Antiviral dynamics and sex differences of AZT and 3TC triphosphate concentrations
Polly Clayden, HIV i-Base
A report in the 17 October issue of AIDS investigates intracellular zidovudine triphosphate and lamivudine triphosphate concentrations in HIV-positive individuals, and the associations between these concentrations and patient characteristics and anti HIV activity.
Peripheral blood mononuclear cells (PBMCs) were obtained at multiple planned intervals from antiretroviral-naîve adult patients enroled in a study of zidovudine, lamivudine and indinavir, and triphosphate levels were determined by immunoassay and high-performance liquid chromatography and mass spectrometry. Plasma HIV-RNA, CD4 cell counts, and plasma drug concentrations were collected over 18 months.
Triphosphate data were available for 33 patients. The investigators found that the estimated half-lives of zidovudine and lamivudine triphosphate were seven and 22 hours, respectively. They noted that triphosphate concentrations were elevated in individuals with low baseline CD4 cell counts and higher in women than in men by 2.3 and 1.6-fold for zidovudine and lamivudine, respectively.
The investigators reported that women (4/33) reached an HIV-RNA level below 50 copies/ml in half the time that men did (median 56 vs 112 days, p=0.02). Of the four women, three were of African descent and there were no differences noted according to race/ethnicity.
They found that zidovudine triphosphate above 30 fmol/106 cells to be independently predictive of time to below 50 copies/ml. Lamivudine triphosphate above 7,017 fmol/106 cells was independently predictive of a sustained virological response (p=0.0008 at week 52).
Zidovudine and lamivudine triphosphate concentrations were independently associated with the antiviral activity of zidovudine, lamivudine, and indinavir. The investigators concluded: “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.”
Anderson PL; Kakuda TN; Kawle S et al. Antiviral dynamics and sex differences of zidovudine and lamivudine triphosphate concentrations in HIV-infected individuals. AIDS 2003; 17(15): 2159-2168