title: 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 IC(95) values for wild-type HIV-1. However, these troughs are well below corrected IC(95) 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 IC(95) by 2-, 7-, and 28-79-fold, respectively. These indinavir and amprenavir troughs exceed IC(95) 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.
authors.affiliation: Department of Antiviral Research, Merck Research Laboratories, West Point, PA 19486, USA. jon_condra@merck.com
authors.forename: J H
authors.initials: JH
authors.lastname: Condra
authors.forename: C J
authors.initials: CJ
authors.lastname: Petropoulos
authors.forename: R
authors.initials: R
authors.lastname: Ziermann
authors.forename: W A
authors.initials: WA
authors.lastname: Schleif
authors.forename: M
authors.initials: M
authors.lastname: Shivaprakash
authors.forename: E A
authors.initials: EA
authors.lastname: Emini
mesh_terms: D002219:Carbamates; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005663:Furans; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000235:genetics; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000627:therapeutic use; D019888:Nelfinavir / Q000008:administration & dosage / Q000627:therapeutic use; D010641:Phenotype; D011485:Protein Binding; D019438:Ritonavir / Q000008:administration & dosage / Q000627:therapeutic use; D019258:Saquinavir / Q000008:administration & dosage / Q000627:therapeutic use; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use
chemical_list: D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D013449:Sulfonamides; C095108:amprenavir; D019469:Indinavir; D019888:Nelfinavir; D019258:Saquinavir; D019438:Ritonavir