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Session 64 Poster Session Therapeutic Drug Monitoring Session Time: 4:30-6:30 pm Room 4E-F

455-W. Virological Failure Is Associated with Decreased 3TC Triphosphate (3TCTP) and Ratio of 3TCTP/Endogenous Deoxycytidine Triphosphate in HIV-Infected Individuals in a Clinical Setting P. Hoggard*1, S. Kewn1, J. Lloyd1, S. Sales1, E. Wilkins2, B. Maher1, E. Meaden1, L. Almond1, T. Jones3, D. Pillay4, C. Sabin5, S. Khoo1, and D. Back1 1Univ. of Liverpool; 2Northern Manchester Gen. Hosp.; 3GlaxoSmithKline; 4Univ. of Birmingham Med. Sch.; and 5Royal Free Hosp., London, UK Background: Cellular factors may be partly responsible for drug resistance to the dideoxynucleoside analogues, possibly due to decreased drug activation. Intracellular phosphorylation of these drugs to their triphosphates is essential for activity. The drug triphosphates (ddNTPs) then compete with endogenous deoxynucleoside triphosphates (dNTPs) for incorporation into HIV reverse transcriptase. The study investigated if active drug triphosphates and their corresponding intracellular ratios (ddNTP/dNTPs) were different in patients responding to and failing combination antiretroviral therapy. Methods: All patients recruited had regular attendance at the adherence clinic of North Manchester General Hospital. Patients were receiving recommended combination therapy. Both patients responding (viral load <400 copies/mL; n=50) and failing therapy (2 consecutive viral loads > 400; n= 41) were recruited. Nucleoside analogue triphosphates were assessed at a single time-point (0-12 hours after dosing). Both dNTP and ddNTP were determined in PBMCs (5-10 million cells) by template primer extension assays. Statistical analysis was performed by Mann Whitney U test. Results: Median data are shown in the table. Failures (n) Responders (n) p value (95% CI) Viral load 3360 (50) 82 (41) <0.001 (-10150 to-2062) CD4 count 330 (50) 360 (41) 0.174 (-30 to 140) dTTP 0.190 (49) 0.157 (34) 0.276 (-0.109 to 0.024) dCTP 0.198 (38) 0.242 (28) 0.930 (-0.089 to 0.101) dGTP 0.028 (17) 0.030 (24) 0.704 (-0.040 to 0.020) CBVTP 0.173 (19) 0.123 (24) 0.164 (-0.126 to 0.09) 3TCTP 2.917 (24) 1.712 (37) 0.031 (0.094 to 1.772) Intracellular levels of 3TCTP and the ratio of 3TCTP/dCTP were lower in failures than non-failures. In all patients receiving therapy including ABC and 3TC, a weak relationship between the ratios of CBVTP/dGTP and 3TCTP/dCTP was seen (n=12, r2= 0.421, p = 0.037). Conclusions: There was no difference in the intracellular levels of endogenous dNTPs between the 2 groups. This suggests that the activation state of the cell is not significantly different in patients either responding to or failing combination antiretroviral therapy. However, in patients receiving 3TC as part of therapy, there was an association between 3TCTP concentrations and virological failure.

©2002 9th Conference on Retroviruses and Opportunistic Infections