Tamori A, Hai H, Uchida-Kobayashi S, Enomoto M, Kozuka R, Motoyama H, Kawamura E, Hagihara A, Teranishi Y, Yoshida K, Morikawa H, Murakami Y, Kawada N

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ABSTRACT

Background. The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). Material and methods. A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy. The patients were treated with 100 mg asunaprevir twice daily plus 60 mg daclatasvir once daily for 24 weeks. The primary endpoint was SVR 24 weeks after completing treatment. In addition, we evaluated the improvement of liver function and development of HCC for 1 year from the end of treatment (EOT). Results. The SVR24 rate was 96% (47/49) in the cirrhotic group and 96% (91/95) in the non-cirrhotic group (p = 0.69). During treatment, grade III/IV adverse events occurred more frequently in cirrhotic patients (10/49; 20.4%) than in non-cirrhotic patients (10/96; 10.4%) (p = 0.099). After EOT, alanine aminotransferase and AFP levels were significantly decreased in cirrhotic patients with SVR. In addition, serum levels of albumin and platelet counts were significantly increased. On the other hand, the rates of HCC recurrence (43%) and development (7.4%) were higher in cirrhotic patients than in the non-cirrhotic patients (12.5% and 1.1%, respectively). Conclusion. RAS-oriented asunaprevir/daclatasvir therapy has a strong anti-HCV effect in patients with HCV genotype 1b. However, careful management is necessary in patients with cirrhosis.

REFERENCES

1. Pearlman BL. Protease inhibitors for the treatment of chronic hepatitis C genotype-1 infection: the new standard of care. Lancet Infect Dis 2012; 12: 717-28.

2. Imai Y, Tamura S, Tanaka H, Hiramatsu N, Kiso S, Doi Y, Inada M, et al. Reduced risk of hepatocellular carcinoma after interferon therapy in aged patients with chronic hepatitis C is limited to sustained virological responders. J Viral Hepat 2010; 17: 185-91.

3. Asahina Y, Tsuchiya K, Tamaki N, Hirayama I, Tanaka T, Sato M, Yasui Y, et al. Effect of aging on risk for hepatocellular carcinoma in chronic hepatitis C virus infection. Hepatology 2010; 52: 518-27.

4. Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839-50.

5. Hayashi N, Izumi N, Kumada H, Okanoue T, Tsubouchi H, Yatsuhashi H, Kato M, et al. Simeprevir with peginterferon/ ribavirin for treatment-naïve hepatitis C genotype 1 patients in Japan: CONCERTO-1, a phase III trial. J Hepatol 2014; 61: 219-27.

6. Tamori A, Yoshida K, Kurai O, Kioka K, Hai H, Kozuka R, Motoyama R, et al. Randomized trial of combined triple therapy comprising two types of peginterferon with simeprevir in patients with HCV genotype 1b. Hepatol Res 2016; 46: 1311- 20.

7. Hayashi N, Nakamuta M, Takehara T, Kumada H, Takase A, Howe AY, Ludmerer SW, et al. Vaniprevir plus peginterferon alfa-2b and ribavirin in treatment-naive Japanese patients with hepatitis C virus genotype 1 infection: a randomized phase III study. J Gastroenterol 2016; 51: 390-403.

8. Kumada H, Suzuki Y, Ikeda K, Toyota J, Karino Y, Chayama K, Kawakami Y, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014; 59: 2083-91.

9. JSH Guidelines for the Management of Hepatitis C Virus Infection: 5.1th edition 2016. In Japanese http://www.jsh.or.jp/ files/uploads/HCV_GL_ver5.1_Oct08_final.pdf

10. Kao JH, Jensen DM, Manns MP, Jacobson I, Kumada H, Toyota J, Heo J, et al. Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis. Liver Int 2016; 36: 954-62.

11. Shepherd SJ, Abdelrahman T, MacLean AR, Thomson EC, Aitken C, Gunson RN. Prevalence of HCV NS3 pre-treatment resistance associated amino acid variants within a Scottish cohort. J Clin Virol 2015; 65: 50-3.

12. AASLD and IDSA. Recommendations for Testing, Managing, and Treating Hepatitis C 2014. Available at http:// www.hcvguidelines.org

13. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa 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: 1105-9.

14. Hai H, Tamori A, Enomoto M, Morikawa H, Uchida-Kobayashi S, Fujii H, Hagihara A, et al. Relationship between inosine triphosphate genotype and outcome of extended therapy in hepatitis C virus patients with a late viral response to pegylated-interferon and ribavirin. J Gastroenterol Hepatol 2014; 29: 201-7.

15. Iio E, Shimada N, Abe H, Atsukawa M, Yoshizawa K, Takaguchi K, Eguchi Y, et al. Efficacy of daclatasvir/asunaprevir according to resistance-associated variants in chronic hepatitis C with genotype 1. J Gastroenterol 2017; 52: 94- 103.

16. Ogawa E, Furusyo N, Yamashita N, Kawano A, Takahashi K, Dohmen K, Nakamuta M, et al. Effectiveness and safety of daclatasvir plus asunaprevir for HCV genotype 1b patients aged 75 and over with or without cirrhosis. Hepatol Res 2016 [in print].

17. Morio K, Imamura M, Kawakami Y, Morio R, Kobayashi T, Yokoyama S, Nagaoki Y, et al. Real-World Efficacy and Safety of Daclatasvir and Asunaprevir Therapy for Hepatitis C Virus-Infected Cirrhosis Patients. J Gastroenterol Hepatol 2016 [in print].

18. Miyaki E, Imamura M, Hiraga N, Murakami E, Kawaoka T, Tsuge M, Hiramatsu A, et al. Daclatasvir and asunaprevir treatment improves liver function parameters and reduces liver fibrosis markers in chronic hepatitis C patients. Hepatol Res 2016; 46: 758-64.

19. Mandorfer M, Kozbial K, Schwabl P, Freissmuth C, Schwarzer R, Stern R, Chromy D, et al. Sustained virologic response to interferon-free therapies ameliorates HCV-induced portal hypertension. J Hepatol 2016; 65: 692-9.

20. Conti F, Buonfiglioli F, Scuteri A, Crespi C, Bolondi L, Caraceni P, Foschi FG, et al. Early occurrence and recurrence of hepatocellular carcinoma in HCV-related cirrhosis treated with direct-acting antivirals. J Hepatol 2016; 65: 727-33.

21. Reig M, Mariño Z, Perelló C, Iñarrairaegui M, Ribeiro A, Lens S, Díaz A, et al. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon- free therapy. J Hepatol 2016; 65: 719-26.

22. Oze T, Hiramatsu N, Yakushijin T, Miyazaki M, Yamada A, Oshita M, Hagiwara H, et al. Post-treatment levels of α-fetoprotein predict incidence of hepatocellular carcinoma after interferon therapy. Clin Gastroenterol Hepatol 2014; 12: 1186-95.

23. Minami T, Tateishi R, Nakagomi R, Fujiwara N, Sato M, Enooku K, Nakagawa H, et al. The impact of direct-acting antivirals on early tumor recurrence after radiofrequency ablation in hepatitis C-related hepatocellular carcinoma. J Hepatol 2016; 65: 1272-3.

24. Mizokami M, Yokosuka O, Takehara T, Sakamoto N, Korenaga M, Mochizuki H, Nakane K, et al. Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. Lancet Infect Dis 2015; 15: 645-53.

25. Kumada H, Chayama K, Rodrigues L Jr., Suzuki F, Ikeda K, Toyoda H, Sato K, et al. Randomized phase 3 trial of ombitasvir/ paritaprevir/ritonavir for hepatitis C virus genotype 1b-infected Japanese patients with or without cirrhosis. Hepatology 2015; 62: 1037-46.