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Protease Inhibitors Temporarily Suppress HIV Replication

Protease Inhibitors Temporarily Suppress HIV Replication

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

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.


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