Protease Inhibitor-Associated Hyperbilirubinemia

Last updated April 18, 2015
Case Authors: 
H. Nina Kim, MD, MS
Associate Professor of Medicine
Division of Infectious Diseases
Department of Medicine
University of Washington School of Medicine
Learning Objectives: 
  1. Describe the mechanism for protease inhibitor-associated hyperbilirubinemia.
  2. Summarize the incidence and clinical significance of protease inhibitor-associated hyperbilirubinemia.

Display Group

  1. 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;372:646-55.
  2. Lankisch TO, Behrens G, Ehmer U, et al. Gilbert's syndrome and hyperbilirubinemia in protease inhibitor therapy--an extended haplotype of genetic variants increases risk in indinavir treatment. J Hepatol. 2009;50:1010-8.
  3. Gulick RM, Mellors JW, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med. 1997;337:734-9.
  4. Hammer SM, Squires KE, Hughes MD, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997;337:725-33.
  5. Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr. 2004;36:1011-9.
  6. Sanne I, Piliero P, Squires K, Thiry A, Schnittman S. Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr. 2003;32:18-29.
  7. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461-71.
  8. Rayner CR, Esch LD, Wynn HE and Eales R. Symptomatic hyperbilirubinemia with indinavir/ritonavir-containing regimen. Ann Pharmacother. 2001;35:1391-5.
  9. Boffito M, Maitland D, Dickinson L, et al. Pharmacokinetics of saquinavir hard-gel/ritonavir and atazanavir when combined once daily in HIV Type 1-infected individuals administered different atazanavir doses. AIDS Res Hum Retroviruses. 2006;22:749-56.
  10. Smith DE, Jeganathan S and Ray J. Atazanavir plasma concentrations vary significantly between patients and correlate with increased serum bilirubin concentrations. HIV Clin Trials. 2006;7:34-8.
  11. Rodríguez-Nóvoa S, Morello J, González M, et al. Increase in serum bilirubin in HIV/hepatitis-C virus-coinfected patients on atazanavir therapy following initiation of pegylated-interferon and ribavirin. AIDS. 2008;22:2535-7.
  12. Rotger M, Taffe P, Bleiber G, et al. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia. J Infect Dis. 2005;192:1381-6.
  13. Ward D, Curtin J, Richardson J, Baker R, Moorman A, Buchacz K, Brooks J. Hyperbilirubinemia among patients in the HIV Outpatient Study (HOPS) receiving atazanavir. In: The 3rd IAS Conference on HIV Pathogenesis and Treatment. Rio de Janeiro, Brazil, 2005. Abstract TuPe2.1B02.
  14. Laprise C, Baril JG, Dufresne S, Trottier H. Atazanavir and other determinants of hyperbilirubinemia in a cohort of 1150 HIV-positive patients: results from 9 years of follow-up. AIDS Patient Care STDS. 2013;27:378-86.
  15. Zucker SD, Qin X, Rouster SD, et al. Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci. U S A 2001;98:12671-6.
  16. Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS and Humphreys WG. In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos. 2005;33:1729-39.
  17. Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995;333:1171-5.
  18. Ribaudo HJ, Daar ES, Tierney C, et al. Impact of UGT1A1 Gilbert variant on discontinuation of ritonavir-boosted atazanavir in AIDS Clinical Trials Group Study A5202. J Infect Dis. 2012;207:420-5.
  19. Johnson DH, Venuto C, Ritchie MD, et al. Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202. Pharmacogenet Genomics. 2014;24:195-203.
  20. Lankisch TO, Moebius U, Wehmeier M, et al. Gilbert's disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype. Hepatology. 2006;44:1324-32.
  21. Rodriguez Novoa S, Barreiro P, Rendon A, et al. Plasma levels of atazanavir and the risk of hyperbilirubinemia are predicted by the 3435C-->T polymorphism at the multidrug resistance gene 1. Clin Infect Dis. 2006;42:291-5.
  22. Nettles RE, Child MJ, Bertz RJ and Schnittman S. Gilbert syndrome and the development of antiretroviral therapy-associated hyperbilirubinemia: genetic screening is unnecessary. J Infect Dis. 2006;193:1611-1612.