Session Title: Category 5g. VIRAL HEPATITIS: g. HEPATITIS C - CLINICAL (THERAPY)
Presentation Date: Apr 15, 2010
DYNAMICS OF APOPTOTIC ACTIVITY IN PATIENTS WITH CHRONIC HEPATITIS C TREATED WITH ALBINTERFERON ALFA-2B OR PEGINTERFERON ALFA-2A
B. Kronenberger1*, E. Herrmann1, C. Chen2, M. Fiscella2, G. Subramanian2, J. McHutchison3, Y. Benhamou4, M. Sulkowski5, D. Nelson6, S. Zeuzem1, for the ACHIEVE Study Group
1J.W. Goethe University Hospital, Frankfurt/Main, Germany, 2Human Genome Sciences, Inc., Rockville, MD, 3Duke Clinical Research Institute, Durham, NC, USA, 4Hôpital Pitié-Salpêtrière, Paris, France, 5Johns Hopkins Center for Viral Hepatitis, Baltimore, MD, 6University of Florida, Gainesville, FL, USA. *email@example.com
Background and aims: The main modes of cell death (necrosis and apoptosis) that lead to elimination of infected cells and correlation with attaining a sustained virologic response (SVR) in chronic hepatitis C (CHC) are of importance in better defining the mechanisms of response to interferon therapy. Apoptotic activity was analyzed in a substudy of the phase 3 trials of albinterferon alfa-2b (albIFN) conducted in genotypes 1, 2, and 3 CHC patients.
Methods: Apoptotic activity in serum was quantified by measuring cytokeratin-18 M30 isoform levels using the M30 Apoptosense® ELISA. Serum was collected at baseline, treatment weeks 4 and 12, end of treatment, and 12-24 weeks after treatment in treatment-naïve CHC patients (n=255) randomized to treatment with peginterferon alfa-2a 180 µg qwk, or albIFN 900 or 1200 µg q2wk, all with ribavirin. Treatment durations were 48 weeks for genotype 1 and 24 weeks for genotype 2 or 3 patients. Declines in apoptosis, alanine aminotransferase, and HCV RNA during treatment were calculated in relation to baseline values.
Results: Baseline apoptotic activity (M30 levels) correlated with alanine aminotransferase (r=0.49), γ-glutamyl transpeptidase (r=0.37), and fibrosis score (r=0.30; all P< .001), but not with HCV RNA (r=0.09; P=.19). Furthermore, M30 levels correlated with insulin resistance according to homeostasis model assessment of insulin resistance index (r=0.31) and steatosis (r=0.27; both P< .01). A low baseline apoptosis level (< 265 U/mL) was associated with SVR (P=.015). Median baseline apoptotic activity was higher in genotype 3 (305 U/mL) vs genotypes 1 (249 U/mL) and 2 (257 U/mL). During treatment, overall median apoptotic activity declined significantly (P< .001); significant declines were found in patients with genotypes 1 (P< .001) and 3 (P=.006), but not genotype 2 (P=.37). In genotype 1 patients, apoptotic activity during treatment was lower in those who achieved an SVR vs those who did not (150 vs 191 U/mL; P=.03).
Conclusions: Apoptotic activity in CHC patients was associated with fibrosis, steatosis, insulin resistance, and HCV genotype. Apoptotic activity declined during treatment. Low apoptosis levels were associated with SVR, especially in genotype 1 CHC patients.