The Bay Area Reporter - October 8, 1999
Matt Sharp ACT UP Golden Gate Writers Pool

But AIDS drugs are not a panacea. Side effects of the therapies are becoming increasingly worrisome. Besides the short-term manageable side effects, we are beginning to see the long-term effects on metabolism such as lipidystrophy, insulin resistance and the damage done to crucial organs. Also, some recent anecdotal data suggests a third of the people on antiviral drugs never get their virus to undetectable levels. Confounding issues of when to start, switch, and stop therapies are no more understood now than they were when the drugs first came on the horizon. Also, less than 50 percent of people who have been treated with several antiviral drugs are able to get responses with "salvage therapy" or treatment that may bring virus replication under control. The spectrum of AIDS treatment and care today has truly become more perplexing, confusing, and chaotic as the millennium approaches.

On the positive front however, HIV therapies have opened the door to an understanding of the immune system never before studied or accepted by the dogmatic virology discipline. What we have learned is that because of antivirals, there may come a day when the drugs will be only a part of the overall strategy to control HIV, coupled with the natural immune response. It is still very confusing and will take more time to sort out. However, as the epidemic moves into the millennium, much has been learned, but with each answer more questions are raised.

ICAAC

The recent 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) held in San Francisco last week sought to address important questions about where we are today with AIDS treatment strategies and the role of the immune system. One of the major medical conferences addressing research in HIV, the meeting didn't bring earth-shattering news or any breakthroughs, but did bring new insights to the complex and confusing state of research in AIDS.

In terms of side effects the most disconcerting reports are showing a disturbing new imbalance of lactic acid in people on antivirals. A federal Food and Drug Administration (FDA) report showed 60 cases of lactic acidosis or hyperlactacidemia, a build up of lactic acid that is probably related to lipidystrophy. Presenting as liver function abnormalities and fatigue, the cases are few, but are beginning to cause a stir. Fifty-five percent mortality was reported in this report, obviously something to be very concerned about.

Several cohorts looking at elevation of lipids and body shape changes were reported at ICAAC. Although any new data is good to see, nothing seems to be definitively explaining the prevalence or cause of the syndrome, or providing real conclusive evidence for treatment. At an early metabolic symposium prior to the conference, Donald Kotler, a leading metabolic researcher, explained that we understand less today about metabolic dysfunction in HIV than we did a year ago. Treatments for both abnormal lipids and glucose levels, and for body shape changes remain illusive though some progress is being made.

In one interactive session, Carl Grunfeld, a leading researcher from the University of California, San Francisco (UCSF), focused the discussion by explaining that clinicians must not lump all metabolic problems under the banner of lipidystrophy, that body composition and metabolic alterations might have different if overlapping causes, but that the causes may differ. He also explained that mild metabolic abnormalities are commonly seen and severe ones are rare. Still, sorting out the confusing syndrome may take longer than expected.

Understanding the immune response in HIV

One researcher said that a year ago our understanding of the immune system could be likened to first grade and that today we are only at second grade level. But this new level of understanding, along with serious concerns about drug toxicities, has led researchers to begin to understand the important function of immune system control of HIV. Much discussion took place regarding the flushing of reservoirs of HIV specifically in lymph nodes so that antiviral therapy could kill most of the virus in the body. Drug interruptions, while intriguing, were shown to be an interesting, yet formidable area of future research with many unknowns.

With regard to drug resistant patients, the news was quite sobering. Reasons for treatment failure are inadequate potency of the drug combination, poor adherence, difference in how drugs are metabolized, negative drug interactions, drug toxicity, advanced HIV disease, and viral resistance and cross resistance. Salvage therapy proves to be disappointing, focusing the problem on development of better drugs. However, there is more reason to employ use of genotypic and phenotypic testing in order to tease out a treatment option for salvage patients, if one can acquire the tests and then interpret the results. Yet another complication in the era of AIDS care we find ourselves in today.

New antivirals now available

Finally, a few positive reports of early trials of new antiviral agents for late-stage patients were presented at ICAAC. The most promising was Trimeris Inc./Roche's T-20, a novel inhibitor of HIV fusion. In a Phase II trial at 16 weeks, 60 percent of participants had a clinically significant reduction of HIV; 36 percent reached undetectable levels. This is truly promising given that out of 55 patients who were enrolled in the study, there was a median use of 11 prior antivirals, and 93 percent had been on drugs from the three approved classes. Indeed, the new drug is proving to not be cross-resistant to the older drugs. Side effects were few.

Gilead's PMPA, called Tenofovir showed a 0.83 log drop in viral load in the highest dose arm. More potent than its sister drug Preveon, which goes before the FDA's advisory committee for approval November 1, the drug is now available in compassionate use programs. So far, there is no report of kidney enzyme elevations, as seen with Preveon.

Abbott's newest protease inhibitor (PI) ABT-378, to be capsuled and therefore combined with their older protease inhibitor, Ritonavir, looks good in people who had been on one PI but had never taken a NNRTI. Seventy-eight percent of participants in this arm came up with less than 400 copies of viral RNA. This new drug will be available at the same time as Tenofovir in compassionate use.

Overall, HIV treatment doesn't necessarily look bleak for the millennium but it was clear at ICAAC that employing the natural immune response with better, safer, more potent antiviral agents will hopefully bring us towards improved survival and quality of life for the survivors of HIV and AIDS.

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