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AIDS: Still Searching

Medicine: Dispatches From the Front Lines

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Five years ago, Dr. David Ho and Dr. Martin Markowitz developed highly active anti-retroviral therapy (HAART) -- combinations of two or more potent anti-HIV drugs like protease inhibitors that seemed to transform aids into an inconvenient but manageable illness, at least in the developed world. But some people -- up to 50 percent in some populations -- still don't get better. Even patients who can deal with the noxious long-term side effects of HAART and its complex treatment regimens (up to two dozen pills in all, taken anywhere from two to five times a day) can't avoid the bomb that dropped in 1997: HIV, it turns out, can hide. It insinuates itself into resting T cells and just sits there, untouchable by drugs and invisible to the immune system. "HAART therapies," says UCLA's Dr. Steve Miles, "don't get rid of the fact that the virus has stuck its genetic information into us."

A few new drugs in development may help. The second generation of anti-retrovirals and protease inhibitors are leaner, meaner compounds, some of which may kill resistant viruses. This month, Markowitz begins a clinical trial at the Aaron Diamond AIDS Research Center with three new drugs that are more potent, more convenient, and, at least initially, less toxic than what's currently available. And there are three drugs on the horizon that block HIV in new and different ways. Two fusion inhibitors are in clinical trials, and, if things go well, a drug that prevents HIV from latching onto cells will head into trials this year.

Simpler treatment regimens are also within reach. "I think the prospect for 2001 is once-a-day dosing," Markowitz says. "Maybe we can do even better than that." One strategy for weaning people off HAART is to harness the body's own immune system to combat HIV by discontinuing the drugs once HIV levels are extremely low, in the hopes that the body will mount its own defense. Others, like Markowitz and Ho, use a therapeutic vaccine to boost the immune system while patients are still on HAART.

But for 95 percent of HIV-positive people worldwide, these advances are meaningless; only a vaccine will stop the spread of the disease. Last June, California biotech firm VaxGen launched the first Phase III clinical trial of a preventive vaccine in the twenty-year history of aids. But while it has been shown to be safe and capable of stimulating antibody production, the vaccine has been greeted with extreme skepticism by many scientists.

HIV is a wily enemy, and antibodies alone aren't enough to control the virus. "More recently," says Ho, "we have found that much of the control of HIV is mediated by cytotoxic T-lymphocytes CTLs." Currently, the hottest strategies for vaccines employ DNA or live viral vectors that are able to provoke just this kind of CTL immune response. A few of these vaccines are inching their way into preliminary trials in humans, but there's a long way to go. Meanwhile, 16,000 people become infected with HIV each day. "It's going to get a lot worse before it gets better," warns Ho.


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