Journal
AIDS
Volume 14, Issue 14, Pages 2137-2144Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/00002030-200009290-00010
Keywords
HIV; zidovudine; lamivudine; nucleoside reverse transcriptase inhibitor; combination therapy
Categories
Funding
- NCI NIH HHS [P30 CA79458] Funding Source: Medline
- NCRR NIH HHS [MO1 RR00400] Funding Source: Medline
- NIAID NIH HHS [R01 AI33835] Funding Source: Medline
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Objective: To quantitate intracellular concentrations of zidovudine and lamivudine triphosphate and explore relationships with virologic and immunologic responses to antiretroviral therapy. Design: Eight antiretroviral-naive, HIV-infected persons with CD4 T cell counts > 100 X 10(6) cells/l, and HIV RNA in plasma > 5000 copies/ml participating in a prospective, randomized, open-label study of standard dose versus concentration-controlled therapy with zidovudine, lamivudine, and indinavir. Methods: Peripheral blood mononuclear cells and plasma were collected frequently throughout the study for quantitation of intracellular zidovudine triphosphate and lamivudine triphosphate concentrations, and zidovudine and lamivudine concentrations in plasma. CD4 T cells and HIV RNA in plasma (Roche Amplicor Ultrasensitive Assay) were measured at baseline and every 4 weeks throughout the study. Relationships among intracellular and plasma concentrations, and CD4 T cells and HIV RNA in plasma were investigated with regression analyses. Results: Significant relationships were observed between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate and the baseline level of CD4 cells. Lamivudine triphosphate concentrations were related in a linear manner to the apparent oral clearance of lamivudine from plasma. A direct linear relationship was found between the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. The percent change in CD4 cells during therapy and the rate of decline in HIV RNA in plasma were related to the intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate. Conclusion: These studies into the intracellular clinical pharmacology of nucleoside reverse transcriptase inhibitors illustrate potential clinical implications as determinants of therapeutic success. Moreover, these findings provide several leads and a strong impetus for future investigations with nucleoside reverse transcriptase inhibitors particularly when given in combination and sequentially. (C) 2000 Lippincott Williams & Wilkins.
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