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.

“Triglycerides are frequently raised, have health implications, and are easily managed with measures that can include a safe supplement such as Omacor/Lovaza (omega-3 acid ethyl esters),” said Dr. Barry Peters, head of the Academic Unit of HIV and STDs at King’s College London and lead author of the study.

According to Dr. Peters and his colleagues, the study results indicate that the fatty acids may decrease triglycerides levels as effectively as triglyceride-lowering drugs such as statins while producing fewer side effects. The results also support the use of fatty acid therapy to lower triglyceride levels in HIV positive persons during antiretroviral therapy.

However, Dr. Peters pointed out that fatty acid treatment works significantly only on triglyceride (and not cholesterol) levels even though it is much less toxic than other treatments.

The authors suggested that future work in this field might include larger studies that examine the effect of fatty acid therapy during different antiretroviral regimens and in different demographic groups.

Triglycerides are a common form of lipid (fat) that the body uses to store excess energy. According to the American Heart Association, blood triglyceride levels of less than 150 mg/dL are considered normal.

High levels of triglycerides in the blood can clog arteries and are associated with an increased risk of heart disease and stroke.

Previous studies have shown that treatment with antiretroviral drugs, particularly protease inhibitors, can increase blood cholesterol and triglyceride levels (see related AIDS Beacon news).

Statins, such as atorvastatin (Lipitor) and Crestor (rosuvastatin), and fibrates, such as Tricor (fenofibrate) and Lopid (gemfibrozil), are two classes of drugs commonly used to lower cholesterol and triglyceride levels.

Although statins are often more effective than fibrates at lowering cholesterol, statins have been shown to interact with some antiretroviral drugs. They also can produce liver- and muscle-related side effects.

Omega-3 polyunsaturated fatty acids are thought to be a kind of “healthy fat” that lowers cholesterol levels and the risk of heart disease. Nuts, seeds, leafy greens, and fish oils are rich sources of such fatty acids.

In previous studies, some researchers investigating the use of omega-3 fatty acid supplements during antiretroviral therapy found a triglyceride-lowering effect, while others did not. In this study, researchers aimed to examine the effect of short-term fatty acid therapy, in combination with fibrates, in people experiencing high triglyceride levels during antiretroviral therapy for HIV.

Forty-eight HIV positive individuals on antiretroviral therapy participated in this study. All participants had stable, well-controlled infection and blood triglyceride levels between 300 and 1,000 mg/dL. All but one participant were male, and 90 percent were Caucasian.

Study participants were divided into two groups. One group received a combination of two fatty acids (docosahexanoic acid (DHA) and eicosapentanoic acid (EPA)), while the other received a placebo, for 12 weeks.

Both groups additionally took fibrates during this period and adhered to a low-cholesterol diet.

The researchers took blood samples from the patients before treatment and at four, seven and 12 weeks of treatment. Several parameters, including triglycerides, cholesterol levels, CD4 (white blood cell) counts, and amount of virus in the blood were measured.

The researchers also monitored side effects associated with treatment.

After 12 weeks of treatment, fasting triglyceride levels were 27 percent lower than pre-treatment levels in patients who received treatment with fatty acids. Participants who received the placebo, on the other hand, showed a 13 percent increase in triglycerides.

While total cholesterol and levels of “good” cholesterol were unchanged, levels of “bad” cholesterol decreased during fatty acid treatment.

The occurrence of side effects was not significantly higher in participants who received the fatty acid treatment than in participants who received the placebo. Based on these findings, the researchers concluded that the use of fatty acids with fibrates may be well tolerated.

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

A review of results from several studies on Reyataz indicates that relative to other antiretrovirals, Reyataz may be associated with fewer side effects in certain areas – such as heart problems – but more in other areas, such as kidney problems.

Results also showed that Reyataz alone was able to control viral loads (amount of virus in the blood) as effectively as Norvir-boosted Reyataz, with fewer side effects in some cases.

Reyataz (atazanavir), which was approved by the U.S. Food and Drug Administration (FDA) in 2003, is a once-daily protease inhibitor. It is usually taken with Norvir (ritonavir), which allows Reyataz to be taken once daily rather than twice daily without losing efficacy.

In this review, the authors discussed recent findings related to Reyataz treatment and side effects that were presented at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, held in Rome this past July (see related AIDS Beacon news).

Reyataz Is Associated With Fewer Heart And Bone Problems But Possibly More Kidney Problems

Results from several studies presented at the conference indicate that Reyataz may be linked to fewer heart- and bone-related problems, as well as less chronic diarrhea in people with HIV, compared to other antiretrovirals. However, some studies also found that Reyataz use was associated with more kidney problems.

One study discussed in the review examined the effect of different antiretroviral regimens on left ventricular mass. The left ventricle is the main pumping chamber of the human heart. An increase in its mass is common in people with high blood pressure or other heart problems and can be measured by a test called an echocardiogram.

The study involved 190 people with HIV above the age of 39 years old. Results showed that exposure to Reyataz was associated with lower left ventricular mass. On the other hand, exposure to Viramune (nevirapine) was significantly related to increased left ventricular mass. The results suggest that Reyataz-based regimens might be associated with a lower risk of heart problems compared to other antiretroviral regimens.

Three other side effects of Reyataz were examined in the reviewed studies – chronic diarrhea, loss of bone mineral density, and kidney problems.

One study measured the rate of chronic diarrhea (persisting for four weeks or more) during antiretroviral treatment in 254 HIV-positive adults. While exposure to protease inhibitors in general was associated with a higher risk of chronic diarrhea, Reyataz was associated with a lower risk. The study showed that three out of four people who experienced chronic diarrhea switched treatment.

A 96-week study used X-ray imaging to compare the bone mineral density of HIV-positive people on Norvir-boosted Reyataz or Kaletra (lopinavir/ritonavir)-based regimens. The results showed that although people in both groups lost bone mineral density, the changes were relatively smaller in those treated with Reyataz.

Finally, studies presented in the review examined kidney-related side effects in patients with HIV undergoing antiretroviral therapy.

One study measured kidney function by estimating the rate at which blood passes through the tiny filters in the kidney. The study included HIV-positive individuals on a regimen of two nucleoside reverse transcriptase inhibitors (NRTIs), plus Sustiva (efavirenz) or protease inhibitors. Sustiva is a non-nucleoside reverse transcriptase inhibitor.

Results showed that treatment with Reyataz did not significantly diminish the filtration rate, but that exposure to Kaletra or Prezista was associated with significant reduction of estimated kidney function.

However, another similar study found that both Kaletra and Reyataz were associated with lower filtration rates in the kidney compared to non-protease inhibitors, when combined with NRTIs. The authors concluded that treatment-naïve individuals on protease inhibitor-based regimens might be at an increased risk for mild-to-moderate kidney disease.

According to the review, a separate study also found that exposure to Reyataz was associated with a significantly higher rate of kidney stone development, as compared to several other antiretrovirals such as Sustiva and Prezista (darunavir).

The most frequent side effect associated with Reyataz use was found to be an increase of bilirubin levels in the blood. Bilirubin is a normal breakdown product of hemoglobin, and its accumulation is thought to be indicative of diminished kidney function.

Unboosted Reyataz May Be As Effective As Boosted Reyataz, With Fewer Side Effects

The studies also revealed that eliminating Norvir can sometimes reduce treatment-associated side effects without loss of effectiveness.

The review presented results from two studies assessing the effectiveness and safety of Reyataz alone versus Norvir-boosted Reyataz. One study assessed the long-term effectiveness and safety of Reyataz alone versus Norvir-boosted Reyataz, both combined with Epzicom (abacavir/lamivudine). The other study retrospectively examined the effect of Reyataz alone versus Norvir-boosted Reyataz, both combined with two NRTIs, in patients with well-controlled disease.

Results from both studies showed that unboosted Reyataz was as effective as Norvir-boosted Reyataz in controlling viral load. In the first study, for example, after 144 weeks 77 percent of participants in the group without Norvir successfully achieved and maintained an undetectable viral load, compared to 73 percent of participants in the group that took Norvir. The difference was not considered significant.

Eliminating Norvir was associated with fewer side effects (13 percent of participants, compared to 23 percent of participants who received Norvir) and better fat metabolism, such as lower cholesterol and triglyceride levels, in the first study.

However, Reyataz was found to produce a favorable fat profile both by itself and with Norvir in the second study.

“[The first study] does indeed provide strong data from a randomized-controlled trial that supports a strategy of taking individuals who are fully suppressed on a Reyataz/Norvir-containing regimen, and then withdrawing the Norvir and adjusting the dose of Reyataz for unboosted use,” said Dr. Eric Daar, Division Chief of HIV Medicine at the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, who was not affiliated with the studies or the review. He added that this idea has probably not gained traction so far because there has not been a compelling reason to not use Norvir.

“The landscape may change in the near future with the availability of the alternative pharmacologic booster, cobicistat, under review by the FDA for use with Reyataz,” noted Dr. Daar.

“In the immediate future, the biggest Reyataz-related issues will be how to choose between boosting with Norvir versus cobicistat,” he added.

Future Directions In Reyataz-Related Research

“The next big treatment issues related to Reyataz will likely focus on its use as part of novel combinations, e.g. NRTI-sparing when used with CCR5 antagonists or integrase inhibitors,” said Dr. Daar.

“Over the next few years we will have data from a fully powered head-to-head comparison of Reyataz/Norvir with Prezista/Norvir (ACTG 5257), which may impact its use in clinical practice,” he added.

For more information, please refer to the article in HIV and AIDS Review (abstract).

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.

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 authors of the review also found that assisted reproduction options can help people with fertility problems and can be a safe choice for HIV serodiscordant couples (a couple in which one partner is HIV positive and the other is HIV negative), although the risk of HIV transmission cannot be eliminated completely.

Based on their results, the authors suggested more research into future fertility treatments designed to minimize the risk of transmission, as well as further studies to evaluate the effects of HIV and antiretroviral therapy on fertility in people with HIV.

Prior to the advent of highly active antiretroviral therapy (HAART), the prospect of parenthood raised a number of issues for people with HIV, including a high risk of transmission to a partner and to the infant before or after birth. However, the use of antiretrovirals has significantly decreased mother-to-child transmission of HIV, with rates of transmission as low as 1 percent in the United States.

HIV is most common among people of reproductive age. As a result, a growing number of people with HIV desire to have children and are planning to become pregnant (see related AIDS Beacon news).

In this review, the authors addressed the potential role of HIV and antiretrovirals in people with HIV and infertility issues, as well as treatment options and fertility procedures for infertile and serodiscordant couples.

Infertility In HIV-Positive Women And Men

Results on the causes of infertility in men and women with HIV have been conflicting, but in general appear to indicate that people with HIV, particularly people with advanced HIV infections or AIDS, are less fertile than HIV-negative men and women.

Results of a study of African women with HIV showed that they were 25 percent to 40 percent less fertile than HIV-negative women. In addition, some studies have shown decreased fertility rates in HIV-positive women in the United States.

However, according to the review authors, it is still unclear whether HIV itself causes infertility or whether the problem is due to other conditions that women with HIV are more prone to. For example, additional factors that may result in infertility in HIV-infected women include stress, weakened immune systems, weight loss, drug abuse, and the presence of other sexually transmitted diseases.

Attempts to determine the role of HIV itself in infertility have had mixed results. HIV-positive women are more likely to have an anovulatory cycle, a common cause of infertility in which a woman has a menstrual cycle without the ovaries releasing an egg. HIV-positive women are also more likely to have amenorrhea, or a complete absence of a menstrual cycle in a woman of reproductive age.

However, the causes of anovulation and amenorrhea in HIV-positive women are unknown, and recent studies suggest that HIV infection itself is not linked to amenorrhea once other factors, such as weight and age, are taken into account.

Some studies have also suggested a link between HIV infection and ovarian failure in HIV-infected women. For example, researchers in one small study found that 8 percent of HIV-positive female participants had levels of the follicle-stimulating hormone, a hormone required for growth and development in the ovaries, similar to those in menopausal women. However, a larger study found no such link between the hormone and HIV, and another found no evidence of premature ovarian aging in HIV-positive women.

For women who are not on antiretroviral therapy, complications with pregnancy may occur more often. In one study, almost 19 percent of HIV-positive women experienced pregnancy loss compared to 12 percent of uninfected women. However, more recent studies have shown that HAART reduces pregnancy loss in women with HIV.

In men, studies have shown that several sexual problems that affect fertility are more common with HIV infection. 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.

Also, men with HIV are more likely to experience decreased sex drive and an estimated 60 percent experience erectile or ejaculatory dysfunction.

Sperm function also appears to be affected by HIV, with healthier men having fewer problems with their sperm. According to the review authors, men with higher CD4 (white blood cell) counts tend to have better semen volume, sperm motility, and sperm counts, all of which affect fertility, than men with lower CD4 counts.

Effects Of Antiretroviral Therapy On Fertility

The effects of antiretrovirals on fertility have also been unclear. Since advanced HIV infection tends to decrease fertility, starting HAART can improve the likelihood of pregnancy. However, there are also indications that the drugs can have negative effects on fertility.

Researchers from a study in Africa found that the use of antiretroviral therapy increased fertility in HIV-positive women (see related AIDS Beacon news). A study in the U.S., however, found that women on therapy were less likely to conceive. The reason for the difference in results is not clear.

In addition, according to the review authors, the use of some antiretrovirals, particularly zidovudine (Retrovir) and other older nucleoside reverse transcriptase inhibitors (NRTIs), may affect fertility in people with HIV.

Previous studies have shown that NRTIs, particularly older NRTIs, may cause damage to mitochondria, which are small structures within cells that supply cellular energy. In particular, NRTI use may damage the mitochondria in sperm and eggs, leading to infertility.

Other studies have shown that HIV-positive men on HAART may have damaged sperm, decreased sperm count, and decreased sperm motility.

Fertility Treatment Options For People With HIV

For people with HIV who have fertility problems or who have an HIV-negative partner and are worried about transmitting the virus, assisted reproductive technology can achieve pregnancy by artificial or partially artificial means.

Three common assisted reproduction techniques include intrauterine insemination, in vitro fertilization, and intracytoplasmic sperm injection.

Intrauterine insemination is a procedure where the sperm is placed directly in the woman’s uterus. In vitro fertilization, another technique, involves fertilizing eggs with sperm outside the body and then transplanting the embryos into the uterus. Finally, intracytoplasmic sperm injection is an in vitro fertilization process in which a single sperm cell is injected directly into an egg. For men who are HIV-positive, these procedures are combined with sperm washing, which separates virus and infected immune cells from the sperm.

All three techniques have been used successfully in people with HIV, and none of the studies reviewed by the authors had any instances of transmission in serodiscordant couples. However, the authors noted that before trying to conceive, patients should reduce the risk as much as possible using HAART to suppress levels of the virus.

The authors also noted that people with HIV can face many difficulties in accessing reproductive health care. Currently, fewer than 3 percent of U.S. fertility practices provide assisted reproductive services to HIV-positive patients.

In addition, the Centers for Disease Control and Prevention have not endorsed in vitro fertilization or intracytoplasmic injection for people with HIV, and many states outlaw placing bodily fluids from an HIV-positive person into a patient.

However, the review also highlighted a report from the American Society of Reproductive Medicine that suggested that discriminating against HIV-positive patients may be illegal under the federal Americans with Disabilities Act, since HIV and AIDS are considered disabilities by the government.

For more information, please see the study in Fertility and Sterility (abstract).

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).

Based on their results, the authors of the study suggested that intervention programs be implemented to reduce the risk of heart disease in people with HIV taking antiretrovirals.

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 (see related AIDS Beacon news).

These side effects can lead to serious health problems, such as heart disease and diabetes.

In this study, researchers investigated the rates of high cholesterol and triglyceride levels and risk for cardiovascular disease in 113 people with HIV who were on antiretroviral therapy. The average age of study participants was 39 years old and 68 percent were male.

Results showed that two-thirds of study participants (67 percent) had problems with their cholesterol or triglyceride levels. Almost 54 percent of participants had low levels of “good” cholesterol and 36 percent had high levels of triglycerides; 27 percent had borderline-high or high cholesterol.

Results also showed that participants taking a protease inhibitor-based regimen had a more than five-fold higher risk for abnormal cholesterol or triglyceride levels than patients on antiretroviral therapy without protease inhibitors.

In addition, almost 40 percent of individuals with HIV had changes in body fat distribution, particularly body fat accumulation.

The researchers also assessed the risk for heart disease in 97 participants. Results showed that 37 percent of the HIV-positive men and 40 percent of the HIV-positive women had a high risk for heart disease.

The researchers found no link between age, length of HIV infection, gender, viral load (amount of HIV in the blood), or CD4 (white blood cell) count and risk of abnormal cholesterol or triglyceride levels.

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

The authors of the review recommended that in certain cases, patients should consider switching drug regimens or stopping antiretroviral therapy during chemotherapy.

The authors also emphasized the need for more clinical trial data about the combined use of antiretroviral therapy and anti-cancer drugs in patients with both cancer and HIV.

With the introduction of highly active antiretroviral therapy (HAART), AIDS-related complications and death have become less common; AIDS-defining cancers like Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer have decreased.

However, non-AIDS-defining cancers, including Hodgkin’s lymphoma and anal, lung, and testicular cancer, have become more common in HIV-positive people (see related AIDS Beacon news).

As a result, information about potential drug interactions and the combination of antiretroviral and cancer drugs in HIV-positive cancer patients is increasingly important. To date, little is known about the possible overlapping side effects of antiretrovirals and cancer drugs and the interactions of the two different types of drugs.

Antiretrovirals May Worsen Side Effects Of Certain Cancer Drugs

One major concern about combining antiretroviral therapy and chemotherapy is the potential for overlapping side effects. Several antiretrovirals have similar side effects as certain chemotherapy agents, and combining the two may increase the rate or severity of these effects.

Several of the side effect concerns deal with older antiretrovirals. Zidovudine (Retrovir), for example, has been associated with low white blood cell counts (neutropenia), which puts some patients at risk for infections. Many chemotherapy regimens are also associated with low white blood cell counts.

The review authors recommended that an alternative to zidovudine be used when possible during chemotherapy; if not, chemotherapy drugs that have less effect on white blood cells should be used and the patient’s white blood cell count should be carefully monitored.

Other anti-HIV drugs like didanosine (Videx) and stavudine (Zerit) are often associated with peripheral neuropathy, a nerve condition that causes pain, numbness, or tingling in the extremities. Since some classes of cancer drugs, specifically platinums (e.g., cisplatin, carboplatin), taxanes (such as paclitaxel (Taxol), Taxotere (docetaxel)), and vinca-alkaloids (e.g., vincristine (Oncovin), vinblastine (Velban)), may also cause peripheral neuropathy, the review authors recommended that physicians substitute a different chemotherapy drug with fewer overlapping side effects, substitute a different antiretroviral, or ask patients to temporarily discontinue antiretroviral therapy.

Some newer antiretrovirals may also cause problems when combined with chemotherapy drugs. The anti-HIV drugs Reyataz (atazanavir), Kaletra (lopinavir/ritonavir), and Invirase (saquinavir mesylate) are associated with longer QT intervals, a problem in which the heart takes an abnormally long time to recharge between beats.

Several anticancer drugs – including anthracyclines such as doxorubicin (Adriamycin) or daunorubicin (Cerubidine), arsenic trioxide (Trisenox), Sprycel (dasatinib), Tykerb (lapatinib), Tasigna (nilotinib), Sutent (sunitinib), and tamoxifen – are also linked with longer QT intervals. Because of the risk of sudden death associated with long QT intervals, the review authors recommended avoiding combinations of these drugs.

The authors noted that newer anticancer agents are more selective at killing cancer cells and may cause fewer side effects.

Interactions Between Anticancer Drugs And Antiretrovirals

Since antiretrovirals and chemotherapy drugs are often metabolized by the body in the same way, there is a high potential for drug-drug interactions. These may result in drug concentrations in the blood that are higher or lower than expected, leading to more side effects or reduced efficacy.

Since not many studies have been conducted on antiretroviral-chemotherapy drug interactions, scientists have tried to predict which drugs may interact based on what is known about how the drugs are metabolized.

In terms of antiretrovirals, the reviewers noted that Norvir (ritonavir)-boosted regimens may be of concern because Norvir is known to affect an enzyme that metabolizes many cancer drugs. Many physicians search for alternatives to Norvir-based regimens during chemotherapy.

Preliminary results from a study on Sutent presented this week at the American Society of Clinical Oncology meeting suggest that patients taking Norvir-based antiretroviral therapy may be more likely to experience side effects. The study, part of the AIDS Malignancy Consortium set of clinical trials, is one of the first to investigate drug-drug interactions for chemotherapy drugs and antiretrovirals.

For chemotherapy drugs, the reviewers suggested, based on drug interaction predictions, that anticancer drugs like camptothecins (e.g., Hycamtin (topotecan), irinotecan (Camptosar)), alkylating agents (such as melphalan (Alkeran), busulfan), corticosteroids (e.g., dexamethasone (Decadron), prednisone), epipodophyllotoxins (such as etoposide, Vumon (teniposide)), taxanes, tyrosine-kinase inhibitors (e.g., Gleevec (imatinib), Sutent), and vinca-alkaloids may be especially likely to be affected by HAART.

There is also some evidence from case studies that Targretin (bexarotene), cyclophosphamide (Cytoxan), Taxotere, irinotecan, and vinblastine might interact with antiretroviral drugs.

According to the review authors, there is currently no guidance for dose adjustments of antiretroviral or chemotherapy drugs, partly because patients with HIV were excluded from early cancer treatment trials. Although the exclusion of HIV patients from cancer treatment trials is no longer allowed, the study authors indicated that it may take several years before guidelines will be available.

The authors noted that maintenance of the chemotherapy dosing and schedule is thought to be most important in treating cancer, and therefore cancer treatment must sometimes take priority over HIV treatment, despite the risks associated with stopping HAART. However, they also stated that oncologists must recognize that continuous HAART is necessary to prevent resistant strains of HIV, opportunistic infections, and eventual death.

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