Study Signals Promise for New HIV Therapy Approach

An experimental drug helped to check the HIV enzyme integrase in monkeys, according to research published Thursday, a hopeful step in the fight to block HIV's reproduction and spread in humans. The news follows years of failed attempts at targeting integrase, but more testing would be required to prove that Merck & Co.'s approach can truly work.

"I don't want your readers to think I'm doing cartwheels over this," said Dr. Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases. But, he added, "This is the next step in the process that the field, myself included, has been looking for, for some time now. It's a very important target."

An integrase inhibitor would open up a potential third front in fighting HIV. Numerous older drugs work by blocking two of the three enzymes -- reverse transcriptase and protease -- that HIV uses to incorporate its genes into cells and to spread. In a second, newer approach, Fuzeon works by preventing the virus from invading immune-system cells. But the loss of older drugs' effectiveness means a new approach is needed.

Integrase, the third enzyme, is crucial to the melding of HIV genes with patients' own DNA. That step is vital to HIV's ability to hide inside cells so it can rebound, said Fauci. It has also been extremely difficult to block this process. After initial human studies, GlaxoSmithKline and Shionogi & Co. abandoned one integrase inhibitor candidate last year, and they are now searching for stronger candidates.

In the current study, six monkeys newly infected with a combination monkey-human version of HIV received Merck's candidate, L-870812. These animals experienced mild decreases in CD4 cells, and four had HIV levels drop to undetectable levels, said lead researchers Daria Hazuda and Steven Young. Six untreated monkeys saw CD4 levels plummet and viral levels jump; when treated almost three months later, the ill monkeys all improved somewhat, but not nearly so much as the newly infected monkeys.

Merck is also studying integrase inhibitor pill candidates in a few people to assess the safety and check for early signs of viral suppression. Results due next year will determine whether larger studies should be performed on the drug candidates.

The study, "Integrase Inhibitors and Cellular Immunity Suppress Retroviral Replication in Rhesus Macaques," was published July 8 online at Science magazine's Web site (2004;10.1126/science.1098632).

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