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A milliliter is a tiny amount of fluid, barely a drop. But in 1994, more than 650,000 AIDS viruses swarmed in every milliliter of Dawn Averitt's blood, seeking out and destroying her few surviving immune-system T cells. Desperate, she entered a clinical trial for a protease inhibitor. Within weeks doctors couldn't detect any virus in her blood, and her T cells started to rise.
About a year and a half later, her virus reappeared on lab tests, turning her into what researchers call a "treatment failure." Averitt, a leading AIDS activist, thought she knew what to expect: The virus would re-saturate her blood and continue the destruction of her immune system. That was the dominant theory, and, for a year and a half, she went to every doctor's visit expecting exactly that bad news.
But something curious happened. The level of HIV in her blood remained low, and she didn't lose any T cells. She felt fine, too. Her immune system wasn't getting any better, but it wasn't getting any worse. She was in a kind of limbo.
So is the entire AIDS field, because it turns out that patients like Averitt are common. As many as half of HIV patients "fail" on the drug cocktails that have cut annual AIDS deaths for two years in a row. The drug-failure rate inching up over time is causing tremendous anxiety, as was apparent at a major AIDS meeting, the Sixth Conference on Retroviruses and Opportunistic Infections, which drew almost 3500 doctors, researchers, and advocates to Chicago last week.
"It's disturbing that as time goes on you have fewer people responding to therapy," says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. Indeed, every treatment failure can make the virus stronger, because HIV can develop drug-resistant mutations that allow it to escape not only the particular medications it has encountered but whole classes of drugs. In short, a patient's first shot is her best, but up to half of patients are failing their first regimen.
That's why Lawrence Deyton keeps thinking about the blip he noticed the other day. As director of AIDS services for the Department of Veterans Affairs, Deyton is responsible for the care of more HIV patients than anyone in the country 18,600 and ever since the advent of protease inhibitors, all the signs at the VA have been good. But Deyton recently noticed that the length of hospital stays, which had been dropping, bumped up slightly: "I wondered if that would be the turning point." After all, he says, it's only a matter of time until the "virologic failures" turn into clinical failures until disease and death go back up. A pessimistic view? "I'd put it this way," he answers. "It's realistic."
"This whole idea that things will come crashing down, it's just not what we're seeing," counters Roy Gulick, a physician and director of the Cornell HIV clinical trials unit at New York Presbyterian Hospital. Several prominent doctors concur. The Wall Street Journal dubbed the results of Gulick's most famous study a three-year trial of the drug indinavir, which has failed to contain HIV in one-third of patients "disheartening." But, Gulick says, "I take the opposite view. After three years, two-thirds of patients still have undetectable virus. And it's not like the whole field is going to stop. There's a new batch of drugs active against resistant virus."
This split made the Retrovirus Conference feel like two separate meetings, one warily optimistic, the other ominously pessimistic. And it was Dr. Steven Deeks, a physician and researcher at San Francisco General Hospital, who had the Rorschach test: a cohort of patients like Dawn Averitt, virologic failures who have retained strong immune systems and good health for almost two years. "You can look at my data," he says, "and see a justification for any theory you have."
Here's what Deeks has found: When drugs completely suppress the virus so that it can't be detected in blood, patients show the best immune-system regeneration, with their T-cell counts rising the highest. But when drugs only partially suppress the virus, or when they push it below the level of detection for a while but then let it creep back up, patients still show a sustained improvement. It's not as robust as the group in whom the virus is totally suppressed, but it's much better than untreated patients or those for whom the drugs don't work at all. These "partial responders" to treatment have held onto their gains for almost two years. What's more, preliminary studies show that they don't just have more T cells, but ones that are longer-living and less overtaxed than in untreated controls.
What's happening? The simplest explanation is that in partial responders the virus has mutated into a strain that is moderately resistant to the drugs. If so, classical Darwinian theory predicts bad news: The virus will continue to mutate, growing stronger in the presence of the drugs. Levels of virus will eventually rise, and the immune system will sink.
But there are other possibilities: Perhaps the drugs, through some unknown mechanism, directly fortify the immune system. Or maybe they render the virus less deadly so that it can replicate benignly without killing T cells or, at least, without killing them as often. That's what a Canadian study found: In the test tube, protease inhibitors reduced HIV's ability to induce cell death, and this diminished virulence seemed to have nothing to do with the virus's capacity to replicate.
The plain truth is that no one knows exactly what is happening. "We have changed the disease," says Averitt, "so we don't know as much about it. We used to be able to predict, but now nobody knows what to expect."
Of course, patients who are partial responders face the hardest dilemma. If they abandon their drugs altogether, the virus almost always soars to harmful levels. But if they stay on their regimen, the virus has a much better chance to mutate into super-resistant strains that can evade even drugs they've not yet taken, rendering useless the so-called salvage regimens they're holding in reserve. Yet if they switch medications right away, there's no guarantee the new combination will work as well as the one they're on, and they might be using up another one of their limited options before they really need to.
Averitt decided to stay on her regimen until her limbo ended.
A year ago, her viral count took a steep turn upward and her T cells started to plummet exactly what pessimists predict will happen to Deeks's cohort. Averitt started sounding the alarm: "I said we're living in a dream world with these therapies, and the bottom will drop out."
Meanwhile, she switched to a five-drug regimen that drove her virus back down below the level of detection. She firmly believes this new regimen is just another stepping stone, not a permanent solution. Nevertheless, another year of watching doctors and patients rejigger treatment to stave off disease has ameliorated her sense of doom. "We may have slowed the disease down enough to give science a fighting chance," she says.
At least two drugs in early development appear to work against HIV strains resistant to other medications in their class, and the first of a whole new category of drugs called fusion inhibitors has entered human trials. But even assuming that these products pan out, the first of them is more than a year from the market. More immediately, a newly approved drug called efavirenz is working better than expected and offers the advantage of having to be taken only once a day. And a new protease inhibitor called ABT-378 also looks potent.
Finally, evidence continues to mount that the immune system can, under certain very special circumstances, control HIV on its own, without any drugs. At least three top American research teams, including New York's Aaron Diamond AIDS Research Center, have begun trials that take selected patients off all therapy, in the hopes of learning how to mobilize what Stefano Vella, a prominent Italian researcher, calls "our other drug, the immune system."
Such progress leads David Barr, a veteran activist who now heads an AIDS policy think tank, to believe that "we're not going to wake up to a crash." But he fears something "more insidious: the disease creeping up and picking us off one by one." If that happens, he says, "AIDS will become more isolating, because deaths won't be happening on a community level, just to the individual."
As for Averitt, having been diagnosed with HIV when she was 19, she recently threw a big bash to celebrate turning 30. At her party, she recalls, "Everyone said, 'You have to aim for 40.' But the enormity of that! I mean, can I be so cocky to think I'll make it for another 10 years? I'm making long-range plans, but I certainly don't think any drug will carry me all the way I just hope it'll get me to the next breakthrough.
"When I was little, I used to have horrible nightmares of someone breaking in and chasing me from room to room as I tried to keep ahead of him. And in some ways, that's what this is. We're running as fast as we can, and so are the scientists, but the virus is always about to catch us."
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