(Last updated: March 28, 2014; last reviewed: March 28, 2014)
Atazanavir is classified as Food and Drug Administration (FDA) Pregnancy Category B.
Animal Carcinogenicity Studies
In in vitro and in vivo assays, atazanavir shows evidence of clastogenicity but not mutagenicity. Two-year carcinogenicity studies in mice and rats were conducted with atazanavir. In female mice, the incidence of benign hepatocellular adenomas was increased at systemic exposures 2.8- to 2.9-fold higher than those in humans at the recommended therapeutic dose (300 mg atazanavir boosted with 100 mg ritonavir once daily). There were no increases in the incidence of tumors in male mice at any dose. In rats, no significant positive trends in the incidence of neoplasms occurred at systemic exposures up to 1.1-fold (males) or 3.9-fold (females) higher than those in humans at the recommended therapeutic dose.1
No effect of atazanavir on reproduction or fertility in male and female rodents was seen at systemic drug exposures. The area under the curve (AUC) at this exposure level in rats was 0.9-fold in males and 2.3-fold in females compared with the exposures achieved in humans at the recommended therapeutic dose.1
In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg atazanavir boosted with 100 mg ritonavir once daily). In developmental toxicity studies in rats, maternal dosing that resulted in maternal toxicity and produced systemic drug exposure 1.3 times the human exposure also resulted in weight loss or suppression of weight gain in the offspring. However, offspring were unaffected at lower maternal doses that produced systemic drug exposure equivalent to that observed in humans at the recommended therapeutic dose.1
In a retrospective analysis from London of atazanavir used in 31 women during 33 pregnancies (20 of whom were receiving atazanavir at conception), there were two miscarriages at 12 and 16 weeks, 26 infants born, and five women still pregnant.2 No infant required phototherapy and no birth defects were seen; none of the infants were HIV-infected. In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposure to atazanavir in humans have been monitored to be able to detect at least a 2-fold increase in risk of overall birth defects. No such increase in birth defects has been observed with atazanavir. The prevalence of birth defects with first-trimester atazanavir exposure was 2.1% (16 of 746 births; 95% confidence interval [CI], 1.2%–3.5%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention (CDC) surveillance.3
Placental and Breast Milk Passage
In studies of women receiving ritonavir-boosted atazanavir-based combination therapy during pregnancy, cord blood atazanavir concentration averaged 13% to 21% of maternal serum levels at delivery.1,4,5 Atazanavir is excreted in the milk of lactating rats. In a study of three women, the median ratio of breast milk atazanavir concentration to that in plasma was 13%.6
Human Studies in Pregnancy
Several studies have investigated the pharmacokinetics (PKs) and virologic outcomes of ritonavir-boosted atazanavir in pregnancy.7 Overall, most pregnant patients achieved undetectable HIV RNA at the time of delivery.1,4,5,8,9 In a retrospective study reporting trough atazanavir concentrations in 19 pregnant women receiving atazanavir 300 mg and ritonavir 100 mg once daily at a median of 30 weeks’ gestation (14 in the third trimester), all but 2 women had a trough atazanavir concentration >100 ng/mL.2 In studies that have evaluated full PK profiles of atazanavir when administered daily as 300 mg with 100 mg ritonavir during pregnancy, atazanavir AUC was lower during pregnancy than in historic data from HIV-infected non-pregnant patients.4,5,8,10,11 In one of the studies there was no difference between atazanavir AUC during pregnancy and postpartum, but AUC at both times was lower than in non-pregnant HIV-infected historic controls.4 In the other studies, atazanavir AUC was lower during pregnancy than in the same patients postpartum and in non-pregnant control populations.5,8-11
Although use of ritonavir-based atazanavir combined with tenofovir and emtricitabine as a complete once-a-day dosing combination antiretroviral (ARV) regimen is becoming increasingly common in pregnancy, tenofovir reduces atazanavir exposure by 25% in non-pregnant adults.10 This drug-drug interaction also is present during pregnancy, with a 25% reduction in atazanavir AUC in pregnant women also receiving tenofovir compared with the same women postpartum and a 50% reduction compared with postpartum levels in women who did not receive tenofovir.5
Use of an increased dose of atazanavir of 400 mg with 100 mg ritonavir once daily during pregnancy has been investigated in two studies.8,9 In both studies pregnant women receiving the increased dose without tenofovir had an atazanavir AUC equivalent to that seen in historic non-pregnant HIV-infected controls receiving standard-dose atazanavir without tenofovir. Pregnant women receiving the increased atazanavir dose with tenofovir had an AUC equivalent to that seen in non-pregnant HIV-infected patients receiving standard-dose atazanavir and tenofovir.8,9 Although some experts recommend increased atazanavir dosing in all women during the second and third trimesters, the package insert recommends increased atazanavir dosing only for ARV-experienced pregnant women in the second and third trimesters also receiving either tenofovir or an H2-receptor antagonist. For additional details about dosing with interacting concomitant medications, please see Table 7. Antiretrovirals in Pregnancy: Pharmacokinetics, Toxicity and Dosing Recommendations.
Elevation in indirect (unconjugated) bilirubin attributable to atazanavir-related inhibition of hepatic uridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment with atazanavir. The effects of elevated maternal indirect bilirubin throughout pregnancy on the fetus are unknown. Dangerous or pathologic postnatal elevations in bilirubin have not been reported in infants born to mothers who received atazanavir during pregnancy.1,2,4,5,8,12-14 Although some studies have suggested that neonatal bilirubin elevations requiring phototherapy occur more frequently after prenatal atazanavir exposure, decisions to use phototherapy to treat infants with hyperbilirubinemia frequently are subjective and guidelines for phototherapy of infants vary between countries, making it difficult to compare the severity of hyperbilirubinemia between patients within a study and in different studies.12,13 Elevated neonatal bilirubin in atazanavir-exposed neonates is not associated with UGT-1 genotypes associated with decreased UGT function.14
In an evaluation of neurodevelopment in 374 HIV-exposed uninfected infants aged 9 to 15 months, the adjusted mean on the Language domain of the Bayley-III test was significantly lower for infants with perinatal exposure to atazanavir compared to other drugs.15 In a study of language assessments among 792 1- and 2-year-old HIV-exposed uninfected children, atazanavir was also associated with increased risk of late language emergence at age 12 months (adjusted odds ratio 1.83, 95% CI, 1.10-3.04) compared with atazanavir-unexposed infants but the association was not significant at 24 months.16
Hypoglycemia (glucose <40 mg/dL) that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis has been reported in three of 38 atazanavir-exposed infants with glucose samples collected in the first day of life. All three hypoglycemic infants’ glucose samples were adequately collected and processed in a timely fashion.1 This finding of infant hypoglycemia is similar to a prior report in which two (both nelfinavir) of 14 infants exposed to PIs (nelfinavir, saquinavir, and indinavir) developed hypoglycemia in the first day of life.17