The Virus Fights Back

At the World AIDS conference, hope mingles with troubling news about drug-resistant HIV

GENEVA— At least three separate research teams here at the 12th World AIDS Conference announced that strains of HIV resistant to many drugs, including the powerful protease inhibitors, have been transmitted from one person to another. None of these cases was from New York, but among the nearly 14,000 conference participants was a couple from Manhattan, one of whom recently contracted a highly resistant strain of HIV from the other.

AIDS activist Stephen Gendin took years to become resistant to most HIV drugs, using them one after another as they came on the market, desperate to save his life. But now his partner, Kyle McDowell, is starting out with Gendin's resistant strain. "This eliminates most treatment," says McDowell.

Such cases re-emphasize the importance of prevention. But they also point to the implacable logic of HIV, which has killed almost 12 million people, infects another person every five seconds, and now is mutating under the pressure of powerful but not curative drugs. "It's not surprising at all" that resistant strains have begun to circulate, says Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.

Indeed, given the astonishing vigor of this virus, many of the conference's scientific findings were sobering but not surprising. Among the most important are that HIV continues to replicate even when patients are taking potent medication, and that in the very first days after the virus enters the body, it infiltrates certain long-lived cells that then harbor it for many years. So even if a patient has an ordinary strain of HIV that is vulnerable to the drugs—and even if that patient is among the lucky 10 per cent of infected people who live in a First World country, where the expensive drugs are available—still, says

Fauci, "it will be very difficult to eradicate this virus" from the body.

Yet the AIDS death rate continues to drop all across the developed world, and "I don't think deaths will go back up," maintains Bernard Hirschel, the doctor who chaired the conference. Like many researchers, Hirschel and Fauci believe it might not be necessary to eradicate every last virus from a patient's body. They point to growing evidence that suggests the immune system can control HIV under the right circumstances, and that an AIDS-ravaged immune system can be regenerated with therapy. As David Ho, director of New York's Aaron Diamond AIDS Research Center, puts it, "Control without eradication is something we might call remission."

Whether the goal is eradication or remission, the lynchpin of therapy is a cocktail of three or more drugs, often involving a protease inhibitor, that patients must take every day to suppress the virus. But McDowell and Gendin are resistant to at least nine of the 11 currently approved drugs—and possibly to all of them.

Gendin has known for more than a year that he carries a multidrug-resistant strain of HIV. He and McDowell never engaged in the riskiest behavior—having Gendin ejaculate into McDowell during anal intercourse—but sometimes Gendin would enter McDowell without a condom, withdrawing before climax. (In a case documented by San Francisco researchers, the source partner also withdrew before ejaculation; HIV is known to be present in preseminal fluid.) In addition, McDowell was often the insertive partner, and he didn't use a condom either. This, too, could have led to his infection.

Several studies presented at the conference suggested that some people are relaxing their safer-sex standards because they believe the new treatments have made AIDS manageable. Prevention workers will undoubtedly have to combat this misconception, but McDowell's story makes it clear that people engage in unprotected sex for reasons that are tangled and personal.

"For 10 years I was so safe," McDowell explains. His riskiest activity was to fellate without a condom, a practice generally considered low risk, and which he would do only once or twice a year. His friends, he says, considered his standards "maddeningly tight." Then McDowell turned 30, which, he says, "had a lot to do" with why he's now infected. He remembers thinking, "Oh my god, I let my twenties go." So he let himself enjoy "a few stolen insertions" with Gendin. Those gave him morning-after anxiety, but twice over a one-year period he tested HIV-negative, which bolstered what turned out to be a false sense of security.

Having sex without a condom "really made me feel profoundly erotically close," McDowell recalls. "When Stephen was not feeling well, it seemed the only way to be intimate." And when problems arose in the relationship, McDowell says, "I wanted to fix it with something highly symbolic." So they would have "makeup sex" that sometimes became "really intense." There was, he says, "something profoundly rich about risking my life for Stephen."

"This notion of sharing everything is being romanticized, and that's dangerous," warns Martin Delaney, a leading AIDS activist. Indeed, many activists believe Gendin had already romanticized "barebacking," as unprotected sex is called, when he wrote an article in the AIDS magazine POZ last summer about having skin-to-skin intercourse with another man who was also HIV-positive. That article sparked a heated controversy, because even between two infected people, a drug-resistant strain might be transmitted, unleashing a secondary infection that could sabotage a drug regimen. But many people with HIV consider that possibility theoretical.

Of course, there is no doubt about the danger to an HIV-negative partner. "So why was I doing something risky?" Gendin asks. "I don't know. If someone handed me a knife, I wouldn't throw it around." Now he feels "guilty and confused."

Researchers feel worried.

In San Francisco, one out of 35 newly infected patients was found to have a virus resistant to all four approved protease inhibitors and most of the AZT family of drugs.

In Switzerland, two out of 67 recently infected patients were found to be carrying strains highly resistant to protease inhibitors, and several more were resistant to other drugs.

U.S. military researchers found two out of 16 untreated patients with mutations that confer resistance to protease inhibitors.

There are likely to be more such cases, if only because more than 40 per cent of U.S. patients are being prescribed substandard drug combinations, which greatly increases the risk of resistance. Moreover, 30 to 50 per cent of all patients have trouble taking their medicine as directed, which also induces resistance.

Even so, Fauci, Ho, and Frederick Hecht, the lead researcher in the San Francisco case, all warn against exaggerating the danger. It's likely that "most new infections are coming from people who don't know they're infected and haven't been treated," says Martin Markowitz of the Aaron Diamond Center, who has been studying recently infected patients for three years. And such individuals are unlikely to carry drug-resistant virus.

AZT, the first approved AIDS medication, has been on the market for a full decade, yet only about 16 per cent of HIV-positive people in San Francisco start out with a strain that is resistant to that drug. Helene Gayle, director of the AIDS program at the Centers for Disease Control, says that the proportion of people newly infected with strains resistant to protease inhibitors will likely rise only to "the single digits or teens." But, she notes, for a deadly disease like AIDS that would still constitute "a real disaster," because those unlucky patients would effectively be thrust back to an era when doctors had few or no options for treatment. Indeed, the San Francisco case was discovered partly because the patient did not respond well to his drugs.

HIV doesn't need to be super-resistant to wreak havoc. Ordinary HIV is virulent enough. In the first days after infection, the virus infiltrates so-called "resting T-cells." Since those cells are long-lived, HIV can lurk in them for years, dormant but capable of re-emerging and continuing the progression toward AIDS. If drugs could completely shut off virus replication, then this pool of cells would die off in an estimated three to five years.

But last year, evidence emerged from Fauci's lab that the drugs don't completely suppress the virus. And in Geneva, Ho presented proof that HIV keeps replicating even when the drugs appear to be working so well that very sensitive tests cannot detect any virus in the blood. HIV's under-the-radar replication keeps infecting the resting T-cells, foiling attempts to eradicate the virus. Ho's conclusion: "We have overestimated the potency of our [medical] regimens."

Trial results of several promising new drugs were reported, but it remains to be seen if they will have a more powerful effect. Probably the most encouraging was a drug called efavirenz (brand name Sustiva), made by DuPont. It was shown to be at least as potent as the strongest protease inhibitor, though its long-term efficacy is not yet known. In marked contrast to the corporate PR, Paul Friedman, the scientist who led the discovery and development of efavirenz, was humble: "This virus," he says, "is very, very difficult."

Indeed, Ho's work suggests that even under the most intense drug pressure, HIV not only keeps replicating, it also mutates and evolves. But when he charted the changes in HIV's genes, he didn't see any evidence of evolution toward drug resistance. So, he reasons, "there must be some compartment where virus can grow without any selective pressure for drug resistance." This sanctuary might be an anatomical organ, or it could be certain kinds of cells present in different organs. Ho's finding could be a fluke due to his small sample size—he studied only seven patients. But Emilio Emini, who heads pharmaceutical giant Merck's AIDS effort, says that "slow evolution of resistance mutations" has occurred in patients on apparently effective drug regimens. He thinks that explains some cases in which the drugs appear to be working perfectly, yet the virus eventually breaks through, rising back up to dangerous levels.

Whether this ongoing replication maintains HIV in the body or actually leads to drug resistance, Ho suggests intensifying therapy, and, indeed, some doctors are recommending that their patients take four drugs instead of three. But the drugs often cause side effects. Widely publicized have been fat and cholesterol disturbances, possibly leading to coronary problems in the most severe cases. So other doctors are taking the opposite approach and suggesting that their patients delay starting therapy if they are healthy and have relatively intact immune systems.

Their logic was vividly illustrated in a plenary speech by activist Mark Harrington of Treatment Action Group, or TAG. Harrington recounted his personal history of HIV and showed slides of his lymph nodes, a key immune-system site. Just after the last international AIDS conference two years ago, HIV had ravaged Harrington's lymph nodes, which literally looked tattered on the slide. His CD4 cell count, a common measure of immune function, had plummeted to 152; healthy people typically have more than 1000. But now, following two years of effective therapy, Harrington's CD4 count has soared to 925 and he has "nice, plump, healthy" lymph nodes. "I'm lucky I waited" to begin therapy, Harrington said. "I could be dead if I had listened to those same researchers who now say hit hard and hit early."

But Fauci draws draws a different lesson from Harrington's experience: Harrington was lucky not because he waited until he lay at death's door to start treatment, but rather because effective drugs were finally developed. Fauci suggests that anyone who has a high degree of virus replication, even those who are very healthy, should start therapy, because suppressing the virus can protect the immune system. The cold fact is that no one knows the optimal moment to start therapy.

PERHAPS THE BEST NEWS from Geneva is that most patients who respond well to treatment are slowly regaining their immune systems. Brigitte Autran, a leading immunologist from France, has studied more than 300 patients who were fairly advanced in HIV disease. Among those who responded well to the drugs and almost never missed a dose, CD4 counts have risen steadily "with no plateau," says Autran. She looked at many other aspects of the immune system, such as the ability of cells to respond to various bacteria and viruses, and in virtually every test the immune system showed steady improvement.

Autran thinks "there is no limitation" to the capacity of the immune system to revive itself, though she estimates that full recovery will take four to eight years. That process might be speeded up by special immune-enhancing drugs, such as interleukin 2, or IL2, which showed excellent results in several studies presented at the conference. But even with IL2, the immune responses specific to HIV almost never come back.

The human immune system is exquisitely precise; the cells and antibodies that protect against the flu, for example, do nothing against herpes or TB. The reason HIV is so devastating is that it kills the very immune-system cells that orchestrate the body's counterattack against it. These cells are called HIV-specific helper T-cells, and the virus wipes them out in just three to 18 months after it has entered the body. Unfortunately, Autran has seen no revival of HIV-specific helper cells, even after two years of immune recovery. (The only researcher who has seen such recovery in advanced patients is Franco Lori, who has seen it in six of 12 patients treated with the AIDS drug ddI and an experimental drug called hydroxyurea.) But to control HIV and achieve what Ho calls remission, HIV-specific immune responses are required.

A few patients—less than 1 per cent—control the virus on their own, without ever taking drugs, and many of these "long-term nonprogressors" have very strong HIV-specific responses. Furthermore, Harvard's Bruce Walker and the University of Seattle's Julie McElrath have each found that if patients are treated very early, within weeks of getting infected, suppressing the virus prevents the destruction of the critical HIV-specific helper cells. Encouraged by anecdotal cases of patients who went off their medication yet have been controlling HIV without drugs, Walker and Hirschel are each planning trials to see if that experience can be duplicated. In the meantime, doctors strongly warn patients against stopping their drugs, lest HIV come roaring back.

The trials by Hirschel and Walker will use patients who started therapy soon after being infected. But the vast majority of people with HIV don't know they are infected until long after they have lost their HIV-specific responses. Can anything be done for them? Perhaps. In a "late-breaker" study, New York University Medical Center's Fred Valentine showed that an HIV vaccine developed by the late Jonas Salk stimulates strong HIV-specific helper responses in midstage patients being treated with combination therapy. Patients who did not get the vaccine but did receive standard treatment showed no such gain.

In the future, then, it is possible that patients will be treated with standard drug cocktails to suppress their virus, plus IL2 to hasten recovery of their immune systems, plus an AIDS vaccine to stimulate their HIV-specific immunity. After all that, maybe, just maybe, some patients would be able to stop taking the toxic and demanding drug cocktails and have their immune system control the virus on its own. But even if that goal isn't achieved, invigorating the immune system might extend the effectiveness of drugs, buying patients the most valuable thing: time.Research assistance: Tyler Schnoebelen

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