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Update on Experimental Antiretrovirals

October 2007

Researchers, doctors and treatment activists often use the term pipeline to refer to the collection of all experimental HIV drugs currently being developed. The 2007 Conference on Retroviruses and Opportunistic Infections (CROI), held in Los Angeles and the International AIDS Society Conference on HIV Pathogenesis Treatment and Prevention (IAS), held in Sydney, Australia, were full of presentations on drugs currently moving through this pipeline. This article reviews some of the most important or interesting presentations in the antiretroviral pipeline.

First Up Selzentry (Maraviroc)

Selzentry became the first oral entry inhibitor approved to treat HIV. Selzentry tries to block HIV by attaching to a receptor, called CCR5, or simply R5, which HIV often uses to gain entry into cells. In addition to being the fist drug in its class -- referred to as R5 antagonists -- it is also the first HIV drug which targets a part of an immune system cell rather than the virus.

Selzentry at CROI

Researchers presented data from the pivotal phase II/III studies of Selzentry during the late breaker session at CROI. The studies, called MOTIVATE 1 and 2, looked at Selzentry in people with extensive HIV treatment experience. Both studies compared Selzentry, taken either once or twice a day, to a placebo. Everyone in the study also took a combination of additional HIV drugs, selected by resistance testing, which is called optimized background therapy (OBT).

After 24 weeks, close to twice as many people -- around 60% vs. 30% -- taking either dose of Selzentry had HIV levels below 400 copies/mL. Not surprisingly, the more active drugs people had in their OBT, the more likely they were to reduce HIV levels to undetectable levels. When people had only one other active drug in their regimen, only 9% of people on placebo reached undetectable levels of HIV, compared to 43% taking Selzentry. If people had two other active drugs, there was a similarly large difference: 19% vs. 52%. When people took three or more other active HIV drugs, there wasn't a big difference between the Selzentry and placebo groups.

One of the most important questions about Selzentry (and other R5 inhibitors) revolves around something called tropism. This refers to which receptors HIV uses to gain entry to a cell. All versions of HIV use the CD4 receptor. But HIV also uses either R5, another receptor called CXCR4 (X4), or both. It has been noted that about half of people's HIV will shift from using mostly R5 to mostly X4 in later stage, more aggressive HIV disease. This has led some to think of X4 HIV as stronger, or more virulent, than R5 HIV which is much more common in earlier disease. But nobody really knows whether the emergence of X4 virus in later HIV and more aggressive disease is a cause of disease progression or a consequence of it.

Activists and researchers have been concerned that blocking HIV from using the R5 receptor might result in HIV shifting to use X4, and possibly bring on a more aggressive form of the disease. Researchers in the Selzentry studies used a test called the Trofile assay to make sure that all study volunteers had R5 tropic virus (HIV that uses only R5) at the beginning of the study. At the study's conclusion, it was found that about 2/3 of the people who failed treatment despite receiving Selzentry had shifted to either X4 only or to a virus that can use both (dual tropic) or a mixed population (mixed tropic). Most often the shift was to either dual or mixed tropic HIV. However, this tropism shift did not seem to result in rapid disease progression, which is the greatest concern. More long-term follow up on people who fail on Selzentry is planned.

There were similar levels of side effects for people taking Selzentry and those taking the placebo, with no signs of any serious drug-specific adverse effects. This will need to be validated by more long-term follow up.

Selzentry at IAS

A study presented during the late-breaker session at the 4th IAS Conference showed that the Selzentry was slightly less effective than Sustiva (efavirenz) when used as part of a HAART regimen for people taking HIV drugs for the first time.

The MERIT study looked at over 700 people with R5-only HIV who had never taken anti-HIV drugs. People were randomly assigned to take either 300mg of Selzentry twice a day or 600mg of Sustiva once a day. Everyone in the study also took Combivir (AZT + 3TC). A once-a-day Selzentry arm was stopped early, due to poor results.

After 48 weeks of the study, similar numbers of people in both arms had stopped taking their combination, but for different reasons. Almost three times as many people taking Selzentry dropped out due to treatment failure. More people in the Sustiva group stopped due to intolerance -- mostly neuropsychological side effects associated with Sustiva.

Nearly 70% of people taking Sustiva had HIV levels below 50 copies vs. 64% of people taking Selzentry. Surprisingly, this difference was only seen among people in the study from the southern hemisphere. There were several reasons hypothesized for this difference -- different types (clades) of HIV or problems with the R5 screening test -- but this finding remains unexplained.

Another somewhat surprising finding was that the people taking Selzentry experienced larger increases in CD4 counts -- an average of 169 cells vs. 142. The difference happened mostly in the first 8 weeks of the study. This is consistent with other research on Selzentry and other R5 drugs. For example, a study presented at last year's International AIDS Conference in Toronto found larger gains in CD4 cells among people with X4 or dual/mixed HIV who were taking Selzentry, despite no effect of HIV levels. Some have speculated that this is due to the movement of CD4 cells out of lymph nodes rather than a real increase in the number of cells. Others think this drug might have affects on the immune system independent of reducing HIV levels. More research is needed to understand this important issue.

The differences seen between Selzentry and Sustiva in this study were small, but it must still be seen as a setback. The FDA approved Selzentry for people with extensive treatment experience soon. Only about half of treatment experienced people have R5-only HIV, vs. around four in five people who have never taken HIV drugs. Many people think this makes Selzentry (and other drugs that target CCR5) a more appropriate option for people as first or second line therapy. This study does not rule out Selzentry for first line therapy, but its failure to match up to Sustiva -- one of the most widely used first line drugs -- casts a shadow for sure. However, a better understanding of the difference seen between people in the northern and southern hemispheres may change this perception. Additionally, some people may give greater weight to the lower toxicity levels seen with Selzentry and not base their treatment decisions solely on viral load.

There are two outstanding issues about Selzentry. The first is the Trofile test. The test is now required for anyone wanting to start taking Selzentry, since there is no point in using Selzentry in people who have X4 virus. The test is very expensive (well over $1,000) and it is unclear who is going to pay for it. There will be a three-week turn around time for this test as well.
The second issue is the concern that some have over the drug's mechanism. As mentioned this will be the first HIV drug ever to target a component of the immune system, rather than HIV itself. Targeting cell receptors has been done in other diseases, most notably cancer, but it not very well studied. Because the functions of the R5 receptor may not be fully understood, some doctors and others are concerned that targeting it might have unintended consequences. These concerns are reasonable, but there haven't been any signals of such trouble from the clinical trials of Selzentry so far.

The FDA approved Selzentry in August and it arrived in pharmacies in mid September. As expected the drug is approved for use by people with R5 HIV and experience taking HIV drugs.

Isentress (Raltegravir): A New Benchmark?

Isentress at CROI

Following closely behind Selzentry is another entirely new kind of HIV drug called Isentress (raltegravir, MK-0518). Isentress is expected to become the first integrase inhibitor (II) to gain FDA approval. Integrase is an enzyme that is required for HIV to mix its genetic information (called pro-viral DNA) with the DNA inside the nucleus of a cell.

Data from two large studies of Isentress were presented during the CROI late breakers. These studies, called BENCHMRK 1 and 2, were similar in design to the Selzentry studies mentioned before. Researchers compared people taking Isentress to people taking a placebo -- with both groups taking optimized background therapy (OBT) as well. The people enrolled in these studies had extensive experience with HIV drugs and were required to have developed resistance to all three prior classes of drugs. On the whole, they were a somewhat more treatment-experienced group that those in the Selzentry studies.

After 24 weeks, 77% of people taking Isentress had HIV levels below 400 copies/mL, compared to 41-43% of people taking the placebo. The same was seen with a stricter measure -- HIV levels below 50 copies/mL -- with around 60% for people taking Isentress vs. 33-36% for people taking the placebo.

The researchers looked at how both Fuzeon (enfuvirtide, T20) and Prezista (darunavir) contributed to the outcomes. When people were taking Isentress plus both Fuzeon and Prezista, a remarkable 98% had HIV levels below 400, compared to 87% of people taking the placebo. When they were using either Fuzeon or Prezista, but not the other, still 90% had HIV levels below 400 vs. 55-63% taking the placebo. The biggest difference was seen in people who were taking neither Prezista nor Fuzeon, where 74% or people taking Isentress had HIV levels below 400 compared to only 29% on placebo.

Significantly fewer people (16% vs. 51%) taking Isentress had virus level rebound during study. Two resistance mutations were observed in most of the people who had HIV levels rise while taking Isentress. There was no difference in the rates or types of side effects or lab abnormalities seen in people taking Isentress compared to those on placebo.

Results like this have never been seen in studies looking at heavily treated people with virus resistant to multiple types of drugs. For comparison, in a similar study of the protease inhibitor Aptivus (tipranavir), only around 1/3 of people taking the drug had undetectable HIV levels after 24 weeks (compared to 1/5 of people taking other protease inhibitors). Results this remarkable are bound to change the expectations for treating drug-resistant HIV infection.

Isentress at IAS

There were two important presentations of Isentress at IAS, both from the same study. The study presented had two parts. In the fist part, 40 people who had never taken anti-HIV drugs were randomized into 5 groups. For the fist 10 days, people took either one of four doses of Isentress (100, 200, 400 or 600mg, twice a day) or a placebo alone (called monotherapy). People in all of the Isentress dosing arms had significant reductions in HIV levels, averaging around 2.2 logs, or about a 99.8% reduction in HIV levels.

In second phase, about 200 people were again randomized into five groups. In each group, 40 people took one of the four doses of Isentress, or the NNRTI Sustiva. Everyone also took Epivir (lamivudine, 3TC) and Viread (tenofovir). Data from this 24-week study were presented at last year's International AIDS Conference, which showed that people in each of the Isentress arms had faster reductions in HIV levels compared to those on Sustiva. Eventually the number of people in all arms of the study with HIV levels below 50 copies was similar in all groups.

The 48-week data presented here in Sydney was similar to what was seen earlier. Follow-up data were also shown here that Isentress had little to no effect on levels of cholesterol and triglycerides, when compared to Sustiva. There were six treatment failures in this study, five in people taking Isentress and one taking Sustiva. Among the five who were taking Isentress, two had mutations which are known to reduce HIV's susceptibility to Isentress. The others showed resistance mutations to the other drugs in the study, mostly the M184V mutation associated with resistance to Epivir.

The other presentation on Isentress concerned something called second phase viral decay. In most studies of HIV drugs, two distinct periods or phases of reductions in HIV levels have been observed. An initial steep decline, called fist phase viral decay, is usually followed by a more gradual decline, called second phase viral decay. Data were presented here that showed that in addition to reducing HIV levels faster than Sustiva, Isentress also reduces HIV levels more robustly in the second phase. It is not known what affect this difference will make, but it will be followed closely.

The excitement surrounding Isentress was illustrated well in an earlier presentation, when audience members were asked to choose what new and existing drugs they would choose for a person whose current regimen was failing. Isentress was the most often picked, followed by Prezista. Unlike Selzentry, which will only work for people with R5-only HIV and requires a screening test, almost anyone will be able to use Isentress when it becomes available. It represents an entirely new mechanism of action, so pre-existing resistance will not be an issue. It appears well tolerated and effective, both in treatment experienced people and now in people taking HIV drugs for the first time as well.

As reported here, in September the antiviral advisory committee of the FDA unanimously recommended accelerated approval for Isentress. While not required to the FDA usually follows the committee's recommendations. A ruling from the FDA is expected in October.

Elvitegravir (GS-9137)

Elvitegravir (GS-9137) is an experimental integrase inhibitor being developed by Gilead. Unlike Isentress, elvitegravir requires a booster dose of Norvir (ritonavir). It is being studied in combination with boosted protease inhibitors in treatment experienced people.

Elvitegravir at CROI

There were two presentations on elvitegravir at CROI. The first presentation was on a study comparing ten days of elvitegravir monotherapy to boosted protease inhibitors. Everyone in the study had documented resistance to at least on protease inhibitor. People were randomly chosen to take one of two doses (50, 125mg) of elvitegravir once daily, or a boosted protease inhibitor. Everyone also took two NRTIS. After 24 weeks, people taking 25mg of elvitegravir averaged a l.7 log reduction compared to 1.2 logs for people taking a PI. More people stopped the study due to adverse side effects in the PI group, compared to the elvitegravir groups.

The second presentation examined the development of resistance to elvitegravir. In a lab, samples of HIV were exposed to different concentrations of elvitegravir until resistance developed. Two distinct mutations developed leading to varying levels of resistance. Somewhat of a surprise was that when the researchers exposed the resistant HIV to two other integrase inhibitors, the HIV remained fully susceptible to the other drugs. Earlier research has suggested that HIV that grows resistant to Isentress will be resistant to elvitegravir. This study suggests that HIV which develops resistance to elvitegravir might remain sensitive to Isentress. More research is needed to further understand this issue.

Elvitegravir at IAS

There was one presentation on elvitegravir at IAS. The study looked at three doses of elvitegravir (20, 50 and 125mg) taken with 100mg of Norvir (ritonavir), compared to Norvir-boosted protease inhibitors. Everyone in the study also took OBT. At the beginning of the study, Prezista and Aptivus were not allowed. They were allowed later, once drug interactions were understood.

The results were mixed. The lowest dose group in the study was stopped early, due to poor results. Everyone in that group was offered the 125mg dose, in an open label (they know what they are taking) rollover study. After 16 weeks, people taking 125mg of elvitegravir had an average drop in HIV levels of 1.7 logs (~97%) vs. 1.2 logs (92%) for the comparator protease inhibitors. Around 40% of people taking elvitegravir were able to reduce HIV levels below 50 copies. This compares to 40-49% in the studies of Selzentry and over 60% in the Isentress studies.

Elvitegravir requires a low dose of Norvir as a booster. This is similar to most protease inhibitors, especially when used by people with extensive HIV treatment experience. It is the first non-protease inhibitor to require a boost. This means that it will probably need to be used alongside a boosted protease inhibitor, and only by people with extensive treatment experience.


Following Selzentry and Isentress, the next new HIV drug likely to be evaluated by the FDA is etravirine (TMC-125). Etravirine is a non nucleoside reverse transcriptase inhibitor (NNRTI). This class of HIV drugs includes Sustiva (efavirenz), Viramune (nevirapine) and the seldom used Rescriptor (delavirdine). The importance of etravirine is that it can work against HIV that has grown resistant to the older NNRTIs. When HIV develops resistance to one drug, it can sometimes also become resistant to other drugs from the same class. This is called cross resistance. The three currently approved NNRTIs are highly cross-resistant. This means that most people have one chance at this important class of drugs, as HIV that is resistant to one NNRTI is highly likely to be equally resistant to the others. Etravirine is different. It was designed to overcome resistance to other NNRTIs.
Pivotal data were presented on the experimental NNRTI etravirine (TMC-125) at the 4th IAS Conference. The DUET-1 and DUET-2 trials compared etravirine to a placebo in people with extensive experience taking HIV drugs and documented resistance to NNRTIs. Everyone in the study took a background combination of anti-HIV drugs contaning Prezista.

After 48 weeks significantly more people taking etravirine in both studies had HIV levels below 50 copies. In DUET 1, 56% of people taking etravirine had HIV levels below 50 copies compared to 39% of people taking the placebo (62% vs. 44% in DUET 2). On average people taking etravirine experienced reductions in HIV levels or around 2.3-2.4 logs, compared to 1.7 logs for people taking the placebo. CD4 cell counts rose on average of 78-89 for people taking etravirine, compared to 64-66 for people in taking the placebo.

Not surprisingly the more active drugs that people were taking in the study, the better their results. People who had no additional active drugs in their regimen, 44-47% taking etravirine had HIV levels below 50 copies, compared to 7-9% on the placebo. The difference grew smaller as more active drugs were available, but etravirine still appeared to add benefit.
Etravirine also appears to work best against HIV that has fewer NNRTI associated mutations. If one or fewer NNRTI mutations were detected at baseline, 60-75% of people taking etravirine achieve HIV levels below 50 copies. If three NNRTI mutations were present, that number dropped to 45%; with 4 down to 25%. When five NNRTI mutations were detected, only 15% of people reached HIV levels below 50 copies.

The most common side effect associated with etravirine in the DUET studies was rash, which occurred in about 17% of people in the two studies. Most rashes were mild to moderate, and rarely (2%) led people to stop taking their treatment. Rash was more common in women, but no association with CD4 count was seen. These are promising results for people who can no longer take NNRTIs due to resistance.

Rilpivarine (TMC-278)

In contrast to etravirine, which is aimed at people who have failed on another NNRTI, rilpivarine (TMC-278) is being studied as an alternative to Sustiva and Viramune (nevirapine) for first line NNRTI use. It also works against HIV that is resistant to the older NNRTIs. However, it is highly cross-resistant with etravirine.

There was a significant presentation on rilpivarine (TMC-278) at CROI. A study compared three doses of rilpivarine (25, 75 and 150mg, all once a day) to Sustiva, along with two NRTIs [usually Truvada (emtricitibine + tenofovir)] in people taking HIV drugs for the first time. After 48 weeks, similar reductions in HIV levels were seen in people taking all three doses compared to Sustiva. On average, around 80% of people had HIV levels below 50 copies. There were similar numbers of adverse events in all groups in the study, with fewer rashes and central nervous system side effects reported by people taking rilpivarine compared to Sustiva.

At IAS, data were also presented on the affect of rilpivarine on cholesterol and triglycerides. The study compared one group of people taking one of three doses of rilpivarine to another taking the NNRTI, Sustiva. Everyone in the study was also taking 2 NRTIs -- mostly Retrovir (zidovudine, ATZ) or Viread plus either Epivir or Emtriva (emtricitibine, FTC).

After 48 weeks, people taking rilpivarine saw no significant changes in total cholesterol, HDL, LDL, HDL to LDL ratio or triglycerides. People taking Sustiva experienced elevations in total cholesterol, HDL, LDL and triglycerides. No data were presented on body shape changes or other metabolic measures. However, the lack of effect of rilpivarine on metabolic parameters seen in this study is a hopeful development.

The data presented here are a small part of the picture for this drug, which will need to show that it is as potent and durable as Sustiva as well. After many years without any successful new drug development in this important class, the development of etravirine and rilpivarine are welcome. A couple of other new NNRTIs are also being studied in pre-clinical settings.

UK-453,061: Another New NNRTI

Preliminary data were presented on UK-453,061, an experimental NNRTI, at IAS. The compound is being developed by Pfizer and does not appear to be cross-resistant with the currently available NNRTIs like Sustiva and Viramune.

A short-term, dose-ranging monotherapy study followed 48 people who were randomly assigned to take one of seven different doses of UK-453,061 or a placebo for 7 days. HIV levels were checked daily for the first week and 6 additional times within 40 days. Drug levels were also measured one day after the last dose.

HIV levels dropped the most in people who received 500mg twice a day or 750mg once a day -- 1.62 and 1.79 logs respectively. HIV levels began to rise around three days after the last dose of drug was given, returning to baseline after around 20 days. There were few side effects reported in the study. Of particular note was the lack of rash seen in the study -- a side effect seen with all other NNRTIs to date. More studies of these two doses are planned.

These data are hopeful but very preliminary. The NNRTI class is widely used, but all of the current drugs have significant drawbacks. Alongside the Tibotec drugs etravirine (TMC-125) and rilpivarine (TMC-278), Pfizer's UK-453,061 offers a renewed sense of optimism for this crucial class of anti-HIV drugs.

Old Targets: NRTIs and PIs

While not generating the kind of excitement that the novel targets garnered, there were some presentations on new drugs from the nucleoside analogue reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI) classes that were also of note. Although these drugs don't have close to the potential to shift the way HIV is treated that the integrase and entry inhibitors might, the developments remain important as people continue to need options in these well understood groups of HIV drugs.

There was a presentation about an NRTI called racivir (PSI 5004), being developed for people who have developed resistance to Epivir or Emtriva Everyone in the study was on a failing drug regimen with Epivir, with a specific drug resistance mutation called M184V. A total of 26 people were randomized to switch to racivir while 16 stayed on Epivir. After 28 days, people taking racivir had their viral loads reduced by an average of .4 logs, compared to the people who stayed on Epivir whose viral load went up an average of .13 log. These results just border on being useful and it's possible they could be improved with more knowledge of the ideal dose. There was also a poster presentation on another novel NRTI called nikivir, which is being developed in Russia. The data were from lab studies, so it is too early to know if this will be a viable drug.


Results from a small phase II study of the experimental NRTI apricitabine were presented at the IAS conference. Apricitabine is designed to work against HIV that harbors a genetic mutation- called M184V- that is associated with resistance to the two NRTIs, Epivir and Emtriva. This drug-resistance mutation is common; effective alternatives for people with this form of resistance are greatly needed.

The double blind study compared two different doses of apricitabine (600 and 800mg, both twice a day) to 150mg of Epivir, twice a day, in people on failing regimens with Epivir. People were randomized either to add one of the two doses of apricitabine, or continue to take Epivir. After 21 days of functional monotherapy, people would switch to the best available combination of anti-HIV drugs, which could not contain either Epivir or Emtriva.

Data were presented from the 21-day, functional monotherapy phase of the study. People taking both doses of apricitabine experienced more significant declines in HIV levels, compared to those taking Epivir. People taking 600mg of apricitabine averaged a .9 log drop in HIV levels, while people taking 800mg had a drop of around .7 logs. Not surprisingly, people who continued to take Epivir had almost no decrease in HIV levels. There were no serious side effects seen in the study, and no new resistance was detected during this 21-day period. The longer term, second phase of the study is ongoing.

NRTIs are the oldest and most studied type of HIV drug. They are also considered to be the least potent. Historically they have played a supporting role in HIV drug therapy, due at least in part to the lack of alternatives. As more classes of HIV drugs become available, the role of this class of drugs is beginning to be scrutinized. More research is necessary before significant changes to the current structure of HAART are undertaken. For now, a new NRTI that will work against HIV that is resistant to the widely used drugs Epivir and Emtriva is welcome.

Genetic Testing and Ziagen

Results presented at IAS Conference confirmed and earlier finding that a simple screening test can be used to predict whether people are at risk for a serious allergic reaction to the anti-HIV drug Ziagen (abacavir). Ziagen is a component of the two fixed-dose combination pills, Epzicom (abacavir + lamivudine) and Trizivir (abacavir + lamivudine + zidovudine).

Results from earlier research as well as clinical practice have shown that between 5-8% of people will have a serious allergy to abacavir. This is called an abacavir hypersensitivity reaction or HSR. Symptoms of abacavir HSR include rash, fever, gastrointestinal upset and malaise. They can range from mild to severe, usually worsen with time and can become serious or fatal, especially if the drug is stopped and restarted.

Previous retrospective studies have shown that people with a genetic variation, called HLA-B5701, were more likely to have this reaction to abacavir. The PREDICT-1 study randomized almost 2,000 people to either take or not take the screening test before starting a HAART regimen with Ziagen. People who tested positive on the screening test were not started on abacavir. Those who tested negative or who didn't take the screening test started HAART regimens that contained abacavir. Suspected cases of abacavir HSR were confirmed using a skin patch test.

Researchers compared the rates of both suspected and confirmed abacavir HSR in people who took the screening test (who tested negative for HLA-B5701) and people who didn't get the test. Almost 8% of people who did not take the screening test had suspected abacavir HSR, compared to 3.4% of people who were given the screening test. More importantly, no one given the screening test had a confirmed case of abacavir HSR compared to around 3% of people who didn't get the test.

It is important to point out that 84% of the people in this study were Caucasian. Research shows that the HLA-B5701 variation is most common among Caucasians. Clinicians have widely reported lower rates of abacavir HSR among people of African and Hispanic origin. Results from a retrospective analysis of HLA testing, called the SHAPE study, found it to be an effective screening tool for people of Asian and Latin ancestry. The sample size of people of African descent was too small to determine the usefulness of HLA testing for this group.

This study has two important implications. First, it shows that HLA screening is very effective at predicting people's risk of abacavir HSR. Secondly it suggests that abacavir HSR is probably over-diagnosed. Use of HLA testing might allow for greater confidence in using abacavir as part of a HAART regimen. This is particularly important as abacavir is considered by most to be one of the most potent NRTIs, along with Viread, and fear of HSR has been a main reason for many people avoiding its use.

Protease Inhibitors

The only new PIs that were presented at CROI were pre-clinical. A poster presentation was made on a compound from Gilead called GS-874 that showed it had a high genetic barrier to resistance and might have less impact on fats and other metabolic markers than other PIs. However, Gilead has since dropped plans for any further development of the GS-874. The other drug was GRL-98065, which shows activity against HIV with a high level of resistance to other PIs.

Comparing Prezista Against Kaletra

At IAS, Dr. Valdez-Madruga presented groundbreaking data comparing the protease inhibitor Prezista (darunavir) to Kaletra (lopinavir + ritonavir) in people with extensive treatment experience. After 48 weeks, a significantly higher percentage of people taking Prezista (77-67%) had HIV levels below 500 copies. The same was true when looking at the percentages below 50 copies, with 71% of people taking Prezista compared to 60% of people taking Kaletra achieving these very low virus levels. On average people taking Prezista experienced 30% greater reductions in HIV levels as well. More people taking Kaletra experienced virologic failure compared to Prezista. (Virologic failure is defined as either never achieving HIV levels below 400 copies, or having HIV levels rebound after being suppressed.) Increases in CD4 T cell counts were similar between groups.
The side effect profiles looked somewhat different as well. More people taking Kaletra (42% vs. 32%), had diarrhea, while rash was more common among people taking Prezista. Most of the adverse events in the study were mild to moderate, and few led people to leave the study.

This study is groundbreaking because it is the first head-to-head study of any protease inhibitor compared to Kaletra in which the PI being studied was proven superior to Kaletra. Kaletra has been a preferred PI for some time, due both to impressive durability and an extensive track record in research and clinical practice. Over the past few years, several companies have conducted trials of their own competitor PIs, and been able to show that they were non-inferior. In basic terms, proving non-inferiority means that the two drugs are more or less equivalent.

Proving superiority to Kaletra had never been achieved. Approved in late 2006, Prezista has thus far shown itself to be a potent and effective option for people with drug-resistant HIV. Studies are underway looking at Prezista in people taking HIV drugs for the first time, which are also head-to-head comparisons to Kaletra.

The PI that is garnering the most attention right now is called PPL-100. It merits attention because it is the first new PI in a long time that does not require Norvir boosting. Merck recently bought this compound for development. There were no data presented on it at CROI, but we will continue to follow the development of this drug closely.

Other Drugs in the Pipeline

Uncertainty for Vicriviroc

There was a presentation on Schering's CCR5 antagonist vicriviroc (Schering D) at IAS. In this study, 118 people on a failing HIV drug regimen who were shown to have R5-only HIV were randomized to take one of three doses (5, 10 or 15mg) once a day of vicriviroc or a placebo plus the best combination of ARV available to them. The 5mg arm of this study was stopped early, due to high levels of virologic failure. People in both the 10 and 15mg arms had sustained reductions in HIV levels after 48 weeks of therapy, averaging over a l.5 log reduction.

However, only around a third of people taking vicriviroc in this study achieved viral loads below 50 copies. While this is higher than the 10% taking the placebo, the result is mediocre. Also of some concern is that around 15% of people taking vicriviroc saw their HIV switch from R5-only to X4 or dual/mixed population. There hasn't been adequate follow up on these people, but to date there hasn't been evidence of rapid disease progression associated with this switch, and most people's virus population seems to revert to R5 when they stop taking vicriviroc.

It is fair to say there is some uncertainty about this drug. This is mostly due to the mediocre results from the studies to date. There are also concerns about higher rates of cancers in people taking vicriviroc in this study -- although the study's Data Safety and Monitoring Board (an independent group of scientists, doctors and community members who review the results from the study to ensure no harm is done to the study participants) didn't feel like that the study should be shut down.

Another area of concern for vicriviroc and all CCR5 drugs, is the screening test -- called the Trofile assay -- necessary to determine if people can take this class of drugs. There is a growing concern about the ability of the test to detect low levels of X4 or dual/mixed HIV, which could expose people to a higher risk of treatment failure.


Results were presented at the IAS meeting from a study of PRO140, a monoclonal antibody entry inhibitor that blocks the CCR5 receptor. PRO140 is different from other drugs that target CCR5, like Selzentry and vicriviroc in two important ways. First, unlike these other drugs, PRO140 must be given as an intravenous infusion: through a needle directly in to the blood. Second, it targets a different part of the CCR5 protein, meaning it should still work against HIV that has grown resistant to the oral R5 drugs.

The study followed 49 people who were given a single dose of PRO-140 as a monotherapy. All volunteers had only R5 only HIV (HIV that uses the R5 receptor) and had been off all other anti-HIV drugs for at least three months. They were given one of three different doses (0.5, 2 or 5 mg/kg) of PRO-140 or a placebo by infusion. Changes in HIV levels were checked periodically for 60 days.

People given the two higher doses of PRO-140 in this study had significant drops in HIV levels. At the highest dose, the average drop was 1.8 logs. Reductions in HIV levels were greatest 10 days after infusion, and rose back to pre-infusion levels after around 30 days. There were no serious side effects reported in the study, and only one person taking PRO-140 experienced a shift in HIV type from R5-only to dual/mixed HIV.

The magnitude of reduction in HIV levels seen from a single dose was impressive. While the optimal dosing schedule for this drug hasn't been determined, the fact that the lower HIV levels were maintained for so long after infusion suggests that it might be given every 10 days to 2 weeks.

Monoclonal antibodies are large proteins that are expensive to manufacture. With so many powerful, easy-to-use oral HIV drugs available many people question the need for such therapies. However, the results from this single-dose study were impressive enough for the drug to move forward. More studies are planned to start later this year.

The Pipeline: Where Do We Stand?

The 2007 CROI and IAS meetings and the subsequent months were dominated by news on Isentress and Selzentry, and for good reason. They are two effective and well tolerated drugs from entirely new classes. Along with Prezista approved in 2006 and etravirine (likely to be approved in early 2008), this has been a uniquely productive period in HIV drug development, especially for drug-resistant HIV.

What about just a bit further down the line? While it is always difficult to speculate on the pace of HIV drug development, there is little doubt that beyond 2008 there is likely to be a slow down. However, there are many drugs, including some quite interesting ones, in development right now. Well over 100 new HIV drugs are in some stage of development, including 28 in human clinical studies. Most of these are unlikely to pan out, especially the ones in pre-clinical testing. However, some are likely to make it through, and others are being added to the list all of the time. While we may never again see a moment in time like now where so many new and promising compounds come to the end of the development process so close together, but HIV drug development continues.

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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.
See Also
More on HIV Medications
HIV Drugs in Development