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Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States

Protease Inhibitors

Atazanavir (Reyataz, ATV)

(Last updated: August 6, 2015; last reviewed: August 6, 2015)

Atazanavir is classified as Food and Drug Administration Pregnancy Category B.

Animal Studies

Carcinogenicity 
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.

Reproduction/Fertility
No effect of atazanavir on reproduction or fertility in male and female rodents was seen at area under the curve (AUC) levels that were 0.9-fold in males and 2.3-fold in females compared with the exposures achieved in humans at the recommended therapeutic dose.

Teratogenicity/Developmental Toxicity
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 A more recent study demonstrated an association of maternal PI use (including atazanavir) with lower progesterone levels which correlated with lower birthweight in mice, but this potential mechanism requires further study.2
 
Placental and Breast Milk Passage
Atazanavir is excreted in the milk of lactating rats. 

Human Studies in Pregnancy

Pharmacokinetics
Several studies have investigated the pharmacokinetics (PKs) and virologic outcomes of ritonavir-boosted atazanavir in pregnancy.3 Overall, most pregnant patients achieved undetectable HIV RNA at the time of delivery.1,4-7 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 two women had a trough atazanavir concentration >100 ng/mL.8 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.4,6,7,9,10 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.6 In the other studies, atazanavir AUC was lower during pregnancy than in the same patients postpartum and in non-pregnant control populations.4,5,7,9,10
 

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

Teratogenicity/Developmental Toxicity
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

 
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.21 
 


 

References

  1. Reyataz [package insert]. Food and Drug Administration. 2014. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021567s028lbl.pdf. Accessed June 10, 2015.
  2. 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. Available at http://www.ncbi.nlm.nih.gov/pubmed/25030058.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. Natha M, Hay P, Taylor G, et al. Atazanavir use in pregnancy: a report of 33 cases. Presented at: 14th Conference on Retroviruses and Opportunistic Infections. 2007. Los Angeles, CA.
  9. 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.
  10. 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.
  11. 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.
  12. Williams PL, Crain M, Yildirim C, et al. Congenital anomalies and in utero antiretroviral exposure in HIV-exposed uninfected infants. In press. JAMA. 2014. 
  13. 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.
  14. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 1989–31 July 2014. Wilmington, NC: Registry Coordinating Center. 2014. Available at http://www.APRegistry.com.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.

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