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Semin Liver Dis 2003; 23(2): 167-172
DOI: 10.1055/s-2003-39947
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Hepatotoxicity of Nucleoside Reverse Transcriptase Inhibitors

Valentina Montessori1,2 , Marianne Harris2 , Julio S.G. Montaner2,3
  • 1Clinical Assistant Professor, University of British Columbia, Vancouver, Canada
  • 2the BC Centre for Excellence in HIV and AIDS, Vancouver, Canada
  • 3University of British Columbia, Vancouver, Canada
Further Information

Publication History

Publication Date:
11 June 2003 (online)

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ABSTRACT

Hepatotoxicity is an adverse effect of all available classes of antiretrovirals, including nucleoside reverse transcriptase inhibitors (NRTI). A syndrome of hepatic steatosis and lactic acidosis has been recognized as a rare, potentially fatal complication since the advent of NRTI monotherapy in the early 1990s. Today, NRTI remain the backbone of antiretroviral combination regimens, and, with the success of current treatment strategies, exposure to two or more of these agents may occur over a number of years. Hepatic steatosis and lactic acidosis are accordingly being observed more frequently, along with a more recently recognized syndrome of chronic hyperlactatemia. These as well as other adverse effects of NRTI are mediated by inhibition of human DNA polymerase γ, resulting in mitochondrial dysfunction in the liver and other tissues. Early recognition and intervention are essential to avert serious outcomes.

KEYWORDS

NRTI - hepatotoxicity

REFERENCES

  • 1 Sulkowski M S, Thomas D L, Chaisson R E, Moore R D. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B infection.  JAMA . 2000;  283 74-80
    CrossrefPubMedGoogle Scholar
  • 2 Reisler R, Servoss J, Sherman K. et al .Incidence of hepatotoxicity and mortality in 21 adult antiretroviral treatment trials. ACTG Liver Diseases Focus Group. In: Program and Abstracts of the 1st IAS Conference on HIV Pathogenesis and Treatment. July 8-11, 2001; Buenos Aires, Argentina. Abstract 43
    Google Scholar
  • 3 Lewis W, Dalakis M C. Mitochondrial toxicity of antiviral drugs.  Nat Med . 1995;  1 417-421
    PubMedGoogle Scholar
  • 4 Lai K K, Gang D L, Zawacki J K, Cooley T P. Fulminant hepatic failure associated with 2',3'-dideoxyinosine (ddI).  Ann Intern Med . 1991;  115 283-284
    PubMedGoogle Scholar
  • 5 Bissuel F, Bruneel F, Habersetzer F. et al . Fulminant hepatitis with severe lactic acidosis in HIV-infected patients on didanosine therapy.  J Intern Med . 1994;  235 367-371
    CrossrefPubMedGoogle Scholar
  • 6 Olano J P, Borucki M J, Wen J W. Massive hepatic steatosis and lactic acidosis in a patient with AIDS who was receiving zidovudine.  Clin Infect Dis . 1995;  21 973-976
    PubMedGoogle Scholar
  • 7 Sundar K, Suarez M, Banogon P E, Shapiro J P. Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome: report of two patients and review of the literature.  Crit Care Med . 1997;  25 1425-1430
    PubMedGoogle Scholar
  • 8 Lenzo N P, Garas B A, French M A. Hepatic steatosis and lactic acidosis associated with stavudine treatment in an HIV patient: a case report.  AIDS . 1997;  11 1294-1296
    PubMedGoogle Scholar
  • 9 Brinkman K, ter Hofstede J M H, Burger D M, Smeitink J AM, Koopmans P P. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway.  AIDS . 1998;  12 1735-1744
    PubMedGoogle Scholar
  • 10 Chariot P, Drogou I, de Lacroix-Szmania I. et al . Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion.  J Hepatol . 1999;  30 156-160
    CrossrefPubMedGoogle Scholar
  • 11 Fortgang I, Belitsos P, Chaisson R, Moore R. Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analogue antiretroviral therapy.  Am J Gastroenterol . 1995;  90 1433-1436
    PubMedGoogle Scholar
  • 12 Brinkman K, ter Hofstede H, Veerkamp M J. et al .Fatal lactic acidosis following HAART containing stavudine (d4T), lamivudine (3TC) and saquinavir. Presented at the 12th International AIDS Conference. 1998 Abstract 1182
    Google Scholar
  • 13 Church J, Mitchell W, Gonzalez-Gomez I. et al .Near-fatal metabolic acidosis, liver failure, and mitochondrial (mt) DNA depletion in an HIV-infected child treated with combination antiretroviral therapy (ART). Presented at the 7th Conference on Retroviruses and Opportunistic Infections. January-February 2000; San Francisco, CA. Abstract 58
    Google Scholar
  • 14 ter Hofstede H, de Marie S, Foudraine N. et al .Four cases of fatal lactic acidosis due to mitochondrial toxicity of NRTI treatment: analysis of clinical features and risk factors. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000; San Francisco, CA
    Google Scholar
  • 15 Aggarwal A, al-Talib K, Alabrash M. Type B lactic acidosis in an AIDS patient treated with zidovudine.  Md Med J . 1996;  45 929-931
    PubMedGoogle Scholar
  • 16 Cooper D. Lactic acidosis and hepatic dysfunction associated with HAART: pathogenesis, clinical manifestations and predictors. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000; San Francisco, CA
    Google Scholar
  • 17 Acosta B S, Grimsley E W. Zidovudine-associated type B lactic acidosis and hepatic steatosis in an HIV-infected patient.  South Med J . 1999;  92 421-423
    PubMedGoogle Scholar
  • 18 Lonergan J T, Behling C, Pfander H. et al . Hyperlactatemia and hepatic abnormalities in 10 human immunodeficiency virus-infected patients receiving nucleoside analogue combination regimens.  Clin Infect Dis . 2000;  31 162-166
    CrossrefPubMedGoogle Scholar
  • 19 Harris M, Chan K, Tesiorowski A. et al . Random venous lactate levels among HIV positive patients on antiretroviral therapy (in press).  J Acquir Immune Defic Syndr. 2003; 
    PubMedGoogle Scholar
  • 20 Delgado J, Harris M, Tesiorowski A, Montaner J SG. Symptomatic elevations of lactic acid and their response to treatment manipulation in HIV infected individuals-a case series.  Clin Infect Dis . 2001;  33 2072-2074
    CrossrefPubMedGoogle Scholar
  • 21 Lonergan J T, Havlir D, Behling C. et al .Hyperlactatemia in 20 patients receiving NRTI combination regimens. Presented at the 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000; San Francisco, CA
    Google Scholar
  • 22 Gerard Y, Maulin L, Yazdanpanah Y. et al . Symptomatic hyperlactatemia: an emerging complication of antiretroviral therapy.  AIDS . 2000;  14 2723-2730
    PubMedGoogle Scholar
  • 23 John M, Moore C B, James I R. et al . Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy.  AIDS . 2001;  15 717-723
    PubMedGoogle Scholar
  • 24 Medina D J, Tsai C-H, Hsiung G D, Cheng Y-C. Comparison of mitochondrial morphology, mitochondrial DNA content, and cell viability in cultured cells treated with three anti-human immunodeficiency virus dideoxynucleosides.  Antimicrob Agents Chemother . 1994;  38 1824-1828
    PubMedGoogle Scholar
  • 25 Martin J L, Brown C E, Matthews-Davis N, Reardon J E. Effects of antiviral nucleoside analogs on human DNA polymerases and mitochondrial DNA synthesis.  Antimicrob Agents Chemother . 1994;  38 2743-2749
    PubMedGoogle Scholar
  • 26 Barbaro G, Lorenzo G, Asti A. et al . Hepatocellular mitochondrial alterations in pateints with chronic hepatitis C: ultrastructural and biochemical findings.  Am J Gastroenterol . 1999;  94 2198-2205
    CrossrefPubMedGoogle Scholar
  • 27 Lafeuillade A, Hittinger G, Chadapaud S. Increased mitochondrial toxicity with ribavirin in HIV/HCV co-infection.  Lancet . 2001;  357 280-281
    CrossrefPubMedGoogle Scholar
  • 28 Johns D. The other human genome: mitochondrial DNA and disease.  Nat Med . 1996;  2 1065-1068
    PubMedGoogle Scholar
  • 29 Plymale D R, Tang D S, Comardelle A M. et al . Both necrosis and apoptosis contribute to HIV-1 induced killing of CD4 cells.  AIDS . 1999;  13 1827-1839
    CrossrefPubMedGoogle Scholar
  • 30 Cote H, Brumme Z L, Alexander C A. et al . Application of a novel assay to monitor peripheral blood mitochondrial DNA levels in HIV-infected patients on combination antiretroviral therapy.  N Engl J Med . 2002;  346 811-820
    CrossrefPubMedGoogle Scholar
  • 31 Fouty B, Frerman F, Reves R. Riboflavin to treat nucleoside analogue-induced lactic acidosis.  Lancet . 1998;  352 291-292
    CrossrefPubMedGoogle Scholar
  • 32 Luzzati R, Del Bravo P, Di Perri G, Luzzani A, Concia E. Riboflavine and severe lactic acidosis.  Lancet . 1999;  353 901-902
    CrossrefPubMedGoogle Scholar
  • 33 Schramm C, Wanitschke R, Galle P R. Thiamine for the treatment of nucleoside analogue-induced severe lactic acidosis.  Eur J Anaesthesiol . 1999;  16 733-735
    CrossrefPubMedGoogle Scholar
  • 34 Brinkman K, Vrouenraets S, Kauffmann R, Weigel H, Frissen J. Treatment of nucleoside reverse transcriptase inhibitor-induced lactic acidosis.  AIDS . 2000;  14 2801-2802
    CrossrefPubMedGoogle Scholar
  • 35 Przyrembel H. Therapy of mitochondrial disorders.  J Inherit Metab Dis . 1987;  10(Suppl 1) 129-146
    PubMedGoogle Scholar
  • 36 Campos Y, Huertas R, Lorenzo G. et al . Plasma carnitine insufficiency and effectiveness of L-carnitine therapy in patients with mitochondrial myopathy.  Muscle Nerve . 1993;  43 884-890
    PubMedGoogle Scholar
  • 37 Mathews P, Ford B, Dandurand R. et al . Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease.  Neurology . 1993;  43 884-890
    PubMedGoogle Scholar
  • 38 Claessens Y E, Cariou A, Chiche J D. et al . L-carnitine as a treatment of life-threatening lactic acidosis induced by nucleoside analogues.  AIDS . 2000;  14 472-473
    CrossrefPubMedGoogle Scholar
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