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Second-Generation HIV Drug Treats Resistant Virus

"Second coming" of HIV cocktails may slow the spread of drug-resistant virus
pills in cocktail glass



© ISTOCKPHOTO/CLAUDIA CASTALDI
Results from a highly anticipated clinical study show that an experimental drug suppressed the human immunodeficiency virus (HIV) to undetectable levels in people with highly drug-resistant forms of the pathogen. The drug, TMC125 (etravirine), is the first of its kind in nearly a decade and is one of three new drugs capable of treating drug-resistant HIV that the Food and Drug Administration (FDA) is expected to approve this year.

The new drugs offer the hope of treatment to perhaps thousands of HIV patients who have stopped responding to other medications, says William Towner, medical director of the Kaiser Permanente HIV/AIDS research trials program and member of the study team, which reported its findings online today in The Lancet. By keeping the virus at undetectable levels, researchers believe they can slow the spread of drug-resistant varieties.

The phase III study tracked 591 U.S. patients whose infections were resistant to the most common types of antiretrovirals, the medications used to treat HIV. Along with their preexisting regimens they were given the recently approved drug TMC114 (darunivir) as well as either TMC125 or a placebo. After 24 weeks, virus levels were undetectable—defined as less than 50 copies per milliliter of blood—in 62 percent of patients receiving TMC125, compared with 44 percent that received only the other drugs.

Tibotec, the company that developed TMC125 and darunivir, sponsored the trial and was involved in analyzing the data.

Drug manufacturers have developed more than 20 antiretroviral compounds since 1987 when the antiretroviral drug AZT came to market. All but one fall into one of three categories—either nucleoside or nonnucleoside reverse transcriptase inhibitors or protease inhibitors—based on the part of the virus they target.

Combining drugs from multiple classes into so-called cocktails makes it harder for the rapidly mutating virus to evolve resistance, but adding a single drug to a failing cocktail quickly breeds resistance to it, too. And when a member of one class fails it can take the rest along with it. A single mutation renders HIV immune to the three existing nonnucleoside transcriptase inhibitors.

TMC125 is a new, fourth member that picks up where the others leave off. When combined with darunivir and a third drug, it led to undetectable virus in 82 percent of 82 patients, according to the study.

"This is the first example that a second generation of this class can actually be part of a new regimen," says HIV researcher Eric Daar of the Los Angeles Biomedical Research Center and the David Geffen School of Medicine at U.C.L.A.

The development of protease inhibitors in the mid-1990s first made it possible to bring the virus to undetectable levels, but additional drugs trickled in one at a time, Towner says. "For many years we've had to make this hard choice" when a cocktail fails, he says. "Do we add the one [new] drug and burn our bridges … or do we wait for two drugs?"

Earlier this year phase III results came in for two other new drugs, Pfizer's maraviroc and Merck's raltegravir, each of which is the first in a new antiretroviral category and leads to undetectable levels of drug-resistant virus in about half of studied cases. All three compounds have been submitted for FDA approval.

They would join the second-generation protease inhibitors darunivir and Pfizer's tipranivir, both approved in the last two years. "This is the second coming of HIV medical therapy," Towner says. "That's what makes [TMC]125 so exciting."

Daar says there is no recent tally of multidrug-resistant HIV but he estimates that tens of thousands may harbor such infections. Towner says that in his clinical practice in Los Angeles, 15 to 20 percent of his 300-plus HIV patients have a highly resistant virus. "It hasn't exploded into a wildfire yet,'' he says, "but the potential exists."

Doctors and patients will never apply medications perfectly, Towner says, hence the existence of multidrug-resistant HIV. But with new cocktails on the horizon, he adds, "the hope would be that in a sizeable number of patients we could avoid any drug resistance."

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