PDF herunterladen
Z Gastroenterol 2012; 50(1): 57-72
DOI: 10.1055/s-0031-1282015
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Expertenempfehlungen zur Triple-Therapie der HCV-Infektion mit Boceprevir und Telaprevir

Expert Opinion on Boceprevir- and Telaprevir-Based Triple Therapies of Chronic Hepatitis C
C. Sarrazin
1   Klinikum der Goethe-Universität, Medizinische Klinik 1, Frankfurt am Main
,
T. Berg
2   Universitätsklinikum Leipzig, Klinik für Gastroenterologie und Rheumatologie, Sektion Hepatologie, Leipzig
,
M. Cornberg
3   Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
,
M. Dollinger
4   Klinik und Poliklinik für Innere Medizin I, Martin-Luther-Universität, Halle
,
P. Ferenci
5   Univ. Klinik für Innere Medizin 3, Klin. Abteilung für Gastroenterologie und Hepatologie, Medizinische Universität Wien
,
H. Hinrichsen
6   Gastroenterologisch-Hepatologisches Zentrum, Kiel
,
H. Klinker
7   Medizinische Klinik und Poliklinik II, Schwerpunkt Infektiologie, Universitätsklinikum Würzburg
,
M. Kraus
8   Medizinische Klinik II, Kreiskliniken Altötting-Burghausen
,
M. Manns
3   Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
,
S. Mauss
9   Zentrum für HIV und Hepatogastroenterologie, Düsseldorf
,
M. Peck-Radosavljevic
5   Univ. Klinik für Innere Medizin 3, Klin. Abteilung für Gastroenterologie und Hepatologie, Medizinische Universität Wien
,
H. Schmidt
10   Klinik und Poliklinik für Transplantationsmedizin, Universitätsklinikum Münster
,
U. Spengler
11   Medizinische Klinik und Poliklinik I, Universitätsklinikum Bonn
,
H. Wedemeyer
3   Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover
,
S. Wirth
12   HELIOS Klinikum Wuppertal, Zentrum für Kinder- und Jugendmedizin, Universität Witten/Herdecke
,
S. Zeuzem
1   Klinikum der Goethe-Universität, Medizinische Klinik 1, Frankfurt am Main
› Institutsangaben
Weitere Informationen

Publikationsverlauf

07. September 2011

23. November 2011

Publikationsdatum:
05. Januar 2012 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Zusammenfassung

Mit der aktuell erfolgten Zulassung der beiden Proteaseinhibitoren Boceprevir und Telaprevir zur Behandlung der chronischen Hepatitis C-Virus-Infektion (HCV-Infektion) im Rahmen einer Triple-Therapie in Kombination mit pegyliertem Interferon alpha und Ribavirin ändert sich die Standardtherapie für Patienten mit einer HCV-Genotyp-1-Infektion. Mit der Triple-Therapie kommt es zu einer signifikanten Steigerung der Raten des dauerhaften virologischen Ansprechens von 38 − 44 % auf 63 − 75 % bei der Erstbehandlung bzw. von durchschnittlich 17 − 21 % auf 59 − 66 % bei vortherapierten Patienten im Vergleich zur dualen Kombinationstherapie mit pegyliertem Interferon alpha und Ribavirin allein. Ein wesentlicher Vorteil der Triple-Therapie besteht zudem in der Möglichkeit einer Therapieverkürzung auf 24 − 28 Wochen bei einem Großteil der Patienten mit einer Ersttherapie als auch bei Patienten mit Rückfall auf eine Vortherapie. Allerdings unterscheiden sich die Therapieregime hinsichtlich des Einsatzes einer pegylierten Interferon alpha/Ribavirin-Einleitungsphase („Lead-in“), der Dauer der Gabe des Proteaseinhibitors, der Gesamttherapiedauer, der HCV-RNA-Untersuchungen für eine Therapieverkürzung als auch der Stoppregeln zwischen der Gabe von Boceprevir und Telaprevir erheblich. Weiterhin sind die Entwicklung von viralen Resistenzen, das Management neuer Nebenwirkungen sowie mögliche schwere, klinisch relevante Medikamenteninteraktionen beim Einsatz der beiden Proteaseinhibitoren zu beachten. Das vorliegende Expertenpositionspapier soll einen Überblick über die vorliegenden Daten der klinischen Studien zum Boceprevir und Telaprevir und eine Anleitung zum praktischen Management der Triple-Therapie geben.

Abstract

With the approval of boceprevir and telaprevir the standard treatment of chronic hepatitis C virus (HCV) genotype 1 infection will be the triple therapy of a HCV protease inhibitor together with pegylated interferon alfa and ribavirin. In clinical studies a significant increase of sustained virological response rates from 38 − 44 % to 63 − 75 % for treatment-naïve and from 17 − 21 % to 59 − 66 % in treatment-experienced patients in comparison to the dual combination therapy with pegylated interferon alfa and ribavirin alone has been demonstrated. In addition, a large number of treatment-naïve patients and relapsers benefit from shorten treatment durations to 24 − 28 weeks. However, important differences exist between the administration of boceprevir and telaprevir in terms of a pegylated interferon alfa/ribavirin lead-in phase, the duration of dosing of the protease inhibitor, the overall treatment duration, HCV RNA measurements for response guided treatment durations and stopping rules. Furthermore, triple therapies with boceprevir and telaprevir may be associated with selection of resistant viral variants, new adverse events and clinically relevant drug-drug interactions. The present review gives an overview on the results of underlying clinical studies together with a guideline for the practical management of boceprevir- and telaprevir-based triple therapies.

Schlüsselworter

Virushepatitis - Hepatitis C - Triple-Therapie

Key words

viral hepatitis - hepatitis C - triple therapy
 

  • Literatur

  • 1 Wiegand J, Buggisch P, Boecher W et al. Early monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET acute-HCV-II study. Hepatology 2006; 43: 250-256
    CrossrefPubMedGoogle Scholar
  • 2 Sarrazin C, Berg T, Ross RS et al. Prophylaxis, Diagnosis and Therapy of Hepatitis C Virus (HCV) Infection: The German Guidelines on the Management of HCV Infection. Z Gastroenterol 2010; 48: 289-351
    Google Scholar
  • 3 Bacon BR, Gordon SC, Lawitz E et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1207-1217
    CrossrefPubMedGoogle Scholar
  • 4 Zeuzem S, Andreone P, Pol S et al. Telaprevir for retreatment of HCV infection. New England Journal of Medicine 2011; 364: 2417-2428
    CrossrefPubMedGoogle Scholar
  • 5 Foster GR, Hezode C, Bronowicki JP et al. Telaprevir Alone or With Peginterferon and Ribavirin Reduces HCV RNA in Patients With Chronic Genotype 2 But Not Genotype 3 Infections. Gastroenterology 2011; 141: 881-889
    CrossrefPubMedGoogle Scholar
  • 6 Benhamou Y, Moussalli J, Ratziu V et al. Results of a prove of concept study (C210) of telaprevir monotherapy and in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype 4 HCV patients. J Hepatol 2009; 50 (Suppl. 01) S6
    PubMedGoogle Scholar
  • 7 Jacobson IM, McHutchison JG, Dusheiko G et al. Telaprevir for previously untreated chronic hepatitis C virus infection. New England Journal of Medicine 2011; 364: 2405-2416
    CrossrefPubMedGoogle Scholar
  • 8 Poordad F, McCone Jr J, Bacon BR et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: 1195-1206
    CrossrefPubMedGoogle Scholar
  • 9 Sarrazin C, Zeuzem S. Resistance to Direct Antiviral Agents in Patients With Hepatitis C Virus Infection. Gastroenterology 2010; 138: 447-462
    CrossrefPubMedGoogle Scholar
  • 10 Craxi A. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol 2011; 55: 245-264
    CrossrefPubMedGoogle Scholar
  • 11 Sarrazin C, Schwendy S, Möller B et al. Improved responses to pegylated interferon alfa-2b and ribavirin by individualizing treatment for 24-72 weeks. Gastroenterology 2011; epub
    PubMedGoogle Scholar
  • 12 Di Martino V, Richou C, Cervoni JP et al. Response-guided peg-interferon plus ribavirin treatment duration in chronic hepatitis C: Meta-analyses of randomized, controlled trials and implications for the future. Hepatology 2011; Jun 14. doi: 10.1002/hep. 24480. [epub ahead of print]
    PubMedGoogle Scholar
  • 13 Farnik H, Lange CM, Sarrazin C et al. Meta-analysis shows extended therapy improves response of patients with chronic hepatitis C virus genotype 1 infection. Clin Gastroenterol Hepatol 2010; 8: 884-890
    CrossrefPubMedGoogle Scholar
  • 14 Stattermayer AF, Stauber R, Hofer H et al. Impact of IL28B genotype on the early and sustained virologic response in treatment-naive patients with chronic hepatitis C. Clin Gastroenterol Hepatol 2011; 9: 344-350
    CrossrefPubMedGoogle Scholar
  • 15 Sarrazin C, Shiffman ML, Hadziyannis SJ et al. Definition of rapid virologic response with a highly sensitive real-time PCR-based HCV RNA assay in peginterferon alfa-2a plus ribavirin response-guided therapy. J Hepatol 2010; 52: 832-838
    CrossrefPubMedGoogle Scholar
  • 16 Kau A, Vermehren J, Sarrazin C. Treatment predictors of a sustained virologic response in hepatitis B and C. J Hepatol 2008; 49: 634-651
    CrossrefPubMedGoogle Scholar
  • 17 Ge D, Fellay J, Thompson AJ et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461: 399-401
    CrossrefPubMedGoogle Scholar
  • 18 Suppiah V, Moldovan M, Ahlenstiel G et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009; 41: 1100-1104
    CrossrefPubMedGoogle Scholar
  • 19 Tanaka Y, Nishida N, Sugiyama M et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41: 1105-1109
    CrossrefPubMedGoogle Scholar
  • 20 McHutchison JG, Everson GT, Gordon SC et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827-1838
    CrossrefPubMedGoogle Scholar
  • 21 Kwo PY, Lawitz EJ, McCone J et al. Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. Lancet 2010; 376: 705-716
    CrossrefPubMedGoogle Scholar
  • 22 Sarrazin C, Rouzier R, Wagner F et al. SCH 503034, a novel hepatitis C virus protease inhibitor, plus pegylated interferon alpha-2b for genotype 1 nonresponders. Gastroenterology 2007; 132: 1270-1278
    CrossrefPubMedGoogle Scholar
  • 23 Susser S, Welsch C, Wang Y et al. Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 2009; 50: 1709-1718
    CrossrefPubMedGoogle Scholar
  • 24 Reesink HW, Zeuzem S, Weegink CJ et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 2006; 131: 997-1002
    CrossrefPubMedGoogle Scholar
  • 25 Forestier N, Reesink HW, Weegink CJ et al. Antiviral activity of telaprevir (VX-950) and peginterferon alfa-2a in patients with hepatitis C. Hepatology 2007; 46: 640-648
    CrossrefPubMedGoogle Scholar
  • 26 Sarrazin C, Kieffer TL, Bartels D et al. Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 2007; 132: 1767-1777
    CrossrefPubMedGoogle Scholar
  • 27 Kieffer TL, Sarrazin C, Miller JS et al. Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients. Hepatology 2007; 46: 631-639
    CrossrefPubMedGoogle Scholar
  • 28 McHutchison JG, Manns MP, Muir AJ et al. Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010; 362: 1292-1303
    CrossrefPubMedGoogle Scholar
  • 29 Hezode C, Forestier N, Dusheiko G et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839-1850
    CrossrefPubMedGoogle Scholar
  • 30 Sherman KE, Flamm SL, Afdhal N et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365: 1014-1024
    CrossrefPubMedGoogle Scholar
  • 31 Berg T, McHutchison J, Adda N et al. SVR with telaprevir, peg-interferon alfa-2a and ribavirin in HCV patients with well-characterized prior null response, partial response, viral breakthrough or relapse after peg-interferon and ribavirin. Journal of Hepatology 2010; 52 (Suppl. 01) S2
    PubMedGoogle Scholar
  • 32 Vermehren J, Kau A, Gartner BC et al. Differences between two real-time PCR based assays (RealTime HCV, Cobas AmpliPrep/Cobas TaqMan) and one signal amplification assay (Versant HCV RNA 3.0) for HCV RNA detection and quantification. J Clin Microbiol 2008; 46: 3880-3891
    CrossrefPubMedGoogle Scholar
  • 33 Kuntzen T, Timm J, Berical A et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology 2008; 48: 1769-1778
    CrossrefPubMedGoogle Scholar
  • 34 Vierling JM, Ralston R, Lawitz EJ et al. Long-Term Outcomes Following Combination Treatment with Boceprevir Plus Peg-Intron/Ribavirin (P/R) in Patients with Chronic Hepatitis C, Genotype 1 (Chc-G1). Journal of Hepatology 2010; 52: 470-S471
    PubMedGoogle Scholar
  • 35 Sullivan JC, De Meyer S, Bartels DJ et al. Evolution of treatment-emergent resistant variants in telaprevir phase 3 clinical trials. Journal of Hepatology 2011; 54 (Suppl. 01) S4
    PubMedGoogle Scholar
  • 36 Sulkowski M, Poordad F, Manns M et al. Anemia during tratment with peginterferon alfa-2b/ribavirin with or without boceprevir is associated with higher SVR rates: analysis of previously untreated and previous-treatment-failure patients. J Hepatol 2011; 54 (Suppl. 01) 194-S195
    PubMedGoogle Scholar
  • 37 Sulkowski M, Reddy KR, Afdhal N et al. Anemia had no effect on efficacy outcomes in treatment-naive patients who received telaprevir-based regimen in the Advance and Illuminate phase 3 studies. J Hepatol 2011; 54 (Suppl. 01) S195
    PubMedGoogle Scholar
  • 38 Charlton M. Telaprevir, boceprevir, cytochrome P450 and immunosuppressive agents – A potentially lethal cocktail. Hepatology 2011; 54: 3-5
    CrossrefPubMedGoogle Scholar
  • 39 Ghosal A, Yuan Y, Tong W et al. Characterization of human liver enzymes involved in the biotransformation of boceprevir, a hepatitis C virus protease inhibitor. Drug Metab Dispos 2011; 39: 510-521
    CrossrefPubMedGoogle Scholar
  • 40 Kasserra C, Hughes E, Treitel M et al. Clinical pharmacology of boceprevir: metabolism, excretion, and drug-drug interactions. 18th CROI 2011; abstract 118
    PubMedGoogle Scholar
  • 41 van Heeswijk R, Vandevoorde A, Boogaerts G et al. Pharmacokinetic interactions between antiretroviral agents and the investigational HCV protease inhibitor telaprevir in healthy volunteers. 18th CROI 2011; abstract 119
    PubMedGoogle Scholar
  • 42 Garg V, van Heeswijk R, Eun LJ et al. Effect of telaprevir on the pharmacokinetics of cyclosporine and tacrolimus. Hepatology 2011; 54: 20-27
    CrossrefPubMedGoogle Scholar
  • 43 Sulkowski M, Dieterich D, Sherman K et al. Interim analysis of a phase 2a double-blind study of telaprevir in combination with pegIFN-a2a and ribavirin in HIV/HCV co-infected patients. 18th CROI 2011; abstract 146LB
    PubMedGoogle Scholar
  • 44 Vogel M, Dominguez S, Bhagani S et al. Treatment of acute HCV infection in HIV-positive patients: experience from a multicentre European cohort. Antivir Ther 2010; 15: 267-279
    CrossrefPubMedGoogle Scholar
  • 45 Fried MW, Hadziyannis SJ, Shiffman ML et al. Rapid virological response is the most important predictor of sustained virological response across genotypes in patients with chronic hepatitis C virus infection. J Hepatol 2011; 55: 69-75
    CrossrefPubMedGoogle Scholar
  • 46 McHutchison JG, Lawitz EJ, Shiffman ML et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 2009; 361: 580-593
    CrossrefPubMedGoogle Scholar
  • 47 Ferenci P, Laferl H, Scherzer TM et al. Peginterferon alfa-2a and ribavirin for 24 weeks in hepatitis C type 1 and 4 patients with rapid virological response. Gastroenterology 2008; 135: 451-458
    CrossrefPubMedGoogle Scholar
  • 48 Mangia A, Minerva N, Bacca D et al. Individualized treatment duration for hepatitis C genotype 1 patients: A randomized controlled trial. Hepatology 2008; 47: 43-50
    CrossrefPubMedGoogle Scholar
  • 49 Berg T, von Wagner M, Nasser S et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology 2006; 130: 1086-1097
    CrossrefPubMedGoogle Scholar
  • 50 Sanchez-Tapias JM, Diago M, Escartin P et al. Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment. Gastroenterology 2006; 131: 451-460
    CrossrefPubMedGoogle Scholar
  • 51 Bronowicki JP, Ouzan D, Asselah T et al. Effect of ribavirin in genotype 1 patients with hepatitis C responding to pegylated interferon alfa-2a plus ribavirin. Gastroenterology 2006; 131: 1040-1048
    CrossrefPubMedGoogle Scholar
  • 52 Zeuzem S, Buti M, Ferenci P et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol 2006; 44: 97-103
    CrossrefPubMedGoogle Scholar
  • 53 Buti M, Lurie Y, Zakharova NG et al. Randomized trial of peginterferon alfa-2b and ribavirin for 48 or 72 weeks in patients with hepatitis C virus genotype 1 and slow virologic response. Hepatology 2010; 52: 1201-1207
    CrossrefPubMedGoogle Scholar
  • 54 Yu ML, Dai CY, Huang JF et al. Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology 2008; 47: 1884-1893
    CrossrefPubMedGoogle Scholar
  • 55 Liu CH, Liu CJ, Lin CL et al. Pegylated interferon-alpha-2a plus ribavirin for treatment-naive Asian patients with hepatitis C virus genotype 1 infection: a multicenter, randomized controlled trial. Clin Infect Dis 2008; 47: 1260-1269
    CrossrefPubMedGoogle Scholar