Elbasvir/grazoprevir in Asia-Pacific/Russian participants with chronic hepatitis C virus genotype 1, 4, or 6 infection

Jacob George, Eduard Burnevich, I-Shyan Sheen, Jeong Heo, Nguyen Van Kinh, Tawesak Tanwandee, Pin-Nan Cheng, Do Young Kim, Won Young Tak, Svetlana Kizhlo, Konstantin Zhdanov, Vasily Isakov, Liwen Liang, Pauline Lindore, Joy Ginanni, Bach-Yen Nguyen, Janice Wahl, Eliav Barr, Michael Robertson, Paul Ingravallo, Rohit Talwani, C‐CORAL Study Investigators, Jacob George, Eduard Burnevich, I-Shyan Sheen, Jeong Heo, Nguyen Van Kinh, Tawesak Tanwandee, Pin-Nan Cheng, Do Young Kim, Won Young Tak, Svetlana Kizhlo, Konstantin Zhdanov, Vasily Isakov, Liwen Liang, Pauline Lindore, Joy Ginanni, Bach-Yen Nguyen, Janice Wahl, Eliav Barr, Michael Robertson, Paul Ingravallo, Rohit Talwani, C‐CORAL Study Investigators

Abstract

The prevalence of hepatitis C virus (HCV) infection in Asian countries is high. This study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in participants with HCV infection from Asia-Pacific countries and Russia. In this phase 3, randomized, placebo-controlled, double-blind study, treatment-naive participants with HCV genotype (GT) 1, 4, or 6 infection were randomized to EBR 50 mg/GZR 100 mg (immediate-treatment group [ITG]) or placebo (deferred-treatment group [DTG]) once daily for 12 weeks (Protocol PN-5172-067, NCT02251990). The primary efficacy variable was a nonrandomized comparison of sustained virologic response at 12 weeks after the end of therapy (SVR12) for the ITG with a historical control. The primary safety outcome was a randomized comparison between the ITG and DTG. Three hundred thirty-seven participants were randomized to the ITG (n = 251) or DTG (n = 86); 199 (59.2%) participants were Asian, and 250 (74.4%) had HCV GT1b infection. Overall, 232/250 (92.8%) participants in the ITG achieved SVR12 (97.5% confidence interval, 89.1, 96.5). Of the 18 participants who failed to attain SVR12, 1 was lost to follow-up and 17 had virologic failure, 13 of whom had HCV GT6 infection. The incidence of adverse events was similar between participants receiving EBR/GZR and placebo (50.8% versus 51.2%; difference, -0.3%; 95% confidence interval, -12.3, 11.9). Conclusion: EBR/GZR for 12 weeks provides an effective and well-tolerated regimen for chronic HCV GT1 infection in treatment-naive people from Asia-Pacific countries and Russia, particularly for the large population with GT1b infection. EBR/GZR is not recommended for the treatment of individuals with HCV GT6 infection. (Hepatology Communications 2018;2:595-606).

Figures

Figure 1
Figure 1
Study flow diagram.
Figure 2
Figure 2
Rates of sustained virologic response at week 12 after cessation of study therapy. Data represent mean ± 97.5% CI.
Figure 3
Figure 3
Subgroup analyses. Data represent mean ± 97.5% CI.
Figure 4
Figure 4
NS5A RASs at baseline in participants with GT1, 4, or 6 infection. (A) Prevalence of RASs; (B) effect on rates of SVR12.

References

    1. Sievert W, Altraif I, Razavi HA, Abdo A, Ahmed EA, AlOmair A, et al. A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011;31(Suppl. 2):61‐80.
    1. Gower E, Estes C, Blach S, Razavi‐Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 2014;61(Suppl.):S45‐S57.
    1. Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol 2013;10:553‐562.
    1. AASLD/IDSA . HCV Guidance: recommendations for testing, managing, and treating hepatitis C virus. . Published September 21, 2017. Accessed December 2017.
    1. European Association for the Study of the Liver . EASL recommendations on treatment of hepatitis C 2016. J Hepatol 2017;66:153‐194.
    1. Lim SG, Dan YY. A 2015 roadmap for the management of hepatitis C virus infections in Asia. Korean J Intern Med 2015;30:423‐433.
    1. Omata M, Kanda T, Wei L, Yu M‐L, Chuang W‐L, Ibrahim A, et al. APASL consensus statements and recommendation on treatment of hepatitis C. Hepatol Int 2016;10:702‐726.
    1. Zepatier (elbasvir and grazoprevir) prescribing information. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2017.
    1. European Medicines Agency . EPAR summary for the public. Zepatier: elbasvir/grazoprevir. . Accessed August 2017.
    1. CATIE . Zepatier for hepatitis C approved in Canada. . Accessed August 2017.
    1. Harper S, McCauley JA, Rudd MT, Ferrara M, DiFilippo M, Crescenzi B, et al. Discovery of MK‐5172, a macrocyclic hepatitis C virus NS3/4a protease inhibitor. ACS Med Chem Lett 2012;3:332‐336.
    1. Summa V, Ludmerer SW, McCauley JA, Fandozzi C, Burlein C, Claudio G, et al. MK‐5172, a selective inhibitor of hepatitis C virus NS3/4a protease with broad activity across genotypes and resistant variants. Antimicrob Agents Chemother 2012;56:4161‐4167.
    1. Lahser FC, Bystol K, Curry S, McMonagle P, Xia E, Ingravallo P, et al. The combination of grazoprevir, a hepatitis C virus (HCV) NS3/4A protease inhibitor, and elbasvir, an HCV NS5A inhibitor, demonstrates a high genetic barrier to resistance in HCV genotype 1a replicons. Antimicrob Agents Chemother 2016;60:2954‐2964.
    1. Liu R, Curry S, McMonagle P, Yeh WW, Ludmerer SW, Jumes PA, et al. Susceptibilities of genotype 1a, 1b, and 3 hepatitis C virus variants to the NS5A inhibitor elbasvir. Antimicrob Agents Chemother 2015;59:6922‐6929.
    1. Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK‐5172) and elbasvir (MK‐8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C‐WORTHY): a randomised, open‐label phase 2 trial. Lancet 2015;385:1075‐1086.
    1. Sulkowski M, Hezode C, Gerstoft J, Vierling J, Mallolas J, Pol S, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK‐5172) and elbasvir (MK‐8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono‐infection and HIV/hepatitis C virus co‐infection (C‐WORTHY): a randomised, open‐label phase 2 trial. Lancet 2015;385:1087‐1097.
    1. Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ben Ari Z, Zhao Y, et al. Grazoprevir‐elbasvir combination therapy for treatment‐naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 2015;163:1‐13.
    1. Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour HM Jr, et al. Grazoprevir plus elbasvir in treatment‐naive and treatment‐experienced patients with hepatitis C virus genotype 1 infection and stage 4‐5 chronic kidney disease (the C‐SURFER study): a combination phase 3 study. Lancet 2015;386:1537‐1545. Erratum in: Lancet 2015;386:1824.
    1. Rockstroh JK, Nelson M, Katlama C, Lalezari J, Mallolas J, Bloch M, et al. Efficacy and safety of grazoprevir (MK‐5172) and elbasvir (MK‐8742) in patients with hepatitis C virus and HIV co‐infection (C‐EDGE CO‐INFECTION): a non‐randomised, open‐label trial. Lancet HIV 2015;2:e319‐e327.
    1. Kwo P, Gane E, Peng C‐Y, Pearlman B, Vierling JM, Serfaty L, et al. Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment‐experienced patients with chronic hepatitis C infection. Gastroenterology 2017;152:164‐175.e4.
    1. Sperl J, Horvath G, Halota W, Ruiz‐Tapiador JA, Streinu‐Cercel A, Jancoriene L, et al. Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: a phase III randomized controlled trial. J Hepatol 2016;65:1112‐1119.
    1. Forns X, Gordon SC, Zuckerman E, Lawitz E, Calleja JL, Hofer H, et al. Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype‐1 infection after failure of combination therapy containing a direct‐acting antiviral agent. J Hepatol 2015;63:564‐572.
    1. Dore GJ, Altice F, Litwin AH, Dalgard O, Gane EJ, Shibolet O, et al; C‐EDGE CO‐STAR Study Group . Elbasvir‐grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial. Ann Intern Med 2016;165:625‐634.
    1. Kumada H, Suzuki Y, Karino Y, Chayama K, Kawada N, Okanoue T, et al. The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study. J Gastroenterol 2017;52:520‐533.
    1. Jin Y‐J, Lee J‐W, Lee JI, Park SH, Park CK, Kim YS, et al. Multicenter comparison of PEG‐IFN α2a or α2b plus ribavirin for treatment‐naive HCV patient in Korean population. BMC Gastroenterol 2013;13:74.
    1. Liu C‐H, Liu C‐J, Lin C‐L, Liang C‐C, Hsu S‐J, Yang S‐S, et al. Pegylated interferon‐α‐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.
    1. Dusheiko GM, Manns MP, Vierling JM, Reddy KR, Sulkowski MS, Kwo PY, et al. Safety and tolerability of grazoprevir/elbasvir in patients with chronic hepatitis C (HCV) infection: integrated analysis of phase 2‐3 trials [Abstract 712]. Hepatology 2015;62(Suppl. 1):562A.

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