December 19, 2010

J Hepatol. 2010 Dec 8. [Epub ahead of print]

Lange CM, Bojunga J, Ramos-Lopez E, Wagner MV, Hassler A, Vermehren J, Herrmann E, Badenhoop K, Zeuzem S, Sarrazin C.

Klinikum der J. W. Goethe-Universität Frankfurt am Main, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.

Abstract

AIMS: Vitamin D is an important immune modulator and preliminary data indicated an association between vitamin D deficiency and sustained virologic response (SVR) rates in hepatitis C virus (HCV) genotype 1 patients. We therefore performed a comprehensive analysis on the impact of vitamin D serum levels and of genetic polymorphisms with functional relevance within the vitamin D cascade on chronic hepatitis C and its treatment

METHODS: Vitamin D serum levels, genetic polymorphisms within the vitamin D receptor and 1α-hydroxylase were determined in a cohort of 468 HCV genotype 1, 2 and 3 infected patients who were treated with interferon-alfa based regimens

RESULTS: Chronic hepatitis C was associated with a high incidence of severe vitamin D deficiency compared to controls (25(OH)D(3)<10 ng/ml in 25% versus 12%, p<0.00001). 25(OH)D(3) deficiency correlated with SVR in HCV genotype 2 and 3 patients (50% and 81% SVR for patients with and without severe vitamin D deficiency, respectively, p<0.0001). In addition, the CYPB27-1260 promoter polymorphism rs10877012 had substantial impact on 1-25-dihydroxyvitamin D serum levels (72, 61, and 60 pmol/ml for rs10877012 AA, AC, and CC, respectively, p=0.04) and on SVR rates in HCV genotype 1, 2 and 3 infected patients (77% and 65% versus 42% for rs10877012 AA, AC, and CC, respectively, p=0.02)

CONCLUSIONS: Chronic hepatitis C virus infection is associated with vitamin D deficiency. Reduced 25-hydroxyvitamin D levels and CYPB27-1260 promotor polymorphism leading to reduced 1,25-dihydroxyvitamin D levels are associated with failure to achieve SVR in HCV genotype 1, 2, 3 infected patients.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145801 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Dec 8. [Epub ahead of print]

Costentin CE, Roudot-Thoraval F, Zafrani ES, Medkour F, Pawlotsky JM, Mallat A, Hézode C.

AP-HP, Service d'Hépatologie et de Gastroentérologie, Groupe Hospitalier Henri Mondor-Albert Chenevier, Créteil, 94000 France.

Abstract

Rational The severity of chronic hepatitis C (CHC) is modulated by host and environmental factors. Several reports suggest that caffeine intake exerts hepatoprotective effects in patients with chronic liver disease. The aim of this study was to evaluate the impact of caffeine consumption on activity grade and fibrosis stage in patients with CHC. Methods 238 treatment-naı¨ve patients with histologically-proven CHC were included. Demographic, epidemiological, environmental, virological and metabolic features were collected, including daily consumptions of alcohol, cannabis, tobacco and caffeine during the six month preceding liver biopsy. Daily caffeine consumption was estimated as the sum of mean intakes of caffeinated coffee, tea and caffeine-containing sodas. Histological activity grade and fibrosis stage were scored according to Metavir. Patients (154 men, 84 women, mean age: 45±11 years) were categorized according to caffeine consumption quartiles: group 1 (<225 mg/day, n=59), group 2 (225-407 mg/day, n=57), group 3 (408-678 mg/day, n=62) and group 4 (>678 mg/day, n=60). Results There was a significant inverse relationship between activity grade and daily caffeine consumption: Activity grade >A2 was present in 78%, 61%, 52% and 48% of patients in group 1, 2, 3 and 4, respectively (p<0.001). By multivariate analysis, daily caffeine consumption greater than 408 mg/day was associated with a lesser risk of activity grade >A2 (OR=0.32 (0.12-0.85)). Caffeine intake showed no relation with the fibrosis stage. Conclusions Caffeine consumption greater than 408 mg/day (3 cups or more) is associated with reduced histological activity in patients with CHC. These findings support potential hepatoprotective properties of caffeine in chronic liver diseases.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145804 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Dec 8. [Epub ahead of print]

Scherzer TM, Hofer H, Staettermayer AF, Rutter K, Beinhardt S, Steindl-Munda P, Kerschner H, Kessler HH, Ferenci P.

Medical University of Vienna, Internal Medicine III, Department of Gastroenterology and Hepatology, Austria.

Abstract

BACKGROUND: and Aim: Polymorphisms of the IL28B-gene (rs12979860 and rs8099917) are associated with high sustained virological response (SVR) rates in HCV genotype 1 patients. This study analyses the impact of these IL28B polymorphisms on early treatment response (week 2 and 4) and on SVR in HCV genotype 3 patients.

METHODS: : rs12979860 and rs8099917 were analyzed by the StepOnePlus Real time PCR system in 71 of 72 Caucasian HCV genotype 3 patients participating at our center in a randomized study comparing 400 mg with 800 mg ribavirin/day. HCV RNA was determined at weeks 2 and 4 of 180 μg/week peginterferon alfa-2a/ribavirin treatment. Sixty nine patients completed treatment and follow-up.

RESULTS: : rs12979860 genotyping revealed that 27 (37.5%) pts had C/C, 39 (54.2%) T/C and 5 (6.9%) T/T. Thirteen pts (18.1%) became HCV RNA negative at week 2 and additional 30 (41.7%) at week 4 (rapid virologic response; RVR); thus a total of 43 had a RVR (C/C: 77.8%; C/T or T/T: 50.0%). Irrespective of the ribavirin dose the viral load decline was larger than in those with T allele (C/T or T/T) (week 2: 4.46;[0.36-6.02] median; [range] vs. 3.50;[0.14-5.62]; log IU HCV-RNA/mL; p<0.001; week 4: 4.97;[1.21-6.20] vs. 4.49;[1.16-6.23]; p=0.003). Despite the faster initial viral response in C/C carriers, SVR rates were not different compared to T-allele carriers. Results of the SNP in the rs8099917 region showed similar results.

CONCLUSION: : IL28B polymorphisms modulate early virologic response to peginterferon/ribavirin treatment. In contrast to HCV genotype 1 patients no effect on SVR rates was observed in genotype 3 patients. The clinical relevance of an earlier viral decline of C/C patients needs to be determined.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145807 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Dec 8. [Epub ahead of print]

Martin NK, Vickerman P, Foster GR, Hutchinson SJ, Goldberg DJ, Hickman M.

Department of Social Medicine, University of Bristol, Bristol, UK; Health Policy Unit, London School of Hygiene and Tropical Medicine, London, UK.

Abstract

BACKGROUND&

AIMS: Hepatitis C virus antiviral treatment is effective for individual patients, but few active injecting drug users are treated. We considered the utility of antiviral treatment for primary prevention of hepatitis C.

METHODS: A hepatitis C transmission model amongst injecting drug users was developed, incorporating treatment (62.5% average sustained viral response) with no retreatment after initial treatment failure, potential re-infection for those cured, equal genotype setting (genotype 1: genotype 2/3) and no immunity. In addition, we examined scenarios with varied treatment response rates, immunity, or retreatment of treatment failures.

RESULTS: In the baseline scenario, annually treating 10 infections per 1000 injecting drug users results in a relative decrease in hepatitis C prevalence over 10 years of 31%, 13% or 7% for baseline (untreated endemic chronic infection) prevalences of 20%, 40% or 60%, respectively. Sensitivity analyses show that: including the potential for immunity has minimal effect on the predictions; prevalence reductions remain even if SVR is assumed to be 25% lower among active IDU then current evidence suggests; retreatment of treatment failures does not alter the short-term (<5 year) projections, but does increase treatment gains within 20 years; hepatitis C free life years gained from treating active injecting drug users are projected to be higher than from treating non-injecting drug users for prevalences below 60%.

CONCLUSIONS: Despite the possibility of re-infection, modest rates of hepatitis C treatment amongst active injecting drug users could effectively reduce transmission. Evaluating and extending strategies to treat hepatitis C among active injectors is warranted.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145810 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Nov 11. [Epub ahead of print]

Manns MP, Bourlière M, Benhamou Y, Pol S, Bonacini M, Trepo C, Wright D, Berg T, Calleja JL, White PW, Stern JO, Steinmann G, Yong CL, Kukolj G, Scherer J, Boecher WO.

Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Center for Internal Medicine, Hannover, Germany.

Abstract

BACKGROUND AND AIMS: BI201335 is a highly specific and potent HCV protease inhibitor. This multiple rising dose trial evaluated antiviral activity and safety in chronic HCV genotype-1 patients.

METHODS: 34 treatment-naïve patients were randomized to monotherapy with placebo or BI201335 at 20-240 mg once-daily for 14 days, followed by combination with pegylated interferon alfa/ribavirin (PegIFN/RBV) through Day 28. Nineteen treatment-experienced patients received 48-240 mg BI201335 once-daily with PegIFN/RBV for 28 days. HCV-RNA was measured with Roche COBAS TaqMan.

RESULTS: In treatment naïve patients, median maximal viral load (VL) reductions during 14 day monotherapy were -3.0, -3.6, -3.7 and -4.2 log(10) for the 20, 48, 120, and 240 mg groups. VL breakthroughs (⩾1 log(10) from nadir) were seen in most patients on monotherapy and were caused by NS3/4A variants (R155K, D168V) conferring in vitro resistance to BI201335. Adding PegIFN/RBV at Days 15 to 28 led to continuous viral load reductions in most patients. In treatment-experienced patients, treatment with BI201335 and PegIFN/RBV achieved VL <25 IU/ml at Day 28 in 3/6, 4/7 and 5/6 patients in the 48, 120 and 240 mg dose groups. VL breakthroughs were observed during triple combination in only 3/19 patients. BI201335 was generally well tolerated. Mild rash or photosensitivity was detected in 4 patients. Mild unconjugated hyperbilirubinemia was the only dose-dependent laboratory abnormality of BI201335. BI201335 elimination half-life supports once-daily dosing.

CONCLUSIONS: BI201335 combined with PegIFN/RBV was well tolerated and induced strong antiviral responses. These results support further development of BI201335 in HCV genotype-1 patients.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145839 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Dec 8. [Epub ahead of print]

Forestier N, Larrey D, Guyader D, Marcellin P, Rouzier R, Patat A, Smith P, Bradford W, Porter S, Blatt L, Seiwert SD, Zeuzem S.

J.W. Goethe Universität, Frankfurt, Germany.

Abstract

Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection. Four cohorts of treatment-naïve (TN) patients (100 mg q12h, 100 mg q8h, 200 mg q12h, 200 mg q8h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12h) were investigated. RESULTS: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and without association to treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were -3.9 log(10) IU/mL and -3.2 log(10) IU/mL in TN receiving 200 mg q8h and 200 mg q12h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10) IU/mL of viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with R155K substitution in NS3 regardless of HCV subtype. CONCLUSION: Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/mL reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145848 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Nov 23. [Epub ahead of print]

Grebely J, Matthews GV, Hellard M, Shaw D, van Beek I, Petoumenos K, Alavi M, Yeung B, Haber PS, Lloyd AR, Kaldor JM, Dore GJ; for the ATAHC Study Group.

National Centre in HIV Epidemiology and Clinical Research, University of New South Wales (UNSW), Sydney.

Abstract

BACKGROUND AND AIMS: Adherence to HCV therapy impacts sustained virological response (SVR), but there are limited data on adherence, particularly among injecting drug users (IDUs). We assessed 80/80 adherence (>80% of PEG-IFN doses, >80% treatment), on-treatment adherence and treatment completion in a study of treatment of recent HCV infection (ATAHC)

METHODS: Participants with HCV received pegylated interferon (PEG-IFN) alfa-2a (180 μg/week, n=74); those with HCV/HIV received PEG-IFN alfa-2a with ribavirin (n=35). Everyone received 24 weeks of therapy. Logistic regression analyses were used to identify predictors of PEG-IFN 80/80 adherence.

RESULTS: Of 163, 109 received treatment (HCV, n=74; HCV/HIV, n=35), with 75% ever reporting IDU. The proportion with 80/80 PEG-IFN adherence was 82% (n=89). During treatment, 14% missed >1 dose (on-treatment adherence=99%). Completion of 0-4, 5-19, 20-23 and all 24 weeks of PEG-IFN therapy occurred in 10% (n=11), 14% (n=15), 6% (n=7) and 70% (n=76), respectively. Participants with no tertiary education were less likely to have 80/80 PEG-IFN adherence (AOR 0.29,P=0.045). IDU prior to or during treatment did not impact 80/80 PEG-IFN adherence. SVR was higher among those with >80/80 PEG-IFN adherence (67% vs. 35%,P=0.007), but similar among those with and without missed doses during therapy (73% vs. 60%,P=0.309). SVR in those discontinuing therapy between 0-4, 5-19, 20-23 and 24 weeks was 9%, 33%, 43% and 76%, respectively (P<0.001).

CONCLUSION: High adherence to treatment for recent HCV was observed, irrespective of IDU prior to, or during, therapy. Sub-optimal PEG-IFN exposure was mainly driven by early treatment discontinuation rather than missed doses during therapy.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145855 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Nov 23. [Epub ahead of print]

Fried MW, Hadziyannis SJ, Shiffman ML, Messinger D, Zeuzem S.

University of North Carolina, Chapel Hill, USA.

Abstract

The probability of response to peginterferon and ribavirin is associated with numerous host and virological factors. Attainment of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 during treatment with peginterferon and ribavirin, is highly predictive of sustained virological response (SVR). The aim of the present study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting SVR.

METHODS: A retrospective analysis of 1,383 patients, encompassing genotypes 1-4, treated with peginterferon alfa-2a and ribavirin was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with RVR were identified. The relative significance of RVR compared to other baseline factors for predicting SVR was analyzed by multiple logistic regression analysis.

RESULTS: RVR was achieved by 16% of patients with genotype 1 and 71% and 60% of those with genotype 2 and 3, respectively. Among patients who achieved RVR, the rate of SVR was high across all genotypes and ranged from 88% to 100% (genotypes 1-4). Baseline factors predictive of RVR included genotype, younger age, lower initial viral load, higher ALT ratio, absence of advanced fibrosis, and younger age. Notably, the presence of RVR generated the highest odds ratio (5.47, 95% confidence interval 3.97-7.52) for predicting SVR in multiple logistic regression analysis of these factors.

CONCLUSIONS: Attainment of RVR varies by genotype and is associated with several baseline factors. Patients who achieve RVR have the highest rates of SVR, regardless of genotype. These findings have important implications for predicting and managing response-guided combination antiviral therapies.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145856 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Nov 23. [Epub ahead of print]

Tabatabaei SV, Alavian SM, Keshvari M, Behnava B, Miri SM, Elizee PK, Zamani F, Kafi-Abad SA, Gharehbaghian A, Hajibeigy B, Lankarani KB.

Baqiyatallah University of Medical Sciences, Baqiyatallah Research Center for Gastroenterology and Liver Disease, Tehran, Iran.

Abstract

BACKGROUND AND AIMS: Treatment guidelines contraindicate ribavirin for treatment of hepatitis C virus (HCV) infection in thalassemia major patients. Nevertheless, the current evidence suggests that ribavirin might be tolerated by these patients. Despite this evidence, low dose ribavirin combination therapy has not been compared with peginterferon monotherapy in these patients so far.

MATERIAL AND METHODS: Two hundred eighty thalassemia patients with detectable HCV-RNA PCR (⩾50 IU/mL) and liver histology consistent with chronic HCV infection were self-assigned to receive peginterferon alfa-2a (n=81) monotherapy or its combination therapy with ribavirin, 600-800 mg QD, according to hemoglobin levels (n=199). Treatment experienced patients were eligible for this study.

RESULTS: Sustained virological response (SVR) was significantly higher in patients who received ribavirin (51% vs. 38% P=0.02). In multivariate regression, OR of ribavirin for prediction of SVR was 2.2 (95% CI 1.24-3.91). The SVR was significantly higher in the ribavirin group in subgroups of patients with more than 24 years of age, elevated ALT, ferritin<2006 ng/mL, previous treatment failure, genotype 1, positive history of splenectomy, fibrosis score of 0-4 HAI and viral load<600,000 IU/mL. Treatment discontinuations due to the safety concerns were comparable between the treatment groups (6.5 and 8%). Furthermore, transfusion intervals were almost halved in patients who received low dose ribavirin.

CONCLUSION: According to the present study, adult thalassemia patients with HCV infection can be treated successfully with low dose ribavirin. Hence, we strongly advise combination therapy in thalassemia patients with aforementioned clinical characteristics. Moreover, ribavirin does not seem to be beneficial in thalassemia patients below 18 years of age.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145858 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Nov 23. [Epub ahead of print]

Trépo E, Potthoff A, Pradat P, Bakshi R, Young B, Lagier R, Moreno C, Verset L, Cross R, Degré D, Lemmers A, Gustot T, Berthillon P, Rosenberg W, Trépo C, Sninsky J, Adler M, Wedemeyer H.

Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université libre de Bruxelles, Brussels, Belgium.

Abstract

BACKGROUND AND AIMS: Fibrosis progression in patients with chronic hepatitis C (CHC) is highly variable. A Cirrhosis Risk Score (CRS) based on seven genetic variants has been recently developed for identifying patients at risk for cirrhosis. The objective of this study was to assess the role of the CRS for the early prediction of fibrosis progression in CHC patients with mild liver fibrosis. In addition, we evaluated the potential benefit, for prediction accuracy, of a recently described non-invasive fibrosis staging assay, the Enhanced Liver Fibrosis (ELF) test.

METHODS: Two separate cohorts of HCV patients (Brussels, Belgium/Hannover, Germany) were retrospectively analyzed. Only patients with a fibrosis Ishak or METAVIR score of F0-F1 at baseline were included. Patients were classified as progressors if they showed an increase >=2 fibrosis stages at the second histological evaluation after a follow-up >=5 years. The CRS was calculated locally. Genotyping was performed by PCR and oligonucleotide ligation with the resulting signal detected with a Luminex® 200TM and computer analysis.

RESULTS: In Brussels, 12/25 patients progressed (48%); similarly in Hannover, 16/31 (52%) patients progressed. In both sample sets, the CRS was significantly associated with fibrosis progression (p=0.050 in Brussels; p=0.018 in Hannover). The ELF test was only a significant predictor in Hannover (p=0.015). In multivariate analysis the CRS remained the only variable associated with fibrosis progression (Odds-ratio= 2.23, 95%CI 1.21-4.11 p=0.01).

CONCLUSIONS: Although conducted on a limited number of patients, this study in two independent centres confirms that the CRS predicts fibrosis progression in initially mild CHC.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145859 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Nov 24. [Epub ahead of print]

Drumright LN, Hagan H, Thomas DL, Latka MH, Golub ET, Garfein RS, Clapp JD, Campbell JV, Bonner S, Kapadia F, Thiel TK, Strathdee SA.

At the time of work on study: University of California, San Diego, Department of Medicine, Division of Global Public Health, La Jolla, CA.

Abstract

BACKGROUND & AIMS: Hepatitis C virus (HCV) screening can provide opportunities to reduce disease progression through counseling against alcohol use, but empirical data on this issue are sparse. We determined the efficacy of a behavioral intervention in reducing alcohol use among young, HCV-infected injection drug users (IDUs) (n=355) and assessed whether changes in liver enzymes were associated with changes in alcohol consumption.

METHODS: Both the intervention and attention-control groups were counseled to avoid alcohol use, but the intervention group received enhanced counseling. Logistic regression, ANOVA, and continuous time Markov models were used to identify factors associated with alcohol use, changes in mean ALT and AST levels and change in alcohol use post-intervention.

RESULTS: Six months post-intervention, alcohol abstinence increased 22.7% in both groups, with no difference by intervention arm. Transition from alcohol use to abstinence was associated with a decrease in liver enzymes, with a marginally greater decrease in the intervention group (p=0.05 for ALT; p=0.06 for AST). In multivariate Markov models, those who used marijuana transitioned from alcohol abstinence to consumption more rapidly than non-users (RR=3.11); those who were homeless transitioned more slowly to alcohol abstinence (RR=0.47); and those who had ever received a clinical diagnosis of liver disease transitioned more rapidly to abstinence (RR=1.88).

CONCLUSIONS: Although, behavioral counseling to reduce alcohol consumption among HCV-infected IDUs had a modest effect, reductions in alcohol consumption were associated with marked improvements in liver function. Interventions to reduce alcohol use among HCV-infected IDUs may benefit from being integrated into clinical care and monitoring of HCV infection.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21145862 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Dec 8. [Epub ahead of print]

Oze T, Hiramatsu N, Yakushijin T, Mochizuki K, Oshita M, Hagiwara H, Mita E, Ito T, Fukui H, Inui Y, Hijioka T, Inada M, Kaytayama K, Tamura S, Yoshihara H, Inoue A, Imai Y, Kato M, Miyagi T, Yoshida Y, Tatsumi T, Kiso S, Kanto T, Kasahara A, Takehara T, Hayashi N.

Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Japan.

Abstract

BACKGROUND & AIMS: This study investigated the efficacy and adverse effects of pegylated interferon (Peg-IFN) plus ribavirin therapy in aged patients with chronic hepatitis C (CH-C).

METHODS: A total of 1040 naïve patients with CH-C (genotype 1, n=759; genotype 2, n=281), of whom 240 (23%) over 65years old (y.o.), were treated with Peg-IFN alfa-2b plus ribavirin and assessed after being classified into five categories, according to age.

RESULTS: The discontinuance rate was higher for patients over 70 y.o. (36%), the most common reason being anemia. In the presence of genotype 1, the SVR rate was similar (42-46%) among patients under 65 y.o. and declined (26-29%) among patients over 65 y.o. For patients over 65 y.o., being male (Odds ratio, OR, 3.5, p=0.035) and EVR (OR, 83.3, p<0.001) were significant factors for SVR, in multivariate analysis. The Peg-IFN dose was related to EVR, and when EVR was attained, 76-86% of patients over 65 y.o. achieved SVR. SVR was not achieved (0/35, 0/38, respectively) if a 1-log decrease and a 2-log decrease were not attained at week 4 and week 8, respectively. In the presence of genotype 2, the SVR rate was similar (70-71%) among patients under 70 y.o. and declined among patients over 70 y.o. (43%).

CONCLUSIONS: Aged patients up to 65 y.o. with genotype 1 and 70 y.o. with genotype 2 can be candidates for pegylated interferon (Peg-IFN) plus ribavirin therapy. The response-guided therapy can be applied for aged patients with genotype 1.

Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

PMID: 21145907 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Dec 10. [Epub ahead of print]

Lange CM, Moradpour D, Doehring A, Lehr HA, Müllhaupt B, Bibert S, Bochud PY, Antonino AT, Pascual M, Farnik H, Shi Y, Bechstein WO, Moench C, Hansmann ML, Sarrazin C, Lötsch J, Zeuzem S, Hofmann WP.

Medizinische Klinik 1, Germany; Centre Hospitalier Universitaire Vaudois, University of Lausanne, Rue Bugnon 46, CH-1010 Lausanne, Switzerland.

Abstract

BACKGROUND AND AIM: Recent studies described a major impact of genetic variations near the IL28B gene on the natural course and outcome of antiviral therapy in chronic hepatitis C. We therefore aimed to explore the impact of donor and recipient genotypes of these polymorphisms on hepatitis C virus (HCV) liver graft reinfection.

METHODS: Donor and recipient genotypes of IL28B rs12979860C>T single nucleotide polymorphism were determined in 91 patients with HCV liver graft reinfection, 47 of which were treated with pegylated interferon-α(PEG-IFN-α) and ribavirin. IL28B genetic polymorphisms were correlated with the natural course and treatment outcome of recurrent hepatitis C.

RESULTS: Patients requiring liver transplantation due to end-stage chronic hepatitis C appeared to be selected towards the adverse genotypes rs12979860CT/TT compared to non-transplanted HCV-infected patients (p=0.046). Patients with the donor genotype rs12979860CC had higher peak ALT and HCV RNA serum concentrations than those with CT/TT (p=0.04 and 0.06, respectively). No associations were observed between ALT / HCV RNA serum concentrations and recipient genotypes (p>0.3). More important, donor IL28B rs12979860 CC vs. CT/TT genotypes were associated with rapid, complete early, and sustained virologic response (RVR, cEVR, SVR) to treatment with PEG-IFN-α and ribavirin (p=0.003, 0.0012, 0.008, respectively), but weaker associations of recipient genotypes with RVR, cEVR and SVR were observed as well (p=0.0046, 0.115, 0.118, respectively).

CONCLUSIONS: We provide evidence for a dominant, but not exclusive impact of the donor rather than the recipient IL28B genetic background on the natural course and treatment outcome of HCV liver graft reinfection.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21147186 [PubMed - as supplied by publisher]

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J Hepatol. 2010 Dec 10. [Epub ahead of print]

Zhang L, Jilg N, Shao RX, Lin W, Fusco DN, Zhao H, Goto K, Peng LF, Chen WC, Chung RT.

Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Abstract

BACKGROUND AND AIMS: The combination of pegylated interferon (IFN) α and ribavirin (RBV) is standard therapy for patients with chronic HCV infection. However, it produces a sustained virologic response (SVR) in only half of treated individuals and is associated with significant side effects. Recently several single-nucleotide polymorphisms (SNPs) near the IL28B locus, also known as IFNλ3, were identified to be strong predictors of SVR in patients receiving PEG-IFN and RBV. We sought to determine whether IL28B was capable of inhibiting HCV replication and to determine the pathway by which IL28B exhibits anti-HCV activity.

METHODS: Using the full-length HCV replicon OR6 and the infectious HCV clones JFH1 and Jc1, we assessed the anti-HCV effect of IL28B on HCV and characterized the key steps of the JAK-STAT pathway by real time PCR, luciferase assay, and Western blot. Finally, we evaluated the anti-HCV effect of IL28B in the presence of JAK-STAT pathway inhibitors such as blocking antibodies, a pharmacological inhibitor and siRNAs.

RESULTS: We found that IL28B inhibits HCV replication in a dose- and time- dependent manner. Like IFNα, IL28B induces the phosphorylation of STAT1 and STAT2, ISRE-driven transcription, and expression of known ISGs. The anti-HCV effects of IL28A, IL28B and IL29 were abrogated by an IL10R2 blocking antibody, a pharmacological inhibitor of JAK1/TYK2, and by siRNA against IL28R1, STAT1, STAT2 and IRF9.

CONCLUSIONS: Our data demonstrate that IL28A, IL28B and IL29 signal through the JAK-STAT pathway to inhibit HCV. These data suggest possible applications of new approaches in HCV treatment.

Copyright © 2010. Published by Elsevier B.V.

PMID: 21147189 [PubMed - as supplied by publisher]

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Hepatology. 2010 Oct 6. [Epub ahead of print]

Kramer JR, Hachem CY, Kanwal F, Mei M, El-Serag HB.

Houston VA Health Services Research #38; Development Center of Excellence, Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX.

Abstract

Coinfection with hepatitis A virus (HAV) or hepatitis B virus (HBV) in patients with chronic hepatitis C virus (HCV) is associated with increased morbidity and mortality. The Center for Medicare and Medicaid Services has identified HAV and HBV vaccination as a priority area for quality measurement in HCV. It is unclear to what extent patients with HCV meet these recommendations. We used national data from the Department of Veterans Affairs HCV Clinical Case Registry to evaluate the prevalence and predictors of meeting the quality measure (QM) of receiving vaccination or documented immunity to HAV and HBV in patients with chronic HCV. We identified 88,456 patients who had overall vaccination rates of 21.9% and 20.7% for HBV and HAV, respectively. The QM rates were 57.0% and 45.5% for HBV and HAV, respectively. Patients who were nonwhite or who had elevated alanine aminotransferase levels, cirrhosis, or human immunodeficiency virus were more likely to meet the HBV QM. Factors related to HCV care were also determinants of meeting the HBV QM. These factors included receiving a specialist consult, genotype testing, or HCV treatment. Patients who were older, had psychosis, and had a higher comorbidity score were less likely to meet the HBV QM. With a few exceptions, similar variables were related to meeting the HAV QM. The incidence of superinfection with acute HBV and HAV was low, but it was significantly lower in patients who received vaccination than in those who did not. Conclusion: Quality measure rates for HAV and HBV are suboptimal for patients with chronic HCV. In addition, several patient-related factors and receiving HCV-related care are associated with a higher likelihood of meeting QMs. (HEPATOLOGY 2010;).

PMID: 21157783 [PubMed - as supplied by publisher]

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