HIV: hiding in plain sight.

Despite the progress in keeping HIV at bay, eradication of the virus remains maddeningly elusive

Eradication. In that one word are all the hopes and wishes of HIV researchers, doctors, and patients. The elimination of the virus from even one HIV-infected human body would represent an enormous triumph for science--one that would seem to herald the end of the terrible human toll the AIDS-epidemic continues to exact. With all the advances in AIDS research and treatment over the past year, it is the possibility of eradication that has attracted the most attention.

Yet the focus on eradication has also proved just how difficult the battle against HIV remains and how carefully wishful thinking must be checked with frequent doses of reality. For it is increasingly clear that as much as everyone still hopes for the day when HIV can be exterminated in individuals, that day, should it come at all, is still well in the future. After more than six months, during which eradication seemed tantalizingly near, scientist--and the media--are now damping down the enthusiasm for eradication and stressing the tangible advances that have already been made.

"We can talk about control and a longer life," says Michael Horberg, president-elect of the San Francisco-based Gay and Lesbian Medical Association. "The problem is, people want to make the leap immediately from control to cure." Spencer Cox, a member of Treatment Action Group, an HIV-research and advocacy unit in New York City, adds that while "we're much better off today than we were a year ago today ... we're not as far along as some people would have us believe."

Indeed, it will take years of research to know just how far along science has come, and not just in terms of eradication. "We're still in for the long haul," says Kenneth Mayer, a professor of medicine and community health at Brown University. "Everything that looks promising can't be answered quickly. There's a ten-year follow-up."

The confusion about eradication began during the 11th International Conference on AIDS in Vancouver, Canada, last July, particularly when David Ho, director of the Aaron Diamond AIDS Research Center in New York City, floated the hypothesis that me day it may be possible to eliminate HIV from the bodies of those infected with it. While colleagues credit Ho, who was later named Time magazine's 1996 Man of the Year, with solid research and appropriate caution, his statement unleashed some loose talk.

"At Vancouver there were some unusual statements," says Jeffrey Laurence, director of the ADDS lab at the New York Hospital-Cornell Medical Center and senior scientist for programs at the American Foundation for ADDS Research. "Dr. Ho may have been misquoted or misunderstood, but the hype in a lot of the print media was about eradication."

"There was an overenthusiastic extrapolation of some modestly encouraging data," says. Gary Cohan of Los Angeles's Pacific Oaks Medical Group, the largest private medical practice in the country dedicated to HIV treatment and research. "Being so starved for good news, everybody went for it, even though we had been skeptical for so long."

In fact, what Ho was focusing on was the possibility that aggressive drug therapies in people who have just seroconverted could keep HIV from replicating, leaving it to the off as its host cells are naturally replaced. Originally Ho thought this process could be accomplished in about 18 months and planned to begin removing volunteers from drug therapy this spring to test the premise.

However, at the fourth annual Conference on Retroviruses and Opportunistic Infections, held in Washington, D.C., January 22-26, Ho revised his estimate to three years. "Clearly we don't know" if the virus can be eradicated, Ho told researchers attending the conference. "We need to know what happens in the next six months, next year." As far as asking volunteers to stop taking their drugs, Ho said, "we have never popped the question with our patients."

The admission has left some physicians and researchers in a quandary. "We're on this tightrope right now," says Mayer. "Ho has a hypothesis, which we don't know will work. A lot of us don't want to be too critical publicly because we don't want to disempower hope."

Yet placing too much emphasis on the possibility of eradication is misleading at best. For one thing, the eradication would be confined to people who are newly infected and whose infections are almost immediately caught, a narrow subset of the population infected with HIV.

"We shouldn't be focusing too much on this eradication thing," says Ben Cheng, information coordinator at Project Inform, an AIDS treatment and advocacy group in San Francisco. "It's a great attention grabber, but guess what: It affects very few people. The vast majority of people we know are infected for years. Seeing what we can do with therapies is far more important than the eradication question."

Whether the hypothesis will ever apply to any other group of people is impossible to tell. Says Mayer: "The idea is getting people shortly after they seroconvert, but for the majority of people with longer-term infections, we don't know."

Moreover, HIV is notorious for its trickery in outwitting potential attacks, primarily by mutating so that it becomes resistant to drugs. It may outsmart any eradication attempts by sun ply hiding from view and returning at a more opportune time.

"Even when the virus goes below detectable levels in the blood and lymph nodes, it's there in other places," says Laurence. "It has appeared in the intestines." In one study everyone who had taken triple-combination drug therapy for a year showed DNA from the virus in their intestines, says Laurence, and in half the patients there were indications that the virus was still growing. Scientists also believe HIV can lurk in the brain. Mayer notes that "there's also been some finding in semen as well, another potential sanctuary."

The forms of HIV that are appearing outside the blood are not reproducing, but, says Cox, "the caveat is that it could." Cox cites an instance of a patient who had undetectable levels of HIV in his blood for nine months: "He presumably had started to clear his lymph nodes when he had to stop his drug therapy for a week. In a week his lymph nodes were completely stuffed again with virus."

In one instance that echoes Ho's hypothesis, Brad Saget and Steve Scheibel, two AIDS physicians in San Francisco, treated one patient newly infected with HIV with aggressive combination drug therapy. For 89 weeks the patient had no detectable levels of HIV in his blood or lymph nodes. At that point the doctors removed him from his drugs. Within a week the virus had returned.

Such findings not only underscore the possibility of unknown hiding places for the virus; they also point to the limitations of current methods for detecting HIV--even in the bloodstream. "Undetectable viral load means `below the limit of detection for the test,'" says Cohan. "It doesn't mean it's gone."

Whether and how soon FIN can be eradicated from the body of anyone infected with the virus is not the only point of confusion surrounding the therapeutic gains made last year, which scientists are still trying to digest. Indeed, what is increasingly clear is that the advances still need to be interpreted to understand their full impact on AIDS treatment.

"Last year was a big leap forward, but it was a big leap forward with holes," says Cheng. Cohan explains the situation as "kind of like casting a chorus line. We've got a bunch of great dancers onstage, but we haven't choreographed them yet."

Perhaps the biggest unknown is just how long the latest and most successful treatment regimen to date--which combines three drugs, most commonly AZT, 3TC, and one of the new protease inhibitors--will continue to produce dramatic results. "It's still not known for how long protease inhibitors and triple therapies are going to be effective in people," says Peter Hawley, medical director of the Whitman-Walker Clinic in Washington, D.C. "In smaller subgroups of people, it seems to be a very long time, but there was a lot of evidence at the [retrovirus] conference that shows that's not true across the board."

That is primarily due to the often difficult regimen that drug therapy imposes on patients. The drugs have to be taken at precise times, with no skipped doses, or the effect of the drugs is weakened. "Unfortunately," says Hawley, "most of the patients we deal with are not able to use the drugs appropriately. A large number of people are never going to get the benefits that people potentially can have."

Only strict compliance with the treatment regimen can reduce HIV in the blood to undetectable levels. And such radical suppression of the virus, while it's not synonymous with eradication, is still a very significant goal--one that can make the difference between keeping the virus dormant and having it continue to grow. "When the virus is kept in a state where it's undetectable in the blood, replication is essentially shut down, and the virus does not develop [drug] resistance," says John James, editor and publisher of the San Francisco-based newsletter "AIDS Treatment News." "Even at a relatively low level, the virus can become resistant to drugs, which is why compliance is so important."

For some people, drug resistance is a problem out of the gate. Research suggests that those who were exposed to AZT, for example, don't get the bounce from a protease inhibitor that other patients do when it is added to their current regimen. Doctors can circumvent that problem by changing drug combinations to eliminate drugs that patients have already been using. Still, that solution could present difficulties further on. "We need to tell doctors that treatment decisions they are making today are going to affect treatment options down the line," says Cox.

Despite such gaps the progress made last year remains real. In one dramatic indication, the number of AIDS--related deaths in New York City dropped by 29% in 1996. Not all of that is the result of new drugs, according to Jonathan Jacobs, director of the office of AIDS clinical program management at the New York Hospital--Cornell Medical Center, who reports that "the trend started before protease inhibitors were introduced," Jacobs says. "It had to do with prophylactics [against opportunistic infections] and access to care."

Recent studies also offer promising news about the extent to which the immune system can repair itself after it has been damaged by HIV. "Researchers are seeing lymph nodes with serious structural damage beginning to reorganize themselves," says Cox. "That's more than I expected."

New drugs also offer to extend the promise of last year. For example, Abbott Laboratories has a new-generation protease inhibitor known as ABT-378 that in lab tests has shown itself to be more powerful than the protease inhibitors on the market. Scientists at Merck & Co. are looking at ways of genetically altering integrase, an enzyme HIV needs to replicate, thus stopping the virus in its tracks.

What researchers and physicians need most at this point is time--time to test theories and study patients, to sort out the false promise from the true. "This year will be a year of consolidation," says Cohan. "We'll be able to absorb information and fine-tune our strategies." Laurence puts it more bluntly: "What we're now doing is finding the hope in the hype."