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Updates were made to the Perinatal Guideline on January 22, 2013 and January 29, 2012. For an explanation of the updates, please see the correction notice.

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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:7/31/2012; last reviewed:7/31/2012)

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Atazanavir (Reyataz, ATV) 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/day atazanavir boosted with 100 mg/kg/day ritonavir). 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.

Reproduction/fertility
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.

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/day atazanavir boosted with 100 mg/day ritonavir). 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.

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 2 miscarriages at 12 and 16 weeks, 26 infants born, and 5 women still pregnant.1 No infant required phototherapy and no birth defects were seen; none of the infants was 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 1.9% (13 of 669 births; 95% confidence interval [CI], 1.0%–3.3%) compared with a 2.7% total prevalence in the U.S. population, based on Centers for Disease Control and Prevention (CDC) surveillance.2

Elevation in indirect (unconjugated) bilirubin attributable to atazanavir-related inhibition of hepatic uridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment with atazanavir. Studies have demonstrated that infants born to mothers who received atazanavir during pregnancy do not have pathologic or dangerous bilirubin elevations in the neonatal period.1,3-7

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.3,5,6 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%.8

Human studies in pregnancy
Several studies have investigated the pharmacokinetics (PKs) of atazanavir with ritonavir in pregnancy. In some of these studies, virological results were also analyzed. Overall, most pregnant patients were able to achieve HIV RNA less than 50 copies/mL at time of delivery.9 In some studies, almost all pregnant patients achieved HIV RNA <50 copies/mL at time of delivery.4,6,7 In a retrospective study reporting trough atazanavir concentrations in 19 pregnant women receiving atazanavir 300 mg and ritonavir 100 mg/day at a median of 30 weeks’ gestation (14 in the third trimester), all but 2 women had a trough atazanavir concentration >100 ng/mL.1 Three studies have evaluated full PK profiles of atazanavir when administered daily as 300 mg with 100 mg ritonavir during pregnancy. In all of these studies, atazanavir AUC was lower during pregnancy than in historic data from HIV-infected non-pregnant patients.3-5 In 1 of the 3 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.3 In the other 2 studies, atazanavir AUC was 25% lower during pregnancy than in the same patients postpartum.4,5,9  However, in both these studies (BMS AI424182 and IMPAACT P1026 atazanavir cohort), the postpartum AUC was elevated compared with non-pregnant HIV-infected historic control patients. For example, in study AI424182, 34 women were treated with 300 mg atazanavir plus 100 mg ritonavir at 4 to 12 weeks postpartum and were observed to have a 34% increase in geometric AUC compared with the historic control of HIV-infected, non-pregnant patients (62 μg*hr/mL vs. 46.1 μg*hr/mL respectively).6 Because of the postpartum elevation in AUC in this study, the atazanavir drug label recommends that postpartum patients should be closely monitored for adverse events during the first 2 months after delivery.

Although use of atazanavir with ritonavir 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 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 and tenofovir.9

In the prescribing information for atazanavir,6 the dose recommended for most pregnant women is 300 mg with 100 mg of ritonavir. For additional details about dosing with interacting concomitant medications, please see Table 5 (Antiretroviral Drug Use in Pregnant HIV-Infected Women: Pharmacokinetic and Toxicity Data in Human Pregnancy and Recommendations for Use in Pregnancy).

Neonatal elevations in bilirubin have been reported in some—but not all—studies of infants born to mothers receiving atazanavir during pregnancy.3-5 Phototherapy was needed to control hyperbilirubinemia in 5 of 29 infants in 1 study.7 In study AI424182, 6 of 39 infants received phototherapy.4 Decisions to use phototherapy to treat infants with hyperbilirubinemia frequently are subjective and guidelines for phototherapy of infants vary between countries, making it difficult, therefore, to compare the severity of hyperbilirubinemia between patients within a study and in different studies. Elevated neonatal bilirubin is more likely in infants with uridine diphosphate glucuronosyltransferase 1 genotypes associated with decreased UGT function.4

Hypoglycemia (glucose <40 mg/dL) that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis has been reported in 3 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 (Bristol-Myers Squibb Reyataz product label). This finding of infant hypoglycemia is similar to a prior report in which 2 (both nelfinavir) of 14 infants exposed to PIs (nelfinavir, saquinavir, and indinavir) developed hypoglycemia in the first day of life.11

References

  1. Natha M, Hay P, Taylor G, et al. Atazanavir use in pregnancy:  a report of 33 cases. Paper presented at: 14th Conference on Retoviruses and Opportunistic Infections (CROI); February 25-28, 2007; Los Angeles, CA. Abstract 750.
  2. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 Jan 1989 - 31 January 2012. Wilmington, NC: Registry Coordinating Center; 2012. Available at http://www.APRegistry.com.
  3. Ripamonti D, Cattaneo D, Maggiolo F, et al. Atazanavir plus low-dose ritonavir in pregnancy: pharmacokinetics and placental transfer. AIDS. Nov 30 2007;21(18):2409-2415. Available at http://www.ncbi.nlm.nih.gov/pubmed/18025877.
  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. Oct 2011;12(9):570-579. Available at http://www.ncbi.nlm.nih.gov/pubmed/21569187.
  5. Mirochnick M, Best BM, Stek AM, et al. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. J Acquir Immune Defic Syndr. Apr 15 2011;56(5):412-419. Available at http://www.ncbi.nlm.nih.gov/pubmed/21283017.
  6. Bristol-Myers Squibb Company. Reyataz package insert. 2011; http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021567s025lbl.pdf. Accessed on June 27, 2012.
  7. Mandelbrot L, Mazy F, Floch-Tudal C, et al. Atazanavir in pregnancy: impact on neonatal hyperbilirubinemia. Eur J Obstet Gynecol Reprod Biol. Jul 2011;157(1):18-21. Available at http://www.ncbi.nlm.nih.gov/pubmed/21492993.
  8. 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. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections (CROI); February, 8-11, 2009 ; Montreal, Canada. Abstract 942.
  9. Mirochnick M, Stek A, Capparelli EV, et al. Pharmacokinetics of increased dose atazanavir with and without tenofovir during pregnancy. Paper presented at: 12th International Workshop on Clinical Pharmacology of HIV Therapy; April 13-15, 2011; Miami, FL. Abstract O10.
  10. 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. Jun 2004;48(6):2091-2096. Available at http://www.ncbi.nlm.nih.gov/pubmed/15155205.
  11. 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.