Treatment of fetuses and neonates at risk of infection with HIV poses a significant dilemma since the response of infants to various therapies cannot be predicted by the response of adults, and drug-related toxicities may be more severe or different in children due to age-specificity. These factors are further intensified when considering treatment of gravid patients since fetal exposure can occur, possibly resulting in more severe, long-term effects. Methods for treating uninfected monkey fetuses and infants with AZT, DDI, or AZT and DDI in utero and postnatally have been pursued with the goal of investigating the potential for toxicity during pre- and postnatal life. Studies have focused on treatments in the gravid adult (chronic exposure via alzet~ minipumps, oral treatment), the fetus (direct), and the neonate (minipumps, oral). Treatments were initiated during the second trimester and continued until delivery. The fetus was monitored sonographically during treatment; fetal and maternal blood samples were collected for drug and hematopoietic evaluations. Postnatal studies (4 months) focused on growth and hematopoiesis. The results indicate (1) hematologic toxicity can result in the dam, fetus, and neonate as a result of chronic exposure to AZT, with similar effects with combined treatment, and no changes with DDI alone; (2) whereas equivalent levels of AZT can be obtained in the fetus and the dam, levels of DDI are roughly one-third lower in the fetus when compared to circulating levels in the dam; (3) combining chronic pre- and postnatal AZT exposure can alter postnatal growth rates; reducing the dose of AZT and combining with DDI diminishes these growth-related effects; and (4) the chronic (minipump) approach may be the best method for altering fetal retroviral load and improving postnatal course, since drug levels can be consistently maintained and maternal, fetal, and infant toxicity is low.
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