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AIDS Weekly Plus
Conference Coverage (ICAAC): Abbott Protease Inhibitor Shines in Combinations <p></b>
Daniel J. DeNoon, Senior Editor
October 2, 1995
The HIV protease inhibitor ritonavir (ABT-538) nearly obliterated HIV in some patients who took the drug in combination with two standard AIDS therapies.

Moreover, animal studies show that ritonavir in combination with another protease inhibitor, saquinavir, overcomes pharmacologic barriers to that drug and packs an intense one-two punch against HIV.

Researcher Daniel Norbeck of Abbott Laboratories, which manufactures ritonavir, announced preliminary results of a clinical trial of ritonavir combination therapy at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 17-20, 1995, in San Francisco, California.

Trial participants who received ritonavir in a three-drug combination with zidovudine (AZT) and zalcitabine (ddC) had a durable increase in CD4 counts of 110 cells/(micro)L and a unprecedented 2.5-log decrease in viral burden that was sustained after 20 weeks of treatment.

"In some patients the viral reservoir is indeed empty," Norbeck said.

Despite the observation that HIV became undetectable in these patients, the virus is expected to persist at levels below the detection threshold of the assay used and in latently infected cells. Past experience strongly suggests that the virus will eventually rebound. But the study results are a strong indication that protease inhibitors will greatly add to the efficacy of combination AIDS therapies.

Norbeck also reported animal studies showing that ritonavir greatly increases the activity of the Hoffmann-La Roche protease inhibitor saquinavir.

Saquinavir is an order of magnitude less potent than ritonavir. A problem with saquinavir is its poor oral bioavailability and its rapid hepatic metabolism mediated by the cytochrome P450.

Ritonavir, in addition to its anti-HIV activity, is a potent inhibitor of cytochrome P450. Rat studies show that oral co-administration of ritonavir and saquinavir results in a 290-fold increase in saquinavir concentrations.

"The pharmacologic and virologic interactions of ritonavir and saquinavir are therefore likely to afford a potent, two-dimensional synergy in AIDS therapy," Norbeck said.



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