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Georgieva M, Xenodochidis C, Krasteva N. Old age as a risk factor for liver diseases: Modern therapeutic approaches. Exp Gerontol 2023; 184:112334. [PMID: 37977514 DOI: 10.1016/j.exger.2023.112334] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/12/2023] [Accepted: 11/14/2023] [Indexed: 11/19/2023]
Abstract
Recent scientific interest has been directed towards age-related diseases, driven by the significant increase in global life expectancy and the growing population of individuals aged 65 and above. The ageing process encompasses various biological, physiological, environmental, psychological, behavioural, and social changes, leading to an augmented susceptibility to chronic illnesses. Cardiovascular, neurological, musculoskeletal, liver and oncological diseases are prevalent in the elderly. Moreover, ageing individuals demonstrate reduced regenerative capacity and decreased tolerance towards therapeutic interventions, including organ transplantation. Liver diseases, such as non-alcoholic fatty liver disease, alcoholic liver disease, hepatitis, fibrosis, and cirrhosis, have emerged as significant public health concerns. Paradoxically, these conditions remain underestimated despite their substantial global impact. Age-related factors are closely associated with the severity and unfavorable prognosis of various liver diseases, warranting further investigation to enhance clinical management and develop novel therapeutic strategies. This comprehensive review focuses specifically on age-related liver diseases, their treatment strategies, and contemporary practices. It provides a detailed account of the global burden, types, molecular mechanisms, and epigenetic alterations underlying these liver pathologies.
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Affiliation(s)
- Milena Georgieva
- Institute of Molecular Biology "Acad. Roumen Tsanev", Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
| | - Charilaos Xenodochidis
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
| | - Natalia Krasteva
- Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
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Ohta A, Ogawa E, Murata M, Matsumoto Y, Yamasaki S, Ikezaki H, Furusyo N. Impact of the PNPLA3 genotype on the risk of hepatocellular carcinoma after hepatitis C virus eradication. J Med Virol 2022; 94:5007-5014. [PMID: 35652276 DOI: 10.1002/jmv.27904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/20/2022] [Accepted: 05/31/2022] [Indexed: 11/05/2022]
Abstract
Almost all chronic hepatitis C (CHC) patients can achieve sustained virological response (SVR) with direct-acting antivirals. However, the development of hepatocellular carcinoma (HCC), even after the achievement of SVR, continues to be a serious problem. The aim of this study was to assess the association between host genetic factors and de novo HCC after SVR. This single-center, retrospective study consisted of 442 consecutive CHC patients without a history of HCC who achieved SVR through interferon (IFN)-based and IFN-free therapy. Predictive factors associated with the development of HCC were determined by the Cox proportional hazards model. The single nucleotide polymorphism (SNP) genotyping data of 223 patients were available for analysis. Of the seven SNPs analyzed in this study, only the patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 GG genotype was significantly, positively associated with the development of de novo HCC after adjusting for age, sex, and fibrosis status (adjusted hazard ratio [aHR] 5.66, P=0.003). In multivariable analysis, age (aHR 1.05, P=0.007), advanced fibrosis (aHR 2.69, P=0.019), α-fetoprotein at post-12 weeks of treatment ≥7.0 ng/mL (aHR 3.85, P=0.001), and PNPLA3 GG genotype (aHR 3.02, P=0.004) were extracted as independent predictors of the development of de novo HCC. In conclusion, the PNPLA3 genotype was independently associated with the de novo HCC of CHC patients who achieved SVR. Such detailed knowledge of host genetic factors will be useful for HCC surveillance after HCV elimination. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Azusa Ohta
- Department of Environmental Medicine and Infectious Disease, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.,Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiichi Ogawa
- Department of Environmental Medicine and Infectious Disease, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.,Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Yuji Matsumoto
- Department of Environmental Medicine and Infectious Disease, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.,Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Sho Yamasaki
- Department of Environmental Medicine and Infectious Disease, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.,Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.,Department of Comprehensive General Internal Medicine, Kyushu University Graduate School of Medical Sciences, Faculty of Medical Sciences, Fukuoka, Japan
| | - Norihiro Furusyo
- General Internal Medicine, Taihaku Avenue Clinic, Fukuoka, Japan
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Kalafateli M, Buzzetti E, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS, Cochrane Hepato‐Biliary Group. Pharmacological interventions for acute hepatitis C infection. Cochrane Database Syst Rev 2018; 12:CD011644. [PMID: 30521693 PMCID: PMC6517308 DOI: 10.1002/14651858.cd011644.pub3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) is a single-stranded RNA (ribonucleic acid) virus that has the potential to cause inflammation of the liver. The traditional definition of acute HCV infection is the first six months following infection with the virus. Another commonly used definition of acute HCV infection is the absence of HCV antibody and subsequent seroconversion (presence of HCV antibody in a person who was previously negative for HCV antibody). Approximately 40% to 95% of people with acute HCV infection develop chronic HCV infection, that is, have persistent HCV RNA in their blood. In 2010, an estimated 160 million people worldwide (2% to 3% of the world's population) had chronic HCV infection. The optimal pharmacological treatment of acute HCV remains controversial. Chronic HCV infection can damage the liver. OBJECTIVES To assess the comparative benefits and harms of different pharmacological interventions in the treatment of acute HCV infection through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis and instead we assessed the comparative benefits and harms of different interventions versus each other or versus no intervention using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to April 2016 to identify randomised clinical trials on pharmacological interventions for acute HCV infection. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with acute HCV infection. We excluded trials which included previously liver transplanted participants and those with other coexisting viral diseases. We considered any of the various pharmacological interventions compared with placebo or each other. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on the available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS We identified 10 randomised clinical trials with 488 randomised participants that met our inclusion criteria. All the trials were at high risk of bias in one or more domains. Overall, the evidence for all the outcomes was very low quality evidence. Nine trials (467 participants) provided information for one or more outcomes. Three trials (99 participants) compared interferon-alpha versus no intervention. Three trials (90 participants) compared interferon-beta versus no intervention. One trial (21 participants) compared pegylated interferon-alpha versus no intervention, but it did not provide any data for analysis. One trial (41 participants) compared MTH-68/B vaccine versus no intervention. Two trials (237 participants) compared pegylated interferon-alpha versus pegylated interferon-alpha plus ribavirin. None of the trials compared direct-acting antivirals versus placebo or other interventions. The mean or median follow-up period in the trials ranged from six to 36 months.There was no short-term mortality (less than one year) in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials that reported follow-up beyond one year, there were no further deaths. The number of serious adverse events was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha (rate ratio 2.74, 95% CI 1.40 to 5.33; participants = 237; trials = 2; I2 = 0%). The proportion of people with any adverse events was higher with interferon-alpha and interferon-beta compared with no intervention (OR 203.00, 95% CI 9.01 to 4574.81; participants = 33; trials = 1 and OR 27.88, 95% CI 1.48 to 526.12; participants = 40; trials = 1). None of the trials reported health-related quality of life, liver transplantation, decompensated liver disease, cirrhosis, or hepatocellular carcinoma. The proportion of people with chronic HCV infection as indicated by the lack of sustained virological response was lower in the interferon-alpha group versus no intervention (OR 0.27, 95% CI 0.09 to 0.76; participants = 99; trials = 3; I2 = 0%). The differences between the groups were imprecise or not estimable (because neither group had any events) for all the remaining comparisons.Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. AUTHORS' CONCLUSIONS Very low quality evidence suggests that interferon-alpha may decrease the incidence of chronic HCV infection as measured by sustained virological response. However, the clinical impact such as improvement in health-related quality of life, reduction in cirrhosis, decompensated liver disease, and liver transplantation has not been reported. It is also not clear whether this finding is applicable in the current clinical setting dominated by the use of pegylated interferons and direct-acting antivirals, although we found no evidence to support that pegylated interferons or ribavirin or both are effective in people with acute HCV infection. We could find no randomised trials comparing direct-acting antivirals with placebo or other interventions for acute HCV infection. There is significant uncertainty in the benefits and harms of the interventions, and high-quality randomised clinical trials are required.
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Affiliation(s)
- Maria Kalafateli
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Elena Buzzetti
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryPond StreetLondonUKNW3 2QG
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Kurinchi Selvan Gurusamy
- University College LondonDivision of Surgery and Interventional Science9th Floor, Royal Free HospitalRowland Hill StreetLondonUKNW3 2PF
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Huang CF, Yu ML. Treating hepatitis C in the elderly: pharmacotherapeutic considerations and developments. Expert Opin Pharmacother 2017; 18:1867-1874. [PMID: 29086615 DOI: 10.1080/14656566.2017.1400010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Accepted: 10/30/2017] [Indexed: 12/17/2022]
Abstract
The seroprevalence of hepatitis C virus (HCV) infection tends to be higher in the elderly than in younger populations. Meanwhile, age per sec is an unfavorable determinant that has an impact on liver-related outcomes. Geriatric chronic hepatitis C (CHC) patients would be viewed as a special population and have an urgent need for viral eradication. Areas covered: The antivirals for CHC have evolved from interferon (IFN)-based therapyto interferon-free DAAs. The treatment strategy, in terms of its clinical efficacy and drug safety, in the elderly is presented. Expert opinion: In the previous IFN era, the sustained virological response (SVR) rate of the elderly was lower. More unfavorable safety concerns attributing to the underlying liver disease severity and extra-hepatic presentations further compromised the treatment efficacy. In the IFN-free DAA era, data showing similar SVR rates and safety profiles between the elderly and their counterparts have been demonstrated. Notably, aging is an unfavorable factor for fibrosis regression and HCC development even after HCV eradication. The extent of the improvement of extra-hepatic manifestations in the elderly with SVR is also unclear. The long-term benefits of viral eradication by DAAs in the elderly await further explorations.
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Affiliation(s)
- Chung-Feng Huang
- a Hepatobiliary Division, Department of Internal Medicine , Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung , Taiwan
- b Faculty of Internal Medicine, School of Medicine, College of Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan
- c Department of Occupational Medicine, Kaohsiung Medical University Hospital , Kaohsiung Medical University , Kaohsiung , Taiwan
| | - Ming-Lung Yu
- a Hepatobiliary Division, Department of Internal Medicine , Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung , Taiwan
- b Faculty of Internal Medicine, School of Medicine, College of Medicine , Kaohsiung Medical University , Kaohsiung , Taiwan
- d Institute of Biomedical Sciences , National Sun Yat-Sen University , Kaohsiung , Taiwan
- e Liver Center, Division of Gastroenterology , Massachusetts General Hospital, Harvard Medical School , Boston , MA , USA
- f College of Biological Science and Technology , National Chiao Tung University , Hsin-Chu , Taiwan
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Akutagawa M, Ide K, Kawasaki Y, Yamanaka M, Iketani R, Yamada H, Masaki N. Safety Profile of Telaprevir-Based Triple Therapy in Elderly Patients: A Real-World Retrospective Cohort Study. Biol Pharm Bull 2017; 40:1525-1529. [PMID: 28603159 DOI: 10.1248/bpb.b17-00354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
To compare the rate of treatment discontinuation due to adverse events for telaprevir-based triple (T/PR) and pegylated interferon-alfa-2b and ribavirin (PR) therapy for the treatment of hepatitis C virus (HCV) infection in patients over the age of 65 years, in Japan. Retrospective analysis of the health data of patients over the age of 65 years treated for a HCV infection genotype 1 using T/PR or PR therapy, from 38 prefectures in Japan. The primary outcome was the rate of treatment discontinuation due to adverse events for T/PR and PR. The secondary outcome was to evaluate the prevalence and type of adverse events during the treatment period that resulted in treatment discontinuation for both therapies. For comparison, the T/PR and PR populations were matched using the propensity score method, and adjusted odds ratios (ORs) for treatment discontinuation calculated by multivariate logistic regression analysis. The study group included 1330 patients, 328 in the T/PR group and 1002 in the PR group. The rate of treatment discontinuation due to adverse events in the matched population was lower for T/PR (19.82%) than PR (35.98%) therapy, (adjusted OR, 0.418; 95% confidence interval, 0.292-0.599; p<0.01). Malaise was the principal cause of treatment discontinuation in both groups (T/PR, 30.77%, and PR, 42.37%). Using real-world health data of elderly individuals in Japan, we identified a lower rate of treatment discontinuation for T/PR than PR. Our outcomes provide information for a segment of the population that is generally excluded for clinical trials.
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Affiliation(s)
- Maiko Akutagawa
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Kazuki Ide
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
- Center for the Promotion of Interdisciplinary Education and Research, Kyoto University
| | - Yohei Kawasaki
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
- Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University
| | - Mie Yamanaka
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Ryo Iketani
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Hiroshi Yamada
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka
| | - Naohiko Masaki
- Laboratory Testing Department, National Center for Global Health and Medicine
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Yu JH, Lee JI, Lee KS, Kim JK. Real-life prevalence of resistance-associated variants against non-structural protein 5A inhibitors and efficiency of Daclatasvir + Asunaprevir therapy in Korean patients with genotype 1b hepatitis C. Virol J 2017; 14:164. [PMID: 28836992 PMCID: PMC5571669 DOI: 10.1186/s12985-017-0826-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 08/14/2017] [Indexed: 02/08/2023] Open
Abstract
Background Direct-acting antivirals (DAAs) for chronic hepatitis C (CHC) treatment are tolerable and highly effective in a shorter period of time than before. However, resistance-associated variants (RAVs) can affect the efficacy of DAAs. The aim of this study was to investigate the real-life prevalence of RAVs against non-structural protein 5A (NS5A) inhibitors in Korean patients with genotype 1b chronic hepatitis C. Methods All consecutive patients with CHC genotype 1b who underwent a RAV test at a single referral hospital were enrolled. Results A total of 142 patients (male 53, female 89) were tested for RAVs. The average age of the patients was 58 years. Liver cirrhosis was found in 34.5% (49/142) of patients, and 19.0% (29/142) of patients had previously undergone interferon-based treatment. Twenty-nine patients (20.4%) had RAVs (Y93 or L31). Y93H, L31, or Y93H with L31 were detected in 22 (15.5%), 8 (5.6%), and 1 (0.7%) patients, respectively. The presence of RAV was not affected by previous interferon-based treatment or by the existence of liver cirrhosis. Among 113 patients without baseline NS5A RAVs, 72 patients started daclatasvir (DCV) + asunaprevir (ASV) treatment and 95% (68/72) patients achieved virologic response at week 4. Virologic response at end of treatment and sustained virologic response at 12 weeks after treatment were achieved by 94% (68/72) and 94% (68/72), respectively. Conclusions In Korean patients with genotype 1b CHC, 20.4% (29 of 142) of patients showed RAVs against NS5A inhibitors. Patient without RAVs who received treatment with DCV + ASV showed high virologic response rates in Korea.
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Affiliation(s)
- Jung Hwan Yu
- Gangnam Severance Hospital, Department of Internal Medicine, Yonsei University College of Medicine, 20, 63-gil, Eonju-ro Gangnam-gu, Seoul, 06229, South Korea
| | - Jung Il Lee
- Gangnam Severance Hospital, Department of Internal Medicine, Yonsei University College of Medicine, 20, 63-gil, Eonju-ro Gangnam-gu, Seoul, 06229, South Korea
| | - Kwan Sik Lee
- Gangnam Severance Hospital, Department of Internal Medicine, Yonsei University College of Medicine, 20, 63-gil, Eonju-ro Gangnam-gu, Seoul, 06229, South Korea
| | - Ja Kyung Kim
- Gangnam Severance Hospital, Department of Internal Medicine, Yonsei University College of Medicine, 20, 63-gil, Eonju-ro Gangnam-gu, Seoul, 06229, South Korea.
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Kumada H, Suzuki F, Kamiya N, Orihashi M, Nakayasu Y, Yamada I. Efficacy and safety of telaprevir with pegylated interferon α-2a and ribavirin in Japanese patients. Hepatol Res 2017; 47:514-521. [PMID: 27062488 DOI: 10.1111/hepr.12722] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/16/2016] [Accepted: 04/04/2016] [Indexed: 01/01/2023]
Abstract
AIM To assess the efficacy and safety of telaprevir (TVR) in combination with pegylated interferon α-2a (PEG-IFNα-2a) and ribavirin (RBV) for treatment-naïve patients and relapsed patients compared to previous TVR-based triple therapy in Japan. METHODS The study group included 35 treatment-naïve (median age, 55 years) and 19 relapsed (median age, 55 years) patients with genotype 1 hepatitis C virus infection. Patients received TVR (750 mg every 8 h) for 12 weeks, in combination with PEG-IFNα-2a and RBV. RESULTS The sustained virological response (SVR24 ) rates for naïve and relapsed patients were 85.7% (30/35) and 94.7% (18/19), respectively. The discontinuation rate of all study drugs due to adverse events was 5.6% (3/54). Among the 54 patients, grade 3 skin disorders and grade 3 anemia (<8.0 g/dL) were reported in 2 (3.7%) and 6 patients (11.1%), respectively. Although the overall safety profiles were similar for the TVR/PEG-IFNα-2a/RBV and TVR/PEG-IFNα-2b/RBV regimens (previous study), the proportion of patients discontinuing all study drugs due to adverse events was lower in the patients treated with the TVR/PEG-IFNα-2a/RBV regimen (3/54, 5.6%) than TVR/PEG-IFNα-2b/RBV regimen (44/267, 16.5%). CONCLUSION Telaprevir in combination with PEG-IFNα-2a/RBV provided a high sustained virological response rate for the treatment of genotype 1 hepatitis C virus in both treatment-naïve and relapsed patients in Japan. Telaprevir-based therapy may provide a useful treatment option for patients who are difficult to treat due to NS5A (Y93, L31) and NS3/4A (D168) variants.
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Affiliation(s)
| | | | - Naohiro Kamiya
- SOUYAKU, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Madori Orihashi
- SOUYAKU, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Yoshiyuki Nakayasu
- SOUYAKU, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
| | - Ichimaro Yamada
- IKUYAKU, Integrated Value Development Division, Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan
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Kalafateli M, Buzzetti E, Thorburn D, Davidson BR, Tsochatzis E, Gurusamy KS. Pharmacological interventions for acute hepatitis C infection: an attempted network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011644. [PMID: 28285495 PMCID: PMC6464698 DOI: 10.1002/14651858.cd011644.pub2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) is a single-stranded RNA (ribonucleic acid) virus that has the potential to cause inflammation of the liver. The traditional definition of acute HCV infection is the first six months following infection with the virus. Another commonly used definition of acute HCV infection is the absence of HCV antibody and subsequent seroconversion (presence of HCV antibody in a person who was previously negative for HCV antibody). Approximately 40% to 95% of people with acute HCV infection develop chronic HCV infection, that is, have persistent HCV RNA in their blood. In 2010, an estimated 160 million people worldwide (2% to 3% of the world's population) had chronic HCV infection. The optimal pharmacological treatment of acute HCV remains controversial. Chronic HCV infection can damage the liver. OBJECTIVES To assess the comparative benefits and harms of different pharmacological interventions in the treatment of acute HCV infection through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, we assessed the comparative benefits and harms of different interventions versus each other or versus no intervention using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to April 2016 to identify randomised clinical trials on pharmacological interventions for acute HCV infection. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with acute HCV infection. We excluded trials which included previously liver transplanted participants and those with other coexisting viral diseases. We considered any of the various pharmacological interventions compared with placebo or each other. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on the available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS We identified 10 randomised clinical trials with 488 randomised participants that met our inclusion criteria. All the trials were at high risk of bias in one or more domains. Overall, the evidence for all the outcomes was very low quality evidence. Nine trials (467 participants) provided information for one or more outcomes. Three trials (99 participants) compared interferon-alpha versus no intervention. Three trials (90 participants) compared interferon-beta versus no intervention. One trial (21 participants) compared pegylated interferon-alpha versus no intervention, but it did not provide any data for analysis. One trial (41 participants) compared MTH-68/B vaccine versus no intervention. Two trials (237 participants) compared pegylated interferon-alpha versus pegylated interferon-alpha plus ribavirin. None of the trials compared direct-acting antivirals versus placebo or other interventions. The mean or median follow-up period in the trials ranged from six to 36 months.There was no short-term mortality (less than one year) in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials that reported follow-up beyond one year, there were no further deaths. The number of serious adverse events was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha (rate ratio 2.74, 95% CI 1.40 to 5.33; participants = 237; trials = 2; I2 = 0%). The proportion of people with any adverse events was higher with interferon-alpha and interferon-beta compared with no intervention (OR 203.00, 95% CI 9.01 to 4574.81; participants = 33; trials = 1 and OR 27.88, 95% CI 1.48 to 526.12; participants = 40; trials = 1). None of the trials reported health-related quality of life, liver transplantation, decompensated liver disease, cirrhosis, or hepatocellular carcinoma. The proportion of people with chronic HCV infection as indicated by the lack of sustained virological response was lower in the interferon-alpha group versus no intervention (OR 0.27, 95% CI 0.09 to 0.76; participants = 99; trials = 3; I2 = 0%). The differences between the groups were imprecise or not estimable (because neither group had any events) for all the remaining comparisons.Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. AUTHORS' CONCLUSIONS Very low quality evidence suggests that interferon-alpha may decrease the incidence of chronic HCV infection as measured by sustained virological response. However, the clinical impact such as improvement in health-related quality of life, reduction in cirrhosis, decompensated liver disease, and liver transplantation has not been reported. It is also not clear whether this finding is applicable in the current clinical setting dominated by the use of pegylated interferons and direct-acting antivirals, although we found no evidence to support that pegylated interferons or ribavirin or both are effective in people with acute HCV infection. We could find no randomised trials comparing direct-acting antivirals with placebo or other interventions for acute HCV infection. There is significant uncertainty in the benefits and harms of the interventions, and high-quality randomised clinical trials are required.
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Affiliation(s)
- Maria Kalafateli
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Elena Buzzetti
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryPond StreetLondonUKNW3 2QG
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUK
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Ogawa E, Furusyo N, Yamashita N, Kawano A, Takahashi K, Dohmen K, Nakamuta M, Satoh T, Nomura H, Azuma K, Koyanagi T, Kotoh K, Shimoda S, Kajiwara E, Hayashi J. Effectiveness and safety of daclatasvir plus asunaprevir for patients with hepatitis C virus genotype 1b aged 75 years and over with or without cirrhosis. Hepatol Res 2017; 47:E120-E131. [PMID: 27142311 DOI: 10.1111/hepr.12738] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 04/03/2016] [Accepted: 04/22/2016] [Indexed: 02/08/2023]
Abstract
AIM The aim of this study was to evaluate the efficacy and safety of 24-week daclatasvir (NS5A inhibitor) plus asunaprevir (NS3/4 A protease inhibitor) treatment for elderly patients with hepatitis C virus (HCV) genotype 1b infection. METHODS This prospective, multicenter study consisted of 321 Japanese HCV genotype 1b patients who were interferon-ineligible/intolerant or non-responders to interferon-based regimens, including 103 (32.1%) aged ≥75 years and 127 (39.6%) with cirrhosis. Sustained virological response (SVR) at 24 weeks after the end of treatment and adverse effects were analyzed according to age. RESULTS The overall SVR rate was 90.3%. In terms of by age, 94.5% (69/73), 88.3% (128/145), and 90.3% (93/103) of the patients aged <65, 65-74, and ≥75 years, respectively, achieved SVR. For the entire cohort, pre-existent NS5A resistance-associated variants and prior simeprevir failure were independently associated with treatment failure. According to the analysis of patients without these unfavorable pretreatment factors, 90.8% (89/98) aged ≥75 years achieved SVR, although this was significantly lower than for those aged <65 years (98.5%, 66/67) (P < 0.05). The frequency of adverse effects was comparable for the <75 and ≥75 age groups, the most common being an elevated alanine aminotransferase level (>150 U/L, 8.7%), however, no decompensating events were seen. CONCLUSIONS Daclatasvir plus asunaprevir for HCV genotype 1b was well tolerated and effective for patients without pre-existent NS5A resistance-associated variants or simeprevir failure, irrespective of fibrosis status. However, it was less effective for very old patients aged ≥75 years compared to those aged <65.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Naoki Yamashita
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | | | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - Takeaki Satoh
- Center for Liver Disease, Kokura Medical Center, National Hospital Organization, Kitakyushu, Japan
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | | | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | | | - Jun Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
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Yamagiwa S, Ishikawa T, Waguri N, Sugitani S, Wakabayashi H, Ohkoshi S, Tsukishiro T, Takahashi T, Watanabe T, Terai S. Efficacy and safety of telaprevir- and simeprevir-based triple therapies for older patients with chronic hepatitis C. World J Hepatol 2017; 9:252-262. [PMID: 28261382 PMCID: PMC5316845 DOI: 10.4254/wjh.v9.i5.252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 12/29/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate and compare the efficacy and safety of telaprevir (TVR)-and simeprevir (SMV)-based triple therapies in elderly patients, specifically patients aged 66 years or older. METHODS The present study enrolled 112 and 76 Japanese patients with chronic hepatitis C virus genotype 1b infection who were treated with a 12-wk TVR-based or SMV-based triple therapy, respectively, followed by a dual therapy that included pegylated interferon α and ribavirin (RBV) for 12 wk. The patients were categorized into two groups according to age as follows: A younger group of patients aged ≤ 65 years old and an older group of patients aged > 65 years old. Among the patients treated with TVR-based triple therapy, 34 patients were included in the older group. The median ages were 56 years (range: 28-65 years) in the younger group and 69 years (range: 66-81 years) in the older group. Among the patients treated with SMV-based triple therapy, 39 patients were included in the older group. The median ages were 59 years (range: 36-65 years) in the younger group and 71 years (range: 66-86 years) in the older group. The clinical, biochemical and virological data were analyzed before and during treatment. RESULTS Among the patients treated with the TVR-based triple therapy, no significant difference in the sustained virological response (SVR) was found between the younger (80.8%) and older (88.2%) groups. The SVR rates for patients with the interleukin 28B (IL28B) (rs8099917) TG/GG-genotypes (73.9% and 60.0% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (86.3% and 92.9%, respectively). The cumulative exposure to RBV for the entire 24-wk treatment period (as a percentage of the target dose) was significantly higher in the younger group than in the older group (91.7% vs 66.7%, respectively, P < 0.01), but the cumulative exposure to TVR was not significantly different between the younger and older groups (91.6% vs 81.9%, respectively). A multivariate analysis identified the TT-genotype of IL28B (OR = 8.160; 95%CI: 1.593-41.804, P = 0.012) and the adherence of RBV (> 60%) (OR = 11.052; 95%CI: 1.160-105.273, P = 0.037) as independent factors associated with the SVR. Adverse events resulted in discontinuation of the treatment in 11.3% and 14.7% of the younger and older groups, respectively. Among the patients treated with the SMV-based triple therapy, no significant difference in the SVR rare was found between the younger (81.1%) and older (82.1%) groups. The SVR rates for patients with the IL28B TG/GG-genotypes (77.8% and 64.7% in the younger and older groups, respectively) were significantly lower than for patients with the IL28B TT-genotype (88.2% and 100%, respectively). A multivariate analysis identified the TT-genotype of IL28B as an independent factor associated with the SVR (OR = 9.677; 95%CI: 1.114-84.087, P = 0.040). Adverse events resulted in discontinuation of the treatment in 7.0% and 14.3% of patients in the younger and older groups, respectively. CONCLUSION Both TVR- and SMV-based triple therapies can be successfully used to treat patients aged 66 years or older with genotype 1b chronic hepatitis C. Genotyping of the IL28B indicates a potential to achieve SVR in these difficult-to-treat elderly patients.
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Affiliation(s)
- Satoshi Yamagiwa
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Toru Ishikawa
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Nobuo Waguri
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Soichi Sugitani
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Hiroto Wakabayashi
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Shogo Ohkoshi
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Takashi Tsukishiro
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Toru Takahashi
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Toshiaki Watanabe
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
| | - Shuji Terai
- Satoshi Yamagiwa, Shuji Terai, Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
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Inoue T, Hmwe SS, Shimada N, Kato K, Ide T, Torimura T, Kumada T, Toyoda H, Tsubota A, Takaguchi K, Wakita T, Tanaka Y. Clinical Significance of Two Real-Time PCR Assays for Chronic Hepatitis C Patients Receiving Protease Inhibitor-Based Therapy. PLoS One 2017; 12:e0170667. [PMID: 28118381 PMCID: PMC5261727 DOI: 10.1371/journal.pone.0170667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/09/2017] [Indexed: 12/20/2022] Open
Abstract
The aim of this study was to determine the efficacy of two hepatitis C virus (HCV) real-time PCR assays, the COBAS AmpliPrep/COBAS TaqMan HCV test (CAP/CTM) and the Abbott RealTime HCV test (ART), for predicting the clinical outcomes of patients infected with HCV who received telaprevir (TVR)-based triple therapy or daclatasvir/asunaprevir (DCV/ASV) dual therapy. The rapid virological response rates in patients receiving TVR-based triple therapy were 92% (23/25) and 40% (10/25) for CAP/CTM and ART, respectively. The false omission rate (FOR) of ART was 93.3% (14/15), indicating that CAP/CTM could accurately predict clinical outcome in the early phase. In an independent examination of 20 patients receiving TVR-based triple therapy who developed viral breakthrough or relapse, the times to HCV disappearance by ART were longer than by CAP/CTM, whereas the times to HCV reappearance were similar. In an independent experiment of WHO standard HCV RNA serially diluted in serum containing TVR, the analytical sensitivities of CAP/CTM and ART were similar. However, cell cultures transfected with HCV and grown in medium containing TVR demonstrated that ART detected HCV RNA for a longer time than CAP/CTM. Similar results were found for 42 patients receiving DCV/ASV dual therapy. The FOR of ART was 73.3% (11/15) at week 8 after initiation of therapy, indicating that ART at week 8 could not accurately predict the clinical outcome. In conclusion, although CAP/CTM and ART detected HCV RNA with comparable analytical sensitivity, CAP/CTM might be preferable for predicting the clinical outcomes of patients receiving protease inhibitor-based therapy.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory, Nagoya City University Hospital, Nagoya, Japan
| | - Su Su Hmwe
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Noritomo Shimada
- Ootakanomori Hospital, Kashiwa, Japan
- Division of Gastroenterology and Hepatology, Shin-Matsudo Central General Hospital, Matsudo, Japan
| | - Keizo Kato
- Division of Gastroenterology and Hepatology, Shin-Matsudo Central General Hospital, Matsudo, Japan
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Takashi Kumada
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Akihito Tsubota
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yasuhito Tanaka
- Department of Clinical Laboratory, Nagoya City University Hospital, Nagoya, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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12
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Kohjima M, Kurokawa M, Enjoji M, Yoshimoto T, Nakamura T, Ohashi T, Fukuizumi K, Harada N, Murata Y, Matsunaga K, Kato M, Kotoh K, Nakamuta M. Analysis of renal function during telaprevir-based triple therapy for chronic hepatitis C. Exp Ther Med 2016; 11:1781-1787. [PMID: 27168803 DOI: 10.3892/etm.2016.3133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 11/05/2015] [Indexed: 12/23/2022] Open
Abstract
Telaprevir (TVR) is used for the treatment of chronic hepatitis C in a combination therapy with pegylated-interferon and ribavirin. Although renal dysfunction is one of the critical adverse outcomes of this treatment, little is known regarding the mechanism of its onset. The present study assessed the association of renal function with TVR dose and viral response. Hematological, biochemical, urinary and virological parameters of renal function were examined during the TVR-based triple therapy of patients infected with hepatitis C virus (HCV) genotype 1b. Serum creatinine levels were increased and the estimated glomerular filtration rate (eGFR) was decreased in every patient during TVR administration, but these values recovered to normal levels following cessation of TVR. Fractional excretion of sodium was <1% at days 3 and 7, appearing similar regardless of baseline renal function. Urinary β2-microglobulin levels were elevated and were significantly higher in patients with renal dysfunction, as compared with those not exhibiting renal dysfunction (P<0.05). The reduction in renal function was milder in patients treated with a reduced TVR dose, and these patients had a significantly lower risk of developing renal dysfunction (P<0.05). Using a multivariate analysis, TVR dose and eGFR at the initiation of treatment were identified as significant contributory factors in the development of renal dysfunction. Reduction in TVR dose did not lead to a significant increase in the viral kinetics of HCV or detrimental effects on the sustained viral response (SVR) rate. It is hypothesized that renal dysfunction during TVR treatment is caused by damage of the renal tubule, in addition to pre-renal dysfunction, and that reduction in TVR dose reduces the rate of renal dysfunction without causing a significant decrease in the SVR rate.
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Affiliation(s)
- Motoyuki Kohjima
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Miho Kurokawa
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Munechika Enjoji
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Tsuyoshi Yoshimoto
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Tsukasa Nakamura
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Tomoko Ohashi
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Kunitaka Fukuizumi
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Naohiko Harada
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
| | - Yusuke Murata
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Kazuhisa Matsunaga
- Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814-0180, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka 812-8582, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan
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Ikezaki H, Furusyo N, Hiramine S, Ura K, Mitsumoto-Kaseida F, Takayama K, Shimizu M, Toyoda K, Ogawa E, Kainuma M, Murata M, Hayashi J. Association of IL28B rs8099917 genotype and female sex with spontaneous clearance of hepatitis C virus infection: a Japanese cross-sectional study. Arch Virol 2016; 161:641-8. [PMID: 26660164 DOI: 10.1007/s00705-015-2703-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 11/24/2015] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus (HCV) infection is a serious global health problem. Previous studies have suggested that the interleukin 28B (IL28B) rs8099917 genotype is related to spontaneous clearance of HCV in Caucasian populations. Our objective was to investigate the association of the IL28B rs8099917 genotype with spontaneous clearance of HCV by community-dwelling Japanese. A cross-sectional community-based population study of 993 Japanese residents was conducted. Based on anti-HCV antibody and HCV RNA levels, 50 subjects were assigned to the spontaneous-clearance group, 155 to the chronic-infection group, and 788 to the control group. Logistic regression analysis was done to examine the roles of the IL28B rs8099917 genotype and sex. To analyze the interactions between these factors, an "IL28B rs809991 genotype × sex" interaction term was included in the multivariate analysis. Significantly more subjects in the spontaneous-clearance group than in the chronic-infection group had the favorable IL28B rs8099917 genotype and were female. Multivariate logistic regression analysis extracted the favorable IL28B rs8099917 TT genotype (odds ratio [OR] 9.39; 95% confidence interval [CI], 2.16-40.83, P = 0.003) and female sex (OR, 2.27; 95% CI, 1.16-4.45, P = 0.017) as factors contributing to the spontaneous clearance of HCV. No significant interaction was found between the IL28B rs8099917 genotype and sex (P for interaction = 0.428). Both the favorable IL28B rs8099917 genotype and female sex were associated with the spontaneous clearance of HCV in this Japanese population.
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Affiliation(s)
- Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan.
- Nutritional Epidemiology Program, Jean Mayor USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, 02111, USA.
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan.
| | - Satoshi Hiramine
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Kazuya Ura
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Fujiko Mitsumoto-Kaseida
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Koji Takayama
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Motohiro Shimizu
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Kazuhiro Toyoda
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Mosaburo Kainuma
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 8128582, Japan
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Hara-Doi Hospital, Fukuoka, 8138588, Japan
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Uchida Y, Kouyama JI, Naiki K, Sugawara K, Ando S, Nakao M, Motoya D, Inao M, Imai Y, Nakayama N, Mochida S. Significance of variants associated with resistance to NS5A inhibitors in Japanese patients with genotype 1b hepatitis C virus infection as evaluated using cycling-probe real-time PCR combined with direct sequencing. J Gastroenterol 2016; 51:260-70. [PMID: 26245700 DOI: 10.1007/s00535-015-1106-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Accepted: 07/13/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Dual oral therapy with daclatasvir plus asunaprevir yielded an SVR rate of 85% among patients with genotype 1b HCV. Treatment failure mainly occurred in patients with pre-existing HCV with NS5A-Y93H mutation. The significance of the mutation was evaluated. METHODS The percent of serum NS5A-Y93H strains relative to the total strains was quantified using cycling-probe real-time PCR combined with direct sequencing in 444 patients with genotype 1b HCV, and the factors associated with mutation were analyzed. The mutation rates during interferon therapy were measured sequentially. RESULTS NS5A-Y93H strains (1-100% of the total strains) were detected in 87 patients (19.6%). Mutant strains were detected more frequently among women than among men, in patients with a favorable allele in the IL28B-related gene SNP than among those with unfavorable alleles, and among patients without HCC and/or with serum AFP levels less than 6.0 ng/ml than among those with HCC and/or levels of 6.0 ng/ml or more. A multivariate analysis revealed that IL28B-related gene polymorphisms were significant factors associated with mutant strains. Although the frequency of patients with mutant strains was equivalent among patients depending on their previous interferon therapies, a sequential analysis during the interferon administrations revealed that the mutant strains disappeared earlier than the wild-type strains. CONCLUSIONS NS5A-Y93H mutation was associated with sex, serum AFP levels, and IL28B-related gene polymorphisms in patients infected with genotype 1b HCV. The indications for NS5A inhibitor use should be determined based on these factors, since mutant strains seem to be sensitive to interferon.
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Affiliation(s)
- Yoshihito Uchida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Jun-Ichi Kouyama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Kayoko Naiki
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Kayoko Sugawara
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Satsuki Ando
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Masamitsu Nakao
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Daisuke Motoya
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Mie Inao
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Yukinori Imai
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Nobuaki Nakayama
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan
| | - Satoshi Mochida
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Machi, Iruma-Gun, Saitama, 350-0495, Japan.
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Influence of insulin resistance on the development of hepatocellular carcinoma after antiviral treatment for non-cirrhotic patients with chronic hepatitis C. Infect Agent Cancer 2016; 11:9. [PMID: 26913058 PMCID: PMC4765113 DOI: 10.1186/s13027-016-0056-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 02/04/2016] [Indexed: 02/07/2023] Open
Abstract
Background Insulin resistance is considered to be an important factor in the progression of fibrosis and the enhancement of the risk of hepatocellular carcinoma (HCC) for chronic hepatitis C patients. The aim of this study was to assess the effect of insulin resistance on the development of HCC by non-cirrhotic chronic hepatitis C patients treated with pegylated interferon alpha-2b (PEG-IFNα2b) and ribavirin. Methods This retrospective study consisted of 474 Japanese non-cirrhotic patients with chronic hepatitis C. The cumulative incidence of HCC was estimated using the Kaplan-Meier method, according to insulin resistance by the homeostasis model assessment of insulin resistance (HOMA-IR) and treatment outcome. Results The overall sustained virological response (SVR) rate was 45.1 % (214/474, genotype 1: 35.4 % [129/364] and genotype 2: 77.3 % [85/110]). Twenty-one (4.4 %) patients developed HCC during the follow-up period. The 5-year cumulative incidence of HCC of the SVR group (2.6 %) was significantly lower than that of the non-SVR group (9.7 %) (log-rank test: P = 0.025). In multivariable logistic regression analysis, HOMA-IR (≥2.5) (hazard ratio [HR] 12.8, P = 0.0006), fibrosis status (F3) (HR 8.85, P < 0.0001), and post-treatment alanine aminotransferase (ALT) level (≥40 U/L) (HR 4.33, P = 0.036) were independently correlated to the development of HCC. Receiver operating characteristic analysis to determine the optimal threshold value of HOMA-IR for predicting the development of HCC in the non-SVR group showed that the areas under the curve was high (0.80, cutoff value: 3.0). Only three patients (1.4 %) who achieved SVR developed HCC. Two of them had severe insulin resistance and did not show improvement in HOMA-IR after achieving SVR. Conclusions Insulin resistance has a strong impact on the development of HCC by non-cirrhotic patients who have PEG-IFNα2b and ribavirin treatment failure.
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Ura K, Furusyo N, Ogawa E, Hayashi T, Mukae H, Shimizu M, Toyoda K, Murata M, Hayashi J. Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker that can predict the efficacy of direct-acting anti-viral-based triple therapy for chronic hepatitis C. Aliment Pharmacol Ther 2016; 43:114-24. [PMID: 26503582 DOI: 10.1111/apt.13431] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Revised: 07/28/2015] [Accepted: 09/25/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND The Wisteria floribunda agglutinin-positive human Mac-2-binding protein (WFA(+) -M2BP) is a new liver fibrosis glycobiomarker with unique fibrosis-related glyco-alteration. WFA(+) -M2BP is also a useful surrogate marker for the risk of developing hepatocellular carcinoma and for the liver functional reserve. AIM To evaluate the diagnostic ability of WFA(+) -M2BP for liver fibrosis in the clinical setting and the clinical utility of WFA(+) -M2BP for predicting the efficacy of direct-acting anti-viral (DAA) treatment for chronic hepatitis C patients. METHODS The study included 159 genotype 1 hepatitis C patients who received DAA-based treatment (telaprevir or simeprevir) combined with pegylated-interferon alpha plus ribavirin (108 telaprevir- and 51 simeprevir-based triple treatment). The relation between baseline serum WFA(+) -M2BP and treatment efficacy was evaluated. RESULTS The serum WFA(+) -M2BP level significantly increased with the progress of liver fibrosis. Area under the receiver operating characteristic curve analysis identified 2.17 as the cut-off index (COI) for WFA(+) -M2BP for diagnosing advanced fibrosis. The sustained virological response (SVR) rate was significantly, negatively correlated with the serum WFA(+) -M2BP level. Multiple logistic regression analysis found a low serum WFA(+) -M2BP level (<2.17 COI) to be independently associated with SVR (odds ratio, 4.35, P = 0.027). Even for prior nonresponders and patients with the interleukin-28B minor allele or histological advanced fibrosis, treatment outcome was favourable for patients with a low serum WFA(+) -M2BP level. CONCLUSION Serum WFA(+) -M2BP is a non-invasive liver fibrosis marker useful for predicting the efficacy of DAA-based triple therapy for chronic hepatitis C patients.
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Affiliation(s)
- K Ura
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.,Department of Environmental Medicine and Infectious Disease, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - N Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.,Department of Environmental Medicine and Infectious Disease, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - E Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.,Department of Environmental Medicine and Infectious Disease, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - T Hayashi
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - H Mukae
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - M Shimizu
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - K Toyoda
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - M Murata
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.,Department of Environmental Medicine and Infectious Disease, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - J Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
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Impact of HCV kinetics on treatment outcome differs by the type of real-time HCV assay in NS3/4A protease inhibitor-based triple therapy. Antiviral Res 2015; 126:35-42. [PMID: 26692214 DOI: 10.1016/j.antiviral.2015.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2015] [Revised: 11/27/2015] [Accepted: 12/07/2015] [Indexed: 12/21/2022]
Abstract
Repeated measurement of the HCV RNA level is essential for properly monitoring treatment efficacy. The aim of this study was to determine the utility of two HCV real-time assays in the evaluation of the impact of hepatitis C virus (HCV) kinetics on the outcome of triple therapy with NS3/4A protease inhibitors (PIs), telaprevir or simeprevir. This study consisted of 171 Japanese patients infected with HCV genotype 1. All 3266 serum samples taken during and post treatment were tested with both the COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HCV Test v2.0 and the Abbott RealTime (ART) HCV Test. Of the 2597 samples undetectable (lower limit of detection [<LOD]) for HCV RNA by the CAP/CTM assay from the on and post treatment, 400 (15.4%) (369 detectable/less than the lower limitation of quantification [<LLOQ] and 31 quantifiable) were detectable by the ART assay. HCV RNA < LOD within the first four weeks by ART was associated with sustained virological response (SVR) for the difficult-to-treat group that included patients with advanced fibrosis or prior partial/null response. In contrast, for the non-difficult-to-treat group, almost all of the late responders by ART achieved SVR, unlike by CAP/CTM. Despite HCV RNA being once < LOD by ART, 33.1% patients experienced the reappearance of residual HCV RNA (detectable/<LLOQ) during treatment. This event in the first 12 weeks (with PI-treatment period) was not related to treatment failure, however, relapse was observed in all patients with a reappearance of residual HCV RNA after 12 weeks (without PI-treatment period). The superior ability to detect low-level HCV RNA by ART could be useful for predicting SVR by difficult-to-treat patients in the early period and relapse in the late period.
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Ogawa E, Furusyo N, Kajiwara E, Nomura H, Kawano A, Takahashi K, Dohmen K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J. Comparative effectiveness and safety study of triple therapy with simeprevir or telaprevir for non-cirrhotic patients with chronic hepatitis C virus genotype 1b infection. J Gastroenterol Hepatol 2015; 30:1759-67. [PMID: 26095167 DOI: 10.1111/jgh.13016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Revised: 05/03/2015] [Accepted: 05/10/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIM The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to pegylated-interferon alpha (PEG-IFNα) and ribavirin (triple therapy) has greatly improved treatment outcome. The aim of this study was to compare the effectiveness and safety of simeprevir-based or telaprevir-based triple therapy for non-cirrhotic patients in real-world clinical practice. METHODS This multicenter study consisted of 835 consecutive Japanese HCV genotype 1b patients treated in a clinical setting, 716 of whom were enrolled (simeprevir = 256 and telaprevir = 460). Logistic regression was carried out after propensity score matching to assess the sustained virological response at week 12 after the end of treatment (SVR12). RESULTS In the propensity-matched cohort (253 matched pairs), the SVR12 rates of the patients who underwent simeprevir-based or telaprevir-based triple therapy were 85.0% and 84.2%, respectively, by intention-to-treat analysis. Prior treatment response to PEG-IFNα/ribavirin and IL28B genotype was independently associated with SVR12 in both groups. No significant differences in the SVR12 rates stratified by prior treatment response to PEG-IFNα/ribavirin were found between the simeprevir (treatment-naïve 89.1%, prior relapse 94.3%, prior partial response 65.0%, and prior null response 33.3%) and telaprevir (treatment-naïve 87.8%, prior relapse 90.1%, prior partial response 68.4%, and prior null response 50.0%) groups. The incidence of adverse effects, such as anemia, severe rash, and the elevation of serum creatinine, was markedly higher in the telaprevir group. CONCLUSIONS Considering the effectiveness and safety, simeprevir-based triple therapy will continue to be a useful treatment option in Japan for treatment-naïve or prior relapse patients with a favorable IL28B genotype.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiji Kajiwara
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | | | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | - Takeaki Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan
| | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | | | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
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Ogawa E, Furusyo N, Dohmen K, Kajiwara E, Kawano A, Nomura H, Takahashi K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J. Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure. J Viral Hepat 2015; 22:992-1001. [PMID: 26075320 DOI: 10.1111/jvh.12427] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Accepted: 04/24/2015] [Indexed: 02/07/2023]
Abstract
Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.
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Affiliation(s)
- E Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - N Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - K Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | - E Kajiwara
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - A Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - H Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - K Takahashi
- Department of Medicine, Hamanomachi Hospital, Fukuoka, Japan
| | - T Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan
| | - K Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - M Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - T Koyanagi
- Department of Medicine, Fukuoka City Hospital, Fukuoka, Japan
| | - K Kotoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - S Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - J Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
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Abstract
Chronic hepatitis C virus (HCV) infection is the leading cause for the development of liver cirrhosis and hepatocellular carcinoma, however, it also causes metabolic disorders. Insulin resistance is representative of these metabolic disorders, and not only leads to the development of diabetes but also affects the outcome of antiviral treatment with interferon. Historically, the standard of care for chronic HCV infection was pegylated interferon and ribavirin, but only 40-50% of HCV genotype 1 patients achieve a sustained virological response (SVR). We successfully established a pretreatment prediction model for the treatment outcome using a homeostasis model assessment of insulin resistance (HOMA-IR) and the interleukin 28B genotype (rs 8099917). In recent years, antiviral agents targeting viral proteins critical for HCV replication have become available. Of these, telaprevir, an HCV NS3/4A serine protease inhibitor, has been available in Japan since 2011. As a result, about 80% of patients with HCV genotype 1 can achieve SVR. Nonetheless, insulin resistance is associated with treatment failure, especially for difficult-to-treat patients. In the near future, almost all patients with chronic HCV infection will achieve virological clearance with combined direct antiviral agents, however, insulin resistance will remain a risk for hepatocellular carcinoma. Therefore, the prevention of obesity and avoidance of excessive alcohol intake are very important after achieving SVR.
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Hiramine S, Furusyo N, Ogawa E, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Satoh T, Azuma K, Kawano A, Koyanagi T, Kotoh K, Shimoda S, Hayashi J. Importance of virological response in the early stage of telaprevir-based triple therapy for hepatitis C. World J Hepatol 2015; 7:2688-2695. [PMID: 26609346 PMCID: PMC4651913 DOI: 10.4254/wjh.v7.i26.2688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 05/03/2015] [Accepted: 09/07/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the efficacy of virological response (VR) to telaprevir (TVR)-based triple therapy in predicting treatment outcome of hepatitis C.
METHODS: This prospective, multicenter study consisted of 253 Japanese patients infected with hepatitis C virus (HCV) genotype 1b. All received 12 wk of TVR in combination with 24 wk of pegylated-interferon-α (IFN-α) and ribavirin. Serum HCV RNA was tested at weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. VR was defined as undetectable serum HCV RNA. Sustained virological response (SVR) was VR at 24 wk after the end of treatment and was regarded as a successful outcome.
RESULTS: Of 253 patients, 207 (81.8%) achieved SVR. The positive predictive value of VR for SVR was 100% at week 2, after which it gradually decreased, and was over 85% to week 12. The negative predictive value (NPV) gradually increased, reaching 100% at week 12. The upslope of the NPV showed a large increase from week 4 (40.6%) to week 6 (82.4%). There was a moderate concordance between the SVR and VR at week 6 (kappa coefficient = 0.44), although other VRs had poor concordance to SVR. Multiple logistic regression analysis extracted VR at week 6 (P < 0.0001, OR = 63.8) as an independent factor contributing to SVR. In addition, the interleukin-28B single nucleotide polymorphism and response to previous pegylated-IFN-α and ribavirin therapy were identified as independent factors for SVR.
CONCLUSION: VR at week 6, but not at week 4, is an efficient predictor of both SVR and non-SVR to TVR-based triple therapy.
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Ohkoshi S, Hirono H, Yamagiwa S. Direct antiviral agent treatment of decompensated hepatitis C virus-induced liver cirrhosis. World J Gastrointest Pharmacol Ther 2015; 6:114-119. [PMID: 26558145 PMCID: PMC4635151 DOI: 10.4292/wjgpt.v6.i4.114] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 07/15/2015] [Accepted: 09/10/2015] [Indexed: 02/06/2023] Open
Abstract
Recently, direct antiviral agents (DAAs) have been increasingly used for the treatment of chronic hepatitis C virus (HCV) infections, replacing interferon-based regimens that have severe adverse effects and low tolerability. The constant supply of new DAAs makes shorter treatment periods with enhanced safety possible. The efficacy of DAAs for treatment of compensated liver cirrhosis (LC) is not less than that for treatment of non-cirrhotic conditions. These clinical advantages have been useful in pre- and post-liver transplantation (LT) settings. Moreover, DAAs can be used to treat decompensated HCV-induced LC in elderly patients or those with severe complications otherwise having poor prognosis. Although encouraging clinical data are beginning to appear, the actual efficacy of DAAs for suppressing disease progression, allowing delisting for LT and, most importantly, improving prognosis of patients with decompensated HCV-LC remains unknown. Case-control studies to examine the short- or long-term effects of DAAs for treatment of decompensated HCV-LC are urgently need.
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Abstract
Hepatitis C virus (HCV) infection in the elderly population is a global medical burden and healthcare utilization concern. The majority of patients with hepatitis C in the USA are "baby boomers," who were born between 1945 and 1965. Consistently worldwide, HCV infection in elderly population is overrepresented and poses public health concerns. These individuals have been infected now for over two decades and are presenting with advanced liver disease. Traditionally, the use of pegylated interferon-based therapy has been limited in the elderly because of its adverse effects. The sustained virologic responses have also tended to be lower in the elderly than in younger adults. The emergence of non-interferon-based therapy with direct acting antiviral agents has expanded the pool of patients eligible for treatment. These agents have been found to be effective, tolerable, and safe in the elderly population.
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Simon TG, Kim AY, Stamm LM, Liu L, Mo H, Doehle B, Pang PS, Brainard DM, McHutchison JG, Gustafson J, Lauer GM, Chung RT. The safety and efficacy of ledipasvir/sofosbuvir for the treatment of a nosocomial outbreak of HCV in patients with significant cardiovascular disease. Antivir Ther 2015; 21:185-94. [PMID: 26440471 DOI: 10.3851/imp2997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND There is an unmet need for interferon- and ribavirin-free treatment for chronic HCV infection in patients with comorbidities including cardiovascular disease (CVD). The aim of this study was to evaluate the rates of sustained virological response (SVR) and adverse events in a cohort of patients with nosocomially acquired HCV genotype-1b following 12 weeks of therapy with fixed-dose combination (FDC) ledipasvir/sofosbuvir (LDV/SOF). METHODS This is a prospective, single-centre, open-label study of five non-cirrhotic patients with HCV genotype-1b and significant comorbid CVD, conducted at the Massachusetts General Hospital. All patients were prescribed an FDC tablet (LDV 90 mg/SOF 400 mg) once daily for 12 weeks. Serial measurements of safety parameters, virology, host immune correlates and adherence were performed. The primary outcome was the proportion of patients with SVR (plasma HCV RNA level <25 IU/ml), 12 weeks after treatment completion (SVR12). RESULTS All five patients (100%) achieved SVR12, with no episodes of on- or post-treatment relapse. The most commonly reported adverse events were gastrointestinal illness and upper respiratory viral-type illness. There were no serious adverse events or discontinuations of medication attributable to the study drug. Deep sequencing analysis revealed no baseline NS3, NS5A or NS5B resistance-associated variants. CONCLUSIONS In this open-label, uncontrolled, pilot study enrolling patients with HCV genotype-1b and significant CVD, administration of a fixed-dose, oral combination of LDV and SOF for 12 weeks was associated with high rates of SVR and minimal adverse events. Larger prospective studies that also include patients with cirrhosis and prior treatment non-responders are necessary.
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Affiliation(s)
- Tracey G Simon
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
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Quigley JM, Bryden PA, Scott DA, Kuwabara H, Cerri K. Relative efficacy and safety of simeprevir and telaprevir in treatment-naïve hepatitis C-infected patients in a Japanese population: A Bayesian network meta-analysis. Hepatol Res 2015; 45:E89-98. [PMID: 25559771 DOI: 10.1111/hepr.12467] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 11/07/2014] [Accepted: 12/20/2014] [Indexed: 02/07/2023]
Abstract
AIM Simeprevir (SMV) is an oral, once-daily protease inhibitor for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. In phase II/III randomized controlled trials (RCT) conducted in Japan, SMV, in combination with peginterferon-α and ribavirin (PEG IFN/RBV), demonstrated potent efficacy in HCV genotype 1-infected patients relative to PEG IFN/RBV and was generally well tolerated. Telaprevir (TVR) in combination with PEG IFN/RBV is licensed for the treatment of HCV in Japan. In the absence of head-to-head comparisons of TVR and SMV in a Japanese population, we undertook a network meta-analysis (NMA) to examine the relative efficacy and safety of SMV and TVR in combination with PEG IFN/RBV. METHODS A systematic review identified SMV and TVR RCT in Japanese treatment-naïve patients. Bayesian NMA was performed assuming fixed study effects. RESULTS Three studies met our inclusion criteria: two SMV and one TVR. SMV showed a higher mean odds ratio (OR) of achieving SVR versus TVR (OR, 1.68 (95% credible interval 0.66-4.26)). SMV showed a lower mean OR of discontinuation: overall, 0.35 (0.12-1.00); and due to AE, 0.87 (0.23-3.34) versus TVR. SMV showed a lower mean OR of experiencing anemia 0.20 (0.07-0.56) and rash 0.41 (0.17-0.99) but a higher mean OR of experiencing pruritus 1.26 (0.46-3.47) versus TVR. CONCLUSION In this indirect treatment comparison, SMV, in combination with PEG IFN/RBV, showed a favorable risk-benefit profile compared with TVR with PEG IFN/RBV in Japanese treatment-naïve HCV patients.
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Affiliation(s)
| | - Peter A Bryden
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| | | | | | - Karin Cerri
- London School of Economics and Political Sciences, London, UK.,Janssen Pharmaceutica, Beerse, Belgium
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26
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Ogawa E, Furusyo N, Kajiwara E, Nomura H, Kawano A, Takahashi K, Dohmen K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J. Comparative safety study on severe anemia by simeprevir versus telaprevir-based triple therapy for chronic hepatitis C. J Gastroenterol Hepatol 2015; 30:1309-16. [PMID: 25777545 DOI: 10.1111/jgh.12945] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/28/2015] [Indexed: 01/19/2023]
Abstract
BACKGROUND AND AIM The addition of hepatitis C virus (HCV) NS3/4A protease inhibitors to the pegylated interferon (PEG-IFN) α and ribavirin combination regimen (triple therapy) has dramatically improved treatment outcome. Unfortunately, anemia remains a common adverse effect. This study was done to compare the development of severe anemia during simeprevir- or telaprevir-based triple therapy. METHODS This retrospective multicenter study consisted of 837 consecutive Japanese HCV genotype 1 patients treated in a real-world clinical setting, 811 of whom were enrolled (simeprevir 281, telaprevir 530). The inosine triphosphate pyrophosphatase (ITPA) genotype at rs1127354 was determined for all studied patients. Logistic regression was done after propensity score matching to assess the risk of development of severe anemia. RESULTS Propensity score matching of the entire study population yielded 266 matched pairs. Severe anemia (nadir hemoglobin < 9.0 g/dL) was developed during the treatment period by 81 (30.5%) and 144 (54.1%) patients treated with simeprevir and telaprevir, respectively. Treatment with simeprevir was independently associated with a lower risk of severe anemia (odds ratio 0.25, 95% confidence interval 0.16-0.38, P < 0.0001). Moreover, ITPA genotype, age, hemoglobin level, and estimated glomerular filtration rate at baseline were also independent factors associated with the development of severe anemia. CONCLUSIONS Patients treated with simeprevir-based triple therapy have a lower risk of the development of severe anemia than those treated with telaprevir. Moreover, ITPA genotype and age may be useful for individualizing treatment to reduce the risk of anemia-related adverse effects.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiji Kajiwara
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | | | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | - Takeaki Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu, Japan
| | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | | | - Kazuhiro Kotoh
- Department of Medicine and Bioregulatory Science, Kyushu University, Fukuoka, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
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Abstract
PURPOSE OF REVIEW Aging is a condition in which a person gradually loses the ability to maintain homeostasis, due to structural alteration or dysfunction. Aging is a major risk factor for most chronic diseases. As the liver has a remarkable ability to regenerate, this review assessed the effect of aging on clinical liver disease with references to preclinical models when relevant to pathogenesis. RECENT FINDINGS Aging has been shown to not only enhance vulnerability to acute liver injury but also increase susceptibility of the fibrotic response. Aging is associated with the severity and poor prognosis of various liver diseases including nonalcoholic fatty liver disease, alcoholic liver disease, hepatitis C, and liver transplantation. SUMMARY Treatment of older patients with liver disease may require different or longer interventions. Transplantation of an older liver will be less tolerant of subsequent injury. Future studies are needed to understand more about the molecular mechanism of aging and contribute to the development of a noble treatment strategy that can block the progression of aging-induced liver diseases.
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Affiliation(s)
- Hee Kim
- Department of Internal Medicine, Chonbuk National University Medical School, Jeonju, South Korea
| | - Tatiana Kisseleva
- Department of Internal Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA
| | - David A. Brenner
- Department of Internal Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA
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Takayama K, Furusyo N, Ogawa E, Ikezaki H, Shimizu M, Murata M, Hayashi J. Direct-acting antiviral-based triple therapy on alpha-fetoprotein level in chronic hepatitis C patients. World J Gastroenterol 2015; 21:4696-4706. [PMID: 25914481 PMCID: PMC4402319 DOI: 10.3748/wjg.v21.i15.4696] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/09/2014] [Accepted: 01/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the impact of telaprevir-based triple therapy on the serum alpha-fetoprotein (AFP) level of chronic hepatitis C patients.
METHODS: A total of 210 patients with chronic hepatitis C genotype 1 of high viral load (baseline serum hepatitis C virus RNA > 5.0 log10 IU/mL) were divided into two groups by type of treatment: triple therapy with telaprevir, pegylated-interferon-α (PEG-IFNα), and ribavirin (RBV) for 24 wk (n = 88), or dual therapy with PEG-IFNα and RBV for 48 wk (n = 122). The relationship between virological response and the change in the serum AFP level from baseline to 24 wk after the end of treatment was examined.
RESULTS: No significant difference in mean baseline AFP level was found between the triple and dual therapy groups (8.8 ng/mL vs 7.8 ng/mL). Triple therapy produced significant declines in the AFP level in sustained virological response (SVR) and non-SVR patients (7.8 ng/mL at baseline to 3.5 ng/mL at 24 wk after the end of treatment, P < 0.001 and 14.3 ng/mL to 9.5 ng/mL, P = 0.004, respectively). In contrast, dual therapy resulted in a significant decline in AFP level only in SVR patients (4.7 ng/mL to 2.8 ng/mL, P < 0.001), but not in non-SVR patients (10.2 ng/mL to 10.1 ng/mL). Among patients with a high-baseline AFP level (≥ 10 ng/mL), the decline in the AFP level was significantly higher in the triple therapy than in the dual therapy group (15.9 ng/mL vs 1.6 ng/mL, P = 0.037).
CONCLUSION: Regardless of virological response, telaprevir-based triple therapy reduced the serum AFP level.
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Gurusamy KS, Toon CD, Thorburn D, Tsochatzis E, Davidson BR. Pharmacological treatments for chronic hepatitis C liver disease: a network meta-analysis. Hippokratia 2015. [DOI: 10.1002/14651858.cd011641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Kurinchi Selvan Gurusamy
- Royal Free Campus, UCL Medical School; Department of Surgery; Royal Free Hospital Rowland Hill Street London UK NW3 2PF
| | - Clare D Toon
- West Sussex County Council; Public Health Research Unit; The Grange, County Hall Campus Tower Street Chichester West Sussex UK PO19 1QT
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive Health; Sheila Sherlock Liver Centre; Pond Street London UK NW3 2QG
| | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive Health; Sheila Sherlock Liver Centre; Pond Street London UK NW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical School; Department of Surgery; Royal Free Hospital Rowland Hill Street London UK NW3 2PF
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Oze T, Hiramatsu N, Yakushijin T, Yamada R, Harada N, Morishita N, Oshita M, Mita E, Ito T, Inui Y, Inada M, Tamura S, Yoshihara H, Imai Y, Kato M, Miyagi T, Yoshida Y, Tatsumi T, Kasahara A, Hayashi N, Takehara T. The real impact of telaprevir dosage on the antiviral and side effects of telaprevir, pegylated interferon and ribavirin therapy for chronic hepatitis C patients with HCV genotype 1. J Viral Hepat 2015; 22:254-62. [PMID: 25081140 DOI: 10.1111/jvh.12289] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 05/14/2014] [Indexed: 01/28/2023]
Abstract
Triple therapy with telaprevir, pegylated interferon and ribavirin has been reported to improve antiviral efficacy but have potentially severe adverse effects in patients with chronic hepatitis C. To avoid the severe effects of telaprevir, lowering the dose has been suggested. However, impact of dosage changes on antiviral and adverse effects remains unclear. One hundred and sixty-six Japanese patients with HCV genotype 1 were treated with triple therapy. The drug exposure of each medication was calculated by averaging the dose actually taken. The overall SVR rate was 82%. The telaprevir discontinuation rate was 26%. The factors associated with discontinuation were an older age (≥65 y.o.) and a higher average dose during treatment. The telaprevir discontinuation rates were 42%, 25% and 14% in patients at ≥35, 25-35 and <25 mg/kg/day of telaprevir and 58% in older patients at ≥35 mg/kg/day of TVR. The factors associated with SVR were treatment-naïve, relapse to previous treatment, higher average telaprevir dose during treatment and completion of treatment. The SVR rate was higher, at 91%, in patients at 25-35 mg/kg/day of telaprevir than the 71% and 78% observed in those at <25 and ≥35 mg/kg/day of drug. In Japanese patients, a mean telaprevir dose of 25-35 mg/kg/day during treatment can augment its efficacy in triple therapy for patients with HCV genotype 1.
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Affiliation(s)
- T Oze
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
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Abstract
Although HCV infection mainly induces liver injury, chronic disease is systemic. Moreover, host and viral factors, as well as comorbidities, may influence the chance of achieving a sustained virological response or disease outcome. Although there are sufficient data on the use of peg-interferon and ribavirin in patients with comorbidities, there is very little data on first generation protease inhibitors, which include significant drug-drug interactions and have therefore been administered with caution in these patients. The availability of new, more effective direct acting antivirals should significantly change this scenario. All these issues are discussed in this review.
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Affiliation(s)
- Vincenzo Boccaccio
- Department of Internal Medicine, A.O. Fatebenefratelli e Oftalmico, Milan, Italy
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Tamori A, Kioka K, Sakaguchi H, Enomoto M, Hai H, Kawamura E, Hagihara A, Fujii H, Uchida-Kobayashi S, Iwai S, Morikawa H, Murakami Y, Kawasaki Y, Tsuruta D, Kawada N. Effects on anemia of drug adjustment in patients with chronic hepatitis C during telaprevir-combined therapy. Ann Hepatol 2015; 14:28-35. [PMID: 25536639 DOI: 10.1016/s1665-2681(19)30798-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
AIM Anemia is the most common adverse event in patients with chronic hepatitis C virus (HCV) treated with telaprevir (TVR) combined triple therapy. We examined the effects of drug dose adjustment on anemia and a sustained viral response (SVR) during combination therapy. MATERIAL AND METHODS This study enrolled 62 patients treated with TVR (2,250 mg) for 12 weeks plus pegylated interferon-alpha-2b and ribavirin for 24 weeks. The patients were assigned randomly to the TVR-standard or -reduced groups before treatment. At the occurrence of anemia (hemoglobin < 12 g/dL), the TVR-reduced group received 1500 mg TVR plus the standard dose of ribavirin, whereas the TVR-standard group received the standard TVR dose (2,250 mg) and a reduced dose of ribavirin (200 mg lower than prescribed originally). The safety and SVR at 24 weeks were compared between the TVR-standard (n = 28) and TVR-reduced (n = 25) groups. RESULTS No differences in the proportion of patients who became HCV RNA-negative were detected between the TVR-standard and -reduced groups (72 and 72% at week 4, 79 and 84% at the end of treatment, and 76 and 80% at SVR24, respectively). Two groups had comparable numbers of adverse events, which led to the discontinuation of TVR in 14 patients of TVR-standard group and in 14 of TVR-reduced group. A lower incidence of renal impairment was observed in the TVR-reduced group (6%) than the TVR-standard group (11%, not statistically significant). CONCLUSIONS TVR dose adjustment could prevent anemia progression without weakening the anti-viral effect during triple therapy in HCV-patients.
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Affiliation(s)
- Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kiyohide Kioka
- Department of Hepatology Osaka City General Hospital, Osaka Japan
| | | | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hoang Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hideki Fujii
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | | | - Shuji Iwai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hiroyasu Morikawa
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoshiki Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuko Kawasaki
- Department of Hepatology Osaka City General Hospital, Osaka Japan
| | - Daisuke Tsuruta
- Department of Dermatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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Kawano A, Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Dohmen K, Nomura H, Takahashi K, Satoh T, Azuma K, Tanabe Y, Shimoda S, Kotoh K, Hayashi J. Bacterial infection as an adverse effect of telaprevir-based triple therapy for chronic hepatitis C infection. Intern Med 2015; 54:567-72. [PMID: 25790806 DOI: 10.2169/internalmedicine.54.3457] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE There is little information regarding the incidence of bacterial infections as an adverse effect of telaprevir (TVR)-based triple therapy. This study was performed in order to evaluate the baseline and on-treatment predictors of bacterial infections in patients treated with TVR-based triple therapy. METHODS This multicenter study evaluated 430 patients with chronic hepatitis C who received 12 weeks of TVR in combination with 24 weeks of pegylated interferon α2b plus ribavirin. The occurrence of a bacterial infection during anti-viral treatment was defined as the onset of local or systemic inflammation as a result of pathogenic bacteria. RESULTS Bacterial infections occurred in 21 of the 430 (4.9%) patients during TVR-based triple therapy. Among these subjects, 71.4% (15 of 21) experienced bacterial infections during the initial eight weeks of treatment. Urinary tract infections were the most frequent infection, observed in 2.8% of cases (12 of 430). The rate of urinary tract infection among women (11 of 215, 5.1%) was significantly higher than that observed among men (1 of 215, 0.5%) (p<0.0001). According to a multivariable logistic regression analysis, the only significant independent predictor was the pretreatment serum albumin level (p=0.0008). Of the 21 patients who experienced bacterial infections, only one (4.8%) had to discontinue the treatment; however, the others were able to continue anti-viral treatment in combination with antibiotic treatment. CONCLUSION Clinicians should be concerned regarding the incidence of bacterial infections among patients treated with TVR-based triple therapy, especially those with a low serum albumin level.
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Affiliation(s)
- Akira Kawano
- Department of Internal Medicine, Kitakyushu Municipal Medical Center, Japan
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Shimada N, Tsubota A, Atsukawa M, Abe H, Ide T, Takaguchi K, Chuganji Y, Toyoda H, Yoshizawa K, Ika M, Sato Y, Kato K, Kumada T, Sakamoto C, Aizawa Y, Sata M. A 48-week telaprevir-based triple combination therapy improves sustained virological response rate in previous non-responders to peginterferon and ribavirin with genotype 1b chronic hepatitis C: A multicenter study. Hepatol Res 2014; 44:E386-E396. [PMID: 24606109 DOI: 10.1111/hepr.12323] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Revised: 03/02/2014] [Accepted: 03/05/2014] [Indexed: 02/08/2023]
Abstract
AIM The sustained virological response (SVR) rate of non-responders to peginterferon and ribavirin therapy (PR) is low for 24-week telaprevir-based triple combination therapy (T12PR24), compared to that of treatment-naïve patients or previous-treatment relapsers. This study investigated which characteristics of non-responders were associated with a better SVR rate to 48-week therapy (T12PR48). METHODS A total of 103 Japanese non-responders with genotype 1b chronic hepatitis C received telaprevir-based therapy. Among them, 81 patients (50 partial and 31 null responders) received T12PR24 and 22 (seven partial and 15 null responders) who agreed to the extended therapy received T12PR48. RESULTS Multivariate logistic regression analysis for SVR identified the interleukin-28B (IL28B) rs8099917 TT genotype (P = 0.0005, odds ratio [OR] = 10.38), extended rapid virological response (P = 0.0008, OR = 7.02), T12PR48 regimen (P = 0.0016, OR = 9.31) and previous partial responders (P = 0.0022, OR = 5.89). Among partial responders, the SVR rate did not differ significantly between T12PR48 (85.7%) and T12PR24 (70.0%). Among null responders, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 22.6%, P = 0.0037). Among patients with the IL28B non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (68.8% vs 37.7%, P = 0.0288). Moreover, among null responders with the non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 9.1%, P = 0.0009). CONCLUSION T12PR48 improves the SVR rate in null responders, patients with the non-TT genotype, and null responders with a non-TT genotype.
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Affiliation(s)
- Noritomo Shimada
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Japan
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Fujino H, Imamura M, Nagaoki Y, Kawakami Y, Abe H, Hayes CN, Kan H, Fukuhara T, Kobayashi T, Masaki K, Ono A, Nakahara T, Honda Y, Naeshiro N, Urabe A, Yokoyama S, Miyaki D, Murakami E, Kawaoka T, Hiraga N, Tsuge M, Hiramatsu A, Hyogo H, Aikata H, Takahashi S, Miki D, Ochi H, Ohishi W, Chayama K. Predictive value of the IFNL4 polymorphism on outcome of telaprevir, peginterferon, and ribavirin therapy for older patients with genotype 1b chronic hepatitis C. J Gastroenterol 2014; 49:1548-56. [PMID: 24362944 DOI: 10.1007/s00535-013-0924-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 12/03/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND Older patients with chronic hepatitis C have a lower virological response to interferon (IFN) treatment compared to younger patients. The efficacy of telaprevir (TVR) and PEG-IFN plus ribavirin combination therapy and the predictive value of recently identified IFN lambda (IFNL) 4 polymorphisms on the outcome of therapy for older patients have not been addressed. METHODS We assessed predictive factors for sustained virological response (SVR) to triple therapy in 226 younger (≤65 years) and 87 older (>65 years) Japanese patients with chronic genotype 1 hepatitis C. IFNL4 polymorphism ss469415590 was analyzed by Invader assay. RESULTS The SVR rate for older patients was slightly lower than for younger patients (69 vs. 82%, P = 0.043). In the older group, the SVR rate for patients with the IFNL4 TT/TT genotype was significantly higher than patients with TT/ΔG or ΔG/ΔG genotypes (81.8 and 42.9%, P = 0.003). In multivariate regression analysis, rapid virological response (OR 36.601, P = 0.002) and IFNL4 TT/TT genotype (OR 19.502, P = 0.009) were identified as significant independent predictors for SVR in older patients. Treatment-related decreases in hemoglobin and increases in serum creatinine were higher in older patients than younger patients. Reduction of initial TVR dose to 1,500 mg per day alleviated these adverse events without compromising SVR rate in older patients. CONCLUSIONS Analysis of IFNL4 polymorphisms is a valuable predictor in older patients receiving TVR triple therapy. 1,500 mg per day is a suitable initial TVR dose for older Japanese patients.
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Affiliation(s)
- Hatsue Fujino
- 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
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Nishikawa H, Enomoto H, Nasu A, Aizawa N, Saito M, Tamori A, Kawada N, Kimura T, Osaki Y, Nishiguchi S. Clinical significance of pretreatment serum interferon-gamma-inducible protein 10 concentrations in chronic hepatitis C patients treated with telaprevir-based triple therapy. Hepatol Res 2014; 44:E397-E407. [PMID: 24628684 DOI: 10.1111/hepr.12326] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 03/08/2014] [Accepted: 03/10/2014] [Indexed: 02/08/2023]
Abstract
AIM We aimed to determine whether pretreatment serum interferon-γ-inducible protein (IP)-10 concentration can predict response to telaprevir (TVR)-based triple therapy in patients with genotype 1 chronic hepatitis C (CHC), and to examine the effects of IP-10 concentration on liver histology. METHODS Baseline IP-10 concentrations were measured in 97 patients with genotype 1 CHC treated with TVR-based triple therapy, and the associations between baseline IP-10 and treatment outcome were assessed by univariate and multivariate analyses. Associations between baseline serum IP-10 concentration and laboratory data and liver histological findings were also investigated. RESULTS Median IP-10 concentration in these patients was 461.83 pg/mL (range, 151.35-4297.62). Multivariate analysis showed that IL28B genotype (P = 0.025) and IP-10 level (P = 0.004) were factors significantly predictive of rapid virological response (RVR), whereas in pretreatment factors only, IL28B genotype (P = 0.001) and liver fibrosis (P = 0.035) were independent predictors of sustained virological response. Using a cut-off IP-10 concentration of 460 pg/mL, patients with IL28B risk allele and low IP-10 had a significantly higher RVR rate than those with high IP-10 (P = 0.005). IP-10 concentration was significantly correlated with liver fibrosis (P = 0.001) and inflammation activity (P = 0.006) and had the highest areas under the curve for liver histological findings. CONCLUSION Baseline serum IP-10 level is a useful predictor of virological response in patients with genotype 1 CHC treated with TVR-based triple therapy, especially in patients with IL28B risk allele. IP-10 was well correlated with liver fibrosis and inflammation.
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Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Takita M, Hagiwara S, Kudo M, Kouno M, Chishina H, Arizumi T, Kitai S, Yada N, Inoue T, Minami Y, Ueshima K. Efficacy and safety of telaprevir-based antiviral treatment for elderly patients with hepatitis C virus. Oncology 2014; 87 Suppl 1:110-7. [PMID: 25427742 DOI: 10.1159/000368154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Telaprevir-based antiviral therapy has been the primary treatment for chronic hepatitis C genotype 1 at a high viral load since November 2011. On the other hand, a number of patients have been reported to require withdrawal from or reduced doses of drugs due to side effects, such as eruptions, anemia, and renal dysfunction. In addition, as hepatitis C patients are growing older, it is imperative to investigate the tolerability of triple combination therapy for elderly patients. SUBJECTS AND METHODS The study subjects comprised 35 patients who received telaprevir combination therapy after November 2011. They were divided into group A (age: <65 years; n = 21) and group B (age: ≥65 years; n = 14) in order to compare the treatment completion rate, sustained virological response at week 24 (SVR24), and adverse events between the groups. RESULTS The treatment completion rate was 82.8% (29/35) in all subjects, 90.4% (19/21) in group A, and 78.5% (11/14) in group B. The rate was lower in group B but without a significant difference between the groups (p = 0.804). The SVR24 rate was 88.5% (31/35) in all subjects, 90.4% (19/21) in group A, and 85.7% (12/14) in group B, without a significant difference between the groups (p = 0.161). CONCLUSION Although the incidence of anemia was higher in group B, there was no significant difference in the treatment completion or SVR24 rate between the groups. Telaprevir combination therapy is suggested to be tolerable for elderly hepatitis C patients.
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Affiliation(s)
- Masahiro Takita
- Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka-Sayama, Japan
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Uchida Y, Kouyama JI, Naiki K, Mochida S. A novel simple assay system to quantify the percent HCV-RNA levels of NS5A Y93H mutant strains and Y93 wild-type strains relative to the total HCV-RNA levels to determine the indication for antiviral therapy with NS5A inhibitors. PLoS One 2014. [PMID: 25397971 DOI: 10.1371/journal.pone.0112647pone-d-14-33428] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM Oral treatment with asunaprevir and daclatasvir has been reported to yield a SVR ratio of 80% in patients with genotype 1b HCV infection, however, treatment failure has been reported, especially in patients with HCV strains showing the NS5A-Y93H mutation at baseline. An assay system to detect such strains was established to facilitate selection of appropriate candidates for this antiviral therapy. METHODS Primer sets and 2 types of cycling probe mixtures were designed, and real-time PCR was performed with HCV-RNA purified from 332 patients with genotype 1b HCV infection, and the results were compared with those obtained by direct sequencing. RESULTS Both the wild-type and mutant strains were quantified, with a threshold of 4.0 Log copies/mL, in 295 of the 332 patients (88.9%), and the percentage of the mutant strains relative to the total HCV-RNA level in the serum was calculated. The percentage was 0% in 237 patients (80.3%) and 100% in 23 patients (7.8%), identical to the results of direct sequencing. Both wild-type and mutant strains were detected in the remaining 35 patients (11.9%), at levels between 1% and 99%, despite the mutant strains having been undetectable by direct sequencing in 11 patients with percentages of these strains of less than 25%. CONCLUSION A novel assay system to quantify the percent RNA of Y93H mutant strains relative to the total HCV-RNA level was established. This system may be useful to determine the indication for treatment with NA5A inhibitors in patients with HCV.
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Affiliation(s)
- Yoshihito Uchida
- Department of Gastroenterology & Hepatology, Saitama Medical University, Saitama, Japan
| | - Jun-ichi Kouyama
- Department of Gastroenterology & Hepatology, Saitama Medical University, Saitama, Japan
| | - Kayoko Naiki
- Department of Gastroenterology & Hepatology, Saitama Medical University, Saitama, Japan
| | - Satoshi Mochida
- Department of Gastroenterology & Hepatology, Saitama Medical University, Saitama, Japan
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Uchida Y, Kouyama JI, Naiki K, Mochida S. A novel simple assay system to quantify the percent HCV-RNA levels of NS5A Y93H mutant strains and Y93 wild-type strains relative to the total HCV-RNA levels to determine the indication for antiviral therapy with NS5A inhibitors. PLoS One 2014; 9:e112647. [PMID: 25397971 PMCID: PMC4232421 DOI: 10.1371/journal.pone.0112647] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 10/10/2014] [Indexed: 02/07/2023] Open
Abstract
Aim Oral treatment with asunaprevir and daclatasvir has been reported to yield a SVR ratio of 80% in patients with genotype 1b HCV infection, however, treatment failure has been reported, especially in patients with HCV strains showing the NS5A-Y93H mutation at baseline. An assay system to detect such strains was established to facilitate selection of appropriate candidates for this antiviral therapy. Methods Primer sets and 2 types of cycling probe mixtures were designed, and real-time PCR was performed with HCV-RNA purified from 332 patients with genotype 1b HCV infection, and the results were compared with those obtained by direct sequencing. Results Both the wild-type and mutant strains were quantified, with a threshold of 4.0 Log copies/mL, in 295 of the 332 patients (88.9%), and the percentage of the mutant strains relative to the total HCV-RNA level in the serum was calculated. The percentage was 0% in 237 patients (80.3%) and 100% in 23 patients (7.8%), identical to the results of direct sequencing. Both wild-type and mutant strains were detected in the remaining 35 patients (11.9%), at levels between 1% and 99%, despite the mutant strains having been undetectable by direct sequencing in 11 patients with percentages of these strains of less than 25%. Conclusion A novel assay system to quantify the percent RNA of Y93H mutant strains relative to the total HCV-RNA level was established. This system may be useful to determine the indication for treatment with NA5A inhibitors in patients with HCV.
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Affiliation(s)
- Yoshihito Uchida
- Department of Gastroenterology & Hepatology, Saitama Medical University, Saitama, Japan
| | - Jun-ichi Kouyama
- Department of Gastroenterology & Hepatology, Saitama Medical University, Saitama, Japan
| | - Kayoko Naiki
- Department of Gastroenterology & Hepatology, Saitama Medical University, Saitama, Japan
| | - Satoshi Mochida
- Department of Gastroenterology & Hepatology, Saitama Medical University, Saitama, Japan
- * E-mail:
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40
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Shimada N, Toyoda H, Tsubota A, Ide T, Takaguchi K, Kato K, Kondoh M, Matsuyama K, Kumada T, Sata M. Baseline factors and very early viral response (week 1) for predicting sustained virological response in telaprevir-based triple combination therapy for Japanese genotype 1b chronic hepatitis C patients: a multicenter study. J Gastroenterol 2014; 49:1485-94. [PMID: 24287582 DOI: 10.1007/s00535-013-0918-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Accepted: 11/11/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Genetic polymorphisms near Interleukin 28B (IL28B) (rs8099917) and a rapid virological response (RVR) have been reported as predictors for a sustained virological response (SVR) to telaprevir (TVR)-based triple combination therapy. However, the association between SVR and viral kinetics earlier than week 4 after initiation of therapy remains unclear. Thus, we evaluated the SVR prediction ability of baseline factors and reduced hepatitis C virus (HCV) RNA levels at week 1 after the initiation of TVR-based therapy in Japanese genotype-1b chronic hepatitis C (CHC) patients. METHODS A total of 156 Japanese CHC patients received a 24-week regimen of TVR-based therapy. Baseline factors and reduction in HCV RNA levels at weeks 1 and 4 after the initiation of therapy were analyzed for SVR prediction. RESULTS Multiple logistic regression analysis for SVR in TVR-based therapy identified the IL28B TT genotype, a reduction of ≥ 4.7 log10 IU/mL in HCV RNA levels at week 1, RVR, and treatment-naïve/relapse. Whereas the SVR rate was higher than 90 % regardless of the reduction in HCV RNA levels at week 1 in patients with the TT genotype, a reduction of ≥ 4.7 log10 IU/mL in HCV RNA levels at week 1 was the strongest predictor of SVR in patients with the non-TT genotype, as determined by multiple logistic regression analysis (P = 0.0043). CONCLUSIONS The IL28B TT genotype is the most important baseline factor for predicting SVR, and a ≥ 4.7 log10 IU/mL reduction in HCV RNA at week 1 is a useful very early on-treatment predictor of SVR, especially in the non-TT genotype.
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Affiliation(s)
- Noritomo Shimada
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, 1-380 Shinmatsudo, Matsudo, Chiba, 270-0034, Japan,
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Abstract
INTRODUCTION The population of patients with hepatitis C is aging. In some countries, the prevalence of hepatitis C virus (HCV) is actually greater in older patients than in younger individuals. It is also anticipated that hepatitis C will increasingly become a disease of older persons. However, patients older than 70 years are typically excluded from clinical trials. The decision to treat older patients is complex and cannot be made at the sole discretion of the physician. AREAS COVERED There is an urgent need to analyze treatment outcomes in the elderly to examine response rates in order to aid in therapeutic decision making. EXPERT OPINION In geriatric HCV-infected patients, dual therapy with pegylated IFN plus ribavirin is associated with a lower sustained virologic response and a higher discontinuation rate. Even the first-generation protease inhibitors are associated with high rates of side effects, in particular in elderly patients with a high prevalence of comorbidities. The recent development of interferon-sparing regimens could change the treatment paradigm in this setting, and a much larger number of patients could have access to the antiviral therapy programs.
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Affiliation(s)
- Fabio Conti
- University of Bologna, Department of Medical and Surgical Sciences , Via Massarenti, 9, 40138 Bologna , Italy
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Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Satoh T, Azuma K, Kawano A, Tanabe Y, Kotoh K, Shimoda S, Akahoshi T, Maehara Y, Hayashi J. Efficacy and safety of splenectomy in telaprevir-based triple therapy for chronic hepatitis C patients with thrombocytopenia and advanced fibrosis. J Gastroenterol Hepatol 2014; 29:1728-35. [PMID: 24731162 DOI: 10.1111/jgh.12619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/22/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM Thrombocytopenia (TCP) of chronic hepatitis C patients with cirrhosis has a negative impact on the management of interferon-based treatment. The aim of this study is to evaluate the efficacy and safety of telaprevir-based triple therapy for patients who have undergone splenectomy (Spx). METHODS This prospective, multicenter study consisted of 80 patients, including 32 Spx and 48 non-Spx/TCP (platelet count: 60-99 × 10(9) /L) patients with advanced fibrosis infected with hepatitis C virus genotype 1b. All received 12 weeks of telaprevir in combination with 24 weeks of pegylated interferon (PEG-IFN) α2b and ribavirin. RESULTS The sustained virological response (SVR) rate of the Spx group (75.0%) was significantly higher than that of the non-Spx/TCP group (52.1%) (P < 0.05). Under favorable conditions such as treatment-naïve/prior relapse and interleukin-28B (IL28B) TT allele (rs8099917), the SVR rates of the Spx group were significantly higher than those of the non-Spx/moderate TCP (60-79 × 10(9) /L) groups (91.3% vs 50.0% and 93.8% vs 37.5%, respectively; both P < 0.05). Adequate PEG-IFNα2b adherence was associated with SVR. However, the percentage of patients who achieved 80% adherence to PEG-IFNα2b in the non-Spx/moderate TCP (42.9%) group was significantly lower than that of the Spx (79.3%) and non-Spx/mild TCP (80-99 × 10(9) /L) (80.0%) groups. Treatment discontinuation due to adverse effects and the development of bacterial infection did not differ between the Spx and non-Spx/TCP groups. CONCLUSION The increase of platelet count after Spx contributed to treatment success, especially for moderate to severe TCP patients who are treatment-naïve/prior relapse or IL28B TT allele.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
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Abe H, Tsubota A, Shimada N, Atsukawa M, Kato K, Takaguchi K, Asano T, Chuganji Y, Sakamoto C, Toyoda H, Kumada T, Ide T, Sata M, Aizawa Y. Predictors of response to 24-week telaprevir-based triple therapy for treatment-naïve genotype 1b chronic hepatitis C patients. Gastroenterol Res Pract 2014; 2014:549709. [PMID: 25197269 PMCID: PMC4150495 DOI: 10.1155/2014/549709] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 07/19/2014] [Accepted: 08/04/2014] [Indexed: 01/20/2023] Open
Abstract
We evaluated the genetic variation in rs8099917, substitutions in core amino acid (aa) 70, and the number of aa substitutions in the interferon sensitivity-determining region (ISDR) on the prediction of sustained virological response (SVR) in treatment-naïve hepatitis C virus (HCV) genotype 1b (G1b) patients. This multicenter study involved 150 Asian treatment-naïve patients infected with HCV G1b who received 12 weeks of telaprevir in combination with 24 weeks of peginterferon-α-2b and ribavirin. The baseline and treatment-related factors potentially associated with SVR were determined by multivariate logistic regression analysis. Virological response was analyzed on an intent-to-treat basis. Cessation of the therapy due to adverse effects occurred in only 2 patients, who discontinued the trial at 10 weeks and at 2 weeks due to cerebral infarction and renal impairment, respectively. Among the 150 patients in whom the final virological response was determined, only genotype TT in rs8099917 was identified as a pretreatment predictor (P = 7.38 × 10(-4)). Achievement of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 of treatment, was identified as an after-starting-treatment predictor (P = 2.47 × 10(-5)). However, neither a substitution in core aa 70 nor the number of substitutions in the ISDR affected treatment outcome.
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Affiliation(s)
- Hiroshi Abe
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-0062, Japan
| | - Akihito Tsubota
- Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Kashiwa, Chiba, Japan
| | - Noritomo Shimada
- Department of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Chiba, Japan
| | - Keizo Kato
- Department of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Takamatsu, Kagawa, Japan
| | - Toru Asano
- Department of Gastroenterology, Tokyo Metropolitan Bokutoh Hospital, Sumida-ku, Tokyo, Japan
| | - Yoshimichi Chuganji
- Department of Gastroenterology, Tokyo Metropolitan Bokutoh Hospital, Sumida-ku, Tokyo, Japan
| | - Choitsu Sakamoto
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Takashi Kumada
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Gifu, Japan
| | - Tatsuya Ide
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Michio Sata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Yoshio Aizawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine Katsushika Medical Center, 6-41-2 Aoto, Katsushika-ku, Tokyo 125-0062, Japan
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Takayama K, Furusyo N, Ogawa E, Shimizu M, Hiramine S, Mitsumoto F, Ura K, Toyoda K, Murata M, Hayashi J. A case of successful treatment with telaprevir-based triple therapy for hepatitis C infection after treatment failure with vaniprevir-based triple therapy. J Infect Chemother 2014; 20:577-81. [PMID: 25000830 DOI: 10.1016/j.jiac.2014.06.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 05/27/2014] [Accepted: 06/05/2014] [Indexed: 01/14/2023]
Abstract
Recently direct-acting antiviral agents, such as hepatitis C virus (HCV) non-structural 3/4A (NS3/4A) protease inhibitors (PI), have been introduced, and triple therapy regimens that include PI with conventional pegylated interferon α and ribavirin have significantly improved the sustained virological response (SVR) rate, up to 80% for both treatment-naïve and treatment-experienced patients with HCV genotype 1. We here report for the first time a case of the successful treatment of HCV genotype 1 infection with a first generation PI drug (telaprevir) based triple therapy after treatment failure with a second generation PI drug (vaniprevir) based triple therapy. A 67-year-old treatment-naïve Japanese man with HCV genotype 1b infection took part in a phase III clinical trial of vaniprevir-based triple therapy. His serum HCV RNA had become undetectable at week 2 and SVR was highly expected, but HCV RNA reappeared at week 4 after vaniprevir treatment. Polymerase chain reaction direct sequence of the HCV NS3/4A gene at week 8 after vaniprevir treatment showed the emergence of a vaniprevir-resistance mutation (D168V), the probable reason for the treatment failure. Six months later, retreatment with telaprevir-based triple therapy was started. Although the dosages of telaprevir and ribavirin had to be reduced due to severe anemia, the patient achieved an SVR. This case shows the value of repeating PI-based triple therapy with a different drug, a process that would reduce the chance of drug resistant mutation.
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Affiliation(s)
- Koji Takayama
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Motohiro Shimizu
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Satoshi Hiramine
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Fujiko Mitsumoto
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Kazuya Ura
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Kazuhiro Toyoda
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
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Kamal SM. Pharmacogenetics of hepatitis C: transition from interferon-based therapies to direct-acting antiviral agents. Hepat Med 2014; 6:61-77. [PMID: 25114601 PMCID: PMC4075960 DOI: 10.2147/hmer.s41127] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis C virus (HCV) has emerged as a major viral pandemic over the past two decades, infecting 170 million individuals, which equates to approximately 3% of the world’s population. The prevalence of HCV varies according to geographic region, being highest in developing countries such as Egypt. HCV has a high tendency to induce chronic progressive liver damage in the form of hepatic fibrosis, cirrhosis, or liver cancer. To date, there is no vaccine against HCV infection. Combination therapy comprising PEGylated interferon-alpha and ribavirin has been the standard of care for patients with chronic hepatitis C for more than a decade. However, many patients still do not respond to therapy or develop adverse events. Recently, direct antiviral agents such as protease inhibitors, polymerase inhibitors, or NS5A inhibitors have been used to augment PEGylated interferon and ribavirin, resulting in better efficacy, better tolerance, and a shorter treatment duration. However, most clinical trials have focused on assessing the efficacy and safety of direct antiviral agents in patients with genotype 1, and the response of other HCV genotypes has not been elucidated. Moreover, the prohibitive costs of such triple therapies will limit their use in patients in developing countries where most of the HCV infection exists. Understanding the host and viral factors associated with viral clearance is necessary for individualizing therapy to maximize sustained virologic response rates, prevent progression to liver disease, and increase the overall benefits of therapy with respect to its costs. Genome wide studies have shown significant associations between a set of polymorphisms in the region of the interleukin-28B (IL28B) gene and natural clearance of HCV infection or after PEGylated interferon-alpha and ribavirin treatment with and without direct antiviral agents. This paper synthesizes the recent advances in the pharmacogenetics of HCV infection in the era of triple therapies.
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Affiliation(s)
- Sanaa M Kamal
- Department of Medicine, Division of Hepatology, Gastroenterology and Tropical Medicine, Ain Shams Faculty of Medicine, Cairo, Egypt ; Department of Medicine, Salman Bin Abdul Aziz College of Medicine, Kingdom of Saudi Arabia
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46
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Malnick S, Maor Y, Melzer E, Tal S. Chronic hepatitis C in the aged: much ado about nothing or nothing to do? Drugs Aging 2014; 31:339-347. [PMID: 24664397 DOI: 10.1007/s40266-014-0170-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis C is a common infection worldwide. It is a major cause of cirrhosis and its complications, including hepatocellular carcinoma and liver transplantation. Treatment of hepatitis C has dramatically improved since its discovery. Current treatment includes pegylated interferon and ribavirin, and the addition of the protease inhibitors telaprevir, boceprevir, or simeprevir, or the polymerase inhibitor sofosbuvir. The rate of sustained viral response, considered a cure, now approaches 80 %. These treatments are complex, with multiple morbidities and drug interactions. The majority of patients with chronic hepatitis C are from the birth cohort of the 'baby boomer' years (1945-1965) with the oldest already 68 years old. In spite of this, most hepatitis C patients in clinical trials have been much younger and this is still the case in the ongoing studies. Thus, the group of patients most likely to require treatment in the future will have decisions made with a relative lack of evidence-based medicine. It is the purpose of this article to review the epidemiology, clinical manifestations, and treatment of hepatitis C with the data available in the aged population.
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Affiliation(s)
- Stephen Malnick
- Department of Internal Medicine C, Kaplan Medical Center, Affiliated with the Hebrew University of Jerusalem, Rehovot, Israel,
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Liu CH, Kao JH. Nanomedicines in the treatment of hepatitis C virus infection in Asian patients: optimizing use of peginterferon alfa. Int J Nanomedicine 2014; 9:2051-2067. [PMID: 24812506 PMCID: PMC4008289 DOI: 10.2147/ijn.s41822] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Asia is endemic for hepatitis C virus (HCV) infection, which is the leading cause of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and liver transplantation worldwide. HCV has six major genotypes and each HCV genotype has its specific geographic distribution. HCV genotypes 1, 2, 3, and 6 are common in Asia. The aim of HCV treatment is to eradicate the virus by effective therapeutic agents; viral clearance is durable after long-term post-treatment follow-up. In most Asian countries, peginterferon alfa (PEG-IFN α) in combination with ribavirin remains the standard of care, and the overall sustained viral response (SVR) rate in Asian HCV patients is higher than that in Western patients. The differences are most significant in patients with HCV genotype 1 (HCV-1) infection, which is attributed to the higher frequency of IFN-responsive or favorable interleukin-28B (IL-28B) genotype in Asian populations than in other ethnic populations. In addition, the introduction of response-guided therapy, where the optimized treatment duration is based on the early viral kinetics during the first 12 weeks of treatment, increases the SVR rate. Recently, telaprevir or boceprevir-based triple therapy was found to further improve the SVR rate in treated and untreated HCV-1 patients and has become the new standard of care in Western and some Asian countries. Many novel direct-acting antiviral agents, either in combination with PEG-IFN α plus ribavirin or used as IFN-free regimens are under active investigation. At the time of this writing, simeprevir and sofosbuvir have been approved in the US. Because the SVR rates in Asian HCV patients receiving PEG-IFN α plus ribavirin therapy are high, health care providers should judiciously determine the clinical usefulness of these novel agents on the basis of treatment duration, anticipated viral responses, patient tolerance, financial burdens, and drug accessibility.
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Affiliation(s)
- Chen-Hua Liu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
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48
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Gatselis NK, Zachou K, Saitis A, Samara M, Dalekos GN. Individualization of chronic hepatitis C treatment according to the host characteristics. World J Gastroenterol 2014; 20:2839-53. [PMID: 24659876 PMCID: PMC3961989 DOI: 10.3748/wjg.v20.i11.2839] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Revised: 11/19/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is a global health problem that affects more than 170 million people worldwide. It is a major cause of cirrhosis and hepatocellular carcinoma, making the virus the most common cause of liver failure and transplantation. The standard-of-care treatment for chronic hepatitis C (CHC) has been changed during the last decade and direct acting antiviral drugs have already been used. Besides, understanding of the pathogenesis of CHC has evolved rapidly during the last years and now several host factors are known to affect the natural history and response to treatment. Recent genome-wide association studies have shown the important role of interleukin-28B and inosine triphosphatase in HCV infection. The present review article attempts to summarize the current knowledge on the role of host factors towards individualization of HCV treatment.
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Shimada N, Tsubota A, Atsukawa M, Abe H, Ika M, Kato K, Sato Y, Kondo C, Sakamoto C, Tanaka Y, Aizawa Y. α-Fetoprotein is a surrogate marker for predicting treatment failure in telaprevir-based triple combination therapy for genotype 1b chronic hepatitis C Japanese patients with the IL28B minor genotype. J Med Virol 2014; 86:461-472. [PMID: 24166425 DOI: 10.1002/jmv.23824] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/27/2013] [Indexed: 12/14/2022]
Abstract
Even when treated with telaprevir-based triple therapy, some patients fail to achieve a sustained virological response. This study identified factors related closely to treatment failure. A total of 146 Japanese genotype 1b chronic hepatitis C patients were enrolled in this prospective, multicenter study and received a 24-week regimen of triple therapy. The end-of-treatment response rate was significantly lower in patients with the interleukin 28B (IL28B) (rs8099917) non-TT genotype (85.2%) than in those with the TT genotype (100%, P = 0.0002). Multiple logistic regression analysis identified high α-fetoprotein levels as an independent factor related to non-end-of-treatment response in patients with the non-TT genotype. A cut-off value of 20 ng/ml was determined for a non-end-of-treatment response; sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 75.0%, 95.7%, 75.0%, 75.0%, and 92.6%, respectively. Multiple logistic regression analysis for a sustained virological response identified the IL28B TT genotype, low α-fetoprotein levels, non-responders, and a rapid virological response. The sustained virological response rate was significantly lower in patients with the non-TT genotype (59.3%) than in those with the TT genotype (96.7%, P < 0.0001). In patients with the non-TT genotype, α-fetoprotein was the most significant predictor for non-sustained virological response by univariate analysis. A cut-off value of 7.4 ng/ml α-fetoprotein was determined for non-sustained virological response; sensitivity, specificity, PPV, NPV, and accuracy were 63.6%, 87.5%, 77.8%, 77.8%, and 77.8%, respectively. For the non-TT patients, serum α-fetoprotein levels may be a surrogate marker for predicting treatment failure in telaprevir-based therapy for genotype 1b chronic hepatitis C.
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Affiliation(s)
- Noritomo Shimada
- Division of Gastroenterology and Hepatology, Shinmatsudo Central General Hospital, Matsudo, Chiba, Japan
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Murata M, Furusyo N, Ogawa E, Mitsumoto F, Hiramine S, Ikezaki H, Takayama K, Shimizu M, Toyoda K, Kainuma M, Hayashi J. A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy. J Infect Chemother 2014; 20:320-4. [PMID: 24477330 DOI: 10.1016/j.jiac.2013.11.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 09/25/2013] [Accepted: 11/01/2013] [Indexed: 01/13/2023]
Abstract
In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.
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Affiliation(s)
- Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Fujiko Mitsumoto
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Satoshi Hiramine
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Koji Takayama
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Motohiro Shimizu
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Kazuhiro Toyoda
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Mosaburo Kainuma
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Jun Hayashi
- Center of Kyushu General Medicine, Haradoi Hospital, Fukuoka, Japan
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