Volume 50, Issue 3 pp. 303-312

Original Article

Favorable outcome of retreatment by direct-acting antivirals for hepatitis C patients with daclatasvir plus asunaprevir combination therapy failure

Hiroki Tojima,

Hiroki Tojima

orcid.org/0000-0002-1646-2344

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan

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Satoru Kakizaki,

Corresponding Author

Satoru Kakizaki

[email protected]

orcid.org/0000-0002-1508-584X

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan

Correspondence: Dr Satoru Kakizaki, Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan. Email: [email protected]Search for more papers by this author

Satoshi Takakusagi,

Satoshi Takakusagi

Department of Gastroenterology, Kusunoki Hospital, Fujioka, Japan

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Takashi Hoshino,

Takashi Hoshino

Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan

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Atsushi Naganuma,

Atsushi Naganuma

Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan

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Tamon Nagashima,

Tamon Nagashima

Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan

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Masashi Namikawa,

Masashi Namikawa

Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan

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Takashi Ueno,

Takashi Ueno

Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan

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Yasushi Shimada,

Yasushi Shimada

Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan

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Takeshi Hatanaka,

Takeshi Hatanaka

orcid.org/0000-0003-3656-285X

Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan

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Daichi Takizawa,

Daichi Takizawa

Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan

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Hirotaka Arai,

Hirotaka Arai

Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan

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Ken Sato,

Ken Sato

orcid.org/0000-0002-3202-7983

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan

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Hitoshi Takagi,

Hitoshi Takagi

Department of Gastroenterology, Kusunoki Hospital, Fujioka, Japan

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Toshio Uraoka,

Toshio Uraoka

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan

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Hiroki Tojima,

Hiroki Tojima

orcid.org/0000-0002-1646-2344

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan

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Satoru Kakizaki,

Corresponding Author

Satoru Kakizaki

[email protected]

orcid.org/0000-0002-1508-584X

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan

Satoshi Takakusagi,

Satoshi Takakusagi

Department of Gastroenterology, Kusunoki Hospital, Fujioka, Japan

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Takashi Hoshino,

Takashi Hoshino

Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan

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Atsushi Naganuma,

Atsushi Naganuma

Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan

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Tamon Nagashima,

Tamon Nagashima

Department of Gastroenterology, National Hospital Organization Shibukawa Medical Center, Shibukawa, Japan

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Masashi Namikawa,

Masashi Namikawa

Department of Internal Medicine, Kiryu Kosei General Hospital, Kiryu, Japan

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Takashi Ueno,

Takashi Ueno

Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan

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Yasushi Shimada,

Yasushi Shimada

Department of Internal Medicine, Isesaki Municipal Hospital, Isesaki, Japan

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Takeshi Hatanaka,

Takeshi Hatanaka

orcid.org/0000-0003-3656-285X

Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Maebashi, Japan

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Daichi Takizawa,

Daichi Takizawa

Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan

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Hirotaka Arai,

Hirotaka Arai

Department of Gastroenterology, Maebashi Red Cross Hospital, Maebashi, Japan

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Ken Sato,

Ken Sato

orcid.org/0000-0002-3202-7983

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan

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Hitoshi Takagi,

Hitoshi Takagi

Department of Gastroenterology, Kusunoki Hospital, Fujioka, Japan

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Toshio Uraoka,

Toshio Uraoka

Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, Maebashi, Japan

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First published: 21 November 2019

https://doi.org/10.1111/hepr.13462

Citations: 5

Conflict of interest: S Kakizaki received research funding from BMS and Gilead Sciences. K Sato received research funding from AbbVie.

Financial support: None declared.

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Abstract

Aim

In patients with hepatitis C virus, treatment failure of daclatasvir plus asunaprevir combination therapy (DCV + ASV) seems to become intractable due to the induction of resistance-associated substitutions. This study aimed to investigate the outcomes of retreatment with direct-acting antivirals (DAAs) in patients with DCV + ASV therapy failure, as well as changes in drug resistance mutations.

Methods

We retrospectively analyzed 44 patients re-treated with DAAs after DCV + ASV failure between December 2015 and April 2018. All patients were analyzed for amino acid substitutions, and additional treatment regimens were selected based on the results and current treatment guidelines.

Results

The sustained virological response rate with second-line treatment was 81.8% (36/44), and relapse occurred in five of 16 patients who received sofosbuvir/ledipasvir and three of seven patients who received DCV/ASV/beclabuvir. Third- and fourth-line treatments were also tried in relapsed cases, and the overall sustained virological response rates were 90.9% (40/44) and 93.2% (41/44), respectively. A high rate of viral clearance was eventually observed. Before second-line treatment, the prevalence of mutations in the NS5A and NS3/4A regions was 100% (44/44) and 86.4% (38/44), respectively. There was no significant increase in the number of amino acid substitutions in patients for whom second-line treatment failed.

Conclusions

Amino acid substitutions were frequently observed in patients with DCV + ASV failure, but most patients achieved a sustained virological response after retreatment with DAAs. Although the spread of drug-resistant viruses due to unsuccessful DAA treatment was a matter of concern, most cases of DCV + ASV failure were overcome with additional treatment.

References

1Chayama K, Hayes CN. HCV drug resistance challenges in japan: The role of pre-existing variants and emerging resistant strains in direct acting antiviral therapy. Viruses 2015; 7: 5328–5342.
10.3390/v7102876
CAS PubMed Web of Science® Google Scholar
2Kumada H, Suzuki Y, Ikeda K et al. Daclatasvir Plus Asunaprevir for Chronic HCV Genotype 1b Infection. Hepatology 2014; 59: 2083–2091.
10.1002/hep.27113
CAS PubMed Web of Science® Google Scholar
3Chayama K, Takahashi S, Toyota J et al. 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.
10.1002/hep.24724
CAS PubMed Web of Science® Google Scholar
4Kumada H, Suzuki F, Suzuki Y et al. Randomized comparison of daclatasvir+asunaprevir versus telaprevir+peginterferon/ribavirin in Japanese hepatitis C virus patients. J Gastroenterol Hepatol 2016; 31: 14–22.
10.1111/jgh.13073
CAS PubMed Web of Science® Google Scholar
5Manns M, Pol S, Jacobson IM et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014; 384: 1597–1605.
10.1016/S0140-6736(14)61059-X
CAS PubMed Web of Science® Google Scholar
6Suzuki Y, Ikeda K, Suzuki F et al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. J Hepatol 2013; 58: 655–662.
10.1016/j.jhep.2012.09.037
CAS PubMed Web of Science® Google Scholar
7Mizokami M, Yokosuka O, Takehara T 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: 645–653.
10.1016/S1473-3099(15)70099-X
CAS PubMed Web of Science® Google Scholar
8Reddy KR, Bourlière M, Sulkowski M et al. Ledipasvir and sofosbuvir in patients with genotype 1 hepatitis C virus infection and compensated cirrhosis: An integrated safety and efficacy analysis. Hepatology 2015; 62: 79–86.
10.1002/hep.27826
CAS PubMed Web of Science® Google Scholar
9Akuta N, Sezaki H, Suzuki F et al. Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens. J Med Virol 2017; 89: 1248–1254.
10.1002/jmv.24767
CAS PubMed Web of Science® Google Scholar
10Akuta N, Sezaki H, Suzuki F et al. Retreatment efficacy and predictors of ledipasvir plus sofosbuvir to HCV genotype 1 in Japan. J Med Virol 2017; 89: 284–290.
10.1002/jmv.24617
CAS PubMed Web of Science® Google Scholar
11Kawakami Y, Ochi H, Hayes CN et al. Efficacy and safety of ledipasvir/sofosbuvir with ribavirin in chronic hepatitis C patients who failed daclatasvir/asunaprevir therapy: pilot study. J Gastroenterol 2018; 53: 548–556.
10.1007/s00535-017-1380-8
CAS PubMed Web of Science® Google Scholar
12Ikeda H, Watanabe T, Shimizu H et al. Efficacy of ledipasvir/sofosbuvir with or without ribavirin for 12 weeks in genotype 1b HCV patients previously treated with a nonstructural protein 5A inhibitor-containing regimen. Hepatol Res 2018; 48: 802–809.
10.1111/hepr.13074
CAS PubMed Web of Science® Google Scholar
13Iio E, Shimada N, Takaguchi K et al. Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy. Hepatol Res 2017; 47: 1308–1316.
10.1111/hepr.12898
CAS PubMed Web of Science® Google Scholar
14Kumada H, Watanabe T, Suzuki F et al. Efficacy and safety of glecaprevir/pibrentasvir in HCV-infected Japanese patients with prior DAA experience, severe renal impairment, or genotype 3 infection. J Gastroenterol 2018; 53: 566–575.
10.1007/s00535-017-1396-0
CAS PubMed Web of Science® Google Scholar
15Akuta N, Sezaki H, Suzuki F et al. Favorable efficacy of glecaprevir plus pibrentasvir as salvage therapy for HCV failures to prior direct-acting antivirals regimens. J Med Virol 2019; 91: 102–106.
10.1002/jmv.25278
CAS PubMed Web of Science® Google Scholar
16Johnson PJ, Berhane S, Kagebayashi C et al. Assessment of liver function in patients with hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol 2015; 33: 550–558.
10.1200/JCO.2014.57.9151
PubMed Web of Science® Google Scholar
17Kanda Y. Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 2013; 48: 452–458.
10.1038/bmt.2012.244
CAS PubMed Web of Science® Google Scholar
18Ito J, Suda G, Yamamoto Y et al. Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection. Hepatol Res 2016; 46: 1294–1303.
10.1111/hepr.12685
CAS PubMed Web of Science® Google Scholar
19Donaldson EF, Harrington PR, O'Rear JJ, Naeger LK. Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir. Hepatology 2015; 61: 56–65.
10.1002/hep.27375
CAS PubMed Web of Science® Google Scholar
20Mawatari S, Oda K, Tabu K et al. New resistance-associated substitutions and failure of dual oral therapy with daclatasvir and asunaprevir. J Gastroenterol 2017; 52: 855–867.
10.1007/s00535-016-1303-0
CAS PubMed Web of Science® Google Scholar
21Mawatari S, Oda K, Tabu K et al. The co-existence of NS5A and NS5B resistance-associated substitutions is associated with virologic failure in Hepatitis C Virus genotype 1 patients treated with sofosbuvir and ledipasvir. PLoS ONE 2018; 13: 1–15.
10.1371/journal.pone.0198642
Web of Science® Google Scholar
22Itokawa N, Atsukawa M, Tsubota A et al. Efficacy of direct-acting antiviral treatment in patients with compensated liver cirrhosis: A multicenter study. Hepatol Res 2019; 49: 125–135.
10.1111/hepr.13256
CAS PubMed Web of Science® Google Scholar
23Poordad F, Sievert W, Mollison L et al. Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection. JAMA - J Am Med Assoc 2015; 313: 1728–1735.
10.1001/jama.2015.3860
PubMed Web of Science® Google Scholar
24Toyota J, Karino Y, Suzuki F et al. Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection. J Gastroenterol 2017; 52: 385–395.
10.1007/s00535-016-1245-6
CAS PubMed Web of Science® Google Scholar
25Takaguchi K, Toyoda H, Tsutsui A et al. Real-world virological efficacy and safety of daclatasvir/asunaprevir/beclabuvir in patients with chronic hepatitis C virus genotype 1 infection in Japan. J Gastroenterol 2019; 54: 742–751.
10.1007/s00535-019-01568-8
CAS PubMed Web of Science® Google Scholar
26Fujita K, Oura K, Yoneyama H et al. Albumin–bilirubin score indicates liver fibrosis staging and prognosis in patients with chronic hepatitis C. Hepatol Res 2019; 49: 731–742.
10.1111/hepr.13333
CAS PubMed Web of Science® Google Scholar
27Miyaki E, Imamura M, Hiraga N et al. Daclatasvir and asunaprevir treatment improves liver function parameters and reduces liver fibrosis markers in chronic hepatitis C patients. Hepatol Res 2016; 46: 758–764.
10.1111/hepr.12621
CAS PubMed Web of Science® Google Scholar
28Tamori A, Hai H, Uchida-Kobayashi S et al. Outcomes for cirrhotic patients with hepatitis C virus 1b treated with asunaprevir and daclatasvir combination. Ann Hepatol 2017; 16: 734–741.
10.5604/01.3001.0010.2732
CAS PubMed Web of Science® Google Scholar
29Tada T, Kumada T, Toyoda H et al. Improvement of liver stiffness in patients with hepatitis C virus infection who received direct-acting antiviral therapy and achieved sustained virological response. J Gastroenterol Hepatol 2017; 32: 1982–1988.
10.1111/jgh.13788
CAS PubMed Web of Science® Google Scholar
30Giannini EG, Crespi M, Demarzo M et al. Improvement in hepatitis C virus patients with advanced, compensated liver disease after sustained virological response to direct acting antivirals. Eur J Clin Invest 2019; 49: e13056.
10.1111/eci.13056
PubMed Web of Science® Google Scholar
31Takehara T, Sakamoto N, Nishiguchi S et al. Efficacy and safety of sofosbuvir–velpatasvir with or without ribavirin in HCV-infected Japanese patients with decompensated cirrhosis: an open-label phase 3 trial. J Gastroenterol 2019; 54: 87–95.
10.1007/s00535-018-1503-x
CAS PubMed Web of Science® Google Scholar
32Nagata H, Nakagawa M, Asahina Y et al. Effect of interferon-based and -free therapy on early occurrence and recurrence of hepatocellular carcinoma in chronic hepatitis C. J Hepatol 2017; 67: 933–939.
10.1016/j.jhep.2017.05.028
CAS PubMed Web of Science® Google Scholar
33Izumi N, Takehara T, Chayama K et al. Sofosbuvir–velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 hepatitis C who failed direct-acting antivirals. Hepatol Int 2018; 12: 356–367.
10.1007/s12072-018-9878-6
PubMed Web of Science® Google Scholar

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Volume50, Issue3

March 2020

Pages 303-312

Favorable outcome of retreatment by direct-acting antivirals for hepatitis C patients with daclatasvir plus asunaprevir combination therapy failure

Abstract

Aim

Methods

Results

Conclusions

References

Citing Literature

References

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Favorable outcome of retreatment by direct-acting antivirals for hepatitis C patients with daclatasvir plus asunaprevir combination therapy failure

Abstract

Aim

Methods

Results

Conclusions

References

Citing Literature

References

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