Antiretroviral Therapy and Hepatotoxicity

  • Norah J. Shire


The advent of antiretroviral therapy (ART) for treatment of HIV has significantly delayed HIV-related disease progression, allowing those infected to live longer without opportunistic infections. To some extent, HIV has become a chronic disease requiring long-term treatment with multidrug regimens. A probability model of the survival benefit of AIDS therapy in the USA demonstrated that the projected perperson survival after a diagnosis of AIDS increased 13.3 years from 19 months with no available treatment to 14.9 years in 2003 [1]. However, risks associated with ART pose challenges to patient care.


Sustained Viral Response Mitochondrial Toxicity Severe Hepatotoxicity Viral Load Rebound Nonnucleoside Polymerase Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis. 2006;194(1):11–9.PubMedCrossRefGoogle Scholar
  2. 2.
    Prati D, Taioli E, Zanella A, Della TE, Butelli S, Del Vecchio E, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137(1):1–10.PubMedGoogle Scholar
  3. 3.
    Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002;123(4):1367–84.PubMedCrossRefGoogle Scholar
  4. 4.
    Table of grading severity of adult adverse experiences. Rockville, MD: Division of AIDS, National Institute of Allergy and Infectious Diseases; 1996.Google Scholar
  5. 5.
    Sulkowski MS, Thomas DL, Chaisson RE, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA. 2000;283(1):74–80.PubMedCrossRefGoogle Scholar
  6. 6.
    Food and Drug Administration. Guidance for industry drug-induced liver injury: premarketing clinical evaluation. 2009.Google Scholar
  7. 7.
    Zimmerman HJ. Drug-induced liver disease. Drugs. 1978;16(1):25–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Chen CH, Vazquez-Padua M, Cheng YC. Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol. 1991;39(5):625–8.PubMedGoogle Scholar
  9. 9.
    Gerschenson M, Nguyen VT, St Claire MC, Harbaugh SW, Harbaugh JW, Proia LA, et al. Chronic stavudine exposure induces hepatic mitochondrial toxicity in adult Erythrocebus patas monkeys. J Hum Virol. 2001;4(6):335–42.PubMedGoogle Scholar
  10. 10.
    Mansuri MM, Hitchcock MJ, Buroker RA, Bregman CL, Ghazzouli I, Desiderio JV, et al. Comparison of in vitro biological properties and mouse toxicities of three thymidine analogs active against human immunodeficiency virus. Antimicrob Agents Chemother. 1990;34(4):637–41.PubMedGoogle Scholar
  11. 11.
    Wu Y, Li N, Zhang T, Wu H, Huang C, Chen D. Mitochondrial DNA base excision repair and mitochondrial DNA mutation in human hepatic HuH-7 cells exposed to stavudine. Mutat Res. 2009;664(1–2):28–38.PubMedGoogle Scholar
  12. 12.
    Walker UA, Bickel M, Lutke Volksbeck SI, Ketelsen UP, Schofer H, Setzer B, et al. Evidence of nucleoside analogue reverse transcriptase inhibitor–associated genetic and structural defects of mitochondria in adipose tissue of HIV-infected patients. J Acquir Immune Defic Syndr. 2002;29(2):117–21.PubMedGoogle Scholar
  13. 13.
    Bissuel F, Bruneel F, Habersetzer F, Chassard D, Cotte L, Chevallier M, et al. Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy. J Intern Med. 1994;235(4):367–71.PubMedCrossRefGoogle Scholar
  14. 14.
    Lewis W, Day BJ, Copeland WC. Mitochondrial toxicity of NRTI antiviral drugs: an integrated cellular perspective. Nat Rev Drug Discov. 2003;2(10):812–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Walker UA. Antiretroviral therapy-induced liver alterations. Curr Opin HIV AIDS. 2007;2(4):293–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2002;46(3):716–23.PubMedCrossRefGoogle Scholar
  17. 17.
    Fleischer R, Boxwell D, Sherman KE. Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis. 2004;38(8):e79–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Videx [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2010.Google Scholar
  19. 19.
    Gingelmaier A, Grubert TA, Kost BP, Setzer B, Lebrecht D, Mylonas I, et al. Mitochondrial toxicity in HIV type-1-exposed pregnancies in the era of highly active antiretroviral therapy. Antivir Ther. 2009;14(3):331–8.PubMedGoogle Scholar
  20. 20.
    Ciaranello AL, Seage III GR, Freedberg KA, Weinstein MC, Lockman S, Walensky RP. Antiretroviral drugs for preventing mother-to-child transmission of HIV in sub-Saharan Africa: balancing efficacy and infant toxicity. AIDS. 2008;22(17):2359–69.PubMedCrossRefGoogle Scholar
  21. 21.
    Ribaudo HJ, Haas DW, Tierney C, Kim RB, Wilkinson GR, Gulick RM, et al. Pharmacogenetics of plasma efavirenz exposure after treatment discontinuation: an Adult AIDS Clinical Trials Group Study. Clin Infect Dis. 2006;42(3):401–7.PubMedCrossRefGoogle Scholar
  22. 22.
    Rodriguez-Novoa S, Barreiro P, Rendon A, Jimenez-Nacher I, Gonzalez-Lahoz J, Soriano V. Influence of 516 G  >  T polymorphisms at the gene encoding the CYP450-2B6 isoenzyme on efavirenz plasma concentrations in HIV-infected subjects. Clin Infect Dis. 2005;40(9):1358–61.PubMedCrossRefGoogle Scholar
  23. 23.
    Rotger M, Colombo S, Furrer H, Bleiber G, Buclin T, Lee BL, et al. Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients. Pharmacogenet Genomics. 2005;15(1):1–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Kappelhoff BS, van Leth F, Robinson PA, MacGregor TR, Baraldi E, Montella F, et al. Are adverse events of nevirapine and efavirenz related to plasma concentrations? Antivir Ther. 2005;10(4):489–98.PubMedGoogle Scholar
  25. 25.
    Leist M, Gantner F, Kunstle G, Wendel A. Cytokine-mediated hepatic apoptosis. Rev Physiol Biochem Pharmacol. 1998;133:109–55.PubMedGoogle Scholar
  26. 26.
    Blackard JT, Kang M, St Clair JB, Lin W, Kamegaya Y, Sherman KE, et al. Viral factors associated with cytokine expression during HCV/HIV co-infection. J Interferon Cytokine Res. 2007;27(4):263–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Babu CK, Suwansrinon K, Bren GD, Badley AD, Rizza SA. HIV induces TRAIL sensitivity in hepatocytes. PLoS One. 2009;4(2):e4623.PubMedCrossRefGoogle Scholar
  28. 28.
    Burns-Naas LA, Meade BJ, Munson AL. Toxic responses of the immune system. In: Klaassen CD, editor. Toxicology. USA: McGraw-Hill; 2001. p. 419–70.Google Scholar
  29. 29.
    Martin AM, Nolan D, James I, Cameron P, Keller J, Moore C, et al. Predisposition to nevirapine hypersensitivity associated with HLA-DRB1*0101 and abrogated by low CD4 T-cell counts. AIDS. 2005;19(1):97–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Shenton JM, Popovic M, Chen J, Masson MJ, Uetrecht JP. Evidence of an immune-mediated mechanism for an idiosyncratic nevirapine-induced reaction in the female Brown Norway rat. Chem Res Toxicol. 2005;18(12):1799–813.PubMedCrossRefGoogle Scholar
  31. 31.
    Ciccacci C, Borgiani P, Ceffa S, Sirianni E, Marazzi MC, Altan AM, et al. Nevirapine-induced hepatotoxicity and pharmacogenetics: a retrospective study in a population from Mozambique. Pharmacogenomics. 2010;11(1):23–31.PubMedCrossRefGoogle Scholar
  32. 32.
    Schouten JT, Krambrink A, Ribaudo HJ, Kmack A, Webb N, Shikuma C, et al. Substitution of nevirapine because of efavirenz toxicity in AIDS clinical trials group A5095. Clin Infect Dis. 2010;50(5):787–91.PubMedCrossRefGoogle Scholar
  33. 33.
    Wit FW, Kesselring AM, Gras L, Richter C, van der Ende ME, Brinkman K, et al. Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA cohort study. Clin Infect Dis. 2008;46(6):933–40.PubMedCrossRefGoogle Scholar
  34. 34.
    Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, et al. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002;359(9312):1121–2.PubMedCrossRefGoogle Scholar
  35. 35.
    Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359(9308):727–32.PubMedCrossRefGoogle Scholar
  36. 36.
    Orkin C, Wang J, Bergin C, Molina JM, Lazzarin A, Cavassini M, et al. An epidemiologic study to determine the prevalence of the HLA-B*5701 allele among HIV-positive patients in Europe. Pharmacogenet Genomics. 2010;20(5):307–14.PubMedCrossRefGoogle Scholar
  37. 37.
    Soni S, Churchill DR, Gilleece Y. Abacavir-induced hepatotoxicity: a report of two cases. AIDS. 2008;22(18):2557–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37(5):1202–19.PubMedCrossRefGoogle Scholar
  39. 39.
    Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129(1):113–21.PubMedCrossRefGoogle Scholar
  40. 40.
    Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42(1):132–8.PubMedCrossRefGoogle Scholar
  41. 41.
    Fortgang IS, Belitsos PC, Chaisson RE, Moore RD. Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy. Am J Gastroenterol. 1995;90(9):1433–6.PubMedGoogle Scholar
  42. 42.
    Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS. 2000;14(3):F25–32.PubMedCrossRefGoogle Scholar
  43. 43.
    Ingiliz P, Valantin MA, Duvivier C, Medja F, Dominguez S, Charlotte F, et al. Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy. Hepatology. 2009;49(2):436–42.PubMedCrossRefGoogle Scholar
  44. 44.
    McGovern BH, Ditelberg JS, Taylor LE, Gandhi RT, Christopoulos KA, Chapman S, et al. Hepatic steatosis is associated with fibrosis, nucleoside analogue use, and hepatitis C virus genotype 3 infection in HIV-seropositive patients. Clin Infect Dis. 2006;43(3):365–72.PubMedCrossRefGoogle Scholar
  45. 45.
    Sulkowski MS, Mehta SH, Torbenson M, Afdhal NH, Mirel L, Moore RD, et al. Hepatic steatosis and antiretroviral drug use among adults coinfected with HIV and hepatitis C virus. AIDS. 2005;19(6):585–92.PubMedCrossRefGoogle Scholar
  46. 46.
    Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology. 2004;126(2):586–97.PubMedCrossRefGoogle Scholar
  47. 47.
    Loulergue P, Callard P, Bonnard P, Pialoux G. Hepatic steatosis as an emerging cause of cirrhosis in HIV-infected patients. J Acquir Immune Defic Syndr. 2007;45(3):365.PubMedGoogle Scholar
  48. 48.
    Guaraldi G, Squillace N, Stentarelli C, Orlando G, D’Amico R, Ligabue G, et al. Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors. Clin Infect Dis. 2008;47(2):250–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Ryan P, Blanco F, Garcia-Gasco P, Garcia-Merchan J, Vispo E, Barreiro P, et al. Predictors of severe hepatic steatosis using abdominal ultrasound in HIV-infected patients. HIV Med. 2009;10(1):53–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Crum-Cianflone N, Dilay A, Collins G, Asher D, Campin R, Medina S, et al. Nonalcoholic fatty liver disease among HIV-infected persons. J Acquir Immune Defic Syndr. 2009;50(5):464–73.PubMedCrossRefGoogle Scholar
  51. 51.
    Puoti M, Torti C, Ripamonti D, Castelli F, Zaltron S, Zanini B, et al. Severe hepatotoxicity during combination antiretroviral treatment: incidence, liver histology, and outcome. J Acquir Immune Defic Syndr. 2003;32(3):259–67.PubMedCrossRefGoogle Scholar
  52. 52.
    Sherman KE, Shire NJ, Cernohous P, Rouster SD, Omachi JH, Brun S, et al. Liver injury and changes in hepatitis C Virus (HCV) RNA load associated with protease inhibitor-based antiretroviral therapy for treatment-naive HCV-HIV-coinfected patients: lopinavir-ritonavir versus nelfinavir. Clin Infect Dis. 2005;41(8):1186–95.PubMedCrossRefGoogle Scholar
  53. 53.
    Chung RT, Evans SR, Yang Y, Theodore D, Valdez H, Clark R, et al. Immune recovery is associated with persistent rise in hepatitis C virus RNA, infrequent liver test flares, and is not impaired by hepatitis C virus in co-infected subjects. AIDS. 2002;16(14):1915–23.PubMedCrossRefGoogle Scholar
  54. 54.
    Vento S, Garofano T, Renzini C, Casali F, Ferraro T, Concia E. Enhancement of hepatitis C virus replication and liver damage in HIV-coinfected patients on antiretroviral combination therapy. AIDS. 1998;12(1):116–7.PubMedGoogle Scholar
  55. 55.
    Crane M, Oliver B, Matthews G, Avihingsanon A, Ubolyam S, Markovska V, et al. Immunopathogenesis of hepatic flare in HIV/hepatitis B virus (HBV)-coinfected individuals after the initiation of HBV-active antiretroviral therapy. J Infect Dis. 2009;199(7):974–81.PubMedCrossRefGoogle Scholar
  56. 56.
    Bellini C, Keiser O, Chave JP, Evison J, Fehr J, Kaiser L, et al. Liver enzyme elevation after lamivudine withdrawal in HIV-hepatitis B virus co-infected patients: the Swiss HIV Cohort Study. HIV Med. 2009;10(1):12–8.PubMedCrossRefGoogle Scholar
  57. 57.
    Nuesch R, Ananworanich J, Srasuebkul P, Chetchotisakd P, Prasithsirikul W, Klinbuayam W, et al. Interruptions of tenofovir/emtricitabine-based antiretroviral therapy in patients with HIV/hepatitis B virus co-infection. AIDS. 2008;22(1):152–4.PubMedCrossRefGoogle Scholar
  58. 58.
    Zucker SD, Qin X, Rouster SD, Yu F, Green RM, Keshavan P, et al. Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci USA. 2001;98(22):12671–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, 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(11):1729–39.PubMedCrossRefGoogle Scholar
  60. 60.
    Torti C, Lapadula G, Antinori A, Quirino T, Maserati R, Castelnuovo F, et al. Hyperbilirubinemia during atazanavir treatment in 2,404 patients in the Italian atazanavir expanded access program and MASTER Cohorts. Infection. 2009;37(3):244–9.PubMedGoogle Scholar
  61. 61.
    Lankisch TO, Moebius U, Wehmeier M, Behrens G, Manns MP, Schmidt RE, et al. Gilbert’s disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype. Hepatology. 2006;44(5):1324–32.PubMedCrossRefGoogle Scholar
  62. 62.
    Gulick RM, Lalezari J, Goodrich J, Clumeck N, Dejesus E, Horban A, et al. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008;359(14):1429–41.PubMedCrossRefGoogle Scholar
  63. 63.
    Lennox JL, Dejesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796–806.PubMedCrossRefGoogle Scholar
  64. 64.
    Raffi F, Battegay M, Rusconi S, Opravil M, Blick G, Steigbigel RT, et al. Combined tipranavir and enfuvirtide use associated with higher plasma tipranavir concentrations but not with increased hepatotoxicity: sub-analysis from RESIST. AIDS. 2007;22(13):1977–80.CrossRefGoogle Scholar
  65. 65.
    Steigbigel RT, Cooper DA, Teppler H, Eron JJ, Gatell JM, Kumar PN, et al. Long-term efficacy and safety of Raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin Infect Dis. 2010;50(4):605–12.PubMedCrossRefGoogle Scholar
  66. 66.
    Cooper CL, Parbhakar MA, Angel JB. Hepatotoxicity associated with antiretroviral therapy containing dual versus single protease inhibitors in individuals coinfected with hepatitis C virus and human immunodeficiency virus. Clin Infect Dis. 2002;34(9):1259–63.PubMedCrossRefGoogle Scholar
  67. 67.
    den Brinker M, Wit FW, Wertheim-van Dillen PM, Jurriaans S, Weel J, van Leeuwen R, et al. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS. 2000;14(18):2895–902.CrossRefGoogle Scholar
  68. 68.
    Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology. 2002;35(1):182–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Neau D, Winnock M, Castera L, Bail BL, Loko MA, Geraut L, et al. Prevalence of and factors associated with hepatic steatosis in patients coinfected with hepatitis C virus and HIV: Agence Nationale pour la Recherche contre le SIDA et les hepatites virales CO3 Aquitaine Cohort. J Acquir Immune Defic Syndr. 2007;45(2):168–73.PubMedCrossRefGoogle Scholar
  70. 70.
    Vispo E, Mena A, Maida I, Blanco F, Cordoba M, Labarga P, et al. Hepatic safety profile of raltegravir in HIV-infected patients with chronic hepatitis C. J Antimicrob Chemother. 2010;65(3):543–7.PubMedCrossRefGoogle Scholar
  71. 71.
    Saves M, Vandentorren S, Daucourt V, Marimoutou C, Dupon M, Couzigou P, et al. Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations. Aquitaine Cohort, France, 1996–1998. Groupe dEpidemiologie Clinique de Sida en Aquitaine (GECSA). AIDS. 1999;13(17):F115–21.PubMedCrossRefGoogle Scholar
  72. 72.
    Verucchi G, Calza L, Manfredi R, Chiodo F. Incidence of liver toxi­city in HIV-infected patients receiving isolated dual nucleoside analogue antitretroviral therapy. J Acquir Immune Defic Syndr. 2003;33(4):546–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Lonergan JT, Behling C, Pfander H, Hassanein TI, Mathews WC. Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens. Clin Infect Dis. 2000;31(1):162–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Antela A, Ocampo A, Gomez R, Lopez MJ, Marino A, Losada E, et al. Liver toxicity after switching or simplifying to nevirapine-based therapy is not related to CD4 cell counts: results of the TOSCANA Study. HIV Clin Trials. 2010;11(1):11–7.PubMedCrossRefGoogle Scholar
  75. 75.
    Chu KM, Boulle AM, Ford N, Goemaere E, Asselman V, Van Cutsem G. Nevirapine-associated early hepatotoxicity: incidence, risk factors, and associated mortality in a primary care ART programme in South Africa. PLoS One. 2010;5(2):e9183.PubMedCrossRefGoogle Scholar
  76. 76.
    Bruck S, Witte S, Brust J, Schuster D, Mosthaf F, Procaccianti M, et al. Hepatotoxicity in patients prescribed efavirenz or nevirapine. Eur J Med Res. 2008;13(7):343–8.PubMedGoogle Scholar
  77. 77.
    Law WP, Dore GJ, Duncombe CJ, Mahanontharit A, Boyd MA, Ruxrungtham K, et al. Risk of severe hepatotoxicity associated with antiretroviral therapy in the HIV-NAT Cohort, Thailand, 1996–2001. AIDS. 2003;17(15):2191–9.PubMedCrossRefGoogle Scholar
  78. 78.
    McMahon DK, Dinubile MJ, Meibohm AR, Marino DR, Robertson MN. Efficacy, safety, and tolerability of long-term combination antiretroviral therapy in asymptomatic treatment-naive adults with early HIV infection. HIV Clin Trials. 2007;8(5):269–81.PubMedCrossRefGoogle Scholar
  79. 79.
    Steigbigel RT, Cooper DA, Kumar PN, Eron JE, Schechter M, Markowitz M, et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med. 2008;359(4):339–54.PubMedCrossRefGoogle Scholar
  80. 80.
    González de Requena D, Calcagno A, Bonora S, Ladetto L, D’Avolio A, Sciandra M, et al. Unexpected drug–drug interaction between tipranavir/ritonavir and enfuvirtide. AIDS. 2006;20(15):1977–9.PubMedCrossRefGoogle Scholar
  81. 81.
    Julg B, Bogner JR, Goebel FD. Severe hepatotoxicity associated with the combination of enfuvirtide and tipranavir/ritonavir: case report. AIDS. 2006;20(11):1563.PubMedCrossRefGoogle Scholar
  82. 82.
    Servoss JC, Kitch DW, Andersen JW, Reisler RB, Chung RT, Robbins GK. Predictors of antiretroviral-related hepatotoxicity in the adult AIDS Clinical Trial Group (1989–1999). J Acquir Immune Defic Syndr. 2006;43(3):320–3.PubMedCrossRefGoogle Scholar
  83. 83.
    Labarga P, Soriano V, Vispo ME, Pinilla J, Martin-Carbonero L, Castellares C, et al. Hepatotoxicity of antiretroviral drugs is reduced after successful treatment of chronic hepatitis C in HIV-infected patients. J Infect Dis. 2007;196(5):670–6.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Experimental MedicineInfections Diseases, Merck, Sharp, and Dohme Corp.North WalesUSA

Personalised recommendations