help more co-infected patients clear the virus,” said Dr. Robert Kauffman, senior vice president and chief medical officer at Vertex.

HIV and hepatitis C virus co-infection is very common; researchers estimate that a quarter to a third of people with HIV also have hepatitis C. People who are infected with both viruses are less likely to spontaneously clear the hepatitis C virus from their systems than people with hepatitis C only. Co-infected patients are also less likely to respond to hepatitis C treatment, which currently consists of Pegasys (peginterferon-alfa-2a) or PegIntron (peginterferon-alfa-2b) plus ribavirin (Rebetol, Copegus) for 48 weeks.

Incivek, which was approved by the United States Food and Drug Administration in May of this year for the treatment of hepatitis C (in combination with peginterferon-alfa and ribavirin), has been shown to improve hepatitis C cure rates compared to peginterferon-alfa and ribavirin alone.

However, it was not approved at the time for people with both HIV and hepatitis C, due to lack of information on efficacy in people who are co-infected.

In this ongoing Phase 2 study, researchers are comparing the efficacy of Incivek plus Pegasys and ribavirin to Pegasys and ribavirin alone in adult patients with both hepatitis C and HIV.

The trial includes 60 HIV-positive adults with genotype-1 hepatitis C. Twenty-two percent of participants are not on antiretroviral therapy, 40 percent are taking Atripla (efavirenz/emtricitabine/tenofovir), and 38 percent are taking Norvir (ritonavir)-boosted Reyataz (atazanavir) plus Viread (tenofovir) and Emtriva (emtricitabine) or Epivir (lamivudine).

The average participant age at the start of the study was 46 years old. Most (88 percent) are male; 27 percent are African-American. None of the participants have previously been treated for hepatitis C.

Study participants were randomly assigned to receive 12 weeks of Incivek or a placebo, both in combination with Pegasys and ribavirin, followed by 36 weeks of Pegasys and ribavirin alone.

Patients taking Atripla took a larger dose of Incivek (1,125 mg every eight hours) than patients taking a Reyataz-based regimen or no antiretrovirals (750 mg every eight hours).

Results showed that after 24 weeks, 74 percent of participants taking Incivek had undetectable levels of hepatitis C virus, compared to 55 percent of participants taking only Pegasys and ribavirin.

CD4 (white blood cell) counts dropped in both the Incivek and placebo groups during the course of the study, although there was no difference in the magnitude of the change between the two groups. All participants successfully maintained undetectable HIV viral loads throughout the 24 weeks.

The most common side effects in participants taking Incivek were abdominal pain, vomiting, nausea, fever, dizziness, depression, and itchiness. No participants contracted the severe rash that is a known possible side effect of Incivek (see related AIDS Beacon news).

Overall, 27 percent of participants discontinued treatment during the first 24 weeks; 2 percent discontinued due to side effects, 7 percent due to non-adherence to the drug regimen, and the rest for other reasons.

For more information, please see the press release from Vertex Pharmaceuticals.

The study authors also said that a comparison of their results with studies of HIV-negative, older adults suggests that people with HIV have around a three- to four-fold higher risk for cancer and heart attacks and a five-fold higher risk for diabetes than people of the same age without HIV.

Based on their results, the authors recommended that older adults with HIV be screened for additional illnesses and try to minimize risk factors for these diseases, such as being overweight.

With the advent of highly active antiretroviral therapy (HAART), many people with HIV are living well into older age; a recent study found that life expectancy for people with HIV is now close to that of people without HIV (see related AIDS Beacon news). In addition, the rate of new HIV infections in older adults continues to rise.

As people with HIV age, however, they become more prone to many of the same age-related illnesses as people without HIV, including cancer, heart disease, and diabetes.

According to the study authors, previous studies have looked at the rates of individual diseases, such as diabetes, in aging people with HIV; however, few studies have looked at the rates of age-related diseases overall in this population.

In this study, the researchers aimed to determine the rates of such age-related diseases in people with HIV aged 50 and above compared to younger adults with HIV.

The study included 8,444 HIV-positive adults aged 16 years or older, with a median age of 45 years old. Most participants (71 percent) were male. The median age at HIV diagnosis was 29 years old, and the median length of HIV infection was 15.4 years.

The researchers categorized participants into three age groups: younger than 50 (68 percent of participants), 50 to 64 years old (26 percent), and 65 or older (5 percent).

Results showed that participants older than age 50 were more likely to have other illnesses and to die than participants younger than 50. In particular, older participants were at a higher risk for bacterial pneumonia, stroke, blocked coronary (heart) arteries, heart attack, bone fractures, osteoporosis, diabetes, inflammation of the pancreas, and non-AIDS-defining cancers.

The risks remained higher in older participants after adjusting for CD4 (white blood cell) counts, viral loads (amount of HIV in the blood), sex, current or former smoking, current or former injection drug use, and length of HIV infection.

However, older study participants were not at a higher risk of HIV-related illnesses.

Results also showed that female participants had about a three-fold higher risk of osteoporosis than male participants.

In addition, former injection drug users were at a higher risk of bacterial pneumonia, liver problems, and death; current injection drug users were at a higher risk of liver problems and death. Former smokers were at a higher risk of death; current smokers were at a higher risk of bacterial pneumonia and death.

Higher CD4 counts were linked to a slightly lower risk of bacterial pneumonia, bone fractures due to bone fragility, osteoporosis, new AIDS-defining illnesses, and death. Higher viral loads were associated with an increased risk of HIV-related illnesses.

Study participants with longer HIV infections were slightly less likely to develop HIV-related illnesses.

During the course of the study, 2 percent of participants died. The leading causes of death were cancer (23 percent), infectious diseases (15 percent), and heart-related diseases (12 percent).

A comparison with other European studies on illnesses in aging HIV-negative adults suggested that people with HIV were about 4 times more likely to get cancer, 3.5 times more likely to have a heart attack, and over 5 times more likely to have diabetes than people of the same age without HIV.

However, the study authors noted that these are just estimates, since their study did not include a matched HIV-negative study population for a true comparison.

For more information, please see the study in Clinical Infectious Diseases (abstract).

HIV Drug Patch Shows Efficacy In Preclinical Tests – Results from preclinical studies indicate that a new investigational skin patch is effective at delivering antiretroviral drugs. The patch contained a non-nucleoside reverse transcriptase inhibitor that is in early stages of development. Results showed that the patch successfully released 96 percent of the drug over seven days. The study authors stated that the skin patch could be an easier alternative to pills for people with HIV who have problems with adherence. The patch will be tested further in a Phase 1 clinical trial. For more information, please see the study abstract (pdf) and press release at the American Association of Pharmaceuticals Scientists website or the U.S. News and World Report article.

HPV Vaccine May Prevent Anal Cancer In Men Who Have Sex With Men – Results from a large international study indicate that the human papillomavirus (HPV) vaccine Gardasil effectively prevents anal pre-cancerous lesions in men who have sex with men. The study included 602 men aged 16 to 26 years old. Results showed that the vaccine reduced the rate of pre-cancerous lesions by 78 percent. To be effective the vaccine must be given before men acquire HPV, which causes most cases of anal cancer. Researchers have estimated that people with HIV are 30 to 50 times more likely to get anal cancer than people without HIV, and men who have sex with men are around 60 times more likely to get anal cancer. For more information, please see the study in the New England Journal of Medicine (abstract) or the article from Agence France-Presse.

United States Conference On AIDS Begins November 10 – The 2011 United States Conference on AIDS (USCA) will be held November 10 to 13 in Chicago. Topics covered during the conference include HIV prevention, treatment, and research as well as housing and public policy. Among the speakers are David Furnish, Chairman of the Elton John AIDS Foundation; Mondo Guerra, the HIV-positive former contestant from the television show Project Runway; and Senator Jack Jackson (AZ), a member of the President’s Advisory Council on HIV/AIDS. Over 3,000 people are expected to attend this year’s conference. For more information or to register for the conference, please see the USCA 2011 website.

The Quad regimen is a fixed-dose, single tablet consisting of the investigational booster drug cobicistat, the investigational integrase inhibitor elvitegravir, and Truvada (emtricitabine/tenofovir).

According to a representative from Gilead, the company is seeking approval only for previously untreated HIV-positive adults at this time.

The submission is based on results from two Phase 3 studies showing that the Quad pill is as safe and effective as Atripla (efavirenz/emtricitabine/tenofovir) and as Reyataz (atazanavir) plus Truvada, respectively (see related AIDS Beacon news articles for the Atripla and Reyataz studies).

“Based on data from our pivotal studies, we believe that the Quad has the potential to be an important new treatment option for people living with HIV, and we are pleased to have reached this significant milestone less than six weeks after the unblinding of the second pivotal Phase 3 study,” said Norbert Bischofberger, executive vice president of Research and Development and chief scientific officer of Gilead Sciences, in a press release.

If approved, the Quad pill would be the third all-in-one regimen for treatment of HIV. The first, Gilead’s Atripla, was approved in 2006; the second, Gilead’s Complera (rilpivirine/emtricitabine/tenofovir), was approved in August.

Gilead also noted that if the regimen is approved, the Quad pill would be the first all-in-one combination regimen that is integrase-inhibitor based; currently, the only approved integrase inhibitor is Isentress (raltegravir).

The two Phase 3 clinical trials, on which the submission is based, showed that 88 percent and 90 percent of participants, respectively, successfully achieved and maintained undetectable viral loads (amount of HIV in the blood) after 48 weeks of the Quad regimen.

By comparison, 84 percent of participants taking Atripla and 87 percent taking Norvir (ritonavir)-boosted Reyataz plus Truvada achieved and maintained undetectable viral loads after 48 weeks.

Gilead had previously stated, based on results of a Phase 2 clinical trial, that the side effects for the Quad pill were similar to those of Atripla. In both cases, the common side effects were abnormal dreams or nightmares, fatigue, dizziness, diarrhea, drowsiness, headaches, anxiety, nausea, bloating, and rash. However, fewer participants in the Quad treatment group experienced abnormal dreams or nightmares, dizziness, or anxiety.

Gilead indicated that it would present the full results from the Atripla and Reyataz Phase 3 clinical trials at scientific conferences in 2012.

For more information, please see the Gilead Sciences press release.

People With HIV And Tuberculosis Should Not Wait To Start Antiretroviral Therapy – Results from three large studies indicate that starting antiretroviral therapy two to four weeks after starting tuberculosis treatment reduces the number of AIDS-related illnesses and deaths in people with both HIV and tuberculosis who have low CD4 (white blood cell) counts, 50 to 200 cells per microliter or less. Earlier guidelines recommended that people wait to start antiretroviral therapy for at least eight weeks to reduce the rate of immune reconstitution inflammatory syndrome (IRIS), a potentially serious condition in which the recovering immune system overreacts to other illnesses in the body. The studies found that the benefits of starting therapy sooner outweighed the risks from IRIS. For more information, please see the article in the San Francisco Chronicle or the first, second, and third studies in the New England Journal of Medicine.

Theratechnologies Applies For Approval Of Egrifta In Mexico – Theratechnologies, via an affiliate of its partner Sanofi, has applied for marketing approval of Egrifta (tesamorelin) in Mexico. If approved, Egrifta will be the first drug in Mexico to treat lipodystrophy, a condition of abnormal fat distribution that is a side effect of certain anti-HIV medications. Based on targeted approval times, a decision would be expected in late 2011 or early 2012. Egrifta was approved in the U.S. in November of last year, and Theratechnologies’ partners have since applied for approval in Europe, Israel, Canada, Brazil, and Argentina. For more information, please see the Theratechnologies press release.

Vertex Pharmaceuticals Initiates Phase 3 Trial Of 12-Week Treatment Course For Hepatitis C – Vertex Pharmaceuticals is initiating a Phase 3 clinical trial to test the efficacy of a 12-week course of the hepatitis C drug Incivek (telaprevir) in people with a certain genetic variant, IL28B CC, that makes them respond particularly well to treatment. Currently, Incivek must be taken for at least 24 weeks. Participants who respond well to Incivek will also take a shortened course of peginterferon-alfa (Pegasys) plus ribavirin (Copegus), either 12 or 24 weeks total. All other patients will receive the standard 48 weeks of peginterferon-alfa plus ribavirin. For more information, please see the Vertex Pharmaceuticals press release.

The results might help explain why highly active antiretroviral therapy is not always effective in treating some HIV-associated neurological problems, since these cells live longer than the more typical immune cells infected by HIV. The results also might allow physicians to predict who is at greatest risk for HIV-associated dementia.

“Our goal is to determine if there are biological markers in the cerebrospinal fluid of people [before they develop] HIV-associated dementia that predict current and/or continued neurological disease,” said Professor Ronald Swanstrom, a professor at the University of North Carolina School of Medicine and senior author of the study, in correspondence with The AIDS Beacon.

HIV-associated dementia is a severe neurological disease that develops when the HIV virus infects the central nervous system. Although the introduction of highly active antiretroviral therapy (HAART) has reduced the rate of HIV-associated dementia, HAART is not always effective in treating less severe HIV-associated neurological problems.

Results from a prior study by the same authors showed that the amount of HIV virus in the cerebrospinal fluid, the clear fluid in the spaces inside and around the brain and spinal cord, dropped much more slowly in people with HIV-associated neurological problems after starting antiretroviral therapy, compared to people with HIV without neurological problems.

In this study, the researchers attempted to determine the reason for this slower decrease in people with HIV-associated neurological disorders.

The researchers examined cerebrospinal fluid samples from 11 HIV-positive adults starting antiretroviral therapy. Eight of the participants had HIV-associated dementia. Two of these participants also had cerebrospinal fluid samples available from before they developed dementia.

Results showed that participants with HIV-associated dementia had two different HIV virus types in the cerebrospinal fluid. One of these HIV virus types reproduced in relatively short-lived immune cells called T cells, like HIV usually does. The other type reproduced in macrophages, which are longer-lived white immune cells.

Further analysis showed that the macrophage-infecting HIV was more common in patients who showed a slow decrease in the amount of HIV in the cerebrospinal fluid after beginning antiretroviral therapy. In contrast, rapid reduction in the amount of HIV in the cerebrospinal fluid was associated with the HIV virus infecting T cells only.

The authors hypothesized that the slow decrease in people with macrophage-infecting HIV occurs because these macrophages live longer than T cells, so the virus persists longer after antiretroviral therapy is initiated.

Antiretrovirals do not kill infected immune cells; they prevent HIV from infecting new cells. This means that if infected cells take longer to die on their own, it will take longer for HIV levels to drop.

The researchers also examined the samples from the two participants whose cerebrospinal fluid had been collected before they developed dementia.

Results showed that one of the two had the macrophage-infecting HIV in their cerebrospinal fluid for up to two years before being diagnosed with dementia. The other participant did not have macrophage-infecting HIV before their dementia diagnosis but did at the time of diagnosis. This finding suggests that the macrophage-infecting HIV developed rapidly around the time the participant was diagnosed with HIV-associated dementia.

The researchers now want to test to see if having this type of HIV is a predictor of future HIV-associated dementia.

“We now have funding to look at virus in the cerebrospinal fluid of a group of people who are starting therapy with CD4 T cell counts below 300 cells per microliter,” said Professor Swanstrom.

“We want to know how often we see virus growing in the central nervous system in people without HIV-associated dementia and whether we can measure neurological impairment associated with localized infection in the cerebrospinal fluid,” he added.

For more information, please see the study in PLoS Pathogens.

Incivek Is Now Available In Canada – The new hepatitis C drug Incivek (telaprevir) is now available in Canada for people with genotype 1 hepatitis C. Incivek was approved by Health Canada in August, in combination with peginterferon-alfa (Pegasys, PegIntron) and ribavirin (Copegus, Rebetol). Vertex Pharmaceuticals, which markets Incivek, announced that it will launch a patient support program in Canada to provide financial assistance for eligible patients. Incivek received approval in the U.S. in May, along with Victrelis (boceprevir), a second new hepatitis C treatment in the same drug class. For more information, please see the Vertex Pharmaceuticals press release.

Man Convicted Of Assault For Transmitting HIV Despite Disclosure Of His Status – An HIV-positive man in Minneapolis, MN, has been convicted of first-degree assault for infecting his partner with HIV. Daniel Rick was convicted despite the fact that he disclosed his status to his partner, who consented to unprotected sexual intercourse. Many states criminalize exposing a partner to HIV without disclosing a person’s status; however, conviction when a person’s status has been disclosed is unusual. One advocate on lesbian, gay, bisexual, and transgender legal issues has called the case “a dangerous precedent.” Rick has also been charged with exposing two men to HIV without disclosing his status. For more information, please see the articles in the United Press International and the Huffington Post.

In addition, participants taking Isentress (raltegravir) reported fewer side effects than participants taking Sustiva (efavirenz).

“These results offer further insight into the virologic and immunologic response seen with Isentress in combination therapy when compared to [Sustiva] at 192 weeks in treatment-naïve adult patients with HIV-1,” said Dr. Jürgen Rockstroh, a professor of medicine at the University of Bonn in Bonn-Venusberg, Germany, in a press release. Dr. Rockstroh presented the results yesterday at the European AIDS Conference (EACS) in Belgrade, Serbia.

U.S. pharmaceutical company Merck, which sponsored the trial, released results in July from a Phase 2 clinical trial that also showed similar long-term safety and efficacy of Isentress compared to Sustiva (see related AIDS Beacon news).

The antiretroviral Isentress is approved both for treatment-experienced adults with HIV and as a first-line treatment for people who have not previously taken antiretrovirals. Isentress is currently the only approved integrase inhibitor, although two other investigational integrase inhibitors – dolutegravir and elvitegravir – are in Phase 3 clinical trials.

Sustiva, which is a non-nucleoside reverse transcriptase inhibitor, is often combined with Truvada (emtricitabine/tenofovir)  in the form of Atripla (efavirenz/emtricitabine/tenofovir). Atripla is the most commonly prescribed first-line regimen for people with HIV.

Both Sustiva and Isentress, in combination with Truvada, are listed in HIV treatment guidelines as “preferred” regimens for people starting antiretroviral therapy for the first time.

In this study, researchers are comparing the long-term safety and efficacy of Isentress and Sustiva.

The study includes 563 previously untreated HIV-positive adults. Participants were randomly assigned to take either Sustiva once daily or Isentress twice daily, both in combination with Truvada.

Results after 192 weeks (about three and a half years) show that 76 percent of participants taking Isentress have successfully achieved and maintained undetectable viral loads (amount of HIV in the blood), compared to 67 percent of participants taking Sustiva.

In addition, participants taking Isentress have had an average increase in CD4 (white blood cell) counts of 361 cells per microliter over this period, versus an average increase of 301 cells per microliter in participants taking Sustiva.

Fewer patients taking Isentress reported side effects (50 percent) than those taking Sustiva (80 percent), although the rate of serious side effects was similar for the two groups (18 percent).

Overall, 5 percent of participants taking Isentress and 8 percent of participants taking Sustiva discontinued the drugs due to side effects.

For more information, please see the Merck press release.

“The positive trends we reported between 2000 and 2009 in this study probably result from improvements in tolerability and ease of use of drug regimens, and in the availability of drugs with non-overlapping resistance profiles,” wrote the study authors.

“Our results are consistent with recent studies indicating that the proportion of overall clinic populations with suppressed viral load has increased with time,” they added.

However, the study authors also noted that the development of new drugs that work on drug-resistant HIV will continue to be necessary, since people starting antiretroviral therapy today will eventually develop HIV that is resistant to current newer antiretrovirals.

Drug resistance is one of the main causes of antiretroviral drug failure. Individuals are considered resistant to an anti-HIV drug if their viral load (amount of HIV in the blood) does not remain low after treatment and/or testing confirms the presence of an HIV strain that is resistant to one or more classes of antiretroviral drugs.

According to the study authors, resistance to all three main classes of antiretrovirals – nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors – has become less common with the advent of combination antiretroviral therapy. However, the prognosis for patients who do develop triple-class drug resistance after combination therapy has not been well studied.

In this study, researchers examined the treatment outcomes, including development of AIDS and risk of death, over time for people with multi-drug resistant HIV. More specifically, they monitored individuals whose HIV was resistant to at least two different NRTIs, one NNRTI, and one protease inhibitor.

The study included 2,476 HIV-positive individuals aged 16 years or older who started antiretroviral therapy between 1998 and 2001. All participants had triple-class drug resistant HIV. The median participant age at the time of treatment failure due to drug resistance was 40 years old. A majority of participants (67 percent) were male.

Results showed that the rate of participants who successfully achieved undetectable viral loads after changing drug regimens due to treatment failure increased from 20 percent in 2000 to 58 percent in 2008. In addition, the researchers found that 49 percent of participants who experienced initial treatment failure in 2008 still had undetectable viral loads in 2009, compared to 17 percent of participants in 2001 who experienced initial treatment failure in 2000.

The researchers also found that men who have sex with men were more likely to respond to treatment than heterosexual men and women or injection drug users. In addition, participants with lower viral loads and higher CD4 (white blood cell) counts at the time of treatment failure were more likely to successfully achieve undetectable viral loads after changing regimens, as were participants who were monitored in later calendar years during the study.

Results also showed that there were half as many AIDS-defining illnesses among participants in 2008 to 2009 as in 2000 to 2002. The death rate also dropped by half, but the difference was not considered significant.

Injection drug users, participants younger than 30 or older than 50, and people who had an AIDS-defining illness were most likely to die during the study.

For more information, please see the study in The Lancet Infectious Diseases (abstract).

AIDS.gov Opens “Facing AIDS 2011” Campaign For World AIDS Day – To commemorate World AIDS Day on December 1, AIDS.gov is raising awareness through its “Facing AIDS 2011” campaign. Interested individuals are encouraged to download a “Facing AIDS” flier from the website and share why they are facing AIDS. Participants can take photos of themselves with their flier and then upload their images to the Facing AIDS website. All participants are encouraged to share their photos online with family and friends. Instructions on how to plan community events for the campaign are also available. For more information on how to participate, please see the AIDS.gov website.

Gilead Sciences Signs Agreement To Develop New Type Of Antiretroviral Drugs – Gilead Sciences has signed a licensing agreement with pharmaceutical company Boehringer Ingelheim to develop and market a new type of antiretroviral drug, initially pioneered by Boehringer Ingelheim. The new drugs are integrase inhibitors but work differently than Isentress (raltegravir) or the investigational drug elvitegravir. As a result, they are expected to be effective against HIV that is resistant to current integrase inhibitors. The agreement includes the investigational drug BI 224436, which has been tested in a Phase 1 clinical trial. For more information, please see the Gilead Sciences press release.

Theratechnologies Begins Development On New Lipodystrophy Drug – Theratechnologies announced last week that it has discovered a new potential drug in the same class as Egrifta (tesamorelin) and will begin pre-clinical testing of the new compound for treatment of lipodystrophy, a condition of abnormal fat distribution that is a side effect of certain anti-HIV medications. Theratechnologies stated that the new drug candidate appears to be as effective as Egrifta but may not need to be injected, as Egrifta is. Egrifta, which was approved in the U.S. in November of last year, was the first drug approved to treat lipodystrophy. For more information, please see the Theratechnologies press release.

“The results of this study showed that 800 mg [of Isentress] given once daily in combination therapy was inferior to 400 mg [of Isentress] twice daily in combination therapy,” said Robert Consalvo, global director of communications at U.S. pharmaceutical company Merck, which sponsored the study.

“Given the superior efficacy of 400 mg [of Isentress] twice daily, patients are recommended to take it twice daily in combination therapy in accordance with the approved product labeling. Once-daily [Isentress] is not recommended for any patients,” he added.

Isentress (raltegravir) is the first HIV integrase inhibitor approved by the U.S. Food and Drug Administration (FDA). Currently it is prescribed as a twice-daily dose of 400 mg each, in combination with other antiretrovirals as part of highly active antiretroviral therapy.

In recent years, the FDA has approved once-daily rather than twice-daily dosages of several antiretrovirals. For example, the protease inhibitor Prezista (darunavir) was approved in a once-daily dosage in 2008, two years after the drug’s initial approval by the FDA.

According to the study authors, once-daily dosing is more convenient and might promote better adherence to antiretroviral regimens. Better adherence allows for slower disease progression and helps prevent the development of drug-resistant HIV strains.

In this Phase 3 trial, researchers investigated the efficacy of once-daily Isentress versus twice-daily Isentress, both in combination with Truvada (emtricitabine/tenofovir).

The study included 775 adults with HIV who had not previously been treated. All participants had viral loads (amount of HIV in the blood) of more than 5,000 copies per milliliter of blood at the start of the study. Most participants were male (80 percent) and Caucasian (71 percent). The median participant age was 38 years old.

Prior to treatment, 39 percent of study participants had viral loads of more than 100,000 copies per milliliter blood. Additionally, 24 percent of participants had CD4 (white blood cell) counts of less than 200 cells per microliter of blood.

Half of the study participants were randomly assigned to take Isentress once daily, 800 mg every 24 hours. The other half were assigned to take Isentress twice daily, 400 mg every 12 hours.

Results showed that after 48 weeks, 83 percent of study participants in the once-daily group and 89 percent of participants in the twice-daily group successfully achieved undetectable viral loads. The difference was large enough that once-daily Isentress was not considered equivalent in efficacy to twice-daily dosing.

In addition, participants in the once-daily group took longer to achieve undetectable viral loads and were more likely to experience treatment failure than those in the twice-daily group (14 percent of participants versus 9 percent).

The average increase in participant CD4 cell counts at 48 weeks was 210 cells per microliter of blood for the once-daily group and 196 cells per microliter of blood for the twice-daily group. The difference was not considered statistically significant.

Serious side effects were reported by 7 percent of participants in the once-daily group and 10 percent of participants in the twice-daily group. The most common side effects were diarrhea, upper respiratory tract infection, headache, bronchitis, depression, sinusitis, influenza, vomiting, back pain, and high blood pressure.

Overall, 13 percent of the study participants in the once-daily Isentress group and 8 percent of participants in the twice-daily Isentress group discontinued the drug due to side effects or other reasons.

For more information, please see the study in The Lancet (abstract).

Large HIV Prevention Trial For Women Modified Due To Viread Inefficacy – A large trial that is testing the efficacy of Truvada (emtricitabine/tenofovir) pills, Viread (tenofovir) pills, and a Truvada vaginal gel in preventing HIV transmission to women has been modified because of interim results showing that Viread pills are ineffective. Based on the results, women in the Vaginal and Oral Interventions to Control the Epidemic (VOICE) study who were taking Viread will stop taking the drug and will no longer be included in the study. Women taking Truvada pills or the Truvada vaginal gel will continue as planned. For more information, please see the National Institutes of Health press release or the article on the Science Magazine website.

Phase 1 Clinical Trial Shows New HIV Vaccine May Be Highly Effective – Results from a Phase 1 clinical trial of a new preventative HIV vaccine in Spain show that 90 percent of healthy HIV-negative adults who received the vaccine showed an immune response; 85 percent still had an immune response one year after vaccination. This is a much higher percentage than researchers have observed in previous vaccine clinical trials. However, the scientists still have to show that the vaccine actually reduces the risk of contracting HIV. The researchers also plan to test the vaccine as a therapeutic vaccine in people who already have HIV to see if it reduces the severity of infection. For more information, please see the press release from Consejo Superior de Investigaciones Científicas or the articles on the ABC news and Fox news websites.

Clinical Trial To Test Victrelis In People With HIV And Hepatitis C Is Currently Recruiting Participants – A Phase 4 clinical trial that will test the efficacy of Victrelis (boceprevir) in HIV-positive adults with hepatitis C virus compared to HIV-negative adults with hepatitis C is currently recruiting participants. Study participants will receive Victrelis in combination with peginterferon-2b (PegIntron) and ribavirin (Rebetol). Eligible participants must not have taken the antiretrovirals Ziagen (abacavir), zidovudine (Retrovir), didanosine (Videx), stavudine (Zerit), Sustiva (efavirenz), or Intelence (etravirine) within the past six months. Additional medication and health restrictions also apply. For more information, please see the U.S. Clinical Trials Registry.

“There are a lot of so-called ‘descriptive’ studies in HIV controllers: physicians and researchers observed different characteristics that are more frequent in these persons than in people who have a progressive infection with high amounts of virus in the absence of antiviral treatment,” said Dr. Daniel Kaufmann, an assistant professor of medicine at Massachusetts General Hospital and an author of the review.

“However, for a large number of these findings, we do not know if they actually play a role in the control of HIV, or if the results are rather a consequence of a preserved immune system in these persons,” he added.

“For example, if a certain type of cells in the blood works better in HIV controllers, does this mean that they fight the virus efficiently, or is it simply because they have not been damaged during the course of the HIV infection? There is thus a need for studies that determine the cause-effect relationships in terms of viral control,” said Dr. Kaufmann.

HIV controllers are individuals infected with HIV whose immune systems are able to naturally control the virus, meaning they have low or undetectable viral loads (amount of HIV in the blood) without the use of antiretroviral drugs. HIV controllers typically also have a significantly slower decline in their number of CD4 cells (white blood cells that are targeted and infected by HIV).

Various studies have attempted to determine how controllers are able to control HIV naturally without using antiretroviral drugs. In this review, Dr. Kaufmann and colleagues discussed the factors that may lead to effective HIV control, what is still unknown, and how understanding HIV controllers may lead to more effective treatments for HIV.

Viral Factors Involved In HIV Control

According to the review authors, one hypothesis for why HIV controllers can effectively repress their HIV is that they are infected with strains that are weaker in the first place.

According to this idea, the strain of HIV that infects an HIV controller has mutations that prevent it from replicating effectively, resulting in lower viral loads and a more easily controlled infection. For example, researchers have shown that HIV strains that have a mutation that makes them resistant to nucleoside reverse transcriptase inhibitors (NRTIs) are not able to replicate as well as HIV strains without this mutation.

However, according to the review authors, this hypothesis has been difficult to test because HIV controllers have such small amounts of HIV in their bodies that it is hard to tell how well the virus can replicate.

In addition, while there are some indicators that the HIV strains in HIV controllers do not replicate effectively, it is possible that this is due to an effect of the controllers’ immune systems – in other words, that the controllers caused the HIV to not replicate very well, rather than weak HIV strains leading to milder infections and HIV control.

The review authors stated that more research is necessary to understand what role, if any, poorly replicating HIV strains contribute to creating effective HIV control.

Human Factors Involved In Viral Control

In addition to possible viral factors, researchers have shown that alterations in certain human genes are associated with the ability to effectively control HIV. For example, there are several variants in the gene for the immune protein human leukocyte antigen (HLA) – HLA B*5701, B*5703, and B*2705 – that are associated with HIV controller status.

HLA is a protein that is involved in capturing and displaying proteins from viruses and bacteria to immune cells so the immune cells can recognize and destroy the invading microbes.

In addition, CD4 cells in many HIV controllers may not be as susceptible to HIV entry and infection as CD4 cells in other HIV-positive individuals. For example, previous studies have shown that alterations in the CCR5 gene protect HIV controllers against HIV infection and also delay disease progression.

HIV requires the CCR5 protein, which is located on the surface of white blood cells, in order to attach to and infect these cells. People naturally born with two copies of an alternate form of the CCR5 gene, called Δ32, are almost entirely immune to HIV.

In one study, almost 18 percent of HIV controllers had the alternate CCR5 gene, compared to10 percent of Caucasians in the general population.

Alterations in other human immune genes that are involved in fighting viruses, such as APOBEC3G, tetherin, and SAM-HD1, may also reduce the ability of HIV to replicate in controllers.

In addition to these genetic factors, researchers have found a number of differences in the immune systems of HIV controllers. However, according to the review authors, it is unclear whether these differences lead to the ability to control HIV, or are instead a consequence of HIV control.

For example, researchers have found that a certain type of immune cell, called a central memory CD4 T-cell, may survive longer and better in HIV controllers. These cells are involved in “remembering” viruses and bacteria that the immune system has encountered before so that it can fight them more effectively in the future.

There are also indications that several aspects of HIV controllers’ immune systems work better. According to the review authors, several types of immune cells seem to be more active and effective against HIV in controllers than in people whose infections progress over time. This includes an ability to create more effective antibodies against HIV. Antibodies are proteins that help the immune system identify and fight infectious pathogens like bacteria and viruses.

Finally, researchers have found that HIV controllers have less immune activation and inflammation than people with progressive HIV infections, although they still have more than people without HIV. Scientists hypothesize that chronic immune activation and inflammation caused by HIV infection wear out the immune system over time, leading to the loss of CD4 and other immune cells as well as the development of inflammatory diseases such as atherosclerosis (hardening of the arteries). Although this process may still happen in HIV controllers, it may be slower and less severe than in HIV progressors.

Implications For The Future

According to the review authors, scientists have made significant progress in understanding how HIV controllers differ from HIV progressors.

One of the most important implications, they wrote, is that HIV controllers show that it is possible for the human immune system to successfully control HIV infections without the use of antiretrovirals. Researchers hope that if the immune system is stimulated properly most people would be able to control their infections rather than progressing to AIDS.

In addition, by monitoring how controllers keep HIV from replicating, researchers may find more targets for future drugs and treatments to fight HIV.

However, the review authors noted that much about HIV controllers is still unknown, including whether many of the observed changes cause HIV control or are a consequence of reduced HIV replication. Researchers are also uncertain whether knowing how controllers prevent HIV from replicating will actually allow them to replicate the feat.

“A specific challenge with regard to HIV controllers is that in a lot of them, at least part of their capacity to control the infection is due to their genetic makeup – which is inherited from the parents.  Can these factors be ‘mimicked’ by new therapies, in people and in animal models?  This is an open question,” said Dr. Kaufmann.

The study authors agreed that further research is necessary to determine how control is achieved, which factors are important and which are just byproducts of control, and how these factors can be used to help with future treatments for HIV.

For more information, please see the study in Clinical Immunology (abstract).

EMA Advisory Committee Recommends Approval For Edurant And Eviplera In Europe – An advisory committee to the European Medicines Agency (EMA) has recommended that Edurant (rilpivirine) be approved for the treatment of HIV in previously untreated adults with viral loads (amount of HIV in the blood) of 100,000 copies per milliliter or less. Edurant is marketed outside the U.S. by the pharmaceutical company Janssen, a unit of Johnson & Johnson. The committee also recommended that Gilead Sciences’ new once-daily combination antiretroviral pill Eviplera (rilpivirine/emtricitabine/tenofovir), known as Complera in the U.S., be approved for the same patient population. The recommendations improve the chances for approval of the drugs in Europe; a decision is expected within two to three months. Edurant was approved in the U.S. in May, and Complera was approved in August. For more information, please see the Johnson & Johnson and Gilead Sciences press releases.

Gene Therapy Successfully Reduces Viral Loads In People With HIV (ICAAC 2011) – Sangamo Biosciences released updated results on its Phase 1 gene therapy clinical trial last Sunday showing that the treatment successfully reduced viral loads (amount of HIV in the blood) in all six of the trial’s participants without the use of antiretroviral drugs. One participant, who had a genetic variation that makes people naturally more resistant to HIV, successfully achieved an undetectable viral load. Sangamo reported no major side effects from the treatment. The results were presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago. Sangamo previously reported that the gene therapy treatment increased CD4 (white blood cell) counts in people with HIV (see related AIDS Beacon news). For more information, please see the Reuters article or the Sangamo Biosciences press release.

Bristol-Myers Squibb Reports 83 Percent Hepatitis C Cure Rate In Phase 2 Study (ICAAC 2011) – Results from a Phase 2 clinical trial indicate that Bristol-Myers Squibb’s investigational hepatitis C drug BMS-790052 yielded an 83 percent cure rate after 48 weeks in previously untreated adults with genotype 1 hepatitis C when combined with peginterferon alfa-2a (Pegasys) plus ribavirin (Copegus, Rebetol). Eight percent of participants reported serious side effects (anemia, or low red blood cell counts). Based on the results, Bristol-Myers Squibb has initiated a Phase 3 clinical trial with the drug. The results were presented last Saturday at ICAAC. For more information, please see the study (abstract) at the ICAAC website or the Bristol-Myers Squibb press release. For more information on the Phase 3 clinical trial, please see the U.S. Clinical Trials Registry.

However, the study authors did find a decreased risk of AIDS or death for people with HIV who initiated treatment at CD4 (white blood cell) counts of less than 500 cells per microliter.

Based on the results, the study authors said that patients and physicians should carefully weigh the benefits and drawbacks of starting treatment early.

“The drugs used to treat HIV are expensive, treatment is life-long, and the side effects can be serious. So we really need to know if the patient’s investment will pay off, how large the benefit is likely to be, and how long it will take to realize it,” said Prof. Michele Jonsson Funk, a research assistant professor at the University of North Carolina School of Medicine and one of the authors of the study.

“I think the most important finding (given what we have learned in recent years from other large, observational, clinical cohort studies) is that the jury is still out on the benefit of initiating therapy at CD4 [counts] greater than 500, at least in terms of the patient’s own HIV disease progression,” she added.

However, the study authors also noted that the study looked only at risk of AIDS and death, and that it is possible that starting treatment early could affect other outcomes such as risk of heart disease and neurological problems.

“If there was a substantial benefit in terms of reducing cardiovascular or cancer outcomes, that could certainly make a compelling case for earlier initiation,” said Prof. Jonsson Funk.

The question of when people with HIV should start antiretroviral therapy is still largely unresolved. Previous studies have shown a definite benefit in starting treatment at CD4 counts of 350 or below, and several studies have also shown that starting at a CD4 count threshold of 500 cells per microliter is beneficial (see related AIDS Beacon news). Based on these results, current U.S. treatment guidelines recommend starting therapy at a CD4 count of 500 or below.

However, there is a question of whether starting treatment even earlier, at CD4 counts above 500 cells per microliter, could lead to better health outcomes. For example, some studies have suggested that starting therapy as soon as a person is diagnosed as HIV positive and while CD4 counts are still high may result in better preservation of the immune system and potentially fewer HIV-related health problems over time (see related AIDS Beacon news).

On the other hand, starting treatment earlier is more expensive and leads to longer exposure to antiretroviral drugs and their side effects, which have been linked to health problems such as diabetes and heart disease. Earlier treatment initiation also means patients must adhere to an antiretroviral regimen for a longer period of time.

In this study, researchers evaluated the effects of starting treatment at CD4 counts of 800 cells per microliter and below to see if early treatment reduced participants’ risk of progressing to AIDS or dying.

The study included 9,455 HIV-positive patients aged 13 years old or older from Europe, Australia, and Canada. The median age at time of HIV diagnosis was 30 years old, and the median length of infection before starting the study was 1.3 years. All participants had CD4 counts of less than 800; none had previously taken antiretrovirals.

The researchers classified participants according to their CD4 counts: 0 to 49 cells per microliter, 50 to 199, 200 to 349, 350 to 499, and 500 to 799. They then monitored outcomes for participants who decided to initiate treatment during each month of the study compared to participants who decided to wait. The study was conducted from January 1996 to May 2009. Participants were followed for a median of five years.

Results showed that for participants with CD4 counts below 500, initiating antiretroviral therapy resulted in a lower risk of progressing to AIDS and fewer deaths than deferring treatment. For example, participants with CD4 counts between 350 and 499 cells per microliter who started treatment had a 25 percent lower risk of progressing to AIDS or dying than participants who chose not to start therapy.

For participants with the lowest CD4 counts, 0 to 49 cells per microliter, treatment initiation was associated with a 68 percent lower risk of AIDS or death.

However, the researchers found no effect for participants with CD4 counts of 500 cells per microliter or above.

The study authors also noted that although there was a benefit to starting treatment in participants with CD4 counts between 350 and 499 cells per microliter, this benefit was small and was not evident for up to two years after starting treatment. As a result, they suggested that people with HIV whose CD4 counts fall within this range consider the risks and benefits of antiretroviral therapy before starting treatment.

For more information, please see the study in the Archives of Internal Medicine (abstract) or the University of North Carolina School of Medicine press release.

The drop was driven primarily by a decrease in the number of HIV strains that were resistant to protease inhibitors.

The results were presented Sunday by the company Monogram Biosciences, which conducts HIV resistance testing, at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago.

“These changes in the resistance pattern of patients infected with HIV, who were routinely tested for drug resistance, highlights the efficacy of the standard of care and the continued availability of new antiretroviral drugs in the USA,” said Agnes Paquet, a biostatistician at Monogram Biosciences and lead author of the study, in a press release.

“These trends also highlight a decrease in the number of patients with multidrug-resistant virus: a group for whom very little treatment options were available until 2006,” she added. “The results…may have important implications for antiretroviral drug selection, clinical trial design, as well as future drug discovery and development.”

Drug resistance is one of the main causes of antiretroviral drug failure. Individuals are considered resistant to an anti-HIV drug if their viral load (amount of HIV in the blood) does not remain low after treatment and/or testing confirms the presence of an HIV strain that is resistant to one or more classes of antiretroviral drugs.

Since drug resistance can have such a large impact on the efficacy of an antiretroviral drug regimen, people with HIV often undergo resistance testing prior to starting or changing treatment.

Resistance testing involves examining the genes of the HIV in a person’s blood to see if the virus has certain mutations known to make it resistant to particular antiretrovirals. In addition, researchers test to see how well antiretrovirals work to inhibit the virus’ replication in the laboratory.

In this study, researchers analyzed 68,587 HIV resistance tests performed on samples from HIV-positive patients between 2003 and 2010 to see whether patterns of HIV resistance have changed over time.

Results showed that the percentage of HIV strains that were resistant to all three major classes of antiretrovirals – protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs) – declined from 29 percent in 2003 to 11 percent in 2010.

According to the study authors, most of this decrease occurred after 2007.

Further analysis showed that the percentage of strains resistant to protease inhibitors dropped from 52 percent in 2003 to 26 percent in 2010. Resistance to NRTIs decreased from 77 percent to 70 percent of HIV strains, and resistance to NNRTIs dropped from 70 percent to 61 percent of strains over the same time period.

The study authors hypothesized that the decrease in strains resistant to protease inhibitors is due to the introduction of newer, stronger drugs in this class, such as Prezista (darunavir), approved in 2006, and Aptivus (tipranavir), approved in 2005.

However, the researchers also found that the number of HIV strains resistant to only one class of antiretrovirals increased, from 31 percent of HIV strains in 2003 to 54 percent in 2010. The number of strains resistant to two antiretroviral drug classes remained approximately the same, 40 percent in 2003 compared to 35 percent in 2010.

For more information, please see the study (abstract) at the ICAAC website or the Monogram Biosciences press release.

Based on the results, Dr. Norbert Bischofberger, executive vice president of Research and Development and chief scientific officer of Gilead Sciences, said in a press release that Gilead would begin working toward approval of the Quad pill by the end of the year, rather than early next year as previously stated.

“The 90 percent response rate observed on the Quad arm in this study is an unprecedented result and speaks to the potency, safety, and convenience of an integrase-based single-tablet regimen,” said Dr. Bischofberger.

The trial results are the second set of Quad results released this year; Gilead also released results from another Phase 3 study in August showing that the Quad pill is as effective as Atripla, the most commonly prescribed first-line regimen for treatment of HIV (see related AIDS Beacon news).

The Quad regimen is a fixed-dose, single tablet consisting of the investigational booster cobicistat, the investigational integrase inhibitor elvitegravir, and Truvada (emtricitabine/tenofovir).

According to U.S. treatment guidelines, Reyataz (atazanavir) plus Truvada is considered a preferred antiretroviral regimen for people with HIV who are starting treatment for the first time.

The current study includes 708 HIV-positive adults who had not previously been treated with antiretrovirals and who had viral loads (amount of HIV in the blood) of at least 5,000 copies per milliliter at the start of the study. Half of the study participants were randomly assigned to take the Quad pill once daily; the rest were assigned to take Norvir (ritonavir)-boosted Reyataz plus Truvada.

Results showed that after 48 weeks, 90 percent of participants taking the Quad pill had successfully achieved an undetectable viral load, compared to 87 percent of participants taking boosted Reyataz plus Truvada.

More study participants discontinued Reyataz plus Truvada (5.1 percent of participants) due to side effects than the Quad pill (3.1 percent). The difference was primarily due to high levels of bilirubin in participants taking Reyataz, which is a known side effect of Reyataz that can cause jaundice.

Gilead reported that other side effects were similar between the two study groups.

Gilead plans to present the intermediate study results in more detail at a scientific conference early next year. The trial is currently ongoing and will continue until all participants have been followed for 96 weeks.

For more information, please see the Gilead press release.

The results were presented Sunday at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Chicago.

“The study was done to try to gather additional data in terms of the efficacy and tolerability of [Isentress] in those particular patient populations. We now have more data to provide these patients when we’re talking about treatment options and what the results have been specifically with an [Isentress]-containing regimen,” said Dr. Kathleen Squires, director of Infectious Diseases at Thomas Jefferson University Hospital and lead author of the study.

The study, sponsored by U.S. pharmaceutical company Merck, which makes Isentress (raltegravir), explored whether the drug would have different effects in men than in women and in black versus non-black adults from several countries.

Women and blacks are frequently underrepresented in clinical trials for antiretroviral drugs, despite the fact that blacks in particular are highly affected by HIV as a population. In the original Phase 3 clinical trials for Isentress, for example, fewer than 20 percent of participants were female, and fewer than 15 percent were black.

This study included 209 HIV-positive adults from the U.S., Brazil, the Dominican Republic, Jamaica, and Southern Africa, 75 percent of whom were black and 47 percent of whom were female. The trial included patients who had not previously been treated for HIV (10 percent of participants), patients who had failed antiretroviral treatment in the past (47 percent), and patients who had previously stopped treatment due to drug intolerances (43 percent).

Results showed that after 48 weeks, 66 percent of previously treated patients successfully achieved undetectable viral loads (amount of HIV in the blood). In addition, 76 percent of patients with drug intolerances and 76 percent of patients who had not previously been treated for HIV successfully achieved undetectable viral loads after 48 weeks.

There were no significant differences between men and women or between black versus non-black participants for any of the study groups. Dr. Squires also noted that values were consistent with results from previous clinical trials in previously treated and previously untreated HIV-positive adults.

A total of 15 percent of participants discontinued treatment with Isentress during the course of the study. Drug-related side effects were reported by 27 percent of female participants versus 15 percent of male participants, and 22 percent of black versus 17 percent of non-black study participants.

The most common side effects were abdominal discomfort, diarrhea, nausea, vomiting, muscle pain, and headache.

For more information, please see the study (abstract) at the ICAAC website or the Merck press release.

Office Of National AIDS Policy To Hold Discussions On National HIV/AIDS Strategy – The Office of National AIDS Policy is planning to hold several discussions with members of the HIV community, including researchers, clinicians, and people with HIV, on implementation of the National HIV/AIDS Strategy. The first talk will be at the University of Alabama in Birmingham on September 27 and is entitled “Incorporation of Prevention and Care Research Into HIV Programs.” Additional talks will be held October 4 in Seattle; October 20 in Philadelphia; late October in Baton Rouge, LA (date to be decided); and early November in Des Moines, IA (date to be decided). Additional dates and locations will be announced later. For more information, please see the AIDS.gov website.

Atlanta Police Department Sued For Discriminating Against HIV-Positive Man – An HIV-positive man who was denied a job as a police officer in Atlanta after a pre-employment medical exam revealed his HIV status has sued the city of Atlanta for discrimination. The man claims that the city violated the Americans with Disabilities Act (ADA) and other federal and state laws; HIV is considered a protected illness under the ADA. Atlanta claims that the man was rejected for reasons other than his HIV status, but that they were also justified in not hiring him because his status represents a “direct threat” to the health and safety of others. For more information, please see the article in The GA Voice.

AIDS Institute Releases New Guidelines On HIV Testing And Treatment During Pregnancy – New York’s AIDS Institute has released two new guides, “HIV Testing During Pregnancy and at Delivery” and “Acute HIV Infection in Pregnancy.” The guides are the first two sections of a new set of guidelines on managing HIV infection in pregnant women. The remaining sections will be posted as they are completed. The guidelines are being formulated in cooperation with the Johns Hopkins University Division of Infectious Diseases. For more information, please see the HIV Testing During Pregnancy and at Delivery and Acute HIV Infection in Pregnancy guidelines.

The results were presented Wednesday at the AIDS Vaccine 2011 Conference in Bangkok, Thailand.

“We hope that this may lead to a training of the immune system to better control the virus,” said Dr. Jan van Lunzen, medical director of the Infectious Diseases Unit at the University Medical Centre Hamburg-Eppendorf in Germany and an investigator of the trial, at a press conference.

“Eventually, and this would be the holy grail, [we hope] to make chronically infected patients into elite controllers by doing therapeutic vaccinations, but this is the future story,” he added.

Based on the results, Bionor Pharma, which makes the vaccine, is planning an additional Phase 1/2 clinical trial that will combine Vacc-4x with Revlimid (lenalidomide), a drug that is currently approved to treat the blood cancer multiple myeloma. Revlimid is an immunomodulatory agent, which means that it induces immune responses and inhibits inflammation. Revlimid also enhances the activity of T cells and natural killer cells, which are specialized immune cells. Bionor hopes that adding Revlimid will increase the efficacy of Vacc-4x.

Dr. van Lunzen indicated that the clinical trial will likely begin in early 2012 in Germany.

Bionor will also continue to monitor the participants from the Phase 2b trial and will test whether an additional vaccine booster will further enhance Vacc-4x’s efficacy.

The purpose of therapeutic vaccines, which are still experimental, is to reduce or eliminate the need for HIV treatment. Therapeutic HIV vaccines work by enhancing the body’s natural immune response, helping to control HIV in people already infected with the virus. This is in contrast to preventative vaccines, which are used in HIV-negative individuals to prevent infection.

The Vacc-4x vaccine is a therapeutic vaccine that contains protein fragments similar to those found within the HIV virus. The vaccine’s developers hope that when the vaccine is injected, patients’ immune systems will have an enhanced ability to recognize and kill HIV-infected cells.

The purpose of this clinical trial was to determine whether immunization with Vacc-4x could help participants successfully control the virus for a period of time without antiretroviral therapy.

The trial included 135 HIV-positive adults on antiretroviral therapy. All trial participants had undetectable viral loads (amount of virus in the blood) at the start of the study.

Two thirds of the participants were randomly assigned to receive the vaccine while the remaining one third received a placebo. The vaccine was given six times, at weeks 1, 2, 3, 4, 16, and 18. At week 28, participants with CD4 (white blood cell) counts of 350 cells per microliter or higher stopped antiretroviral therapy.

Participants started antiretroviral therapy again if their CD4 counts fell below 350 cells per microliter or their viral loads went above 300,000 copies per milliliter.

Preliminary results indicated that the vaccine did not result in an increase in participants’ CD4 counts or an increase in the number of participants who successfully stayed off antiretroviral therapy. As a result, Bionor initially decided not to further pursue development of the vaccine (see related AIDS Beacon news).

However, further analysis and longer follow up showed that the vaccine reduced participants’ viral loads by 70 percent compared to their viral loads prior to starting antiretroviral therapy. Participants who received the placebo did not experience a reduction in viral load.

In addition, 30 percent of participants who received the vaccine successfully remained off antiretroviral therapy for over a year, compared to 18 percent of participants who received the placebo.

For more information, please see the press conference at the AIDS Vaccine 2011 Conference website or the Bionor Pharma press release.

The guidelines also note that hormone therapy, which is often used to facilitate gender reassignment, may affect the results of screening tests and can also interact with antiretroviral therapy. As a result, the guide states that, before interpreting test results or determining antiretroviral dosages, clinicians should carefully establish whether patients are taking hormones.

The AIDS Institute is a division of the New York State Department of Health. The guidelines were developed in collaboration with clinicians from the Johns Hopkins University Division of Infectious Diseases.

According to the authors of the guidelines, rates of HIV infection among transgendered adults are not known, although 22 percent of male-to-female transgendered minorities and 68 percent of male-to-female transgendered sex workers are HIV positive.

Transgendered individuals may be less likely to seek treatment for their HIV due to stigma or fear of being judged. As a result, the guidelines suggest that HIV care providers familiarize themselves with transgender culture and terminology as well as issues specific to HIV-positive transgender adults in order to best communicate with transgendered patients.

Although some transgendered individuals with HIV have undergone gender reassignment surgery, in many cases patients retain some or all of their birth genitalia. As a result, they may still be susceptible to illnesses associated with their birth sex, such as cervical cancer, that are more common in people with HIV (see related AIDS Beacon news). The guidelines therefore recommend that individuals with some or all of their birth genitalia still undergo routine screening appropriate for their birth sex, such as pelvic exams or Pap smears for female-to-male transgendered adults.

However, the authors also note that clinicians should explain why the screening is necessary and be sensitive to patients’ fears or anxiety, particularly in patients who have been physically or sexually abused; in some cases, screening can be delayed until patients feel ready.

Transgendered individuals with HIV should also undergo routine testing for sexually transmitted diseases as well as annual screening for mental health and substance abuse problems, with referrals to counseling services when appropriate.

For transgendered individuals taking hormone therapy, special care must be taken in interpreting screening test results and determining antiretroviral dosages. For example, according to the guide, testosterone may cause shrinkage of the cervix in female-to-male transgendered adults, which can appear similar to pre-cervical cancer.

In addition, antiretrovirals can affect the concentrations of hormones in the blood. People taking antiretrovirals may therefore need to increase their hormone dosages to achieve the same hormone levels as people not taking antiretrovirals.

However, if hormone dosages are increased due to concomitant use of antiretroviral therapy, poor adherence to antiretroviral therapy can cause dangerously high hormone levels. The authors of the guidelines therefore advised that patients on antiretroviral therapy who are taking hormones must strictly adhere to their antiretroviral treatment regimen.

Hormone therapy can also increase the risk of several other conditions, such as heart disease or reproductive cancers, some of which are already more common in people with HIV.

The guidelines note that HIV status does not affect the safety or standard of care for gender reassignment surgery or other surgeries, such as breast augmentation, in transgendered individuals.

For more information, please see the Care of the HIV-Infected Transgender Patient guidelines.

Based on their results, the researchers stated that treatment of anemia in people with HIV is critical. They also noted that anemia is a reliable indicator of the prognosis of HIV-positive patients.

Anemia, a condition in which a person has an insufficient amount of red blood cells, is common in people with HIV and can be caused by the virus itself, certain antiretrovirals such as zidovudine (Retrovir), and poor nutrition such as lack of iron in the diet.

Symptoms of anemia include fatigue, weakness, and shortness of breath; in severe cases, anemia can cause chest pain and heart problems.

According to the study authors, previous research has indicated that anemia may be associated with poorer quality of life in people with HIV, faster disease progression, and higher risk of death. In this study, the researchers aimed to determine the rate of anemia in HIV-positive patients and whether anemia and other blood cell problems were related to risk of death.

The study included 701 people with HIV who were 16 years of age or older and received care at a Brazilian hospital between August and November 2009. The average participant age was 42 years, and 62 percent were male. Most participants (83 percent) were on antiretroviral therapy, and 65 percent had undetectable viral loads (amount of HIV in the blood).

The researchers measured participants’ hemoglobin levels (a measure of red blood cell count), CD4 (white blood cell) counts, viral loads, and the levels of other blood cells such as platelets (which help blood clot) and certain immune cells. They also recorded the number of participants who died within a year.

Results showed that 37 percent of study participants had anemia, including 61 percent of participants with CD4 counts below 200 cells per microliter. Participants with low CD4 counts were also more likely to have low levels of platelets and important immune cells such as neutrophils, which help fight off infectious diseases.

In addition, the researchers found that participants with anemia were more likely to die than participants without anemia. In participants with CD4 counts below 200 cells per microliter, 77 percent of deaths occurred in patients with low hemoglobin levels. In participants with CD4 counts above 200 cells per microliter, 89 percent of deaths occurred in patients with low hemoglobin levels.

The researchers found no link between low blood cell levels, including anemia, and viral loads.

For more information, please see the study in the International Journal of Infectious Diseases (abstract).

However, the alternate form of the CCR5 gene did not significantly impact survival rates among individuals on antiretroviral therapy.

The authors of the study suggested that testing people with HIV for the alternate form of CCR5 may be useful in understanding HIV infection but should not influence the decision of when to initiate or modify antiretroviral therapy.

HIV requires the CCR5 protein, which is located on the surface of white blood cells, in order to attach to and infect these cells. People naturally born with two copies of an alternate form of the CCR5 gene, called Δ32, are almost entirely immune to HIV.

According to the study authors, even having just one copy of the alternate form of the CCR5 gene is associated with better response to antiretroviral therapy, lower risk of treatment failure, lower risk of death in HIV-positive children, and lower risk of progression to AIDS in HIV-positive people who are being treated.

In this study, the authors investigated whether this alternate version of the CCR5 gene influenced survival in 507 HIV-positive patients. All participants were Caucasian and most (80 percent) were male. The median participant age at the start of the study was 30 years. Participants were followed from January 1996 to June 2010.

The authors also assessed the effect of a variety of other factors on the death rates in people with HIV, such as age, CD4 (white blood cell) counts, viral loads (amount of HIV in the blood), gender, co-infections with other diseases such as hepatitis C, progression to AIDS, antiretroviral regimens and use, and route of HIV transmission.

Overall, 14 percent of participants had one copy of the alternate CCR5 gene form; the rest had the regular form of the CCR5 gene.

During the course of the study, there were 97 deaths (19 percent of participants), 57 percent of which were AIDS-related and 43 percent of which were non-AIDS related.

The most common AIDS-related causes of death were pneumonia, cancer, and tuberculosis. The most common non-AIDS causes of death were drug overdose and heart and liver complications.

Results showed that the alternate gene was twice as common in participants who survived the entire study period; 15 percent of participants who survived had the alternate gene form, versus 7.5 percent of participants who died. The researchers calculated that people with HIV without the alternate gene form are 2.5 times as likely to die as people with the alternate gene form.

However, the effect was observed only for participants who were not taking antiretroviral therapy; having the alternate CCR5 gene did not affect survival chances for participants on antiretrovirals.

In addition, the variant was more common in participants who still had asymptomatic HIV infections at the start of the study (22 percent), versus participants with symptomatic infections (10 percent).

Overall, 10 percent of patients with the alternate CCR5 gene died during the course of the study, most (71 percent) from AIDS-related complications. There were no significant differences in cause of death between participants with the alternate form versus participants with the regular form of the gene.

Results also showed that other factors associated with a higher risk of death included male sex, a prior AIDS diagnosis, no antiretroviral treatment history or treatment for less than a month, not having a CD4 count of at least 500 cells per microliter for at least six months during the course of the study period, or having a CD4 count of less than 100 cells per microliter at the most recent clinic visit.

For more information, please see the study in PLoS One.

The results conflict with those from two earlier studies that found that Truvada is more effective, particularly for people who start treatment with higher viral loads (amount of HIV in the blood). However, another large study had found no difference between the two.

“These results support the use of either NRTI [nucleoside reverse transcriptase inhibitor] backbone in the initial therapy of antiretroviral therapy-naive patients and would support continuing Epzicom as a ‘preferred’ NRTI option,” wrote the study authors.

They also noted that the reason for the discrepancy in results is not clear.

Epzicom (abacavir/lamivudine) and Truvada (emtricitabine/tenofovir) both consist of two NRTIs and are commonly prescribed as the “backbone” of antiretroviral regimens, in combination with a third antiretroviral from a different drug class.

Results of previous studies comparing the two backbones have been conflicting. One large study found that Epzicom was not as effective as Truvada, with participants who had initial viral loads higher than 100,000 copies per milliliter of blood experiencing treatment failure significantly faster on Epzicom than on Truvada. In addition, a second study found that participants taking Epzicom were less likely to successfully achieve an undetectable viral load after 48 weeks.

However, results of another large study found no difference in efficacy between the two regimens, including for participants with high initial viral loads. Two additional studies in which participants switched from Truvada to Epzicom or vice versa also found similar efficacy between the drugs.

Since there are some safety concerns with Epzicom (some people can experience a rare but potentially fatal hypersensitivity reaction), the U.S. Department of Health and Human Services currently considers Truvada the “preferred” NRTI backbone, while Epzicom is considered an “alternative” backbone.

However, according to the study authors, Epzicom is still considered a preferred option in several international and European treatment guidelines.

In this study, the researchers aimed to determine whether there was a difference in efficacy or tolerability between the two regimens. The researchers examined the medical records of 1,764 HIV-positive adults who started antiretroviral therapy for the first time after January 1, 2000.

The median age of participants was 40 years old; most (86 percent) were male. None were injection drug users.

All participants took either Epzicom (588 participants) or Truvada (1,176 participants) in combination with Sustiva (efavirenz), Viramune (nevirapine), Kaletra (lopinavir/ritonavir), or Norvir (ritonavir)-boosted Reyataz (atazanavir).

For each participant, the researchers examined the risk of treatment failure, risk of switching or stopping backbone regimens due to side effects or any other reason, and time to successfully achieve undetectable viral loads.

The median follow-up time was 34 months for participants taking Epzicom and 20 months for participants taking Truvada.

Results showed that there was no difference in the risk of treatment failure between the two regimens regardless of participants’ initial viral loads, although participants taking the protease inhibitors Kaletra or Reyataz were more likely to experience treatment failure with both Epzicom and Truvada.

The researchers also found no difference in the risk of stopping or switching backbone regimens. Instead, female participants, those living in Ontario or Quebec (versus British Columbia), and those taking Kaletra were at higher risk of stopping or switching their initial regimens.

The authors speculated that the higher risks of treatment failure and regimen stopping or switching in participants taking protease inhibitors were due to physicians prescribing these drugs to more challenging patients, rather than actual problems with protease inhibitor-based regimens.

In addition, the median time to successfully achieve undetectable viral loads was four months for both participants taking Epzicom and participants taking Truvada. After 24 weeks, participants taking Epzicom had a 55 percent chance of having undetectable viral loads, compared to a 60 percent chance for participants taking Truvada. The difference was not considered significant.

For more information, please see the study in the Journal of Acquired Immune Deficiency Syndromes (abstract).

In a recent review, Dr. Derek Jones from the David Geffen School of Medicine at the University of California, Los Angeles discussed the use of a variety of facial fillers to treat HIV-related facial fat loss.

According to Dr. Jones, side effects from temporary facial fillers can be less severe than those from permanent fillers such as silicone, and problems with the injection of temporary fillers (such as inappropriate placement) can be easier to correct. However, temporary fillers need to be replaced and may take several injections to achieve the desired effect. They may also not be as effective for more severe cases of facial fat loss.

Temporary Facial Fillers

Dr. Jones discussed three types of temporary facial fillers in his review: hyaluronic acid, calcium hydroxylapatite, and poly-L-lactic acid.

As a person ages, the amount of hyaluronic acid in the skin decreases, leading to wrinkles and drooping skin. The breakdown of hyaluronic acid is also accelerated with sun exposure. Injectable hyaluronic acid fillers can replace the body’s hyaluronic acid and reduce the appearance of sagging skin and wrinkles.

There are currently four hyaluronic acid fillers approved by the United States Food and Drug Administration (FDA): Juvederm Ultra and Ultra Plus, Restylane/Perlane, Prevelle Silk, and Elevess. In addition, Dr. Jones stated that the filler Belotero is expected to be approved soon, and Juvederm Voluma is currently under FDA review.

Different brands of fillers provide varying degrees of volume, durability, and other factors.

According to Dr. Jones, the fillers Restylane, Juvederm, and Belotero are effective in treating the nasolabial folds, commonly known as smile or laugh lines. Previous studies have shown that each of these fillers can correct laugh lines for up to a year or longer, especially after repeat treatments.

In addition, the hyaluronic acid filler Voluma is safe and effective in providing volume to compensate for fat loss around the cheek areas in people with HIV.

Juvederm and Restylane are available with the local anesthetic drug lidocaine to relieve pain during injection.

The most common side effects for FDA-approved hyaluronic fillers are pain at the injection site, bruising, and swelling. These usually resolve within a few days after treatment.

However, Dr. Jones noted that more serious complications can occur, such as blue tinting to the skin, damage to the nerves, or death of the skin layers when the fillers are injected improperly (such as not deeply enough within the skin or too close to facial nerves); these complications can be avoided with proper injection techniques.

If hyaluronic acid fillers are improperly placed or complications arise, the filler can be degraded using injections of hyaluronidase, which dissolves the hyaluronic acid.

Another temporary facial filler is Radiesse (calcium hydroxylapatite). Calcium hydroxylapatite is a component of human bone and teeth and has been used for dental implants and coatings for more than 20 years.

When Radiesse is injected, the gel breaks down and stimulates the growth of collagen, a protein important in maintaining youthful skin.

The gel is approved to treat moderate to severe wrinkles and folds, including nasolabial folds, and HIV-associated fat loss.

Studies have shown that Radiesse is more effective and durable than collagen injections. In a study with HIV-positive patients, 80 percent had reduced fat loss after three months of treatment, and 59 percent of patients had reduced fat loss after six months of treatment.

Major side effects of calcium hydroxylapatite include swelling, bruising, and redness of the skin. Swelling and bruising can last about one week after injections, and skin redness can last for about two to three weeks after treatment.

The gel can be mixed with lidocaine to minimize pain during injection.

The final facial filler Dr. Jones discussed in his review is Sculptra (poly-L-lactic acid), which is also FDA-approved for HIV-associated fat loss.

The filler is given as monthly injections over the course of four to six months to restore face volume. The corrections can last for about one to two years.

A previous study conducted by European researchers showed that HIV-positive patients receiving Sculptra injections every two weeks for six weeks had significantly increased skin thickness at 48 and 72 weeks. No serious side effects were observed.

However, other studies have shown that Sculptra can cause lumps and nodules under the skin; proper injection techniques and regular massage of the filler after injection can help prevent lump formation.

Dr. Jones noted that in his experience, Sculptra is not effective for more advanced cases of HIV-related facial fat loss.

For more information, please see the study in Clinics In Plastic Surgery (abstract).

A recent review of facial fillers indicates that a variety of fillers are available that are safe and effective for treating antiretroviral-related facial fat loss in people with HIV.

The author suggested that surgeons properly select facial fillers, with a focus on the look of the entire face rather than specific regions, to create and restore proportion and harmony in the face. He noted that often surgeons must use a combination of several different types of fillers to obtain the best results.

Facial fat loss (lipoatrophy) is a common side effect of antiretroviral therapy, particularly for older antiretrovirals such as stavudine (Zerit) or zidovudine (Retrovir).

Although the condition does not pose any significant health risk, facial fat loss can have serious psychological consequences, such as negative self-image and depression. In extreme cases, patients may choose to discontinue treatment.

Switching to more modern treatment regimens can help prevent the condition from worsening; however, facial fat loss is extremely slow to heal. Instead, patients may choose to use injected facial fillers to replace the lost fat.

Medicare and Medicaid cover the use of facial fillers to correct facial fat loss in people with HIV under certain circumstances (see related AIDS Beacon news), and procedures may be paid for by private insurance.

In this review, Dr. Derek Jones from the David Geffen School of Medicine at the University of California, Los Angeles discussed the uses, side effects, and effectiveness of several facial fillers for the treatment of HIV-related facial fat loss.

Facial fillers fall into two categories: permanent fillers, which do not dissolve or get reabsorbed over time, and temporary fillers, which typically last one to two years. In his review, Dr. Jones discussed several fillers of each type.

Permanent Facial Fillers

According to Dr. Jones, some physicians do not favor common permanent fillers, such as liquid silicone injections, due to potential safety issues. However, Dr. Jones noted that they can give better and more durable results than temporary fillers, particularly for more serious cases of facial fat loss.

Liquid injectable silicone is a common permanent filler that was first used in the 1950s. At the time there was no standardized Food and Drug Administration (FDA)-approved product, and in the early 1990s all forms of silicone implants were banned by the FDA due to possible toxicity.

In the late 1990s, the FDA approved two forms of highly purified silicone, Silikon-1000 and Adatosil-5000, for use as retinal implants in the eye. These are also now used for soft-tissue augmentation, particularly Silikon-1000, although they are not officially approved by the FDA for this use.

In one clinical trial, highly purified silicone was studied in 77 HIV-positive patients. Patients received Silkon-1000 at monthly intervals. The authors of the trial determined that the number of treatments, amount of silicone needed, and the time to reach optimal facial correction were directly related to the severity of facial loss in the patient.

In another recent study, 135 patients with HIV were followed for at least five years after liquid silicone treatment. Results showed that silicone is safe and effective for treatment of HIV-associated facial fat loss.

Four patients in this study experienced localized hardening of the skin after treatment, which was moderate in severity and easily treated.

The second permanent facial filler Dr. Jones discussed in his review is polymethylmethacrylate, marketed as Artefill. Artefill is a facial filler approved by the FDA in 2006 to treat nasolabial folds, also known as smile or laugh lines. Artefill is also used to correct frown lines, lip lines, and mouth corners.

Artefill injections stimulate the body to produce more collagen, a protein important in maintaining youthful skin, in the face. According to Dr. Jones, results from recent studies showed that Artefill is effective in treating facial fat loss in people with HIV, acne scars, and cheek loss.

Side effects can include lumpiness and skin inflammation; Artefill can also cause permanent changes in skin texture or color if not injected properly.

Dr. Jones noted that after injections, patients should be evaluated four to six weeks later to determine if additional treatment is needed. Optimal correction usually requires two to three treatments.

For more information, please see the study in Clinics In Plastic Surgery (abstract).

AIDS.gov Blog Features Highlights From Atlanta HIV Prevention Conference – The AIDS.gov blog, run by the U.S. Department of Health and Human Services (HHS), featured highlights from each day of the National HIV Prevention Conference in Atlanta last week. The posts included discussion of the National HIV/AIDS Strategy, important studies presented at the conference on preventing HIV transmission, and progress in implementing prevention strategies and campaigns. The posts were written by Dr. Ronald Valdiserri, the HHS Deputy Secretary for Health, Infectious Diseases and Director of the Office of HIV/AIDS Policy. For more information, please see the AIDS.gov blog.

International AIDS Vaccine Initiative Finds Promising HIV Vaccine Antibodies – Last week, researchers reported the discovery of 17 promising new anti-HIV antibodies, proteins manufactured by the body’s immune system to mark and neutralize pathogens in the body for destruction. According to the researchers, the antibodies are 10 to 100 times more effective at blocking HIV than previous anti-HIV antibodies that have been isolated. The researchers also noted that the proteins present a promising avenue for creating a vaccine to prevent HIV infection. The next step will be for researchers to begin trying to design a vaccine based on the new antibodies. For more information, please see the study in Nature (abstract) or the press release from the International AIDS Vaccine Initiative.

CDC Adds Information Page About HIV In Transgendered Individuals – The CDC has added a new information page to its HIV/AIDS website on HIV in transgendered adults. The page has information on rates of HIV infection in this population, challenges with regard to HIV prevention, and steps the CDC is taking to better understand and monitor HIV infections in transgendered individuals. According to the CDC, transgendered individuals are three times more likely than men and nearly nine times more likely than women to become infected with HIV. For more information, please see the CDC website.

The discovery could help explain why HIV persists, although at undetectable levels, during treatment with antiretrovirals. This could, in turn, help scientists better understand how to eradicate these residual HIV reservoirs in the body, leading them one step closer to a cure for HIV.

“It’s important to determine whether or not cell-to-cell replication is causing a reservoir, particularly in terms of finding a cure,” said Dr. Alex Sigal, a researcher at the California Institute of Technology and lead author of the study, in a press release.

“We’re really looking for a cure, but to get to a cure, you have to fully understand the disease first,” he added.

Once a person is infected with HIV, the virus spreads from immune cell to immune cell within the body. Typically this occurs when HIV bursts from an infected cell, spreads through the blood or body fluids, then attaches to and infects a new cell.

Antiretrovirals are highly effective at interfering with this process by preventing the virus from replicating and infecting new cells. However, antiretrovirals do not eliminate HIV completely, and there is some evidence that very low levels of replication continue even in the presence of the drugs.

To date researchers are still uncertain about the nature of this residual HIV and whether it consists of actively replicating virus, latent or dormant HIV that reactivates if antiretrovirals are stopped, or some other form.

In this study, researchers hypothesized that one source of HIV reservoirs could be HIV that passes directly from one cell to another, rather than moving freely through blood or other body fluids. In this model, infected immune cells would directly hand off HIV to another cell.

The difference in the two transmission routes is somewhat similar to throwing a football versus handing it off to another player directly.  Different strategies are needed to stop the two methods.

Direct “cell-to-cell” transmission could allow HIV to keep replicating and infecting cells even in the presence of antiretrovirals by minimizing the virus’ exposure to the drugs (somewhat like avoiding an interception in football). This direct type of transmission is known to occur in certain places in the human body, such as the lymph nodes.

To test their hypothesis that cell-to-cell transmission could help HIV defeat antiretrovirals, the researchers placed uninfected cells in solution with either free HIV virus or other cells that were already infected with HIV. They then monitored the rate of infection of the new cells by both pathways. They also measured the impact that antiretrovirals had on the rates of infection.

Results showed that the antiretrovirals successfully stopped most infections via the “traditional” free-floating HIV pathway. In the presence of Viread (tenofovir), for example, this type of infection was reduced by 96 percent.

In contrast, cell-to-cell transmission of HIV was reduced by only 30 percent in the presence of Viread, meaning the antiretroviral had little ability to prevent new cells from being infected by this type of transmission.

In addition, the researchers found that infection of a single cell with multiple virus particles, which is more likely to happen with cell-to-cell transmission due to the direct contact between cells, also made HIV less sensitive to antiretrovirals by increasing the chances that at least one virus would successfully escape the drugs.

However, the researchers found that computer models of the rate of infections and replication by cell-to-cell transmission indicated that it may be only one pathway for HIV to persist in the presence of antiretrovirals. For example, the researchers hypothesized that HIV reservoirs may be made up of both HIV that is transmitted cell-to-cell and also latent HIV that needs to be reactivated to eliminate it.

This would mean that to cure HIV, researchers would need both to target latent HIV (see related AIDS Beacon news) and find a way to better prevent cell-to-cell transmission.

The researchers stated that the next step would be to perform similar experiments in actual human tissues, in which cell-to-cell transmission is known to occur, to verify their findings.

For more information, please see the study in Nature (abstract) and the press release from the California Institute of Technology.

Sustiva (efavirenz), which is in the same antiretroviral class as Edurant (rilpivirine) and an ingredient in Atripla (efavirenz/emtricitabine/tenofovir), is still considered the preferred treatment.

Edurant is a non-nucleoside reverse transcriptase inhibitor (NNRTI) marketed by Tibotec Pharmaceuticals, a subsidiary of Johnson & Johnson. Edurant was approved by the U.S. Food and Drug Administration (FDA) in May.

In addition, Edurant is a component of the once-daily combination pill Complera (rilpivirine/emtricitabine/tenofovir), which was approved by the FDA last week. Complera, which is marketed by Gilead Sciences, is intended as an alternative to Atripla, which is currently the most commonly prescribed first-line regimen for HIV.

Edurant and Complera were approved based on clinical trials showing that they are as effective as Sustiva and Atripla in people who have not previously been treated for HIV. However, the FDA noted at the time that the drugs were not as effective in people starting treatment with viral loads (amount of HIV in the blood) higher than 100,000 copies per milliliter.

In addition, patients taking Edurant or Complera who failed therapy were more likely to show drug resistance than patients taking Sustiva or Atripla.

As a result, HHS has decided to list Edurant as an alternative NNRTI for people starting treatment for the first time, while keeping Sustiva as the preferred NNRTI. The recommendation also affects Complera, which contains Edurant.

HHS defines an alternative regimen as one that is safe and effective but may have disadvantages compared to preferred regimens. Alternative antiretrovirals may be preferred for some individuals due to side effects, allergic reactions, drug resistance, or other factors.

HHS also noted that there is insufficient information on the safety and efficacy of Edurant and Complera in pregnant HIV-positive women. Edurant and Complera are not recommended for children under 18 because appropriate dosages have not yet been determined for this age group.

In addition, HHS warned against use of Edurant and Complera in combination with stomach acid reducers.  Specifically, the antiretrovirals should not be used with proton pump inhibitors, such as omeprazole (Prilosec) and Nexium (esomeprazole), and should be used with caution with antacids and H₂ receptor antagonists, such as cimetidine (Tagamet) or famotidine (Pepcid).

For more information, please see the AIDSinfo website.

“Achieving non-inferiority to the current standard of care in HIV therapy is a major developmental milestone for our Quad regimen,” said Norbert Bischofberger, executive vice president of Research and Development and chief scientific officer of Gilead Sciences, in a press release.

“We are very pleased with these results, which are in line with our expectations and allow us to begin preparations for a U.S. regulatory filing in the first quarter of 2012,” he added.

The Quad regimen is a fixed-dose, single tablet consisting of the investigational booster cobicistat, the investigational integrase inhibitor elvitegravir, and Truvada (emtricitabine/tenofovir). It is currently being developed by Gilead Sciences.

Atripla, which is also made by Gilead, is a fixed-dose, single tablet that combines Sustiva (efavirenz) with Truvada. Atripla is currently the most commonly prescribed first-line regimen for treatment of HIV.

The study includes 700 HIV-positive adults starting antiretroviral therapy for the first time. All participants started the study with viral loads (amount of HIV in the blood) of at least 5,000 copies per milliliter.

Half of the participants (348) were randomly assigned to receive the Quad pill, while the other half (352) were assigned to receive Atripla.

Results showed that after 48 weeks, 88 percent of participants taking the Quad pill had successfully achieved undetectable viral loads, compared to 84 percent of participants taking Atripla.

In addition, participants taking the Quad pill had a larger average increase in CD4 (white blood cell) count (239 cells per microliter) compared to participants taking Atripla (206 cells per microliter).

Gilead reported that the types and rates of side effects were similar for the two drugs. Participants also discontinued the Quad pill and Atripla at similar rates due to side effects.

The trial will continue for an additional 48 weeks. Gilead stated that it expects to present the clinical trial results in more detail at a conference later this year.

The Quad pill is also currently in a Phase 3 clinical trial to compare its safety and efficacy to that of Norvir (ritonavir)-boosted Reyataz (atazanavir) plus Truvada. Interim results from this trial are expected later this quarter.

Gilead also announced last week that the U.S. Food and Drug Administration had approved its other once-daily combination pill, Complera (rilpivirine/emtricitabine/tenofovir), known informally as “Btripla” (see related AIDS Beacon news).

In addition, Gilead and Tibotec Pharmaceuticals recently announced an agreement to develop a new once-daily combination antiretroviral pill that combines the protease inhibitor Prezista (darunavir) with the investigational booster cobicistat.  The companies are also currently in negotiations to develop a pill combining Prezista, cobicistat, Emtriva (emtricitabine), and an investigational new form of Viread (tenofovir) called GS 7340 (see related AIDS Beacon news).

For more information, please see the Gilead Sciences press release or the U.S. Clinical Trials Registry.

The guidelines contain updated recommendations in several areas, including when to start antiretroviral therapy and factors to consider in selecting an antiretroviral regimen. The guidelines also contain new sections on rates and management of various side effects related to the use of antiretrovirals.

The guidelines are intended for use by doctors and other health care professionals when treating HIV-positive children and teens. They were last updated in August 2010.

Key updates to various sections of the guidelines are summarized below.

Start Of Antiretroviral Therapy

Suggestions for when to initiate antiretroviral therapy vary according to age group.

Antiretroviral therapy is now recommended for children five years or older who have CD4 (white blood cell) counts of less than 500 cells per microliter, even if their symptoms are mild or nonexistent. Previous guidelines recommended treatment at a CD4 count threshold of 350 cells per microliter.

The guidelines continue to recommend treatment for children aged one year or older who have normal CD4 counts but HIV viral loads (amount of HIV in the blood) of 100,000 copies per milliliter of blood or higher, regardless of whether or not they have symptoms.

For children under the age of 12 months, the guidelines also continue to recommend starting antiretroviral therapy regardless of CD4 count, viral load, or the presence or absence of symptoms. Several studies have shown that starting therapy early in children of this age significantly reduces the chances a child will progress to AIDS or die.

In children with normal CD4 counts whose HIV viral loads are less than 100,000 copies per milliliter and who have mild or no symptoms initiation of treatment can be either considered or deferred.

Selection Of Antiretroviral Regimens

As with adults, all HIV-positive children should be treated using combination therapy that includes at least three different antiretroviral drugs from two different classes.

For children aged 14 days to three years, the preferred initial treatment regimen is now Kaletra (lopinavir/ritonavir) plus two nucleoside reverse transcriptase inhibitors (NRTIs). Viramune (nevirapine)-based regimens are now considered an alternative regimen in this age group.

However, due to recent information on toxicity of Kaletra in newborn infants, particularly premature infants, Kaletra should not be given to newborns until at least 42 weeks from the date of the mother’s last menstrual period and 14 days after birth (see related AIDS Beacon news).

For children older than six years, Reyataz (atazanavir) boosted with low-dose Norvir (ritonavir) has been added as a second preferred protease inhibitor for initial treatment regimens; Kaletra is already considered a preferred protease inhibitor for this age group.

The preferred dual-NRTI regimen backbones for initial therapy in children are zidovudine (Retrovir) plus Epivir (lamivudine) or Emtriva (emtricitabine) (any age), Ziagen (abacavir) plus Epivir or Emtriva (children three months or older), and Viread (tenofovir) plus Epivir or Emtriva (children 12 years or older who have finished puberty).

Two new alternate dual-NRTI backbones have been added to the guidelines: didanosine (Videx) plus Epivir or Emtriva (any age), and Viread plus Epivir or Emtriva (children 12 years or older in intermediate stages of puberty). Viread plus Epivir or Emtriva is now listed as a possibility under special circumstances for children 12 years or older in the initial stages of puberty.

The guidelines do not recommend use of the new antiretroviral Edurant (rilpivirine) in children for initial antiretroviral regimens due to lack of information on dosages for children and the absence of a child-friendly formulation of the drug.

The guide continues to recommend that patients who have never received antiretroviral therapy complete antiretroviral drug resistance testing before choosing which drugs to use for treatment.

Monitoring Of HIV-Positive Children

The updated guidelines now note that transient viral load increases of up to 1,000 copies per milliliter (“blips”) are normal and should not be considered a sign of treatment failure.

The guide also recommends that urinalysis be conducted in children at their first visit and repeated every six to 12 months. Urinalysis usually measures aspects of a person’s urine such as pH, presence or absence of blood or protein, and signs of a possible bacterial infection.

Other Changes

A new table has been added to the guidelines that describes central nervous system-related side effects related to antiretroviral use. The table includes information on symptoms, which antiretrovirals the side effects are associated with, how common they are, risk factors, and how to manage the effects.

Similar tables related to gastrointestinal side effects (such as nausea or vomiting), kidney toxicity, and peripheral neuropathy (a nerve condition that causes pain, numbness, or tingling in the extremities) have also been included in the updated guidelines.

The guide also contains updates or additional information for a number of antiretrovirals related to their administration in children or adolescents. For example, once-daily dosing of Prezista (darunavir) is not recommended for children under 12 years of age or previously treated children under 18 years of age, but may be considered in children who are 12 to 18 years of age, weigh more than 88 lbs (40 kg), and have never received antiretroviral therapy.

For more information, please see the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (pdf).

Based on their results, the authors of the study emphasized the importance of properly diagnosing and treating depression in HIV-positive individuals.

“The results of our study indicate that mood disturbances are still common in individuals with HIV despite modern treatment. It is important for HIV patients to recognize that these symptoms exist and to seek treatment for them. In the same vein, clinicians should be aware that mood symptoms often co-occur in HIV infection, and they should regularly evaluate their patients and refer them for appropriate care,” said Dr. David Moore, lead investigator of the study, in correspondence with The AIDS Beacon.

“Our hope is that our study highlights for patients, families, and providers that risk of depression and suicide exist for persons living with HIV/AIDS, and that this risk needs to be taken seriously and treatments should be considered. Suicide can be a difficult topic to discuss, but if it is not taken on directly, it can lead to poor and unwanted outcomes,” he added.

Depression is common in people with HIV (see related AIDS Beacon news), and suicide in particular is a major concern in the HIV-positive community.

Previous studies have identified social isolation, lack of social support, and abuse of illegal drugs as prominent risk factors and indicators for suicidal behavior in people with HIV.

However, results from previous studies comparing the rates of suicidal thoughts and behavior among HIV-positive and negative individuals have been conflicting and inconsistent. In addition, many studies were performed before the advent of combination antiretroviral therapy, when the prognosis for people with HIV was much poorer.

In this study, researchers investigated the lifetime rate of suicidal behavior in 1,560 HIV-positive individuals at six medical centers in the United States. They also assessed risk factors for depression and suicidal thoughts in people with HIV.

The authors evaluated participants’ levels of depression using a computerized questionnaire. They also collected information on participants’ sex, age, race, use of psychiatric drugs such as antidepressants, use of antiretrovirals, history of drug or alcohol abuse, and HIV-related outcomes such as CD4 (white blood cell) counts and viral loads (amount of HIV in the blood).

The majority of participants (75 percent) were male, 43 percent were Caucasian, and 43 percent were African-American. The average age of participants was 43 years old.

Results showed that 63 percent of participants reported symptoms of depression currently or at some point in the past. Overall, 26 percent of patients reported having had thoughts of suicide and 13 percent of participants reported having attempted suicide in their lifetimes.

In response to a question about suicidal thoughts and/or attempts in the past two weeks, 79 percent of participants reported no thoughts of suicide, 20 percent reported suicidal thoughts but no intent to commit suicide, and less than 2 percent reported a current suicide attempt.

Participants who had thought about, planned, or attempted suicide reported more severe depression symptoms and significantly lower overall health-related quality of life than participants who had not.

Results also showed that participants who reported a lifetime suicide attempt were significantly less likely to be on a Sustiva (efavirenz)-containing antiretroviral regimen. The authors speculated that physicians are not as likely to prescribe Sustiva to patients with significant psychiatric problems. Sustiva has been linked to side effects that affect the central nervous system such as dizziness, anxiety, depression, and insomnia.

Risk factors that were significantly associated with lifetime suicidal behavior included African-American race (a finding consistent with past studies), use of mood-altering drugs or psychiatric medications, and lower mental health-related quality of life.

The authors explained that increased suicidal behavior in African-American HIV-positive individuals may indicate that the stigma associated with HIV infection increases depression in this population.

The researchers found no link between suicide attempts and length of HIV infection. Participants with a history of thinking about or attempting suicide had higher viral loads, but the study authors hypothesized that this was due to lower medication adherence in depressed participants.

For more information, please see the study in Journal of Affective Disorders (abstract).

Complera will be marketed by Gilead Sciences. According to a representative from the company, Complera will be available in the U.S. starting early next week.

“Complera is the second complete single-tablet regimen that Gilead has introduced, and it represents a collaboration between two organizations that share a vision of simplifying HIV therapy for patients,” said John Martin, chairman and chief executive officer of Gilead Sciences, in a press release.

“Tremendous progress has been made in the field of HIV, but we recognize new therapies are still needed, and we continue to work to advance options that address the needs of patients,” he added.

Complera is a once-daily combination pill made up of Gilead’s Truvada (emtricitabine/tenofovir) and Tibotec Pharmaceuticals’ Edurant (rilpivirine), which was approved by the FDA in May (see related AIDS Beacon news).

According to Gilead’s representative, Complera will cost $1,704.64 for a 30-day supply. The drug will also be added to Gilead’s U.S. Advancing Access program, which provides assistance to people with HIV who do not have insurance or who need financial help.

The new combination regimen is the second all-in-one antiretroviral regimen to be approved by the FDA. The first was Atripla (efavirenz/emtricitabine/tenofovir), which is the most commonly prescribed first-line regimen for HIV. Atripla is also marketed by Gilead.

Complera is intended as an alternative to Atripla, which contains the non-nucleoside reverse transcriptase inhibitor (NNRTI) Sustiva (efavirenz). Sustiva has been linked to side effects that affect the central nervous system such as dizziness, anxiety, depression, and insomnia.

Edurant, which is included in Complera instead of Sustiva, is also an NNRTI, and in clinical trials the side effects for Edurant were similar in nature and frequency to those for Sustiva. However, fewer patients stopped taking Edurant due to side effects (2 percent, versus 7 percent taking Sustiva).

The FDA noted in May, when it approved Edurant, that the drug has some disadvantages relative to Sustiva. Clinical trial participants who failed treatment with Edurant were more likely to show drug resistance than those who failed treatment with Sustiva. They were also more likely to become resistant to the other antiretrovirals they were taking and to other NNRTIs.

In addition, clinical trial participants who started with higher viral loads (amount of HIV in the blood) of greater than 100,000 copies per milliliter were less likely to achieve viral suppression than participants who started with lower viral loads. Overall, 13 percent of trial participants taking Edurant experienced virologic failure, compared to 9 percent taking Sustiva.

According to the agreement between Gilead and Tibotec, Gilead will be responsible for marketing Complera in the U.S., Canada, Latin America, the European Union, Australia, and New Zealand. Tibotec will be responsible for marketing Complera in Japan, the Middle East, Eastern Europe, and Africa.

Tibotec and Gilead also recently announced an agreement to develop a new once-daily combination antiretroviral pill that combines the protease inhibitor Prezista (darunavir) with the investigational booster cobicistat, and the companies are currently in negotiations to develop a pill combining Prezista, cobicistat, Emtriva (emtricitabine), and an investigational new form of Viread (tenofovir) called GS 7340.

In addition, Gilead is developing a new once-daily combination pill, informally known as the “Quad” pill, that contains Truvada, cobicistat, and the investigational integrase inhibitor elvitegravir. Gilead stated in July that it plans to apply for approval of the “Quad” pill in 2012.

For more information, please see the press releases from Gilead Sciences and the FDA.

“With the advent of combination antiretroviral therapy, HIV-infected children are expected to live well into adulthood. However, the increased cardiovascular [heart] disease risk associated with HIV and/or antiretroviral therapy presents new challenges and serious implications for quality of life and life expectancy for this population,” wrote Dr. Allison Ross, from Emory University School of Medicine, and Dr. Grace McComsey, from Case Western Reserve University, in an editorial recently published in the Journal of Acquired Immune Deficiency Syndromes (JAIDS).

“Formal guidelines are the first crucial step in minimizing cardiovascular disease complications and maximizing quality of life in this vulnerable population,” they added.

Dr. Ross and Dr. McComsey suggested that guidelines should address the best course for treating high cholesterol and triglyceride levels in children with HIV: changing antiretroviral regimens, managing high levels through diet and exercise, and/or treating children with cholesterol-lowering drugs.

The authors noted that there are currently not enough studies on managing high cholesterol and triglyceride levels in HIV-positive children and recommended that guidelines be based on studies in adults with HIV until studies in children have been conducted.

Although antiretroviral therapy slows the progression of HIV and has helped prevent HIV-related deaths, it can lead to side effects such as weight gain, high cholesterol and triglyceride levels, and insulin resistance or pre-diabetes.

Results of several previous studies have indicated that the use of protease inhibitors, in particular, is associated with high levels of cholesterol in people with HIV, including children (see related AIDS Beacon news).

In the two studies also published in JAIDS this month, researchers investigated the rates of high cholesterol and triglyceride levels in HIV-positive children taking antiretrovirals, as well as the long-term management of these conditions.

The first study included 447 HIV-positive children treated at St. Mary’s and Great Ormond Street Hospitals in London between 1995 and 2007. Researchers monitored the children’s cholesterol and triglyceride levels and collected information on which antiretrovirals they were taking. Children were followed for a median of 4.5 years.

Results showed that children who had not yet started antiretroviral therapy had normal cholesterol and triglyceride levels, on average, except for low “good” cholesterol levels (low “good” cholesterol levels are linked to a higher risk of heart attack in adults).

However, children taking either protease inhibitors or non-nucleoside reverse transcriptase inhibitors experienced elevated cholesterol and triglyceride levels, with protease inhibitors causing the largest increases per year of treatment. By the end of the study, 10 percent of the children had cholesterol levels above the 95th percentile for their age. Three of the children met current American Academy of Pediatrics criteria for treatment with cholesterol-lowering drugs.

Researchers in the second study followed 240 HIV-positive American children who had high cholesterol for two years to monitor the rate of successful treatment of the condition and how the children were treated.

Results showed that during the two years, 15 children (6 percent) started treatment with cholesterol-lowering drugs and 27 percent changed their antiretroviral regimens at least once.

Overall, 34 percent of the study participants successfully achieved normal cholesterol levels by the end of the study period; the rest continued to have abnormally high cholesterol levels.

Further analysis showed that children who changed their antiretroviral regimens were 2.4 times more likely to achieve normal cholesterol levels than children who did not. Children 13 years old or older were also 2.4 times more likely to achieve normal cholesterol levels.

For more information, please see the editorial, London study (abstract), and American study (abstract) in JAIDS.

Federal Government Reverses Limits On Emergency Funding To State ADAPs – The federal Health Resources and Services Administration (HRSA) has reversed a previous decision to limit emergency funding to AIDS Drug Assistance Programs (ADAPs) to $3 million per state. Instead, states will be allowed to receive at least as much emergency assistance as they received last year. In July, Congress authorized $50 million in emergency funding for ADAPs, which provide free antiretrovirals to low-income people with HIV. Several state ADAPs have faced budget crises, and 13 states currently have waiting lists. Activists protested HRSA’s initial decision to limit the emergency funds to a maximum of $3 million per state, which is less than some states, such as Florida, received last year in emergency funds. For more information, please see the article in The Florida Independent.

Bristol-Myers Squibb Recruits Participants For Phase 2 Clinical Trial Of New Antiretroviral – Bristol-Myers Squibb (BMS) is currently recruiting participants for a Phase 2 clinical trial of its investigational antiretroviral BMS-663068. BMS-663068 is a new type of antiretroviral that prevents HIV from entering and infecting cells. The trial will test the new drug at four different dosages, including both once-daily and twice-daily dosages, in combination with Isentress (raltegravir) and Viread (tenofovir). Eligible participants must have been treated for HIV previously but cannot have taken Isentress. Participants must also have viral loads (amount of HIV in the blood) of 1,000 copies per milliliter or higher. BMS expects to recruit approximately 250 participants. For more information, please see the U.S. Clinical Trials Registry.

Based on these findings, the authors of the review concluded that moderate exercise may also be beneficial for older HIV-positive adults.

“We recommend a combination of endurance and resistance exercises three times per week for at least six weeks to improve cardiovascular, metabolic, and muscle function,” wrote the authors of the review.

“Combined moderate to vigorous aerobic and resistance exercise for 20 to 40 minutes, three times per week, is safe and effective in older adults and has many benefits to decrease symptom burden, decrease disease progression, and increase quality of life,” they added.

However, they noted that more research is necessary on the risks and benefits of exercise in older adults with HIV.

As people with HIV live longer due to the efficacy of combination antiretroviral therapy, HIV-positive adults over the age of 50 represent a growing proportion of the population. According to the review authors, a study from 2006 found that 27 percent of the HIV-positive population is now 50 years old or older.

Due to the effects of HIV and the antiretrovirals used to treat it, people with HIV are more prone to several age-related illnesses, including heart disease, diabetes, unintended weight loss, and others. Studies have shown that people with HIV tend to get these illnesses earlier and at higher rates than people without HIV.

Previous research has shown that exercise can be beneficial in younger HIV-positive adults for preventing or ameliorating these illnesses. However, according to the review authors, little research has been done on the benefits of exercise in HIV-positive adults who are over the age of 50.

In this review, the authors examined exercise research from 20 randomized clinical trials that included either younger HIV-positive adults, frail HIV-negative adults over the age of 65, or HIV-negative adults over the age of 55 with conditions such as pre-diabetes or high cholesterol.

All studies included aerobic and/or resistance training exercises. Aerobic exercises involve activities such as walking, swimming, or bicycle riding that elevate heart and breathing rates. Resistance or strength training involves lifting weights or other activities, such as sit-ups or push-ups, that are intended to increase muscle mass and strength.

Most studies found improvements in participants’ health after implementing an aerobic and/or resistance-based exercise program for all three patient groups,.

In younger HIV-negative adults, all but two of the 12 studies that were reviewed showed that exercise significantly improved participants’ estimated maximum heart rate – a measure of heart health – and muscle strength and size compared to participants who did not exercise.

In frail older adults without HIV results were more mixed. Results from most studies suggested that exercise improved physical performance and strength in study participants; however, some studies found that exercise was not effective, possibly because participants were too frail. The review authors suggested that for highly frail adults, exercise programs may need to be tailored to individuals’ capabilities.

For HIV-negative adults with metabolic conditions such as insulin resistance or high cholesterol, the authors found that all of the studies reviewed indicated that participants who exercised had significantly reduced insulin resistance and improved metabolic factors, such as cholesterol levels, compared to participants who did not exercise.

Based on the study results, the review authors made the following exercise recommendations for HIV-positive adults over the age of 50:

• Aerobic exercises should be performed for 20 to 40 minutes at least three days per week for at least six weeks. Moderate- to high-intensity exercise levels were most effective.
• Individuals should aim for a heart rate during exercise that is between 50 and 90 percent of their estimated maximum heart rate (as calculated based on their weight and age). Exercisers should start at lower intensity and aim for at least a 5 percent increase in intensity each week.
• Individuals should stretch for 5 to 10 minutes before and after aerobic exercises to prevent injury.
• Resistance exercises should be performed following aerobic exercises, on the same days, for at least six weeks, three days per week.
• Exercises should begin with one or two sets of six to eight repetitions for each muscle group, then increase to three sets of eight to 10 repetitions for each muscle group, with 20 to 30 second rest periods between each set.

Finally, the reviewers noted that prolonged, intense exercise can have negative effects on the immune system and make people more susceptible to viral and bacterial infections, which may be particularly risky for people with HIV. As a result, they recommended that adults with HIV refrain from strenuous physical activity for more than 90 minutes at a time.

For more information, please see the review in the Journal of the Association of Nurses in AIDS Care (abstract).

This question was debated by researchers at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011) in Rome last month.

Gene therapy is an experimental approach that is currently in early stages of clinical testing. Gene therapy involves modifying a person’s DNA (the genetic information in cells) so that it becomes, for example, resistant to HIV infection (see related AIDS Beacon news).

In most cases of gene therapy, cells are taken from the patient’s body, genetically modified in the laboratory, and then injected back into the patient.

Dr. Sharon Lewin, director of the Infectious Disease Unit at Alfred Hospital in Melbourne, Australia, argued in a session titled “Controversies in HIV Cure Research” that gene therapy is not the strategy most likely to lead to a cure for HIV due to its impracticality.

“Gene therapy is scientifically flawed, high risk, and will never get to the clinic,” said Dr. Lewin in her presentation.

Dr. Lewin argued that cure strategies based on drugs that activate latent HIV are far more promising. Latent HIV is virus that lies dormant in cells during antiretroviral therapy but activates again once treatment is stopped to renew the infection.

A number of clinical trials are currently underway to test whether certain drugs can reactivate latent HIV so that it can be eliminated from the body’s cells. According to Dr. Lewin, these treatments have an advantage in that they are available now for testing, are less expensive and more general than gene therapy (which involves intensive individualized treatment for each person), and usually have side effects that are mild and reversible. This is not necessarily the case with gene therapy, which attempts to create permanent changes in a person’s genes.

In addition, she pointed out that there are at least 22 different potential drugs for targeting latent HIV that are in Phase 1, 2, or 3 clinical trials, several of which are already approved by the U.S. Food and Drug Administration for other uses.

Although she acknowledged that drugs, in general, are not as targeted as gene therapy, she also noted that researchers are working on ways to make the drugs target latent HIV more specifically, rather than affecting all the cells in the body.

Overall, Dr. Lewin criticized the practicality of gene therapy as a cure for HIV, particularly in developing countries. “We need a cure that is scalable, deliverable, and cheap,” she concluded.

Dr. Keith Jerome, from the Fred Hutchinson Cancer Research Center in Seattle, disagreed with Dr. Lewin and argued that gene therapy is indeed the correct approach for curing HIV.

“The principle has been proven in the only HIV cure to date,” said Dr. Jerome, in reference to “The Berlin Patient,” a man who received a bone marrow transplant from a carefully selected donor with a mutated form of the CCR5 gene.

HIV requires the CCR5 protein, which is on the surface of white blood cells, in order to attach to and infect the cell. People naturally born with an alternate form of the CCR5 gene are almost entirely immune to HIV. Since his transplant, no sign of HIV has been detected in The Berlin Patient. Currently, the most advanced gene therapy strategies are attempts to replicate this success in other people with HIV.

Dr. Jerome argued that HIV is a genetic disease and therefore needs genetic treatment strategies to cure it. HIV works by incorporating itself into a cell’s DNA and then using the cell’s normal processes to replicate. Current treatments cannot remove the HIV once it has been incorporated, and Dr. Jerome argued that drugs that target DNA are not specific enough and are likely to have significant effects on other cell processes.

Instead, he said, treatments need to target and change specific genes, which means gene therapy is necessary.

Dr. Jerome did admit that more work needs to be done before gene therapy is a viable option for treatment. Researchers need to work more on developing therapies that are specific, have higher success rates in modifying genes, and do not require toxic preparative treatments before therapy, he said.

However, he noted that scientists have been making significant breakthroughs in the field and that researchers now have the necessary tools to make gene therapy work.

“Gene therapy is the path to a cure,” Dr. Jerome concluded.

For more information, please see Dr. Lewin’s and Dr. Jerome’s presentations (pptx) at the IAS 2011 conference website.

Based on their results, the researchers concluded that the gel is a promising treatment for HIV-related facial fat loss and suggested that clinical trials should be conducted to compare the safety and efficacy of the gel to the current standard treatment, polylactic acid implants (Sculptra).

Facial fat loss (lipoatrophy) that results in hollowed cheeks is a common side effect of antiretroviral therapy, particularly for older antiretrovirals such as stavudine (Zerit) or zidovudine (Retrovir).

Although the condition does not pose any significant health risk, facial fat loss can have serious psychological consequences, such as negative self-image and depression. In extreme cases, patients may choose to discontinue treatment.

Switching to more modern treatment regimens can help prevent the condition from worsening; however, according to the study authors, facial fat loss is extremely slow to heal. Instead, patients may choose to use injected facial fillers to replace the lost fat. The current approved treatment for facial fat loss is polylactic acid implants, which are effective but typically need to be replenished within about two years. In addition, the implants have been associated with lumps and nodules under the skin.

Polyacrylamide hydrogel is a facial filler that is being studied as a treatment for HIV-associated facial fat loss.  It is approved and marketed in Europe under the names Eutrophill and Aquamid, but it is not yet approved for use in the United States.

Previous studies have suggested that the gel is safe and effective in people with HIV. In this study, researchers sought to verify these findings and determine whether the gel affected patient quality of life.

The study included 111 patients treated at two French clinics between 2005 and 2007. Most participants (89 percent) were male and had taken antiretrovirals for a median of nine years. All participants had severe antiretroviral-related facial fat loss, as assessed by the researchers.

Participants received between two and six injections of Eutrophill gel every two to four weeks for six months. Researchers evaluated the thickness of participants’ cheeks and other facial regions before and after treatment. They also assessed patients’ satisfaction with the treatment, changes in participants’ quality of life, and effects on their feelings of anxiety or depression. The study authors also monitored for any treatment side effects.

Participants were evaluated at the start of the study and 6, 12, and 24 months after treatment initiation. Twenty-six percent of patients received at least one additional injection between months 6 and 12 of the study, and 35 percent of patients received at least one additional injection between months 12 and 24.

Results showed that participants’ average cheek thickness increased by 4.4 mm 12 months after treatment, with an additional average increase of 0.9 mm 24 months after treatment.

In addition, external reviewers who examined photographs of patients at 6 months, 12 months, and 24 months after treatment initiation noted an improved appearance in 88 percent of study participants at all time points.

Study participants also reported a significant increase in overall life satisfaction after 6, 12, and 24 months. However, the proportion of participants reporting high anxiety (48 percent) or depression (25 percent) did not change over the course of the study.

The researchers found no serious side effects related to the treatment. Three patients developed nodules under the skin due to the injections and three patients experienced temporary local inflammation. None of the participants interrupted treatment due to side effects.

For more information, please see the study in AIDS Research and Human Retroviruses (pdf).

“Cumulative antiretroviral therapy exposure risk is modest compared to the traditional risk factors for osteoporosis,” said Dr. Roger Bedimo from the Veterans Affairs North Texas Health Care System, who presented the results last week at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

“A significant increase in the fracture rate was noted in the HAART [highly active antiretroviral therapy] era, but we cannot infer that this is due to antiretroviral exposure per se,” he added. Dr. Bedimo noted that the increase could be due to longer survival times, for example, rather than a direct effect of the antiretrovirals on bone loss.

Traditional risk factors for bone fractures include older age, low weight or body mass index, smoking, excessive alcohol consumption, and corticosteroid use. Corticosteroids are drugs used to treat conditions such as asthma and arthritis.

Previous studies have shown that low bone density and bone fractures are more common in people with HIV than in uninfected individuals (see related AIDS Beacon news).

Additional risk factors for bone fractures in people with HIV may include hepatitis B and C infections and proton pump inhibitor use. Proton pump inhibitors are drugs used to reduce acid levels in the stomach; common drugs in this class include omeprazole (Prilosec), lansoprazole (Prevacid), and Nexium (esomeprazole).

Previous studies have also indicated that certain antiretroviral drugs may be associated with low bone density in people with HIV. In particular, use of the nucleoside reverse transcriptase inhibitor Viread (tenofovir) and boosted protease inhibitors have been linked to low bone density. Viread is also a component of Truvada (emtricitabine/tenofovir) and Atripla (efavirenz/emtricitabine/tenofovir).

However, it is not clear if these antiretrovirals are associated directly with an increased risk for bone fractures or just low bone density.

In this study, researchers investigated whether the use of antiretrovirals over time is associated with increased bone fractures. The study included 56,660 HIV-positive adults who received care through the Veterans Health Administration between 1984 and 2009.

More than 98 percent of the study participants were men, with an average age of 45 years old. Participants were followed for a median of 4.5 years.

The authors assessed how many participants reported wrist, back, or hip fractures during this time. According to the researchers, these types of fractures are most likely to occur due to osteoporosis, or low bone density.

Results showed that 951 patients sustained at least one fracture. In particular, 124 patients sustained back fractures, 486 patients sustained wrist fractures, and 341 patients sustained hip fractures.

Results also showed that the rate of fractures increased over time. Participants in the HAART era (1996 to 2009) reported bone fractures at a rate that was 2.5 times higher than participants in the pre-HAART era.

Further analysis showed that use of Viread or Kaletra (lopinavir/ritonavir) was associated with a 13 percent increased risk of bone fractures in the HAART era, after taking into account age, race, and other risk factors.

The researchers found no link between the risk of bone fracture and the use of Ziagen (abacavir), zidovudine (Retrovir), stavudine (Zerit), non-nucleoside reverse transcriptase inhibitors, or other protease inhibitors (boosted or unboosted).

However, the researchers noted that traditional risk factors were more highly associated with an increased risk of bone fractures. Caucasian race increased the risk by 61 percent, smoking by 49 percent, older age by 48 percent, and low body mass index by 48 percent.

Dr. Bedimo also stated that cumulative antiretroviral exposure is likely not directly linked to a higher bone fracture risk in the HAART era. Instead, he suggested that the effects could be due to patients living longer or the fact that fewer participants were taking sub-optimal treatment regimens or no antiretrovirals at all and thus would have a higher risk of going on to develop long-term complications such as bone fractures.

For more information, please see the study abstract and presentation on the IAS 2011 conference website.

Additionally, the authors of the study observed that older age, low CD4 (white blood cell) counts, advanced HIV infections, and less education were associated with a higher risk of HIV-associated neurological disorders.

“Cognitive impairment persists in the HAART [highly active antiretroviral therapy] era. However, we do see a small but significant downtrend, indicating that HAART is somehow protective,” said Dr. Valerio Tozzi, who presented the results last week at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

HIV infects the central nervous system – the brain and spinal cord – very quickly after initial infection, frequently leading to cognitive impairment. This impairment can affect the ability to think and reason, concentrate, remember things, process information, learn, and speak.

Despite the advent of antiretroviral therapy, HIV-associated neurological disorders remain common in people with HIV. Some studies have shown that neurological impairment can persist even after successfully achieving viral suppression and immune recovery.

In this study, researchers conducted a 15-year survey to assess the rates and risk factors for HIV-associated neurological disorders over time.

The study included 1,375 HIV-positive participants. The authors conducted several neurological tests to assess each participant for impairments in memory, motor skills, mental processing, and visual-spatial abilities.

Results showed that the rate of neurological disorders declined over time, although they remained common: 38 percent of study participants in the period from 2008 to 2010 were diagnosed with cognitive disorders, compared to 46 percent of study participants assessed during 1996 to 1998. The severity of disorders also decreased during this period, with more participants having asymptomatic disorders and fewer having mild impairment or HIV-associated dementia.

Results also showed that participants with more years on HAART were less likely to have neurological problems.

Additionally, patients with neurological impairment were an average of four years older, had more advanced HIV infections, had lower CD4 counts (an average of 351 cells per microliter, compared to 483 cells per microliter in participants without cognitive disorders), and had an average of 2.5 fewer years of education.

For more information, please see the study abstract and presentation on the IAS 2011 conference website.

The researchers noted that the drop in lipodystrophy rates is likely due to lower smoking rates and the use of newer antiretrovirals that have less effect on patients’ metabolism.

The results were presented last week at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

Lipodystrophy is a common side effect associated with HIV treatments. It causes changes in fat distribution that can lead to alterations in body shape, increased levels of cholesterol and triglycerides in the blood, and a greater risk of heart problems.

Symptoms of lipodystrophy include loss of fat in the legs, face, arms, and buttocks; and an increase of fat in the stomach, upper back or neck, and breasts.

In this study, researchers from Alfred Hospital in Melbourne, Australia investigated how common lipodystrophy was in 1998 and today, when more modern antiretrovirals are available that have fewer side effects. They also examined risk factors for lipodystrophy.

The study, conducted in 2010, included 100 HIV-positive men on antiretroviral therapy who had no history of heart disease. The researchers also included data from a 1998 study at the same hospital on 144 HIV-positive men with no history of heart disease.

Results showed that the rate of lipodystrophy is still high but has fallen since 1998: 58 percent of participants in the 2010 study had lipodystrophy, compared to 69 percent of participants in the 1998 study.

This was in spite of the fact that 2010 study participants were an average of 10 years older and had taken antiretrovirals a median of nearly eight years longer, both of which increase the risk for lipodystrophy.

Results also showed, however, that 2010 study participants were more likely to report themselves as having lipodystrophy: 35 percent of participants in 2010 reported having lipodystrophy compared to 21 percent of participants in 1998.

Study participants from 2010 were less likely to be taking protease inhibitors or older drugs such as stavudine (Zerit) and zidovudine (Retrovir), which are associated with lipodystrophy. They were more likely to take non-nucleoside reverse transcriptase inhibitors, and almost 20 percent were taking entry inhibitors and/or integrase inhibitors, which are newer classes of antiretrovirals that were not available in 1998.

Participants in 2010 weighed an average of 7.7 lb (3.5 kg) more than participants in 1998 but had lower average cholesterol and triglyceride levels. They were also less likely to smoke (36 percent of participants in 2010 versus 51 percent of participants in 1998).

Risk factors for lipodystrophy in the 2010 study group included high “bad” cholesterol levels. Taking Viread (tenofovir) or Ziagen (abacavir) was associated with a lower risk of lipodystrophy.

Results also showed that participants in the 2010 study had better control over their HIV than participants in the 1998 study. Median CD4 (white blood cell) counts were 265 cells per microliter higher in the 2010 study group than in the 1998 group, and 90 percent of 2010 participants had undetectable viral loads (amount of HIV in the blood), compared to 57 percent of participants in the 1998 study.

For more information, please see the study abstract or presentation (pdf) at the IAS 2011 conference website.

Based on their results, the researchers recommended further research into treatment regimens that do not contain nucleoside reverse transcriptase inhibitors (NRTIs) – such as Truvada – which currently form the backbone of antiretroviral therapy. They also noted that longer trials with more participants would be needed to confirm the long-term safety and efficacy of non-NRTI-based regimens.

The results were presented last week at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

Traditional combination antiretroviral therapy regimens consist of two NRTIs plus at least one additional anti-HIV drug from a different class. However, due to side effects associated with NRTIs and the fact that some patients cannot take them due to allergies or other conditions, researchers have begun exploring alternative “NRTI-sparing” regimens (see related AIDS Beacon news).

In this study, researchers examined the efficacy of the non-NRTI-based regimen of Kaletra (lopinavir/ritonavir) plus Selzentry (maraviroc) versus the more traditional regimen of Kaletra plus Truvada (emtricitabine/tenofovir). Truvada is a combination of two NRTIs, while Kaletra is a protease inhibitor and Selzentry is a CCR5 inhibitor, which is a relatively new type of antiretroviral.

The trial included 38 HIV-positive adults who had not previously been treated for HIV. Half the participants were randomly assigned to receive Kaletra plus Selzentry, and the other half were assigned to take Kaletra plus Truvada. The researchers then assessed participants’ CD4 (white blood cell) counts and viral loads (amount of HIV in the blood) at 4, 12, 24, 36, and 48 weeks after starting treatment.

Results showed that after 48 weeks, participants in the non-NRTI Kaletra plus Selzentry group had significantly higher increases in CD4 counts than participants in the Kaletra plus Truvada group. The average increase in CD4 count for the Kaletra/Selzentry group was 226 cells per microliter, compared to 125 cells per microliter in the Kaletra/Truvada group.

Additionally, most participants in the non-NRTI group (83 percent) achieved undetectable viral loads by week 12, compared to less than half of patients in the Truvada group. By 48 weeks, 95 percent of participants in the Kaletra/Selzentry group had undetectable viral loads, compared to 83 percent of participants in the Kaletra/Truvada group.

The researchers also noted that three participants taking Kaletra plus Truvada had to interrupt treatment due to diarrhea. Overall one person in the Kaletra/Truvada group discontinued treatment, compared to none in the Kaletra/Selzentry group.

For more information, please see the study abstract and presentation (pdf) on the IAS 2011 conference website.

In addition, participants taking Isentress (raltegravir) reported fewer side effects than those taking Sustiva (efavirenz).

“In this Phase 2 study, Isentress demonstrated comparable efficacy and tolerability to efavirenz [Sustiva] at 240 weeks in treatment-naïve adult patients with HIV-1,” said primary investigator Dr. Eduardo Gotuzzo in a press release. Dr. Gotuzzo presented the results last week at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

He also noted that the effects of Isentress on cholesterol levels were minimal over the course of the study.

“Because physicians consider many factors when selecting antiretroviral therapy for adult HIV-1 patients new to treatment, the results seen in this Phase 2 study with Isentress in combination therapy showing a modest impact on LDL [“bad” cholesterol] and triglycerides provide important insights,” said Dr. Gotuzzo.

The antiretroviral Isentress is currently the only approved integrase inhibitor, although two other investigational integrase inhibitors – dolutegravir and elvitegravir – are currently in Phase 3 clinical trials.

Isentress is approved both for treatment-experienced adults with HIV and as a first-line treatment for people who have not previously taken antiretrovirals.

In this study, researchers compared the safety and efficacy of Isentress to those of Sustiva over an extended period to see how Isentress performed long-term.

Sustiva, in combination with Truvada (emtricitabine/tenofovir) in the form of Atripla (efavirenz/emtricitabine/tenofovir), is the most commonly prescribed first-line regimen for people with HIV.

Both Sustiva and Isentress, when taken with Truvada, are listed in HIV treatment guidelines as “preferred” regimens for people starting antiretroviral therapy for the first time.

The study included 198 treatment-naïve HIV-positive adults. Participants were initially randomly assigned to take either Sustiva or one of four different Isentress dosages, both in combination with Truvada. After 48 weeks, all 160 participants taking Isentress were moved to the 400 mg twice daily dosage; the remaining 38 participants continued to take Sustiva once daily. The trial lasted 240 weeks.

Results showed that at the end of the study, 69 percent of participants taking Isentress had successfully achieved and maintained an undetectable viral load (amount of HIV in the blood), compared to 63 percent of participants taking Sustiva.

In addition, participants taking Isentress had an average increase in CD4 (white blood cell) count of 302 cells per microliter over this period, versus an average increase of 276 cells per microliter in participants taking Sustiva.

The differences between the two study groups were not large enough to be considered significant.

Fewer patients taking Isentress reported side effects (55 percent) than those taking Sustiva (76 percent). Consistent with other clinical trials, participants taking Sustiva were more likely to report neuropsychiatric symptoms such as dizziness, headache, abnormal dreams, insomnia, and nightmares.

Participants in both groups experienced increases in cholesterol and triglycerides; however, the changes in the Sustiva group were larger than those in the Isentress group, particularly for overall cholesterol levels.

Other side effects, such as nausea and diarrhea, were similar between the two groups.

For more information, please see the study abstract or presentation (pptx) at the IAS 2011 conference website, or the Merck press release.

Kaletra Can Be Taken With Cholesterol Drug Livalo (IAS 2011) – Results from another study presented last week at IAS 2011 indicate that it is safe for people with HIV/AIDS to take Kaletra (lopinavir/ritonavir) in combination with the cholesterol drug Livalo (pitavastatin). Based on the results of the trial, the U.S. Food and Drug Administration updated Livalo’s prescribing information last month to remove a warning about taking Livalo with Kaletra. The trial included 24 HIV-negative adults who took Kaletra plus Livalo for 24 days. Results showed that Kaletra and Livalo did not significantly affect one another’s levels in the blood. Changes of a drug’s levels in the blood can compromise its efficacy and safety. There were no additional side effects from taking the two drugs together. Kaletra still should not be taken with the cholesterol drugs Zocor (simvastatin) or lovastatin (Mevacor). For more information, please see the study abstract at the IAS 2011 conference website or the Kowa Pharmaceuticals press release.

Drugs For Neglected Diseases Initiative Launches New Program For Pediatric Antiretrovirals – The Drugs for Neglected Diseases Initiative (DNDi), a Switzerland-based not-for-profit research organization, has announced the launch of a new program aimed at developing child-friendly formulations of antiretrovirals for HIV-positive children. The program will focus first on developing an improved protease inhibitor-based first-line regimen for children under three years old. Researchers will also work to determine appropriate dosages, safety profiles, and child-friendly formulations for several existing antiretrovirals. For more information, please see the DNDi press release.

“Elvitegravir represents a new suitable option for treatment-experienced patients,” said Dr. Jean-Michel Molina from the Hopital Saint Louis in Paris, who presented the results yesterday at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

“Elvitegravir was overall pretty well tolerated, with a safety profile that was comparable to that of [Isentress],” he added. He noted that the drug is also being investigated in previously untreated patients as a component of the proposed “Quad” (cobicistat/elvitegravir/emtricitabine/tenofovir) combination pill.

Based on the results, Gilead stated in a press release that it plans to apply for U.S. Food and Drug Administration and European Medicines Agency approval of elvitegravir and the “Quad” combination pill in 2012. If approved, the “Quad” pill would be a once daily all-in-one antiretroviral regimen.

Elvitegravir is a potential new integrase inhibitor that is being developed by Gilead Sciences. Currently the only approved integrase inhibitor is Isentress (raltegravir), marketed by U.S. pharmaceutical company Merck. Isentress is approved both as a first-line treatment for HIV and for people who are treatment experienced.

In this Phase 3 study, investigators are comparing the efficacy of elvitegravir and Isentress in HIV-positive adults who had previously taken antiretrovirals from at least two different drug classes. The study includes 702 participants, a majority of whom (63 percent) were resistant to two or more classes of antiretrovirals at the start of the trial.

Half of the participants were randomly assigned to receive elvitegravir once daily and the other half Isentress twice daily. All participants are also taking a boosted protease inhibitor plus a third antiretroviral as part of their combination therapy.

The most common background regimen is Norvir (ritonavir)-boosted Prezista (darunavir) plus Viread (tenofovir). Participants taking Reyataz (atazanavir) or Kaletra (lopinavir/ritonavir) receive a lower dose of elvitegravir, 85 mg daily instead of 150 mg.

Results showed that after 48 weeks, 59 percent of participants taking elvitegravir successfully achieved and maintained undetectable viral loads (amount of HIV in the blood), compared to 58 percent of participants taking Isentress.

Improvements in CD4 (white blood cell) counts were also similar between the two groups: an average increase of 138 cells per microliter in participants taking elvitegravir versus 147 cells per microliter in participants taking Isentress.

Results also showed that 27 percent of participants who failed treatment with elvitegravir developed resistance to integrase inhibitors, versus 21 percent of participants who failed treatment with Isentress. The difference was not large enough to be considered significant.

The most common moderate to severe side effects in both groups were diarrhea, upper respiratory tract infections and bronchitis, back pain, and depression. Discontinuation rates due to side effects were also similar between the two groups: 3 percent of participants in the elvitegravir group and 4 percent in the Isentress group, respectively.

Although the trial was originally scheduled to run for 48 weeks, Gilead announced earlier this year that it would extend the trial to 96 weeks to obtain additional long-term safety and efficacy data on elvitegravir (see related AIDS Beacon news). The study is currently ongoing and is expected to be completed by the end of the year.

For more information, please see the study presentation or the abstract at the IAS 2011 conference website, or the Gilead Sciences press release.

“Dolutegravir administered once daily…showed a rapid and sustained response at all doses explored through week 48,” said Dr. Jan van Lunzen, who presented the results yesterday at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

“The drug in all dose groups was well tolerated, with fewer discontinuations occurring than in the [Sustiva] comparator arm,” he added.

Based on the results, Dr. van Lunzen stated that several Phase 3 clinical trials have been initiated with the highest dolutegravir dosage tested.

Dolutegravir (S/GSK1349572) is a potential new integrase inhibitor being developed by ViiV Healthcare (a joint venture by GlaxoSmithKline and Pfizer). Currently, the only approved integrase inhibitor is Isentress (raltegravir), which is marketed by U.S. pharmaceutical company Merck.

The clinical trial was designed to test the safety and efficacy of several dolutegravir dosages relative to Sustiva (efavirenz), which, when combined with Truvada (emtricitabine/tenofovir) in the form of Atripla (efavirenz/emtricitabine/tenofovir), is the most commonly prescribed first-line regimen to treat HIV.

The study includes 205 participants, who were randomly assigned to one of four groups. The first group is being treated with 10 mg of dolutegravir once daily, the second takes 25 mg of dolutegravir once daily, the third receives 50 mg of dolutegravir once daily, and the fourth takes Sustiva. All groups take the drugs in combination with either Truvada or Epzicom (abacavir/lamivudine).

Results showed that after 48 weeks, most participants in all four groups had successfully achieved an undetectable viral load (amount of HIV in the blood): 91 percent, 88 percent, 90 percent, and 82 percent of the participants, respectively.

Sixteen week results presented at a previous conference suggested that participants taking dolutegravir achieved an undetectable viral load faster than participants taking Sustiva. The 48 week results showed that the more rapid response to dolutegravir was sustained throughout the study period.

Participants taking dolutegravir had slightly higher increases in CD4 (white blood cell) counts after 48 weeks than participants taking Sustiva (231 cells per microliter versus 174 cells per microliter), but the difference was not large enough to be considered significant.

There were fewer moderate to severe side effects reported in the dolutegravir trial groups than in the Sustiva group (8 percent of participants versus 20 percent). Participants taking dolutegravir also had smaller increases in “bad” cholesterol levels during the course of the trial than participants taking Sustiva, with little or no increase in cholesterol levels overall.

In total, two participants stopped taking dolutegravir and four stopped taking Sustiva due to side effects.

The trial will continue for an additional 48 weeks.

Two Phase 3 clinical trials for dolutegravir are currently recruiting participants. The first trial will test the safety and efficacy of dolutegravir versus Isentress in treatment experienced patients who have not previously been treated with integrase inhibitors. The second trial will test the efficacy of dolutegravir in people who have failed therapy with Isentress.

Two other Phase 3 trials are ongoing but are not currently recruiting participants.

For more information, please see the study presentation or abstract on the IAS 2011 conference website.

“Lersivirine is a next generation non-nucleoside reverse transcriptase inhibitor…[that] has potent activity against HIV,” said Dr. Anton Pozniak, who presented the results today at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011).

“Both lersivirine doses [tested] achieved similar viral load suppression to [Sustiva],” he added.

Dr. Pozniak suggested that lersivirine may also be an option for people who are resistant to Sustiva (efavirenz), since the two drugs work slightly differently. However, he noted that the results will need to be confirmed in a larger Phase 3 clinical trial.

Lersivirine (UK-453061) is a potential new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed by ViiV Healthcare, a joint venture of the pharmaceutical companies Pfizer and GlaxoSmithKline.

The Phase 2b clinical trial is designed to test the safety and efficacy of lersivirine versus those of Sustiva, which is also an NNRTI. Both antiretrovirals are taken in combination with Truvada (emtricitabine/tenofovir); Sustiva plus Truvada is equivalent to Atripla (efavirenz/emtricitabine/tenofovir), the most frequently prescribed first-line regimen for people with HIV in the United States.

The trial includes 193 HIV-positive participants who had not been treated with antiretrovirals prior to starting the study. Participants were randomly assigned to receive either 500 mg lersivirine once daily plus Truvada (65 participants), 750 mg lersivirine once daily plus Truvada (65 participants), or Sustiva plus Truvada (63 participants).

Results showed that after 48 weeks, 79 percent of participants taking lersivirine had achieved an undetectable viral load (amount of HIV in the blood) compared to 86 percent of participants taking Sustiva. The difference in efficacy between the two drugs was not large enough to be considered significant.

Increases in CD4 (white blood cell) counts were similar across the three groups, at 191, 195, and 188 cells per microliter for the 500 mg lersivirine, 750 mg lersivirine, and Sustiva groups, respectively.

The reported side effects for lersivirine were different than those for Sustiva. The most common side effects in the lersivirine groups were nausea (23 percent and 42 percent for the 500 mg and 750 mg groups, respectively) and headache (23 percent and 17 percent for the 500 mg and 750 mg groups, respectively). The most common side effects in the Sustiva group were abnormal dreams (19 percent) and dizziness (21 percent).

Severe side effects were less common in the lersivirine groups, at 6 percent and 14 percent for the 500 mg and 750 mg dosage groups respectively, compared to 22 percent in the Sustiva group.

Overall, three participants from each lersivirine group and five participants in the Sustiva group discontinued the drugs due to side effects.

The trial is scheduled to continue for an additional 48 weeks.

For more information, please see the study presentation or abstract at the IAS 2011 conference website.

“Based on the results, we are now offering [antiretroviral therapy to] all HIV-infected participants in the delayed arm, regardless of CD4 count,” said Dr. Myron Cohen, who presented the results today at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention (IAS 2011). The results were also released today in the New England Journal of Medicine.

The study authors recommended that antiretroviral therapy be further considered as a treatment strategy for preventing HIV transmission. They also stated that a longer follow-up period is necessary before they can give a recommendation on whether earlier antiretroviral treatment is beneficial to people with HIV for health reasons.

The Phase 3 clinical trial, which included participants in Boston as well as in international locations such as India and Africa, was designed to test whether people with HIV who start treatment earlier are less likely to transmit the virus to their partners. This strategy is known as “treatment as prevention” and rests on the idea that people taking antiretrovirals will have lower levels of HIV in their blood, semen, and vaginal fluids, reducing the risk of transmission.

This is in contrast to pre-exposure prophylaxis, a different strategy in which uninfected men and women take antiretrovirals to prevent infection from their HIV-positive partners. Results from two large studies that were released last week showed that pre-exposure prophylaxis is also effective at reducing transmission (see related AIDS Beacon news).

The new study included 1,763 serodiscordant couples in which one partner was HIV positive and the other HIV negative. In half of the couples, the HIV-positive partner was assigned to start treatment immediately upon enrolling in the study at CD4 (white blood cell) counts between 350 and 550 cells per microliter. In the other half, the HIV-positive partners started antiretroviral therapy after their CD4 counts dropped to 250 cells per microliter or less or they developed an AIDS-related illness.

Nearly all of the couples (94 percent) were heterosexual, and a majority of participants (61 percent) were between the ages of 26 and 40, with a median age of 32 years. Initial CD4 counts, viral loads (amount of virus in the blood), and reported levels of condom use were similar for couples in the two groups.

All participants received free condoms and guidance on safe sex practices at each study visit. Participants were followed for a median of 1.7 years.

Results showed that starting antiretroviral therapy early reduced the number of illnesses experienced by the HIV-positive partners in the study and significantly reduced transmission of HIV to the HIV-negative partners.

A total of 105 AIDS-related illnesses or deaths occurred during the study, 40 in the early treatment group and 65 in the delayed treatment group, for a total higher risk of 67 percent in the late treatment group. This was primarily due to tuberculosis infections, which occurred in three of the early treatment group participants versus 17 of the late treatment group participants.

Participants in the early treatment group also had higher CD4 counts than the late treatment group a year after starting treatment, with a median of 603 cells per microliter versus 418 cells per microliter, respectively.

In addition, there were a total of 39 HIV transmission events during the study, 28 of which were confirmed to be between partners (rather than from an outside source). One transmission occurred in the early treatment group and 27 in the delayed treatment group, indicating a 96 percent reduction in risk for participants whose HIV-positive partners started treatment early rather than later.

Furthermore, the single confirmed transmission in the early treatment group occurred very soon, within three months, after treatment initiation; all 27 transmissions in the late treatment group occurred before participants started treatment.

The most common side effects in both treatment groups were infections, psychiatric and nervous system problems, metabolic or nutrition problems, and stomach problems; rates of these side effects were similar between the two groups.

However, participants in the early treatment group were more likely to have severe blood-related side effects, such as low white blood cell levels (neutropenia) or abnormal phosphate levels.

For more information, please see the “Treatment is Prevention” conference session, which includes four presentations on the study, at the IAS 2011 website; or the study in the New England Journal of Medicine.

Gilead Sciences Agrees To License New HIV Drugs To Generic Drug Companies In Developing Countries – Gilead Sciences has signed agreements with several generic drug companies in India that will allow them to produce low-cost versions of the antiretrovirals Viread (tenofovir) and Emtriva (emtricitabine) for developing countries. The agreements will extend to the investigational drugs elvitegravir, cobicistat, and the combination “Quad” pill (cobicistat/elvitegravir/emtricitabine/tenofovir) if the drugs are approved. The agreement makes Gilead the first company to join the Medicines Patent Pool, an effort to bring newer antiretrovirals that are still under patent protection to people in developing nations. However, the agreement has faced criticism from Médecins Sans Frontières (also known as Doctors Without Borders) for excluding certain middle-income countries, such as Thailand and Brazil. For more information, please see the press releases from Gilead Sciences and Médecins Sans Frontières.

AIDSinfo Updates “HIV And Its Treatment” Factsheets – AIDSinfo, a website run by the Department of Health and Human Services (DHHS), has updated its factsheets on “HIV and Its Treatment” to include information from the latest DHHS treatment guidelines for adults and adolescents. The factsheets are intended for people with HIV and their friends or families and include information on current treatment recommendations, HIV testing, transmission prevention, and other topics. For more information, please see the updated factsheets (pdf) or the AIDSinfo website.

The conference – held every two years – brings together over 5,000 scientists, policy makers, health workers, activists, business leaders, and people with HIV and AIDS.

The meeting will include new research on a variety of topics, including basic science aspects of HIV and AIDS, new treatments and treatment strategies, complications of HIV and antiretroviral therapy, and progress toward a cure for HIV.

Beginning next week, The AIDS Beacon will feature select topics and research from IAS 2011.

Plenary speakers will include Dr. Giovanni Di Perri from the University of Turin in Italy, who will discuss HIV treatment in 2011, and Dr. Eric Verdin from the University of California, San Francisco, who will discuss HIV cure research.

Researchers will also present updated information on the safety and efficacy of several investigational antiretrovirals, including lersivirine, a potential new non-nucleoside reverse transcriptase inhibitor from Pfizer; and dolutegravir, an investigational integrase inhibitor from GlaxoSmithKline.

In addition, there will be sessions on premature aging of people with HIV, the next generation of HIV treatments, and progress toward a therapeutic vaccine for HIV. Therapeutic vaccines are vaccines that try to reduce or eliminate the need for antiretrovirals in people who already have HIV.

To increase access to the conference, IAS 2011 organizers will post updates to the IAS 2011 blog. The conference also has a Facebook page, a Twitter feed, and a YouTube channel.

For more information please see the IAS 2011 conference website.

When taken daily, the antiretrovirals reduced transmission risk by 60 percent to 70 percent. Due to the strength of the results one of the two trials was modified to discontinue the placebo group early, with all participants being placed on the drugs for prevention purposes.

“These are exciting results for global HIV prevention. We now have findings from two studies showing that [pre-exposure prophylaxis] can work for heterosexuals, the population hardest hit by HIV worldwide,” said Dr. Kevin Fenton, director of the Centers for Disease Control’s National Center for HIV/AIDS, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention, in a press release.

The studies are particularly relevant for serodiscordant couples, in which one partner is HIV positive and the other is HIV negative.

Based on the results, the United States Centers for Disease Control and Prevention (CDC) has stated that it will begin working on guidelines for heterosexual men and women in the U.S.

“The next important step is to fully review the data and assess when and how [pre-exposure prophylaxis] should best be used for HIV prevention among heterosexuals,” said Dr. Jonathan Mermin, director of the CDC’s Division of HIV/AIDS Prevention.

Viread And Truvada Decrease HIV Infection Risk

Viread (tenofovir), which is also a component of Truvada (emtricitabine/tenofovir), is an antiretroviral drug marketed by Gilead Sciences. Results from a previous clinical trial showed that a daily dose of Truvada reduced the risk of HIV infection in men who have sex with men by 44 percent (see related AIDS Beacon news).

The purpose of the two new clinical trials was to see if Viread and Truvada are similarly effective in heterosexual serodiscordant couples. The strategy of taking antiretrovirals to prevent HIV infection is known as pre-exposure prophylaxis.

The first trial, conducted by the CDC in Botswana, included 1,219 men and women aged 18 to 39 years. Half the participants received Truvada once daily while the other half took a placebo. All participants were instructed in HIV prevention, including condom use, and tested regularly for HIV.

Preliminary results showed that 9 of 601 participants taking Truvada (1.5 percent) contracted HIV during the study period, compared to 24 of 599 participants taking a placebo (4 percent), for a total reduction in HIV infection risk of 63 percent.

Further analysis showed that participants with steady access to the drugs (excluding those who may not have had access during the entire study period) had an overall risk reduction of 78 percent. The CDC reported no significant safety concerns, with the most common side effects being nausea, vomiting, and dizziness.

The trial is completed but the CDC is still in the process of analyzing the results, including the impact of adherence on the drug’s efficacy.

The second clinical trial, conducted by the University of Washington in Kenya and Uganda, included 4,758 serodiscordant couples. One third of the HIV-negative partners in the study received Viread once daily, one third took Truvada once daily, and the remaining one third received a placebo. As in the CDC trial, all participants were instructed in safe sex practices and tested regularly for HIV.

Results showed a total of 18 new HIV infections among the partners taking Viread, 13 in partners taking Truvada, and 47 among those taking a placebo. The reduction in infection risk was found to be 62 percent for patients taking Viread and 73 percent for patients taking Truvada, although the difference between the drugs was not considered large enough to be statistically significant.

The researchers also found high levels of treatment adherence, with more than 97 percent of assigned doses actually taken. The rates of serious medical problems during the trial were similar for patients receiving the antiretrovirals and those receiving the placebo.

The trial is ongoing but participants receiving the placebo have been switched to taking either Viread or Truvada.

A third clinical trial testing the efficacy of once-daily Truvada in pill form versus as a vaginal gel for pre-exposure prophylaxis is still ongoing.

CDC: Guidelines On Pre-Exposure Prophylaxis For Heterosexual Men And Women Are Coming

As a result of the two successful trials, the CDC plans to release guidelines in the U.S. for use of Viread or Truvada in heterosexual couples. The CDC has recommended that couples wait for the guidelines, which will include topics like how to handle pregnancies, before using the drugs as a preventative measure.

However, for those considering taking Viread or Truvada now, officials at the CDC have issued the following recommendations:

• HIV-negative individuals should confirm, via HIV testing, that they are still HIV negative before starting pre-exposure prophylaxis. They should also continue to be tested regularly for HIV.
• Antiretrovirals taken as a preventative measure should always be combined with other safe sex strategies, such as regular condom use. They are not meant to be a stand-alone barrier to infection.
• The drugs must be taken daily.
• Antiretrovirals should only be used after consulting with a physician and in conjunction with regular monitoring.

The CDC also noted that there is no information yet on whether pre-exposure prophylaxis is effective in injection drug users. There is also insufficient information to provide a recommendation to women who are pregnant, planning to become pregnant, or breastfeeding.

Pre-Exposure Prophylaxis Gains Steam But Is Still Somewhat Controversial

The use of pre-exposure prophylaxis in the U.S. is still somewhat controversial. The AIDS Healthcare Foundation (AHF), a California-based treatment and advocacy group, recently asked the Food and Drug Administration (FDA) not to approve Truvada for pre-exposure prophylaxis, based on the trial results for men who have sex with men (see related AIDS Beacon news).

“The first of our numerous concerns is that the…study results do not pass the threshold for effectiveness. The 44 percent efficacy that was achieved is well below the threshold generally agreed upon as necessary to be considered effective,” wrote AHF.

“The impact of a prophylactic with an efficacy rate of 60 percent would be considered low. It is unclear why the threshold of acceptability has been lowered so significantly in the case of [Truvada].”

The AHF argued that the drug was not effective enough in preventing HIV transmission and could lead to riskier sexual behavior and transmission of drug-resistant HIV. In addition, the AHF pointed to an earlier study showing that Truvada was ineffective at preventing HIV infection in women; it is still unclear why that study was less successful.

However, the new results, which show higher efficacy rates for heterosexual men and women, could increase the probability of Truvada or Viread receiving FDA approval for pre-exposure prophylaxis. Even if not approved, the drugs could still be prescribed “off-label” – for a purpose other than a drug’s approved function – but Gilead would not be able to market the drugs for pre-exposure prophylaxis and insurance companies and government health plans may be less likely to cover it.

For more information, please see the press releases from the CDC and the University of Washington (pdf).

NIAID Makes Five Year, Multi-Million Dollar Grants Toward HIV Cure Research – The National Institute of Allergy and Infectious Diseases (NIAID) announced today that it has granted more than $14 million per year for up to five years toward research for a cure for HIV. The new grants, part of the Martin Delaney Collaboratory of funding toward an HIV cure, focus on studying and eliminating reservoirs of latent HIV (HIV that lies dormant during antiretroviral therapy until treatment is stopped). Recipients include the Fred Hutchinson Cancer Research Center, the University of North Carolina at Chapel Hill, the University of California, San Francisco, and the Vaccine & Gene Therapy Institute of Florida. For more information please see the NIAID press release.

Theratechnologies Applies For Marketing Approval Of Egrifta In Israel – Theratechnologies, via its partner Sanofi, has applied for marketing approval of Egrifta (tesamorelin) in Israel. If approved, Egrifta will be the first drug in Israel to treat lipodystrophy, a condition of abnormal fat distribution that is a side effect of certain anti-HIV medications. Based on average approval times in Israel, a decision would be expected in mid-2013. Egrifta was approved in the U.S. in November of last year, and Theratechnologies’ partners have since applied for approval in Europe and Canada. For more information, please see the Theratechnologies press release.

The authors did note that, consistent with results from an earlier study, the participants who started treatment at the lower dose had levels of Kaletra in the blood that were below the “minimum effective concentration,” which is the lowest amount of a drug in the blood that scientists believe is needed for the drug to work.

However, since the participants successfully maintained undetectable viral loads throughout the study period, the authors argued that the lower dose should nonetheless be studied further in larger trials.

Kaletra (lopinavir/ritonavir) is a protease inhibitor that is a common component of antiretroviral therapy. Each pill contains 200 mg of the protease inhibitor lopinavir plus 50 mg of the boosting agent Norvir (ritonavir), which helps increase the amount of lopinavir in the blood to make it more effective.

The current dosage for adults is four Kaletra pills per day, taken either once daily (all four pills at once) or twice daily (two pills at a time).

As with other protease inhibitors, results from previous studies have shown that patients taking Kaletra may be at a higher risk developing high cholesterol and high triglyceride levels and diabetes.

Researchers have become increasingly concerned about the long-term health implications of these side effects as people with HIV live longer and take antiretrovirals for longer periods of time.

According to the study authors, research has shown that it may be possible to safely lower the dosage of Kaletra for patients who have not previously been treated with protease inhibitors. A recent French study, for example, found that a total dosage of two thirds the current amount was still effective, with 25 of 28 study participants maintaining undetectable viral loads (amount of HIV in the blood) after 48 weeks of treatment and two of the three remaining participants having detectable but low viral loads.

In this study, researchers evaluated the efficacy of a half dose of Kaletra – two pills daily – in six HIV-positive adults, four of whom were women.

Four of the participants started antiretroviral therapy at a normal dose of Kaletra, while two had chosen to reduce their dosage to half the regular dose (one pill twice daily) when starting therapy. Two of the four participants taking the normal dose were taking Kaletra alone, and two took it in combination with Truvada (emtricitabine/tenofovir). The two participants taking a reduced dose were also taking Truvada.

After a median of 15 months, the four participants taking the full Kaletra dose reduced their dosage to the half dose. The two participants who started therapy with a half dose had been on therapy for 7 and 15 months, respectively.

All participants had undetectable viral loads at the start of the study.

Results showed that after a median of 14 months, all four participants whose dosages had been reduced maintained undetectable viral loads. The two participants who started at half doses of Kaletra still had undetectable viral loads 10 months and 18 months after starting the study.

In addition, the four participants who started at a full dose of Kaletra, all of whom had high triglyceride levels at the start of the study, had normal levels by the end of the study period. The two participants who started at a half dose had normal triglyceride levels throughout the study.

For more information, please see the study in AIDS Patient Care and STDs.

Based on their results, the review authors recommended that people with HIV receive routine screening for diabetes before starting antiretroviral therapy, three to six months after starting therapy, and once a year thereafter.

Diabetes is a chronic disease marked by high levels of sugar (glucose) in the blood that results from the body’s inability to effectively use or produce insulin, a hormone that controls blood sugar levels.

Diabetes is a large and growing problem in the United States, with around 8 percent to 12 percent of the population estimated to have the disease, primarily older adults. Traditional risk factors for diabetes include family history, smoking, ethnicity, increased body weight, and older age.

In their review, the authors examined the evidence for increased risk of diabetes in people with HIV, particularly related to the use of antiretrovirals. They also discussed the diagnosis and management of diabetes in HIV-positive patients.

Diabetes In People With HIV: Risk Factors And Antiretroviral Use

In addition to traditional risk factors, which affect a disproportionate number of people with HIV, antiretroviral therapy may also increase the risk for diabetes.

According to the review authors, results from previous research indicate that HIV-positive individuals on antiretroviral therapy are almost three times more likely to develop diabetes than people with HIV who are not taking antiretrovirals.

The risk of acquiring diabetes varies depending on the type of antiretrovirals used, although results are somewhat conflicting.

Results from several studies have implicated protease inhibitors as a risk factor for diabetes. The rate of diabetes in people with HIV taking protease inhibitors is around 7 percent to 13 percent, compared to around 3 percent for previously untreated people with HIV. Researchers have also shown that protease inhibitor use can lead to insulin resistance and high levels of sugar in the blood.

Crixivan (indinavir), in particular, is linked to a higher risk of diabetes. Results are conflicting for Kaletra (lopinavir/ritonavir), with some studies showing higher risk of insulin resistance and others finding no effect. Other protease inhibitors, such as Reyataz (atazanavir), may not be linked to a higher diabetes risk.

Researchers have also found that the use of certain nucleoside reverse transcriptase inhibitors (NRTIs) may increase the risk for diabetes, with an 8 percent increased risk of high insulin levels for each year of NRTI exposure.

This is particularly the case for older NRTIs such as stavudine (Zerit), zidovudine (Retrovir), and didanosine (Videx); the newer NRTI Viread (tenofovir), which is also a component of Truvada (emtricitabine/tenofovir) and Atripla (efavirenz/emtricitabine/tenofovir), has not been linked to increased risk of diabetes.

Currently, there is no evidence that non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, and CCR5 antagonists increase the risk for diabetes in people with HIV.

Diagnosis And Treatment Of Diabetes In HIV-Positive Individuals

The International AIDS Society has set up guidelines for the diagnosis and treatment of diabetes in people with HIV, which, according to the review authors, are similar to those established by the American Diabetes Association:

• Glucose and lipid levels (such as cholesterol and triglycerides) should be measured in HIV-positive patients before beginning antiretroviral therapy, three to six months after initiating therapy, and then annually afterwards
• Individuals with a family history of diabetes and/or obesity should consider taking a standard oral glucose tolerance test, which measures the body’s ability to use glucose and is used to diagnose diabetes
• Unlike for HIV-negative individuals, HbA1c levels, which are usually used as a measure of blood glucose levels over a two to three month period, are not recommended for use as a diagnostic tool in HIV-positive patients
• For individuals diagnosed with diabetes, regular exercise, a healthier diet, and self-monitoring of blood sugar are suggested for both HIV-negative and -positive patients
• If exercise and diet alone are not keeping patients’ diabetes in control, drug therapies should be used. As in HIV-negative individuals with diabetes, drugs including thiazolidinediones (such as Actos (pioglitazone)) and metformin (Glucophage) can be used. These drugs help the body respond to insulin and control blood sugar levels.

In addition, the review authors suggested that patients discuss the potential of developing diabetes with their doctors when choosing an antiretroviral therapy regimen, since avoiding certain antiretrovirals may decrease the risk for diabetes.

The review authors noted that more research is needed on best treatment of diabetes in people with HIV, as many anti-diabetes drugs have not been investigated in HIV-positive patients. They also noted that thiazolidinediones and metformin have not been shown to decrease the risk of heart disease, a common complication of diabetes, and should therefore be used only to lower blood glucose levels. There is no evidence that they are effective for treating pre-diabetes (insulin resistance or glucose intolerance).

For more information, please see the study in Best Practice & Research Clinical Endocrinology & Metabolism (abstract).

While the majority of infants treated with Kaletra had no symptoms, three premature infants treated with Kaletra experienced life-threatening problems, including extensive heart damage, low levels of sodium in the blood, and high levels of potassium in the blood.

“The association between [Kaletra] and transient adrenal dysfunction in HIV-uninfected newborns suggests that [Kaletra] and more generally ritonavir boosting should be used with caution, if at all, in premature infants, and if this drug regimen is administered to full-term infants, it should be used under electrolyte monitoring,” wrote the authors of the study.

The authors also suggested additional studies to determine the fundamental cause of Kaletra toxicity in newborns, particularly premature infants.

To decrease the risk of transmission of HIV from HIV-positive mothers to their infants, United States Department of Health and Human Services guidelines recommend treating newborns with a six-week course of antiretrovirals immediately after birth. This practice, combined with treatment of HIV-positive women with antiretrovirals during pregnancy and labor, has reduced the mother-to-child HIV transmission rate to around 1 percent.

In the U.S., zidovudine (Retrovir) is the preferred treatment for newborns and premature infants. However, in some cases, such as when the mother is diagnosed with HIV late in pregnancy or has persistent viral replication at delivery, physicians may feel that use of other or additional antiretrovirals, such as Kaletra (lopinavir/ritonavir), is warranted.

Kaletra is available as an oral solution and is considered a preferred treatment option for babies and children. It is approved in the U.S. for HIV-infected newborns older than 14 days and in Europe for children older than two years.

However, the U.S. Food and Drug Administration warned recently that Kaletra may be toxic when given to premature newborns (see related AIDS Beacon news), possibly due to problems with metabolizing one of the ingredients.

In addition, through a screening program for inherited disorders of the adrenal glands, French researchers recently found that children treated with Kaletra at birth had a temporary increase in 17-hydroxyprogesterone (17OHP), a hormone produced mainly by the adrenal glands.

According to the study authors, this finding suggests that the use of Kaletra leads to adrenal dysfunction in children. The adrenal glands are located right above each kidney and produce a range of hormones that are released into the blood. Some of these hormones are needed to maintain the balance of sodium and potassium levels in the body, react to stress, and regulate blood pressure.

Symptoms of adrenal dysfunction include abnormal levels of electrolytes, such as sodium and potassium, and cardiogenic shock, a state in which the heart has been damaged so much that it is unable to supply enough blood to the organs of the body.

In this study, researchers investigated the risk of adrenal gland problems in newborns treated after birth with Kaletra.

In their study, the researchers included 50 newborns treated with Kaletra and 108 newborns treated with zidovudine who were part of the French screening program for inherited disorders of the adrenal glands.

The researchers measured the levels of two adrenal hormones, 17OHP and dehydroepiandrosterone-sulfate (DHEA-S), from blood samples taken two to five days after birth and evaluated the infants’ medical records for symptoms of adrenal dysfunction.

Results showed that 14 percent of babies treated with Kaletra had abnormally high levels of 17OHP, compared to none of the infants treated with zidovudine. In addition, the average 17OHP levels for 42 full-term infants treated with Kaletra were three times higher than the average 17OHP levels for 93 full-term infants on zidovudine.

The average DHEA-S levels were nearly 20 times higher among 18 newborns treated with Kaletra compared to 17 zidovudine-treated infants.

The researchers found the highest levels of 17OHP and DHEA-S in infants who were also exposed to Kaletra before birth, as part of their mothers’ antiretroviral regimens.

Despite the high hormone levels, none of the full-term infants treated with Kaletra had symptoms of adrenal dysfunction. However, three premature babies taking Kaletra who also had been exposed to Kaletra before birth experienced potentially life-threatening symptoms of adrenal gland problems: high levels of potassium and low levels of sodium in the blood and one case of cardiogenic shock.

The researchers noted that these symptoms diminished once treatment with Kaletra was completed.

For more information, please see the study in the Journal of the American Medical Association (abstract).

Additionally, the moderate nervous dysfunction (known as autonomic dysfunction) was associated with higher blood sugar and cholesterol levels, although this was not the case for HIV-negative study participants.

Based on their results, the study authors recommended close monitoring and maintenance of blood sugar and cholesterol levels in people with HIV. They also suggested that further studies be conducted to understand why HIV-positive individuals might be more sensitive to the effects on the nervous system of changes in blood sugar and cholesterol levels.

Autonomic dysfunction is a malfunction of the body’s autonomic nervous system, which controls automatic functions such as heart rate, digestion, and perspiration. Autonomic dysfunction is linked to an increased risk of heart problems.

In particular, heart rate and heart rate variability, or how the time interval between heart beats varies, are linked to measures of congestive heart failure, damage from diabetes, and mortality risk after a heart attack. Normally the heart rate should vary according to certain signals from the body, such as respiration rate or stress levels; lower variability can indicate problems with the autonomic nervous system.

According to the study authors, results from previous studies have shown evidence of autonomic dysfunction in people with HIV, especially individuals with advanced HIV or AIDS. However, there have been few studies investigating autonomic dysfunction in HIV-positive individuals whose HIV is well controlled with antiretroviral therapy.

Although antiretrovirals have the potential to reduce damage to the nervous system caused by HIV, they have also been implicated in high cholesterol levels and pre-diabetes, which could themselves cause autonomic nervous system damage.

In this study, the authors investigated the presence of autonomic dysfunction, as measured by heart rate and heart rate variability, in HIV-positive individuals who had been on antiretroviral therapy for at least one year.

The study included 97 HIV-positive individuals and 52 age- and gender-matched HIV-negative individuals. Participants with HIV had been HIV positive for a median of 11 years and had taken antiretrovirals for a median of seven years; all but one had viral loads (amount of HIV in the blood) of less than 400 copies per milliliter.

None of the participants had any history of heart disease, diabetes, or were taking medication for high blood pressure.

In order to measure heart rate and heart rate variability, the researchers performed an electrocardiogram on each participant for 15 minutes after an initial 10-minute resting period.

The researchers found evidence of moderate autonomic dysfunction in the HIV-positive study group compared to the HIV-negative study group. In particular, HIV-positive participants had faster heart rates than HIV-negative participants, with the time between heartbeats an average of 77 milliseconds (about 8 percent) shorter.

In addition, the heart rate variability was around 10 percent lower in HIV-positive individuals compared to HIV-negative individuals.

Results also showed that the dysfunction was linked to higher blood sugar and cholesterol levels, but only in the HIV-positive participants.

There was no link between dysfunction and duration of HIV infection, viral load, CD4 (white blood cell) count, or duration or type of antiretroviral therapy.

For more information, please see the study in PLoS One.

Massachusetts Considers Legalizing Medical Marijuana – Lawmakers in Massachusetts have sponsored a bill that would legalize medical marijuana in the state. The proposed bill would allow patients suffering from certain medical conditions, including HIV and AIDS, to legally carry four ounces of marijuana or keep up to 24 plants in a secure, locked facility. The bill would also require users to register with the state’s Department of Public Health and would provide for the creation of 19 state-regulated dispensaries. For more information, please see the article in the Boston Herald.

AIDS Healthcare Foundation Asks FDA Not To Approve Truvada For HIV Prevention – The AIDS Healthcare Foundation (AHF), a California-based AIDS activist and treatment group, has sent a letter to the U.S. Food and Drug Administration (FDA) asking it not to approve the drug Truvada (tenofovir/emtricitabine) for prevention of HIV transmission. The drug has been shown to reduce infection risk when taken daily by HIV-negative men who have sex with men. AHF argues that the drug is not effective enough and that approval would encourage more risky sexual behavior and promote the spread of drug-resistant HIV. For more information, please see the article in the PharmaLetter.

Bristol-Myers Squibb Signs Agreement To Bring Reyataz To Sub-Saharan Africa And India – Bristol-Myers Squibb announced this week that it has signed an agreement with Matrix Laboratories Limited to allow Matrix to produce the protease inhibitor Reyataz (atazanavir), as well as the older drugs stavudine (Zerit) and didanosine (Videx), in sub-Saharan Africa and India. The agreement will include provisions for pediatric dosages of didanosine and Reyataz. The agreement is part of Bristol-Myers Squibb’s “Global Access Program,” which is intended to expand access to HIV drugs in developing countries. For more information, please see the Bristol-Myers Squibb press release.

Based on their results, the authors of the study suggested that genetic factors that may contribute to abnormal body fat redistribution and high cholesterol levels could eventually be used to guide HIV treatment decisions.

Drug-associated side effects are one of the major concerns associated with the use of antiretroviral therapy. Common long-term side effects of treatment include lipodystrophy, characterized by abnormal body fat redistribution, and metabolic syndrome, which includes insulin resistance, high cholesterol levels, high blood pressure, obesity, and type 2 diabetes.

According to the authors, studies of HIV-positive patients treated with antiretrovirals have shown that lipodystrophy can result in serious psychological problems and stigma, eventually leading to treatment non-adherence. Metabolic syndrome increases the risk of heart disease.

In this study, researchers from Italy examined the link between various genetic variations and the risk of lipodystrophy and high cholesterol in HIV-positive people starting antiretroviral therapy.

The study included 174 Caucasians who had started antiretroviral therapy. The majority (68 percent) of participants were male, and the median age was 38 years at treatment initiation.

Researchers analyzed participants’ DNA for seven possible genetic variations that they suspected, based on previous research, could be linked to a higher risk of lipodystrophy or metabolic syndrome. They also collected information on participants’ age, gender, weight, antiretroviral regimen, and viral load (amount of HIV in the blood).

Most of the participants (83 percent) received a protease inhibitor-based regimen as their initial regimen; the remainder were treated with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen.

During a median follow-up period of about four years, more than half of the participants developed some form of lipodystrophy. Almost 30 percent developed abdominal fat accumulation, and 36 percent developed lipoatrophy, which involves abnormal fat wasting on the face, limbs, and buttocks.

In addition, 29 percent of participants developed high overall levels of cholesterol. About 36 percent developed high “bad” cholesterol levels over the course of the study, and 19 percent of participants developed high levels of triglycerides. Two-thirds (66 percent) developed low levels of “good” cholesterol; low “good” cholesterol levels are linked to a higher risk of heart attack.

The researchers found that participants with a particular genetic variant, called MDR-1 3435 TT, were less likely to develop abdominal fat accumulation, with a risk one fifth of that of other participants. They also found a second variant, TNF 308 GG, that doubled the risk of abdominal fat accumulation. These variants were present in 26 percent and 78 percent of participants, respectively.

The researchers hypothesized that these variants could have effects on the way the body metabolizes antiretrovirals – reducing the amount of lipodystrophy-causing drugs in the blood, for example – or on the way it regulates fat accumulation and breakdown.

In addition, the researchers found several variants that affected cholesterol and triglyceride levels. The genetic variant TNF 238 GG was associated with a six-fold higher risk of low “good” cholesterol levels, while a second variant, LPL S477X, decreased the risk of high “bad” cholesterol levels by a little less than two thirds. These variants were present in 85 percent and 26 percent of participants, respectively.

For high triglyceride levels, the variant APOEe 3/3 decreased the risk by about three fourths, while the APM1 276 GT variant increased the risk by about three-fold. The variants were present in 65 percent and 34 percent of participants, respectively.

Aside from genetic variants, the researchers found that women were 2.5 times more likely to develop trunk fat accumulation but were less likely to have low “good” cholesterol levels compared to men. Use of an NNRTI rather than a protease inhibitor as a third drug in the initial antiretroviral regimen was also linked to a decreased risk of lower “good” cholesterol levels after starting treatment.

Higher viral loads were associated with about double the risk of developing low “good” cholesterol levels after starting antiretroviral therapy. Co-infection with hepatitis C virus and older age were associated with a higher risk of increased “bad” cholesterol levels.

The researchers stated that further studies that include different populations, such as non-Caucasians, and exposure to varying antiretroviral agents are necessary to confirm their results. They also suggested additional research into the actual mechanisms linking genetic variations with higher or lower risk of lipodystrophy and cholesterol levels.

For more information, please see the study in AIDS Research and Human Retroviruses.

“What is surprising…is that patients who came off the medication many years ago may still be vulnerable to these changes,” said Professor Patrick Chinnery, lead author of the study, in a press release.

The aging appears to be caused by damage to cells’ energy production units, called mitochondria.

“HIV clinics were seeing patients who had otherwise been successfully treated but who showed signs of being much older than their years. This was a real mystery. But colleagues recognized many similarities with patients affected by mitochondrial diseases – conditions that affect energy production in our cells – and referred them to our clinic,” said Prof. Chinnery.

The authors of the study are currently investigating how to repair or prevent the damage caused by the antiretrovirals. Prof. Chinnery noted that exercise has been beneficial to HIV-negative people with these mitochondrial diseases and may help people who have taken nucleoside reverse transcriptase inhibitors (NRTIs) as well.

NRTIs were the first class of drug developed to treat HIV. Today they still provide the backbone for many treatment regimens, with current U.S. guidelines recommending two NRTIs plus a third antiretroviral from a different class as the optimal treatment for HIV.

However, previous studies have shown that NRTIs, particularly older NRTIs, may cause damage to mitochondria, which are small structures within cells that supply cellular energy. According to the study authors, damage to mitochondria has been linked to premature aging.

Mitochondria damage has also been linked to heart disease, dementia, and problems such as neuropathy, a nerve condition that causes pain, numbness, or tingling in the extremities. This could be why some HIV-positive individuals taking antiretrovirals have symptoms of these diseases at an early age.

In this study, researchers investigated the effect of NRTIs on the mitochondria of HIV-positive individuals. In particular, they compared mitochondrial damage in HIV-positive people who had previously taken NRTIs to levels of damage in two groups: HIV-positive people who had not been treated and therefore were not exposed to NRTIs, and HIV-negative people.

The study included 33 HIV-positive adults 50 years of age or under and 10 HIV-negative adults who were similar in age. The researchers collected information on HIV-positive participants’ current and past antiretroviral regimens, including length of NRTI exposure. All participants with NRTI exposure had taken at least one of the following: zidovudine (Retrovir), stavudine (Zerit), didanosine (Videx), or zalcitabine (Hivid).

The researchers also collected small tissue samples from participants’ muscles to examine their mitochondria and the DNA inside the mitochondria. Mitochondria have their own DNA, which is separate from the cell’s normal DNA.

Results showed that participants who had been treated with NRTIs showed more signs of damaged mitochondria than participants who had not been exposed to NRTIs or who were HIV negative. In particular, participants who had been treated with NRTIs had levels of a mitochondrial DNA mutation tied to aging that were similar to those in very elderly healthy adults.

The mutation, called the ‘common deletion,’ occurs spontaneously in adults as they get older and builds up over time. The mutation is irreversible and is thought to lead to many of the symptoms of aging.

Further analysis showed that NRTI exposure did not appear to cause the mitochondrial DNA to mutate faster or more often. Instead, the researchers hypothesized that the drugs caused DNA that had already mutated naturally to copy itself more often, resulting in a greater overall amount of mutated DNA.

The researchers noted that this may be why complications of NRTI treatment that are related to the mitochondria, such as neuropathy, are more common in older HIV-positive adults, who already have a larger number of these mutations.

For more information, please see the study in Nature Genetics (abstract).

In addition, the companies are currently in negotiations to develop a second pill combining Prezista, cobicistat, Emtriva, and an investigational new form of Viread called GS 7340.

“We are excited to be able to study and develop Prezista with an alternative boosting agent in a combination product which has the potential to reduce the number of tablets patients take,” said Dr. Johan Van Hoof, area head of Global Therapeutics for Infectious Diseases and Vaccines at Janssen Pharmaceutica (Tibotec’s parent company), in a press release.

Prezista (darunavir) is currently listed as a preferred protease inhibitor for first-line antiretroviral regimens for people with HIV. Cobicistat is under development by Gilead as a boosting agent similar to Norvir (ritonavir) and is in Phase 3 clinical trials. Gilead expects to file a New Drug Application for cobicistat with the U.S. Food and Drug Administration (FDA) in mid-2012.

The new combination pill would be the second once-daily protease inhibitor pill that combines an antiretroviral with a boosting agent; the other is Abbott Laboratories’ Kaletra (lopinavir/ritonavir). All other protease inhibitors must currently be taken with Norvir as a separate pill.

According to the agreement, the Prezista plus cobicistat combination will be developed and marketed by Tibotec, which is also responsible for filing a New Drug Application for the pill.

The companies stated that the agreement to develop a Prezista plus cobicistat combination pill is contingent on signing a second agreement to create a once-daily combination of Prezista, cobicistat, Emtriva (emtricitabine), and GS 7340. GS 7340, which is still in Phase 1 clinical trials, is a new formulation of Viread (tenofovir) that is expected to be safer and more effective than the current version.

If the agreement is signed, Gilead will be responsible for developing and marketing the second combination pill.

Tibotec and Gilead are also in the process of developing a once-daily combination pill that contains Truvada (tenofovir/emtricitabine) plus Edurant (rilpivirine), Tibotec’s new non-nucleoside reverse transcriptase inhibitor. Edurant was approved by the FDA in May (see related AIDS Beacon news). Tibotec expects the new combination pill to be available in the third quarter of this year.

For more information, please see the press releases from Gilead and Tibotec (pdf).

GeoVax Adds Los Angeles Site To Phase 1 Trial Of Therapeutic HIV Vaccine – Biotechnology company GeoVax Labs has announced that it is adding a third location, in Los Angeles, to its Phase 1 trial of a therapeutic vaccine to treat HIV. The first two sites are in Atlanta and Birmingham, AL. The trial is testing the safety and efficacy of the vaccine in controlling HIV replication in people already infected with the virus; participants will stop taking antiretrovirals for 12 weeks as part of the trial. GeoVax expects to enroll 10 participants. For more information, please see the GeoVax press release or the U.S. Clinical Trials Registry.

Tibotec Therapeutics Changes Name To Janssen Therapeutics – Tibotec Therapeutics, the maker of the HIV drugs Prezista (darunavir), Intelence (etravirine), and Edurant (rilpivirine), has changed its name to Janssen Therapeutics. The name change is an attempt to create a common link between all of the Janssen companies, which are subsidiaries of Johnson & Johnson and include Janssen Pharmaceuticals and Janssen Biotech. The company’s new website includes links to information on its antiretrovirals and patient assistance programs to help low-income patients pay for the drugs. For more information, please see the Johnson & Johnson press release or the Janssen Therapeutics website.

Reminder: Free HIV Testing Today – As part of National HIV Testing day, many locations nationwide will offer free HIV testing today (see related AIDS Beacon news). To find a testing location, please see the Centers for Disease Control’s National HIV Testing Day website.

The report also revealed widespread stigma and discomfort around people with HIV. However, about 40 to 50 percent of young adult respondents said they would like to have more information on topics such as HIV prevention and testing, and more than half of the respondents thought the government spent too little on HIV and AIDS.

“Since 1990, misperceptions about transmission [of HIV] have stubbornly persisted across the public,” said Mollyann Brodie, senior vice president and director of the Kaiser Family Foundation’s Public Opinion and Survey Research Program, in a presentation of the survey earlier this week.

She noted, however, that the high percentage of respondents who supported increased funding for HIV and AIDS did so in spite of hearing less about HIV today than in previous years.

“Perhaps a heightened sense of urgency among the public is not necessarily a precondition to the sense that resources can help,” said Brodie.

The survey is Kaiser’s eighth national survey of Americans since 1995 and is intended to capture the public’s knowledge and attitudes toward HIV and AIDS over time. The survey included a random sample of 2,583 adults and was conducted by telephone.

Results showed that almost half of survey respondents thought that the United States is making progress against HIV and AIDS, and only 7 percent thought it was the most pressing health problem facing the U.S. today.

Almost 90 percent said people with HIV were able to lead healthy, productive lives, although only half thought it was now a chronic, manageable disease like diabetes or high blood pressure.

However, the survey revealed that many Americans still have reservations about interacting with HIV-positive people. A third of respondents answered, incorrectly, that HIV could be transmitted by sharing a drinking glass, a toilet seat, or a pool with someone with HIV.

About 20 percent of respondents said they would feel uncomfortable working with someone with HIV, 35 to 40 percent would be uncomfortable having an HIV-positive person as a roommate, and 45 to 60 percent would feel uncomfortable having someone with HIV prepare their food.

Sixteen percent of respondents said they sometimes think that AIDS is a punishment for society’s decline in moral standards.

However, respondents also acknowledged that people with HIV face widespread stigma, with 77 percent stating that people with HIV face some or a lot of discrimination and prejudice.

Financially, a majority of survey participants, 53 percent, thought the federal government spent too little on HIV and AIDS. Two thirds also thought that most people with HIV do not get the medications they need, and 50 to 60 percent thought Congress, the president, pharmaceutical companies, and other government and industry leaders were not doing enough to help solve the problem of HIV in the U.S.

Three quarters of survey respondents could not name an individual who stands out as a leader in the fight against HIV and AIDS in the U.S.

About 40 percent of respondents said they personally knew someone who had tested positive for HIV, has AIDS, or had died from AIDS. African-Americans were most likely to have personal experience with HIV, and 74 percent were worried about immediate family members getting infected.

For more information, please see the 2011 Survey of Americans on HIV/AIDS (pdf) or the Kaiser Family Foundation website.

The authors noted that their results provide further justification for listing Truvada as a preferred combination regimen and Combivir and Epzicom as alternative regimens.

However, the study appears to be based on the separate costs of Truvada and Sustiva pills rather than Atripla, the once-daily pill that combines Truvada and Sustiva. The study also did not take into account the possibility of generic Combivir, which was approved by the U.S. Food and Drug Administration last month (see related AIDS Beacon news) and is expected to be available later this year.

The study authors also pointed out that some studies have suggested that Truvada may not be as effective for people who start treatment at lower viral loads, in which case Truvada may not be as cost-effective for these patients.

According to the study authors, rising drug costs and longer life expectancies for people with HIV mean that the costs of antiretroviral therapy have now become an important consideration.

In addition to the direct cost of the drugs, total health care costs are affected by the efficacy of a person’s first-line therapy and his or her long-term health. Low viral loads (amount of HIV in the blood) and high CD4 (white blood cell) counts, which are achieved with treatment, prevent disease progression and other illnesses associated with HIV.

First-line therapies are also more likely to have easier dosage schedules and are usually less expensive than later antiretroviral regimens. As a result, the longer a person can stay on first-line therapy, the lower his or her long-term health costs are expected to be.

Currently, U.S. treatment guidelines for HIV recommend that first-line therapy consist of two nucleoside reverse transcriptase inhibitors (NRTIs) plus at least one drug from another antiretroviral class. Truvada (emtricitabine/tenofovir), a combination of two NRTIs, is listed as the preferred combination of NRTIs, and the non-nucleoside reverse transcriptase inhibitor Sustiva (efavirenz) is listed among the preferred drugs to use in combination with NRTIs..

The two-NRTI combination pills Combivir (lamivudine/zidovudine) and Epzicom (abacavir/lamivudine) are listed as alternatives to Truvada.

In this study, the authors compared the cost-effectiveness of Truvada, Combivir, and Epzicom, each used with Sustiva, as first-line treatments in HIV-positive adults.

The authors developed a computer model for each first-line therapy that included annual drug costs, drug efficacy, medical costs related to treatment of side effects and HIV-related illnesses, the cost of switching antiretroviral regimens when a first-line regimen is no longer effective, and the estimated costs of second- and third-line treatment regimens based on current treatment guidelines.

Information such as drug efficacy, side effects, and failure rates were obtained from a 144-week study of Sustiva plus Truvada or Combivir and a 48 week study of Sustiva plus Combivir or Epzicom.

Results showed that Truvada was the most cost-effective NRTI combination for a first-line treatment regimen, with patients predicted to remain on the drug for almost eight years. Estimated lifetime costs for HIV treatment for people starting with Truvada plus Sustiva were $747,327.

Patients taking Epzicom were predicted to remain on the therapy for six years and accrue lifetime costs for HIV treatment of $777,090, and patients on Combivir were predicted to remain on it for almost six years with lifetime costs of $778,287.

The lower overall cost for Truvada was primarily a result of its greater efficacy, which delayed disease progression and allowed patients to remain on treatment longer.

For more information, please see the study in Value in Health (abstract).

The AIDS Institute is a division of the New York State Department of Health. The guidelines were developed in collaboration with clinicians from the Johns Hopkins University Division of Infectious Diseases.

“These guidelines have been developed to assist providers with the transition process to ensure that HIV-infected young adults are successfully and seamlessly integrated into an adult care setting. Recommendations are meant to serve as a guide and will need to be tailored to the individual patient,” wrote the authors of the guidelines.

The guidelines also include tools and assessments that can be used to plan the transition and determine whether young adults have the necessary skills and knowledge to successfully take charge of their own care.

HIV-positive teens and young adults make up a growing percentage of the HIV-positive population in New York and nationally. Youths between the ages of 13 and 24 made up more than 17 percent of new HIV diagnoses in New York in 2008 and more than 19 percent of new diagnoses in the United States in 2009.

In addition, many children who contracted HIV from their mothers during pregnancy are now entering adolescence and young adulthood.

As a result, the guidelines state that many young adults with HIV will need to transition to adult HIV care and take greater responsibility for their health, insurance, and other medical needs. This transition typically occurs between the ages of 22 and 24 years.

The authors note that the actual timing of transition is likely to depend on individual traits, such as level of maturity, presence of learning disabilities, and other issues such as homelessness. In addition, they recommended that clinicians be sensitive to issues that might affect the choice of adult HIV care provider, such as a young adult’s sexual orientation, substance abuse problems, teen pregnancies, and other potential issues.

They also recommended choosing an adult provider who is familiar with the care of children and teens with HIV, particularly since youths infected by their mothers during pregnancy may have more advanced HIV infections and longer treatment histories.

Teens and young adults who are getting ready to transition to adult HIV care should be educated about their disease and how to manage it, according to the guidelines. In particular, they should know the following:

• Their HIV status, if not already known
• The biology of HIV and disease progression
• How HIV is treated
• How transmission is prevented
• Their medical history, such as past treatment regimens, opportunistic infections, etc.
• How to obtain and keep insurance
• How to access public assistance programs (such as Medicare or housing assistance) if needed
• How to make and keep medical appointments and fill prescriptions
• Symptoms of HIV progression
• When emergency medical assistance might be needed.

To avoid some of the confusion that can be caused by transitioning to adult care, in which it might be necessary to have many specialists rather than one clinician (e.g., separate physicians for gynecological care, mental health, etc.), the guidelines recommend that young adults be transferred to comprehensive or multidisciplinary sites as often as possible, where on-site access to other forms of care is available.

They also recommended that care be transferred when the youth’s disease state is stable, to avoid unnecessary additional complications or changes. They also suggest at least one follow-up meeting between the adult provider and pediatric care provider to make sure the transition has been accomplished successfully.

For more information, please see the Transitioning HIV-Infected Adolescents into Adult Care guidelines.

Theratechnologies Applies For Approval Of Egrifta In Canada – Theratechnologies has applied for approval of Egrifta (tesamorelin) from the Therapeutic Products Directorate of Health Canada. If approved, Egrifta will be the first drug in Canada to treat lipodystrophy, a condition of abnormal fat distribution that is a side effect of certain anti-HIV medications. Based on average approval times for Health Canada, a decision would be expected late next year. Theratechnologies applied for approval of Egrifta in Europe earlier this month via its partner Ferrer Internacional S.A., and the drug was approved in the U.S. in November of last year. For more information, please see the Theratechnologies press release.

June 27 Marks National HIV Testing Day – This year, June 27 will mark the 17th annual National HIV Testing Day. The day is organized by the National Association of People With AIDS (NAPWA), and its purpose is to publicize and promote regular HIV testing, particularly in at-risk populations such as African Americans and men who have sex with men. Communities and health centers will be offering HIV testing nationwide, in many cases free of charge. For more information or to find a local testing center, please see NAPWA’s National HIV Testing Day website.

Salix Pharmaceuticals Recruiting HIV-Positive Participants For Phase 3 Trial Of Diarrhea Drug – Salix Pharmaceuticals, a small pharmaceutical company based in North Carolina, is currently recruiting HIV-positive participants for a Phase 3 clinical trial of its investigational anti-diarrhea drug crofelemer. Participants must be on antiretroviral therapy and have had HIV-associated diarrhea for at least four weeks. Crofelemer successfully completed a Phase 3 clinical trial in people with HIV in November of last year in which three dosages (125 mg, 250 mg, and 500 mg daily) were tested; this new trial will test the safety and tolerability of a 125 mg dose twice daily. Salix is currently recruiting participants at locations in Arizona, Arkansas, California, Florida, and Georgia and expects to add additional locations at a later date. For more information, please see the U.S. Clinical Trials Registry.

“Our study suggests that more sensitive genotypic HIV drug resistance assays, such as deep HIV sequencing, may help clinicians design antiretroviral treatment combinations better suited for [patients] infected with multidrug-resistant viruses,” said Dr. Roger Paredes, a key investigator of the study, in correspondence with The AIDS Beacon.

“Deep sequencing may help [clinicians] choose more effective drugs as well as avoid antiretrovirals to which, in fact, the virus is resistant,” he added.

Drug resistance is one of the main causes of antiretroviral drug failure. HIV-positive individuals are considered resistant to an anti-HIV drug if their viral load (amount of HIV in the blood) does not remain low after drug therapy or testing confirms the presence of an HIV strain that is resistant to one or more classes of antiretrovirals.

Resistance testing examines the genes of the HIV in a person’s blood to detect whether the virus has mutations that make it resistant to particular drugs. Previous studies have indicated that even low levels of drug-resistant HIV increase the chances of treatment failure, although those studies have primarily involved previously untreated people with HIV (see related AIDS Beacon news)

The authors of this study investigated whether an enhanced form of resistance testing, known as deep sequencing, could provide better assessments of drug resistance in heavily pre-treated HIV patients when compared to the more traditional form of resistance testing, called population sequencing.

Deep sequencing detects the same mutations as population sequencing but is more sensitive, so it can detect mutations present in 1 percent or more of the HIV circulating in a person’s blood. Population sequencing can usually only detect mutations present in 15 percent or more of the HIV.

Seven HIV-positive individuals participated in the study. Participants had taken a median of 15 antiretroviral drugs for a median of 13 years. The average age of the participants was 44, and five of the seven were male.

All participants had shown resistance to the three main classes of antiretrovirals: nucleoside-reverse transcriptase inhibitors (NRTIs), protease inhibitors, and non-nucleoside reverse transcriptase inhibitors. In addition, all participants had failed salvage therapy with at least one of the following: Prezista (darunavir), Aptivus (tipranavir), Intelence (etravirine), or Isentress (raltegravir).

Results showed that deep sequencing detected all of the drug resistant mutations found by population sequencing, plus additional resistance mutations in six of the seven participants.

In particular, deep sequencing improved the assessment of resistance to Intelence, showing higher risk of resistance in two patients with signs of failing Intelence-based therapy. The technique also slightly modified assessments of HIV resistance against Sustiva (efavirenz), Crixivan (indinavir), and NRTIs in various participants to indicate higher risks of resistance, compared to the population sequencing.

The two methods identified the same participants as having drug resistance to Aptivus and Isentress, and the deep sequencing confirmed that four of five participants who had failed Isentress-based antiretroviral therapy did not show resistance to the drug and could potentially take it again.

Dr. Paredes stated that the researchers are currently conducting a larger study to investigate whether the use of deep sequencing can lead to improved treatment outcomes for treatment-experienced patients starting salvage therapy with Norvir (ritonavir)-boosted protease inhibitors, Intelence, or Isentress.

For more information, please see the study in PLoS One.

Spring Issue Of ‘Mental Health AIDS’ Is Now Available – The federal government’s Substance Abuse and Mental Health Services Administration (SAMHSA) has released the spring issue of its quarterly newsletter ‘Mental Health AIDS.’ The newsletter covers psychological and mental-health related issues in people with HIV. This issue focuses primarily on prevention, but also discusses topics such as the approval of Egrifta (tesamorelin), factors affecting medication adherence, and stress management. For more information, please see the Mental Health AIDS Newsletter Spring 2011 (pdf).

AIDS Play ‘The Normal Heart’ Wins Three Tony Awards – Larry Kramer’s play ‘The Normal Heart,’ about HIV/AIDS activists in New York City in the early 1980s, has won the Tony award for Best Revival of a Play. Additionally, cast members John Benjamin Hickey and Ellen Barkin won Tony awards for Best Featured Actor and Best Featured Actress, respectively, in a Play. The play opened on Broadway in April and will continue through July 10. For more information, please see the Tony Awards website or The Normal Heart website.

“Providing care and treatment to people living with HIV/AIDS is a key goal for our agency,” said Mary Wakefield, administrator of the Health Resources and Services Administration (HRSA), in a press release.

“The Guide for HIV/AIDS Clinical Care is precisely the kind of information that we strive to disseminate as widely as possible, so that we can share our expertise, stimulate ideas, and encourage best practices for those working with this community,” she added.

The guidelines, originally published in 1993 and last updated in 2006, are meant to be simple and comprehensive, so that clinicians who do not treat people with HIV on a regular basis can become familiar with the management and complications of the disease.

The guidelines are broader and more basic than the Department of Health and Human Services (DHHS) treatment guidelines, although HRSA used the DHHS guides in creating the Guide for HIV/AIDS Clinical Care.

The guide notes that as HIV specialists become scarcer and care transitions to primary care physicians, the need for such guidelines will become greater (see related AIDS Beacon news).

The guidelines are organized into ten sections:

• The HIV Clinic: Providing Quality Care, which discusses topics such as clinic management, HRSA performance measures for HIV and AIDS care, and caring for patients who are incarcerated or are from racial or sexual minorities
• Testing and Assessment, which covers taking patient histories, initial physical exams, indications of when patients should start antiretroviral therapy, and common tests such as resistance testing, viral load (amount of HIV in the blood) testing, and CD4 (white blood cell) counts
• Health Care Maintenance and Disease Progression, which includes preventing opportunistic infections (infections that occur in people with compromised immune systems) and preventing HIV transmission
• HIV Treatment, which covers antiretroviral therapy as well as treating women, including pregnant women
• Common Complaints, includes common problems, infections, and side effects experienced by people with HIV, how they are diagnosed, and how they should be treated
• Comorbidities, Coinfections, and Complications, which includes additional information on lipodystrophy (abnormal fat redistribution that is a common side effect of certain antiretrovirals), heart disease, and several common coinfections like herpes and hepatitis
• Antiretroviral Interactions and Adverse Events, which is on side effects and common drug-drug interactions for antiretrovirals, including interactions with birth control pills and other hormonal contraceptives
• Neuropsychiatric Disorders, which discusses common psychiatric problems and disorders in people with HIV, including dementia, depression, insomnia, and post-traumatic stress disorder
• Oral Health, includes diagnosing and treating common oral complaints and problems in people with HIV
• Resources and References, which covers additional online sources of information about HIV and AIDS for patients and clinicians, information on antiretrovirals available in the United States and Mexico, and further discussion of appropriate antiretroviral regimens.

The guidelines are online, and free paper copies can also be requested.

For more information, please see the Guide For HIV/AIDS Clinical Care or the HRSA press release.

Smithsonian Opens Exhibit On History Of HIV And AIDS – The National Museum of American History, one of the Smithsonian museums, has opened a special exhibit on HIV and AIDS to mark the 30th anniversary of HIV in the U.S. Entitled “HIV and AIDS Thirty Years Ago,” the exhibit discusses the history of the epidemic in the nation and worldwide and its effects on individuals and society. The exhibit also includes a website on the history of HIV and AIDS. For more information, please see the National Museum of American History press release or the exhibit website.

Emory University Creates Online Map Of HIV/AIDS In The U.S. – The Rollins School of Public Health at Emory University has created an interactive, online map of HIV and AIDS in the U.S. The map, called AIDSVu, includes information on HIV rates by zip code for most of the country and highlights the areas of greatest prevalence – primarily the Northeast, South, and Southwest. Viewers can also see HIV rates by gender, race/ethnicity, and age group. For more information, please see the Emory University press release or the AIDSVu website.

Theratechnologies Applies For Marketing Approval Of Egrifta In Europe – Theratechnologies, via its partner Ferrer Internacional S.A., has applied for marketing approval of Egrifta (tesamorelin) from the European Medicines Agency (EMA). If approved, Egrifta will be the first drug in Europe to treat lipodystrophy, a condition of abnormal fat distribution that is a side effect of certain anti-HIV medications. Based on average approval times for the EMA, a decision would be expected mid to late next year. Egrifta was approved in the U.S. in November of last year. Ferrer has licensed the right to market Egrifta in Europe and is responsible for all required regulatory activity associated with the approval. For more information, please see the Theratechnologies press release.

“Many of us have been touched by the disease, be it a family member, a loved one, or a friend,” said Surgeon General Dr. Regina Benjamin in a White House video chat earlier this week. Dr. Benjamin’s only brother died from AIDS nine months after being diagnosed with the disease, shortly before the advent of highly active antiretroviral therapy (HAART).

In an interview with The AIDS Beacon, Dr. David Margolis, a professor of medicine and infectious diseases physician at the University of North Carolina School of Medicine, said that researchers have made a lot of progress with the disease but still face difficulties in the years ahead.

“One way of looking at it, we’ve done an amazing job of controlling the disease and allowing people to live largely normal lives. On the other hand, we have so far to go,” he said.

Three Decades Of Scientific Progress

In some ways, the story of HIV and AIDS represents a triumph for modern science. In 30 years, AIDS has gone from a disease of completely unknown origin to a well-understood and treatable illness.

“We’ve accomplished more in so many ways, in dealing with HIV, than almost anything in medicine that I can think of,” said Dr. Margolis.

In the first reports in 1981 and 1982 from the Centers for Disease Control (CDC) of what would later be called AIDS, researchers had no notion of what the disease was or what caused it, much less how to treat it. By 1983, however, scientists had discovered the virus behind AIDS and how it was transmitted. By 1985 there was a blood test available to diagnose those infected with the virus, and by 1987, scientists had developed the first drug to treat it: zidovudine (Retrovir), then called AZT.

Today there are more than 30 drugs approved to treat HIV, and while they cannot cure it, they can keep the virus suppressed to such low levels that it is not detectable in standard blood tests. Those who are diagnosed and treated early can expect to live roughly a normal lifespan.

For a field that moves as slowly as science, said Dr. Margolis, the feat is remarkable. “I can’t think of any other disease, certainly, that has gone from nothing to this in 30 years,” he said.

Dab Garner, an HIV activist and educator, agreed that enormous progress has been made since the 1980s. “Hopefully I will be around to celebrate my 60th year of living with HIV and AIDS,” he said. The thought was almost unheard of when he was diagnosed with HIV in 1982; he was 19 years old at the time, and did not expect to live to see his 20th birthday.

The Journey Ahead: Still A Long Way To Go

As far as research as come, however, most in the HIV/AIDS community agree that there is still a long way to go, both in terms of scientific progress and social issues and policy.

In 1984, Margaret Heckler, secretary of the U.S. Department of Health and Human Services, thought a vaccine for AIDS would be available within the next two years. Twenty seven years later, there is still no vaccine to prevent AIDS and no cure for it. The virus has spread to an estimated 34 million people around the world and is thought to have killed more than 25 million since 1981.

“As we enter the fourth decade of the HIV and AIDS epidemic, the current situation in which large numbers of new infections occur and HIV-infected persons require lifelong therapy is clearly not sustainable,” wrote Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), and Prof. Carl Dieffenbach, director of NIAID’s Division of AIDS, in an article published this week in the Annals of Internal Medicine.

In their article, Dr. Fauci and Prof. Dieffenbach outlined three goals for HIV/AIDS researchers in the years ahead. These include expanding access to HIV testing and treatment; finding a cure for HIV; and finding more effective ways to prevent the disease, such as a vaccine.

The authors admitted that achieving these goals would be difficult. However, with multiple clinical trials underway to test vaccines and methods for reducing or eliminating HIV from the body, the scientific community is more hopeful than ever that eradicating the virus is possible. (For more information on progress toward a cure for HIV, please see the related AIDS Beacon series.)

“I am hoping both [a vaccine and a cure] will happen during my lifetime so people do not continue to have to suffer through a lifetime of dealing with medications, side effects, stigma, and the financial burden of living with HIV and AIDS,” said Garner, who has been living with HIV for 29 years.

Aside from the scientific aspects, progress in eliminating HIV also requires focusing on difficult social and financial issues, such as how to bring expensive antiretroviral medications to those who need them but often cannot afford them. Worldwide, researchers estimate that only a third of people who need treatment for HIV receive it, and in the U.S. there are currently over 8,000 people on waiting lists for antiretrovirals, a record high.

In Garner’s home state of Florida, the legislature is considering tightening eligibility requirements for its AIDS Drug Assistance Program (ADAP), which provides free antiretrovirals to low-income people with AIDS. Garner, who has battled for more funding for ADAPs and other programs to help those with HIV via his Dab the AIDS Bear Project, expressed disappointment in the prospect.

“I hope there will continue to be access to life-saving anti-HIV medications and other services for Americans living with HIV and AIDS until a cure is found. No one should have to die from HIV and AIDS because they cannot afford treatment,” he said.

Dr. Margolis agreed that battling HIV in the future would require both scientific progress and tackling difficult social issues.

“All the things that are tied up in HIV infection – poverty, drug abuse, mental health issues, societal power issues – fixing them will help deal with HIV, and addressing them will make the world a better place too, at the same time,” he said.

Remembering Those Who Have Been Lost

As the 30th anniversary draws near, both Garner and Dr. Margolis said the date reminds them of the people they have known – patients, friends, and family members – who have been lost to HIV over the years. In the U.S., the CDC estimates that more than half a million people have died of AIDS.

“At the end of [the movie] ‘Longtime Companion’, there is a scene on the beach after a cure is found and everyone you knew who died from AIDS comes back to meet on the beach to celebrate a cure being found for HIV,” said Garner. The film, released in 1990, was one of the first to touch on the AIDS epidemic.

“Since I have known over 10,000 men, women, and children who have lost their battle with AIDS, including three partners and my god-daughter, it will have to be a very large beach. But what a sight for sore eyes they would all be,” he added.

Dr. Margolis agreed. “That’s a terrible thing that hopefully other people won’t have to experience, but still in most parts of the world, many people are still experiencing,” he said.

Garner said he hopes that the anniversary will renew the focus on HIV and AIDS in the U.S., both in terms of education and prevention, and for those who are struggling financially to get the medications they need.

But most of all, he hoped that those who lost their battle with the disease will not be forgotten. “I hope on this 30th anniversary we remember all those who have lost their battle with AIDS, not only in our country, but around the world. It seems all too often we have forgotten those who sacrificed and are no longer with us.”

For more information on the 30th anniversary of HIV in the U.S., including timelines, events, and the history of AIDS in the U.S., please see the AIDS.gov website.

Dab Garner, an HIV activist and educator who was diagnosed with HIV in 1982, welcomed the renewed attention on the virus.

“I have been glad to see there has been mainstream coverage of the anniversary of HIV now that we have over 50,000 newly diagnosed HIV infections a year in our country,” he said in an interview with The AIDS Beacon.

Garner was also hopeful that the anniversary would bring attention and financial support to struggling HIV programs nationwide, which have been hard-hit by economic difficulties.

“Hopefully, the media attention will help with HIV/AIDS awareness, education, and prevention, while also drawing attention to the 8,000 American men and women on ADAP [AIDS Drug Assistance Program] waiting lists in the United States,” he added.

HIV In The 1980s: A Mysterious And Feared Killer

Although researchers now believe HIV likely entered the U.S. in the 1970s or earlier, the presence of the new virus was not recognized until the early 1980s.

In the first CDC reports from 1981 and 1982, physicians noticed clusters of gay men with unusual illnesses in New York and California: Kaposi’s Sarcoma, an aggressive cancer caused by the usually innocuous herpes virus, and Pneumocystis carinii pneumonia (PCP, now called Pneumocystis jiroveci pneumonia), a fungal infection of the lungs.

Researchers suspected the cases were connected but were unsure how they were spreading. Hypotheses ranged from sexual contact, to lifestyle factors shared by gay men, to exposure to drugs or stimulants. Physicians dubbed the new illness “Gay-Related Immune Deficiency.”

Soon, however, the illness began showing up in other populations, including women and children. The most commonly afflicted, in addition to gay men, were injection drug users, hemophiliacs, and immigrants from Haiti. In 1982 the name of the disease was formally changed to AIDS, Acquired Immune Deficiency Syndrome. People who were diagnosed with AIDS were given weeks to months to live.

By 1986, there were over 25,000 confirmed cases of AIDS in the U.S., half of which had been fatal, and the Surgeon General estimated that there were 1.5 million people infected with the virus.

At the time there were no treatments for the virus; the first antiretroviral, zidovudine (Retrovir), then called AZT, would not be approved until 1987, and would have only temporary success as HIV quickly became drug resistant.

The first real successes at treating HIV would not come until 1996, with the development of highly active antiretroviral therapy (HAART) – combining three or more antiretrovirals from at least two different drug classes.

With HAART, people with HIV for the first time could contemplate the idea of living a relatively normal lifespan.

“There have been huge changes since those first couple of years,” said Garner.

“We now have life saving anti-HIV medications to help people live with HIV that we did not have for the first 15 years. Because of this, people living with HIV can now have hope, whereas most could not before the life saving medications became available in 1996,” he added.

Still, despite these successes, there are some things that have not changed.

“There is presently no cure for AIDS. There is presently no vaccine to prevent AIDS,” wrote Surgeon General Edward C. Koop in 1986. Despite scientific advances and a vast amount of research, the words are as true today as they were then. However, many hope that a cure for HIV is finally on the horizon (see related AIDS Beacon news).

As the U.S. commemorates its 30th year of the AIDS epidemic, many are discussing what the next 30 years will bring. The AIDS Beacon will further discuss efforts in this direction later this week.

Events Focus On Past, Future Of HIV In The United States

The government and other organizations are holding several events to mark the anniversary of the CDC’s report. The events focus both on historical accounts of the HIV epidemic in the U.S. as well as the future of HIV research and policy.

Yesterday, Dr. Anthony Fauci, Director of the National Institutes of Allergy and Infectious Diseases (NIAID), gave a talk on his experiences with HIV, entitled “30 Years of AIDS: A Personal Journey.” Today, the White House held a 30 minute video chat, “30 Years of AIDS,” to answer questions submitted online and via Facebook. Recordings of both events will be posted to the AIDS.gov website.

Several other events will be taking place over the next few months.

Starting June 10, the CDC will be holding lectures at various times and locations around Atlanta to discuss the history of HIV, prevention efforts, policy and activism, and other topics related to HIV and AIDS. The series will culminate in two talks at the annual National HIV Prevention Conference, August 14 to 17 in Atlanta.

In addition, on June 15, the government will host a webinar on “The State and Future of HIV/AIDS” at 3 p.m. EST. The webinar is aimed at federal staff and grant recipients who work with HIV/AIDS programs. Participants must register by June 10 and can ask questions. Officials from several government agencies will participate, including NIAID, the White House Office of National AIDS Policy, and the Department of Veterans Affairs.

Information on these events, as well as other events to commemorate the anniversary, can be found at the AIDS.gov website.

CDC Organizes “HIV/AIDS: 30 Years of Leadership and Lessons” Lecture Series – To commemorate the 30th anniversary of the first official report of AIDS by the Centers for Disease Control (CDC), the CDC has put together a series of lectures on the past, present, and future of HIV and AIDS in the U.S. The lectures will begin on June 10 and go through the month of August. They will be held at different locations throughout Atlanta. The talks will discuss key moments that shaped the development of HIV over the past three decades as well as issues such as HIV testing, prevention, and social issues and activism. In addition, the CDC will be sponsoring an online community that will allow individuals affected by HIV to share their stories and experiences. For more information or the lecture series schedule, please see the CDC website.

EMEA Advisory Committee Recommends Approval For Victrelis In Europe – An advisory committee to the European Medicines Agency (EMEA) has recommended that U.S. pharmaceutical company Merck’s new hepatitis C treatment, Victrelis (boceprevir) be approved for use in combination with the current standard hepatitis C treatment, peginterferon alfa (PegIntron or Pegasys) plus ribavirin (Copegus, Rebetol). The recommendation improves the chances for approval of the drug in Europe; a decision is expected within two to three months. Victrelis was approved in the U.S. earlier this month, along with Incivek (telaprevir), a second new hepatitis C treatment in the same drug class. For more information, please see the Merck press release.

NIAID, White House Mark The 30th Anniversary Of HIV/AIDS – The National Institute of Allergy and Infectious Diseases (NIAID) and the White House will be holding events next week to mark the 30th anniversary of the first reports of AIDS in the U.S. NIAID Director Anthony Fauci will give a talk, titled “Thirty Years of HIV/AIDS: A Personal Journey,” at 2 p.m. EST on May 31, which will be streamed live over the Internet. In addition, the White House will hold a live video chat, including a question and answer session, at 1 p.m. EST on June 1. Viewers may submit questions online ahead of time or live during the chat. For more information, please see the Aids.gov website.

HRSA Releases “Living With HIV” Educational Video – The HIV/AIDS Bureau of the Health Resources and Services Administration (HRSA) has released an educational video entitled “Living With HIV.” The video features patients talking about their personal experiences with HIV and AIDS, including their lifestyles and the stigma they have faced due to the disease. The video is part of The Living History project at the HIV/AIDS Bureau. For more information, please see the Aids.gov website or the video on YouTube.

Incivek (telaprevir), which will be marketed in the U.S. by Vertex Pharmaceuticals, is approved for use in combination with the current standard of treatment for hepatitis C, peginterferon alfa (PegIntron or Pegasys) plus ribavirin (Copegus, Rebetol). It is approved both for people who have not previously received interferon-based treatment and for people who did not adequately respond to interferon-based therapy in the past.

“With the approval of Incivek, there are now two important new treatment options for hepatitis C that offer a greater chance at a cure for some patients with this serious condition,” said Dr. Edward Cox, director of the Office of Antimicrobial Products at the FDA’s Center for Drug Evaluation and Research, in an FDA press release.

“The availability of new therapies that significantly increase responses while potentially decreasing the overall duration of treatment is a major step forward in the battle against chronic hepatitis C infection,” he added.

Incivek will be marketed in Europe, South America, Australia, and the Middle East by Janssen, a subsidiary of Johnson & Johnson. A representative from Janssen told The Beacon that it will be marketed under a different brand name in Europe, not Incivek. Janssen would not confirm when the drug might be available internationally. Incivek will be marketed in Japan and other Far East countries by Mitsubishi Tanabe Pharma.

Incivek is the second drug that has been approved for hepatitis C this month. The first was Victrelis (boceprevir), marketed by U.S. pharmaceutical company Merck (see related AIDS Beacon news).

The approval is based on clinical trial results showing that Incivek increased cure rates for hepatitis C – called a sustained virologic response, or SVR – from around 45 percent to about 80 percent in patients new to treatment (see related AIDS Beacon news).

Hepatitis C is a liver disease caused by the hepatitis C virus (HCV). If untreated, infection with HCV can cause damage and scarring to the liver, liver cancer, and eventually liver failure. Once the liver fails, a liver transplant is necessary for a patient to survive. Some people who are infected can spontaneously clear the virus themselves; the rest need treatment with antiviral drugs.

Incivek has not yet been approved for people with HIV-HCV co-infection. Vertex is currently conducting clinical trials to evaluate the drug’s safety and efficacy in people who are infected with both HIV and HCV (see related AIDS Beacon news). According to an FDA representative, the clinical trials are expected to be completed and submitted to the FDA by the end of 2014.

As with Victrelis, the approved dosing schedule for Incivek is somewhat complicated. Most patients taking Incivek will undergo response-guided therapy. Under this model, the length of treatment varies depending on how well a patient responds to the drugs.

Patients will take Incivek, ribavirin, and Pegasys or PegIntron for 12 weeks. If they have undetectable HCV levels after 4 and 12 weeks of treatment, patients continue to take ribavirin plus Pegasys/PegIntron for an additional 12 weeks (for a total treatment length of 24 weeks). If they have detectable HCV levels at 4 or 12 weeks, they take ribavirin plus Pegasys/PegIntron for an additional 36 weeks (48 weeks of treatment total).

Patients who have previously been treated with interferon-based therapy and did not respond or had only a partial response will take the full 48-week course of treatment. Vertex also recommends that patients with cirrhosis (scarring of the liver) consider the 48-week treatment course, even if they have undetectable HCV levels at 4 and 12 weeks.

If HCV is still detectable after 24 weeks, Vertex recommends discontinuing treatment with all three drugs.

Incivek is taken three times daily with food, every seven to nine hours, in the form of two 375 mg pills. Vertex is currently conducting studies evaluating twice-daily dosing instead of three times daily.

According to Vertex, the response-guided therapy will allow many patients to take a shortened course of therapy (24 weeks rather than the standard 48 weeks for just peginterferon alfa plus ribavirin), due to undetectable HCV levels at 4 and 12 weeks. Vertex stated in its press release that it estimated more than 60 percent of new or relapsed patients will be able to take the shortened treatment course.

Vertex is also currently investigating a possible 12-week total treatment course for patients with a certain genetic mutation. Previous studies have shown that these patients, who have a so-called “CC genotype,” tend to respond very well to hepatitis C treatment. Vertex estimates that this could include around a third of previously untreated patients.

The most commonly reported side effects for patients taking Incivek were rash, low red blood cell count (anemia), nausea, fatigue, headache, diarrhea, itching, and anal or rectal irritation and pain. The rash was experienced by over half of patients taking Incivek; in around 1 percent of patients, it was severe enough that patients stopped treatment.

Vertex stated in its press release that Incivek will arrive in pharmacies this week. The company has also initiated a patient assistance program for Incivek, which provides the drug free to people who are uninsured and who meet certain income requirements (annual household income of no more than $100,000).

Vertex will also offer a co-pay assistance program, which pays insurance co-pays and co-insurance costs of up to 20 percent of the cost of Incivek. There are no income restrictions for the co-pay assistance program.

Incivek will cost $49,200 for the entire course of treatment. For comparison, Victrelis will cost between $31,000 and $53,000 for an entire course of therapy. These numbers do not include the cost of peginterferon alfa or ribavirin.

For more information, please see the FDA website or the Vertex press release.

This article was updated at 2:40 pm to include information on international marketing and availability of Incivek. The article was updated at 5:10 pm to include additional information on the timing of HIV-HCV clinical trial completion for Incivek.

Edurant (rilpivirine) will be marketed by Tibotec Therapeutics, a subsidiary of Johnson & Johnson. Tibotec also markets the anti-HIV drugs Intelence (etravirine) and Prezista (darunavir).

“Patients may respond differently to various HIV drugs or experience varied side effects. FDA’s approval of Edurant provides an additional treatment option for patients who are starting HIV therapy,” said Dr. Edward Cox, director of the FDA’s Office of Antimicrobial Products at the Center for Drug Evaluation and Research, in an FDA press release.

The approval adds a new non-nucleoside reverse transcriptase inhibitor (NNRTI) to the list of approved anti-HIV drugs. It also increases the chances that a new combination pill, containing Edurant plus Truvada (emtricitabine/tenofovir), will be approved by the FDA.

The combination pill, which is intended as an alternative to Atripla (efavirenz/emtricitabine/tenofovir), will be marketed by Gilead Sciences. Gilead applied for approval of the combination pill in November 2010, and a decision is expected in August.

The approval of Edurant is based on clinical trial results showing that the drug is as effective as Sustiva (efavirenz) in treatment-naïve people with HIV. Sustiva is the most commonly prescribed NNRTI in the U.S. and, according to current treatment guidelines, is the preferred NNRTI for people who have not previously been treated for HIV. Sustiva is also a component in Atripla, the most commonly prescribed antiretroviral regimen.

After 48 weeks of treatment, 83 percent of study participants taking Edurant achieved viral suppression (undetectable amount of HIV in the blood), compared to 80 percent of participants taking Sustiva.

Edurant is taken as a once-daily 25 mg pill and must be taken with food.   Its approval by the FDA is for use in combination with other antiretrovirals.

The FDA noted in its press release that Edurant does have some disadvantages relative to Sustiva. Clinical trial participants who failed treatment with Edurant were more likely to show drug resistance than those who failed treatment with Sustiva. They were also more likely to become resistant to the other antiretrovirals they were taking and to other NNRTIs.

In addition, clinical trial participants who started with higher viral loads (amount of HIV in the blood) of greater than 100,000 copies per milliliter were less likely to achieve viral suppression than participants who started with lower viral loads. Overall, 13 percent of trial participants taking Edurant experienced virologic failure, compared to 9 percent taking Sustiva.

Side effects for Edurant were similar in nature and frequency to those for Sustiva. The most common side effects were depression, difficulty sleeping (insomnia), headache, and rash. However, fewer patients stopped taking Edurant due to side effects (2 percent, versus 7 percent taking Sustiva).

A representative from Tibotec told The Beacon that the company expects to start shipping Edurant to pharmacies in the first half of June. The drug will cost $21 per pill, or around $7,700 per year. Sustiva currently costs around $7,200 per year, assuming a normal adult dose of 600 mg daily.

Tibotec also plans to add Edurant to its patient assistance program, which provides Tibotec’s anti-HIV drugs free to low-income patients, as well as to its other patient support programs.

For more information, please see the FDA press release or the Tibotec press release.