(Last updated: August 6, 2015; last reviewed: August 6, 2015)
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 was no increase 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
Human Studies in Pregnancy
Although use of atazanavir/ritonavir combined with tenofovir disoproxil fumarate (tenofovir) and emtricitabine as a complete once-a-day dosing combination antiretroviral therapy (cART) regimen is becoming increasingly common in pregnancy, tenofovir reduces atazanavir exposure by 25% in non-pregnant adults.9 This drug-drug interaction also is present during pregnancy, with a 30% lower third-trimester atazanavir AUC in pregnant women receiving concomitant tenofovir compared with women who were not receiving concomitant tenofovir. The increase in atazanavir AUC postpartum relative to that in the third trimester was similar for women taking concomitant tenofovir and for those not taking concomitant tenofovir.7
Use of an increased dose of atazanavir of 400 mg with 100 mg ritonavir once daily during pregnancy has been investigated in two studies.4,5 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 with tenofovir.4,5 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. Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy.
Placental and Breast Milk Passage
In studies of women receiving atazanavir/ritonavir-based combination therapy during pregnancy, cord blood atazanavir concentration averaged 13% to 21% of maternal serum levels at delivery.1,6,7
In a study of three women, the median ratio of breast milk atazanavir concentration to that in plasma was 13%.11
In a multicenter U.S. cohort of HIV-exposed, uninfected children, first trimester atazanavir exposure was associated with increased odds of congenital anomalies of skin (aOR = 5.24, P = 0.020) and musculoskeletal system (aOR = 2.55, P = 0.007).12 On the other hand, there was no association of first-trimester atazanavir exposure and birth defects in a French cohort, though this study had <50% power to detect an adjusted odds ratio of 1.5.13 The Antiretroviral Pregnancy Registry has monitored sufficient numbers of first-trimester exposures to atazanavir in humans to be able to detect at least a 2-fold increase in risk of overall birth defects and no such increase in birth defects has been observed with atazanavir. The prevalence of birth defects with first-trimester atazanavir exposure was 2.2% (20 of 922 births; 95% confidence interval [CI], 1.3% to 3.3%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.14
Maternal PI use (including atazanavir) was associated with lower progesterone levels, but the clinical significance of this finding requires further study.2
Other Safety Data
Elevation in indirect (unconjugated) bilirubin attributable to atazanavir-related inhibition of hepatic uridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment with atazanavir, including during pregnancy.15 The effects on the fetus of elevated maternal indirect bilirubin throughout pregnancy are unknown. Dangerous or pathologic postnatal elevations in bilirubin have not been reported in infants born to mothers who received atazanavir during pregnancy.1,4,6-8,16-18 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.16,17 Elevated neonatal bilirubin in atazanavir-exposed neonates is not associated with UGT-1 genotypes associated with decreased UGT function.18
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 those with exposure to other drugs.19 In a study of language assessments among 792 one- and 2-year-old HIV-exposed uninfected children, atazanavir-exposed children had an 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 children but the association was not significant at 24 months.20
|Formulation||Dosing Recommendations||Use in Pregnancy|
Note: Must be combined with low-dose RTV boosting in pregnancy
Standard Adult Dose
With RTV Boosting:
PK in Pregnancy
Dosing in Pregnancy
Low placental transfer to fetus.b
Must be given as low-dose RTV-boosted regimen in pregnancy.
Oral powder (but not capsules) contains phenylalanine, which can be harmful to patients with phenylketonuria.
a Individual antiretroviral drug dosages may need to be adjusted in renal or hepatic insufficiency (for details, see Adult Guidelines, Appendix B, Table 7).
Key to Abbreviations: ARV = antiretroviral; ATV = atazanavir; COBI = cobicistat; EFV = efavirenz; PK = pharmacokinetic; PPI = proton pump inhibitors; RTV = ritonavir; TDF = tenofovir disoproxil fumarate