Severe transaminitis after interferon–ribavirin therapy in HIV/ HCV-coinfected patients: influence of a sustained HCV response F. Bani-Sadr, 1 E. Krastinova, 1 D. Fromentin, 1 L. Piroth, 2 E. Rosenthal, 3 Y. Quertainmont, 4 C. Perronne, 5 P. Cacoub, 6 S. Pol, 7 F. Carrat 1 and the ANRS CO 07–Ribavic Study team 1 Groupe Hospitalier Universitaire Est, INSERM U 707, Universite´ Pierre et Marie Curie, UMR-S 707, (UPMC-Paris 6) Paris, France; 2 Centre Hospitalier Universitaire, Dijon, France; 3 Centre Hospitalier Universitaire de Nice, Nice, France; 4 Centre Hospitalier du Kremlin Biceˆtre, LE KREMLIN-BICETRE, France; 5 Centre Hospitalier Universitaire Raymond Poincare´, Universite´ de Versailles, Garches, France; 6 Groupe Hospitalier Universitaire Est, UMR 7087, Universite´ Pierre et Marie Curie (UPMC-Paris 6) Paris, France; and 7 Universite´ Paris Descartes, APHP, Unite´dÕHe´patologie Paris et INSERM U-567, Institut Cochin, Hoˆpital Cochin, Paris, France Received June 2011; accepted for publication October 2011 SUMMARY. Chronic hepatitis C is an independent risk factor for severe drug hepatotoxicity. Successful treatment of chronic hepatitis C may modulate drug hepatotoxicity, as it is associated with a decline in hepatic enzyme release and halts fibrosis progression in HIV/HCV-coinfected patients. The aim of this study was to determine biological and/or clinical determinants of alanine aminotransferase and/or aspartate aminotransferase elevation (>five-fold above the upper limit of normal in patients with normal baseline levels or >3.5-fold increase from baseline in those with increased baseline levels) in a large prospective cohort of HIV/HCV- coinfected patients on HAART who had previously been treated for HCV infection. Median follow-up exceeded five years. Cox proportional hazards models were used. At base- line, 248 patients had been receiving antiretroviral therapy for a mean of 6.3 (± 3.2) years. Seventy-one patients (29%) had a sustained HCV viral response (SVR). During follow-up, 66 patients (26.6%) received a second course of HCV therapy and 29 (44%) of them had an SVR. Severe transaminitis occurred in 64 patients (26%). In multivariate analysis, no SVR (HR 33.33, 95% CI 4.54–222, P = 0.001) and stavu- dine-based therapy (HR 2.11, 95% CI 1.12–3.99, P = 0.018) remained significantly associated with severe transaminitis. A SVR to anti-HCV therapy is thus associated with a mark- edly reduced risk of severe transaminitis during antiretrovi- ral therapy. Treatment of HCV infection should therefore be a priority in HIV-coinfected patients. Stavudine is associated with an increased risk of severe transaminitis. Keywords: antiretroviral therapy, AST/ALT elevation, HCV sustained viral response, HIV/HCV coinfection, severe cytolysis, stavudine, transaminitis. In HIV-monoinfected patients, liver toxicity is one of the most problematic adverse effects of antiretroviral therapy. Chronic hepatitis C is an independent risk factor for severe hepatotoxicity and is associated with a three-fold increase in the risk of grade 3 or 4 cytolysis [1]. Four main mechanisms of hepatotoxicity have been reported in HIV-infected patients: (i) mitochondrial toxicity owing to nucleoside reverse transcriptase inhibitors (NRTI); (ii) hypersensitivity reactions involving the liver (nevirapine, efavirenz and abacavir); (iii) direct hepatic toxicity with protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTIs); and (iv) immune reconstitution [1]. Drug hepa- totoxicity can be mediated by any of these mechanisms in patients with HCV coinfection and correlates with the his- tological stage of hepatitis C in HIV-coinfected patients [2]. Successful treatment of chronic hepatitis C may modulate drug hepatotoxicity, as it reduces liver enzyme release and improves fibrosis in HCV-monoinfected patients and steatosis in patients infected by HCV genotype 3 and halts fibrosis progression in HIV/HCV-coinfected patients [3–6]. The aim of this study was to determine the incidence and biological and/or clinical determinants of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) elevation in a large prospective cohort of HIV/HCV-coinfected patients on HAART who had previously been treated for HCV infection. Median follow-up exceeded 5 years. METHODS The results of the ANRS HC0 2 RIBAVIC study, a randomized controlled trial comparing ribavirin 800 mg daily plus Abbreviations: ALT, alanine aminotransferase; AST, aspartate ami- notransferase; NNRTI, non-nucleoside reverse transcriptase inhibi- tors; PI, protease inhibitors; SVR, sustained HCV viral response. Correspondence: Dr. Firouze´ Bani-Sadr, Inserm U707, Faculte´ de Me´decine Hoˆpital Saint Antoine, 27 rue de Chaligny, 75 475 Paris Cedex 12-France. E-mail: firouze.bani-sadr@tnn.ap-hop-paris.fr Journal of Viral Hepatitis, 2012, 19, 431–435 doi:10.1111/j.1365-2893.2011.01570.x Ó 2012 Blackwell Publishing Ltd