Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals

Abstract

Nucleoside analog reverse transcriptase inhibitors (NRTI) are used in virtually all anti-HIV regimens. Clinical response depends on the intracellular formation of the pharmacologically active triphosphate moiety. Our objective was to quantify the pharmacological characteristics of zidovudine and lamivudine triphosphate in HIV-infected individuals. Peripheral blood mononuclear cells were obtained at multiple planned intervals from antiretroviral-naive adults participating in a study of zidovudine, lamivudine and indinavir, and triphosphate levels were determined by immunoassay and high-performance liquid chromatography/mass spectrometry. Plasma HIV-RNA, CD4 cell counts, and plasma drug concentrations were collected over 18 months. Data were analysed using non-parametric, regression and time-to-event methods. Thirty-three subjects were evaluated. The estimated half-lives of zidovudine and lamivudine triphosphate were 7 and 22 h, respectively. Triphosphate concentrations were elevated in individuals with low baseline CD4 cell counts. Triphosphate concentrations in women were higher than in men by 2.3 and 1.6-fold for zidovudine and lamivudine, respectively. Women reached an HIV-RNA level under 50 copies/ml twice as fast as men. Zidovudine triphosphate above 30 fmol/10(6) cells was independently predictive of the time to under 50 copies/ml. Lamivudine triphosphate above 7017 fmol/10(6) cells was independently predictive of a longer virological response. Indinavir concentrations were related to antiviral responses in univariate analyses. Zidovudine and lamivudine triphosphate concentration thresholds were independently associated with the antiviral activity of zidovudine, lamivudine, and indinavir. The significantly elevated triphosphate concentrations in women and individuals with low baseline CD4 cell counts, groups that historically experience high rates of serious NRTI toxicities, provide a hypothesis for the pathogenesis of these events.