International AIDS Conference: Toronto
The 16th International AIDS Conference was held in Toronto, Canada in August 2006. Once a scientific meeting, over the years "big International" has been transformed into a massive, multi-faceted meeting encompassing nearly every aspect of the pandemic -- from sessions on reducing HIV stigma, marches in support of sex workers and needle exchange to star power press conferences by Bill Gates and Bill Clinton.
While not the hot bed of breaking science that it used to be, this year's conference had plenty to keep treatment activists busy. Project Inform posted quick breaking news items throughout the meeting. This article is an overview of some of the most interesting and important treatment focused presentations.
A few years ago, much of the excitement for new anti-HIV drugs focused on a new class of drugs called entry inhibitors. While there is still interest in these drugs, excitement is shifting to another new type, called integrase inhibitors. Integrase is a type of protein, called an enzyme, which HIV uses to mix its genetic material with a cell's own genes. While drugs targeting HIV's other major enzymes (reverse transcriptase and protease) have been available for years, developing a drug to work against integrase has proven a more daunting task. This appears to be changing, and rapidly.
MK-0518, being developed by Merck, is expected to be the first integrase inhibitor to go before the Food and Drug Administration (FDA) for approval. Merck presented data earlier in 2006 that showed remarkable results using MK-0518 in people who have previously used anti-HIV therapy (called treatment experienced people). There were two important developments related to MK-0518 in Toronto.
First, Merck presented data on MK-0518 use among people on anti-HIV therapy for the first time. They compared MK-0518 to Sustiva (efavirenz), both taken with Epivir (lamivudine, 3TC) and Viread (tenofovir). Similar proportions of people taking MK-0518 and Sustiva achieved undetectable viral loads. After 24 weeks about 80% of both groups had HIV levels below 50 copies.
What drew the attention of treatment activists and researchers was the speed at which people's viral load declined when taking MK-0518. After only four weeks, 60-78% (depending on dose) of people taking MK-0518 had HIV levels below 50 copies, compared to only about 20% of those on Sustiva. Similarly after eight weeks, 75-83% of people on MK-0518 had HIV levels below 50 copies, while only about 37% of people taking Sustiva did. By 24 weeks, however, the effects of the two different regimens were roughly the same, so the striking effect of MK-0518 was how quickly it reduced viral load to undetectable levels. It is too early to fully understand what this rapid reduction in viral load in people taking MK-0518 means. However, earlier studies have suggested a strong connection between how quickly HIV levels drop and how long lasting that response is.
The second development happened on the last day of the conference when Merck announced their plans to open an expanded access program (EAP) for MK-0518 within a few weeks. U.S. enrollment for the MK-0518 EAP has now opened. In order to qualify, people must have resistance to at least one drug from the NRTI, NNRTI and PI classes and be unable to fully suppress HIV replication on their current regimen. There are no CD4+ cell count or viral load requirements. For more information, please read our reporting.
Other Integrase Inhibitors
Two other companies that are developing integrase inhibitors made announcements in Toronto as well. Gilead Sciences reported a lack of drug interactions between their integrase inhibitor, GK-9137 (taken with a booster dose of Norvir [ritonavir]) and their two other anti-HIV drugs, Emtriva (emtricitibine, FTC) and Viread (tenofovir). This bodes well for a possible future fixed-dose combination pill of those three drugs.
GlaxoSmithKline and Shionogi announced completion of their phase I safety study of their joint venture in developing the integrase inhibitor, 364735. No data were presented, but the companies did report that the results allowed them to choose a dose to move forward with for their Phase II study, set to open later in 2006. The companies also announced they will present data from the Phase I study at an 'upcoming medical conference in 2007'.
Integrase inhibitors may be the subject of most of the buzz these days in anti-HIV drug development, but they are not the only ones expected to become available in the near future. The first oral entry inhibitor, a new NNRTI for people with resistance, and possibly one or two other new drugs are on the horizon. For quick notes on all of the experimental anti-HIV drugs in the pipeline, see Pipeline Update: Short Notes on New Anti-HIV Drugs in Development.
Maraviroc looks likely to be the first entry inhibitor pill to become widely available to people with HIV. While late 2005 saw a series of setbacks for this new class of anti-HIV drugs, maraviroc continues to move through the clinical studies process. The most interesting data were presented on the final day, during the 'late breaker' session.
Pfizer, developer of maraviroc, studied 186 people with dual tropic HIV -- meaning their HIV could use either of two major receptors (CCR5 or CXCR4) in order to enter a cell. (For more information on these receptors, read Project Inform's publication, Understanding HIV: CCR5 and Fusin.) HIV that uses CXCR4 is believed to be more aggressive and disease-causing than HIV that uses CCR5. People who have virus that uses both receptors are thought to be at particular risk for HIV disease progression.
Everyone in the study received what researchers believed was the best possible standard anti-HIV therapy. Additionally, one group was given a placebo and two other groups took one of two doses of maraviroc, given either once or twice daily. The main goal of the study was to see whether people taking maraviroc would experience any harm from blocking CCR5 and theoretically causing the more aggressive CXCR4 virus to dominate.
After 24 weeks, most people responded well to therapy, with no evidence of a harmful effect from blocking CCR5. The placebo group and the group taking maraviroc once daily had almost identical reductions in viral load of .91 log and .97 log respectively. The group on maraviroc twice daily fared a little better with 1.2 log reduction in viral load, but this was not statistically significant. The lack of strong response to maraviroc was somewhat disappointing, but the company was quick to point out that the study was not designed to measure the overall potency of maraviroc.
The one surprising finding was that the groups on maraviroc had larger increases in CD4+ cells (59 and 62 cells) than the placebo group (36 cells). This seems to have allayed fears that using the R5-blocking drug would cause a shift toward HIV that destroyed more CD4+ cells. Why this improved CD4+ response occurred in spite of the lack of a significant improvement in viral suppression over the placebo group is unclear. The numbers of people in studies is relatively small and the period of follow-up was only 24 weeks, so it is premature to say that this question has been fully answered.
Dr. Cal Cohen presented data on Tibotec's second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (formerly called TMC-125). The study, called TMC-215C223, compared two doses of etravirine (400mg and 800mg, both twice a day) together with a potent anti-HIV regimen (optimized background therapy) to a potent regimen that didn't include etravirine.
While most people (39 of 40) taking only the optimized background stopped during the study -- mostly due to increases in HIV levels while on therapy -- less than 10% of people on regimens with etravirine experienced rebounds in HIV levels. This is a hopeful finding.
Less impressive were the numbers of people able to achieve robust reductions in HIV levels. Among people taking 400mg of etravirine twice daily, only 23% had viral loads below 50 copies after 48 weeks. The higher dose group -- 800mg of etravirine twice a day -- had similar results, with 22% achieving viral suppression to below 50.
Digging a bit deeper it seems that people who had the least evidence of NNRTI resistance (fewer resistance mutations) had the largest drops in viral load. People with a single mutation taking the 800mg dose experienced an impressive 1.67 log reduction in HIV levels, while people with two mutations achieved a drop of 1.38 logs. People with more than three only experienced a modest 0.54 log drop. These results suggest that etravirine will be most useful for people with limited NNRTI experience and of less use for people with NNRTI resistance.
The company has chosen the 800mg twice daily dose with which to move forward. The company expects to file for approval for this drug sometime in 2007. It is available through an EAP now. For more information, read this information on the etravirine EAP.
In addition to the data presented on drugs we expect to see in the next year or so, research on experimental anti-HIV drugs deeper in the pipeline was also presented.
Data on another CCR5 inhibitor, called vicriviroc (by Schering-Plough), were presented. Roy Gulick, MD of Cornell University showed data from an AIDS Clinical Trials Group study, ACTG 5211, comparing three doses of vicriviroc (5, 10 and 15mg) to placebo in treatment experienced people. The 5mg arm of the study was stopped early due to poor results. The results for the other groups looked like this:
These results are encouraging for vicriviroc, but there are concerns as well. There were five cases of cancer among people in the vicriviroc groups compared to two in the placebo group. It is too early to know whether this is due to the drug or just from chance. Project Inform will watch this issue closely.
Robin Hardwicke presented data comparing Tanox' entry inhibitor TNX-355 + optimized background therapy to optimized background therapy alone. Compared to optimized background therapy alone, more people taking TNX-355 were able to reduce viral load by more than 1 log (35% vs. 11%). They also had greater increases in CD4+ cell counts (about 50 cells vs. 1). TNX -355 is a monoclonal antibody that blocks HIV from connecting to CD4+ cells. It is delivered by intravenous infusion twice per month. While IV infusion may seem burdensome, the fact that it is given only twice a month makes it seem more reasonable.
Compared to the results seen lately with Prezista (darunavir) and MK-0518, the results seen with TNX-355 are only modest. However, this represents a new approach to battling HIV (see Pipeline Update: Short Notes on New Anti-HIV Drugs in Development) and in that context, the results are encouraging. Concerns about the way it is given (IV infusion every two weeks) and eventual cost have some activists openly questioning the role of this drug. The data presented here in Toronto did little to change the somewhat murky picture for TNX-355.
Beyond the pipeline of drugs in human studies, there was interesting information on new drug targets. One such presentation was on APOBEC3G. APOBEC3G is a powerful anti-HIV enzyme that naturally occurs in human cells. Over the past few years, scientists have studied this enzyme, trying both to understand how it works and, perhaps more importantly, how HIV overcomes it. Warner Green of the Gladstone Institute for Virology discussed research on this subject done by his group.
Again, APOBEC3G is a factor inside of cells that has anti-HIV activity. Researchers have found that an HIV gene product called Vif interferes with APOBEC3G in two ways. First, Vif binds to APOBEC3G resulting in the cell breaking the factor down and rendering it inactive against HIV. Second, Vif signals the cell to produce less APOBEC3G -- a process called down-regulation. The combined effect is the almost total depletion of APOBEC3G from cells. Finding ways to interfere with the interaction between Vif and APOBEC3G is an attractive target for anti-HIV drug development. If you can keep Vif from attaching to the natural anti-HIV enzyme APOBECG3, it should be able to persist at high enough levels in the cell to block the virus.
The conference also featured some noteworthy presentations on existing, approved anti-HIV drugs. Here are some highlights.
One interesting study compared a regimen with the GlaxoSmithKline protease inhibitor, Lexiva (fosamprenavir/ritonavir), to the "gold standard" regimen with Kaletra (lopinavir/ritonavir) from Abbott Labs. Regimens with Kaletra are one of only two first line anti-HIV regimens highly recommended by the Federal Guidelines. (The other is a regimen with Sustiva.) While there is little doubt that the Kaletra regimen is both highly potent and very durable, it has not been directly compared to a number of other regimens.
The study included 878 people taking either Kaletra or Lexiva, with Epzicom. (Epzicom is a tablet of Epivir + Ziagen [abacavir].) People who experienced an allergic reaction to Ziagen (about 6%) were allowed to switch to a different drug.
After 48 weeks, the percent of people who had undetectable HIV levels (under 50 copies) was virtually identical in the two groups, though a slightly higher percent of those taking Lexiva had viral loads below 400 copies. Average gain in CD4+ cell counts was also similar, with the Lexiva group gaining 176 cells and the Kaletra group gaining 191. Drug-related side effects were similar for both, as was the number of people who stopped therapy due to side effects.
The importance of this study for people just starting therapy is that Lexiva represents a third reasonable alternative to the highly recommended therapy options, giving people greater choice. However, it will take some time before this finding is reflected in the Federal Guidelines.
The overall significance of this study is somewhat moderated by another study that compared a similar Kaletra regimen to a Sustiva regimen. Researchers compared the two regimens most highly recommended in the Federal Guidelines (explained above), both taken with two NRTIs. The study also included a group taking only a combination of the two drugs, Kaletra + Sustiva, without any NRTIs.
The study followed 753 volunteers for an average of 112 weeks. At the end, there was no statistically significant difference in viral load among the three groups. However, there was a clear trend favoring Sustiva + two NRTIs and Sustiva + Kaletra as compared to Kaletra + two NRTIs. The Kaletra + NRTIs arm showed a shorter time to rebounds in HIV levels, which was a surprise to many. However, since the finding was not statistically significant, it is difficult to say just how important the observation is and whether it should affect treatment decisions.
Perhaps the most important finding of the study was that the group on Sustiva + Kaletra performed at least as well as the best conventional arm (Sustiva + two NRTIs). There is a growing interest among people with HIV, doctors and researchers in finding regimens that do not require people to take two NRTIs. Since 1996, nearly all regimens have included two NRTIs. Findings over the last several years have raised concerns over the toxicity of these drugs, and some researchers and activists believe people might fare better without them.
The combination of Sustiva + Kaletra points the way toward regimens that are highly potent and durable without using NRTIs. We believe this kind of research will eventually lead to widespread use of two-drug regimens and perhaps even one-drug regimens that work as well as today's three-drug combinations, but hopefully with fewer side effects.
Monotherapy (an anti-HIV drug regimen of one drug) was once among the most feared words in anti-HIV therapy. Now, it is making a bit of a comeback.
Spurred by a small study by Dr. Joe Gathe that showed surprisingly good results using the anti-HIV drug Kaletra alone, scientists have been re-examining the current three-or-more drug rule. Two presentations in Toronto highlight further research on this topic.
The 96-week MONARK study compares a relatively small group of people (136) taking Kaletra + Combivir (a pill of Epivir + Retrovir [AZT , zidovudine]) to people on Kaletra alone. Using a conservative analysis (called intent-to-treat) after 48 weeks of follow-up, 71% of people taking Kaletra monotherapy had viral load below 50 copies, compared to 75% of those on Kaletra + Combivir.
A much bigger difference was seen when just looking at people still in the study at 48 weeks (called as-treated). Looked at this way, 84% of people on Kaletra alone had viral loads below 50 copies, while 98% of people on the Kaletra + Combivir combination had HIV levels below 50. This suggests that when people are able to tolerate three-drug combinations, they may be more likely to achieve undetectable viral loads with the current three-drug approach than this experimental one-drug approach. However, for those who can't tolerate and/or aren't able to access three drugs, Kaletra monotherapy might offer an alternative.
There are two ways to interpret these results. One way is to look at the somewhat better results for people taking the traditional three-drug combination, and conclude that this tried-and-true method is superior. Another way is to see that by either analysis, most people taking Kaletra alone were able to achieve and maintain undetectable viral loads.
The lead investigator of this study claimed that everyone taking Kaletra alone who started the study with less than 100,000 copies of virus achieved viral load under 50 copies at 48 weeks. This suggests that a person's initial viral load before starting treatment may be an important factor in determining whether it is safe to use monotherapy. However, this needs to be confirmed in larger and longer studies.
In another study, people with undetectable viral loads taking a three-drug combination of Kaletra + two NRTIs were randomized either to stick with their three-drug combination or switch to a maintenance regimen of Kaletra alone. This approach to therapy is frequently called an "induction/maintenance strategy" or a detensification strategy. After 48 weeks, 85% of people taking Kaletra alone maintained viral loads below 50 compared to 90% of people taking Kaletra + two NRTIs. The difference was not considered statistically significant.
There are four important reasons to continue looking at reducing the number of drugs people with HIV must take. The first is long-term side effects. Hopefully by reducing the number of drugs people take, the less long-term, accumulated toxicity will result. Second, fewer drugs in a regimen could lead to more regimens available to people over the course of their lives. Third, fewer pills are simply easier to take. Fourth, taking fewer drugs can greatly reduce the cost of therapy. In the international setting, this reduced cost could result in a much greater number of people being treated.
While these monotherapy reports look encouraging, people should not rush to stop combination therapy or de-intensify their regimens. Lessons learned from other research on simplifying regimens showed us that short-term success fell apart over the long-term and many who acted on early data risked developing resistance. This is definitely important research to follow, but it's likely too soon to start making changes in therapy based on these results.
The results of these two studies are encouraging and argue for more research on simpler anti-HIV drug regimens. Earlier in 2006, preliminary findings were presented on monotherapy using another boosted protease inhibitor, Reyataz (atazanavir). For a drug to be a good candidate for monotherapy it must be potent and be difficult for HIV to develop resistance to. Such drugs are said to have a high genetic barrier to resistance, which means HIV must acquire a number of mutations before it shows resistance to a drug. Currently, only boosted PIs meet these criteria (like Kaletra), but novel drug targets, like integrase inhibitors, might offer more potential for this approach down the line.
The 2006 International AIDS Conference in Toronto is unlikely to be remembered for any major scientific breakthroughs or advances. The enormity of the pandemic was evidenced by both the number of delegates -- over 30,000 -- and the scope of work they represented. As we begin to look past the 25-year anniversary of the pandemic, there is much to be hopeful for. New drugs and new ways of using old drugs are on the way. Basic science on HIV drugs and HIV disease, continues to expand our understanding of the disease, moving us closer each day to our ultimate goal -- a cure for HIV/AIDS.
This article was provided by Project Inform. It is a part of the publication Project Inform Perspective. Visit Project Inform's website to find out more about their activities, publications and services.