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      Effect of Peginterferon or Ribavirin Dosing on Efficacy of Therapy With Telaprevir in Treatment-Experienced Patients With Chronic Hepatitis C and Advanced Liver Fibrosis : A Multicenter Cohort Study

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          Abstract

          We investigated the safety, efficacy, and impact of ribavirin and peginterferon dose reduction on complete early virologic response and sustained virologic response (SVR) to triple therapy with telaprevir in treatment-experienced patients with advanced liver fibrosis.

          Treatment was initiated for 211 patients who failed treatment with peginterferon and ribavirin, with bridging fibrosis (F3, n = 68) or cirrhosis (F4, n = 143), including 103 (49%) null-responders (NR), 30 (14%) partial responders (PR), and 78 (37%) relapsers (REL). Impaired liver function (ILF) platelets <100,000/mm 3 or albumin <35 g/L were present in 40 patients. The distribution of hepatitis C virus subtypes was: 1a, 1b, or 1, with undetermined subtype for 10 (5%), 187 (89%), and 14 (6%) patients, respectively. Treatment was started with peginterferon alpha-2a or alpha-2b, ribavirin, and telaprevir at standard doses.

          The overall SVR24 rate was 56% and was lower in cirrhotic patients (NR: 35%, PR: 40%, and REL: 63%, respectively) than in patients with bridging fibrosis (NR: 50%, PR: 75%, and REL: 75%, respectively). The lowest probability of SVR24 was in NRs with ILF (26%). The SVR24 rate significantly decreased in NRs receiving <60% vs >60% of the total ribavirin dose (23% vs 44%, respectively) or <80% vs >80% of the total ribavirin dose (33% vs 48%, respectively). A significant SVR24 decrease was noted subsequent to a total peginterferon dose reduction, both when comparing patients who received <60% vs >60% of the total dose (NR: 0% vs 44%; REL: 33% vs 68%) and patients who received <80% vs >80% of the total dose (NR: 17% vs 50%; REL: 46% vs 71%).

          Serious adverse events were observed in 31 patients (15%). Deaths occurred in 4 patients. All of the deceased subjects were cirrhotic members of the ILF (baseline serum albumin level <35 g/L and/or platelet count <100,000/mm 3) group.

          Ribavirin dose reduction did not affect efficacy in REL but did in NR. Peginterferon dose reduction decreased the SVR24 rate for all groups, particularly in prior NR. ILF increased the risk of fatal complications with a low probability to achieve SVR24. One solution might be to provide wide and early access to novel, efficient, and safe interferon-free combinations to treatment-experienced patients, particularly those with liver cirrhosis.

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          Telaprevir for previously untreated chronic hepatitis C virus infection.

          Ira M Jacobson, John G McHutchison, Geoffrey Dusheiko … (2011)
          In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).
          Article 0 comments Cited 447 times – based on 0 reviews     Review now
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            Telaprevir for retreatment of HCV infection.

            Stefan Zeuzem, Pietro Andreone, Stanislas Pol … (2011)
            Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).
            Article 0 comments Cited 275 times – based on 0 reviews     Review now
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              Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.

              T Poynard, P Bedossa, P Opolon (1997)
              Our aim was to assess the natural history of liver fibrosis progression in hepatitis C and the factors associated with this progression. We recruited 2235 patients from the Observatoire de l'Hépatite C (OBSVIRC) population, the Cohorte Hépatite C Pitié-Salpétrière (DOSVIRC) population, and the original METAVIR population. All the patients had a biopsy sample compatible with chronic hepatitis C as assessed by the METAVIR scoring system (grades the stage of fibrosis on a five-point scale, F0 = no fibrosis, F4 = cirrhosis, and histological activity on a four-point scale, A0 = no activity, A3 = severe activity). No patient had received interferon treatment before the liver biopsy sample was obtained. We assessed the effect of nine factors on fibrosis progression: age at biopsy; estimated duration of infection; sex; age at infection; alcohol consumption; hepatitis C virus C (HCV) genotype; HCV viraemia; cause of infection; and histological activity grade. We defined fibrosis progression per year as the ratio between fibrosis stage in METAVIR units and the duration of infection (1 unit = one stage, 4 units = cirrhosis). The median rate of fibrosis progression per year was 0.133 fibrosis unit (95% CI 0.125-0.143), which was similar to the estimates from previous studies (0.146 to 0.154). Three independent factors were associated with an increased rate of fibrosis progression: age at infection older than 40 years, daily alcohol consumption of 50 g or more, and male sex. There was no association between fibrosis progression and HCV genotype. The median estimated duration of infection for progression to cirrhosis was 30 years (28-32), ranging from 13 years in men infected after the age of 40 to 42 years in women who did not drink alcohol and were infected before the age of 40. Without treatment, 377 (33%) patients had an expected median time to cirrhosis of less than 20 years, and 356 (31%) will never progress to cirrhosis or will not progress for at least 50 years. The host factors of ageing, alcohol consumption, and male sex have a stronger association with fibrosis progression than virological factors in HCV infection.
              Article 0 comments Cited 201 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Medicine (Baltimore)
                Journal ID (iso-abbrev): Medicine (Baltimore)
                Journal ID (publisher-id): MEDI
                Title: Medicine
                Publisher: Wolters Kluwer Health
                ISSN (Print): 0025-7974
                ISSN (Electronic): 1536-5964
                Publication date Collection: September 2015
                Publication date (Electronic): 25 September 2015
                Volume: 94
                Issue: 38
                Electronic Location Identifier: e1411
                Affiliations
                From the ID Clinic, Myslowice, Poland (EJ, AP); Klinika Chorob Zakaznych i Hepatologii, Uniwersytet Medyczny, Białystok, Poland (RF, TL); Uniwersytet J. Kochanowskiego i Wojewodzki Szpital Zespolony, Kielce, Poland (DZ-M, WK); Department of Infectious Diseases and Hepatology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland (DK); Hospital of Infectious Diseases, Warsaw, Poland (HB); Infectious Diseases Clinic, Wroclaw, Poland (BD, WD); Poradnia Wirusowych Zapalen Watroby SU, Kraków, Poland (ML-S); NZOZ Poradnia Chorob Watroby, Zielona Gora, Poland (WL); Department of Infectious Diseases, Hepatology, and Liver Transplantation, Pomeranian Medical University, Szczecin, Poland (KJ); Department of Gastroenterology and Hepatology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland (JM); Department of Basic Biomedical Science, School of Pharmacy, Division of Laboratory, Medicine in Sosnowiec, Medical University of Silesia, Katowice, Poland (JM); Oddzial Obserwacyjno-Zakazny, Szpital im. Zeromskiego, Kraków, Poland (BP-K); Oddzial Obserwacyjno-Zakazny, Szpital Wojewodzki, Koszalin, Poland (JW); Oddzial Chorób Zakaznych, Walbrzych, Poland (KA); Klinika Chorob Infekcyjnych i Alergologii WIM, Warsaw, Poland (MD); Oddzial Obserwacyjno-Zakazny, Szpital Rejonowy, Raciborz, Poland (IO); Ośrodek Leczenia WZW, Centrum Medyczne, Lancut, Poland (AR); Warsaw Medical University and Hospital of Infectious Diseases, Warsaw, Poland (AH); and Faculty of Health Science, Medical University, Wroclaw, Poland (WD).
                Author notes
                Correspondence: Ewa Janczewska, ID Clinic, Janowska 19, 41-400 Myslowice, Poland (e-mail: e.janczewska@ 123456poczta.fm ).
                Article
                Accession ID: 01411
                DOI: 10.1097/MD.0000000000001411
                PMC ID: 4635741
                PubMed ID: 26402801
                SO-VID: d8ee5be0-d7a4-4d2d-8715-0c6be75ac03d
                Copyright © Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
                License:

                This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                Date received : 9 March 2015
                Date revision received : 9 July 2015
                Date accepted : 27 July 2015
                Categories
                Subject: 4900
                Subject: Research Article
                Subject: Observational Study (Strobe Compliant)
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