Intracellular nucleoside triphosphate concentrations in HIV-infected patients on dual nucleoside reverse transcriptase inhibitor therapy.
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/10(6) peripheral 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/10(6) PBMC, 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.


CONCLUSIONS
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.
Moore
Jeff D
JD
University of Alabama at Birmingham, Division of Clinical Pharmacology, Birmingham, AL, USA.
Acosta
Edward P
EP
Johnson
Victoria A
VA
Bassett
Roland
R
Eron
Joseph J
JJ
Fischl
Margaret A
MA
Long
Mary C
MC
Kuritzkes
Daniel R
DR
Sommadossi
Jean-Pierre
JP
D019380:Anti-HIV Agents / Q000097:blood / Q000627:therapeutic use*; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives* / Q000097:blood; D054306:Dideoxynucleotides / Q000097:blood*; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000627:therapeutic use*; D018119:Stavudine / Q000097:blood / Q000627:therapeutic use; D013942:Thymine Nucleotides / Q000097:blood*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use
D019380:Anti-HIV Agents; D054306:Dideoxynucleotides; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; C417268:lamivudine triphosphate; D019259:Lamivudine; D015215:Zidovudine; D003570:Cytidine Triphosphate; C052873:zidovudine triphosphate; D018119:Stavudine