Developmental toxicity of the HIV-protease inhibitor indinavir in rats

Background: Indinavir is an antiviral agent used for the treatment of HIV i nfection. We studied its developmental toxicity in rats. Methods: Pregnant animals were treated ovally with 500 mg indinavir/kg body weight (bw) from day 6 to 15 of gestation (once daily) or from day 9 to 11 (twice daily). Fetuses were evaluated for external and skeletal anomalies on day 21 of gestation. In addition, 19 rats were treated from day 9 of ges tation to day 24 postnatally with 500 mg indinavir/kg bw once daily; a cont rol group of 17 rats was treated with the vehicle accordingly. Developmenta l landmarks were recorded. Sixteen offspring each were studied on postnatal days 7, 14, 21, and 35 for hepatic enzyme activity. Liver tissue was exami ned by electron microscopy. Results: Fetal examination on day 21 of pregnancy showed no treatment-relat ed effects on number, weight, and viability of the fetuses; however, an inc reased incidence was noted in the supernumerary ribs and variations of the vertebral ossification centers in both indinavir-treated groups. Postnatal evaluation showed delayed fur development, eye opening, and descensus testi s. The most striking finding was unilateral anophthalmia, observed in 7 pup s (3%) from 2 out of 19 litters exposed to indinavir, but not in controls. Only minor changes in hepatic monooxygenase activities occurred in dams. El ectron microscopy of liver samples showed hepatocellular inclusions of lipi ds and myelin figure-like structures in maternal livers and infiltration wi th granulocytes in offspring livers. Conclusions: Further studies on reproductive toxicity, including combinatio ns of three or more antiretroviral agents as used therapeutically, are need ed to determine the hazards of such a treatment. (C) 2000 Wiley-Liss, Inc.