PEDIATRICS Vol. 94 No. 5 November 1994, pp. 724-731
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Clinical and Pharmacokinetic Evaluation of Long-Term Therapy With Didanosine in Children with HIV Infection

Brigitta U. Mueller MD1, Karina M. Butler MB, BCh1, Vicki L. Stocker RN, MSN1, Frank M. Balis MD1, Philip A. Pizzo MD1, Pim Brouwers PhD1, Robert N. Husson MD1, Linda L. Lewis MD1, Paul Jarosinski PD2, and David Venzon PhD3

1 Pediatric Branch, Clinical Oncology Program, National Cancer Institute, Bethesda, MD
2 Pharmacy Department, Warren Grant Magnuson Clinical Center, National Cancer Institute, Bethesda, MD
3 Biostatistics and Data Management Section, Clinical Oncology Program, National Cancer Institute, Bethesda, MD

Background. Didanosine has demonstrated promising antiviral activity and a tolerable toxicity profile in short term studies. We describe a cohort of HIV-infected children who were treated for a prolonged period of time with didanosine.

Methods. Children (6 months to 18 years of age) with symptomatic HIV infection or an absolute CD4 count < 0.5 x 109 cells/L, received oral didanosine at doses between 20 mg/m2 to 180 mg/m2 every 8 hours. Clinical, immunological, and virological parameters were assessed at least every 2 months. The pharmacokinetics of didanosine were evaluated in 85 patients.

Results. Previously untreated 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 was well tolerated and no new toxicities were observed. The absolute CD4 count increased by ge .05 x 109 cells/L in 28 of 87 (32%) of patients after 6 months of therapy. Responses were also sustained in 41% of these children after 3 years of therapy. Children entering the study with a CD4 count >0.1 x 109 cells/L (n = 51) had a marked survival advantage (P = .00002) with an estimated survival probability after 3 years of 80% compared to 39% for children with lower CD4 counts. Although the area under the curve of didanosine increased proportionally with the dose, there was considerable interpatient variability at each dose level. There was no apparent relationship between surrogate markers of clinical outcome and plasma drug concentration.

Conclusions. Didanosine was well tolerated with chronic administration, and toxicities were uncommon and usually reversible. In 41% of patients, the CD4 count increased and was maintained at the higher level even after years of treatment.

Submitted on May 4, 1994
Accepted on June 22, 1994




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