Correlation between human immunodeficiency virus genotypic resistance and virologic response in patients receiving nelfinavir monotherapy or nelfinavir with lamivudine and zidovudine.

The relationship between detectable human immunodeficiency virus (HIV) genotypic resistance and virologic response was compared in patients receiving nelfinavir as monotherapy (16 weeks) or in combination with lamuvidine and zidovudine (48 weeks). Two patient groups were defined on the basis of the presence or absence of substitutions associated with nelfinavir, a protease (PR) inhibitor, and/or a reverse transcriptase (RT) inhibitor. HIV RNA levels <50 copies/mL were achieved in 17 (85%) of 20 combination-therapy patients without genotypic resistance (PR-RT(-)) versus only 1 (17%) of 6 patients with genotypic resistance (PR-RT(+)). PR-RT(-) patients exhibited greater and more durable virus suppression compared with PR-RT(+) patients. All 6 PR-RT(+) patients had virus with M184V (lamuvidine resistance); 3 isolates also contained D30N (nelfinavir resistance). M184V preceded D30N in all determinable instances. In this study, suppression of HIV replication to <50 copies/mL was associated with durable response and reduced incidence of resistance. Results also indicate that combination regimens can fail despite the absence of detectable genotypic PR resistance.

Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir.

Nelfinavir mesylate (formerly AG1343) is a potent and selective inhibitor of human immunodeficiency virus (HIV) protease approved for the treatment of individuals infected with HIV. Nucleotide sequence analysis of protease genes from plasma HIV type 1 (HIV-1) RNA revealed a unique aspartic acid (D)-to-asparagine (N) substitution at residue 30 (D30N) in 25 of 55 patients treated with nelfinavir for a median of 13 weeks. Although the appearance of D30N was occasionally associated with concurrent or sequential emergence of other changes (e.g., at residues 35, 36, 46, 71, 77, and 88), genotypic changes associated with phenotypic resistance to other protease inhibitors were not observed (e.g., at residues 48, 50, 82, and 84) or were only rarely observed (e.g., at residue 90). In phenotypic assays, viral isolates with high-level resistance to nelfinavir remained susceptible to indinavir, saquinavir, ritonavir, and amprenavir (formerly VX-478/141W94). Similar results were observed in phenotypic assays utilizing HIV-1 NL4-3, which contained the D30N substitution alone or in combination with substitutions at other residues (e.g., residues 46, 71, and 88). These data indicate that the initial pathway of resistance to nelfinavir is unique and suggest that individuals failing short courses of nelfinavir-containing regimens may respond to regimens containing other protease inhibitors.