Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions to Reduce Perinatal HIV Transmission in the United States

Protease Inhibitors

Atazanavir (Reyataz, ATV)

Summary

• Atazanavir (ATV) concentrations are reduced during pregnancy.
  • Only ritonavir-boosted ATV (ATV/r) should be used in pregnancy, as drug levels are too low if unboosted ATV or cobicistat (COBI)-boosted ATV (ATV/c) is used in pregnancy.
  • ATV levels are further reduced when given concomitantly with tenofovir disoproxil fumarate (TDF) or an H2-receptor antagonist.
  • Intracellular ATV levels in women taking the standard dose (ATV/r 300 mg/100 mg) once without concomitant TDF appear reassuringly stable throughout pregnancy.
  • An increased dose (ATV/r 400 mg/100 mg once daily with food) during the second and third trimesters should be used if ATV is given concomitantly with TDF or an H2-receptor antagonist.
• First-trimester exposure to ATV is not associated with increased risk of congenital anomalies.
• Regimens with protease inhibitors (PIs), including ATV/r, may be associated with increased rates of preterm delivery.

Human Studies in Pregnancy

Pharmacokinetics

ATV/r without Concomitant TDF

In studies that evaluated full pharmacokinetic (PK) profiles of daily ATV/r 300 mg/100 mg without concomitant TDF during pregnancy, the ATV area under the curve (AUC) was lower during pregnancy than the ATV AUC reported in other studies of nonpregnant adults with HIV.^1-4 In one of the studies, no difference was observed in the ATV AUC during pregnancy and postpartum, but the AUC at both times was lower than the AUC observed in historic, nonpregnant controls with HIV.⁴ In the other studies, the ATV AUC was lower during pregnancy than it was in the same patients postpartum and in nonpregnant control populations.^1-3,5 Intracellular ATV levels in women taking ATV/r 300 mg/100 mg appear stable throughout pregnancy.⁶ Genetic variants appear to partially explain the interpatient variability in third-trimester ATV exposure seen in pregnant women who receive ATV/r.⁷

In studies that evaluated the use of a once-daily increased dose (ATV/r 400 mg/100 mg) during pregnancy,^3,5 pregnant women who received this dose without TDF had an ATV AUC that was equivalent to the ATV AUC seen in historic nonpregnant controls with HIV who received the standard ATV 300-mg dose without TDF. Viral suppression (<50 copies/mL) before delivery was observed in 90% to 100% of women receiving standard or increased-dose regimens; none of the infants had evidence of HIV infection.^3,5 

ATV/r with Concomitant TDF

ATV/r combined with TDF and emtricitabine (FTC) provides a complete, once-daily antiretroviral therapy regimen for use during pregnancy. However, the ATV AUC of pregnant women in the third trimester who received concomitant TDF was 30% lower than the ATV AUC of women who were not receiving concomitant TDF, an effect similar to that seen in nonpregnant adults.^1,2 The magnitude of the increase in ATV AUC postpartum relative to ATV AUC in the third trimester in women taking concomitant TDF was similar to that in women not taking concomitant TDF.¹ On the other hand, a smaller PK study demonstrated that concomitant TDF did not result in a lower ATV AUC or a higher risk of ATV trough concentrations (C_trough) <0.15 mg/L (the target C_trough for antiretroviral-naive patients) in pregnant women during their third trimester.⁸ In a therapeutic drug monitoring study of 103 women (most of whom were African) in Paris, the proportions of women with an ATV C_trough of <0.15 mg/L were similar for women who did and women who did not take concomitant TDF.⁹

Pregnant women who received the increased ATV 400-mg dose with TDF had an ATV AUC equivalent to that seen in nonpregnant patients with HIV who received the standard ATV 300-mg dose with TDF.^3,5 An increased dose of ATV during the second and third trimesters is recommended for antiretroviral-experienced pregnant women who also are receiving either TDF or an H2-receptor antagonist.¹⁰ For additional details about interactions between concomitant medications, see Drug-Drug Interactions in the Adult and Adolescent Antiretroviral Guidelines.

ATV Boosted with Cobiscistat

The pharmaco-enhancing effect of COBI on ATV is impacted during pregnancy. Pregnant women who received ATV boosted with COBI had ATV C_trough that were 66% and 72% lower during the second and third trimesters, respectively, compared with paired postpartum data (P = 0.0625 and P = 0.0313, respectively).¹¹ Concomitant use of ATV and COBI is not recommended during pregnancy because of these substantial reductions in drug exposures (see Cobicistat).¹²

Placental and Breast Milk Passage

In studies of women receiving ATV/r combination therapy during pregnancy, cord blood ATV concentration averaged 13% to 21% of maternal serum levels at delivery.^1,4,13

In a study of three women, the median ratio of breast milk ATV concentration to plasma ATV concentration¹⁴ was 0.13.

Teratogenicity/Adverse Pregnancy Outcomes

In a multicenter study that evaluated a U.S. cohort of children who were exposed to HIV but who did not contract HIV, first-trimester ATV exposure was associated with increased odds of congenital anomalies of the skin (adjusted odds ratio [aOR] 5.24; P = 0.02) and musculoskeletal system (aOR 2.55; P = 0.007).¹⁵ On the other hand, there was no association between first-trimester ATV exposure and birth defects in a French cohort, although this study ¹⁶ had <50% power to detect an aOR of 1.5. The Antiretroviral Pregnancy Registry has monitored sufficient numbers of first-trimester exposures to ATV in humans to be able to detect at least a 1.5-fold increase in the risk of overall birth defects and at least a twofold increase in the risk of cardiovascular and genitourinary defects (the most common classes of birth defects in the general population). No such increase in the risk of birth defects has been observed with ATV. Among the cases of first-trimester ATV exposure that have been reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.5% (37 of 1,478 live births; 95% confidence interval [CI], 1.8% to 3.4%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.¹⁷

Please Antiretroviral Drug Regimens and Maternal and Neonatal Outcomes for a discussion of the potential association between the use of boosted PIs and preterm delivery.

Other Safety Data

Elevation in indirect (unconjugated) bilirubin that can be attributed to ATV-related inhibition of the hepatic uridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment with ATV, including during pregnancy.¹⁸ In late pregnancy, an increased dose (ATV/r 400 mg/100 mg) without concomitant TDF, compared with the standard dose of ATV/r without concomitant TDF, is associated with twice the risk of elevated maternal bilirubin levels.³ It is unknown whether elevated maternal indirect bilirubin throughout pregnancy has any effect on the fetus. Dangerous or pathologic postnatal elevations in bilirubin have not been reported in infants born to mothers who received ATV during pregnancy.^{1,3,4,13,19-21} Maternal bilirubin levels do not correlate well with neonatal bilirubin levels.²² In some studies, neonatal bilirubin elevations that require treatment with phototherapy occur more frequently after prenatal ATV exposure. However, decisions to use phototherapy frequently are subjective, and guidelines for phototherapy vary across countries, making it difficult to compare the severity of hyperbilirubinemia among patients within a study and across different studies.^19,20 Elevated neonatal bilirubin in neonates exposed to ATV is not associated with UGT-1 genotypes that have been linked to decreased UGT function.²¹

In an evaluation of neurodevelopmental outcomes in 374 infants aged 9 to 15 months who were exposed to HIV but who did not contract HIV, the adjusted mean scores on the language and social-emotional domains of the Bayley-III test were significantly lower for infants with perinatal exposure to ATV than for infants who were exposed to other drugs.^23,24 In a study of language assessments among 792 children aged 1 to 2 years who were exposed to HIV but who did not contract HIV, children with ATV exposure had an increased risk of late language emergence at age 12 months (aOR 1.83; 95% CI, 1.10–3.04) compared with children without ATV exposure, but this association was not significant at 24 months.²⁵

Hypoglycemia (glucose <40 mg/dL) that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis was reported in 3 of 38 ATV-exposed infants who had glucose samples collected during the first day of life. All three hypoglycemic infants’ glucose samples were adequately collected and processed in a timely fashion.¹³ This report of infant hypoglycemia is similar to a prior report in which two of 14 infants who were exposed to PIs (i.e., nelfinavir, saquinavir, or indinavir) developed hypoglycemia during the first day of life; both infants with hypoglycemia had been exposed to nelfinavir.²⁶

Animal Studies

Carcinogenicity

In in vitro and in vivo assays, ATV shows evidence of clastogenicity but not mutagenicity. Two-year carcinogenicity studies in mice and rats were conducted with ATV. In female mice, the incidence of benign hepatocellular adenomas increased at systemic exposures that were 2.8-fold to 2.9‑fold higher than those seen in humans who received the recommended therapeutic dose (ATV/r 300 mg/100 mg once daily). There was no increase in the incidence of tumors in male mice at any dose and no significant increase in the incidence of neoplasms in rats at systemic exposures up to 1.1-fold (in males) or 3.9-fold (in females) higher than those seen in humans who received the recommended therapeutic dose.¹³

Reproduction/Fertility

No effect of ATV on reproduction or fertility in male and female rodents was observed at drug exposure levels (as measured by AUC) that were 0.9-fold (in males) and 2.3‑fold (in females) higher than the exposures achieved in humans who received the recommended therapeutic dose.¹³

Teratogenicity/Adverse Pregnancy Outcomes

In animal reproduction studies, no evidence of teratogenicity was observed in offspring born to animals that had systemic ATV exposure levels (as measured by AUC) that were 0.7 times (in rabbits) and 1.2 times (in rats) those observed in humans who received the recommended therapeutic dose. In developmental toxicity studies in rats, maternal dosing (through pregnancy and lactation) that produced systemic ATV exposure that was 1.3 times the human exposure resulted in reversible neonatal growth retardation. However, offspring were unaffected at lower maternal doses that produced systemic drug exposures equivalent to those observed in humans who received the recommended therapeutic dose.¹³ A separate study demonstrated an association between maternal PI use (including the use of ATV) and lower progesterone levels, which correlated with lower birthweight in mice.^27,28 Maternal administration of ATV (with TDF/FTC or abacavir/lamivudine) was associated with delayed postnatal (infant) growth and neurodevelopment in mice.²⁹

Placental and Breast Milk Passage

ATV maternal-to-fetal (transplacental) transfer is reduced, possibly because ATV is a substrate of the p‑glycoprotein, which is an adenosine triphosphate–binding cassette transporter responsible for drug efflux across the placenta.³⁰

ATV is excreted in the milk of lactating rats. Maternal ATV use in rats that produced systemic ATV exposure that was 1.3 times the human exposure was associated with neonatal growth restriction that reversed after weaning.¹³

Excerpt from Table 14

Note: When using fixed-dose combination (FDC) tablets, refer to other sections in Appendix B and Table 14 in the Perinatal Guidelines for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.

References

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20. Atrio JM, Sperling RS, Posada R, et al. Maternal atazanavir usage in HIV-infected pregnant women and the risk of maternal and neonatal hyperbilirubinemia. J Acquir Immune Defic Syndr. 2013;63(5):e158-159. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23970241.
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25. Rice ML, Zeldow B, Siberry GK, et al. Evaluation of risk for late language emergence after in utero antiretroviral drug exposure in HIV-exposed uninfected infants. Pediatr Infect Dis J. 2013;32(10):e406-413. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24067563.
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