Drug Safety

, Volume 28, Issue 1, pp 53–66 | Cite as

Hepatotoxicity of Antiretrovirals

Incidence, Mechanisms and Management
Review Article

Abstract

Hepatotoxicity is a relevant adverse effect derived from the use of antiretrovirals that may increase the morbidity and mortality among treated HIV-infected patients and challenges the treatment of HIV infection. Although several antiretrovirals have been reported to cause fatal acute hepatitis, they most often cause an asymptomatic elevation of transaminase levels. In addition to ruling out a variety of processes not related to the use of antiretrovirals or to the HIV infection, for appropriate management of the complication it is necessary to deduce the possible pathogenic mechanisms of the hepatotoxicity. Among these mechanisms, direct drug toxicity, immune reconstitution in the presence of hepatitis C virus (HCV) and/or hepatitis B virus (HBV) co-infections, hypersensitivity reactions with liver involvement and mitochondrial toxicity play a major role, although several other pathogenic pathways may be involved. Liver toxicity is more frequent among subjects with chronic HCV and/or HCB co-infections and alcohol users. Complex immune changes that alter the response against hepatitis virus antigens might be involved in the elevation of transaminase levels after suppression of the HIV replication by highly active antiretroviral therapy (HAART) in patients co-infected with HCV/HBV. The contribution of each particular drug to the development of hepatotoxicity in a HAART regimen is difficult to determine. The incidence of liver toxicity is not well known for most of the antiretrovirals. Although it is most often mild, fatal cases of acute hepatitis linked to the use of HAART have been reported across all families of antiretrovirals. Acute hepatitis is related to hypersensitivity reactions in the case of non-nucleosides and to mitochondrial toxicity in the case of nucleoside analogues. Alcohol intake and use of other drugs are other co-factors that increase the incidence of transaminase level elevation among HIV-infected patients. The management of liver toxicity is based mainly on its clinical impact, severity and pathogenic mechanism. Although low-grade HAART-related hepatotoxicity most often spontaneously resolves, severe grades may require discontinuation of the antiretrovirals, for example when there is liver decompensation, hypersensitivity reaction or lactic acidosis.

References

  1. 1.
    Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with HIV infection. Clin Infect Dis 2001; 32: 492–7PubMedCrossRefGoogle Scholar
  2. 2.
    Clark S, Creighton S, Portmann B, et al. Acute liver failure associated with antiretroviral treatment for HIV: a report of six cases. J Hepatol 2002; 36: 295–301PubMedCrossRefGoogle Scholar
  3. 3.
    Lewden C. Factors associated with mortality in HIV infected adults initiating PI. J Infect Dis 2002; 186: 710–4PubMedCrossRefGoogle Scholar
  4. 4.
    Selik R, Byers R, Dworkin M. Trends in diseases reported on US death certificates that mentioned HIV infection, 1987-1999. J Acquir Immune Defic Syndr 2002; 29: 378–87PubMedGoogle Scholar
  5. 5.
    Gerberding J. Occupational exposure to HIV in health care settings. New Engl J Med 2003; 348: 826–33PubMedCrossRefGoogle Scholar
  6. 6.
    CDC. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures-worldwide, 1997-2000. MMWR Morb Mortal Wkly Rep 2001; 49: 1153–6Google Scholar
  7. 7.
    Benn P, Mercey D, Brink N, et al. Prophylaxis with a nevirapine-containing triple regimen after exposure to HIV-1. Lancet 2001; 357: 687–8PubMedCrossRefGoogle Scholar
  8. 8.
    Guay L, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomized trial. Lancet 1999; 354: 795–802PubMedGoogle Scholar
  9. 9.
    Zucker S, Qin X, Rouster S, et al. Mechanism of indinavir-induced hyperbilirubinemia. Proc Natl Acad Sci U S A 2001; 98: 12671–6PubMedCrossRefGoogle Scholar
  10. 10.
    AIDS Clinical Trials Group. Table of grading severity of adult adverse experiences. Rockville (MD): Division of AIDS, National Institute of Allergy and Infectiosus Disease, Bethesda, 1996Google Scholar
  11. 11.
    Sulkowski M, Thomas D, Chaisson R, et al. Hepatotoxicity associated with antiretroviral therapy in adults infected with HIV and the role of hepatitis C or B virus infection. JAMA 2000; 283: 74–80PubMedCrossRefGoogle Scholar
  12. 12.
    Rodríguez-Rosado R, García-Samaniego J, Soriano V. Hepatotoxicity after introduction of highly active antiretroviral therapy [letter]. AIDS 1998; 12: 1256PubMedCrossRefGoogle Scholar
  13. 13.
    Saves M, Vandentorren S, Daucourt V, et al. Severe hepatic cytolysis: incidence and risk factors in patients treated by antiretroviral combinations. Aquitaine Cohort, France, 1996-1998. AIDS 1999; 13: F115–21PubMedCrossRefGoogle Scholar
  14. 14.
    Den Brinker M, Wit F, Wertheim-van Dillen P, 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: 2895–902CrossRefGoogle Scholar
  15. 15.
    Saves M, Raffi F, Clevenbergh P, et al. Hepatitis B or hepatitis C virus infection is a risk factor for severe hepatic cytolysis after initiation of a protease inhibitor-containing antiretroviral regimen in HIV-infected patients. Antimicrob Agents Chemother 2000; 44: 3451–5PubMedCrossRefGoogle Scholar
  16. 16.
    Núñez M, Lana R, Mendoza J, et al. Risk factors for severe hepatic injury following the introduction of HAART. J Acquir Immune Defic Syndr 2001; 27: 426–31PubMedGoogle Scholar
  17. 17.
    Bonfanti P, Landonio S, Ricci E, et al. Risk factors for hepatotoxicity in patients treated with highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2001; 27: 316–8PubMedGoogle Scholar
  18. 18.
    D’Arminio Monforte A, Bugarini R, Pezzotti P, et al. Low frequency of severe hepatotoxicity and association with HCV coinfection in HIV-positive patients treated with HAART. J Acquir Immune Defic Syndr 2001; 28: 114–23Google Scholar
  19. 19.
    Aceti A, Pasquazzi C, Zechini B, et al. Hepatotoxicity development during antiretroviral therapy containing protease inhibitors in patients with HIV: the role of hepatitis B and C virus infection. The LIVERHAART Group. J Acquir Immune Defic Syndr 2002; 29: 41–8PubMedGoogle Scholar
  20. 20.
    Wit F, Weverling G, Weel J, et al. Incidence and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis 2002; 186: 23–31PubMedCrossRefGoogle Scholar
  21. 21.
    Giannini E, Risso D, Botta F, et al. Validity and clinical utility of the aspartate aminotransferase-alanine aminotransferase ratio in assessing disease severity and prognosis in patients with hepatitis C virus-related chronic liver disease. Arch Intern Med 2003; 163: 218–24PubMedCrossRefGoogle Scholar
  22. 22.
    Dieterich D. Hepatitis C virus and HIV: clinical issues in coinfection. Am J Med 1999; 107:(6B) 79S–84SPubMedCrossRefGoogle Scholar
  23. 23.
    Soriano V, Garcia-Samaniego J, Rodriguez-Rosado R, et al. Hepatitis C and HIV infection: biological, clinical, and therapeutic implications. J Hepatol 1999; 31: 119–23PubMedCrossRefGoogle Scholar
  24. 24.
    Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in HIV and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology 1999; 30: 1054–8PubMedCrossRefGoogle Scholar
  25. 25.
    Núñez M, Ríos P, Martín-Carbonero L, et al. Role of hepatitis C virus genotype in the development of severe transaminase elevation after the introduction of antiretroviral therapy. J Acquir Immune Defic Syndr 2002; 30: 65–8PubMedGoogle Scholar
  26. 26.
    Arribas J, Ibáñez C, Ruiz-Antoran B, et al. Acute hepatitis in HIV-infected patients during ritonavir treatment. AIDS 1998; 12: 1722–4PubMedGoogle Scholar
  27. 27.
    Cooper C, Parbhakar M, Angel J. Hepatotoxicity associated with antiretroviral therapy containing dual versus single protease inhibitors in individuals coinfected with hepatitis C virus and HIV. Clin Infect Dis 2002; 34: 1259–63PubMedCrossRefGoogle Scholar
  28. 28.
    Pai V, Koranyi K, Nahata M. Acute hepatitis and bleeding possibly induced by zidovudine and ritonavir in an infant with HIV infection. Pharmacotherapy 2000; 20: 1135–40PubMedCrossRefGoogle Scholar
  29. 29.
    Brau N, Leaf H, Wieczorek R, et al. Severe hepatitis in three AIDS patients treated with indinavir. Lancet 1997; 349: 924–5PubMedCrossRefGoogle Scholar
  30. 30.
    Matsuda J, Gohchi K. Severe hepatitis in patients with AIDS and haemophilia B treated with indinavir [letter]. Lancet 1997; 350: 364PubMedCrossRefGoogle Scholar
  31. 31.
    Flexner C. HIV protease inhibitors. N Engl J Med 1998; 338: 1281–92PubMedCrossRefGoogle Scholar
  32. 32.
    Kontorinis N, Dieterich D. Hepatotoxicity of antiretroviral therapy. AIDS Rev 2003; 5: 36–43PubMedGoogle Scholar
  33. 33.
    González-Requena D, Núñez M, González-Lahoz J, et al. Liver toxicity of lopinavir-containing regimens in HIV-infected patients with and without hepatitis coinfection. AIDS Res Hum Retroviruses 2004; 20: 698–700PubMedCrossRefGoogle Scholar
  34. 34.
    Brinkman K, ter Hofstede H, Burger D, et al. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998; 12: 1735–44PubMedCrossRefGoogle Scholar
  35. 35.
    Frieman J, Helfert K, Hamrell M, et al. Hepatomegaly with severe steatosis in HIV-seropositive patients. AIDS 1993; 7: 379–85CrossRefGoogle Scholar
  36. 36.
    Bissuel F, Bruneel F, Habersetzer F, et al. Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy. J Intern Med 1994; 235: 367–71PubMedCrossRefGoogle Scholar
  37. 37.
    ter Hofstede H, De Marie S, Foudraine N, et al. Clinical features and risk factors of lactic acidosis following long term antiretroviral therapy: 4 fatal cases. Int J STD AIDS 2000; 11: 611–6PubMedCrossRefGoogle Scholar
  38. 38.
    Gisolf E, Dreezen C, Danner S, et al. Risk factors for hepatotoxicity in HIV-1-infected patients receiving ritonavir and saquinavir with or without stavudine. Promethius Study Group. Clin Infect Dis 2000; 3: 1234–9CrossRefGoogle Scholar
  39. 39.
    Sanne I. Severe liver toxicity in patients receiving two nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor: on behalf of the FTC-302 Study Investigators and the FTC-302 Independent Clinical Steering Committee [abstract]. AIDS 2000; 14Suppl. 4: 12Google Scholar
  40. 40.
    Martínez E, Blanco J, Arnaiz J, et al. Hepatotoxicity in HIV-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS 2001; 15: 1261–8PubMedCrossRefGoogle Scholar
  41. 41.
    Bonnet F, Lawson-Ayayi S, Thiebaut R, et al. A cohort study of nevirapin tolerance in clinical practice: French Aquitaine Cohort, 1997-1999. Clin Infect Dis 2002; 35: 1231–7PubMedCrossRefGoogle Scholar
  42. 42.
    Palmon R, Koo B, Shoultz D, et al. Lack of hepatotoxicity associated with nonnucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr 2002; 29: 340–5PubMedGoogle Scholar
  43. 43.
    De Maat M, Mathot R, Veldkamp A, et al. Hepatotoxicity following nevirapine containing regimens in HIV-1-infected individuals. Pharmacol Res 2002; 46: 295–300PubMedCrossRefGoogle Scholar
  44. 44.
    Sulkowski M, Thomas D, Mehta S, et al. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002; 35: 182–9PubMedCrossRefGoogle Scholar
  45. 45.
    Martín-Carbonero L, Núñez M, González-Lahoz J, et al. Incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. HIV Clin Trials 2003; 4: 115–20PubMedCrossRefGoogle Scholar
  46. 46.
    Harris D, Gonin R, Alter H, et al. The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med 2001; 134: 120–4PubMedGoogle Scholar
  47. 47.
    Núñez M, González de Requena D, Gonzalez-Lahoz J, et al. Interactions between nevirapine plasma levels, chronic hepatitis C, and the development of liver toxicity in HIV-infected patients. AIDS Res Hum Retroviruses 2003; 19: 187–8PubMedCrossRefGoogle Scholar
  48. 48.
    González de Requena D, Núñez M, Jimenez-Nacher I, et al. Liver toxicity caused by nevirapine. AIDS 2002; 16: 290–1CrossRefGoogle Scholar
  49. 49.
    Prakash M, Poreddy V, Tiyyagura L, et al. Jaundice andhepatocellular damage associated with nevirapine therapy. Am J Gastroenterol 2001; 96: 1571–4PubMedCrossRefGoogle Scholar
  50. 50.
    Alonso G, Fuertes A, De Dios S, et al. DRESS syndrome associated with nevirapine therapy. Arch Intern Med 2001; 161: 2501–2CrossRefGoogle Scholar
  51. 51.
    Shapiro M, Ward K, Stern J. A near-fatal hypersensitivity reaction to abacavir: case report and literature review. AIDS Read 2001; 11: 222–6PubMedGoogle Scholar
  52. 52.
    Hewitt R. Abacavir hypersensitivity reaction. Clin Infect Dis 2002; 34: 1137–42PubMedCrossRefGoogle Scholar
  53. 53.
    Johnson S, Chan J, Bennett C. Hepatotoxicity after prophylaxis with a nevirapine-containing antiretroviral regimen. Ann Intern Med 2002; 137: 146–7PubMedGoogle Scholar
  54. 54.
    Tancrede-Bohin E, Grange F, Bournerias I, et al. Hypersensitivity syndrome associated with zalcitabine therapy [letter]. Lancet 1996; 347: 971PubMedCrossRefGoogle Scholar
  55. 55.
    Lonergan J, Behling C, Pfander H, et al. Hyperlactatemia and hepatic abnormalities in 10 HIV-infected patients receiving nucleoside analogue combination regimens. Clin Infect Dis 2000; 31: 162–6PubMedCrossRefGoogle Scholar
  56. 56.
    Coghlan M, Sommadossi J, Jhala N, et al. Symptomatic lactic acidosis in hospitalized antiretroviral-treated patients with HIV infection: a report of 12 cases. Clin Infect Dis 2001; 33: 1914–21PubMedCrossRefGoogle Scholar
  57. 57.
    Fouty B, Frerman F, Reves R. Riboflavin to treat nucleoside analogue-induced lactic acidosis. Lancet 1998; 352: 291–2PubMedCrossRefGoogle Scholar
  58. 58.
    Claessen Y, Cariou A, Chiche J, et al. L-Carnitine as a treatment of life-threatening lactic acidosis induced by nucleoside analogues. AIDS 2000; 14: 472–3CrossRefGoogle Scholar
  59. 59.
    Johri S, Alkhuja S, Siviglia G, et al. Steatosis-lactic acidosis syndrome associated with stavudine and lamivudine therapy. AIDS 2000; 14: 1286–7PubMedCrossRefGoogle Scholar
  60. 60.
    Birkus G, Hitchcock M, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002; 46: 716–23PubMedCrossRefGoogle Scholar
  61. 61.
    Carr A, Samaras K, Chisolm D, et al. Pathogenesis of HIV-1 protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia and insulin resistance. Lancet 1999; 353: 2093–9PubMedCrossRefGoogle Scholar
  62. 62.
    John M, Flexman J, French A. Hepatitis C virus-associated hepatitis following treatment of HIV-infected patients with HIV protease inhibitors: an immune restoration disease? AIDS 1998; 12: 2289–93PubMedCrossRefGoogle Scholar
  63. 63.
    Gavazzi G, Bouchard O, Leclercq P, et al. Change in transaminases in hepatitis C virus- and HIV-coinfected patients after highly active antiretroviral therapy: differences between complete and partial virologic responders? AIDS Res Hum Retroviruses 2000; 16: 1021–3PubMedCrossRefGoogle Scholar
  64. 64.
    Chung R, Evans S, Yang Y, 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 coinfected subjects. AIDS 2002; 16: 1915–23PubMedCrossRefGoogle Scholar
  65. 65.
    Mastroianni C, Trinchieri V, Santopadre P, et al. Acute clinical hepatitis in an HIV-seropositive hepatitis B carrier receiving protease inhibitor therapy. AIDS 1998; 12: 1939–40PubMedGoogle Scholar
  66. 66.
    Manegold C, Hannoun C, Wywiol A, et al. Reactivation of Hepatitis B virus replication accompanied by acute hepatitis in patients receiving highly active antiretroviral therapy. Clin Infect Dis 2001; 32: 144–8PubMedCrossRefGoogle Scholar
  67. 67.
    Díaz B, Martín-Carbonero L, Pérez-Olmeda M, et al. Normalization of liver enzymes in an HIV-hepatitis C virus-co-infected patient after potent antiretroviral therapy [letter]. AIDS 2002; 16: 1193PubMedCrossRefGoogle Scholar
  68. 68.
    Pérez-Olmeda M, García-Samaniego J, Soriano V. Hepatitis C viraemia in HIV-HCV co-infected patients having immune restoration with highly active antiretroviral therapy [letter]. AIDS 2000; 14: 212PubMedCrossRefGoogle Scholar
  69. 69.
    Puoti M, Gargiulo F, Roldan E, et al. Liver damage and kinetics of hepatitis C virus and HIV replication during the early phases of combination antiretroviral treatment. J Infect Dis 2000; 181: 2033–6PubMedCrossRefGoogle Scholar
  70. 70.
    Torre D, Tambini R, Cadario F, et al. Evolution of coinfection with HIV and hepatitis C virus in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2001; 33: 1579–85PubMedCrossRefGoogle Scholar
  71. 71.
    Bissell D, Gores G, Laskin D, et al. Drug-induced liver injury: mechanisms and test systems. Hepatology 2001; 33: 1009–13PubMedCrossRefGoogle Scholar
  72. 72.
    Leist M, Gantner F, Kunstle G, et al. Cytokine-mediated hepaticapoptosis. Rev Physiol Biochem Pharmacol 1998; 133: 109–55PubMedGoogle Scholar
  73. 73.
    McCarthy J, Hilfiker R. The use of single-nucleotide polymorphism maps in pharmacogenomics. Nat Biotechnol 2000; 18: 505–8PubMedCrossRefGoogle Scholar
  74. 74.
    Knowles S, Uetrecht J, Shear N. Idiosyncratic drug reactions: the reactive metabolite syndromes. Lancet 2000; 356: 1587–91PubMedCrossRefGoogle Scholar
  75. 75.
    Foli A, Benvenuto F, Piccinini G, et al. Direct analysis of mitochondrial toxicity of antiretroviral drugs. AIDS 2001; 15: 1687–94PubMedCrossRefGoogle Scholar
  76. 76.
    Walker U, Setzer B, Venhoff N. Increased long-term mitochondrial toxicity in combinations of nucleoside analogue reverse-transcriptase inhibitors. AIDS 2002; 16: 2165–73PubMedCrossRefGoogle Scholar
  77. 77.
    Puoti M, Torti C, Ripamonti D, et al. Severe hepatotoxicity during combination antiretroviral treatment: incidence, liver histology, and outcome. J Acquir Immune Defic Syndr 2003; 32: 259–67PubMedCrossRefGoogle Scholar
  78. 78.
    Rutschmann O, Negro F, Hirschel B, et al. Impact of treatment with HIV protease inhibitors on hepatitis C viremia in patients coinfected with HIV. J Infect Dis 1998; 177: 783–5PubMedCrossRefGoogle Scholar
  79. 79.
    Vento S, Garofano T, Renzini C, et al. Enhancement of hepatitis C virus replication and liver damage in HIV-coinfected patients on antiretroviral combination therapy. AIDS 1998; 12: 116–7PubMedGoogle Scholar
  80. 80.
    Stone S, Lee S, Keane N, et al. Association of increased hepatitis C virus (HCV)-specific IgG and soluble CD26 dipeptidyl peptidase IV enzyme activity with hepatotoxicity after highly active antiretroviral therapy in human immunodeficiency virus-HCV-coinfected patients. J Infect Dis 2002; 186: 1498–502PubMedCrossRefGoogle Scholar
  81. 81.
    Spellberg B, Edwards J. Type 1/type 2 immunity in infectious diseases. Clin Infect Dis 2001; 32: 76–102PubMedCrossRefGoogle Scholar
  82. 82.
    Jardi R, Rodriguez F, Buti M, et al. Role of hepatitis B, C, and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference. Hepatology 2001; 34: 404–10PubMedCrossRefGoogle Scholar
  83. 83.
    Cooper C, Cameron D. Review of the effect of highly active antiretroviral therapy on HCV RNA levels in HIV and HCV coinfection. Clin Infect Dis 2002; 35: 873–9PubMedCrossRefGoogle Scholar
  84. 84.
    Soriano V, Sulkowski M, Bergin C, et al. Care of patients with chronic hepatitis C and HIV co-infection: recommendations from the HIV-HCV international panel. AIDS 2002; 16: 813–28PubMedCrossRefGoogle Scholar
  85. 85.
    Leitze Z, Nadeem A, Choudhary A, et al. Nevirapine-induced hepatitis treated with corticosteroids? AIDS 1998; 12: 1115–7PubMedGoogle Scholar
  86. 86.
    Johnson S, Chan J, Bennett C. Hepatotoxicity after prophylaxis with a nevirapine-containing antiretroviral regimen. Ann Intern Med 2002; 137: 146–7PubMedGoogle Scholar
  87. 87.
    Núñez M, Pérez-Olmeda M, Diaz B, et al. Activity of tenofovir on hepatitis B virus replication in HIV-coinfected patients failing or partially responding to lamivudine. AIDS 2002; 16: 2352–4PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Service of Infectious Diseases, Enfermedades InfecciosasInstituto de Salud Carlos IIIMadridSpain

Personalised recommendations