Updated
Dec. 29, 2020
Reviewed
Dec. 29, 2020

Protease Inhibitors

Atazanavir (Reyataz, ATV)

Animal Studies

Carcinogenicity
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

Reproduction/Fertility
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, possibly because ATV is a substrate of the p-glycoprotein, which is an ATP-binding cassette transporter responsible for drug efflux across the placenta.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

Pharmacokinetics
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 studies that evaluated full PK profiles of daily ATV/r 300 mg/100 mg during pregnancy, the ATV AUC was lower during pregnancy than the ATV AUC reported in other studies of nonpregnant adults with HIV.6,8,9,11 In one of the studies, there was no difference in the ATV AUC during pregnancy and postpartum, but the AUC at both times was lower than the AUC observed in nonpregnant historic controls with HIV.8 In the other studies, the ATV AUC was lower during pregnancy than it was in the same patients postpartum and in nonpregnant control populations.6,7,9,11 Intracellular ATV levels in women taking ATV/r 300 mg/100 mg appear stable throughout pregnancy.12 Genetic variants appear to partially explain the interpatient variability in third-trimester ATV exposure seen in pregnant women who receive ATV/r.13

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.9,11 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.9 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 <0.15 mg/L (the target trough concentration for antiretroviral-naive patients) in pregnant women during their third trimester.14 In a therapeutic drug monitoring (TDM) study of 103 women (most of whom were African) in Paris, the proportions of women with an ATV trough concentration of <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/r 400 mg/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 the 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 antiretroviral-experienced pregnant women who also are receiving either TDF or an H2-receptor antagonist. TDM of ATV in pregnancy may also be useful.15 For additional details about interactions between concomitant medications, please see Drug-Drug Interactions in the Adult and Adolescent Antiretroviral Guidelines.

The pharmacoenhancing 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, respectively, than historical ATV trough concentrations in nonpregnant adults with HIV.16 Concomitant use of ATV and COBI is not recommended during pregnancy because of these substantial reductions in drug exposures (see Cobicistat).17

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 0.13.18

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).19 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 1.5.20 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 2.2% (31 of 1,403 live births; 95% confidence interval [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.21

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 the hepatic uridine diphosphate glucuronosyltransferase (UGT) enzyme occurs frequently during treatment with ATV, including during pregnancy.22 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.1,6,8,9,23–25 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.23,24 Elevated neonatal bilirubin in neonates exposed to ATV is not associated with UGT-1 genotypes that have been linked to decreased UGT function.25

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.26,27 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.28

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.1 This report of infant hypoglycemia is similar to a prior report in which 2 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.29

Excerpt from Table 10

Note: When using FDC tablets, refer to other sections in Appendix B and Table 10 for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.

Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendationsa Use in Pregnancy
Atazanavir
(ATV)
Reyataz

Note: Generic products are available for some formulations.

Note: ATV must be combined with low-dose RTV boosting in pregnancy.

(ATV/c)
Evotaz
ATV (Reyataz)
Capsules:
  • 100 mg (generic product only)
  • 150 mgd
  • 200 mgd
  • 300 mgd
Oral Powder:
  • 50 mg packet
ATV/c (Evotaz):
  • ATV 300 mg/COBI 150 mg tablet
Standard Adult Doses
In ARV-Naive Patients without RTV Boosting:
  • ATV 400 mg once daily with food; ATV without RTV boosting is not recommended when used with TDF, H2-receptor antagonists, PPIs, or during pregnancy.
In ARV-Naive Patients with RTV Boosting:
  • ATV/r 300 mg/100 mg once daily with food 
  • When combined with EFV in ARV-naive patients: ATV/r 400 mg/100 mg once daily with food
In ARV-Experienced Patients:
  • ATV 300 mg plus RTV 100 mg once daily with food
  • Do not use with PPIs or EFV
In ARV-Experienced Patients Who Are Receiving an H2-Receptor Antagonist:
  • ATV/r 300/100 mg once daily with food
In ARV-Experienced Patients Who Are Receiving an H2-Receptor Antagonist and TDF:
  • ATV/r 400 mg/100 mg once daily with food 
Powder Formulation:
  • Oral powder is taken with RTV once daily with food at the same recommended adult dose as the capsules.
ATV/c (Evotaz):
  • One tablet once daily with food

Pregnancy
PKs in Pregnancy
ATV (Reyataz):
  • ATV concentrations are reduced during pregnancy, and they are further reduced when ATV is given concomitantly with TDF or an H2-receptor antagonist.
ATV/c (Evotaz):
  • Use of ATV/c is not recommended during pregnancy, because ATV trough concentrations are 80% to 85% lower than the ATV concentrations seen in nonpregnant adults.

Dosing in Pregnancy

ATV (Reyataz):

  • Use of unboosted ATV is not recommended during pregnancy.
  • Use of ATV is not recommended for ARV-experienced pregnant women who are taking TDF and an H2-receptor antagonist.
  • Use of an increased dose (ATV/r 400 mg/100 mg once daily with food) during the second and third trimesters results in plasma ATV concentrations equivalent to those seen in nonpregnant adults receiving standard dosing. Although some experts recommend increased ATV dosing in all women during the second and third trimesters, the package insert recommends increased ATV dosing only for ARV-experienced pregnant women in the second and third trimesters who are also receiving either TDF or an H2-receptor antagonist.
ATV/c (Evotaz):
  • Insufficient data to make dosing recommendation in pregnancy (see COBI).
For guidance about the use of combination products in pregnancy, please see the specific sections on other components (i.e., COBI).
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 bilirubin 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:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3
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

References

  1. Atazanavir (Reyataz) [package insert]. Food and Drug Administration. 2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021567s044,206352s008lbl.pdf
  2. 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: https://www.ncbi.nlm.nih.gov/pubmed/25030057.
  3. 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: https://www.ncbi.nlm.nih.gov/pubmed/25030058.
  4. 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.
  5. 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: https://www.ncbi.nlm.nih.gov/pubmed/23676668.
  6. 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: https://www.ncbi.nlm.nih.gov/pubmed/21569187.
  7. 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: https://www.ncbi.nlm.nih.gov/pubmed/23392467.
  8. 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: https://www.ncbi.nlm.nih.gov/pubmed/18025877.
  9. 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: https://www.ncbi.nlm.nih.gov/pubmed/21283017.
  10. 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: https://www.ncbi.nlm.nih.gov/pubmed/25599649.
  11. 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: https://www.ncbi.nlm.nih.gov/pubmed/15155205.
  12. 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.
  13. 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.
  14. 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: https://www.ncbi.nlm.nih.gov/pubmed/24992294.
  15. 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: https://www.ncbi.nlm.nih.gov/pubmed/24825070.
  16. Momper J, Stek A, Wang J, et al. Pharmacokinetics of atazanavir boosted with cobicistat during pregnancy and postpartum. Presented at: Workshop on Clinical Pharmacology of HIV, Hepatitis, and other Antiviral Drugs. 2019. Noordwijk, Netherlands.
  17. 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.
  18. 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.
  19. 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: https://www.ncbi.nlm.nih.gov/pubmed/25383770.
  20. 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: https://www.ncbi.nlm.nih.gov/pubmed/24781315.
  21. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral pregnancy registry international interim report for 1 January 1989–31 January 2020. Wilmington, NC: Registry Coordinating Center. 2020. Available at: http://www.apregistry.com.
  22. 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: https://www.ncbi.nlm.nih.gov/pubmed/24370933.
  23. 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: https://www.ncbi.nlm.nih.gov/pubmed/21492993.
  24. 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: https://www.ncbi.nlm.nih.gov/pubmed/23970241.
  25. 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: https://www.ncbi.nlm.nih.gov/pubmed/23782005.
  26. 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: https://www.ncbi.nlm.nih.gov/pubmed/23340561.
  27. 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.
  28. 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: https://www.ncbi.nlm.nih.gov/pubmed/24067563.
  29. 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: https://www.ncbi.nlm.nih.gov/pubmed/12648312.

Protease Inhibitors

Atazanavir (Reyataz, ATV)

Excerpt from Table 10

Note: When using FDC tablets, refer to other sections in Appendix B and Table 10 for information about the dosing and safety of individual drug components of the FDC tablet during pregnancy.

Generic Name
(Abbreviation)
Trade Name
Formulation Dosing Recommendationsa Use in Pregnancy
Atazanavir
(ATV)
Reyataz

Note: Generic products are available for some formulations.

Note: ATV must be combined with low-dose RTV boosting in pregnancy.

(ATV/c)
Evotaz
ATV (Reyataz)
Capsules:
  • 100 mg (generic product only)
  • 150 mgd
  • 200 mgd
  • 300 mgd
Oral Powder:
  • 50 mg packet
ATV/c (Evotaz):
  • ATV 300 mg/COBI 150 mg tablet
Standard Adult Doses
In ARV-Naive Patients without RTV Boosting:
  • ATV 400 mg once daily with food; ATV without RTV boosting is not recommended when used with TDF, H2-receptor antagonists, PPIs, or during pregnancy.
In ARV-Naive Patients with RTV Boosting:
  • ATV/r 300 mg/100 mg once daily with food 
  • When combined with EFV in ARV-naive patients: ATV/r 400 mg/100 mg once daily with food
In ARV-Experienced Patients:
  • ATV 300 mg plus RTV 100 mg once daily with food
  • Do not use with PPIs or EFV
In ARV-Experienced Patients Who Are Receiving an H2-Receptor Antagonist:
  • ATV/r 300/100 mg once daily with food
In ARV-Experienced Patients Who Are Receiving an H2-Receptor Antagonist and TDF:
  • ATV/r 400 mg/100 mg once daily with food 
Powder Formulation:
  • Oral powder is taken with RTV once daily with food at the same recommended adult dose as the capsules.
ATV/c (Evotaz):
  • One tablet once daily with food

Pregnancy
PKs in Pregnancy
ATV (Reyataz):
  • ATV concentrations are reduced during pregnancy, and they are further reduced when ATV is given concomitantly with TDF or an H2-receptor antagonist.
ATV/c (Evotaz):
  • Use of ATV/c is not recommended during pregnancy, because ATV trough concentrations are 80% to 85% lower than the ATV concentrations seen in nonpregnant adults.

Dosing in Pregnancy

ATV (Reyataz):

  • Use of unboosted ATV is not recommended during pregnancy.
  • Use of ATV is not recommended for ARV-experienced pregnant women who are taking TDF and an H2-receptor antagonist.
  • Use of an increased dose (ATV/r 400 mg/100 mg once daily with food) during the second and third trimesters results in plasma ATV concentrations equivalent to those seen in nonpregnant adults receiving standard dosing. Although some experts recommend increased ATV dosing in all women during the second and third trimesters, the package insert recommends increased ATV dosing only for ARV-experienced pregnant women in the second and third trimesters who are also receiving either TDF or an H2-receptor antagonist.
ATV/c (Evotaz):
  • Insufficient data to make dosing recommendation in pregnancy (see COBI).
For guidance about the use of combination products in pregnancy, please see the specific sections on other components (i.e., COBI).
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 bilirubin 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:
          High: >0.6
          Moderate: 0.3–0.6
          Low: <0.3
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

Download Guidelines