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      Treatment of chronic HCV genotype 1 infection with telaprevir: a Bayesian mixed treatment comparison of fixed-length and response-guided treatment regimens in treatment-naïve and –experienced patients

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          Abstract

          Background

          Telaprevir (TVR) has been approved for response-guided-therapy (RGT) of chronic hepatitis C (HCV) genotype-1-infection in treatment-naïve and –experienced patients. In RGT-regimens patients that did not achieve extended rapid-virological-response (eRVR) within the first 4–12 weeks undergo treatment for 48-weeks, whereas in fixed-length-treatment (FLT) patients are treated for a fixed-duration regardless of their RVR.

          Methods

          This systematic review and Bayesian mixed-treatment-comparison (MTC) aimed to compare the efficacy and safety of standard-therapy with pegylated-interferon-α/ribavirin (Peg-IFN-α/RBV (48 weeks), group A), FLT with TVR, Peg-IFN-α/RBV for 12 weeks with a long (+36 weeks, group B) or short (+12 weeks, group C) tail of Peg-IFN-α/RBV treatment, and RGT with 12 weeks of TVR, Peg-IFN-α/RBV followed by 12 weeks of Peg-IFN-α/RBV (group D) or no therapy (group E).

          Results

          We identified seven randomized controlled trials including 3505 patients. Compared to standard-treatment (group A), treatment-naïve patients allocated to groups B, C, and D were significantly more likely to achieve sustained-virological-response (SVR, odds ratios (OR): B vs. A 3.5 (credibility interval [CrI] 2.2-5.4), C vs. A 3.0 (CrI 1.8-4.9), D vs. A 3.4 (CrI 2.5-4.6)). Treatment-experienced patients achieved increased SVR rates when they were treated in group B (OR: 8.2 (CrI 5.0-13.5)), C (OR 7.0 (CrI 3.9-12.8)), or simulated group D (OR 8.2 (CrI 4.3-15.3)). Patients treated with short RGT (simulated group E) did also have a significant improvement when they were treatment-experienced (simulated OR 3.6 (CrI 1.6-8.2)), whereas the effect was not significant in treatment-naïve patients (OR E vs. A 1.6 (CrI 0.9-2.7)).

          Conclusion

          Long FLT and RGT regimens are useful treatment options for HCV-genotype-1 in both treatment-naïve and -experienced patients. A short 24-weeks FLT regimen does not seem to be inferior and should further be evaluated in clinical trials to reduce side effects and costs of treatment.

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          Most cited references24

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          Boceprevir for untreated chronic HCV genotype 1 infection.

          Fred Poordad, Jonathan McCone, Bruce Bacon … (2011)
          Peginterferon-ribavirin therapy is the current standard of care for chronic infection with hepatitis C virus (HCV). The rate of sustained virologic response has been below 50% in cases of HCV genotype 1 infection. Boceprevir, a potent oral HCV-protease inhibitor, has been evaluated as an additional treatment in phase 1 and phase 2 studies. We conducted a double-blind study in which previously untreated adults with HCV genotype 1 infection were randomly assigned to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (the control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 received placebo plus peginterferon-ribavirin for an additional 20 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks. Nonblack patients and black patients were enrolled and analyzed separately. A total of 938 nonblack and 159 black patients were treated. In the nonblack cohort, a sustained virologic response was achieved in 125 of the 311 patients (40%) in group 1, in 211 of the 316 patients (67%) in group 2 (P<0.001), and in 213 of the 311 patients (68%) in group 3 (P<0.001). In the black cohort, a sustained virologic response was achieved in 12 of the 52 patients (23%) in group 1, in 22 of the 52 patients (42%) in group 2 (P=0.04), and in 29 of the 55 patients (53%) in group 3 (P=0.004). In group 2, a total of 44% of patients received peginterferon-ribavirin for 28 weeks. Anemia led to dose reductions in 13% of controls and 21% of boceprevir recipients, with discontinuations in 1% and 2%, respectively. The addition of boceprevir to standard therapy with peginterferon-ribavirin, as compared with standard therapy alone, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. (Funded by Schering-Plough [now Merck]; SPRINT-2 ClinicalTrials.gov number, NCT00705432.).
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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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              Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.

              M P Manns, J. G. McHutchison, S Gordon … (2001)
              A sustained virological response (SVR) rate of 41% has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this randomised trial, peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin. 1530 patients with chronic hepatitis C were assigned interferon alfa-2b (3 MU subcutaneously three times per week) plus ribavirin 1000-1200 mg/day orally, peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin, or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000-1200 mg/day for 48 weeks. The primary endpoint was the SVR rate (undetectable hepatitis C virus [HCV] RNA in serum at 24-week follow-up). Analyses were based on patients who received at least one dose of study medication. The SVR rate was significantly higher (p=0.01 for both comparisons) in the higher-dose peginterferon group (274/511 [54%]) than in the lower-dose peginterferon (244/514 [47%]) or interferon (235/505 [47%]) groups. Among patients with HCV genotype 1 infection, the corresponding SVR rates were 42% (145/348), 34% (118/349), and 33% (114/343). The rate for patients with genotype 2 and 3 infections was about 80% for all treatment groups. Secondary analyses identified bodyweight as an important predictor of SVR, prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight (mg/kg). Side-effect profiles were similar between the treatment groups. In patients with chronic hepatitis C, the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin. The benefit is mostly achieved in patients with HCV genotype 1 infections.
              Article 0 comments Cited 409 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Armin D Goralczyk
                Silke Cameron
                Ahmad Amanzada
                Journal
                Journal ID (nlm-ta): BMC Gastroenterol
                Journal ID (iso-abbrev): BMC Gastroenterol
                Title: BMC Gastroenterology
                Publisher: BioMed Central
                ISSN (Electronic): 1471-230X
                Publication date Collection: 2013
                Publication date (Electronic): 14 October 2013
                Volume: 13
                Page: 148
                Affiliations
                [1 ]Division of Gastroenterology and Endocrinology, University Medical Center Goettingen, Georg-August-University Goettingen, Goettingen, Germany
                [2 ]Division of Gastroenterology and Endocrinology, University Medical Center, Robert-Koch-Straße 40, Goettingen, 37075, Germany
                Article
                Publisher ID: 1471-230X-13-148
                DOI: 10.1186/1471-230X-13-148
                PMC ID: 3852825
                PubMed ID: 24118976
                SO-VID: 47235056-b7e2-4ec3-9413-37dd44e06509
                Copyright © Copyright © 2013 Goralczyk et al.; licensee BioMed Central Ltd.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 27 June 2013
                Date accepted : 11 October 2013
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Gastroenterology & Hepatology
                Keywords: chronic hcv infection,protease inhibitor,telaprevir,bayesian mixed treatment comparison
                Data availability:
                ScienceOpen disciplines: Gastroenterology & Hepatology
                Keywords: chronic hcv infection, protease inhibitor, telaprevir, bayesian mixed treatment comparison

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