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Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons
C V Fletcher1, S P Kawle, T N Kakuda
1Department of Experimental and Clinical Pharmacology, University of Minnesota Academic Health Sciences Center, Minneapolis 55455, USA.
Insights
Intracellular concentrations of zidovudine and lamivudine triphosphate correlate with CD4 cell counts and HIV RNA decline in patients receiving antiretroviral therapy. These findings highlight the clinical pharmacology of nucleoside reverse transcriptase inhibitors.
Area of Science:
- Pharmacology
- Virology
- Immunology
Background:
- Nucleoside reverse transcriptase inhibitors (NRTIs) are key components of antiretroviral therapy (ART).
- Understanding the intracellular pharmacokinetics of NRTIs is crucial for optimizing treatment outcomes.
- Previous studies have focused on plasma concentrations, but intracellular levels may better reflect drug efficacy.
Purpose of the Study:
- To quantify intracellular zidovudine triphosphate and lamivudine triphosphate concentrations in HIV-infected individuals.
- To explore the relationship between these intracellular drug levels and virologic and immunologic responses to ART.
- To investigate the correlation between intracellular NRTI concentrations and CD4 T cell counts and plasma HIV RNA levels.
Main Methods:
- Prospective, randomized, open-label study involving eight antiretroviral-naive HIV-infected participants.
- Standard dose versus concentration-controlled therapy with zidovudine, lamivudine, and indinavir.
- Frequent collection of peripheral blood mononuclear cells and plasma for drug concentration analysis; CD4 T cell counts and HIV RNA levels measured regularly; regression analyses used to explore relationships.
Main Results:
- Significant positive correlations were found between intracellular zidovudine triphosphate and lamivudine triphosphate concentrations and baseline CD4 cell counts.
- Intracellular lamivudine triphosphate concentrations showed a linear relationship with lamivudine oral clearance.
- Both intracellular zidovudine triphosphate and lamivudine triphosphate concentrations were directly related to the percentage change in CD4 cells and the rate of HIV RNA decline.
Conclusions:
- Intracellular concentrations of zidovudine triphosphate and lamivudine triphosphate are significant determinants of therapeutic success in HIV treatment.
- These findings underscore the clinical implications of intracellular NRTI pharmacology.
- Further research into NRTI combinations and sequential therapies is warranted, guided by these pharmacokinetic insights.
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.
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