A PRELIMINARY EVALUATION OF NELFINAVIR MESYLATE, AN INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS (HIV)-1 PROTEASE, TO TREAT HIV-INFECTION

A phase I/II dose-ranging open-label 28-day monotherapy study of the s afety, pharmacokinetics, and antiviral activity of nelfinavir mesylate (Viracept), an inhibitor of human immunodeficiency virus (HIV)-1 prot ease, was done in 65 HIV-l-infected subjects, After 28 days, 54 respon ding subjects entered an open-label extension that allowed for the add ition of nucleoside inhibitors of reverse transcriptase and dose escal ation to maintain durability. The drug was well-tolerated and demonstr ated robust antiviral activity, with demonstrable superiority of the 7 50 mg and 1000 mg three times daily regimens. Thirty subjects who cont inued to receive therapy at 12 months attained a persistent 1.6 log(10 ) reduction in HIV RNA, accompanied by a mean increase in CD4 cells of 180-200/mm(3). Studies of viral genotype and phenotype after virus re bound revealed that the initial active site mutation allowing for nelf inavir resistance is mediated by a unique amino acid substitution in t he HIV-1 protease D30N, which does not confer in vitro phenotypic cros s-resistance to the currently available protease inhibitors.