BACKGROUND:
Nucleoside analog reverse transcriptase inhibitors (NRTIs) are used in
virtually all anti-HIV regimens. Clinical response and toxicity depend on
intracellular formation of the pharmacologically active triphosphate moiety,
however few clinical pharmacology studies of NRTI-triphosphates have been
conducted to date. Past observational studies suggest females have stronger
anti-HIV responses and more toxicities to NRTIs compared with males, but no
mechanisms have been suggested for why. Our objective was to quantify ZDV-
and 3TC-TP in HIV-infected adults and to characterize patient and disease
factors associated with these concentrations.
METHODS:
Antiretroviral naïve adults were participating in a study of ZDV, 3TC, and
indinavir (IDV). At 2-hours post dose on each of three intensive plasma
pharmacokinetic studies, and at routine study intervals, PBMCs and paired
plasma were obtained and the times post dosing were recorded. Triphosphate
levels were determined by immunoassay (ZDV-TP) and LC/MS/MS (3TC-TP). Plasma
HIV-RNA and CD4 cell counts were collected over the 18-months of possible
follow-up. Data were analyzed with nonparametric, regression, and time to
event statistical methods.
RESULTS:
ZDV- and 3TC-TP concentrations (n=310) were obtained from 33 subjects;
estimated half-lives were 7 and 22 hours, respectively. Females (n=4; 42
samples) had 2.3-fold higher ZDV-TP (P=0.002) and 1.6-fold higher 3TC-TP
(P=0.003) concentrations compared with males (n=29; 268 samples), and
reached <50 copies/mL of HIV-RNA twice as fast as males (P=0.02). No sex
differences were found in the paired concentrations of ZDV and 3TC in
plasma, times post-dosing, or among any other demographic and ZDV, 3TC, and
IDV data. Low baseline CD4 cells were also associated with elevated
triphosphate concentrations.
CONCLUSION:
In this study, females and subjects with low baseline CD4s had significantly
elevated triphosphates. While there were few females overall, each subject
was intensively sampled and the magnitudes of the sex difference and
statistical significance were substantial. The higher triphosphates in
females provided a plausible explanation for the stronger antiviral response
in females compared with males. Furthermore, female sex and low CD4 counts
have been epidemiologically associated with serious long-term
NRTI-associated toxicity. The findings in this study allow the hypothesis
that high intracellular triphosphate concentrations contribute to the
pathogenesis of these events.
|
Main
New/Newsworthy