NEVIRAPINE METABONOMIC AND HEPATOTOXICITY IN PREGNANCY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Recently, serious liver toxicity and rash have been reported with nevirapine (NVP), and anti-HIV drug, in HIV-1 infected pregnant women. The relationship between the blood levels of NVP and its metabolites and the risk of liver toxicity has not been investigated. In this study using baboons as a model, we will determine if high blood levels of NVP and its metabolites may increase the risk of liver toxicity in the mother and the fetus during pregnancy. A total of 18 pregnant baboons will be equally divided into three treatment groups: group 1 will not receive NVP (control) group 2 will receive NVP at 5 mg/kg twice a day, and group 3 will receive NVP at 10 mg/kg twice a day. Nevirapine will be administered starting at day 70 gestational age. Four blood samples and a small piece of liver from the mother will be collected at 2nd and 3rd trimesters, and four weeks following delivery. A small amount of cord blood will be collected from the fetus at 2nd and 3rd trimesters. One sample each of maternal blood, cord blood, and amniotic fluid will be collected at delivery. All newborn baboons will be sacrificed following delivery and a piece of the newborn liver will be collected and reviewed under the microscope for evidence of liver damage. Currently, NVP is commonly used in the treatment o HVI infection in pregnant women. The results from the proposed study will determine if high blood levels of NVP or its metabolites may increase the risks of liver injuries in the mother and fetus following in utero exposure. The data generated will provide the needed information to establish safer dosages for NVP use during pregnancy and to improve maternal and neonatal outcomes.