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• W1971648486 abstract "1. IntroductionCurrent highly active antiretroviral therapy (HAART) is based on combination regimens with substances from three different classes: nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) (Table 1) . Meanwhile, the benefits of HAART with regard to both survival and quality of life have been demonstrated beyond any doubts [[1]Palella Jr., F.J. Delaney K.M. Moorman A.C. Loveless M.O. Fuhrer J. Satten G.A. et al.Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators.N Engl J Med. 1998; 338: 853-860Crossref PubMed Scopus (8477) Google Scholar]. Yet, HAART-associated toxicity has evolved as the main reason to discontinue or modify antiretroviral therapy [2Mocroft A. Youle M. Moore A. Sabin C.A. Madge S. Lepri A.C. et al.Reasons for modification and discontinuation of antiretrovirals: results from a single treatment centre.AIDS. 2001; 15: 185-194Crossref PubMed Scopus (198) Google Scholar, 3Ferrer E. Consiglio E. Podzamczer D. Grau I. Ramon J.M. Perez J.L. Gudiol F. Analysis of the discontinuation of protease inhibitor therapy in routine clinical practice.Scand J Infect Dis. 1999; 31: 495-499Crossref PubMed Scopus (18) Google Scholar]. Hepatotoxicity appears to be of particular importance in this context as it can occur with any antiretroviral regimen currently in use (Table 2) . Most remarkably, longitudinal surveys have not only reported an increased incidence of hepatic injury in HAART-treated patients but also identified life-threatening hepatotoxic events and end-stage liver disease in patients on antiretroviral treatment [[4]Bica I. McGovern B. Dhar R. Stone D. McGowan K. Scheib R. Snydman D.R. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection.Clin Infect Dis. 2001; 32: 492-497Crossref PubMed Scopus (894) Google Scholar]. Since rational alternatives to HAART are currently not available to control HIV infection, understanding the pathophysiology as well as a profound knowledge of how to prevent and to treat HAART-related liver damage will be a continuous challenge for the present and future generations of hepatologists. In this review, we briefly outline characteristic issues of HAART-related hepatic toxicity, describe possible risk factors and summarize current recommendations for the clinical management of liver toxicity during antiretroviral therapy.Table 1Currently available antiretroviral drugsSubstance nameTrade nameRecommended daily dose (mg)aRecommendation by the manufacturer [67].Average plasma half-life (h)Dosing in patients with severe hepatic insufficiency (mg)bRecommendation by the Johns Hopkins AIDS Service [99].Target therapeutic serum concentration (ng/ml)cModified from www.medpoli.uni-wuerzburg.de/hepinf/dm.htmCytochrome P450 isoenzymes relevant for the drug metabolizationdModified from Eagling et al. [100].Nucleoside reverse transcriptase inhibitorsZidovudineRetrovir®250–300 b.i.d.1200 b.i.d.No dataNo metabolization via cytochrome P450DidanosineVidex®400 dailyeFor a person with 60 kg body weight.1 .5Consider empiric dose reductionLamivudineEpivir®150 b.i.d.1 .15No dataStavudineZerit®40 b.i.d.eFor a person with 60 kg body weight.1ZalcitabineHivid®0.75 t.i.d.fFor a person with 70 kg body weight.2AbacavirZiagen®300 b.i.d.2Non-nucleoside reverse transcriptase inhibitorsDelaviridineRescriptor®400 t.i.d.6Consider empiric dose reductionNo dataNo dataEfavirenzSustiva®600 daily40 –552500CYP3A, CYP2C9NevirapineViramune®200 b.i.d.304500CYP3AProtease inhibitorsIndinavirCrixivan®800 t.i.d.1 .8600 t.i.d.aRecommendation by the manufacturer [67].1000CYP3A, CYP2D6NelfinavirViracept®750 t.i.d. or 1250 b.i.d.4600 t.i.d. or 1000 b.i.d.1000CYP3A, CYP2D6AmprenavirAgenerase®1200 b.i.d.8450 b.i.d.750CYP3A, CYP2C9, CYP2D6RitonavirNorvir®600 b.i.d.3 –5Consider empiric dose reduction4500CYP3A4, CYP2C9, CYP2D6SaquinavirFortovase®1200 t.i.d.10750CYP3A4, CYP2C9Lopinavir-ritonavirKaletra®400/100 b.i.d.5 –6No data5500CYP3A4, CYP2C9a Recommendation by the manufacturer [67]Indinavir package insert by Merck, Sharpe & Dohme Company.Google Scholar.b Recommendation by the Johns Hopkins AIDS Service [99]Johns Hopkins AIDS Service. Available at http://www.hopkins-aids.edu/publications/book/ch4_agents_tab0421.htmlGoogle Scholar.c Modified from www.medpoli.uni-wuerzburg.de/hepinf/dm.htmd Modified from Eagling et al. [100]Eagling V.A. Back D.J. Barry M.G. Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir.Br J Clin Pharmacol. 1997; 44: 190-194Crossref PubMed Scopus (313) Google Scholar.e For a person with 60 kg body weight.f For a person with 70 kg body weight. Open table in a new tab Table 2Incidence of severe hepatic damage during antiretroviral treatment in studies with more than 50 patients enrolledaALT, alanine aminotransferase; AST, aspartate aminotransferase; AZT, zidovudine; DDC, zalcitabine; 3TC, lamivudine; NVP, nevirapine; RTV, ritonavir; SQV, saquinavir; NFV, nelfinavir; IDV, indinavir; EFV, efavirenz.Clinical studyNumber of patientsType of studyDrug regimen (%)Relative frequency of severe hepatotoxicity (ALT/AST elevation of grade 3–4) (%)Statistically significant predictors for hepatotoxicityNucleoside reverse transcriptase inhibitorsSulkowski et al. [51]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 virus infection.J Am Med Assoc. 2000; 283: 74-80Crossref Scopus (889) Google Scholar87Prospective2 NRTIbIndividual choice of drugs not specified.5 .7Chronic viral hepatitisDegree of CD4+ recoverySavès et al. [25]Savès 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 d'Epidemiologie Clinique de Sida en Aquitaine (GECSA).AIDS. 1999; 17: F115-F121Crossref Scopus (164) Google Scholar1249RetrospectiveAZT and DDC (43)5 .7Chronic viral hepatitisAZT and 3TC (38)History of prior hepatic cytolysisNon-nucleoside reverse transcriptase inhibitorsSanne [41]Sanne I. Severe liver toxicity in patients receiving two nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor.AIDS. 2000; 14Google Scholar385ProspectiveNVP with 2 NRTIs9 .4Not specified83EFV with 2 NRTIs0Martinez et al. [40]Martinez E. Blanco J.L. Arnaiz J.A. Perez-Cuevas J.B. Mocroft A. Cruceta A. et al.Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy.AIDS. 2001; 15: 1261-1268Crossref PubMed Scopus (333) Google Scholar610ProspectiveNVP and 2 NRTIsbIndividual choice of drugs not specified.12 .5cThree-fold increase of ALT/AST.Chronic hepatitis CTime of drug exposurePrior hepatic cytolysisCahn et al. [42]Cahn P. Johnson M. Nusrat R. Hall D. Robinson P. The 1090 Study TeamHepatic safety with nevirapine (NVP) and two nucleosides in patients with advanced HIV infection, from a placebo (PBO) controlled clinical endpoint trail (1090).AIDS. 2000; 14: 511Google Scholar2249ProspectiveNVP and 2 NRTIsbIndividual choice of drugs not specified.8 .2Not specifiedPuoti et al. [49]Puoti M. Civili S. Patroni A. Pan A. Tomasoni L.R. Zanini B. et al.Hepatotoxicity associated with non nucleoside reverse transcriptase inhibitors (NNRTI) in 427 patients infected with human immunodeficiency virus.Hepatology. 2001; 34: 452AGoogle Scholar427RetrospectiveNVP with 2 NRTIs4 person/yearChronic hepatitis CEFV with 2 NRTIs6 person/yearAZT co-mediationProtease inhibitorsSulkowski et al. [51]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 virus infection.J Am Med Assoc. 2000; 283: 74-80Crossref Scopus (889) Google Scholar211ProspectiveRTV (10.4)27 .3Chronic viral hepatitisSQV (28)5 .9Administration of RTVNFV (55.4)6 .8Degree of CD4+ recoveryIDV (24.1)5 .9Savès et al. [25]Savès 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 d'Epidemiologie Clinique de Sida en Aquitaine (GECSA).AIDS. 1999; 17: F115-F121Crossref Scopus (164) Google Scholar748RetrospectiveRTV (13)8 .5Chronic viral hepatitisSQV (34)History of prior hepatic cytolysisNFV (1)IDV (51)den Brinker et al. [52]den Brinker M. Wit F.W. Wertheim-van Dillen P.M. 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: 2895-2902Crossref PubMed Scopus (370) Google Scholar394Retrospective2 NRTI, 1–2 PIbIndividual choice of drugs not specified.18Chronic viral hepatitisNunez et al. [101]Nunez M. Lana R. Mendoza J.L. Martin Carbonero L. Soriano V. Risk factors for severe hepatic injury after introduction of highly active antiretroviral therapy.J Acquir Immune Defic Syndr. 2001; 27: 426-431PubMed Google Scholar96Retrospective2 NRTI, 1–2 PIbIndividual choice of drugs not specified.10Chronic hepatitis CAgeAlcohol consumptionPuoti et al. [80]Puoti M, Torti C, Ripamonti D, Barbieri MC, Zaltron S, Putzolu V, et al. Life threatening hepatotoxicity during combination anti-retroviral treatment: incidence, risk factors and outcome (abstract TuPpB 1160). XIII International AIDS Conference, July 2000, Durban, South Africa.Google Scholar716Prospective2 NRTI, 1–2 PIbIndividual choice of drugs not specified.3 .4dTen-fold increase of ALT/AST.Degree of CD4+ recoverya ALT, alanine aminotransferase; AST, aspartate aminotransferase; AZT, zidovudine; DDC, zalcitabine; 3TC, lamivudine; NVP, nevirapine; RTV, ritonavir; SQV, saquinavir; NFV, nelfinavir; IDV, indinavir; EFV, efavirenz.b Individual choice of drugs not specified.c Three-fold increase of ALT/AST.d Ten-fold increase of ALT/AST. Open table in a new tab 2. Problems with the definition of HAART-related liver toxicityReports on drug toxicity should characterize the type and severity of the side effects and also establish a causal relationship between toxicity and the incriminated drug. To facilitate analysis of hepatic toxicity, standardized definitions have been proposed by an international consensus panel [[5]Report of an international consensus meeting. Criteria of drug-induced liver disorders.J Hepatol. 1990; 11: 272-276Abstract Full Text PDF PubMed Scopus (1014) Google Scholar]. Nevertheless, analysis of liver toxicity associated with antiretroviral therapy is hampered by the fact that toxicity has not been reported uniformly along the guidelines of such consensus definitions. Thus, the available information is quite heterogeneous: case reports or studies on small numbers of patients mainly report fatal or near-fatal side effects. In contrast, abnormalities in liver tests have commonly been considered as evidence of liver damage in the larger clinical trials. According to the consensus definitions severe liver damage should be characterized by jaundice, coagulopathy (international normalized ratio, INR>2.5), or encephalopathy [[5]Report of an international consensus meeting. Criteria of drug-induced liver disorders.J Hepatol. 1990; 11: 272-276Abstract Full Text PDF PubMed Scopus (1014) Google Scholar]. However, most clinical trials have defined greater than five-fold elevated aminotransferases as severe hepatotoxicity, irrespective of the degree of impaired liver function. Increases in alkaline phosphatase (AP) have probably been under-reported. Thus, a drug reaction might falsely be considered ‘hepatocellular’, which in actual fact was ‘cholestatic’ or ‘mixed’ in type. Moreover, liver histology has been reported only infrequently. Thus, failure to report hepatic side effects in a standardized manner may have introduced considerable bias into the assessment of the benefit–risk ratio both with respect to incidence and severity of adverse effects due to the prescribed drugs.Establishing causality between liver damage and the drug under consideration is a further difficult issue, as most patients are simultaneously treated with several potentially toxic drugs. Moreover, drug interactions, active drug abuse, or poorly understood interactions between the drugs and concomitant liver disease may make a firm proof of causality impossible.As this review is based on the available literature, it also reflects the shortcomings of the original reports on hepatotoxicity in HAART. However, in an attempt to compensate for these problems, we will first focus on the pathogenic principles, which are supposed to underlie HAART-related liver toxicity, before the clinical impact of HAART-related liver toxicity is discussed. Furthermore, possible effects due to drug interactions and pre-existing liver disease are also covered in separate paragraphs.3. Mechanisms of drug toxicity3.1 Mitochondrial toxicityNucleoside analogues are pharmacologically designed to be incorporated into viral nucleic acids and act as chain terminators, thus inhibiting efficient viral replication. Toxicity of these drugs is caused by inhibiting the human mitochondrial DNA polymerase γ, an enzyme which is physiologically required for mitochondrial DNA replication [[6]Lewis W. Dalakas M.C. Mitochondrial toxicity of antiviral drugs.Nat Med. 1995; 1: 417-422Crossref PubMed Scopus (693) Google Scholar]. In vitro, NRTIs reduced mitochondrial DNA content and altered mitochondrial morphology in a dose-dependent fashion. In cultured cells the relative mitochondrial toxicities were as follows: zalcitabine>stavudine>zidovudine>didanosine>lamivudine>abacavir [[7]Kakuda T.N. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity.Clin Ther. 2000; 22: 685-708Abstract Full Text PDF PubMed Scopus (515) Google Scholar]. Lamivudine, in particular, seems to exert negligible mitochondrial toxicity, since this compound is poorly incorporated into mitochondrial DNA [[8]Hart G.J. Orr D.C. Penn C.R. Figueiredo H.T. Gray N.M. Boehme R.E. Cameron J.M. Effects of (−)-2′-deoxy-3′-thiacytidine (3TC) 5′-triphosphate on human immunodeficiency virus reverse transcriptase and mammalian DNA polymerases alpha, beta, and gamma.Antimicrob Agents Chemother. 1992; 36: 1688-1694Crossref PubMed Scopus (145) Google Scholar].NRTI-induced depletion of mitochondrial DNA impairs the cellular respiratory chain and eventually inhibits oxygen-dependent catabolic pathways such as pyruvate and fatty acid oxidation. Electron microscopy can help to identify this type of cellular damage by demonstrating enlarged mitochondria with matriceal densities and occasional vacuoles [[9]Moyle G. Toxicity of antiretroviral nucleoside and nucleotide analogues. Is mitochondrial toxicity the only mechanism?.Drug Saf. 2000; 23: 467-481Crossref PubMed Scopus (93) Google Scholar]. In more advanced cases, NRTI-induced hepatic injury can readily be recognized by light microscopy, which typically shows microvesicular hepatic steatosis and giant mitochondria together with focal or diffuse features of intrahepatic cholestasis (Fig. 1A) . However, lobular micro-architecture is usually preserved and lymphocellular infiltrates or hepatocellular necrosis are rare.Mitochondria are involved in fatty acid oxidation, the tricarboxylic acid cycle and oxidative phosphorylation. Impairment of mitochondrial fatty acid oxidation leads to an intracellular increase of triglycerides and non-esterified fatty acids, the cause of microvesicular steatosis. Interruption of electron transfer in the mitochondrial respiratory chain results in the increased intracellular release of reactive oxygen species, which severely augment hepatic tissue damage by initiating lipid peroxidation of accumulated fatty acids, by releasing proinflammatory cytokines, by inducing fibrosis or by also damaging mitochondrial and nuclear DNAs [10Fromenty B. Berson A. Pessayre D. Microvesicular steatosis and steatohepatitis: role of mitochondrial dysfunction and lipid peroxidation.J Hepatol. 1997; 26: 13-22Abstract Full Text PDF PubMed Google Scholar, 11Pessayre D. Mansouri A. Haouzi D. Fromenty B. Hepatotoxicity due to mitochondrial dysfunction.Cell Biol Toxicol. 1999; 15: 367-373Crossref PubMed Scopus (248) Google Scholar, 12Day C.P. James O.F. Hepatic steatosis: innocent bystander or guilty party?.Hepatology. 1998; 27: 1463-1466Crossref PubMed Scopus (362) Google Scholar, 13Pessayre D. Berson A. Fromenty B. Mansouri A. Mitochondria in steatohepatitis.Semin Liver Dis. 2001; 21: 57-69Crossref PubMed Scopus (355) Google Scholar, 14Tsukamoto H. Kim C.W. Luo Z.Z. Horn W. Su L.C. Brittenham G.M. Role of lipid peroxidation in in vivo and in vitro models of liver fibrogenesis.Gastroenterology. 1993; 104: A1012Google Scholar]. Finally, loss of mitochondrial integrity results in release of cytochrome C into the cytosol, which activates caspases and triggers apoptosis [15Susin S.A. Zamzami N. Kroemer G. Mitochondria as regulators of apoptosis: doubt no more.Biochim Biophys Acta. 1998; 1366: 151-165Crossref PubMed Scopus (755) Google Scholar, 16Pessayre D. Haouzi D. Fau D. Robin M.A. Moreau A. Neuman M. Hepatocyte apoptosis triggered by natural substances.in: Cameron R.G. Feuer G. Apoptosis and its modulation by drugs. Handbook of experimental pharmacology. Springer, Heidelberg2000: 59-108Crossref Google Scholar]. Thus, fulminant hepatic failure has become a complication of mitochondrial hepatotoxicity caused by nucleoside analogues that has increasingly been recognized in the recent past.3.2 Hypersensitivity reactionsImmune-mediated adverse drug reactions are among the idiosyncratic type of drug reactions. They are infrequent, dose independent, unpredictable and not reproducible in experimental animals. In addition to hepatocellular injury there may be coexistent clinical features that specify an acute immune-mediated hypersensitivity response such as fever, a skin rash or eosinophilia. Among the antiretroviral drugs hypersensitivity reactions have been observed with all NNRTIs, the nucleoside analogue abacavir and the just recently marketed PI amprenavir. Hepatic damage due to hypersensitivity reactions is most frequent in the setting of nevirapine-based regimens but may occur with any of the mentioned drugs [[17]Carr A. Cooper D.A. Pathogenesis and management of HIV-associated drug hypersensitivity.in: Volberding P. Jacobson M.A. AIDS clinical review 1995–96. Marcel Dekker, New York1996: 65-97Google Scholar]. Immune-dependent histopathological features vary and have differing predominance from case to case. They can comprise hepatocellular necrosis, cholestasis, tissue eosinophilia, parenchymal and periportal infiltrates consisting of predominantly lymphocytes and plasma cells. The hepatic lesions resolve when the drug is withdrawn. Continued therapy, however, carries a considerable risk to progress to fulminant hepatic failure. Re-challenge will elicit the same pathology usually within a much shorter interval of time. Despite the typical features of immune-mediated hypersensitivity, the precise immunopathological basis of this type of hepatotoxicity induced by antiretroviral drugs is still poorly defined. Cytokine release is probably involved considering the fact that constitutional symptoms such as fever or hypotension are frequently present. However, it is unclear at present whether the antiretroviral drugs themselves or their metabolites act as the triggering antigens.3.3 Hepatotoxicity of antiretroviral drugs due to other mechanismsFor a variety of antiretroviral agents, the specific mechanisms of hepatotoxicity are still unclear. Thus, confluent hepatocellular necrosis and drop out of hepatocytes with bridging parenchymal collapse have frequently been noted in biopsy specimens of HAART-related liver injury, which could not be attributed to any specific pathomechanism [[18]Clark S.J. Creighton S. Portmann B. Taylor C. Wendon J.A. Cramp M.E. Acute liver failure associated with antiretroviral treatment for HIV: a report of six cases.J Hepatol. 2002; 36: 295-301Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar].This fact particularly applies to PIs, the toxicity of which has only poorly been related to their molecular structure thus far. However, it is noteworthy in this context that ritonavir inhibits the degradation of the sterol regulator element binding protein 1c (SREBC-1c), which up-regulates the activity of several lipogenic genes [[19]Riddle T.M. Kuhel D.G. Woollett L.A. Fichtenbaum C.J. Hui D.Y. HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus.J Biol Chem. 2001; 276: 37514-37519Crossref PubMed Scopus (174) Google Scholar]. Thus, ritonavir leads to an increased hepatic lipid synthesis, which may exert toxic effects on the liver, particularly when fatty acid metabolism is also blocked due to the mitochondrial toxicity of simultaneously given nucleoside analogues.Nevirapine, which is a potent cause of dose-independent drug hypersensitivity, probably can also cause fulminant hepatic failure by a mechanism which appears to be dose-dependent [[20]Cattelan A.M. Erne E. Salatino A. Trevenzoli M. Carretta G. Meneghetti F. Cadrobbi P. Severe hepatic failure related to nevirapine treatment.Clin Infect Dis. 1999; 29: 455-456Crossref PubMed Scopus (68) Google Scholar]. Intrinsic mechanisms of hepatotoxicity are better understood in some NRTIs. Stavudine, for example, can induce apoptosis by DNA-intercalation in a way similar to the cytostatic drugs fludarabin and gemcitabine [[21]Strahl C. Blackburn E.H. Effects of reverse transcriptase inhibitors on telomere length and telomerase activity in two immortalized human cell lines.Mol Cell Biol. 1996; 16: 53-65Crossref PubMed Scopus (356) Google Scholar], and zidovudine localizes to human telomeric DNA which accelerates cellular senescence by telomere shortening [[22]Hashimoto K.I. Tsunoda R. Okamoto M. Shigeta S. Baba M. Stavudine selectively induces apoptosis in HIV type 1-infected cells.AIDS Res Hum Retroviruses. 1997; 13: 193-199Crossref PubMed Scopus (11) Google Scholar].4. Clinical presentation of HAART-related hepatotoxicity4.1 NRTIsThe hepatotoxic potential of NRTIs was first realized with zidovudine at the beginning of the 1990s, leading to a warning by the Food and Drug Administration [[23]Shintaku M. Nasu K. Shimizu T. Fulminant hepatic failure in an AIDS patient: possible zidovudine-induced hepatotoxicity.Am J Gastroenterol. 1993; 88: 464-466PubMed Google Scholar]. With the subsequent release of various other NRTIs, it soon became evident that NRTI combination therapy carries a considerable risk of causing liver damage.Clinical symptoms of NRTI-related hepatotoxicity have an average incidence of 1.3 patients per 1000 person years [[24]Fortgang I.S. Belitsos P.C. Chaisson R.E. Moore R.D. Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy.Am J Gastroenterol. 1995; 90: 1433-1436PubMed Google Scholar]. Asymptomatic elevated aminotransferases greater than five times the upper limit of normal are noted in approximately 6% of patients [[25]Savès 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 d'Epidemiologie Clinique de Sida en Aquitaine (GECSA).AIDS. 1999; 17: F115-F121Crossref Scopus (164) Google Scholar]. Symptoms of liver damage typically develop gradually over several months of drug intake but in some instances have also been observed within a few days after the start of treatment [26Mokrzycki M.H. Harris C. May H. Laut J. Palmisano J. Lactic acidosis associated with stavudine administration: a report of five cases.Clin Infect Dis. 2000; 30: 198-200Crossref PubMed Scopus (132) Google Scholar, 27Olano J.P. Borucki M.J. Wen J.W. Haque A.K. Massive hepatic steatosis and lactic acidosis in a patient with AIDS who was receiving zidovudine.Clin Infect Dis. 1995; 21: 973-976Crossref PubMed Scopus (122) Google Scholar]. Patients usually complain of unspecific symptoms such as abdominal pain, vomiting, anorexia and right upper quadrant tenderness.NRTI-related hepatotoxicity is frequently associated with the presence of a so called lipodystrophy syndrome (LDS), although the LDS and NRTI hepatotoxicity are distinct pathophysiological entities (Table 3) . The LDS occurs after several months of antiretroviral treatment and is attributed to therapy with either NRTIs or PIs. Hepatic mitochondrial toxicity is particularly associated with the NRTI-induced variant of LDS [[28]Carr A. Miller J. Law M. Cooper D.A. 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: F25-F32Crossref PubMed Scopus (571) Google Scholar], which is characterized by lipoatrophy of the face, legs and arms (Fig. 1B). In most instances this peripheral lipodystrophy can be readily distinguished from the PI-related variant characterized by central obesity, gynaecomastia or a ‘buffalo hump’ [[29]Carr A. Samaras K. Burton S. Law M. Freund J. Chisholm D.J. Cooper D.A. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors.AIDS. 1998; 12: F51-F58Crossref PubMed Scopus (2184) Google Scholar]. Thus, the presence of peripheral lipodystrophy should alert the clinician for the possibility of additional hepatic toxicity in patients on NRTIs.Table 3Characteristic features of hepatotoxicity associated with the antiretroviral drugsDrugTypical time of occurrenceLaboratory findings (apart from elevated liver enzymes)Histological hallmarksPresumed mechanism of toxicityNRTIsMore than 6 months after start of treatmentLactate acidosis, lactic dehydrogenase elevation, amylase/lipase elevationMicrovesicular steatosis of hepatocytes, giant mitochondriaMitochondrial damage, inhibition of cellular respirationNevirapine1) During the initial 4 weeksElevated WBC count, elevated IgE-levels, increased eosinophilsNo conclusive dataHypersensitivity reaction2) Gradually increasing over time with drug exposureElevated drug levelsNo conclusive dataDrug overdoseProtease inhibitorsGradually increasing over time with drug exposureHyperlipidaemia?Ballooning degeneration of hepatocytes, Kupffer cell activation, fibrosis in zone 3No data Open table in a new tab Laboratory tests reflect the hepatocellular damage by elevated serum aminotransferases and increased biochemical parameters of cholestasis such as gamma-glutamyl-transpeptidase (γ-GT) or AP. Additional biochemical features comprise elevated amylase, lipase or creatinkinase together with a disturbed acid-base balance, involving lactic acidosis and loss of bicarbonate.Progression of liver damage towards fulminant hepatic failure can occur infrequently [[31]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: 367-371Crossref PubMed Scopus (141) Google Scholar] and at least initially may be mistaken for an acute surgical abdomen [[32]Ellozy S. Massen R. Chao L. Divino C.M. Antiretroviral-induced hepatic steatosis and lactic acidosis: case report and review of the literature.Am Surg. 2001; 67: 680-683PubMed Google Scholar]. Severe pancreatic involvement and metabolic acidosis also herald a high risk for a fatal outcome. However, patients who survived an acute episode of hepatotoxicity finally achieved full hepatic recovery in the majority of reports [26Mokrzycki M.H. Harris C. May H. Laut J. Palmisano J. Lactic acidosis associated with stavudine administration: a report of five cases.Clin Infect Dis. 2000; 30: 198-200Crossref PubMed Scopus (132) Google Scholar, 32Ellozy S. Massen R. Chao L. Divino C.M. Antiretroviral-induced hepatic steatosis and lactic acidosis: case report and review of the literature.Am Surg. 2001; 67: 680-683PubMed Google Scholar]. Incidentally, gradual progression to chronic liver injury has also been described after initial recovery from hepatic damage [[33]Carr A. Morey A. Mallon P. Williams D. Thorburn D.R. Fatal portal hypertension, liver failure, and mitochondrial dysfunction after HIV-1 nucleoside analogue-induced hepatitis and lactic acidaemia.Lancet. 2001; 357: 1412-1414Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar]. The long-term outcome in patients with asymptomatic grade 3 and 4 elevations of liver enzymes is unknown at present. However, a first study is re-assuring as it reported elevated aminotransferases to return to normal within a mean observation period of 287 days in as many as 87% of the patients [[25]Savès 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 d'Epidemiologie Clinique de Sida en Aquitaine (GECSA).AIDS. 1999; 17: F115-F121Crossref Scopus (164) Google Scholar].Liver damage is usually caused via mitochondrial toxicity of the NRTIs, and it is remarkable that in a recent meta-analysis of 21" @default.
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• W1971648486 title "Antiretroviral drug toxicity – a challenge for the hepatologist?" @default.
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