To the Editors:
The main adverse effect associated with atazanavir (ATV) is indirect (unconjugated) hyperbilirubinemia with or without icterus but without concomitant hepatic transaminase elevations. It is reversible upon discontinuation of ATV.1–3 Recent Centers for Disease Control and Prevention guidelines cite ATV, lopinavir, and ritonavir (as booster) as the preferred protease inhibitors (PIs) in combined antiretroviral therapy (cART) during pregnancy.4 A concern for neonatal hyperbilirubinemia has been disputed in cohorts to date: 3 demonstrated hyperbilirubinemia5–7 and 2 did not.8,9 None have demonstrated that neonates have encephalopathic elevations.5,6,8–10 However, 2 reports5,6 show that 15%–20% of neonates required phototherapy that is higher than the overall rate in term infants, which is 5–40 per 1000 births.11
The electronic and paper medical records of women who attended the Mount Sinai Medical Center’s Obstetrics Infectious Diseases Clinic from January 1, 2005, to October 31, 2007, were reviewed. The study was approved by the hospital’s institutional review board. In 2005, an experienced team of obstetricians and infectious diseases faculty began offering ATV based on its efficacy, minimal side effects, and long-term safety data from animal models before its designation as a preferred medication by the Centers for Disease Control and Prevention.4 As per standard practice, the cART regimen for each patient was individualized to his/her medical needs (past cART regimens, adherence, and genotyping). In 2007, ATV utilization increased significantly due to Food and Drug Administration warning about contaminants found in nelfinavir.2 This period was identified before data collection so as to encompass a range of cART regimens and a number of mother–infant subjects for electronic and paper chart abstraction.
Results of maternal serum chemistries were analyzed according to the National Institutes of Health severity grading system, which is a validated classification system used to characterize adverse events as they pertain to HIV and AIDS.12 Grades 3 and 4 elevations were considered clinically significant and compared to pregnancies with grades 1 and 2 elevations. Neonatal bilirubin results were analyzed using the Harriet Lane Handbook Guidelines for phototherapy in infants.13 Hyperbilirubenimia was defined as having the first total bilirubin level greater than 5 mg/dL on day of life 0, 9 mg/dL on day of life 1, or 12 mg/dL on day of life 2. It is usual at our institution to obtain serum bilirubins on all neonates born to HIV-infected women.
Analysis was performed with SPSS software using 2-sided hypothesis testing with a significance level of 0.05. Analysis of variance was used for continuous data. The χ2 analysis was used for categorical data and Fisher exact test for expected values less than 5. Linear and logistic regression was utilized for multivariate analyses.
Fifty-seven women were identified. One patient underwent elective termination; 3 transferred care at 23, 25, and 28 weeks; 1 was lost to follow-up after the initial prenatal visit; and 1 had rupture of membranes at 19-week gestation with induction of labor. Of the remaining 51 women, 28 women received ATV, 18 received another PI (of which 13 received lopinavir/ritonavir), and 5 women received no PI. There were no significant differences with regard to age, parity, ethnicity, CD4, or viral load across all treatment groups at intake or delivery (P = 0.1). There were no significant differences between liver function tests, direct bilirubin, preterm delivery, birth weight, neonatal intensive care unit admission, mode of delivery, or infant bilirubin (P = 0.2). However, there was a statistically significant grade 3 or 4 elevation in serum indirect bilirubin among women on ATV (Table 1) before and after multivariate analysis, which included maternal age, CD4 count, and viral load (P = 0.04). Three neonates required phototherapy, 2 were full-term, and 1 was 31 weeks of estimated gestational age. All 3 were born to mothers on ATV (P = 0.23), and 2 mothers had grade 4 indirect bilirubin elevations. Based on previous publications, 35%–50% of nonpregnant individuals treated with ATV develop indirect hyperbilirubinemia compared to <1% of those treated with another PI lopinavir. In those studies, about one third of individuals were women.3,14,15
As recent guidelines advocate for increased dosing of ATV in the second and third trimesters in certain situations,4 we feel it is important to have additional safety information. Our study would benefit from larger numbers of patients, and we plan an additional study reviewing the information from more recent patients. Consequently, we advise caution and close monitoring of bilirubin levels. The only serious adverse event in our study was in a neonate whose hospitalization was prolonged by 1 day because of hyperbilirubinemia.6 It is unclear if there is an association of ATV with neonatal hyperbilirubinemia and of maternal and newborn hyperbilirubinemia from research to date. For obstetricians, it is important to keep up-to-date on the changing treatment regimens in HIV-infected individuals and to know drug toxicity profiles of commonly prescribed regimens. We did not observe serious toxicities contraindicating use of ATV during pregnancy. We advocate that practitioners monitor HIV-infected pregnant women on ATV-based regimens for hyperbilirubinemia in the antepartum period. In addition, practitioners should examine neonates born to women on ATV-based regimens for jaundice and have a low threshold for monitoring bilirubin.
3. Torti C, Lapadula G, Antinori A, et al.. Hyperbilirubinemia during atazanavir treatment in 2,404 patients in the Italian atazanavir expanded access program and MASTER cohorts. Infection. 2009;37:244–249.
4. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. 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. Available at: http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf
. Accessed September 11, 2012.
5. 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;12:570–579.
6. Mandelbrot L, Mazy F, Floch-Tudal C, et al.. Atazanavir in pregnancy: impact on neonatal hyperbilirubinemia. Eur J Obstet Gynecol Reprod Biol. 2011;157:18–21.
7. Natha M, Hay P, Taylor G, et al.. Atazanavir use in pregnancy: a report of 33 cases. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, CA.
8. Ferreira C, Floch C, Meier F, et al.. Atazanavir in pregnancy: influence on neonatal hyperbilirubinemia. Paper presented at: 15th CROI; February 3-6, 2008; Boston, MA.
9. Ripamonti D, Cattaneo D, Airoldi M, et al.. Atazanavir based HAART in pregnancy. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles, CA.
10. Eley T, Vandeloise E, Child M, et al.. Steady state pharmacokinetics and safety of atazanavir (ATV) after treatment with ATV 300 mg/ritonavir 100 mg QD + ZDV/3TC during the 3rd trimester of pregnancy in HIV+ women. Paper presented at: 15th CROI; February 3-6, 2008; Boston, MA.
11. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med. 2008;358:920–928.
13. Johnson K. Harriet Lane Handbook: A Manual for Pediatric House Officers. 19th ed. Philadelphia, PA: Elsevier; 2012.
14. Molina JM, Andrade-Villanueva J, Echevarria J, et al.. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372:646–655.
15. Molina JM, Andrade-Villanueva J, Echevarria J, et al.. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010;53:323–332.