As soon as HIV was identified in the mid 1980s, scientists began to study its structure and replication mechanism, looking for its weak points. That research identified three essential enzymes: reverse transcriptase, integrase, and protease.
Reverse transcriptase was the first enzyme for which an effective compound was discovered because AZT already existed as an orphan drug. Protease inhibitors came next because there were already structural models for these compounds. But the search for an integrase inhibitor had to start from scratch.
First, researchers had to develop an assay to test for integrase activity so that potential compounds could be screened for possible anti-integrase activity. Unfortunately, early assays were unreliable, frequently giving false-positive results. This led to a lot of dead ends'compounds that looked good initially but that failed to block integrase activity in human cells. Other assays failed to recognize all three areas of integrase activity and initially overlooked a promising compound.
Then, in 1995, the National Institutes of Health convened a meeting on integrase where there was a presentation on the three-dimensional structure of integrase, and several companies reported on potential compounds. But progress was slowed when a promising compound failed because of poor bioavailability.
Finally, in 2005 at the 12th Conference on Retroviruses and Opportunistic Infections, Merck reported on results from a Phase I trial of L-000870810, an integrase inhibitor that dropped viral loads 98% in a 10-day period. But within a few months, development of this drug was stopped after liver and kidney toxicities appeared in dogs that had been on the drug for extended periods of time.
Fortunately, Merck had been working on another integrase inhibitor, MK-0518, and Phase II data was presented at the European AIDS Clinical Society in November 2005. In that study the compound was given as monotherapy in four different dosages to 35 retroviral-naive patients for 10 days. The drop in viral load ranged from 1.7 to 2.2 logs, with 50% of patients dropping below 400.
At the 2006 Conference on Retroviruses and Opportunistic Infections, results were presented from a Phase IIb trial. Here 167 patients, all three-class resistant, were randomized to three different dosages or placebo combined with optimized backbone regimens. At 16 weeks the percentages of viral loads less than 50 ranged from 57% to 72%. The drug was generally well-tolerated; common side effects were diarrhea, nausea, vomiting, fatigue, headache, and itching. The drug was given twice a day with or without food. A Phase III trial at the middle dosage of 400 milligrams twice a day is planned.
Also at the 2006 conference, Gilead presented Phase I data on GS 9137, which was licensed last year from Japan Tobacco. In the trial of 40 patients half were retroviral-experienced. The drug was given as monotherapy for 10 days in five different dosages. Overall, there was a two-log reduction in viral load. All adverse events were grade 1 or 2 and were not associated with the dosing. A dose-ranging Phase II trial is planned.
So far there is no resistance data, but it has been reported that laboratory studies indicate that integrase inhibitors may have a high barrier to resistance. It was also suggested that resistant viruses may be less fit. However, there are also reports that two resistant mutations found in cell cultures already exist in some patients.
Others express concern that integrase inhibitors may have only one chance to work'if they fail to stop the integration of the proviral DNA into the CD4-cell genome, they are no longer effective in that cell and replication can proceed. In contrast reverse transcriptase and protease inhibitors remain active in each and every replication cycle.
Still, it is hopeful to see progress finally being made on our next class of antiretrovirals. Studies are now showing that 78% of people who fail their regimens are resistant to more than one class, and nearly 20% of treatment-naive patients carry resistant virus. So the arrival of integrase inhibitors comes none too soon.
Bowers is board-certified in family practice and is a senior partner with Pacific Oaks Medical Group, one of the largest U.S. practices devoted
to HIV care. E-mail him at email@example.com.
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