CLINICAL AND PHARMACOKINETIC EVALUATION OF LONG-TERM THERAPY WITH DIDANOSINE IN CHILDREN WITH HIV-INFECTION

Background. Didanosine has demonstrated promising antiviral activity a nd a tolerable toxicity profile in short term studies. We describe a c ohort of HIV-infected children who were treated for a prolonged period of time with didanosine. Methods. Children(6 months to 18 years of ag e) with symptomatic HIV infection or an absolute CD4 count < 0.5 x 10( 9) cells/L, received oral didanosine at doses between 20 mg/m(2) to 18 0 mg/m(2) every 8 hours. Clinical, immunological, and virological para meters were assessed at least every 2 months. The pharmacokinetics of didanosine were evaluated in 85 patients. Results. Previously untreate d children (n = 51) and children who had received prior antiretroviral therapy (n = 52) were enrolled in the study (median time on study 22. 6 months; range 2 to 48). The long-term administration of didanosine w as well tolerated and no new toxicities were observed. The absolute CD 4 count increased by greater than or equal to .05 x 10(9) cells/L in 2 8 of 87 (32%) of patients after 6 months of therapy. Responses were al so sustained in 41% of these children after 3 years of therapy. Childr en entering the study with a CD4 count > 0.1 x 10(9) cells/L (n = 51) had a marked survival advantage (P = .00002) with an estimated surviva l probability after 3 years of 80% compared to 39% for children with l ower CD4 counts. Although the area under the curve of didanosine incre ased proportionally with the dose, there was considerable interpatient variability at each dose level. There was no apparent relationship be tween surrogate markers of clinical outcome and plasma drug concentrat ion. Conclusions. Didanosine was well tolerated with chronic administr ation, and toxicities were uncommon and usually reversible. In 41% of patients, the CD4 count increased and was maintained at the higher lev el even after years of treatment.