October 13, 2013

Digestive and Liver Disease

Article in Press

Jens M. Kittnera, , Nora M. Weissa, Jörg Wiltinkb, Jörg M. Schattenberga, Annette Grambihlera, Florian Thieringera, Arndt Weinmanna, Tim Zimmermanna, Sandra Kocha, Marcus Schuchmanna, Peter R. Gallea

Received 20 May 2013; accepted 20 August 2013. published online 14 October 2013.
Corrected Proof

Abstract

Background

In chronic genotype 1 hepatitis C, telaprevir or boceprevir plus peginterferon and ribavirin have become the new standard of care. Aim of this study was to identify factors contributing to the decision whether to defer or treat with the current triple regimens.

Methods

Prospective assessment of eight parameters on 0-4-point scales by the attending physician at a German tertiary referral centre between 1st September 2011 and 31st December 2012.

Results

307 patients were evaluated at least once by one of the 11 hepatologists involved; 267 patients were considered, but only 163 were recommended to receive triple therapy. Multivariate regression analysis revealed that a higher degree of fibrosis was most strongly associated with a recommendation for treatment (OR 2.69), followed by the patients’ demand (OR 2.27), presumed efficacy (OR 1.62), and tolerability (OR 1.58). A high risk of decompensation was associated with the decision to defer (OR 0.39). Speed of progression, compliance, extrahepatic manifestation, gender and age were not significantly related to the recommendation. Treatment was finally started in 101 patients (32.9%).

Conclusion

In chronic genotype 1 hepatitis C, advanced fibrosis and patients’ preference are the main rationales to choose treatment rather than deferral in a real-life setting.

Keywords Boceprevir; Chronic hepatitis C genotype 1; DAAs; Telaprevir; Therapy decision; Real-life data

Source

The Lancet  Volume 12, Issue 9, September 2012, Pages 671–677

Articles

Dr Prof Stanislas Pol, MDa,, Prof Reem H Ghalib, MDb, Prof Vinod K Rustgi, MDc, Prof Claudia Martorell, MDd, Prof Greg T Everson, MDe, Prof Harvey A Tatum, MDf, Prof Christophe Hézode, MDg, Prof Joseph K Lim, MDh, Prof Jean-Pierre Bronowicki, MDi, Prof Gary A Abrams, MDj, Prof Norbert Bräu, MDk, Prof David W Morris, DOl, Prof Paul J Thuluvath, MDm, Prof Robert W Reindollar, MDn, Philip D Yin, MDo, Ulysses Diva, PhDo, Robert Hindes, MDp, Fiona McPhee, PhDo, Dennis Hernandez, PhDo, Megan Wind-Rotolo, PhDq, Eric A Hughes, MDq, Steven Schnittman, MDo

a Hôpital Cochin, Paris, France
b Texas Clinical Research Institute, Arlington, TX, USA
c Metropolitan Research, Fairfax, VA, USA
d The Research Institute, Springfield, MA, USA
e University of Colorado Denver, Aurora, CO, USA
f Options Health Research, Tulsa, OK, USA
g Hôpital Henri Mondor, Créteil, France
h Yale University School of Medicine, New Haven, CT, USA
i INSERM 954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre Les Nancy, France
j Alabama Liver and Digestive Specialists, Montgomery, AL, USA
k James J Peters VA Medical Center, Bronx, NY, USA
l Healthcare Research Consultants, Tulsa, OK, USA
m Mercy Medical Center, Baltimore, MD, USA
n Carolinas Center for Liver Disease, Statesville, NC, USA
o Bristol-Myers Squibb, Research and Development, Wallingford, CT, USA
p Gilead Sciences, Foster City, CA, USA
q Bristol-Myers Squibb, Research and Development, Princeton, NJ, USA

Summary

Background

Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV.

Methods

In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000–1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770.

Findings

48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22–64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61–96%) who received 10 mg daclatasvir, nine of 12 (75%, 53–90%) who received 60 mg daclatasvir, and one of 12 (8%, 1–29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups.

Interpretation

Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection.

Funding

Bristol-Myers Squibb.

Source

Hepatology

Accepted Article (Accepted, unedited articles published online and citable. The final edited and typeset version of record will appear in future.)

Original

Yao-Chun Hsu1,2, Jaw-Town Lin2,3,4, Hsiu J. Ho3, Yu-Hsi Kao5, Yen-Tsung Huang6, Nai-Wan Hsiao7, Ming-Shiang Wu8, Yi-Ya Liu9, Chun-Ying Wu1,9,10,11,12,*

DOI: 10.1002/hep.26892

Copyright © 2013 American Association for the Study of Liver Diseases

Publication History
Accepted manuscript online: 12 OCT 2013 09:51AM EST
Manuscript Accepted: 7 OCT 2013
Manuscript Revised: 23 SEP 2013
Manuscript Received: 25 MAY 2013

Keywords: hepatitis C virus; diabetes mellitus; antiviral therapy; Taiwan National Health Insurance Research Database

Abstract

Hepatitis C virus (HCV) infection is causally associated with insulin resistance and diabetes mellitus. This population-based cohort study aimed to investigate whether antiviral therapy for HCV infection was associated with improved clinical outcomes related to diabetes. From the Taiwan National Health Insurance Research Database, 2,267,270 Taiwanese residents diagnosed with diabetes mellitus were screened for eligibility. HCV infection was defined by a specific diagnosis code and measurement of serum antibody. After excluding patients with serious comorbidity, we enrolled a total of 1,411 eligible patients who received pegylated interferon plus ribavirin (treated cohort), and matched them 1:1 with 1,411 untreated controls by propensity scores (untreated cohort). We also matched the treated cohort 1:4 with 5,644 diabetic patients without HCV infection (uninfected cohort). Participants were followed up for the occurrence of end-stage renal disease (ESRD), ischemic stroke, and acute coronary syndrome (ACS) after receiving antiviral treatment or the corresponding calendar date. From 2003 to 2011, the 8-year cumulative incidences of ESRD in the treated, untreated, and uninfected cohorts were 1.1% (95% confidence interval [CI], 0.3-2.0%), 9.3% (95% CI, 5.9-12.7%), and 3.3% (95% CI, 2.3-4.3%), respectively (p<0.001); those of stroke were 3.1% (95% CI, 1.1-5.0%), 5.3% (95% CI, 3.0-7.5%), and 6.1% (95% CI, 4.8-7.4%), respectively (p=0.01); and those for ACS were 4.1% (95% CI, 2.1-6.1%), 6.6% (95% CI, 3.7-9.5%), and 7.4% (95% CI, 5.9-9.0%), respectively (p=0.05). As compared with the untreated cohort, antiviral treatment was associated with multivariate-adjusted hazard ratios of 0.16 (95% CI, 0.07-0.33%) for ESRD, 0.53 (95% CI, 0.30-0.93) for ischemic stroke, and 0.64 (95% CI, 0.39-1.06) for ACS, respectively. Conclusions: Antiviral treatment for HCV infection is associated with improved renal and cardiovascular outcomes in diabetic patients. (Hepatology 2013;)

Source