Effects of lopinavir-ritonavir combined therapy during the rat pregnancy. Morphological and biochemical aspects.

OBJECTIVE: To evaluate the biochemical and morphological effects in rats subjected to three different dose associations of the protease inhibitors lopinavir and ritonavir administered throughout the entire period of pregnancy. STUDY DESIGN: The animals were treated throughout pregnancy with daily oral doses of lopinavir+ritonavir starting at the day one of pregnancy, and were divided into four groups: E1, 13.3+3.3 mg/kg; E2, 39.9+9.9 mg/kg; E3, 119.7+29.9 mg/kg and C, control (drug vehicle, propyleneglycol). The animals were then sacrificed and maternal blood and fetal and maternal organ samples were taken for morphological and biochemical analysis. RESULTS: No major changes were identified in the group treated with the lowest dose as compared with the control. In the group E2, we found hepatocytes with signs of atrophy, eosinophilic cytoplasm, picnotic nuclei and vasodilatation. The proximal convoluted tubules of maternal kidneys showed eosinophilic areas and hyperchromatic nuclei, as well as signs of vasodilation. In the group treated with the highest dose (group E3), in the maternal kidneys and livers, the morphological changes were similar to those found in E2, although more prominent. Regarding the fetal organs, the single abnormality observed was some liver vasodilation in the group E3 (highest dose). The treatment with lopinavir+ritonavir caused discrete, yet significant, alterations of aspartate aminotransferase activity, blood urea nitrogen and creatinine plasma levels. CONCLUSIONS: Our results showed that the administration of a combination of lopinavir plus ritonavir to pregnant rats can cause morphological as well as functional changes in maternal and fetal liver and kidneys and, in higher than therapeutic doses, might be toxic to those animals.

Effect of chronic ritonavir administration on pregnant rats and their fetuses.

In view of the very important role played by ritonavir in the prevention of maternal-fetal HIV-vertical transmission, the aim of this experimental study was to evaluate its possible effects on several important obstetric parameters. Ritonavir was administered daily to three groups of pregnant rats (E1 = 20 mg/kg; E2 = 60 mg/kg; E3 = 180 mg/kg; n = 10 in every group) from 'zero' up to the 20th day of pregnancy. Controls (n = 10) were injected with the drug vehicle (propyleneglycol) in the same schedule. We evaluated the effects on fetal and maternal weight gain, placental weight, number of implantations and resorptions, malformations, fertility rate, and maternal and fetal death rates. Body weight gain of the E3 group was significantly lower than that of the other groups, most likely due to a toxic effect of the highest dose of ritonavir. Ritonavir did not affect the number of implantations. Group E3 had five resorptions and some reduction in fertility. The mortality rate was significantly affected by ritonavir (2/10 maternal deaths in E2 and 4/10 in E3). On the other hand, no alterations were observed in the fetuses, a finding which could be due at least in part to the protective action of placental P-glycoprotein.