Session Title: Category 5g. VIRAL HEPATITIS: g. HEPATITIS C - CLINICAL (THERAPY)
Presentation Date: Apr 15, 2010
RELATION OF INSULIN RESISTANCE AND HEPATIC STEATOSIS WITH ADVANCED HEPATIC FIBROSIS IN PATIENTS WITH GENOTYPE 1 OR 2/3 CHRONIC HEPATITIS C
A. Thompson1*, M. Grigorescu2, R. Flisiak3, A. Horban4, M. Buti5, V. Rehak6, K. Han7, R. Safadi8, M. Cho9, M. Torbenson10, G. Subramanian11, J. McHutchison12, for the ACHIEVE Study Group
1GI/Hepatology Research Program, Duke Clinical Research Institute, Durham, NC, USA, 2Spitalul Clinic de Urgenta 'Prof Dr Octavian Fodor', Cluj-Napoca, Romania, 3Wojewódzki Szpital Specjalistyczny, Bialystok, 4Wojewódzki Szpital Zakaźny, Warszawa, Poland, 5Vall d'Hebron University Hospital, Barcelona, Spain, 6Nuselská Poliklinika-Remedis, Prague, Czech Republic, 7Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea, 8Hadassah Medical Center, Jerusalem, Israel, 9Pusan National University, Yangsan Hospital, Busan, Republic of Korea, 10Johns Hopkins Center for Viral Hepatitis, Baltimore, 11Human Genome Sciences, Inc., Rockville, MD, 12Duke Clinical Research Institute, Durham, NC, USA. *firstname.lastname@example.org
Background and aims: Hepatic fibrogenesis is a complex, multifactorial process. The relativeroles of insulin resistance (IR) and hepatic steatosis in fibrogenesis in chronic hepatitis C (CHC) have been recent topics of debate, and conflicting data have been published. This substudy therefore, investigated the relationship between IR, hepatic steatosis, and hepatic fibrosis in patients enrolled in the phase 3 ACHIEVE 1 and 2/3 trials.
Methods: 2255 treatment-naïve patients with genotype 1 or 2/3 CHC were enrolled in 2 separate phase 3, active-controlled (peginterferon alfa-2a) studies of albinterferon alfa-2b plus ribavirin for 48 or 24 weeks, respectively. IR was measured at baseline using the homeostasis model for assessment of IR (HOMA-IR). Baseline liver biopsy was evaluated for steatosis, METAVIR grade, and fibrosis stage by a single expert histopathologist. Advanced fibrosis was defined as METAVIR stage F2-4. Steatosis was scored as grade 0 (≤5% steatosis), 1 (6%-30%), 2 (31%-60%), and 3 (≥61%). Other clinical variables considered included age, gender, race, body mass index, alcohol history, HCV viral load and genotype, and serum total cholesterol level. Independent factors associated with advanced hepatic fibrosis were modeled using logistic regression with backwards elimination (SAS v9.1 statistical software).
Results: A complete data set was available for analysis in 1515 nondiabetic patients (genotype 1=819; genotype 2=327; genotype 3=369). Prevalence of METAVIR stages: F0=546 (37%); F1=680 (46%); F2=117 (8%); F3=74 (5%); and F4=76 (5%). Prevalence of steatosis: grade 0=1058 (70%); grade 1=329 (22%); grade 2=81 (5%); and grade 3=34 (2%). Median HOMA-IR was 2.0 (interquartile range 1.3-3.6). The factors identified by multivariable logistic regression to be independently associated with advanced fibrosis were: age, HOMA-IR, hepatic steatosis grade, hepatic inflammatory grade, and serum total cholesterol levels (P< .001); in a subanalysis excluding cirrhotic patients (n=76) that compared patients with significant (F2-3) vs minimal (F0-1) fibrosis, the same 5 factors were independently associated with advanced fibrosis (P< .01).
Conclusions: In this large, well characterized cohort of CHC patients, advanced hepatic fibrosis was independently and positively associated with both IR and hepatic steatosis, in addition to age and hepatic inflammation. Serum total cholesterol was independently, but negatively associated with advanced fibrosis.