ZIDOVUDINE AND DIDANOSINE COMBINATION THERAPY IN CHILDREN WITH HUMAN-IMMUNODEFICIENCY-VIRUS INFECTION

Objective. Zidovudine and didanosine are both beneficial for the treat ment of human immunodeficiency virus (HIV) infection in children. Beca use disease progression and toxicity often limit their long-term use a s single agents, new approaches to using nucleoside analogues are nece ssary to improve current antiretroviral therapy. Design. We conducted a phase I-II study to evaluate the tolerance, pharmacokinetics, and an tiviral activity of the combination of zidovudine and didanosine in ch ildren with HIV infection. Sixty-eight children who were either previo usly untreated or who had manifested hematologic toxicity on full-dose zidovudine were enrolled. Eight dose combinations were studied in the previously untreated children, with doses of zidovudine ranging from 90 to 180 mg/m(2) every 6 hours and doses of didanosine ranging from 9 0 to 180 mg/m(2) every 12 hours. Results. Fifty-four previously untrea ted HIV-infected children were enrolled in this part of the study, of whom 49 remained in the study for a minimum of 24 weeks. For children with previous zidovudine-related hematologic toxicity, three dose leve ls with zidovudine at 60 mg/m(2) every 6 hours orally and didanosine r anging from 90 to 180 mg/m(2) every 12 hours orally were used. A total of 14 children were enrolled in this part of the study, and 12 remain ed on therapy for at least 24 weeks. No evidence of new or enhanced to xicity was observed in either group. After 24 weeks, the median CD4 ce ll count for all patients increased from 331 to 556 cells/mm(3) (P = . 01). For the previously untreated group, the median increase in CD4 co unts was from 386 to 726 cells/mm(3) (P = .003). The median p24 antige n concentration (in those with a detectable level at baseline) decreas ed from 95 to < 31 pg/mL (P < .001). The geometric mean titer of HIV i n plasma decreased from 83.1 to 2.7 tissue culture infectious doses/mL (P = .001). Conclusions. The combination of zidovudine and didanosine was well-tolerated at doses as high as those used in single agent the rapy. Potent in vivo antiviral activity was observed. Combination ther apy with nucleoside analogues may be an important approach to optimizi ng the use of these agents in the treatment of HIV infection.