Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons

Courtney V Fletcher, Sagar P. Kawle, Thomas N. Kakuda, Peter L. Anderson, Dennis Weller, Lane R. Bushman, Richard C. Brundage, Rory P. Remmel

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

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 106 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 and Wilkins.

Original languageEnglish (US)
Pages (from-to)2137-2144
Number of pages8
JournalAIDS
Volume14
Issue number14
DOIs
StatePublished - Nov 2 2000

Fingerprint

HIV
Lamivudine
RNA
Reverse Transcriptase Inhibitors
Zidovudine
T-Lymphocytes
Nucleosides
Indinavir
3'-azido-3'-deoxythymidine 5'-triphosphate
lamivudine triphosphate
Clinical Pharmacology
CD4 Lymphocyte Count
Cell- and Tissue-Based Therapy
Blood Cells
Therapeutics
Regression Analysis

Keywords

  • Combination therapy
  • HIV
  • Lamivudine
  • Nucleoside reverse transcriptase inhibitor
  • Zidovudine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Fletcher, C. V., Kawle, S. P., Kakuda, T. N., Anderson, P. L., Weller, D., Bushman, L. R., ... Remmel, R. P. (2000). Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons. AIDS, 14(14), 2137-2144. https://doi.org/10.1097/00002030-200009290-00010

Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons. / Fletcher, Courtney V; Kawle, Sagar P.; Kakuda, Thomas N.; Anderson, Peter L.; Weller, Dennis; Bushman, Lane R.; Brundage, Richard C.; Remmel, Rory P.

In: AIDS, Vol. 14, No. 14, 02.11.2000, p. 2137-2144.

Research output: Contribution to journalArticle

Fletcher, CV, Kawle, SP, Kakuda, TN, Anderson, PL, Weller, D, Bushman, LR, Brundage, RC & Remmel, RP 2000, 'Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons', AIDS, vol. 14, no. 14, pp. 2137-2144. https://doi.org/10.1097/00002030-200009290-00010
Fletcher, Courtney V ; Kawle, Sagar P. ; Kakuda, Thomas N. ; Anderson, Peter L. ; Weller, Dennis ; Bushman, Lane R. ; Brundage, Richard C. ; Remmel, Rory P. / Zidovudine triphosphate and lamivudine triphosphate concentration-response relationships in HIV-infected persons. In: AIDS. 2000 ; Vol. 14, No. 14. pp. 2137-2144.
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