Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States
The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.
Atazanavir (Reyataz, ATV)
Last Updated: December 24, 2019; Last Reviewed: December 24, 2019
In in vitro and in vivo assays, atazanavir (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 300 mg boosted with ritonavir [RTV] 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.1
No effect of ATV on reproduction or fertility in male and female rodents was observed at drug exposure levels (as measured by area under the curve [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.1
Teratogenicity/Adverse Pregnancy Outcomes
In animal reproduction studies, there was no evidence of teratogenicity 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.1 A separate study demonstrated an association between maternal protease inhibitor (PI) use (including the use of ATV) and lower progesterone levels, which correlated with lower birthweight in mice.2,3
Placental and Breast Milk Passage
ATV maternal-to-fetal (transplacental) transfer is reduced, which may be because ATV is a substrate of the placental drug efflux ATP-binding cassette transporter p-glycoprotein.4
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.1
Human Studies in Pregnancy
Several studies have investigated the pharmacokinetics (PKs) and virologic outcomes of using atazanavir/ritonavir (ATV/r) during pregnancy.5 Overall, most pregnant women achieved undetectable HIV RNA at the time of delivery in these studies.1,6-10 In a retrospective study that measured trough ATV concentrations at a median of 30 weeks gestation in 19 pregnant women (including 14 who were in the third trimester of pregnancy) who received ATV 300 mg and RTV 100 mg once daily, all but two women had trough ATV concentrations >100 ng/mL.11
In studies that evaluated full PK profiles of daily ATV 300 mg with RTV 100 mg during pregnancy, ATV AUC was lower during pregnancy than the ATV AUC reported in other studies of nonpregnant adults with HIV.6,8,9,12,13 In one of the studies, there was no difference between ATV AUC during pregnancy and postpartum, but AUC at both times was lower than the AUC observed in nonpregnant historic controls with HIV.8 In the other studies, ATV AUC was lower during pregnancy than it was in the same patients postpartum and in nonpregnant control populations.6,7,9,12,13 Intracellular ATV levels in women taking ATV 300 mg and RTV 100 mg appear to be stable throughout pregnancy.14 Genetic variants appear to partially explain the interpatient variability in third trimester ATV exposure seen in pregnant women who receive ATV/r.15
ATV/r combined with tenofovir disoproxil fumarate (TDF) and emtricitabine provides a complete, once-daily antiretroviral therapy regimen for pregnant women. 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.9,12 The increase in ATV AUC postpartum relative to ATV AUC in the third trimester was similar for women taking concomitant TDF and for those not taking concomitant TDF.9 On the other hand, a smaller PK study demonstrated that concomitant TDF did not result in lower ATV AUC or a higher risk of ATV trough concentrations <0.15 mg/L (the target trough concentration for treatment-naive patients) in pregnant women during their third trimester.16 In a therapeutic drug monitoring (TDM) study of 103 women (who were mostly African) in Paris, the proportions of women with ATV trough concentration <0.15 mg/L were similar for women who did and women who did not take concomitant TDF.10
In studies that evaluated the use of once-daily ATV 400 mg with RTV 100 mg during pregnancy,6,7 pregnant women who received this increased 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. 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 standard ATV 300 mg dose with TDF.6,7 Although some experts recommend an increased dose of ATV for all women during the second and third trimesters, the package insert recommends the use of an increased dose of ATV during the second and third trimesters only for treatment-experienced pregnant women who are also receiving either TDF or an H2-receptor antagonist. TDM of ATV in pregnancy may also be useful.17 For additional details about interactions between concomitant medications, please see Drug-Drug Interactions in the Adult and Adolescent Antiretroviral Guidelines.
The pharmaco-enhancing effect of cobicistat (COBI) on ATV is impacted during pregnancy. Pregnant women who received ATV boosted with COBI had trough ATV concentrations that were 80% and 85% lower during the second and third trimesters than historical ATV trough concentrations in nonpregnant adults with HIV.18 Concomitant use of ATV and COBI is not recommended during pregnancy because of these substantial reductions in drug exposures (see Cobicistat).19
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.1,8,9
In a study of three women, the median ratio of breast milk ATV concentration to plasma ATV concentration was 0.13.20
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 the musculoskeletal system (aOR 2.55; P = 0.007).21 On the other hand, there was no association between first-trimester ATV exposure and birth defects in a French cohort, although this study had <50% power to detect an aOR of 1.5.22 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 no such increase in birth defects has been observed with ATV. The prevalence of birth defects with first-trimester ATV exposure was 2.2% (29 of 1,328 births; 95% CI, 1.5% to 3.1%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention surveillance.23
Please see Combination 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 hepatic uridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment with ATV, including during pregnancy.24 It is unknown whether elevated maternal indirect bilirubin throughout pregnancy has any effects on the fetus. Dangerous or pathologic postnatal elevations in bilirubin have not been reported in infants born to mothers who received ATV during pregnancy.1,6,8,9,11,25-27 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 between patients within a study and across different studies.25,26 Elevated neonatal bilirubin in neonates exposed to ATV is not associated with UGT-1 genotypes that have been linked decreased UGT function.27
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.28,29 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 to children without ATV exposure, but this association was not significant at 24 months.30
Hypoglycemia (glucose <40 mg/dL) that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis was reported in three 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.1 This report of infant hypoglycemia is similar to a prior report in which two of 14 infants who were exposed to PIs (nelfinavir, saquinavir, and indinavir) developed hypoglycemia during the first day of life; both infants with hypoglycemia had been exposed to nelfinavir.31
Excerpt from Table 8
Note: When using FDC tablets, refer to other sections in Appendix B and Table 8 for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.
|Formulation||Dosing Recommendationsa||Use in Pregnancy|
Note: Generic products are available for some formulations.
Note: ATV must be combined with low-dose RTV boosting in pregnancy.
|Standard Adult Doses
In ARV-Naive Patients without RTV Boosting:
PKs in Pregnancy
|Low placental transfer to fetus.b
No evidence of human teratogenicity (can rule out 1.5-fold increase in overall birth defects).
Must be given with RTV boosting in pregnancy.
Effect of in utero ATV exposure on infant indirect bilirubin levels is unclear. Nonpathologic elevations of neonatal bilirub have been observed in some, but not all, clinical trials to date.
Oral powder (but not capsules) contains phenylalanine, which can be harmful to patients with phenylketonuria.
Use of ATV/c is not recommended during pregnancy. See Recommendations for Use of Antiretroviral Drugs During Pregnancy, Table 4, and Table 5 for discussions about avoiding the use of ATV/c during pregnancy.
a Individual ARV drug doses may need to be adjusted in patients with renal or hepatic insufficiency (for details, see the Adult and Adolescent Antiretroviral Guidelines, Appendix B, Table 10).
b Placental transfer categories are determined by mean or median cord blood/maternal delivery plasma drug ratio:
d Generic product is available.
Key: ARV = antiretroviral; ATV = atazanavir; ATV/c = atazanavir/cobicistat; COBI = cobicistat; EFV = efavirenz; FDC = fixed-dose combination; PK = pharmacokinetic; PPI = proton pump inhibitor; RTV = ritonavir; TDF = tenofovir disoproxil fumarate
- Atazanavir [package insert]. Food and Drug Administration. 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021567s042,206352s007lbl.pdf.
- Papp E, Mohammadi H, Loutfy MR, et al. HIV protease inhibitor use during pregnancy Is associated with decreased progesterone levels, suggesting a potential mechanism contributing to fetal growth restriction. J Infect Dis. 2014;211(1):10-8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25030058.
- Powis KM, Shapiro RL. Protease inhibitors and adverse birth outcomes: is progesterone the missing piece to the puzzle? J Infect Dis. 2015;211(1):4-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25030057.
- Cerveny L, Ptackova Z, Durisova M, Staud F. Interactions of protease inhibitors atazanavir and ritonavir with ABCB1, ABCG2, and ABCC2 transporters: Effect on transplacental disposition in rats. Reprod Toxicol. 2018;79:57-65. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29859254.
- Eley T, Bertz R, Hardy H, Burger D. Atazanavir pharmacokinetics, efficacy and safety in pregnancy: a systematic review. Antivir Ther. 2013;18(3):361-375. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23676668.
- Conradie F, Zorrilla C, Josipovic D, et al. Safety and exposure of once-daily ritonavir-boosted atazanavir in HIV-infected pregnant women. HIV Med. 2011;12(9):570-579. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21569187.
- Kreitchmann R, Best BM, Wang J, et al. Pharmacokinetics of an increased atazanavir dose with and without tenofovir during the third trimester of pregnancy. J Acquir Immune Defic Syndr. 2013;63(1):59-66. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23392467.
- Ripamonti D, Cattaneo D, Maggiolo F, et al. Atazanavir plus low-dose ritonavir in pregnancy: pharmacokinetics and placental transfer. AIDS. 2007;21(18):2409-2415. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18025877.
- Mirochnick M, Best BM, Stek AM, et al. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. J Acquir Immune Defic Syndr. 2011;56(5):412-419. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21283017.
- Le MP, Mandelbrot L, Descamps D, et al. Pharmacokinetics, safety and efficacy of ritonavir-boosted atazanavir (300/100 mg once daily) in HIV-1-infected pregnant women. Antivir Ther. 2015;20(5):507-13. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25599649.
- Natha M, Hay P, Taylor G, et al. Atazanavir use in pregnancy: a report of 33 cases. Presented at: 14th Conference on Retoviruses and Opportunistic Infections. 2007. Los Angeles, CA.
- Taburet AM, Piketty C, Chazallon C, et al. Interactions between atazanavir-ritonavir and tenofovir in heavily pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother. 2004;48(6):2091-2096. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15155205.
- Colbers A, Molto J, Ivanovic J, et al. A comparison of the pharmacokinetics of darunavir, atazanavir and ritonavir during pregnancy and post-partum. Abstract 1013. Presented at: 19th Conference on Retroviruses and Opportunistic Infections. 2012. Seattle, WA.
- Foca E, Calcagno A, Bonito A, et al. Atazanavir intracellular concentrations remain stable during pregnancy in HIV-infected patients. J Antimicrob Chemother. 2017;72(11):3163-3166. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28961777.
- Foca E, Calcagno A, Bonito A, et al. Pharmacokinetic changes during pregnancy according to genetic variants: a prospective study in HIV-infected patients receiving atazanavir-ritonavir. Antimicrob Agents Chemother. 2018;62(7). Available at: https://www.ncbi.nlm.nih.gov/pubmed/29760129.
- Colbers A, Hawkins D, Hidalgo-Tenorio C, et al. Atazanavir exposure is effective during pregnancy regardless of tenofovir use. Antivir Ther. 2015;20(1):57-64. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24992294.
- Else LJ, Jackson V, Brennan M, et al. Therapeutic drug monitoring of atazanavir/ritonavir in pregnancy. HIV Med. 2014;15(10):604-610. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24825070.
- Momper J, Best B, Wang J, et al. Pharmacokinetics of darunavir boosted with cobicistat during pregnancy and postpartum. Presented at: International AIDS Conference. 2018. Amsterdam, Netherlands.
- Boyd SD, Sampson MR, Viswanathan P, Struble KA, Arya V, Sherwat AI. Cobicistat-containing antiretroviral regimens are not recommended during pregnancy: viewpoint. AIDS. 2019;33(6):1089-1093. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30946163.
- Spencer L, Neely M, Mordwinkin N, et al. Intensive pharmacokinetics of zidovudine, lamivudine, and atazanavir and HIV-1 viral load in breast milk and plasma in HIV+ women receiving HAART. Presented at: 16th Conference on Retroviruses and Opportunistic Infections. 2009. Montreal, Canada.
- Williams PL, Crain MJ, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in human immunodeficiency virus-exposed uninfected infants. JAMA Pediatr. 2015;169(1):48-55. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25383770.
- Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24781315.
- Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 January 1989–31 January 2019. Wilmington, NC: Registry Coordinating Center. 2019. Available at: http://www. apregistry.com.
- Floridia M, Ravizza M, Masuelli G, et al. Atazanavir and lopinavir profile in pregnant women with HIV: tolerability, activity and pregnancy outcomes in an observational national study. J Antimicrob Chemother. 2014;69(5):1377-1384. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24370933.
- Mandelbrot L, Mazy F, Floch-Tudal C, et al. Atazanavir in pregnancy: impact on neonatal hyperbilirubinemia. Eur J Obstet Gynecol Reprod Biol. 2011;157(1):18-21. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21492993.
- Atrio JM, Sperling RS, Posada R, Rodriguez Caprio G, Chen KT. 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.
- Eley T, Huang SP, Conradie F, et al. Clinical and pharmacogenetic factors affecting neonatal bilirubinemia following atazanavir treatment of mothers during pregnancy. AIDS Res Hum Retroviruses. 2013;29(10):1287-1292. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23782005.
- Sirois PA, Huo Y, Williams PL, et al. Safety of perinatal exposure to antiretroviral medications: developmental outcomes in infants. Pediatr Infect Dis J. 2013;32(6):648-655. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23340561.
- Caniglia EC, Patel K, Huo Y, et al. Atazanavir exposure in utero and neurodevelopment in infants: a comparative safety study. AIDS. 2016;30(8):1267-1278. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26867136.
- 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.
- Dinsmoor MJ, Forrest ST. Lack of an effect of protease inhibitor use on glucose tolerance during pregnancy. Infect Dis Obstet Gynecol. 2002;10(4):187-191. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12648312.
- AIDSinfo Drug Database
- AIDSinfo Patient Materials: Preventing Mother-to-Child Transmission of HIV
- AIDSinfo Patient Materials: HIV Medicines During Pregnancy and Childbirth
- AIDSinfo Patient Materials: Protecting Baby from HIV
- AETC National HIV Curriculum
- How to Cite These Guidelines
- Perinatal Guidelines Archive