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Prospects seem bright that the first easy-to-administer, truly new HIV drugs in years will soon emerge from the lab, giving doctors and patients hope in the increasingly difficult battle against drug-resistant HIV. Panacos Pharmaceuticals will report on an initial human study of its maturation inhibitor, the first of a new class of anti-HIV drugs, today at the Fifteenth Annual AIDS Conference in Bangkok, Thailand. And a different type of compound developed by Merck performed well in monkey studies that were published last week online by the journal Science.

New classes of drugs are essential in combating the increasingly common strains of HIV that are resistant to todays drugs. By targeting different stages of the viruss replication cycle, compounds such as the two tested by Panacos and Merck should provide new weapons in doctors arsenals.

The two compounds target opposite points in the viral life cycle. Mercks compound blocks an early stage in the infection cycleat least in a monkey model of the disease. The Panacos drug, on the other hand, halts the final steps in the maturation of the virus, so far also only in animal models.

During the 1990s, the development of effective drugs transformed HIV from a death sentence into a chronic illness. Two main classes of drugs now make up the anti-HIV arsenal: reverse transcriptase and protease inhibitors, each of which blocks a different enzyme essential to the virus’s ability to copy itself after infecting human blood cells. Although 13 reverse transcriptase inhibitors and eight protease inhibitors are now approved for human use, resistance to these so-called anti-retroviral drugs is a growing problem, because all of them target only one of two stages in the viral life cycle.

The problem of drug resistance is in a very substantial way compromising the effectiveness of the inhibitors that have been in use for almost 10 years, says Eric Freed, chief of the virus-cell interaction section of the National Cancer Institutes HIV Drug Resistance Program. The dilemma is two-fold. First, patients who have been on anti-retroviral therapy for years will often cycle through all of the available drugs as the virus in their bodies mutates rapidly, acquiring resistance to one drug after another. Moreover, the number of new HIV infections resulting from the transmission of strains that are already resistant to one or more antiretroviral drugs is increasing. Indeed, about 10 to 20 percent of new infections in the United States and Europe are from HIV strains harboring resistance to at least one of the classes of antiretroviral drugs, according to numerous studies done over the last five years. The need for new drugs, Freed says, is extremely pressing.

In order to copy itself once it infects cells, HIV must splice its genetic material into the hosts DNA. Merck’s potential new drug inhibits the enzyme, called integrase, that is responsible for this step. The Merck compound is highly effective in an HIV model in rhesus macaques, according to a study published online in Science Express on July 8. This is not the first integrase inhibitor tested; however, a previous compound, tested by GlaxoSmithKline, did not fare well in human trials. Merck’s new compound seems to be much more active than GlaxoSmithKlines, says Daria J. Hazuda, vice president of virus and cell biology at Merck Research and the studys lead author.

If you could completely block the integration step, you could effectively completely block the replication of the virus, says Robert Craigie, who studies integrase in his work as the molecular virology section chief in the National Institute of Diabetes and Digestive and Kidney Diseases Molecular Biology Lab. Its a very promising step forward, Craigie says. Hazuda says Merck hopes to begin human tests within several years, though theres still a long way to go.

Panacos, meanwhile, has already moved into initial human tests of a new drug that attacks a much later stage in the HIV replication cycle. Today’s announcement by the company pertains to the results of a safety trial of its maturation inhibitor undertaken with healthy, noninfected volunteers. After the viruses are copied in infected cells, they are released to infect new cells. But before they can become infectious, the viruses proteins must mature, reorganizing into a central core structure; Panacoss drug appears to block that step.

This first human test was designed only to assess the drugs safety. The results are excellent, says Carl Wild, Panacoss chief scientific officer. Not only does the drug cause few side effects, but patients may need to take it only once a day. That’s unusual for HIV drugs, many of which require complicated dosing regiments. Freed, who has participated in lab studies of the drug but has no financial ties to Panacos, believes the drug has the potential to benefit patients who have run out of existing medications. Obviously theres a big step that one takes when going from tissue culture to patients, he says, but at least the preliminary clinical data are very encouraging.” Panacos plans to begin tests of the drug in HIV-infected patients later this year.

Like the Panacos drug, Mercks compound has been effective in the test tube against HIV viruses that have shown resistance to multiple drugs. Both of the new compounds could be taken as pills. As a result, researchers see both as offering realistic hope for the first easy-to-administer, truly new HIV treatments in years. While they, too, will eventually face viral resistance, the goal, Freed says, is to stay a step ahead of the virus.

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