American Journal of Gastroenterology ISSN 0002-9270 C  2004 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2004.30049.x Published by Blackwell Publishing Interferon Alpha-2b and Ribavirin for Patients with Chronic Hepatitis C and Normal ALT Ira M. Jacobson, Furqaan Ahmed, Mark W Russo, Edward Lebovics, Douglas T. Dieterich, Stephen P. Esposito, Nancy Bach, Franklin Klion, Hillel Tobias, Louis Antignano, Robert S. Brown Jr., David Gabbaizadeh, Jane Geders, and Hulya Levendoglu. Weill Medical School of Cornell University, New York; New York Medical College, Valhalla; Cabrini Medical Center and New York University School of Medicine, New York; New York Hospital—Queens, Queens; Mount Sinai Medical Center, New York; New York University Medical Center; University of Rochester School of Medicine, Rochester; Columbia Presbyterian Medical Center, New York; Huntington Hospital, Long Island; Mount Kisco Medical Group, Mount Kisco; Brookdale Hospital Medical Center, Brooklyn, New York OBJECTIVES: Most studies establishing the role of antiviral therapy in patients with chronic hepatitis C (CHC) excluded the patients with normal ALT levels. Small trials with interferon monotherapy suggested a limited efficacy and/or de novo ALT elevations. We sought to evaluate the efficacy of two doses of interferon alpha-2b (IFN) with ribavirin (RBV) in patients with normal ALT. METHODS: Patients with biopsy-proven CHC with detectable HCV RNA and at least two normal ALT levels three or more months apart were randomized to receive either 3 or 5 million units of IFN thrice a week plus RBV 1,000–1,200 mg. Therapy was stopped at 24 wk if HCV RNA remained detectable and continued for an additional 24 wk if HCV RNA was undetectable. A final HCV RNA level was obtained 24 wk after discontinuation of therapy. RESULTS: Fifty-six patients were randomized and received at least one dose of treatment. The overall rate of sustained virologic response (SVR) was 32%. SVR rates were higher in genotype 2 and 3 patients (80%) than in genotype 1 patients (24%, p = 0.002). There was a tendency toward higher SVR in genotype 1 patients treated with the higher IFN dose (36% vs 10%, p = 0.07). Five patients had mild, transient ALT elevations. No sustained ALT elevations were noted. CONCLUSIONS: Patients with normal ALT had a rate of SVR comparable to that reported in patients with elevated ALT. Higher dose of interferon tended to be more effective in genotype 1 infected patients. De novo ALT elevations were transient and not clinically significant. Patients with CHC should not be excluded from treatment on the basis of ALT alone. Combination therapy with pegylated interferon and ribavirin should be evaluated in these patients. (Am J Gastroenterol 2004;99:1700–1705) INTRODUCTION Approximately 30% of patients with chronic hepatitis C (CHC) have a persistently normal ALT (1). These patients are more commonly female (2) and tend to have lesser degrees of inflammation and fibrosis on liver biopsy (3–6). Studies also have suggested that these patients have a more benign natu- ral history with slower disease progression (3, 6–8). Patients with normal ALT have traditionally been excluded from most of the major clinical trials that establish the role of antiviral therapy for CHC, because prior to the advent of molecular testing there was uncertainty regarding viremia in these pa- tients. Indeed, early treatment studies used normalization of ALT as a surrogate marker for response. Later, these patients were thought to have a milder form of the disease and poten- tially different response rates. It is now recognized that all normal ALT patients do not have mild liver disease and slower progression. In fact, in some series, up to 14–20% of these patients have advanced fibrosis or cirrhosis on liver biopsy (2, 4, 9) and the degree of liver injury may not differ from the matched controls with elevated ALT (10). Moreover, patients with mild liver dis- ease may want to eradicate their HCV infections and some, including health-care workers and young women contemplat- ing pregnancy, may have a compelling reason to do so. The NIH Consensus Conference in 2002 also reflects this change in approach and has revised its 1997 statement recommending that patients with normal ALT should not be treated outside of clinical trials (11). The new guidelines favor a more indi- vidualized approach taking into account the degree of liver injury and fibrosis, HCV genotype, comorbid illnesses, and patient preferences among other considerations (12). 1700