ObjectiveTo determine the relationships betweenin vivozidovudine (ZDV) phosphorylation in cells from HIV-infected patients and markers associated with disease progression and drug toxicity.DesignA pharmacokinetic study of ZDV metabolism sponsored by the AIDS Clinical Trials Group (protocol 161). Plasma and intracellular pharmacokinetics following a 100 mg oral dose of ZDV were determined at weeks 4 and 24 of initial therapy in adult patients. Plasma concentrations and phosphorylated ZDV were determined by radioimmunoassay, and area under the concentration-time curves (AUC) were compared with clinical data collected during the pharmacokinetic study.SettingAn outpatient setting at the University of Cincinnati AIDS Treatment Center, Cincinnati, Ohio, USA.PatientsHIV-infected adults with CD4+ lymphocyte counts 200–500 × 106cells/I with no prior history of anti-HIV therapy and no active infections requiring systemic therapy. Of 30 patients enrolled, 21 were evaluable.InterventionsNone.Main outcome measuresAUC of plasma ZDV and intracellular total phosphorylated ZDV were compared with change from baseline of the following surrogate markers: CD4+ lymphocyte count, %CD4+ lymphocytes, CD4+/CD8+ cell ratio, serum β2-microglobulin, serum neopterin, neutrophils, red cell count, and hemoglobin.ResultsNo correlations between plasma AUC and markers of therapeutic response were observed. However, significant positive correlations were observed between the AUC of total phosphorylated ZDV and changes in the %CD4+ lymphocytes and CD4+/CD8+ lymphocyte ratio; a negative correlation was observed with change in hemoglobin. Patients who responded to ZDV therapy, as measured by these variables, demonstrated significantly higher intracellular AUC (>3 pmol × h/106cells) than those who did not (approximately 2 pmol × h/106cells).ConclusionsThe ability of HIV-infected patients to phosphorylate ZDV correlates with changes in markers associated with drug effect and toxicity. Potential individualization of therapy through monitoring of total phosphorylated ZDV in patients therefore warrants further exploration.