747   The Effect of Hydroxyurea (HU) on Intracellular Deoxy- and Dideoxynucleoside Triphosphate Ratios in Naive Subjects Receiving ZDV, ABC, 3TC+- NVP over 48 Weeks—CHARM Phosphorylation Substudy.

D. Back*¹, P. Hoggard¹, A. Maherbe², R. Wood², S. Kwen¹, S. Sales¹, S. Khoo¹, C. De Vries³, and J. Gould⁴.
¹Univ. of Liverpool, Liverpool, UK;²Somerset Hosp., Cape Town, South Africa;³IATEC, Amsterdam, The Netherlands; and⁴Glaxo Wellcome, Greenford, UK.

Background:The combination of some NRTIs and HU is synergistic in vitro, and one of the proposed explanations is that HU preferentially decreases the synthesis of endogenous triphosphates (dNTPs), thereby favouring incorporation of drug triphosphate (ddNTP) during the course of HIV-1 DNA synthesis. We have investigated the effect of adding HU to a triple NRTI regimen (ZDV, ABC, 3TC) to gain additional information on the mechanism of action of HU.

Methods:The CHARM study is based on a factorial design in 229 adults receiving ZDV/ABC/3TC. Patients were first randomised to ± NVP and then to ± HU and finally to ± prednisolone in an effort to prevent hypersensitivity to ABC and/or NVP. The pharmacology substudy was in 24 patients from South Africa. PBMCs were isolated at wk 0 (pre-treatment) and wks 2, 6, 12, 24 and 48. After cell extraction, dNTPs and 3TCTP, CBVTP and ZDVTP were measured by enzymatic primer extension assays.

Results:Mixed linear model with subject as random effect and NVP, HU, wks and hrs (0, 2) as fixed effects was used to assess the effect of HU and NVP. Data to 24 weeks are summarised below (*p-value <0.05).

Conclusions:In agreement with previous in vivo data, dATP levels were not lower in the HU arm. Of interest is the significant increase in the CBVTP/dGTP ratio in patients receiving NVP. We conclude that HU does not alter the drug/endogenous triphosphate ratios for ABC or 3TC. We await the 48 week efficacy/toxicity data.