Dideoxyinosine in Children with Symptomatic Human Immunodeficiency Virus Infection

Abstract

Background. 2′,3′-Dideoxyinosine (ddI) is a dideoxynucleoside with potent activity in vitro against the human immunodeficiency virus (HIV). In initial clinical trials in adults, ddI showed evidence of antiretroviral activity with little hematologic toxicity. Methods. We conducted a phase I–II study in 43 children with symptomatic (CDC class P-2) HIV infection. Of these children, 16 (median age, 10 years) had previously received zidovudine, and 27 (median age, 2.6 years) had not. ddI was administered orally in three divided doses totalling 60, 120, 180, 360, or 540 mg per square meter of body-surface area per day for 24 weeks. Eight of the 43 patients did not complete 24 weeks of ddI: 6 died, 1 was withdrawn because of progressive disease, and the other because of toxicity. Results. After oral administration, ddI was rapidly absorbed, although its bioavailability varied greatly among patients. Pancreatitis developed in two children, one receiving ddI at each of the two highest doses. The median CD4 cell count in 38 patients with paired counts increased from 0.218×10 9 per liter (218 per cubic millimeter) at base line to 0.327×10 9 per liter (327 per cubic millimeter) after 20 to 24 weeks (P = 0.001). Those with CD4 cell counts above 0.1×10 9 per liter (100 per cubic millimeter) at base line were significantly more likely to improve in this respect. The median levels of p24 antigen (in 27 patients with detectable levels at entry) declined from 272 pg per milliliter at base line to 77 pg per milliliter at 20 to 24 weeks (P = 0.005). The plasma concentration of ddI correlated significantly with both the degree of decline in the p24 antigen and the degree of improvement in IQ score. Improvement in clinical and immunologic measures occurred in both the previously untreated patients and in those who had been treated with zidovudine. Conclusions. Dideoxyinosine was well tolerated and showed promising antiretroviral activity in HIV-infected children. The correlation between the clinical response and the plasma concentration of ddI indicates that bioavailability is an important consideration in the use of ddI to treat HIV infection and that individualized pharmacokinetic monitoring and dose adjustment may be important for optimal activity. (N Engl J Med 1991; 324:137–44.) © 1991, Massachusetts Medical Society. All rights reserved.