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1
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Lee J, Ahn SB, Yim SY, An J, Jun DW, Ko MJ, Park DA, Yoo JJ. Efficacy and safety of direct-acting antiviral therapy for hepatitis C virus in elderly patients (≥65 years old): A systematic review and meta-analysis. J Viral Hepat 2022; 29:496-517. [PMID: 35357774 DOI: 10.1111/jvh.13679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 02/07/2022] [Accepted: 03/11/2022] [Indexed: 12/09/2022]
Abstract
Direct-acting agents (DAAs) have launched a new era of hepatitis C virus (HCV) treatment. As aged individuals comprise a large percentage of HCV-infected patients, the effectiveness and safety of DAAs in the elderly have come under scrutiny. This meta-analysis aimed to evaluate the efficacy and safety of DAAs in elderly patients. After a systematic search in PubMed (MEDLINE), Embase, OVID MEDLINE, the Cochrane Library and other databases, two investigators reviewed relevant abstracts and selected manuscripts for examination. The sustained virologic response (SVR) and adverse event (AE) rates were calculated with a random-effects model. Ninety studies evaluating SVR rates of elderly patients (≥65 years old) receiving DAAs were selected. DAAs in elderly patients exhibited a notable SVR rate of 96% (95% confidence interval [CI]: 95%-97%), accompanied by comparable rates in subgroup analyses. The comparison of SVR rates in elderly and non-elderly patients indicated no significant discrepancy (odds ratio [OR] 1.01, 95% CI: 1.00-1.01). The overall event rate of AEs was 45% (95% CI: 31%-60%), though AE rates varied by subgroups. Furthermore, AEs were comparatively more frequent (OR 1.15, 95% CI: 1.04-1.28) in the elderly than non-elderly, especially in subgroups such as SAE (OR 1.89, 95% CI: 1.52-2.36) and dose reduction in ribavirin (OR 1.90, 95% CI: 1.53-2.36). However, in the ribavirin (RBV)-free regimen, there was no significant difference in the incidence of AEs between the elderly and non-elderly groups. DAAs have high efficacy in elderly patients. Considering the possibility of AE, the RBV-free regimen should be given prior consideration for the treatment of elderly patients with HCV.
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Affiliation(s)
- Jieun Lee
- College of Medicine, Soonchunhyang University, Cheonan, Korea
| | - Sang Bong Ahn
- Nowon Eulji Medical Center, Department of Internal Medicine, Eulji University College of Medicine, Seoul, Korea
| | - Sun Young Yim
- Department of Internal Medicine, Korea University Hospital, Seoul, Korea
| | - Jihyun An
- Gastroenterology and Hepatology, Hanyang University College of Medicine, Guri, Korea
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Korea
| | - Min Jung Ko
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, Korea
| | - Dong Ah Park
- Division of Healthcare Technology Assessment Research, National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, Korea
| | - Jeong-Ju Yoo
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
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2
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Shin SK, Lee JW, Ra H, Kwon OS, Shin JB, Jin YJ, Lee S, Han KJ, Kim YN, Kim TH, Kim YS, Kim JH. Durability of Sustained Virologic Response and Improvement of Fibrosis Markers after Daclatasvir and Asunaprevir Treatment in Genotype 1b Hepatitis C Virus-Infected Patients: a Real Life and Multicenter Study. J Korean Med Sci 2019; 34:e264. [PMID: 31650719 PMCID: PMC6813423 DOI: 10.3346/jkms.2019.34.e264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 09/03/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The long-term data with direct acting antiviral agents were rare. This study investigated the durability of a sustained virologic response (SVR) and the improvement of fibrosis after daclatasvir and asunaprevir (DCV/ASV) treatment in genotype 1b (GT1b) hepatitis C virus (HCV)-infected patients. METHODS A total of 288 HCV GT1b patients without baseline non-structural 5A (NS5A) resistance-associated substitution (RAS) treated with DCV/ASV were enrolled. Virologic response was measured at 12 weeks and 1 year after treatment completion. In cirrhotic patients, liver function, aspartate transaminase to platelet ratio index (APRI), FIB-4 index, fibrosis index (FI), and liver stiffness measurement (LSM) at baseline and 1 year after treatment completion were evaluated. RESULTS SVR12 was obtained in 278 patients (96.5%). Six patients who checked NS5A RAS after treatment failure were RAS positive. Only one patient showed no durability of SVR. In cirrhotic patients who achieved SVR12 (n = 59), the changes of albumin (3.8 [2.2-4.7] to 4.3 [2.4-4.9] g/dL; P < 0.001), platelet count (99 [40-329] to 118 [40-399] × 10³/mm³; P < 0.001), APRI (1.8 [0.1-14.8] to 0.6 [0.1-4.8]; P < 0.001), FIB-4 index (5.45 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), FI (5.5 [0.6-32.8] to 3.3 [0.4-12.2]; P < 0.001), and LSM (17.2 [5.3-48.0] to 11.2 [3.7-28.1] kPa; P = 0.001) between baseline and 1 year after treatment completion were observed. CONCLUSION DCV/ASV treatment for HCV GT1b infected patients without RAS achieved high SVR rates and showed durable SVR. Cirrhotic patients who achieved SVR12 showed the improvement of liver function and fibrosis markers.
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Affiliation(s)
- Seung Kak Shin
- Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Jin Woo Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Hannah Ra
- Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Oh Sang Kwon
- Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.
| | - Jong Beom Shin
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Young Joo Jin
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Korea
| | - Sangheun Lee
- Department of Internal Medicine, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Ki Jun Han
- Department of Internal Medicine, International St. Mary's Hospital, Catholic Kwandong University College of Medicine, Incheon, Korea
| | - Young Nam Kim
- Department of Internal Medicine, Cheju Halla General Hospital, Jeju, Korea
| | - Tae Hun Kim
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Yun Soo Kim
- Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Ju Hyun Kim
- Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
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3
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Pan CQ, Gayam V, Rabinovich C, Normatov M, Fidman B, Wang D, Garlapati P. Efficacy of Direct-Acting Antivirals for Chronic Hepatitis C in a Large Cohort of Older Adults in the United States. J Am Geriatr Soc 2019; 68:379-387. [PMID: 31647119 DOI: 10.1111/jgs.16206] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Revised: 09/04/2019] [Accepted: 09/08/2019] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Data on the virologic response and tolerability of direct-acting antivirals (DAAs) are lacking in older people because these individuals are underrepresented in clinical trials. This study aimed to assess the effectiveness and tolerability of DAA regimens in older individuals in a large cohort of real-life clinical practice. METHODS In this retrospective study, patients with chronic hepatitis C infection between 2017 and 2018 were divided into patients aged 65 years and older and those younger than 65 years. We evaluated the sustained virologic response rates (SVRs) in both groups. Further subgroup analyses on the SVRs for patients aged 65 to 74, 75 to 84, and 85 years and older were performed. We also analyzed the predictors of treatment response in older individuals. RESULTS Among 1151 eligible patients, 516 were in the older group and 635 were in the younger group. The overall treatment response in the entire cohort was 97.7%. A significantly higher percentage of patients presented with advanced stages of fibrosis in the older group (53.1% vs 39.5%; P = <.001). The SVR rates were similar between the two groups (98.3% vs 97.7%; P = .18). In multivariate models, age was not predictive of SVR after adjusting for confounders. Subgroup analyses in the age groups of 65 to 74, 75 to 84, and older than 85 years showed similar treatment response rates (97.4%, 97.2%, and 86.7, respectively; P = .06) and advanced fibrosis (50.8%, 61.5%, and 53.3%, respectively; P = .14). CONCLUSION Although older people exhibit a significantly higher frequency of fibrosis, DAAs produce high rates of SVR in all age groups, and the age of the patient does not seem to have a significant impact on the efficacy of DAAs including patients in the oldest age category (≥75 y). Treatment should not be withheld in older individuals. J Am Geriatr Soc 68:379-387, 2020.
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Affiliation(s)
- Calvin Q Pan
- Center of Liver Diseases, Capital Medical University Affiliated Beijing Ditan Hospital, Chaoyang District, Beijing, China.,Division of Gastroenterology and Hepatology, NYU Langone Health, New York University School of Medicine, New York, New York
| | - Vijay Gayam
- Interfaith Medical Center, SUNY Downstate University Hospital, Brooklyn, New York
| | | | | | | | - Dan Wang
- St. John's University, Jamaica, New York
| | - Pavani Garlapati
- Interfaith Medical Center, SUNY Downstate University Hospital, Brooklyn, New York
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4
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Saito Y, Imamura M, Uchida T, Osawa M, Teraoka Y, Fujino H, Nakahara T, Ono A, Murakami E, Kawaoka T, Miki D, Tsuge M, Serikawa M, Aikata H, Abe-Chayama H, Hayes CN, Chayama K. Ribavirin induces hepatitis C virus genome mutations in chronic hepatitis patients who failed to respond to prior daclatasvir plus asunaprevir therapy. J Med Virol 2019; 92:210-218. [PMID: 31584207 DOI: 10.1002/jmv.25602] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 09/30/2019] [Indexed: 12/17/2022]
Abstract
Ribavirin (RBV) induces nucleotide (nt) substitutions in hepatitis C virus (HCV) genome nonstructural (NS) regions. Although emergence of drug resistance-associated variants is associated with direct-acting antiviral treatment failure, the effect of RBV on genome substitutions in such patients is unknown. Genotype 1b HCV subgenomic replicon cells were treated with RBV for 120 hours. Six patients with chronic genotype 1b with HCV-infected patients who failed to respond to prior daclatasvir plus asunaprevir (DCV/ASV) therapy were treated with 12 weeks of sofosbuvir and ledipasvir plus RBV after 4 weeks of RBV monotherapy. RBV-induced genome mutations in the HCV NS region (nt3493-9301) in replicon cells and in patients during 4 weeks of RBV monotherapy were analyzed by deep sequencing. RBV-associated G-to-A and C-to-U transitions increased in a dose-dependent manner in HCV replicon cells after the RBV treatment. In patients with prior DCV/ASV treatment failures, the median serum HCV RNA level was 6.25 ± 0.31 log IU/mL at the start of RBV therapy and decreased significantly to 5.95 ± 0.4 log IU/mL (P = .03) after 4 weeks of RBV monotherapy. Although predominant HCV genome substitutions rates were similar between nontreatment and RBV-treatment periods (0.042 and 0.031 per base pair, respectively; P = .248), the frequencies of G-to-A and C-to-U transitions significantly increased after RBV monotherapy. These transitions were enriched, particularly within the HCV NS3 region in all patients. RBV treatment induces G-to-A and C-to-U transitions in the HCV genome even in chronic patients with hepatitis C with prior DCV/ASV treatment failures.
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Affiliation(s)
- Yuhei Saito
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Mitsutaka Osawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Masahiro Serikawa
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
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5
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Mücke MM, Herrmann E, Mücke VT, Graf C, Zeuzem S, Vermehren J. Efficacy and safety of direct-acting antivirals for hepatitis C in the elderly: A systematic review and meta-analysis. Liver Int 2019; 39:1652-1660. [PMID: 31033122 DOI: 10.1111/liv.14126] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 04/19/2019] [Indexed: 01/08/2023]
Abstract
BACKGROUND&AIMS Since the introduction of direct-acting antivirals (DAAs) several studies have reported high efficacy and safety in Hepatitis C infected patients, even in those earlier considered difficult-to-treat. We aimed to assess the efficacy and safety of DAA therapy in elderly patients. METHODS The PubMed MEDLINE, Embase and Cochrane databases were searched through July 2018. Two independent researchers extracted data and assessed the quality and risk of bias. Risk ratios (RRs) were pooled using random effects models. The primary outcome was efficacy of DAA therapy assessed by the RR for non-sustained virologic response (SVR) among patients aged <65 vs ≥65 years. RESULTS Overall, we identified 63 studies including 34 082 patients treated with different DAAs. Risk for non-SVR was comparable in patients <65 and ≥65 years of age (RR 1.00, 95% CI 0.86-1.15; P = 0.979) and even lower in a subgroup analysis of cirrhotic patients ≥65 years of age (RR 0.59, 95% CI 0.35-0.99, P = 0.044). Risk for non-SVR was similar between age groups in all other subgroup analyses. Elderly patients had a significantly increased risk of adverse events (AEs) (RR 1.30, 95% CI 1.11-1.52, P = 0.001), but not for serious adverse events (P = 0.43) or treatment discontinuation (P = 0.15). Risk for anaemia if treated with additional ribavirin was 2.84 (95% CI 1.73-4.66, P < 0.001) in elderly patients compared to patients <65 years. CONCLUSION Our results show that DAAs are highly effective and safe in elderly patients. Ribavirin should be avoided in the elderly as more AEs and particularly anaemia is observed. Further cost-effectiveness analyses are needed to evaluate the socio-economic benefit of treating elderly people without advanced liver disease.
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Affiliation(s)
- Marcus M Mücke
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modeling, Goethe University, Frankfurt am Main, Germany
| | - Victoria T Mücke
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Christiana Graf
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Johannes Vermehren
- Department of Internal Medicine 1, University Hospital Frankfurt, Frankfurt am Main, Germany
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6
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The course of elderly patients with persistent hepatitis C virus infection without hepatocellular carcinoma. J Gastroenterol 2019; 54:829-836. [PMID: 31161311 DOI: 10.1007/s00535-019-01595-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/27/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Little is known about the course of elderly patients with persistent hepatitis C virus (HCV) infection. We investigated the course of HCV infection in this patient population. METHODS Among 9,126 HCV antibody-positive patients who visited our hospital between 1995 and 2015, there were 453 patients with continuous follow-up who survived to age 80. They were included in the study following the inclusion criteria: confirmed persistent detection of HCV RNA, no HCV eradication if anti-HCV therapy occurred before enrollment, and no development of hepatocellular carcinoma (HCC) before enrollment. For all study patients, baseline was defined as the date when they turned 80. Mortality rates after the age of 80 years and cause of death were analyzed. RESULTS During the study period, 155 patients (34.2%) died. Median survival time (MST) after age 80 was 8.8 years, which was comparable to that of the general population (10.1 years). Among 155 deceased patients, the majority (115 patients, 74.2%) died due to non-liver-related disease, followed by HCC (28 patients, 18.1%) and liver-related disease other than HCC (12 patients, 7.7%). Patients with advanced liver fibrosis (FIB-4 index > 3.25, n = 245) had shorter MST than patients with mild liver fibrosis (FIB-4 index ≤ 3.25, n = 208) (7.1 vs. 10.2 years; p = 0.020) due to a higher mortality rate from liver-related complications, including HCC. CONCLUSION Most elderly HCV patients die from non-liver-related disease, especially those with less advanced liver fibrosis.
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7
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Taki S, Tamai H, Ida Y, Shingaki N, Kawashima A, Shimizu R, Moribata K, Maekita T, Iguchi M, Kato J, Nakao T, Kitano M. The Real-World Safety and Efficacy of Daclatasvir and Asunaprevir for Elderly Patients. Gut Liver 2018; 12:86-93. [PMID: 28798288 PMCID: PMC5753689 DOI: 10.5009/gnl17048] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 03/22/2017] [Accepted: 03/22/2017] [Indexed: 01/10/2023] Open
Abstract
Background/Aims Although daclatasvir with asunaprevir was approved in Japan for interferon ineligible or intolerant patients, patients aged ≥75 years were excluded in the phase III trial. The present study aimed to evaluate the safety and efficacy of this therapy for elderly patients aged ≥75 years and to clarify whether an extremely high sustained virological response (SVR) rate can be achieved, even in a real-world setting when patients with resistance-associated substitutions (RASs) to nonstructural protein 5A (NS5A) inhibitors or prior simeprevir failure are excluded. Methods Daclatasvir (60 mg) and asunaprevir (100 mg) were orally administered daily for 24 weeks. Patients without pre-existing NS5A RASs and simeprevir failure were enrolled in this study. Results Overall, 110 patients were treated. The median age was 73 years old. The SVR rates of total patients, those aged ≥75 years, and those aged <75 years were 97% (107/110), 98% (46/47), and 97% (61/63), respectively. The treatment of two patients (2%) was discontinued because of adverse events. Conclusions Daclatasvir with asunaprevir was a safe treatment, even in patients aged ≥75 years. When patients without pre-existing NS5A RASs and prior simeprevir failure were selected, an extremely high SVR rate could be achieved irrespective of age.
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Affiliation(s)
- Shinya Taki
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hideyuki Tamai
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yoshiyuki Ida
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Naoki Shingaki
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Akira Kawashima
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Ryo Shimizu
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Kosaku Moribata
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Takao Maekita
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Mikitaka Iguchi
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Taisei Nakao
- Department of Internal Medicine, Naga Municipal Hospital, Wakayama, Japan
| | - Masayuki Kitano
- Second Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
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8
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Teraoka Y, Uchida T, Imamura M, Hiraga N, Osawa M, Kan H, Saito Y, Tsuge M, Abe-Chayama H, Hayes CN, Makokha GN, Aikata H, Miki D, Ochi H, Ishida Y, Tateno C, Chayama K. Limitations of daclatasvir/asunaprevir plus beclabuvir treatment in cases of NS5A inhibitor treatment failure. J Gen Virol 2018; 99:1058-1065. [PMID: 29916799 DOI: 10.1099/jgv.0.001091] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Combined daclatasvir (DCV)/asunaprevir (ASV) plus beclabuvir (BCV) treatment shows a high virological response for genotype 1b chronic hepatitis C patients. However, its efficacy for patients for whom previous direct-acting antiviral (DAA) therapy failed is not known. We analysed the efficacy of DCV/ASV/BCV treatment for HCV-infected mice and chronic hepatitis patients. Human hepatocyte chimaeric mice were injected with serum samples obtained from either a DAA-naïve patient or a DCV/ASV treatment failure and were then treated with DCV/ASV alone or in combination with BCV for 4 weeks. DCV/ASV treatment successfully eliminated the virus in DAA-naïve-patient HCV-infected mice. DCV/ASV treatment failure HCV-infected mice developed viral breakthrough during DCV/ASV treatment, with the emergence of NS5A-L31V/Y93H HCV resistance-associated variants (RAVs) being observed by direct sequencing. DCV/ASV/BCV treatment inhibited viral breakthrough in NS5A-L31V/Y93H-mutated HCV-infected mice, but HCV relapsed with the emergence of NS5B-P495S variants after the cessation of the treatment. The efficacy of the triple therapy was also analysed in HCV-infected patients; one DAA-naïve patient and four prior DAA treatment failures were treated with 12 weeks of DCV/ASV/BCV therapy. Sustained virological response was achieved in a DAA-naïve patient and one of the DCV/ASV treatment failures through DCV/ASV/BCV therapy; however, HCV relapse occurred in the other patients with prior DCV/ASV and/or sofosbuvir/ledipasvir treatment failures. DCV/ASV/BCV therapy seems to have limited efficacy for patients with NS5A RAVs for whom prior DAA treatment has failed.
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Affiliation(s)
- Yuji Teraoka
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takuro Uchida
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Mitsutaka Osawa
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yuhei Saito
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,3Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,4Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - C Nelson Hayes
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Grace Naswa Makokha
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- 2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,5Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Hidenori Ochi
- 2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,5Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Yuji Ishida
- 2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,6PhoenixBio Co., Ltd, Higashihiroshima, Japan
| | - Chise Tateno
- 2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,6PhoenixBio Co., Ltd, Higashihiroshima, Japan
| | - Kazuaki Chayama
- 1Department of Gastroenterology and Metabolism, Institute of Biomedical and Health, Hiroshima, Japan.,2Liver Research Project Center, Hiroshima University, Hiroshima, Japan.,5Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
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9
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Safety and effectiveness of daclatasvir and asunaprevir dual therapy in patients with genotype 1 chronic hepatitis C: results from postmarketing surveillance in Japan. Hepatol Int 2018; 12:244-253. [DOI: 10.1007/s12072-018-9872-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Accepted: 05/16/2018] [Indexed: 12/26/2022]
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10
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Kawakami Y, Ochi H, Hayes CN, Imamura M, Tsuge M, Nakahara T, Katamura Y, Kohno H, Kohno H, Tsuji K, Takaki S, Mori N, Honda Y, Arataki K, Takahashi S, Kira S, Tamura T, Masuda K, Nakamura T, Kikkawa M, Chayama K. 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. [PMID: 28815329 DOI: 10.1007/s00535-017-1380-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2017] [Accepted: 08/04/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND In Japan, daclatasvir (DCV) and asunaprevir (ASV) therapy was the first IFN-free treatment to be approved, and thousands of patients have since been successfully treated, with an SVR rate of around 90%. The converse, however, is that around 10% of patients fail to achieve viral eradication and must be retreated using a different approach. This study is to evaluate treatment efficacy of ledipasvir/sofosbuvir and ribavirin in patients who failed to respond to DCV and ASV therapy. METHODS Thirty patients were treated with 12 weeks of ledipasvir/sofosbuvir and ribavirin. We evaluated the rate of sustained virological response 12 weeks after the end of treatment (SVR12) and examined the incidence of adverse events during ledipasvir/sofosbuvir and ribavirin treatment. NS5A and NS5B resistance-associated variants (RAVs) in treatment failure cases were examined. RESULTS The overall SVR12 rate was 86.7% (26/30). Large decreases in mean log10 HCV RNA levels were observed in patients without cirrhosis, and the SVR12 rate for these patients was 100% (12/12). In cases of cirrhosis, SVR12 rate was 72.2% (13/18). The common factors in treatment failure cases were the presence of liver cirrhosis and both NS5A L31M/I and Y93H RAVs. The frequency of RAVs did not change before and after treatment among patients who relapsed. CONCLUSION Ledipasvir/sofosbuvir with ribavirin is an effective retreatment option for patients with chronic hepatitis C who failed to respond to prior daclatasvir and asunaprevir therapy.
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Affiliation(s)
- Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Department of Center for Integrated Medical Research, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | | | | | | | - Keiji Tsuji
- Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Shintaro Takaki
- Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Nami Mori
- Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | - Yohji Honda
- Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital, Hiroshima, Japan
| | | | | | | | | | | | | | | | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan.
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
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11
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Ji F, Wei B, Yeo YH, Ogawa E, Zou B, Stave CD, Li Z, Dang S, Furusyo N, Cheung RC, Nguyen MH. Systematic review with meta-analysis: effectiveness and tolerability of interferon-free direct-acting antiviral regimens for chronic hepatitis C genotype 1 in routine clinical practice in Asia. Aliment Pharmacol Ther 2018; 47:550-562. [PMID: 29327780 DOI: 10.1111/apt.14507] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 11/22/2017] [Accepted: 12/17/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Direct-acting antiviral (DAA) regimens have shown high efficacy and tolerability for patients with HCV genotype 1/1b (GT1/1b) in clinical trials. However, robust real-world evidence of interferon (IFN)-free DAA treatment for HCV GT1-infected patients in Asia is still lacking. AIM To systematically review and meta-analyse the effectiveness and tolerability of IFN-free DAA therapy for HCV GT1 infection in Asia. METHODS We included studies that enrolled adult patients with HCV GT1 infection in routine clinical practice in Asia, using IFN-free DAA regimens, and reported sustained virological response (SVR) after 12/24 weeks end-of-treatment by 31 May 2017. The pooled SVR rates were computed with a random-effects model. Subgroup analysis and meta-regression as previously registered in PROSPERO were performed to determine how pre-planned variables might have affected the pooled estimates. RESULTS We included 41 studies from eight countries and regions, comprising of 8574 individuals. The pooled SVR rates for GT1 were 89.9% (95% CI 88.6-91.1, I2 = 55.1%) with daclatasvir/asunaprevir (DCV/ASV) and 98.1% (95% CI 97.0-99.0, I2 = 41.0%) with ledipasvir/sofosbuvir ± ribavirin (LDV/SOF ± RBV). Baseline cirrhosis but not prior treatment history and age, attenuated the effectiveness of both regimens. Baseline resistance associated substitutions (RASs) severely attenuated SVR of DCV/ASV (65.4% vs 94.3%, P < 0.001) and only minimally with LDV/SOF ± RBV (94.5% vs 99.2%, P = 0.003). Patients with renal dysfunction treated with DCV/ASV showed a higher SVR rate (93.9% vs 89.8%, P = 0.046). Patients with hepatocellular carcinoma (HCC) LDV/SOF ± RBV achieved a lower SVR than those without HCC (94.1% vs 98.7%, P = 0.001). CONCLUSION All oral DAA treatment of HCV GT1 resulted in high cure rates in Asian patients in routine clinical practice setting including elderly patients and those with end-stage renal disease.
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Affiliation(s)
- F Ji
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi' an Jiaotong University, Xi'an, China
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - B Wei
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - Y H Yeo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - E Ogawa
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - B Zou
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - C D Stave
- Department of Lane Medical Library, Stanford University Medical Center, Palo Alto, CA, USA
| | - Z Li
- Shaanxi Provincial Clinical Research Center for Hepatic & Splenic Diseases, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - S Dang
- Department of Infectious Diseases, The Second Affiliated Hospital of Xi' an Jiaotong University, Xi'an, China
| | - N Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - R C Cheung
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
- Division of Gastroenterology and Hepatology, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
| | - M H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
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12
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Ozono Y, Nagata K, Hasuike S, Iwakiri H, Nakamura K, Tsuchimochi M, Yamada Y, Takaishi Y, Sueta M, Miike T, Tahara Y, Yamamoto S, Shide K, Hidaka T, Kubuki Y, Kusumoto K, Ochiai T, Kato J, Komada N, Hirono S, Kuroki K, Shigehira M, Shimoda K. Efficacy and safety of sofosbuvir and ledipasvir in Japanese patients aged 75 years or over with hepatitis C genotype 1. World J Hepatol 2017; 9:1340-1345. [PMID: 29359017 PMCID: PMC5756723 DOI: 10.4254/wjh.v9.i36.1340] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 10/10/2017] [Accepted: 11/03/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy and safety of a regimen containing sofosbuvir (SOF) and ledipasvir (LDV) in Japanese patients aged ≥ 75 years with hepatitis C genotype 1.
METHODS This multicenter, retrospective study consisted of 246 Japanese patients with HCV genotype 1 at nine centers in Miyazaki prefecture in Japan. Demographic, clinical, virological, and adverse effects (AE)-related data obtained during and after SOF/LDV therapy were collected from medical records. These patients were divided into two groups, younger (aged < 75 years) and elderly (aged ≥ 75 years). Virological data and AEs were analyzed by age group.
RESULTS The sustained virological response (SVR) rates at 12 wk after treatment were 99.2%, 99.4%, and 98.7% in the overall population and in patients aged < 75 and ≥ 75 years, respectively. Common AEs during therapy were headache, pruritus, constipation, and insomnia. These occurred in fewer than 10% of patients, and their incidence was not significantly different between the younger and elderly groups. Two patients discontinued treatment, one due to a skin eruption and the other due to cerebral bleeding.
CONCLUSION Compared with younger patients, elderly patients had a similar virological response and tolerance to SOF/LDV therapy.
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Affiliation(s)
- Yoshinori Ozono
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Kenji Nagata
- Department of Liver Disease, University of Miyazaki Hospital, Miyazaki 889-1601, Japan
| | - Satoru Hasuike
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Hisayoshi Iwakiri
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Kenichi Nakamura
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Mai Tsuchimochi
- Department of Liver Disease, University of Miyazaki Hospital, Miyazaki 889-1601, Japan
| | - Yuri Yamada
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Yuka Takaishi
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Mitsue Sueta
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Tadashi Miike
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Yoshihiro Tahara
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Shojiro Yamamoto
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Kotaro Shide
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Tomonori Hidaka
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Yoko Kubuki
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
| | - Kazunori Kusumoto
- Department of Internal Medicine, Koga General Hospital, Miyazaki 880-0041, Japan
| | - Toshimasa Ochiai
- Department of Internal Medicine, Koga General Hospital, Miyazaki 880-0041, Japan
| | - Junya Kato
- Department of Internal Medicine, National Hospital Organization Miyakonojo Medical Center, Miyazaki 885-0014, Japan
| | - Naoto Komada
- Department of Internal Medicine, National Hospital Organization Miyakonojo Medical Center, Miyazaki 885-0014, Japan
| | - Shuichi Hirono
- Department of Internal Medicine, Hirono Naika Clinic, Miyazaki 880-0925, Japan
| | - Kazuo Kuroki
- Department of Internal Medicine, Kushima Municipal Hospital, Miyazaki 888-0001, Japan
| | - Masafumi Shigehira
- Department of Internal Medicine, Shigehira Clinic, Miyazaki 885-0005, Japan
| | - Kazuya Shimoda
- Department of Gastoroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Miyazaki 889-1601, Japan
- Department of Liver Disease, University of Miyazaki Hospital, Miyazaki 889-1601, Japan
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13
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Atsukawa M, Tsubota A, Kondo C, Shimada N, Abe H, Kato K, Okubo T, Arai T, Itokawa N, Iio E, Tanaka Y, Iwakiri K. Effectiveness and safety of community-based treatment with sofosbuvir plus ribavirin for elderly patients with genotype 2 chronic hepatitis C. Dig Liver Dis 2017; 49:1029-1035. [PMID: 28499694 DOI: 10.1016/j.dld.2017.04.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 04/17/2017] [Accepted: 04/18/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND The aim of this study was to clarify the effectiveness and safety of sofosbuvir/ribavirin therapy for elderly patients with genotype 2-infected chronic hepatitis C (CHC) in Japan. METHODS A multicenter, retrospective study evaluated the effectiveness and safety of sofosbuvir/ribavirin based on real-world clinical data. RESULTS The subjects consisted of 270 patients, 47.0% of whom were aged ≥65 years. The sustained virological response rates in patients aged <65 and ≥65 years were 98.6% and 95.3%, respectively. Hemoglobin levels decreased during treatment due to ribavirin-related hemolysis, and were significantly lower in patients aged ≥65 years than those aged <65 years at all time-points. A reduction in ribavirin dose was necessary in 31.0% (26/84) of patients with hemoglobin levels <13.0g/dL and in 70.7% (39/127) of those aged >65 years. Although the most frequent adverse event was anemia, no patients discontinued the use of either ribavirin or sofosbuvir. The incidence of ribavirin-related anemia in patients aged ≥65 years was 34.6% and significantly higher compared with that in patients aged <65 years (2.8%). CONCLUSIONS Treatment with sofosbuvir/ribavirin for genotype 2-infected CHC was effective and safe even for elderly patients, although the incidence of adverse events including ribavirin-related anemia was relatively high.
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Affiliation(s)
- Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan.
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo, Japan
| | - Chisa Kondo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan
| | - Noritomo Shimada
- Division of Gastroenterology and Hepatology, Otakanomori Hospital, Kashiwa, Chiba, Japan
| | - Hiroshi Abe
- Department of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
| | - Keizo Kato
- Department of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan
| | - Taeang Arai
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan
| | - Norio Itokawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan
| | - Etsuko Iio
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Yasuhito Tanaka
- Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
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14
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Nagaoki Y, Imamura M, Aikata H, Daijo K, Teraoka Y, Honda F, Nakamura Y, Hatooka M, Morio R, Morio K, Kan H, Fujino H, Kobayashi T, Masaki K, Ono A, Nakahara T, Kawaoka T, Tsuge M, Hiramatsu A, Kawakami Y, Hayes CN, Miki D, Ochi H, Chayama K. The risks of hepatocellular carcinoma development after HCV eradication are similar between patients treated with peg-interferon plus ribavirin and direct-acting antiviral therapy. PLoS One 2017; 12:e0182710. [PMID: 28797106 PMCID: PMC5552231 DOI: 10.1371/journal.pone.0182710] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2017] [Accepted: 07/24/2017] [Indexed: 02/06/2023] Open
Abstract
The risk of hepatocellular carcinoma (HCC) development is reduced following viral elimination by interferon therapy in chronic hepatitis C patients. However, the risk in patients treated with interferon-free direct-acting antivirals (DAAs) is unknown. We evaluated chronic hepatitis C patients who achieved viral eradication by pegylated-interferon plus ribavirin (PEG-IFN/RBV, n = 244) or daclatasvir plus asunaprevir (DCV/ASV, n = 154) therapy. None of the patients had prior history of HCC or antiviral therapy. The median observation period after the end of treatment for the PEG-IFN/RBV and DCV/ASV groups were 96 (range 10–196) and 23 (range 4–78) months, respectively. During the observation period, HCC developed in 13 (5.3%) and 7 (4.5%) patients in the PEG-IFN/RBV and DCV/ASV groups, respectively. The cumulative HCC development rate after 1-, 3- and 5-years (0.4%, 3% and 5% for the PEG-IFN/RBV group and 0.6%, 9% and 9% for the DAA group, respectively) were similar between the two groups. Propensity score matching analysis also showed no significant difference in HCC development rates between the two groups. Serum AFP levels decreased to similar levels between PEG-IFN/RBV and DCV/ASV groups following the achievement of viral eradication. The risk for HCC development following viral eradication by IFN-free DAA therapy may be similar to that in IFN-based therapy.
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Affiliation(s)
- Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Kana Daijo
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Fumi Honda
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Yuki Nakamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Masahiro Hatooka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Reona Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomoki Kobayashi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - C. Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
- * E-mail:
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Kawaoka T, Imamura M, Morio K, Nakamura Y, Tsuge M, Nelson Hayes C, Kawakami Y, Aikata H, Ochi H, Ishiyama K, Ohdan H, Chayama K. Three patients treated with sofosbuvir plus ledipasvir for recurrent hepatitis C after liver transplantation. Clin J Gastroenterol 2017; 10:179-184. [PMID: 28224470 DOI: 10.1007/s12328-017-0722-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 02/08/2017] [Indexed: 01/12/2023]
Abstract
We previously reported results of interferon (IFN)-free daclatasvir and asunaprevir for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). Here we report three patients who achieved viral response with no effect on the blood concentrations of immunosuppressive agents following sofosbuvir plus ledipasvir treatment. The first patient was a 68-year-old female with HCV-related liver cirrhosis who failed to respond to pegylated-IFN and ribavirin (PEG-IFN/RBV) after living donor LT. She had been treated with 50 mg/day of cyclosporine. The second was a 63-year-old male with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. He had been treated with 50 mg/day of cyclosporine. The third was a 63-year-old female with HCV-related liver cirrhosis. She had been treated with tacrolimus. High alanine aminotransferase levels persisted after LT. Liver biopsy examination revealed active hepatitis or chronic rejection. Therefore, sofosbuvir plus ledipasvir therapy was started. However, the combination treatment was stopped at 4 weeks due to development of interstitial pneumonia. Serum HCV RNA became negative at the time treatment was discontinued and remained negative 12 weeks after cessation of therapy in all three cases. Sofosbuvir plus ledipasvir treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.
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Affiliation(s)
- Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yuki Nakamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hidenori Ochi
- Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan
| | - Kouhei Ishiyama
- Programs for Biomedical Research, Division of Frontier Medical Science, Department of Surgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Programs for Biomedical Research, Division of Frontier Medical Science, Department of Surgery, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
- Laboratory for Digestive Diseases, Center for Genomic Medicine, RIKEN, Hiroshima, Japan
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