Background: Intracellular nucleoside reverse transcriptase
inhibitor triphosphate (NRTI-TP) concentrations are
crucial in suppressing HIV replication. Little is known
about how commonly used dual-NRTI regimens affect the
intracellular levels of NRTI-TPs, the active form of these
drugs. This study investigates the effect of dual-NRTI
therapy in intracellular NRTI-TP levels.
Methods: NRTI and NRTI-TP concentrations were
evaluated in HIV-infected patients receiving either
lamivudine (3TC) and stavudine (d4T) or lamivudine with
zidovudine (ZDV); NRTI and NRTI-TP concentrations were
determined using a validated HPLC/MS/MS method.
Plasma HIV-1 RNA levels were determined at baseline
and monthly to examine the relationship between
NRTI-TP concentrations and plasma HIV-1 RNA.
Results: Forty-one subjects completed the study. 3TC-TP
significantly increased between day 1 and week 28 from
1.48 to 5.00 pmol/106peripheral blood mononuclear cells
(PBMC; P< <0.0001). NRTI-TP concentrations for d4T and
ZDV did not significantly increase, with values at week 28
of 0.011 and 0.02 pmol/106PBMC, respectively. Mean
NRTI-TP/plasma ratios were 3%, 0.007% and 0.05% for
3TC, d4T and ZDV, respectively. Linear relationships were
observed between ZDV- and 3TC-TP and changes in
plasma HIV-1 RNA.
Conclusion: Of the three drugs studied, only 3TC-TP
levels increased significantly between day 1 and week 28.
ZDV-TP and 3TC-TP levels were unaffected by dual-NRTI
therapy relative to monotherapy, regardless of the
combination (3TC–ZDV or 3TC–d4T). Intracellular levels
of d4T-TP were similar to previous reports for dual-NRTI
therapy; however, in the case of d4T, these values appear
lower than those achieved with d4T monotherapy.
Intracellular nucleoside triphosphate concentrations
in HIV-infected patients on dual nucleoside reverse
transcriptase inhibitor therapy
Jeff D Moore1,2, Edward P Acosta1*, Victoria A Johnson3, Roland Bassett4,5, Joseph J Eron6,
Margaret A Fischl7, Mary C Long1, Daniel R Kuritzkes8and Jean-Pierre Sommadossi1,9
1University of Alabama at Birmingham, Division of Clinical Pharmacology, Birmingham, AL, USA
2Current position: Avanti Polar Lipids, Inc., Alabaster, AL, USA
3Birmingham Veterans Affairs Medical Centre and University of Alabama at Birmingham School of Medicine, Division of Infectious
Diseases, Birmingham, AL, USA
4Harvard School of Public Health, Boston, MA, USA
5Current position: M.D. Anderson Cancer Centre, Houston, TX, USA
6University of North Carolina at Chapel Hill, NC, USA
7University of Miami, Miami, FL, USA
8Brigham and Women’s Hospital, Cambridge, MA, USA
9Current position: Idenix Pharmaceuticals, Cambridge, MA, USA
*Corresponding author: Tel: +1 205 934 2655; Fax: +1 205 934 6201; E-mail: EAcosta@uab.edu
Antiviral Therapy 12:981–986
Nucleoside reverse transcriptase inhibitors (NRTIs)
remain a cornerstone of highly active antiviral therapy
used for treatment of HIV-1 infection and their efficacy
has been well established [1–5]. However, little is
known about how coadministration of two NRTIs
affects the metabolism and activity of these
compounds. NRTIs have similar mechanisms of
action, requiring host conversion of their inactive
prodrugs to nucleoside triphosphate (NTP) analogues,
which are the biologically active form of the drug.
These NTP analogues compete with the natural
deoxynucleoside triphosphates (dNTP) for binding to
the reverse transcriptase primer:template complex.
Once incorporated into the nascent DNA chain,
© 2007 International Medical Press 1359-6535
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© 2007 International Medical Press
Accepted for publication 31 May 2007