Drug Resistance and Predicted Virologic Responses to Human Immunodeficiency Virus Type 1 Protease Inhibitor Therapy

Abstract

The extent to which human immunodeficiency virus (HIV) type 1 drug resistance compromises therapeutic efficacy is intimately tied to drug potency and exposure. Most HIV-1 protease inhibitors maintain in vivo trough levels above their human serum protein binding—corrected IC₉₅ values for wild-type HIV-1. However, these troughs are well below corrected IC₉₅ values for protease inhibitor—resistant viruses from patients experiencing virologic failure of indinavir and/or nelfinavir. This suggests that none of the single protease inhibitors would be effective after many cases of protease inhibitor failure. However, saquinavir, amprenavir, and indinavir blood levels are increased substantially when each is coadministered with ritonavir, with 12-h troughs exceeding corrected wild-type IC₉₅ by 2-, 7-, and 28–79-fold, respectively. These indinavir and amprenavir troughs exceed IC₉₅ for most protease inhibitor—resistant viruses tested. This suggests that twice-daily indinavir-ritonavir and, to a lesser extent, amprenavir-ritonavir may be effective for many patients with viruses resistant to protease inhibitors.