By Sean Henahan, Access Excellence

SAN FRANCISCO- New data indicating enhanced survival with combination antiretroviral therapies may be some of the best news to come along in along time, report AIDS researchers.

The long-awaited results of the ACTG (AIDS Clinical Trials Group) 175 study were announced to a large standing room only crowd at the at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. The ACTG 175 study was a randomized, double-blind, placebo controlled trial involving 2,467 HIV positive patients randomized to one of four treatment groups.

The patients were randomized to receive either: zidovudine monotherapy; DDI (didanosine) monotherapy; zidovudine plus DDI or zidovudine plus DDC (zalcitabine) in standard doses with appropriate placebos. The trial also was designed to compare immediate versus deferred antiretroviral treatment. The researchers compared how patients did in terms of declines in CD4 count; development AIDS ; or death. Patients were followed for a median of 143 weeks.

About half of the patients had never received antiretroviral treatment while the remaining patients had received previous therapy, mostly zidovudine (also known as AZT). Participants in the study were HIV positive but had no evidence of AIDS and had relatively high CD4 counts (between 200 and 500 mm3).

Overall, 32% of patients receiving zidovudine monotherapy had drops in CD4 counts of 50%, developed AID or died compared with 18% of zidovudine/DDI group, 20% of zidovudine/DDC group and 22% of DDI monotherapy group. Each of the other three treatments was significantly superior to zidovudine monotherapy. This was true whether or not they had received other treatments before, reported Scott Hammer, M.D., of the ACTG 175 Study team.

"Generally, we would say these results support the position that antiretroviral treatment is of benefit in asymptomatic patients with CD4 counts under 500. A change in the approach to the initial management of HIV disease may be signaled by these findings. Combination therapy with zidovudine/DDI, zidovudine/DDC or monotherapy with DDI are reasonable approaches based on these results," said Dr. Hammer.

A virological sub-study of 348 patients indicated that zidovudine monotherapy caused no significant drop in viral load over a 104 week period, while all of the other treatments did produce significant reductions in viral load. The data suggested that either of the combination therapies produced better viral reductions than DDI monotherapy, although DDI monotherapy was significantly better than zidovudine monotherapy, reported David Katzenstein, M.D., Stanford University.

The ACTG-175 results were echoed by those of the Delta trial, announced in London one week later. That trial involved more than 3,000 HIV positive patients randomized to receive AZT alone, AZT with DDI or AZT with DDC. The study showed a similar statistically significant survival benefit for patients receiving the combination therapies compared with placebo as was seen in ACTG-175.

ACTG-175 and the Delta trial involved the use of the leading class of anti-HIV drugs, the nucleoside analogues. Promising results were also announced for members of a new class of AIDS drugs, the protease inhibitors. Researchers reported that one of these drugs, ritonavir, appeared to be quite potent against HIV infection, particularly when given in combination with other antiretroviral agents.

Patients receiving ritonavir had rapid, dose-related reductions in viral load within two weeks. However, as with other antiretrovirals, viral rebound begins to occur at about eight weeks of treatment as resistant mutants evolve. This is less the case when the highest dose was given, in which cases reductions in viral load were sustained for 32 weeks.

In a pilot study, patients were given ritonavir in combination with zidovudine and DDC. This regimen produced a significant increase in CD4 cells, and an unprecedented 2.5 decrease in viral load lasting for the 20 weeks of the study. Titers of infectious blood cells also declined at least two logs in this study.

Indeed, a few patients showed at least a three log deduction or elimination of detectable virus, which increased over time. At five months, one in three patients were PCR negative for plasma HIV RNA, and one in four patients were culture negative for infectious HIV, reported chief investigator Daniel Norbeck, M.D.

In a related study researchers reported that another protease inhibitor, saquinavir appears to show increased potency when given with ritonavir. In animal studies, co-administration of ritonavir and saquinavir greatly increased the metabolism of saquinavir. This interaction appears to mediated by ritonavir's ability to inhibit the hepatic metabolism of saquinavir via the cytochrome P450 pathway. In humans this should profoundly amplify the antiviral activity of saquinavir and potentiate its ability to suppress resistance mutations to ritonavir, noted Dr. Norbeck.

In addition, patients showed "dramatic" increased in both CD4 and CD8 cell counts after treatment, he said. Moreover, the drug was well tolerated, with no patients dropping out of the study. Twenty-one of the 30 patients showed viral load decreases of at least one log and continued on treatment after the 28 day trial.

These studies represent a new direction in AIDS treatment research. For the first time researchers were able to compare treatments in terms of clinical outcomes rather than just using surrogate markers such as CD4 counts, as had been done in previous studies. Also, the studies appeared to validate the use of quantitative biological markers such as viral load in relation to the patients' symptoms, a new development. Finally, the new studies provide considerable support for the growing consensus that treatment involving multiple, synergistic treatments may finally be able to control HIV, slowing or stopping AIDS.

"A good analogy would be tuberculosis," said Dr Tim Peto, a specialist in infectious diseases at John Radcliffe Hospital in Oxford, England. "If you take one drug alone it doesn't work. You have to take three drugs to get a good result."