Objective. To evaluate the pharmacokinetics, tolerance, safety, immunologic effects, and antiviral activity of combination therapy with d4T, ddI, and indinavir in HIV-infected children.

Methods. Twelve children (median age, 8.8 years; range, 4.2 to 13.5 years) with HIV infection (median CD4+ lymphocyte count at baseline, 48 cells/uL; range, eight to 878 cells/uL) and a history of prior nucleoside antiretroviral therapy (zidovudine, ddI, and/or d4T; median duration, >4 years) were treated orally with d4T (1 mg/kg/dose every 12 hours), ddI (90 mg/sq. meter/dose every 12 hours), and indinavir (500 mg/sq. meter/dose every six or eight hours) for at least 12 weeks each as of 12/96. Children were assessed at baseline, and every four weeks thereafter.

Results. There was no obvious pharmacokinetic interaction between the drugs. Interpatient variability in indinavir clearance was high (range, 0.6 to 3.5 L/kg/hr). Appreciable indinavir concentrations (0.151 to 0.977 mg/L) were found in cerebrospinal fluid (CSF) specimens from each of four children studied. Combination therapy was well-tolerated. One child developed transient jaundice (unconjugated bilirubin, 4.3 mg/dL); two other children had indirect hyperbilirubinemia >3.0 mg/dL. Six children had single urinalyses showing crystalluria; possible drug-associated hematuria was observed in three children. Renal dysfunction was not observed. No child required dose reduction or interruption of therapy. Compared to baseline, median CD4+ lymphocyte counts increased by 97 and 207 cells/uL at study weeks four and 12, respectively. Median plasma HIV RNA concentrations declined by 1.4 and 1.3 log10/mL at study weeks four and 12, respectively. HIV RNA was undetectable (<400 copies/mL) in the CSF of four children with undetectable plasma HIV RNA.

Conclusions. Combination therapy with d4T, ddI, and indinavir was well-tolerated and safe in this small group of HIV-infected children. Marked changes in CD4+ lymphocyte counts and plasma HIV RNA concentrations suggest potent antiviral activity. Absence of detectable HIV RNA in the CSF of some treated children suggests antiviral effects within the central nervous system.