Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection

Hiromitsu Kumada, Yoshiyuki Suzuki, Kenji Ikeda, Joji Toyota, Yoshiyasu Karino, Kazuaki Chayama, Yoshiiku Kawakami, Akio Ido, Kazuhide Yamamoto, Koichi Takaguchi, Namiki Izumi, Kazuhiko Koike, Tetsuo Takehara, Norifumi Kawada, Michio Sata, Hidetaka Miyagoshi, Timothy Eley, Fiona McPhee, Andrew Damokosh, Hiroki Ishikawa, Eric Hughes, Hiromitsu Kumada, Yoshiyuki Suzuki, Kenji Ikeda, Joji Toyota, Yoshiyasu Karino, Kazuaki Chayama, Yoshiiku Kawakami, Akio Ido, Kazuhide Yamamoto, Koichi Takaguchi, Namiki Izumi, Kazuhiko Koike, Tetsuo Takehara, Norifumi Kawada, Michio Sata, Hidetaka Miyagoshi, Timothy Eley, Fiona McPhee, Andrew Damokosh, Hiroki Ishikawa, Eric Hughes

Abstract

All-oral combinations of direct-acting antivirals may improve efficacy and safety outcomes for patients with hepatitis C virus (HCV) infection, particularly those who are poor candidates for current interferon/ribavirin-based regimens. In this open-label, phase 3 study, 135 interferon-ineligible/intolerant and 87 nonresponder patients with chronic HCV genotype 1b infection were enrolled at 24 centers in Japan. Patients received daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily for 24 weeks. The primary endpoint was sustained virologic response 24 weeks after treatment (SVR24 ). This study is registered with ClinicalTrials.gov (NCT01497834). SVR24 was achieved by 87.4% of interferon-ineligible/intolerant patients and 80.5% of nonresponder (null and partial) patients; rates were similar in cirrhosis (90.9%) and noncirrhosis (84.0%) patients, and in patients with IL28B CC (84.5%) or non-CC (84.8%) genotypes. Fourteen patients in each group (12.6%) discontinued dual therapy, mainly due to adverse events or lack of efficacy. Nine nonresponder patients received additional treatment with peginterferon/ribavirin per protocol-defined criteria. The rate of serious adverse events was low (5.9%) and varied among patients. The most common adverse events were nasopharyngitis, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST), headache, diarrhea, and pyrexia.

Conclusion: Interferon-free, ribavirin-free all-oral therapy with daclatasvir and asunaprevir for 24 weeks is well tolerated and can achieve a high rate of SVR in patients with HCV genotype 1b who were ineligible, intolerant, or had not responded to prior interferon-based therapy. (Hepatology 2014;59:2083-2091).

Copyright © 2014 The Authors. HEPATOLOGY published by Wiley on behalf of the American Association for the Study of Liver Diseases.

Figures

Fig 1
Fig 1
Patient disposition.
Fig 2
Fig 2
Mean change in HCV RNA during treatment with daclatasvir and asunaprevir in interferon-ineligible/intolerant and nonresponder patients.

References

    1. Poordad F, McCone J, Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195–1206.
    1. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–2416.
    1. Drafting Committee for Hepatitis Management Guidelines; the Japan Society of Hepatology. JSH guidelines for the management of hepatitis C virus infection: A 2014 update for genotype 1. Hepatol Res. 2014;44(Suppl S1):59–70.
    1. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417–2428.
    1. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207–1217.
    1. Huang CF, Yang JF, Dai CY, Huang JF, Hou NJ, Hsieh MY. Efficacy and safety of pegylated interferon combined with ribavirin for the treatment of older patients with chronic hepatitis C. J Infect Dis. 2010;201:751–759.
    1. Hayashi N, Okanoue T, Tsubouchi H, Toyota J, Chayama K, Kumada H. Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat. 2012;19:e134–142.
    1. Gao M. Antiviral activity and resistance of HCV NS5A replication complex inhibitors. Curr Opin Virol. 2013;3:514–520.
    1. McPhee F, Sheaffer AK, Friborg J, Hernandez D, Falk P, Zhai G. Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032) Antimicrob Agents Chemother. 2012;56:5387–5396.
    1. Bifano M, Sevinsky H, Bedford BR, Coumbis J, Eley T, Huang SP. Coadministration of BMS-790052 and BMS-650032 does not result in a clinically meaningful pharmacokinetic interaction in healthy subjects [abstract] Hepatology. 2010;52(Suppl):719A.
    1. McPhee F, Sheaffer AK, Friborg J, Hernandez D, Falk P, Zhai G. Preclinical profile and characterization of the hepatitis C virus NS3 protease inhibitor asunaprevir (BMS-650032) Antimicrob Agents Chemother. 2012;56:5387–5396.
    1. Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med. 2012;366:216–224.
    1. Chayama K, Takahashi S, Toyota J, Karino Y, Ikeda K, Ishikawa H. Dual therapy with the nonstructural protein 5A inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology. 2012;55:742–748.
    1. Ikeda K, Saitoh S, Kobayashi M, Suzuki Y, Tsubota A, Suzuki F. Distinction between chronic hepatitis and liver cirrhosis in patients with hepatitis C virus infection. practical discriminant function using common laboratory data. Hepatol Res. 2000;18:252–266.
    1. Suzuki Y, Ikeda K, Suzuki F, Toyota J, Karino Y, Chayama K. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol. 2013;58:655–662.
    1. Zeuzem S, Soriano V, Asselah T, Bronowicki JP, Lohse AW, Mullhaupt B. Faldaprevir and deleobuvir for HCV genotype 1 infection. N Engl J Med. 2013;369:630–639.
    1. Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014;383:515–523.
    1. Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S. Phase 2b trial of interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 2014;370:222–232.
    1. Gilead Sciences. 2013. Gilead announces SVR12 rates from three phase 3 studies evaluating a once-daily fixed-dose combination of sofosbuvir and ledipasvir for genotype 1 hepatitis C patients. December 18, .
    1. Abbvie, Inc. 2014. AbbVie completes largest phase III program of an all-oral, interferon-free therapy for the treatment of hepatitis C genotype 1. January 31, .
    1. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med. 2014;370:211–221.

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