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).

As a service to its readers, The AIDS Beacon has compiled a list of the news articles and topics that AIDS Beacon readers found most interesting during 2011.

#1: New Drugs For Hepatitis C – Two new drugs for the treatment of hepatitis C, Incivek (telaprevir) and Victrelis (boceprevir), were approved by the U.S. Food and Drug Administration (FDA) in May. The drugs, which mark a shift in the treatment paradigm for hepatitis C, sparked a flurry of interest from Beacon readers. Articles on the drugs’ efficacy and side effects and the drugs’ potential for people who are co-infected with hepatitis C and HIV were top articles on The AIDS Beacon this year.

#2: Progress Toward A Cure For HIV – For the first time in years, researchers began to seriously discuss the possibility of a cure for HIV. The shift came about as a result of the first known person cured of HIV, Timothy Brown, also know as “The Berlin Patient.” Brown served as a proof of concept that a cure is possible; now researchers are trying to figure out how to apply the lessons learned about HIV over the past 30 years to finding a cure for the general population. Beacon readers were particularly interested in a series on the research scientists are pursuing toward a cure and what the future of HIV treatment might look like.

#3: FDA Approves New Anti-HIV Drug Edurant For Treatment-Naïve People With HIV – The FDA announced in May that it had approved the new antiretroviral Edurant (rilpivirine), a non-nucleoside reverse transcriptase inhibitor, for use in people with HIV who have not previously been treated.

#4: Estimated Life Expectancy For HIV-Positive Men Is Greatest When HIV Is Diagnosed Early – Results from a British study of HIV-positive men who have sex with men estimated a life expectancy of 75 years if HIV is diagnosed early, compared with 82 years for individuals without HIV. If HIV is diagnosed late, the researchers estimated life expectancy at 71.5 years.

#5: HIV Experts Recommend Shifting HIV Care To Primary Care Doctors – Dr. Mitchell Katz, a physician with extensive experience in treating patients with HIV and AIDS, argued in an editorial that HIV/AIDS care should shift from HIV specialists to primary care physicians now that, in his opinion, HIV is essentially a chronic, treatable disease. The Institute of Medicine also warned of serious and growing shortages in the HIV healthcare system and recommended shifting more HIV care to primary care doctors.

#6: 30 Years Of HIV: A Lot Of Progress, But Still A Long Way To Go – June 5, 2011, marked the 30th anniversary of the first reports of AIDS in the U.S. Physicians, policy makers, and the HIV-positive community paused to reflect on the progress that has been made in combating the disease, as well as the long road still ahead toward eradicating the virus. The anniversary also provided a time to remember the lives that have been lost to AIDS, both in the U.S. and around the world.

#7: FDA Approves Gilead’s Complera, AKA Btripla, For Use In Previously Untreated People With HIV – In August,the FDA approved Complera (rilpivirine/emtricitabine/tenofovir), informally known as “Btripla,” for use in people with HIV who have not previously been treated with antiretrovirals.

#8: Edurant And Complera Are Classified As Alternative, Not Preferred, HIV Regimens – The Department of Health and Human Services updated antiretroviral treatment guidelines to state that Edurant, which is also a component of Complera, is considered an alternative, but not preferred, antiretroviral for people starting HIV treatment for the first time. Sustiva (efavirenz), which is in the same antiretroviral class as Edurant, is still considered the preferred treatment.

#9: HAART May Affect Chemotherapy Treatment In HIV-Positive Cancer Patients – A review of studies on chemotherapy treatment for HIV-positive cancer patients found that antiretrovirals can exacerbate side effects from chemotherapy drugs and may cause drug-drug interactions that can affect dosages and efficacies.

#10: HIV And Antiretroviral Therapy May Affect Fertility – Results of a review indicated that people with HIV may be at an increased risk for infertility, due to both the virus itself and the use of antiretrovirals. The authors of the review also found that assisted reproduction options can help people with fertility problems and can be a safe choice for couples in which one partner is HIV positive and the other is HIV negative, although the risk of HIV transmission cannot be eliminated completely.

“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.

In particular, by week 72 of the study, three to five times as many patients who deferred treatment had progressed and required antiretroviral therapy than patients who had begun treatment soon after infection. Patients who were treated early initially and then stopped treatment also went significantly longer before additional therapy was necessary.

“The higher than anticipated rate of disease progression among untreated individuals…is a compelling finding of this study and contributes to the growing body of evidence favoring earlier treatment,” wrote the study authors.

“Our results suggest that if immediate therapy is not begun, progression to meeting standard criteria for antiretroviral therapy initiation may occur more rapidly than expected, especially with changing treatment paradigms,” they wrote.

As a result of the large difference between outcomes, the study’s safety monitoring board recommended that it be stopped early.

Previous research has shown that starting antiretroviral treatment early after infection with HIV improves later viral loads, but study findings have been mixed.

According to the study authors, attempts to assess the effect of antiretroviral therapy on viral set point (the point at which the amount of HIV in the blood naturally levels off) in newly infected people have been limited to date, largely because of the difficulty of identifying recently infected individuals.

In this 96-week trial based in the United States and Peru, researchers set out to test whether starting treatment soon after infection would affect the viral set point later, as well as other outcomes such as disease progression.

The study included 130 men and women who were infected with HIV within the last six months but were beyond the acute phase of infection. Individuals in one group received 36 weeks of antiretroviral therapy immediately, then discontinued treatment; a second group deferred treatment until it was necessary due to disease progression.

Patients in either group who required treatment initiation or re-initiation, respectively, due to disease progression were advised to start antiretroviral therapy.

Participants were randomly assigned to the immediate treatment or deferred treatment group.  All participants were previously untreated and had HIV viral loads of at least 500 copies per milliliter.

Treatment consisted of Truvada (emtricitabine/tenofovir) plus Kaletra (lopinavir/ritonavir).

Results showed that by the end of the study, 36 percent of participants in the deferred treatment group required antiretroviral treatment initiation due to low CD4 (white blood cell) counts, high viral loads, or AIDS, compared with 11 percent in the immediate treatment group.

In addition, 20 percent of patients in the deferred treatment group required therapy within the first 36 weeks of the study and 8 percent of participants in the deferred treatment group progressed to AIDS.

Further analysis showed that, including only participants who completed the full 72 weeks of the study period, 50 percent in the deferred treatment group and 10 percent in the immediate treatment group required antiretroviral therapy. Twenty-eight percent of participants in the deferred group required treatment in the first 36 weeks of the study.

Outcomes were better for the immediate treatment group than the deferred treatment group at weeks 36 and 72, as determined by factors such as viral load and disease progression. After stopping initial treatment, participants in the immediate treatment group also took significantly longer to progress to the point at which antiretroviral therapy was necessary than people in the deferred treatment group.

On average, individuals who received immediate antiretroviral therapy experienced an extra 16 weeks beyond the 36 weeks of treatment before their disease began to progress.

However, after 72 weeks, the average viral load was similar in both groups.

Participants with initial CD4 counts of less than 540 cells per microliter or viral loads above about 25,000 copies per milliliter were more likely to require antiretroviral therapy earlier.

Due to the early study discontinuation, the authors were not able to determine whether immediate versus deferred treatment had any effect on viral load set point.

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

The study authors noted that the decrease in life expectancy for HIV-positive men is comparable to the effect of cigarette smoking or having a chronic disease like diabetes.

“Men who have sex with men who are recently infected are estimated to have a good life expectancy, provided they are diagnosed early (and have good access to HIV care),” said Fumiyo Nakagawa, a researcher at UCL Medical School in London and lead author of the study.

“Our model has also estimated that life expectancy is further prolonged if the individual does not smoke, does not interrupt treatment, and has good adherence to treatment,” she added.

Life expectancy refers to the expected number of years of life remaining for an individual at a given age. In the general population, several factors, including sex, race, and lifestyle habits, are known to influence life expectancy. Various factors, like better drugs, earlier detection, and increased experience of physicians in treating HIV, are thought to contribute to increased life expectancy of people with HIV.

A Danish study published earlier this year found that HIV-positive individuals suffer from higher death rates mainly due to HIV and non-HIV related risk factors such as poor response to antiretroviral therapy, co-infection with hepatitis C or other diseases, and drug and alcohol abuse.

According to the study authors, most studies so far have based life expectancy estimates on current death rates in people with HIV. Since drugs’ ability to suppress the amount of HIV in the blood have improved over time, and since therapy benefits on death rates may take years to fully take effect due to slow increases in CD4 (white blood cell) counts, life expectancy for HIV-positive people may have been underestimated.

In this study, researchers used a computer simulation model of HIV infection and the effects of antiretroviral therapy to estimate life expectancy for a man who has sex with men and who becomes HIV positive in 2010 at the age of 30 years old. They also attempted to determine how life expectancy varied depending on how early or late HIV was diagnosed. For comparison, the researchers used general population death rates for men in the United Kingdom for 2009.

The model assumed that a man with HIV would start a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, then switch to a boosted protease inhibitor-based regimen in the case of virologic failure.

The likelihood of treatment interruption was assumed to be 1.5 times higher in individuals with lower treatment adherence. Based on results from previous studies, a 1.5-fold increase in risk for all non-AIDS deaths was assumed for men with HIV throughout life.

Researchers also assumed a 40 percent chance of being a smoker and no hepatitis C co-infection.

Results showed that in a society with a high rate of HIV diagnosis, in which HIV was likely to be diagnosed soon after infection, the median age of death was estimated to be 75 years old. Risk of death within five and 10 years after infection was 2.3 percent and 5.2 percent, respectively. In addition, 57 percent, 78 percent, and 97 percent of men were diagnosed by three, five, and 10 years after infection, respectively.

Under this model, the median time from infection to diagnosis was 2.8 years, and the median CD4 cell count at diagnosis was 432 cells per microliter. In addition, the average time from infection to starting antiretroviral therapy was almost six years. Individuals were estimated to spend an average of 39 years on treatment, of which all but roughly seven years were spent actually receiving antiretroviral therapy (as opposed to periods of interrupted treatment).

The chance of treatment interruption at least once during an individual’s lifetime was estimated at 85 percent. Estimated life expectancy increased by 1.5 years when it was assumed that no treatment interruptions occurred.

It was estimated that 41 percent of individuals will at some stage progress to AIDS. However, only 14 percent of deaths were predicted to be from AIDS-related illnesses, and only 10 percent of men predicted to die of AIDS were also predicted to have resistance to all three major antiretroviral drug classes (nucleoside-reverse transcriptase inhibitors, NNRTIs, and protease inhibitors) plus integrase inhibitors.

Results also showed that in a society with a low HIV diagnosis rate, in which HIV was diagnosed only when symptoms were present, life expectancy for HIV-positive men who have sex with men was 71.5 years, indicating that an average of 10.5 years of life were lost compared to people without HIV.

With a low diagnosis rate, the median CD4 count was 140 cells per microliter at diagnosis; 22 percent, 37 percent, and 74 percent of individuals were diagnosed with HIV within three, five, and 10 years after infection, respectively. Consequently, there was a higher risk of death within 10 years after diagnosis (13 percent compared to 5.2 percent with a high diagnosis rate).

However, the effect of late diagnosis on life expectancy after this time was less significant due to the long-lasting effects of antiretroviral therapy, even in those who start treatment when CD4 cell counts are low.

The researchers estimated that the effect of late diagnosis would be greatest in the first 15 to 20 years after infection. Late diagnoses also increased the probability of transmitting HIV to others because lack of treatment increases risk of HIV transmission.

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

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 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.

Most (84 percent) of the children in the study who did not survive were born before 1994, at least three years before highly active antiretroviral therapy (HAART) became widely available.

“As antiretroviral utilization milestones were achieved throughout the course of this study, in going from single-agent to dual-agent and then to triple-agent therapy (Highly Active Antiretroviral Therapy – HAART), there have been dramatic parallel improvements in mortality rates among the cohort resulting in prolonged overall survival,” said Dr. Bill Kapogiannis, program director of the Adolescent Medicine Trials Network for HIV/AIDS Interventions and lead author of the study.

However, the study authors noted that despite the large reductions in death rates, the average annual death rate of HIV-positive children during the HAART era remained 50-fold higher than the death rate of HIV-negative children of the same age during the same period in the United States.

They hypothesized that this may be due to increased susceptibility to death from other causes besides HIV, such as non-AIDS-defining infections.

“During this period, as deaths associated with opportunistic infections declined, the numbers of deaths not associated with these infections remain and thus, become more prominent,” said Dr. Kapogiannis.

HAART is defined as therapy involving at least three antiretroviral drugs, usually two nucleoside reverse transcriptase inhibitors combined with either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase inhibitor.

Since the introduction of HAART during the mid- to late-1990s, the frequency of deaths in adults and children with HIV has decreased considerably.

According to the study authors, while trends in survival and death among HIV-positive children have been examined in previous clinical trials, these trials have enrolled patients anytime from birth throughout childhood. As a result, deaths early on when children are particularly susceptible to infections might have been overlooked.

In this study, investigators compared death rates from birth in HIV-positive children born between 1986 and 2004. In particular, the researchers examined three time periods: the no antiretroviral therapy/monotherapy period from 1986 through 1990, the monotherapy/dual therapy period from 1991 through 1996, and the HAART period from 1997 through 2004.

The multicenter, retrospective study included HIV-positive pregnant women and their newborns in four cities in the U.S.: New York, Atlanta, Baltimore, and Newark, NJ. A total of 364 HIV-positive children were included in the study.

Results showed that the death rates of children in the first period and the second period were six and two times higher, respectively, than the death rate of children in the HAART era. However, the death rate in the HAART era remained 50 times higher than that of HIV-negative children of the same age.

The six-year survival rates for children born in the three eras were 57 percent, 76 percent, and 91 percent, respectively.

In addition, the 10-year survival rate for children who received HAART at any age was 94 percent, compared to 45 percent for children who did not receive HAART.

Eighty-one percent of deaths in the study occurred in children aged 3 years or less, and 61 percent of deaths occurred in children aged 2 years or less.

Results also showed that the percentage of deaths due to opportunistic infections declined over time, from 32 percent in 1986 to 1990, to 17 percent in 1991 to 1996, to 9 percent in 1997 to 2004.

The three most common causes of death in the study were end-stage AIDS (24 percent), opportunistic infections (19 percent), and pneumonia (15 percent).

Children who died were more likely to be born in the late 1980s or early 1990s, have a birth weight of less than 5.5 pounds (2.5 kg), be born prematurely (less than 37 weeks), or have low weight or height for their age at three months old. Children with thymic dysfunction, children who were infected with HIV before birth, and children who had not received zidovudine (Retrovir) during and before birth to prevent HIV infection were also at greater risk of death.

HIV transmission from mother-to-child before birth was associated with greater risk of death compared with HIV transmission during labor and delivery; however, the effect was only significant until two years of age.

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

“We are encouraged by these interim results with Victrelis in combination therapy in this difficult-to-treat patient population,” said Dr. Roger Pomerantz, senior vice president of Infectious Diseases at U.S. pharmaceutical company Merck, in a press release.

Based on the results, Dr. Pomerantz said that Merck is planning to initiate a Phase 3 study of Victrelis in people with both HIV and hepatitis C later this year.

The results were presented last week at the Infectious Diseases Society of America 2011 Annual Meeting in Boston.

Hepatitis C is a liver disease caused by the hepatitis C virus. If untreated, infection with the hepatitis C virus 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.

HIV patients with hepatitis C are less likely to clear the infection compared to patients with hepatitis C only. Once the infection develops and becomes chronic, HIV patients are less likely to respond to hepatitis C treatment, which currently consists of peginterferon-alfa  (PegIntron, Pegasys) plus ribavirin (Rebetol, Copegus) for 48 weeks.

Victrelis (boceprevir) 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. 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 Victrelis plus PegIntron (peginterferon alfa-2b) and ribavirin to PegIntron and ribavirin alone in adult patients with both hepatitis C and HIV.

The study includes 98 participants who were randomly assigned to receive one of the two above mentioned treatments. All participants had stable HIV infections, were receiving an optimized antiretroviral regimen, and had not previously been treated for hepatitis C.

Since studies have shown that certain HIV antiretrovirals may potentially interact with Victrelis, non-nucleoside reverse transcriptase inhibitors, zidovudine (Retrovir), stavudine (Zerit), and didanosine (Videx) were not allowed during the study.

Most participants were Caucasian (82 percent), and a majority were male (69 percent). The median participant age was 43 years old.

Participants in each of the two treatment groups received four weeks of treatment with PegIntron plus ribavirin. Two-thirds of the participants then initiated treatment with Victrelis three times daily in addition to PegIntron and ribavirin; the remaining participants continued treatment with just PegIntron plus ribavirin.

Results showed that after 24 weeks, 70 percent of participants taking Victrelis had undetectable hepatitis C virus levels, compared to 34 percent of participants taking PegIntron and ribavirin alone.

The most common side effects in the group receiving Victrelis versus the group receiving PegIntron and ribavirin alone were: low white blood cell levels (neutropenia), 13 percent versus 3 percent; bad taste in the mouth, 25 percent versus 15 percent; vomiting, 25 percent versus 15 percent; fever, 34 percent versus 21 percent; headache, 28 percent versus 12 percent; and decreased appetite, 30 percent versus 18 percent.

Serious side effects occurred in 8 percent of the patients receiving Victrelis in combination with PegIntron and ribavirin, compared with 21 percent of patients receiving PegIntron plus ribavirin alone.

Overall, 14 percent of participants receiving Victrelis discontinued treatment due to side effects, compared to 9 percent of participants receiving PegIntron and ribavirin alone.

The trial will continue for an additional 24 weeks. Merck stated that final results are expected in 2012.

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

The guidelines include updated information on initial combination regimens for previously untreated (treatment-naïve) people with HIV.

According to the guidelines, antiretroviral regimens may be classified as preferred regimens, alternative regimens, or acceptable regimens. Preferred regimens are recommended as the best treatment regimens for most people starting antiretroviral therapy.

Alternative regimens, while effective, have potential disadvantages when compared with preferred regimens. Acceptable regimens decrease the amount of HIV virus activity but lack data from large clinical trials on efficacy or might have greater side effects or potential for drug interactions.

The guidelines are intended for use by HIV care practitioners when treating HIV-positive adults and adolescents in the U.S. They were last updated in January.

Updates on antiretroviral initiation in HIV-positive people are summarized below.

Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Regimens

The updated guidelines list Edurant (rilpivirine) as an alternative NNRTI option for initial therapy in treatment-naïve patients (see related AIDS Beacon news). Edurant was approved by the U.S. Food and Drug Administration in May.

Information on Edurant has also been added to the guide’s tables on drug interactions, drug characteristics, and dosing recommendations for people with kidney or liver problems.

In addition, all Viramune (nevirapine)-based regimens have been reclassified in the updated guidelines as acceptable treatment options for patients beginning antiretroviral therapy. Previously, Viramune plus zidovudine/lamivudine (Combivir) was classified as an alternative regimen, while Viramune plus Epzicom (abacavir/lamivudine) and Viramune plus Truvada (emtricitabine/tenofovir) were classified as regimens that were acceptable but required caution when used.

Protease Inhibitor-Based Regimens

The updated guidelines now list Norvir (ritonavir)-boosted Prezista (darunavir) plus Epzicom as an alternative regimen. This regimen was previously listed as an acceptable regimen that required more data.

Regimens with unboosted Lexiva (fosamprenavir) are no longer listed as protease inhibitor options for treatment-naïve patients because these regimens are less effective than other protease inhibitor-based regimens. In addition, patients who experience virologic failure (failure of antiretrovirals to control HIV replication) while taking Lexiva may develop resistance to Prezista.

Isentress-Based Regimens

The new guidelines reclassify Isentress (raltegravir) plus Epzicom as an alternative regimen. The regimen was previously classified as acceptable but in need of additional data.

Dual-Nucleoside Reverse Transcriptase Inhibitor (NRTI) Options

The updated guidelines list zidovudine/lamivudine as an acceptable dual-NRTI option. This option was previously listed as an alternative option, but was reclassified because the combination is associated with greater side effects compared with Truvada and Epzicom and requires twice daily dosing. Zidovudine/lamivudine, however, is still the preferred dual-NRTI for pregnant women receiving antiretroviral therapy to avoid mother-to-child HIV transmission.

Didanosine (Videx) plus Epivir (lamivudine) is no longer listed as a dual-NRTI option for initial treatment because the combination has the least data from clinical trials and has more side effects compared with other dual-NRTI options.

In the updated guidelines, the authors point out that Ziagen (abacavir), which is also a component of Epzicom and Trizivir (zidovudine/lamivudine/abacavir), may increase the risk of heart attack; however, they note that this association is not definitive.

For more information, please see The Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents (pdf).