Coverage of 2007 IAS
(International AIDS Society)

July 2007, Sydney, Australia

Summary of the Anti-Retroviral Clinical Trials Session

July 24, 2007

Data were presented today from six studies, covering five different experimental anti-HIV drugs. Here is a brief summary of each presentation, along with commentary on prospects for each drug.

Comparing Prezista against Kaletra
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 discontinue the study.

This study is groundbreaking because it is the first head-to-head study of any protease inhibitor compared to Kaletra, where the PI being studied was proven superior to Kaletra. Kaletra has been the preferred PI for some time, due both to impressive durability and an extensive track record in research. 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 has 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.

Uncertainty for vicriviroc
The next presentation looked at the CCR5 antagonist vicriviroc. 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 (called optimized background therapy). 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. It is thought that concerns over this test are part of the reason for the delay in the approval of another CCD5 drug called Selzentry (maraviroc).

Study data on the integrase inhibitor, Isentress
The next two presentations were about a single study of the integrase inhibitor, Isentress (raltegravir). 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 of the study, about 200 people were again randomized into 5 groups. In each group, 40 people took one of the four doses of Isentress, or the NNRTI Sustiva (efavirenz). 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 taking 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 6 treatment failures in this study, five in people taking Isentress and one taking Sustiva. Among the 5 who were taking Isentress, 2 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 failure while taking 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 will require 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.

New data presented on rilpivarine
Data were also presented on the affect of the experimental NNRTI, TMC-278 (rilpivarine), on cholesterol and triglycerides. The study compared one group of people taking one of three doses of TMC-278 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 Emrtiva (lamivudine, FTC).

After 48 weeks, people taking TMC-278 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.

TMC-278 is being developed as an alternative to Sustiva for first line NNRTI-based therapy. 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. However, the lack of effect of TMC-278 on metabolic parameters seen in this study is a hopeful development.

New CCR5 drug, 9471, moves forward
The final presentation was on a study of a new CCR5 drug, being developed by Incyte called 9471. This small 23-person phase I study compared people taking 200mg of 9471 once a day alone for 14 days, to people taking a placebo. On average the people taking 9471 experienced a drop in HIV levels of around 1.8 logs, compared to almost no change seen in the placebo arm. There were no serious adverse events in the study. Two people had their HIV shift from R5 to X4 or dual/mixed during the study. Both reverted back when the drug was stopped. Too little is known about this drug, but these data are hopeful enough to move forward in the development process.

Commentary
More studies on anti-HIV drugs will be presented at Wednesday’s ‘late breaker’ session. The studies presented Tuesday ranged from groundbreaking to intriguing to mediocre. Prezista is already approved. The presentation showing it to be superior to Kaletra is bound to make an immediate impact on treatment decisions. Approval of Isentress is expected by the end of the year, based mostly on data of its use in people with extensive treatment experience. The data presented here on its use in people new to HIV therapy suggest a bigger role for this drug down the line. TMC 278 seems to be moving ahead successfully, while many questions remain about vicriviroc. The entrance of anther CCR5 drug, while early in development, gives hope for expanded options down the line.