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Salcher-Konrad M, Nguyen M, Savović J, Higgins JPT, Naci H. Treatment Effects in Randomized and Nonrandomized Studies of Pharmacological Interventions: A Meta-Analysis. JAMA Netw Open 2024; 7:e2436230. [PMID: 39331390 PMCID: PMC11437387 DOI: 10.1001/jamanetworkopen.2024.36230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/04/2024] [Indexed: 09/28/2024] Open
Abstract
Importance Randomized clinical trials (RCTs) are widely regarded as the methodological benchmark for assessing clinical efficacy and safety of health interventions. There is growing interest in using nonrandomized studies to assess efficacy and safety of new drugs. Objective To determine how treatment effects for the same drug compare when evaluated in nonrandomized vs randomized studies. Data Sources Meta-analyses published between 2009 and 2018 were identified in MEDLINE via PubMed and the Cochrane Database of Systematic Reviews. Data analysis was conducted from October 2019 to July 2024. Study Selection Meta-analyses of pharmacological interventions were eligible for inclusion if both randomized and nonrandomized studies contributed to a single meta-analytic estimate. Data Extraction and Synthesis For this meta-analysis using a meta-epidemiological framework, separate summary effect size estimates were calculated for nonrandomized and randomized studies within each meta-analysis using a random-effects model and then these estimates were compared. The reporting of this study followed the Guidelines for Reporting Meta-Epidemiological Methodology Research and relevant portions of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. Main Outcome and Measures The primary outcome was discrepancies in treatment effects obtained from nonrandomized and randomized studies, as measured by the proportion of meta-analyses where the 2 study types disagreed about the direction or magnitude of effect, disagreed beyond chance about the effect size estimate, and the summary ratio of odds ratios (ROR) obtained from nonrandomized vs randomized studies combined across all meta-analyses. Results A total of 346 meta-analyses with 2746 studies were included. Statistical conclusions about drug benefits and harms were different for 130 of 346 meta-analyses (37.6%) when focusing solely on either nonrandomized or randomized studies. Disagreements were beyond chance for 54 meta-analyses (15.6%). Across all meta-analyses, there was no strong evidence of consistent differences in treatment effects obtained from nonrandomized vs randomized studies (summary ROR, 0.95; 95% credible interval [CrI], 0.89-1.02). Compared with experimental nonrandomized studies, randomized studies produced on average a 19% smaller treatment effect (ROR, 0.81; 95% CrI, 0.68-0.97). There was increased heterogeneity in effect size estimates obtained from nonrandomized compared with randomized studies. Conclusions and Relevance In this meta-analysis of treatment effects of pharmacological interventions obtained from randomized and nonrandomized studies, there was no overall difference in effect size estimates between study types on average, but nonrandomized studies both overestimated and underestimated treatment effects observed in randomized studies and introduced additional uncertainty. These findings suggest that relying on nonrandomized studies as substitutes for RCTs may introduce additional uncertainty about the therapeutic effects of new drugs.
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Affiliation(s)
- Maximilian Salcher-Konrad
- Department of Health Policy, London School of Economics and Political Science, London, United Kingdom
- World Health Organization Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies, Pharmacoeconomics Department, Gesundheit Österreich GmbH (GÖG)/Austrian National Public Health Institute, Vienna, Austria
| | - Mary Nguyen
- Department of Health Policy, London School of Economics and Political Science, London, United Kingdom
- Department of Family and Community Medicine, University of California, San Francisco
| | - Jelena Savović
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol and Weston National Health Service Foundation Trust, Bristol, United Kingdom
| | - Julian P. T. Higgins
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- National Institute for Health and Care Research Applied Research Collaboration West, University Hospitals Bristol and Weston National Health Service Foundation Trust, Bristol, United Kingdom
| | - Huseyin Naci
- Department of Health Policy, London School of Economics and Political Science, London, United Kingdom
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Hyun HK, Cho EJ, Park SY, Hong YM, Kim SS, Kim HY, Heo NY, Park JG, Sinn DH, Kang W, Jeong SW, Song MJ, Park H, Lee D, Lee YS, Cho SB, An CS, Rhee HJ, Lee HW, Kim BK, Park JY, Kim DY, Ahn SH, Han KH, Lee JH, Yu SJ, Kim YJ, Yoon JH, Tak WY, Kweon YO, Yoon KT, Cho M, Cheong JY, Park SH, Kim SU. Direct-Acting Antivirals Improve Treatment Outcomes in Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma Treated with Transarterial Chemoembolization: A Nationwide, Multi-center, Retrospective Cohort Study. Dig Dis Sci 2021; 66:2427-2438. [PMID: 32856240 DOI: 10.1007/s10620-020-06533-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 08/03/2020] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS The influence of direct-acting antivirals (DAAs) on chronic hepatitis C (CHC)-related hepatocellular carcinoma (HCC) remains controversial. We investigated the effect of eradicating CHC using DAAs on treatment outcomes in patients with CHC-related HCC treated with transarterial chemoembolization (TACE). METHODS This nationwide, multi-center, retrospective study recruited patients with CHC-related HCC treated with TACE as the first-line anti-cancer treatment, and who achieved a sustained virological response (SVR) using DAAs (DAA group) between 2006 and 2017. Patients achieving an SVR following interferon-based treatment (IFN group) and those without treatment (control group) were also recruited for comparison. RESULTS A total of 425 patients were eligible for the study. Of these, 356 (83.8%), 26 (6.1%), and 43 (10.1%) were allocated to the control, IFN, and DAA groups, respectively. A multivariate analysis showed that liver cirrhosis, segmental portal vein thrombosis, and larger maximal tumor size independently predicted an increased risk of progression (all p < 0.05), whereas, the DAA group (vs. IFN and control groups) independently predicted a reduced risk of progression (hazard ratio (HR) = 0.630, 95% confidence interval 0.411-0.966, p = 0.034). The cumulative incidence rate of HCC progression in the DAA group was significantly lower than that in the IFN and control groups (p = 0.033, log-rank test). In addition, the DAA group (vs. IFN and control groups) was independently associated with a reduced risk of mortality (p = 0.042). CONCLUSIONS DAA treatment provided significantly prolonged progression-free survival in patients with CHC-related HCC treated with TACE compared to that in patients administered IFN or no treatment.
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Affiliation(s)
- Hye Kyung Hyun
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Soo Young Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Young Mi Hong
- Department of Internal Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Soon Sun Kim
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hwi Young Kim
- Department of Internal Medicine, College of Medicine, Ewha Woman University, Seoul, Republic of Korea
| | - Nae-Yun Heo
- Departments of Internal Medicine, Inje University College of Medicine, Busan, Republic of Korea
| | - Jung Gil Park
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Dong Hyun Sinn
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Wonseok Kang
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Song Won Jeong
- Department of Internal Medicine, Soonchunhyang University Hospital Seoul, Soonchunhyang University College of Medicine, Seoul, Republic of Korea
| | - Myeong Jun Song
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hana Park
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yong Sun Lee
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sung Bum Cho
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Chan Sik An
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Hyung Jin Rhee
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Hyun Woong Lee
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Won Young Tak
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Young Oh Kweon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Mong Cho
- Department of Internal Medicine, Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Seung Ha Park
- Departments of Internal Medicine, Inje University College of Medicine, Busan, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei Liver Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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Nagaoki Y, Imamura M, Nishida Y, Daijo K, Teraoka Y, Honda F, Nakamura Y, Morio K, Fujino H, Nakahara T, Kawaoka T, Tsuge M, Hiramatsu A, Kawakami Y, Miki D, Hiyama Y, Ochi H, Chayama K, Aikata H. The impact of interferon-free direct-acting antivirals on clinical outcome after curative treatment for hepatitis C virus-associated hepatocellular carcinoma: Comparison with interferon-based therapy. J Med Virol 2019; 91:650-658. [PMID: 30381831 DOI: 10.1002/jmv.25352] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 10/23/2018] [Indexed: 01/04/2025]
Abstract
BACKGROUND AND AIM To examine the effect on recurrence and survival of treatment by interferon (IFN)-free direct-acting antivirals (DAA) for patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) who underwent primary curative treatment. METHODS This was a retrospective cohort study of 250 patients with HCV who had received curative treatment for primary HCC. As anti-HCV treatment after HCC treatment, 38 patients received IFN-free DAA therapy (DAA patients) and 94 received IFN-based therapy (IFN patients). The recurrence of HCC and overall survival of the patient groups were compared in a case-control study. RESULTS The cumulative HCC recurrence rates at 1, 3, and 5 years were 5%, 39%, and 39% for DAA patients and 0%, 46%, and 62% for IFN patients, respectively (P = 0.370). Multivariate analysis of the HCC recurrence identified treatment responses (sustained virological response [SVR]: hazard ratio [HR] 2.237; P = 0.003) as an independent predictive factor. The cumulative overall survival rates at 3 and 5 years were 96%, 96% for DAA patients and 93%, 73% for IFN patients, respectively ( P = 0.163). Multivariate analysis identified treatment responses (SVR: HR 8.742; P < 0.001) as independent predictors of overall survival. Propensity score matching analysis showed no significant difference in HCC development rates and overall survival rates in the two groups. CONCLUSIONS We found that SVR obtained after curative treatment for primary HCC suppressed recurrence and improved overall survival. And, IFN-free DAA therapy after curative treatment for primary HCC could predict improving overall survival and suppressed HCC recurrence.
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Affiliation(s)
- Yuko Nagaoki
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yuno Nishida
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kana Daijo
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Teraoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Fumi Honda
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuki Nakamura
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Morio
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Yoshiiku Kawakami
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Yuichi Hiyama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
- Laboratory for Digestive Diseases, RIKEN Center for Integrative Medical Sciences, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan
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Bang CS, Song IH. Impact of antiviral therapy on hepatocellular carcinoma and mortality in patients with chronic hepatitis C: systematic review and meta-analysis. BMC Gastroenterol 2017; 17:46. [PMID: 28376711 PMCID: PMC5379714 DOI: 10.1186/s12876-017-0606-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Accepted: 03/28/2017] [Indexed: 12/17/2022] Open
Abstract
Background The long-term clinical outcomes of antiviral therapy for patients with chronic hepatitis C are uncertain in terms of hepatitis C virus (HCV)-related morbidity and mortality according to the response to antiviral therapy. This study aimed to assess the impact of antiviral treatment on the development of HCC and mortality in patients with chronic HCV infection. Methods A systematic review was conducted for studies that evaluated the antiviral efficacy for patients with chronic hepatitis C or assessed the development of HCC or mortality between SVR (sustained virologic response) and non-SVR patients. The methodological quality of the enrolled publications was evaluated using Risk of Bias table or Newcastle-Ottawa scale. Random-effect model meta-analyses and meta-regression were performed. Publication bias was assessed. Results In total, 59 studies (4 RCTs, 15 prospective and 40 retrospective cohort studies) were included. Antiviral treatment was associated with reduced development of HCC (vs. no treatment; OR 0.392, 95% CI 0.275–0.557), and this effect was intensified when SVR was achieved (vs. no SVR, OR: 0.203, 95% CI 0.164–0.251). Antiviral treatment was associated with lower all-cause mortality (vs. no treatment; OR 0.380, 95% CI 0.295–0.489) and liver-specific mortality (OR 0.363, 95% CI 0.260–0.508). This rate was also intensified when SVR was achieved [all-cause mortality (vs. no SVR, OR 0.255, 95% CI 0.199–0.326), liver-specific mortality (OR 0.126, 95% CI 0.094–0.169)]. Sensitivity analyses revealed robust results, and a small study effect was minimal. Conclusions In patients with chronic hepatitis C, antiviral therapy can reduce the development of HCC and mortality, especially when SVR is achieved. Electronic supplementary material The online version of this article (doi:10.1186/s12876-017-0606-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chang Seok Bang
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Republic of Korea
| | - Il Han Song
- Division of Hepatology, Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea, Republic of Korea.
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Favorable Outcomes of Chinese HCV-Related Cirrhotic Patients with Sustained Virological Response after Pegylated Interferon Plus Ribavirin Treatment. BIOMED RESEARCH INTERNATIONAL 2017; 2017:8061091. [PMID: 28232944 PMCID: PMC5292367 DOI: 10.1155/2017/8061091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 12/08/2016] [Accepted: 01/04/2017] [Indexed: 02/07/2023]
Abstract
Few studies have conducted follow-up investigations of the clinical course in HCV-related cirrhotic patients who achieved a sustained virological response (SVR) with pegylated interferon plus ribavirin treatment (PegIFN + RBV). We investigated the clinical course and laboratory data in a prospective cohort study enrolling HCV-related cirrhotic patients who received PegIFN + RBV between August 2008 and July 2013 in China. Complete blood counts, liver function tests, and HCV-RNA were serially examined. Liver-related complications were recorded. To detect hepatocellular carcinoma (HCC), alpha-fetoprotein assays, and ultrasound scans were repeated at 6-month intervals. Twenty-five patients were enrolled, including 8 patients with decompensation events before treatment. Eighteen patients achieved SVR with a mean follow-up period of 25.78 months. During the follow-up period, only one patient exhibited HCV-RNA positivity and no decompensation events were detected, but 4 patients developed HCC after SVR. APRI decreased more in patients with SVR than in patients with non-SVR (median, -1.33 versus 0.86, P < 0.001). The albumin levels and platelet counts significantly increased during the follow-up period after SVR (44.27 ± 4.09 versus 42.63 ± 4.37, P = 0.037 and 173.89 ± 87.36 versus 160.11 ± 77.97, P = 0.047). These data indicated that HCV-related cirrhotic patients with SVR after PegIFN + RBV may have a favorable clinical course and improvements in laboratory data. Moreover, HCC should be monitored.
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Gürbüz Y, Tülek NE, Tütüncü EE, Koruk ST, Aygen B, Demirtürk N, Kınıklı S, Kaya A, Yıldırmak T, Süer K, Korkmaz F, Ural O, Akhan S, Günal Ö, Tuna N, Köse Ş, Gönen İ, Örmen B, Türker N, Saltoğlu N, Batırel A, Tuncer G, Bulut C, Sırmatel F, Ulçay A, Karagöz E, Tosun D, Şener A, Aynıoğlu A, Altunok ES. Evaluation of Dual Therapy in Real Life Setting in Treatment-Naïve Turkish Patients with HCV Infection: A Multicenter, Retrospective Study. Balkan Med J 2016; 33:18-26. [PMID: 26966614 PMCID: PMC4767305 DOI: 10.5152/balkanmedj.2015.15859] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 09/30/2015] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Before the introduction of direct-acting antivirals in the treatment of chronic hepatitis C patients, the combination of peginterferon alpha and ribavirin was the standard therapy. Observational studies that investigated sustained virological response (SVR) rates by these drugs yielded different outcomes. AIMS The goal of the study was to demonstrate real life data concerning SVR rate achieved by peginterferon alpha plus ribavirin in patients who were treatment-naïve. STUDY DESIGN A multicenter, retrospective observational study. METHODS The study was conducted retrospectively on 1214 treatment naïve-patients, being treated with peginterferon alpha-2a or 2b plus ribavirin in respect of the current guidelines between 2005 and 2013. The patients' data were collected from 22 centers via a standard form, which has been prepared for this study. The data included demographic and clinical characteristics (gender, age, body weight, initial Hepatitis C virus RNA (HCV RNA) level, disease staging) as well as course of treatment (duration of treatment, outcomes, discontinuations and adverse events). Renal insufficiency, decompensated liver disease, history of transplantation, immunosuppressive therapy or autoimmune liver disease were exclusion criteria for the study. Treatment efficacy was assessed according to the patient's demographic characteristics, baseline viral load, genotype, and fibrosis scores. RESULTS The mean age of the patients was 50.74 (±0.64) years. Most of them were infected with genotype 1 (91.8%). SVR was achieved in 761 (62.7%) patients. SVR rate was 59.1% in genotype 1, 89.4% in genotype 2, 93.8% in genotype 3, and 33.3% in genotype 4 patients. Patients with lower viral load yielded higher SVR (65.8% vs. 58.4%, p=0.09). SVR rates according to histologic severity were found to be 69.3%, 66.3%, 59.9%, 47.3%, and 45.5% in patients with fibrosis stage 0, 1, 2, 3 and 4, respectively. The predictors of SVR were male gender, genotype 2/3, age less than 45 years, low fibrosis stage, low baseline viral load and presence of early virological response. SVR rates to each peginterferon were found to be similar in genotype 1/4 although SVR rates were found to be higher for peginterferon alpha-2b in patients with genotype 2/3. The number of patients who failed to complete treatment due to adverse effects was 33 (2.7%). The number of patients failed to complete treatment due to adverse effects was 33 (2.7%). CONCLUSION Our findings showed that the rate of SVR to dual therapy was higher in treatment-naïve Turkish patients than that reported in randomized controlled trials. Also peginterferon alpha-2a and alpha-2b were found to be similar in terms of SVR in genotype 1 patients.
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Affiliation(s)
- Yunus Gürbüz
- Department of Infectious Diseases and Clinical Microbiology, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Necla Eren Tülek
- Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Emin Ediz Tütüncü
- Department of Infectious Diseases and Clinical Microbiology, Dışkapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Süda Tekin Koruk
- Department of Infectious Diseases and Clinical Microbiology, Harran University Faculty of Medicine, Şanlıurfa, Turkey
| | - Bilgehan Aygen
- Department of Infectious Diseases and Clinical Microbiology, Erciyes University Faculty of Medicine, Kayseri, Turkey
| | - Neşe Demirtürk
- Department of Infectious Diseases and Clinical Microbiology, Afyon Kocatepe University Faculty of Medicine, Afyonkarahisar, Turkey
| | - Sami Kınıklı
- Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Ali Kaya
- Department of Infectious Diseases and Clinical Microbiology, Mersin University Faculty of Medicine, Mersin, Turkey
| | - Taner Yıldırmak
- Department of Infectious Diseases and Clinical Microbiology, Okmeydanı Training and Research Hospital, İstanbul, Turkey
| | - Kaya Süer
- Department of Infectious Diseases and Clinical Microbiology, Near East University Faculty of Medicine, Nicosia, North Cyprus
| | - Fatime Korkmaz
- Department of Infectious Diseases and Clinical Microbiology, Konya Training and Research Hospital, Konya, Turkey
| | - Onur Ural
- Department of Infectious Diseases and Clinical Microbiology, Selçuk University Faculty of Medicine, Konya, Turkey
| | - Sıla Akhan
- Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Özgür Günal
- Department of Infectious Diseases and Clinical Microbiology, Gaziosmanpaşa University Faculty of Medicine, Tokat, Turkey
| | - Nazan Tuna
- Department of Infectious Diseases and Clinical Microbiology, Sakarya University Faculty of Medicine, Sakarya, Turkey
| | - Şükran Köse
- Department of Infectious Diseases and Clinical Microbiology, Tepecik Training and Research Hospital, İzmir, Turkey
| | - İbak Gönen
- Department of Infectious Diseases and Clinical Microbiology, Süleyman Demirel University Faculty of Medicine, Isparta, Turkey
| | - Bahar Örmen
- Department of Infectious Diseases and Clinical Microbiology, İzmir Katip Çelebi University Atatürk Training and Research Hospital, İzmir, Turkey
| | - Nesrin Türker
- Department of Infectious Diseases and Clinical Microbiology, İzmir Katip Çelebi University Atatürk Training and Research Hospital, İzmir, Turkey
| | - Neşe Saltoğlu
- Department of Infectious Diseases and Clinical Microbiology, İstanbul University Cerrahpaşa Faculty of Medicine, İstanbul, Turkey
| | - Ayşe Batırel
- Department of Infectious Diseases and Clinical Microbiology, Kartal Dr. Lütfi Kırdar Training and Research Hospital, İstanbul, Turkey
| | - Günay Tuncer
- Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Cemal Bulut
- Department of Infectious Diseases and Clinical Microbiology, Ankara Training and Research Hospital, Ankara, Turkey
| | - Fatma Sırmatel
- Department of Infectious Diseases and Clinical Microbiology, Abant İzzet Baysal University Faculty of Medicine, Bolu, Turkey
| | - Asım Ulçay
- Department of Infectious Diseases and Clinical Microbiology, GATA Haydarpaşa Training and Research Hospital, İstanbul, Turkey
| | - Ergenekon Karagöz
- Department of Infectious Diseases and Clinical Microbiology, GATA Haydarpaşa Training and Research Hospital, İstanbul, Turkey
| | - Derviş Tosun
- Department of Infectious Diseases and Clinical Microbiology, Ulus State Hospital, Ankara, Turkey
| | - Alper Şener
- Department of Infectious Diseases and Clinical Microbiology, Çanakkale Onsekiz Mart University Faculty of Medicine, Çanakkale, Turkey
| | - Aynur Aynıoğlu
- Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
| | - Elif Sargın Altunok
- Department of Infectious Diseases and Clinical Microbiology, Kocaeli University Faculty of Medicine, Kocaeli, Turkey
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Waghray A, Murali AR, Menon KVN. Hepatocellular carcinoma: From diagnosis to treatment. World J Hepatol 2015; 7:1020-1029. [PMID: 26052391 PMCID: PMC4450179 DOI: 10.4254/wjh.v7.i8.1020] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2014] [Revised: 01/15/2015] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy worldwide and is a rising cause of cancer related mortality. Risk factors for HCC are well documented and effective surveillance and early diagnosis allow for curative therapies. The majority of HCC appears to be caused by cirrhosis from chronic hepatitis B and hepatitis C virus. Preventive strategies include vaccination programs and anti-viral treatments. Surveillance with ultrasonography detects early stage disease and improves survival rates. Many treatment options exist for individuals with HCC and are determined by stage of presentation. Liver transplantation is offered to patients who are within the Milan criteria and are not candidates for hepatic resection. In patients with advanced stage disease, sorafenib shows some survival benefit.
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Jeng WJ, Lin CC, Chen WT, Sheen IS, Lin CY, Lin SM. Adjuvant therapy for hepatocellular carcinoma after curative treatment. Dig Dis 2014; 32:747-54. [PMID: 25376293 DOI: 10.1159/000368017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy in the world. Although resection and various locoregional therapies can achieve eradication or complete ablation of small HCC, HCC recurrence after these therapies is still common. Although candidates for medical ablation usually exhibit compensated hepatic functional status, the frequent recurrence of HCC after successful ablation contributes to short survival. Therefore, attempts to prevent HCC recurrence are essential to prolong survival. Efforts in preventing HCC recurrence after curative therapies include prevention of early recurrence by improving liver immunity and eliminating microscopic tumor foci or micrometastases, and prevention of late recurrence by reducing the hepatitis activity and using antiviral therapies based on viral suppression/eradication. In HCC with vascular invasion, adjuvant transcatheter arterial chemoembolization should be considered to provide better control. Whether the adjuvant use of sorafenib may suppress microscopic tumor foci or micrometastases may be unveiled in the near future. This review article will update the algorithms, novel medication or study drugs in the prevention of HCC after curative therapies.
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Affiliation(s)
- Wen-Juei Jeng
- Division of Hepatology, Liver Research Unit, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Taipei, Taiwan, ROC
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Kusano H, Akiba J, Ogasawara S, Sanada S, Yasumoto M, Nakayama M, Ueda K, Ueda K, Kurita T, Todoroki K, Umeno Y, Nakashima O, Yano H. Pegylated interferon-α2a inhibits proliferation of human liver cancer cells in vitro and in vivo. PLoS One 2013; 8:e83195. [PMID: 24349459 PMCID: PMC3861497 DOI: 10.1371/journal.pone.0083195] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Accepted: 11/10/2013] [Indexed: 12/29/2022] Open
Abstract
Purpose We investigated the effects of pegylated interferon-α2a (PEG-IFN-α2a) on the growth of human liver cancer cells. Methods The effect of PEG-IFN-α2a on the proliferation of 13 liver cancer cell lines was investigated invitro. Cells were cultured with medium containing 0–4,194 ng/mL of PEG-IFN-α2a, and after 1, 2, 3, or 4 days of culture, morphologic observation and growth assay were performed. After hepatocellular carcinoma (HCC) cells (HAK-1B and KIM-1) were transplanted into nude mice, various doses of PEG-IFN-α2a were subcutaneously administered to the mice once a week for 2 weeks, and tumor volume, weight, and histology were examined. Results PEG-IFN-α2a inhibited the growth of 8 and 11 cell lines in a time- and dose-dependent manner, respectively, although the 50% growth inhibitory concentrations of 7 measurable cell lines on Day 4 were relatively high and ranged from 253 ng/mL to 4,431 ng/mL. Various levels of apoptosis induction were confirmed in 8 cell lines. PEG-IFN-α2a induced a dose-dependent decrease in tumor volume and weight, and a significant increase of apoptotic cells in the tumor. Subcutaneous administration of clinical dose for chronic hepatitis C (3 μg/kg, 0.06 μg/mouse) was effective and induced about 30-50% reduction in the tumor volume and weight as compared with the control. Conclusions Although invitro anti-proliferative effects of PEG-IFN-α2a were relatively weak, PEG-IFN-α2a induced strong anti-tumor effects on HCC cells invivo. The data suggest potential clinical application of PEG-IFN-α2a for the prevention and treatment of HCC.
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Affiliation(s)
- Hironori Kusano
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
- * E-mail:
| | - Jun Akiba
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Sachiko Ogasawara
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Sakiko Sanada
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Makiko Yasumoto
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Masamichi Nakayama
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Keiko Ueda
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Kosuke Ueda
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Takashi Kurita
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Keita Todoroki
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Yumi Umeno
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Osamu Nakashima
- Department of Clinical Laboratory Medicine, Kurume University Hospital, Kurume, Fukuoka, Japan
| | - Hirohisa Yano
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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Testino G, Borro P. Chemoprevention of hepatocellular carcinoma in patients with hepatitis C virus related cirrhosis. World J Hepatol 2013; 5:521-527. [PMID: 24179611 PMCID: PMC3812454 DOI: 10.4254/wjh.v5.i10.521] [Citation(s) in RCA: 4] [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: 05/13/2013] [Accepted: 09/18/2013] [Indexed: 02/06/2023] Open
Abstract
Interferon (IFN) therapy has been reported to decrease the risk of hepatocellular carcinoma (HCC) and improve survival by preventing liver-related deaths in patients with chronic hepatitis C virus (HCV) infection, while the role of IFN therapy on the natural history of hepatitis C related cirrhosis is still under debate. The ideal goal of therapy is to prevent the progression into end-stage disease. The use of IFN in patients with HCV compensated cirrhosis reduces the negative clinical evolution independently of the type of laboratoristic and virological response. In our experience, IFN therapy in HCV compensated cirrhosis is barely useful in prevention of HCC, as cirrhosis itself represents a risk of cancer. Some authors noted that IFN treatment reduces the risk of HCC independently of the virological response. It would probably be interesting to evaluate the efficacy of weekly low-dose pegylated (PEG)-IFN therapy in patients with HCV cirrhosis and to assess potential benefits of long-term PEG-IFN plus Ribavirin treatment.
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Jang JW. Management of viral hepatitis in patients with hepatocellular carcinoma. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2013; 56:1001. [DOI: 10.5124/jkma.2013.56.11.1001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Affiliation(s)
- Jeong Won Jang
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
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12
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Kimer N, Dahl EK, Gluud LL, Krag A. Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C: systematic review and meta-analysis of randomised controlled trials. BMJ Open 2012; 2:bmjopen-2012-001313. [PMID: 23089208 PMCID: PMC4400677 DOI: 10.1136/bmjopen-2012-001313] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C. DESIGN Systematic review and meta-analyses of randomised controlled trials. Prospective cohort studies were included in sensitivity analyses. DATA SOURCES Eligible trials were identified through electronic and manual searches. STUDY SELECTION Eight randomised controlled trials comparing antiviral therapy (interferon or pegylated interferon alone or with ribavirin) versus placebo or no intervention were included. DATA EXTRACTION AND SYNTHESIS Two independent reviewers assessed the methodological quality of studies and extracted data. Random effects meta-analyses were performed. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate sources of intertrial heterogeneity, the risk of bias and the robustness of the results after adjusting for multiple testing. RESULTS Random effects meta-analysis showed that antiviral therapy reduced the risk of HCC (81/1156 vs 129/1174; risk ratio 0.53, 95% CI 0.34 to 0.81). In subgroup analyses, antiviral therapy was more beneficial (test for subgroup differences p=0.03) in virological responders (0.15, 0.05 to 0.45) than in non-responders (0.57; 0.37 to 0.85). No evidence of bias was seen in regression analyses. Sequential analysis confirmed the overall result. The sensitivity analyses showed that the cohort studies found that antiviral therapy reduced the risk of HCC. There was clear statistical evidence of bias in the cohort studies (p=0.02). CONCLUSIONS Antiviral therapy may reduce the risk of HCC in hepatitis C-related fibrosis and cirrhosis. The effect may be seen irrespective of the virological response, but is more pronounced among virological responders compared with non-responders.
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Affiliation(s)
- Nina Kimer
- Department of Medical Gastroenterology, Copenhagen University Hospital
Hvidovre, Hvidovre, Denmark
| | - Emilie Kristine Dahl
- Department of Medical Gastroenterology, Copenhagen University Hospital
Hvidovre, Hvidovre, Denmark
| | - Lise Lotte Gluud
- Department of Internal Medicine, Copenhagen University Hospital
Gentofte, Hellerup, Denmark
| | - Aleksander Krag
- Department of Medical Gastroenterology, Copenhagen University Hospital
Hvidovre, Hvidovre, Denmark
- Department of Internal Medicine, Copenhagen University Hospital
Gentofte, Hellerup, Denmark
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