New recipe for the cocktail?

As AIDS experts dramatically shift their guidelines for drug therapy, those following the previous recommendations ask, "What now?"

After Bill O'Brien of Boston tested HIV-positive in July, he found himself grappling with perhaps the most vexing question of his life: if and when he should start highly active antiretroviral therapy (HAART), the so-called AIDS drug cocktail. He did copious research to weigh all his options and in January decided to start the therapy after reading a federal guideline that suggested people do so when their T-cell count falls below 500--as his had.

Less than a month later, much to O'Brien's frustration, the feds changed the guidelines. As of February 5 the government set 350 T cells as the level at which people should consider therapy. The viral-load marker--a measurement of the amount of the virus in the bloodstream--now reflects the belief that people should wait longer before going on HAART. In other words, "hit hard, hit early," is out, replaced by a strategy that might best be described as "hit hard, hit somewhat later--we think."

While the new guidelines may seem like a sudden retreat, those in the inner circles of HIV research say they have watched the evidence for starting later accumulate gradually. New information keeps emerging about the dangers of the drugs' side effects, which include lipodystrophy (fatty deposits), heart disease, high cholesterol, liver toxicity, weakened bones, and nerve damage. Long-term use of HAART also increases the likelihood that HIV-infected people will develop resistance to the drugs, and this problem can be passed along when other people are infected with the resultant drug-resistant virus. Despite these side effects, most physicians strongly discourage their patients from stopping the therapy--even if they have higher T-cell levels--because doing so could result in a viral rebound.

Anthony Fauci, director of the National Institute of Allergy and Infections Diseases at the National Institutes of Health, portrayed the guidelines change as a shifting in the ratio of known benefits to known risks. Cochairman of the panel that issued the guidelines, Fauci says researchers initially hoped HAART might eradicate the virus from the body. "The risk-benefit ratio of putting somebody on a drug that might have not only short-term but also long-term toxicities weighs in favor of the benefit if in fact you eliminate the virus and, ultimately, will be able to discontinue the drug," he says. "But if you come to the realization that [the person will have to take drugs indefinitely], then you're talking, in terms of the risk part, of cumulative toxicities becoming a much more important factor that needs to be dealt with in the process of deciding when to start."

So where does this leave people who started HAART before they knew that the risk-benefit ratio had shifted? "I don't say to people, `Oops, you made a mistake; sorry, it's too late,'" Fauci says. "After a few years of waiting longer, it may turn out that people who started earlier are doing better. If [the new guidelines] were an absolute slam dunk, then you could say it was a mistake. But the fact is, we still don't know. This is a work in progress."

New information always results in people asking, "What if I had done this?" says Michael Cover, associate executive director for public affairs at Washington, D.C.'s Whitman-Walker Clinic who learned he was HIV-positive in 1998. "That's not a fair way to look at it," Cover says. "Instead, the question is, What is the most strategic treatment plan I can have today?"

Cover went on HAART about six months after testing positive, and he has no regrets. A self-described "worrier," he explained that the decision seemed like the right one for him because he was already deeply apprehensive about leaving the virus untreated. "During the six months that I wasn't on medications, I was waking up every day thinking my viral load had tripled."

Cover stresses the importance of patients' making educated decisions in partnership with their doctors. "One of the hallmarks of the gay community for many years was that we were as informed or more informed about HIV than our doctors. We still need to be informed--we need to understand what these new guidelines mean."

The first thing to understand about the guidelines is that they are merely suggestions that are not meant to apply uniformly to all situations. The panel issuing them has stressed the limitations of the current body of information about antiretroviral therapy. The guidelines themselves even bluntly state, "The optimal time to initiate antiretroviral therapy is not known."

Federico Erebia, an HIV specialist at Fenway Community Health in Boston, underscores the flexibility of the guidelines with an observation about his own practice. "Years ago I had a lot of patients who didn't want to take any medications at all. I learned that a lot of patients who should have started medication based on the previous guidelines did well without it," he says.

Erebia encourages his patients to weigh a number of factors when they decide whether to begin the meds. "The main things I consider are the stability of the numbers and trends or changes in the numbers. I would weigh the CD4+ [T-cell] count probably a little bit more than the viral load, but you have to look at the whole clinical picture."

Erebia's insight exemplifies an important principle in HIV care: the need for infected people to be treated by HIV-experienced physicians. Studies have even suggested that people treated by HIV-experienced physicians have lower mortality rates than those who are not.

To some people, modifying the strategy of hitting early would appear to be an unavoidable consequence of aggressively trying to counter a deadly new virus that took the medical community by surprise. However, Gregg Gonsalves, director of treatment advocacy at Gay Men's Health Crisis in New York City, believes there might be a more effective way to acquire information about the optimal time to start therapy.

"After Vancouver [the 1996 International Conference on AIDS, at which successes with protease inhibitors were first announced], people were practically giddy with the possibility of eradicating HIV with these drugs," Gonsalves says. "What we failed to do was recognize this as a hypothesis and then do studies." To date, Gonsalves says, there have been no major studies on the question of when to start therapy. "There's observational data, but there have not been clinical trials. The observational data have less sensitivity to give you answers than a randomized clinical trial does."

As for O'Brien, the question of when to start is now a moot point. "I haven't been able to dwell on it, because it would really drive me crazy," he says.

After his efforts to educate himself about treatment options led to a mass of conflicting information, O'Brien finally threw up his hands and decided to follow his doctor's advice to go on HAART. So far he has responded well to the regimen, and today he looks back--and forward--with conflicting feelings about his health care situation.

"I feel very good about having access to all of this information, to really good treatment, to the medications. I think, `Why do I have a right to complain about my situation?'" he says. "A decade ago a lot of these meds were not even available. On the one hand, I'm thankful for everything, but on the other hand, I'm overwhelmed by it."

Harmon also writes for Positively Aware.

Find more information on HAART and on federal guidelines for HIV treatment at www.advocate.com