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Semin Liver Dis 2003; 23(2): 173-182
DOI: 10.1055/s-2003-39948
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Toxicity of Non-Nucleoside Analogue Reverse Transcriptase Inhibitors

Nickolas Kontorinis1 , Douglas T. Dieterich2
  • 1Department of Medicine, Mount Sinai School of Medicine, New York, New York
  • 2Vice Chair and Chief Medical Officer, Department of Medicine, Division of Liver Disease, Mount Sinai School of Medicine, New York, New York
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Publication History

Publication Date:
11 June 2003 (online)

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ABSTRACT

The non-nucleoside reverse transcriptase inhibitors (NNRTI) nevirapine (NVP), efavirenz (EFV), and delaviridine (DLV) are increasingly being used to treat HIV infection. Studies have shown excellent tolerance and efficacy and less development of virological resistance with HIV regimens that include NNRTIs. Nevertheless, abnormalities in liver enzymes are common in patients with HIV infection, and there are multiple etiologies for these abnormalities, including drug toxicity, viral hepatitis, opportunistic infections, and substance abuse. In particular, highly active antiretroviral therapy (HAART) can result in hepatotoxicity through a variety of mechanisms, such as mitochondrial toxicity, lipodystrophy syndrome, and steatohepatitis. The NNRTIs have been most frequently implicated in hypersensitivity reactions. NVP-containing HAART regimens may be more hepatotoxic than are those with EFV and DLV, at least for the first 6 weeks, although the data are still contradictory. Coinfection with hepatitis C and B viruses appears to significantly increase the risk of toxicity, and therefore all patients should be screened for viral hepatitis prior to commencing HAART. Close monitoring of transaminases is suggested in all patients commencing HAART, especially those with preexisting liver disease and coinfection with viral hepatitis.

KEYWORDS

Non-nucleoside reverse transcriptase inhibitors - nevirapine - efavirenz - delaviridine - hepatotoxicity - HIV infection - coinfection - hypersensitivity reaction

REFERENCES

  • 1 Kreisberg R. Clinical problem-solving.  We blew it. N Engl J Med . 1995;  332 945-949
    PubMedGoogle Scholar
  • 2 Dieterich D T. Hepatitis C virus and human immunodeficiency virus: clinical issues in co-infection.  Am J Med . 1999;  107 79S-84S
    CrossrefPubMedGoogle Scholar
  • 3 Rodriguez-Rosado R, Garcia-Samaniego J, Soriano V. Hepatotoxicity after introduction of highly active antiretroviral therapy.  AIDS . 1998;  12 1256
    CrossrefPubMedGoogle Scholar
  • 4 AIDS Clinical Trials Group criteria, Division of AIDS. Table for grading severity of adult adverse experiences, August 1992
  • 5 Lewis W, Dalakas M C. Mitochondrial toxicity of antiretroviral drugs.  Nat Med . 1995;  1 417-422
    PubMedGoogle Scholar
  • 6 Moyle G. Toxicity of antiretroviral nucleoside and non-nucleoside analogues. Is mitochondrial toxicity the only mechanism?.  Drug Saf . 2000;  23 467-481
    PubMedGoogle Scholar
  • 7 Carr A, Samaras K, Burton S. et al . A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.  AIDS . 1998;  12 F51
    CrossrefPubMedGoogle Scholar
  • 8 Murata H, Hruz P W, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy.  J Biol Chem . 2000;  275 20251-20254
    CrossrefPubMedGoogle Scholar
  • 9 Spengler U, Lichterfeld M, Rockstroh J K. Antiretroviral drug toxicity-a challenge for the hepatologist?.  J Hepatol . 2002;  36 283-294
    CrossrefPubMedGoogle Scholar
  • 10 Wassef M, Keiser P. Hypersensitivity to zidovudine: report of a case and review of the literature.  Am J Med . 1992;  93 94-96
    CrossrefPubMedGoogle Scholar
  • 11 Warren K J, Boxwell D E, Kim N Y, Drolet B A. Nevirapine-associated Stevens-Johnson syndrome.  Lancet . 1998;  351 567
    CrossrefPubMedGoogle Scholar
  • 12 Moore C B, John M, James I R. et al . Evidence of HIV-1 adaptation to HLA-restricted immune responses at a population level.  Science . 2002;  296 1439-1443
    CrossrefPubMedGoogle Scholar
  • 13 Darby S C, Ewart D W, Giangrande P LF. et al . Mortality from liver cancer and liver disease in haemophiliac men and boys in UK given blood products contaminated with hepatitis C.  Lancet . 1997;  350 1245-1231
    CrossrefPubMedGoogle Scholar
  • 14 Centers for Disease Control and Prevention. 1999 USPHS/ IDSA guidelines for the prevention of opportunistic infections in persons infected with human immunodeficiency virus: US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA).  MMWR Morb Mortal Wkly Rep . 1999;  48 32-34
    PubMedGoogle Scholar
  • 15 Melvin D C, Lee J K, Belsey E. et al . The impact of co-infection with hepatitis C virus and HIV on the tolerability of antiretroviral therapy.  AIDS . 2000;  14 463-446
    PubMedGoogle Scholar
  • 16 den Brinker M, Wit F W, Wertheim-van Dillen M 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 2895-2902
    CrossrefPubMedGoogle Scholar
  • 17 Greub G, Lederberger B, Battegay M. et al . Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus co-infection: the Swiss HIV Cohort Study.  Lancet . 2000;  356 1800-1805
    CrossrefPubMedGoogle Scholar
  • 18 Monforte Ade A, Bugarini R, Pezzotti P. et al . Low frequency of severe hepatotoxicity and association with HCV co-infection in HIV-positive patients treated with HAART.  J Acquir Immune Defic Syndr . 2001;  28 114-123
    CrossrefPubMedGoogle Scholar
  • 19 Monga H K, Rodriguez-Barradas M C, Breaux K. et al . Hepatitis C virus infection-related morbidity and mortality among patients with human immunodeficiency virus infection.  Clin Infect Dis . 2001;  33 240-247
    CrossrefPubMedGoogle Scholar
  • 20 Núñez M, Lana R, Mendoza J L. et al . Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy.  J Acquir Immune Defic Syndr . 2001;  27 426-431
    PubMedGoogle Scholar
  • 21 Rutschman O T, Negro F, Hirschel B. et al . Impact of treatment with human immunodeficiency virus (HIV) protease inhibitors on hepatitis C viremia in patients co-infected with HIV.  J Infect Dis . 1998;  177 783-785
    PubMedGoogle Scholar
  • 22 Pfister M, Labbe L, Hammer S M. et al . Population Pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398.  Antimicrob Agents Chemother . 2003;  47 130-137
    CrossrefPubMedGoogle Scholar
  • 23 Stormer E, von Moltke L L, Perloff M D, Greenblatt D J. Differential modulation of P-glycoprotein expression and activity by non-nucleoside HIV-1 reverse transcriptase inhibitors in cell culture.  Pharm Res . 2002;  19 1038-1045
    CrossrefPubMedGoogle Scholar
  • 24 Clark S J, Creighton S, Portmann B. et al . Acute liver failure associated with antiretroviral treatment for HIV: a report of six cases.  J Hepatol . 2002;  36 295-301
    CrossrefPubMedGoogle Scholar
  • 25 Dieterich D, Stern J, Robinson P. et al .Analyses of 4 key clinical trials to assess the risk of hepatotoxicity with nevirapine: correlation with CD4 + levels, hepatitis B & C seropositivity and baseline liver function tests. In: Program and Abstracts of the 1st IAS Conference on HIV Pathogenesis and Treatment July 8-11, 2001; Buenos Aires, Argentina. Abstract 44
    Google Scholar
  • 26 Stern J O. et al .Hepatic safety of nevirapine: results of the Boehringer Ingelheim viramune hepatic safety project. Presented at the 14th International AIDS conference. July 7-12, 2002; Barcelona, Spain. LBOr15 (postor presentation)
    Google Scholar
  • 27 Yeni P G, Hammer S M, Carpenter C C. et al . Antiretroviral treatment for adult HIV infection in 2002; updated recommendations of the International AIDS Society-USA Panel.  JAMA . 2002;  288 222-235
    CrossrefPubMedGoogle Scholar
  • 28 Centers for Disease Control and Prevention. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures-worldwide, 1997-2000.  MMWR Morb Mortal Wkly Rep . 2001;  49 1153-1154
    PubMedGoogle Scholar
  • 29 Bersoff-Matcha S J, Miller W C, Aberg J A. et al . Sex differences in nevirapine rash.  Clin Infect Dis . 2001;  32 124-129
    CrossrefPubMedGoogle Scholar
  • 30 Sulkowski M S, Thomas D L, Mehta S H. et al . Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections.  Hepatology . 2002;  35 182-188
    CrossrefPubMedGoogle Scholar
  • 31 Lebray P, Benhamou Y, Pol S. et al . NNRTI-related or -unrelated hepatotoxicity?.  Hepatology . 2002;  36 512-513
    CrossrefPubMedGoogle Scholar
  • 32 Palmon R, Koo B CA, Shoultz D A. et al . Lack of hepatotoxicity associated with nonnucleoside reverse transcriptase inhibitors.  J Acquir Immune Defic Syndr . 2002;  29 340-345
    PubMedGoogle Scholar
  • 33 Clarke S, Harrington P, Condon C. et al . Late onset hepatitis and prolonged deterioration in hepatic function associated with nevirapine therapy.  Int J STD AIDS . 2000;  11 336-337
    CrossrefPubMedGoogle Scholar
  • 34 van Leth F, Hassink E, Phanphk P. et al .Results of the 2NN study: a randomized comparative trial of first line antitretiviral therapy with regimens containing either nevirapine alone, efavirenz alone, or both drugs combined together with stavudine and lamivudine. Presented at the 10th Conference on Retroviruses and Opportunistic Infections, February 2003; Boston, MA. Abstract 176. 
    Google Scholar
  • 35 Martinez E, Blanco J L, Arnaiz J A. et al . Hepatotoxicity in HIV-1 infected patients receiving nevirapine-containing antiretroviral therapy.  AIDS . 2001;  15 1261-1268
    CrossrefPubMedGoogle Scholar
  • 36 Reisler R, Servoss J C, Sherman K E. et al .Incidence of hepatotoxicity and mortality in 21 adult antiretroviral treatment trials. 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
  • 37 Abrescia N, D'Abbraccio M, Figoni M. et al . Fulminant hepatic failure after the start of an efavirenz-based HAART regimen in a treatment-naive female AIDS patient without hepatitis virus co-infection.  J Antimicrob Chemother . 2002;  50 763-765
    CrossrefPubMedGoogle Scholar
  • 38 Sutinen J, Hakkinen A M, Westerbacka J. et al . Increased fat accumulation in the liver in HIV-infected patients with antiretroviral therapy-associated lipodystrophy.  AIDS . 2002;  16 2183-2193
    CrossrefPubMedGoogle Scholar
  • 39 van der Valk M, Kastelein J J, Murphy R L. et al . The Atlantic Study Team. Nevirapine-containing antiretroviral therapy in HIV-1 infected patients results in an anti-atherogenic lipid profile.  AIDS . 2001;  15 2407-2414
    CrossrefPubMedGoogle Scholar
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