The Virus Fights Back

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

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."

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