RELATIONSHIP BETWEEN DIDEOXYINOSINE EXPOSURE, CD4 COUNTS, AND P24 ANTIGEN LEVELS IN HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION - A PHASE-I TRIAL

Objective: To determine the relation between exposure to dideoxyinosine (ddI) and increased CD4 cell counts and suppression of serum p24 antigen in patients infected with the human immunodeficiency virus (HIV). Design: Open-label, phase I study. Setting: Two university hospital. Patients were studied in both inpatient and outpatient settings. Patients: Of 36 HIV-infected patients enrolled, 18 had adequate pharmacokinetic information for analysis. Intervention: Dideoxyinosine was administered intravenously every 12 hours for 2 weeks. Patients were switched or oral administration at twice the intravenous dose. Pharmacokinetic profiles were obtained twice during each period. A 40-fold range of dose was examined. Measurements: CD4-positive T-lymphocyte counts and serum p24 antigen levels were determined. Plasma area under the ddl concentration-time curve was determined for a single dose and at steady state. Results: Increases in CD4-positive T-lymphocyte counts were independent of ddI exposure and were proportional to the starting CD4 count. Suppression of circulating p24 antigen was influenced by cumulative exposure to ddI and was statistically significant. Conclusions: The CD4-positive T-lymphocyte count increased at low ddl concentrations or exposures; the extent of this increase was directly proportional to the patient's CD4 count at the start of therapy. Suppression of p24 antigen was related to cumulative exposure to ddI. Therapeutic responses can probably be obtained with ddI, while minimizing long-term toxicity, using daily doses of 10 mg/kg body weight, or less.