Managing Adverse Drug Reactions in the Therapy of Pediatric HIV Infection

The antiretroviral agents used and approved to treat HIV infection in children have all demonstrated individual and drug-class toxicities that limit the doses and combinations that can be used safely (70). The general principles of toxicity management are similar for adults and children. However, for many of the newer therapies (particularly the protease inhibitors), limited short-term and no long-term safety data or experience are available for infants, children, and adolescents. Thus, the amount of information on which to base guidelines for management of antiretroviral toxicities in children, especially when antiretroviral drugs are used in combination, is substantially more limited than that for adults. The data available from PACTG protocol 152 and PACTG protocol 300 indicate that some combinations of nucleoside analogues do not substantially increase the toxicity relative to monotherapy with those agents (54,55).

The toxicities of antiretroviral drugs may occur at different frequencies in children and adults, and the implications of some of the toxicities substantially differ for children. The most obvious difference for children from the listing of toxicities in the adult guidelines is the increased indirect bilirubin associated with indinavir, which is labeled as inconsequential for adults. This toxicity could be of major consequence for newborn and young infants because severe hyperbilirubinemia is associated with kernicterus and would require specific monitoring and treatment should indinavir be administered to neonates. Additional examples of differences of potential toxicities between adults and children include the description of asymptomatic retinal depigmentation in children associated with ddI therapy and the relative lack of pancreatitis in children compared with adults receiving ddI therapy (See Appendix).

Another treatment issue that affects children differently from adults concerns the feasibility of administering poorly palatable liquid antiretroviral formulations to children. Innovative techniques to increase palatability may be needed to enable tolerance of medications (e.g., various methods can be used to increase tolerance of ritonavir [See Appendix]). Indinavir is associated with hematuria and nephrolithiasis secondary to crystallization of the drug in the urine; adequate hydration (i.e., 48 oz of fluid daily) is recommended to reduce the incidence of this side effect. However, ensuring that voluntary fluid intake of this level is achieved may be more difficult in children than in adults.

All efforts should be made to continue therapy in the presence of toxicities that are not life-threatening. Such efforts should include liberal use of adjunctive measures (e.g., granulocyte colony stimulating factor for treatment of neutropenia and erythropoietin and/or transfusions for treatment of anemia). If antiretroviral therapy must be discontinued for an extended period of time, to minimize the risk for developing drug resistance, all antiretroviral agents should be stopped simultaneously rather than continuing one or two agents alone because of potential increased viral replication.

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