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.

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).

A review of Reyataz-related studies at a recent conference suggests that simplified two-drug regimens using Norvir-boosted Reyataz may be as effective as three-drug regimens in patients with well-controlled HIV infection.

According to the review authors, the findings are exciting since treatment simplification and fewer side effects are likely to improve adherence to antiretroviral therapy.

However, 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, warned that the results should be interpreted with caution.

“Based upon the results discussed here, and other data, I would suggest that such a [simplified two-drug] strategy is viable, but not necessarily supported by sufficient data to make it the standard of care,” said Dr. Daar. He added that this data could be used to justify larger randomized-controlled clinical trials to test the two-drug strategy further.

Reyataz (atazanavir) is a relatively new, once-daily protease inhibitor approved for HIV treatment by the U.S. Food and Drug Administration (FDA) in 2003. The U.S. Department of Health and Human Services treatment guidelines list Norvir (ritonavir)-boosted Reyataz plus Truvada (emtricitabine/tenofovir) as a preferred antiretroviral regimen for HIV-positive adults beginning treatment for the first time.

In this review, the authors discussed some of the most relevant recent findings related to Reyataz treatment 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).

Simplified Two-Drug Regimens Based On Norvir-Boosted Reyataz May Be As Effective As Three-Drug Regimens In Some Cases

Results from several studies showed that simplified two-drug regimens based on Norvir-boosted Reyataz were as safe and effective as three-drug regimens.

One small study evaluated the effect of simplifying antiretroviral regimens for HIV-positive adults with well-controlled viral load (amount of virus in the blood). Forty HIV-positive individuals with undetectable viral loads, and no known resistance to protease inhibitors or Epivir (lamivudine), participated in the study.

Participants switched from a regimen of Norvir-boosted Reyataz plus two nucleoside reverse transcriptase inhibitors (NRTIs) to a simplified regimen of Norvir-boosted Reyataz plus the NRTI Epivir. Results from the study suggested that the simplified treatment was safe, rarely resulted in virologic failure, and did not result in the development of drug resistance.

“The results are interesting but limited by the fact that it was a very select patient population, included relatively small [participant] numbers (n=40), and there was no control group,” said Dr. Daar.

“Nevertheless, the results are not surprising in light of other data showing that even Reyataz/Norvir alone in a related patient population was associated with low risk of virologic failure and lack of protease inhibitor resistance,” he added.

Another study showed that Reyataz plus Selzentry (maraviroc), a two-drug regimen, was as effective as Reyataz plus Truvada, which is a three-drug regimen.

Selzentry is a new type of antiretroviral drug approved for HIV treatment by the FDA in 2007. HIV requires the CCR5 protein, which is located on the surface of white blood cells, in order to attach to and infect these cells. Selzentry blocks CCR5, preventing HIV’s entry into the cells.

According to the review, a 48-week Phase 2 study compared the effectiveness of Selzentry plus Reyataz with Truvada plus Reyataz, both in treatment-naïve HIV-positive adults. Results from the study indicated that Selzentry-based treatment achieved viral suppression in a high proportion of patients (75 percent), with a comparable rate of side effects.

Reyataz May Suppress Viral Loads Better Than Prezista

Another study showed that Reyataz is as effective as Prezista (darunavir), another relatively new and commonly prescribed protease inhibitor.

Prezista was approved for by the FDA in 2006. Previous studies have shown that Prezista may have higher antiviral activity than Reyataz in the laboratory. According to the review, one study examined if this increased antiviral activity was associated with better viral suppression in previously untreated people with HIV.

Results showed that after a year of treatment, both regimens resulted in well-controlled viral loads, with all participants achieving viral loads of 200 copies per milliliter or less. However, Reyataz-treated individuals reached undetectable viral levels earlier and in greater proportion that people treated with Prezista.

The study authors concluded that the increased antiviral activity of Prezista did not result in a better clinical outcome than treatment with Reyataz.

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

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.

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.

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 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).

“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).

“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).