WASHINGTON--In the short term, protease inhibitors are quite effective at stopping replication of HIV, thus permitting recovery of the immune system, but, as with other anti-HIV agents, resistance eventually develops and effectiveness wanes, researchers reported at the 2nd National Conference on Human Retroviruses and Related Infections.
Protease inhibitors under development include Abbott's ABT-538, Merck's L524, and Agouron's AG1343. Abbott researchers reported that ABT-538 halted 99% of HIV replication and reduced the number of circulating virus particles by 70% to 99%. With the virus reduced, T cell counts recover, generally by 100/mL or more after 3 months.
In patients studied to date, resistance to ABT-538 generally develops within months, although some patients have yet to develop resistance after 6 months of treatment, according to Abbott.
In phase I studies of Agouron Pharmaceuticals' AG1343, moderate oral doses resulted in sustained plasma drug levels, well in excess of those required to inhibit replication of HIV, as determined by preclinical experiments. Agouron presented results of two randomized, double-blind studies of the agent carried out in healthy volunteers at Besselaar Clinical Research Unit, Leeds, England. The agent was well tolerated in both groups.
"Oral dosing of AG1343 two or three times a day for a total dose of less than 1 g/day results in plasma drug levels 15 to 75 times higher than required in vitro to suppress HIV replication," said Dr. Barry D. Quart, Agouron's vice president, regulatory affairs, who presented the data.
Dr. Quart pointed out that in preclinical animal studies, a single oral dose of AG1343 resulted in drug concentrations in lymph nodes eight times higher than in plasma. This is important since "we now know that lymph nodes are a critical reservoir for HIV," he said.
Combining protease inhibitors that have different resistance patterns or combining these new agents with reverse transcriptase inhibitors might eventually be used to help overcome drug resistance.