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Wide Resistance by HIV

Some HIV strains can resist nearly all the drugs now available in the United States, according to a report in today's Annals of Internal Medicine. Scientists say the study underscores the dire need for new anti-HIV drugs, despite recent success at slowing HIV infections with potent drug cocktails.

The cocktail--"highly active antiretroviral therapy" (HAART)--is a mix of three or four drugs that block two key viral enzymes: reverse transcriptase and protease. HAART works with "great success" when given soon after infection, says virologist Robert Shafer of Stanford University Medical Center, the study's lead author. "The slogan is, `hit 'em hard, hit 'em early,'" he says. But the treatment often fails for patients with long-standing infections, Shafer says, especially those who have taken drugs one after another as they became available.

To check resistance to available drugs, Shafer's team isolated HIV from four people infected with HIV, mixing the cultured virus with eight of 11 drugs now on the market--reverse transcriptase and protease inhibitors that the subjects had taken for up to 9 years. The HIV strains resisted seven of the eight drugs, as well as a new protease inhibitor the patients had never taken--which shows how easily HIV can develop resistance to a drug class, Shafer says. Surprisingly, the four viral strains each had seven identical mutations in the genes for both key enzymes. Because other regions of the viral RNA sequence were different for each strain, the identical drug-fighting mutations must have evolved independently, Shafer says. The team later found many of the same mutations in HIV from 400 other patients who were not responding to long-term retroviral therapy.

AIDS researchers are disappointed but not surprised by the tough new strains. "I had heard people talk about multiple drug resistance, but this formal documentation is important," says Robert Gallo of the Institute of Human Virology at the University of Maryland. Experts agree they need anti-HIV drugs that work by different mechanisms than those now on the market. While just a few mutations appear capable of making HIV impervious to entire classes of drugs, such resistant strains are genetically similar and may be vulnerable to a single new drug, Shafer says. Adds Charles Carpenter of Brown University School of Medicine: "We very badly need to develop new classes of antiretroviral agents."