Coverage of 2006 International
Conference on AIDS

August 14–18, 2006, Toronto, Canada

 

Saving the Best for Last?

Paul Dalton, Treatment Advocate, Project Inform
August 18, 2006

The 16th International AIDS Conference wrapped up in Toronto. The last major scientific presentations were held in the biggest session room Thursday afternoon. It was a truly marathon session, with 18 late-breaker presentations—with only a quick half way to clear the podium and seat the second group of speakers. Here are some quick notes on some of the presentations.

Head-to-Head Studies
A couple of interesting head-to-head studies of currently approved anti-HIV drugs were presented. The first, a study called ACTG 5142, compared different class-sparing strategies. Three regimens were studied. One group took Sustiva (efavirenz) + two NRTIs (PI-sparing); one group took Kaletra (lopinavir/ritonavir) + two nucleosides (NNRTI-sparing); and the third group took Kaletra + Sustiva (NRTI-sparing).

Generally all three groups had good results. The primary end-point of the study (called Time to Loss of Virologic Response, TLOVR) was similar among the three groups. However, there was a small trend favoring the Sustiva + NRTIs combination at 96 weeks:

Table 1
Regimen	Sustiva + two NRTIs	Kaletra + two NRTIs	Kaletra + Sustiva
% of people with VL <50 at 96 weeks	89	83	77

There was a higher rate of side effects in the Sustiva + Kaletra arm, mostly involving increases in blood fats, called lipids. If this was wholly due to potential problems with Kaletra, one would assume to see this in the Kaletra + NRTI group as well.

Another interesting head-to-head study was the KLEAN study, which compared Lexiva (fosamprenavir) boosted with Norvir (ritonavir) to Kaletra (lopinavir/ritonavir). In this study almost 900 people took either the boosted Lexiva regimen or Kaletra + the NRTIs Ziagen (abacavir) and Epivir (3TC, lamivudine).

There were no significant differences between the two groups after 48 weeks, with about 3/4 of people in both groups having viral loads below 400 copies and about 2/3 with viral loads below 50 copies. People in both groups averaged good improvements in CD4+ cell counts: 176 for the Lexiva group and 191 for Kaletra. There were similar rates of side effects and treatment discontinuations between the groups.

Studies like this are important with so many similar anti-HIV drugs available as they can help guide treatment decisions. This study strongly suggests that Lexiva, boosted with Norvir, is a reasonable alternative to Kaletra, in combination with two NRTIs.

DART (Development of AntiRetrovirals Therapy in Africa)
There were two presentations on the DART trial—a multi-faceted study of anti-HIV drugs in Africa. In one presentation, Dr. Hakim showed that a Structured Intermittent Therapy (SIT) strategy of alternating twelve-week cycles on and off anti-HIV drugs was inferior to continuous anti-HIV drug therapy. After an average time of 51 weeks, there was a more than doubling of the risk of disease progression in the SIT group compared to those on continuous treatment. The difference was large enough that this sub-study was stopped early and the people in the SIT arm took continuous therapy.

A second presentation showed a significant drop in the rates of death after the introduction of anti-HIV drugs. Moreover, there was an improvement in CD4+ cell counts in the two years since anti-HIV drugs had been made available. This study is encouraging, but needs to be looked at with caution as it used historic controls, comparing the DART group to an earlier cohort called Entrebbe.

ACT UP Paris staged a small, quiet demonstration directed at the DART trial investigators. In a leaflet distributed to audience members, ACT UP Paris questioned—among other things—the informed consent process for DART, criticized the level of laboratory monitoring of participants, and claimed that participants had been coerced into the study and put at unnecessary risk.

Experimental Anti-HIV Drugs
The end of the late breaker session focused on experimental anti-HIV drugs. Dr. Martin Markowitz presented data on Merck’s experimental integrase inhibitor MK-0518. See Project Inform's coverage for more information on this study. Earlier in the day, Merck announced the opening of an Expanded Access Program (EAP) for this drug.

Data from a Phase IIb safety trial of Pfizer’s experimental anti-HIV drug maraviroc was presented by Dr. Howard Mayer. Maraviroc is one of a new class of anti-HIV drugs that keep HIV from entering immune system cells by binding to a protein on the surface of the cells called CCR5. One of the main concerns activists and scientists have raised about this class of drugs is whether they could be used safely in people with HIV whose virus can use either CCR5 or another protein called CXCR4 to enter cells. For more information, read Project Inform’s publication, Understanding HIV: CCR5 and Fusin.

This study compared two doses of maraviroc (150mg taken once a day or twice a day) vs. a placebo, with everyone taking the best available anti-HIV regimen for them. The people in this study were heavily treatment experienced, with an average CD4+ cell count below 100 and a pre-study viral load over 100,000 copies.

Because the people in this study had either X4-using or a mix of R5- and X4-using virus, it wasn’t expected that a R5-inhibiting drug would provide a strong anti-HIV effect in this group; and, indeed, no difference between the placebo group and the two maraviroc groups was seen in terms of viral load reduction. In general, maraviroc was well tolerated, with few serious adverse events.

Interestingly, while reductions in viral load were similar, people in the two maraviroc groups had greater increases in CD4+ cell counts (60 cells vs. 32 cells). Oddly, the difference was much more pronounced when looking at people whose virus was found to be all X4-using at the time of treatment failure. In this group, people taking the placebo averaged a loss of 104 CD4+ cells while people in the maraviroc groups averaged a gain of about 40 cells. Researchers cannot explain this finding.

Results on another CCR5 drug, called vicriviroc (being developed by Schering-Plough), were also presented at the late breaker. Roy Gulick, MD of Cornell University presented data from ACTG 5211 comparing three doses of vicriviroc (5, 10 and 15mg) to placebo in treatment-experienced people. The results looked like this:

Table 2
Regimen	10mg vicriviroc	15mg vicriviroc	Placebo
Change in VL at 14 days	-1.15 log	-0.92 log	+0.06 log
Change in VL at 24 weeks	-1.86 log	-1.68 log	-0.29 log
Change in CD4+ cell count at 24 weeks	+142	+142	-9

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 arm. It is too early to know whether this is due to the drug, or just from chance. Activist and scientists will watch this issue closely.

Robin Hardwicke presented data comparing Tanox’ experimental entry inhibitor TNX-355 plus a combination of the best available anti-HIV drugs for each person (called optimized background) to optimized background alone. Compared to 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).

Compared to the results seen lately with Prezista, MK-0518 and other drugs studied in people with extensive treatment experience, the results seen so far with TNX-355 are modest, but positive. Concerns about the route of delivery (given by intravenous infusion every two weeks) and eventual cost have many 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.

Data on one wholly new drug was presented today. The drug, called fosalvudine tidoxil is a pro-drug of aluvudine—a NRTI that was stopped due to side effects. Dr. Pedro Cahn presented early Phase I data on various doses of this drug, given a single time to HIV-positive volunteers. The single doses were all well tolerated, and no laboratory abnormalities were seen. One audience member reminded the presenter about one death in the trails of the earlier form of this drug, and urged caution moving forward.

There were a couple of presentations on Kaletra monotherapy.

That wraps up my quick takes on the scientific presentations from the conference. Watch this website for more in-depth coverage of some of these stories in the coming weeks.