Additional Effect of Ribavirin During Peginterferon and Ribavirin Combination Therapy in Coagulation Factor

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AASLD Abstracts

Is Weight Loss a Surrogate Marker of Response to Pegylated Interferon and Ribavirin Therapy in Patients With Chronic Hepatitis C Infection? Deborah L. Chua, Brandon Aden, Ira M. Jacobson, Maya Gambarin-Gelwan Introduction: Known predictors of response to combination pegylated interferon (PEG-IFN) and ribavirin (RBV) for treatment of chronic hepatitis C (CHC) include genotype, race, rapid virologic response, early virologic response and recently identified interleukin-28B polymorphism. There has been conflicting data regarding the relationship between weight loss during antiviral therapy and sustained virologic response (SVR). Purpose: To determine if weight loss during antiviral therapy correlates with SVR to PEG-IFN and RBV therapy in CHC patients. Methods: We conducted a retrospective chart review of approximately 500 randomly selected CHC patients treated with combination PEG-IFN and RBV therapy from 2004 to 2009 in our urban academic hepatology practice. Random selection was accomplished by electronically randomizing an alphabetical list of CHC patients seen in our practice. Patients with acute HCV infection, HBV or HIV co-infection, liver transplant recipients, patients on experimental protocols or extended treatment courses, with unavailable weight data or lost to follow up were excluded. Both treatment-naïve and treatment-experienced patients were included. Univariate and multivariate analysis, including chi-square testing, t-test and logistic regression modeling using SAS 9.2, was completed to assess for association between weight loss and achieving SVR. Results: Data on 194 patients (68% genotype 1; 43% with advanced fibrosis) were analyzed after exclusion criteria applied. 37% of patients had SVR (including treatment-naïve and prior non-responders and relapsers). Baseline characteristics for SVR and non-SVR groups were similar except for genotype (40% in SVR group were genotype 1 vs 84% in non-SVR group) and fibrosis scores (SVR group had lower scores). Overall, 68% had weight loss >1 kg, with 40% SVR in those with weight loss vs 24% SVR among those with no weight loss. Overall, the majority of weight loss (67%) occurred in the first 12 weeks, but for those with weight loss >10kg (10% of patients), only 40% of weight loss occurred by week 12. In multivariate analysis, weight loss > 5kg (28% of patients) was associated with SVR (aOR 2.9, CI 1.04-8.30). Consistent with previous studies, genotypes 2/3 (aOR 7.1, CI 2.94-17.28), lower stage of fibrosis (aOR 1.7, CI 1.162.44) and lower baseline weight (aOR 1.03, CI 1.01-1.06) were also associated with SVR. Conclusions: Our study found an association between SVR and weight loss while controlling for other known predictors of SVR. Our data suggests that weight trend during treatment of CHC patients with combination PEG-IFN and RBV should be monitored as weight loss may be used as a surrogate marker of SVR to the current standard of care.

Su1899 Additional Effect of Ribavirin During Peginterferon and Ribavirin Combination Therapy in Coagulation Factor Takashi Honda, Yoshiaki Katano, Kazuhiko Hayashi, Masatoshi Ishigami, Akihiro Itoh, Yoshiki Hirooka, Hidemi Goto Background and aim: Combination therapy with Ribavirin and Peginterferon (PegIFN) is a standard therapy for chronic hepatitis C virus (HCV). Combination therapy has also been used to treat hemophilia patients with chronic hepatitis C. During combination therapy we observed marked decrease in the requirement of clotting factors in patients with severe and moderate hemophilia; we reported that ribavirin may reduce the use of clotting factors in hemophilia patients with chronic hepatitis C (JAMA,293;10,1190-1192:2005). In the present study, we researched whether coagulation factor could be activated or not during the therapy with ribavirin. Methods: We measured prothrombin time (PT) and international normalized ratio (INR) during combination therapy in fifty seven patients with HCV infection. All patients were underwent 1.5 μg/Kg Peginterferon-alfa-2b weekly and 600-1000mg ribavirin daily for 12 to 72 weeks at Nagoya University Hospital. Without dropout patient we compared PT and INR between before and 4 weeks later from start of therapy(during therapy) with ribavirin, dividing patients into female (n=21), non-hemophilia male (n=21) and hemophilia male (n=13). Factor II, V, VII, VIII, X were also measured between before and during therapy in 26 patients. Results: The mean age of females, non-hemophilia male and hemophilia were 55.2±15.5, 54.2±9.1 and 40.5±10.2 years, respectively. Hemophilia patients were younger than non-hemophilia patients (P<0.05). Pretreatment ALT levels, platelet counts and HCVRNA levels of female, non hemophilia male and hemophilia male were not different, respectively. Pretreatment PT and INR of female, non-hemophilia male and hemophilia male were (PT; 105.1±12.3%, 98.3±18.6%, 97.3±16.2%) and (INR; 0.98±0.02, 1.02±0.09, 1.02±0.08). PT and INR of female, non-hemophilia male and hemophilia male were (PT; 111.8±16.1%, 105.5±16.8%, 106.6±14.6%) and (INR; 0.96±0.002, 0.99±0.05, 0.98±0.05) respectively, during therapy. There were significantly difference between PT and INR during therapy and those of pretreatment levels (P<0.05). The increase rates of PT in three groups were 11.8%, 12.8% and 8.5%; there was no significantly difference between three groups. Factor V, VII, VIII of during treatment were significantly higher than that of pretreatment levels. Treatment efficacy was not affect elevate of coagulation factor. Conclusion: Changes in the coagulation factor during combination therapy with ribavirin for the chronic HCV patients were elevated. The previous report and these results suggested ribavirin could elevate coagulation factor. These results indicated Pegintereferon and ribavirin, especially ribavirin may useful for the advanced fibrosis patients with decreased PT.

Su1898 Peginterferon ALPHA-2A (40KD) Plus Ribavirin for the Treatment of Patients With Chronic Hepatitis C (CHC) and Compensated Liver Cirrhosis in Japan Namiki Izumi, Shuichi Kaneko, Shuhei Nishiguchi, Masatoshi Kudo, Michio Sata, Masao Omata Background and aims: In Japan Peg-IFNα is not currently approved for use in CHC patients with compensated liver cirrhosis. Methods: This multicenter Phase II/III, randomized, parallel-group, comparative trial was partially-blinded for Peg-IFNα2a dose. In part 1 of the trial eligible treatment naive or experienced CHC patients with compensated liver cirrhosis (F4 by liver biopsy) were randomized in a ratio of 1:1:1 to (Group-1) 48 weeks of Peg-IFNα2a 180μg or (Group-2) 90μg/week plus ribavirin (600-1000mg/day) or to (Group-3) untreated observation. In part 2 of the trial additional patients were randomized in a ratio of 1:1 to either 48 weeks of Peg-IFNα2a 180μg or 90μg/week plus ribavirin (600-1000mg/day). The primary efficacy endpoint was the difference in SVR in each treatment group compared to the untreated controls in Part 1 of the trial among all randomized patients receiving ≥1 dose of study medication with ≥1 efficacy observation. Safety and other efficacy analyses were performed in patients from Parts 1 and 2 combined. Results: SVR rates for both PegIFNα2a/ribavirin groups were higher than for the untreated controls (both p<0.01 by Fisher's exact test). SVR rates in Part 1 were similar between Peg-IFNα2a doses. In Parts 1+2 patients with higher adherence levels to both Peg-IFNα2a and ribavirin had higher SVR rates when treated with the 180μg/week dose of Peg-IFNα2a. SVR rates were higher with the 180μg/ week Peg-IFNα2a among difficult to treat patients such as those with genotype 1 and those undergoing re-treatment. Adherence was lower for patients treated with 180μg/week PegIFNα2a primarily as a result of dose modification for neutropenia. While SAEs were reported more frequently in the Peg-IFNα2a180μg/week dose, discontinuations for adverse events were less frequent in this group. The overall safety profile and tolerability were similar for both groups. Conclusions: Peg-IFNα2a plus ribavirin is safe and effective for Japanese patients with compensated liver cirrhosis. Higher SVR rates were observed with 180μg/week Peg-IFNα2a plus ribavirin among patients with higher levels of adherence to both PegIFNα2a and ribavirin.

AASLD Abstracts

Mo1000 Daidzein Improves Mitochondrial Biogenesis After Ischemia/Reperfusion and Partial Hepatectomy Hasibur Rehman, Qinlong Liu, Yasodha Krishnasamy, Yanjun Shi, Rick G. Schnellmann, Zhi Zhong Background. Liver insufficiency and dysfunction occur after major liver resection (MLR) and after transplantation of small-for-size liver grafts. Methods to treat acute liver failure are limited and only supportive. We previously reported suppression of mitochondrial biogenesis (MB) after ischemia/reperfusion (IR) and partial hepatectomy (PHX) and inhibited MB may contribute to liver failure after MLR. The Aim of this study was to examine the effects of daidzein, a stimulator of MB, on the outcome of MLR. Methods. Mice were subjected to sham operation, 70%-PHX, or 25-min ischemia plus 70%-PHX (IR+PHX). Daidzein (50 mg/kg, ip) or an equal volume of diluent was injected immediately after IR+PHX. Livers and blood were collected 24 or 48 h later to evaluate MB, liver regeneration, and liver function. Results. At 24 h after PHX, ATP synthase-β (AS-β), a nuclear DNA (nDNA)-encoded mitochondrial oxidative phosphorylation (OXPHOS) enzyme, decreased ~60% but recovered to control levels after 48 h. In contrast, following IR+PHX liver AS-β decreased by ~50% at 24 h and remained decreased at 48 h. Similarly, liver cytochrome c oxidase (COX) IV, another nDNA-encoded OXPHOS enzyme, and mitochondrial DNA (mtDNA)-encoded OXPHOS enzymes NADH dehydrogenase-3 (ND3) and ND6, were also lower following IR+PHX compared to PHX at 48 h. This wide-spread decrease in mitochondrial enzymes is consistent with suppression of MB. Liver mitochondrial fission proteins (Drp1 and Fis1) increased after PHX but remained low after IR+PHX. Mitochondrial polarization (detected by intravital multiphoton microscopy of rhodamine 123) decreased substantially at 24 h and recovered in ~70% hepatocytes at 48 h after PHX. By contrast, mitochondrial polarization remained low in hepatocytes after IR+PHX. Daidzein increased OXPHOS enzymes to control levels, prevented decreases in mitochondrial fission proteins and improved mitochondrial polarization in mice subjected to IR+PHX. BrdU incorparation occurred in ~20% of hepatocytes at 48 h after PHX but were rarely detectable in livers following IR+PHX, consistent with suppressed liver regeneration. Serum total bilirubin at 48 h was not different

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