Digestive Diseases and Sciences, Vol. 48, No. 7 (July 2003), pp. 1425–1430 ( C  2003) Regression of Fibrosis in Chronic Hepatitis C After Therapy with Interferon and Ribavirin ASMA ARIF, MD,* ROBERT A. LEVINE, MD,* SCHUYLER O. SANDERSON, MD,* LESLIE BANK, MD,* RAJA P. VELU, PhD,‡ ASHOK SHAH, MD,§ THOMAS C. MAHL, MD, ¶ and DANIEL H. GREGORY, MD** Interferon and ribavirin decrease necroinflammation in chronic hepatitis C with or without virological clearance; however, reversibility of fibrosis remains to be established. We evaluated the effect of com- bination therapy on virological and liver histopathological outcomes in 52 na¨ ıve patients and 79 pa- tients unresponsive to interferon monotherapy with predominantly genotype 1 chronic hepatitis C. One hundred four patients completed interferon and ribavirin treatment after 24–48 weeks. Fifty-six paired liver biopsies (mean biopsy interval 28 months) were assessed by the Ishak score. Sustained virological responses were 37% in na¨ ıve patients and 22% in re-treated patients. In virological re- sponders and nonresponders, fibrosis and necroinflammation scores decreased by −0.91 ( P = 0.04) and −0.5 ( P = 0.02) and by −2.8 ( P = 0.001) and −0.66 ( P = 0.06), respectively. Interferon and ribavirin had greater benefit on fibrosis when associated with clearance of HCV RNA. Treatment strategies in virological nonresponders who show fibrosis regression should include consideration of maintenance therapy, if such treatment eventually proves to benefit histological outcomes. KEY WORDS: Ishak score; liver biopsy; ALT improvement; HCV RNA clearance. Treatment strategies for chronic hepatitis C infection have focused on viral eradication rather than histological out- comes (1). In the two large studies by McHutchison et al (2) and Davis et al (3), combination therapy was found to be superior to interferon monotherapy in terms of virolog- ical and biochemical end points and improvement in in- flammatory, but not fibrosis, scores. In both of these stud- ies (2, 3), reduction in hepatic inflammation was observed Manuscript received September 25, 2002; revised Manuscript re- ceived March 25, 2003; accepted March 27, 2003. From the *Department of Medicine, Division of Gastroenterology, and †Department of Pathology, State University of New York, Upstate Medical University, Syracuse, New York, USA; ‡School of Manage- ment, Syracuse University, Syracuse, New York, USA; §Department of Medicine, University of Rochester School of Medicine, Strong Memorial Hospital, Rochester, New York, USA; ¶Department of Medicine, Uni- versity of Buffalo School of Medicine, Veterans Administration Medical Center, Buffalo, New York, USA; and **Department of Medicine, Mary Imogene Bassett Hospital, Cooperstown, New York, USA. This study was funded, in part, by a grant from Integrated Therapeutics Group, Inc., a subsidiary of Schering-Plough Corporation. Address for reprint requests: Dr. Robert A. Levine, Division of Gas- troenterology, Department of Medicine, SUNY Upstate Medical Uni- versity, 750 East Adams Street, Syracuse, New York 13210, USA. only in patients with sustained viral clearance 24 weeks after the end of therapy. There is even less known about fibrosis outcomes to combination therapy in virological nonresponders. The aim of our study was to prospectively evaluate after combination therapy changes in necroinflammatory and fibrosis scores in relation to virological responses. MATERIALS AND METHODS Patients. A total of 134 patients with chronic hepatitis C were enrolled in the study with intent-to-treat. Three patients did not start medication after enrollment and were not included in the intent-to-treat analysis. One hundred thirty-one patients completed combination therapy; 79 were previous nonrespon- ders to monotherapy who failed to clear HCV RNA 6 months after cessation of therapy (retreatment group) and 52 were na¨ ıve (previously untreated). Inclusion and Exclusion Criteria. Eligibility criteria in- cluded hepatitis C antibody positivity, detectable HCV RNA, ala- nine aminotransferase (ALT) >1.5 times the upper limit of nor- mal, and a liver biopsy within 2 years of entering into the study. Patients were excluded from entering the study if the following criteria applied: hypersensitivity to interferon-α or ribavirin, any Digestive Diseases and Sciences, Vol. 48, No. 7 (July 2003) 1425 0163-2116/03/0700-1425/0 C  2003 Plenum Publishing Corporation