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Salama M, Darwesh N, Elsabaawy MM, Abdelsameea E, Gomaa A, Sabry A. Long-Term Outcomes of Patients with Liver Cirrhosis After Eradication of Chronic Hepatitis C with Direct-Acting Antiviral Drugs (DAAs). J Hepatocell Carcinoma 2024; 11:2115-2132. [PMID: 39493267 PMCID: PMC11531736 DOI: 10.2147/jhc.s475810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 10/15/2024] [Indexed: 11/05/2024] Open
Abstract
Purpose This research was designed to determine the long-term outcomes in patients with liver cirrhosis who achieved sustained virological response (SVR) after direct-acting anti-viral drugs (DAAs) based regimens. Patients and Methods This study involved 193 patients with HCV-related cirrhosis who had previously completed DAAs regimens and accomplished SVR. Clinical, laboratory, and radiological features at the first and 3rd-year follow-up after the end of treatment were analyzed. Overall survival (OS) and incidence of liver decompensation or hepatocellular carcinoma (HCC) were determined at the 5-year follow-up. Results About 68.4% of our patients with HCV-related cirrhosis were males and their mean age was 54.8 ± 7.7 years. Follow-up at the first and the 3rd-year showed significant improvements in albumin (P = 0.001), liver enzymes (P = 0.001), alpha-fetoprotein (AFP) (P < 0.001), platelet count (P = 0.001), the model for end-stage liver disease (MELD) score (P = 0.001 and 0.01), FIB4 and Aspartate Aminotransferase-to-Platelet Ratio Index (APRI) scores (p < 0.001). The liver stiffness (LS) also significantly improved (p = 0.001). At the 5th year, the mean OS was 58.3 months, with 14.5% and 17.6% of patients developing de-novo HCC and decompensation, respectively. The mean OS at the 5th-year follow-up was shorter in patients who developed HCC and those with liver decompensation (p = 0.001). Alfa-fetoprotein and LS are predictive factors for HCC development. Conclusion Despite achieving SVR, continuous surveillance for HCC and new-onset decompensation is mandatory in patients with liver cirrhosis.
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Affiliation(s)
- Mohsen Salama
- Department of Hepatology and Gastroenterology, National Liver Institute, Menofia University, Shebeen El-Kom, Menofia, Egypt
| | - Nehad Darwesh
- Department of Hepatology and Gastroenterology, National Liver Institute, Menofia University, Shebeen El-Kom, Menofia, Egypt
| | - Maha Mohammad Elsabaawy
- Department of Hepatology and Gastroenterology, National Liver Institute, Menofia University, Shebeen El-Kom, Menofia, Egypt
| | - Eman Abdelsameea
- Department of Hepatology and Gastroenterology, National Liver Institute, Menofia University, Shebeen El-Kom, Menofia, Egypt
| | - Asmaa Gomaa
- Department of Hepatology and Gastroenterology, National Liver Institute, Menofia University, Shebeen El-Kom, Menofia, Egypt
| | - Aliaa Sabry
- Department of Hepatology and Gastroenterology, National Liver Institute, Menofia University, Shebeen El-Kom, Menofia, Egypt
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Ohama H, Hiraoka A, Tada T, Kariyama K, Itobayashi E, Tsuji K, Ishikawa T, Toyoda H, Hatanaka T, Kakizaki S, Naganuma A, Tada F, Tanaka H, Nakamura S, Nouso K, Tanaka K, Kumada T. Changes in clinical outcomes in Japanese patients with hepatocellular carcinoma due to hepatitis C virus following the development of direct-acting antiviral agents. J Gastroenterol Hepatol 2024; 39:1394-1402. [PMID: 38602340 DOI: 10.1111/jgh.16553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 03/11/2024] [Accepted: 03/20/2024] [Indexed: 04/12/2024]
Abstract
BACKGROUND AND AIM Direct-acting antivirals (DAAs) have been accessible in Japan since 2014. The aim of this study is to compare how the prognosis of patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCV-HCC) changed before and after DAA development. METHODS A retrospective analysis of 1949 Japanese HCV-HCC patients from January 2000 to January 2023 categorized them into pre-DAA (before 2013, n = 1169) and post-DAA (after 2014, n = 780) groups. Changes in clinical features and prognosis were assessed. RESULTS Despite no significant differences in BCLC stage between groups, the post-DAA group exhibited higher rates of sustained virological response (SVR) (45.6% vs. 9.8%), older age (73 vs 69 years), lower levels of AST (40 vs 56 IU/L), ALT (31 vs 46 IU/L), and AFP (11.7 vs 23.6 ng/mL), higher platelet count (13.5 vs 10.8 × 104/μL), better prothrombin time (88.0% vs 81.9%), and better ALBI score (-2.54 vs -2.36) (all P < 0.001). The post-DAA group also showed higher rates of curative treatments (74.1% vs 65.2%) and significantly improved recurrence-free survival (median 2.8 vs 2.1 years). Adjusted for inverse probability weighting, overall survival was superior in the post-DAA group (median 7.4 vs 5.6 years, P < 0.001). Subanalysis within the post-DAA group revealed significantly shorter overall survival for patients without SVR (median 4.8 years vs NA vs NA) compared to pre-SVR or post-SVR patients (both P < 0.001). No significant difference in OS was observed between the pre-SVR and post-SVR groups (P = 1.0). CONCLUSION The development of DAA therapy has dramatically improved the prognosis of HCV-HCC patients.
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Affiliation(s)
- Hideko Ohama
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
- Department of Gastroenterology, Takarazuka City Hospital, Hyogo, Japan
| | - Atsushi Hiraoka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Toshifumi Tada
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Kazuya Kariyama
- Department of Hepatology, Okayama City Hospital, Okayama, Japan
| | - Ei Itobayashi
- Department of Gastroenterology, Asahi General Hospital, Asahi, Japan
| | - Kunihiko Tsuji
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takeshi Hatanaka
- Department of Gastroenterology, Gunma Saiseikai Maebashi Hospital, Gunma, Japan
| | - Satoru Kakizaki
- Department of Clinical Research, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Fujimasa Tada
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Hironori Tanaka
- Department of Gastroenterology, Takarazuka City Hospital, Hyogo, Japan
| | - Shinichiro Nakamura
- Department of Internal Medicine, Japanese Red Cross Himeji Hospital, Himeji, Japan
| | - Kazuhiro Nouso
- Department of Hepatology, Okayama City Hospital, Okayama, Japan
| | - Kazunari Tanaka
- Center of Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Takashi Kumada
- Department of Nursing, Gifu Kyoritsu University, Ogaki, Japan
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Yew KC, Tan QR, Lim PC, Low WY, Lee CY. Assessing the impact of direct-acting antivirals on hepatitis C complications: a systematic review and meta-analysis. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1421-1431. [PMID: 37728622 DOI: 10.1007/s00210-023-02716-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 09/06/2023] [Indexed: 09/21/2023]
Abstract
Direct-acting antivirals (DAA) have become the treatment of choice for hepatitis C. Nevertheless, efficacy of DAA in preventing hepatitis C complications remains uncertain. We evaluated the impact of DAA on hepatocellular carcinoma (HCC) occurrence and recurrence, all-cause mortality, liver decompensation and liver transplantation as compared to non-DAA treated hepatitis C and the association to baseline liver status. A systematic search for articles from March 1993 to March 2022 was conducted using three electronic databases. Randomized, case-control and cohort studies with comparison to non-DAA treatment and reporting at least one outcome were included. Meta-analysis and sub-group meta-analysis based on baseline liver status were performed. Of 1497 articles retrieved, 19 studies were included, comprising of 266,310 patients (56.07% male). DAA reduced HCC occurrence significantly in non-cirrhosis (RR 0.80, 95% CI 0.69-0.92) and cirrhosis (RR 0.39, 95% CI 0.24-0.64) but not in decompensated cirrhosis. DAA treatment lowered HCC recurrence (RR 0.71, 95% CI 0.55-0.92) especially in patients with baseline HCC and waiting for liver transplant. DAA also reduced all-cause mortality (RR 0.43, 95% CI 0.23-0.78) and liver decompensation (RR 0.52, 95% CI 0.33-0.83) significantly. However, DAA did not prevent liver transplantation. The study highlighted the importance of early DAA initiation in hepatitis C treatment for benefits beyond sustained virological response. DAA therapy prevented HCC particularly in non-cirrhosis and compensated cirrhosis groups indicating benefits in preventing further worsening of liver status. Starting DAA early also reduced HCC recurrence, liver decompensation, and all-cause mortality.
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Affiliation(s)
- Kuo Chao Yew
- Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore, Singapore
| | - Quan Rui Tan
- Imperial College London-Nanyang Technological University Lee Kong Chian School of Medicine, Singapore, Singapore
- Ministry of Health Holdings Pte Ltd, Singapore, Singapore
| | - Phei Ching Lim
- Pharmacy Department, Hospital Pulau Pinang, Ministry of Health Malaysia, Georgetown, Penang, Malaysia
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia
| | - Wei Yang Low
- Imperial College London-Nanyang Technological University Lee Kong Chian School of Medicine, Singapore, Singapore
- Ministry of Health Holdings Pte Ltd, Singapore, Singapore
| | - Chong Yew Lee
- School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia.
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Tao XM, Zeng MH, Zhao YF, Han JX, Mi YQ, Xu L. Direct-acting antivirals failed to reduce the incidence of hepatocellular carcinoma occurrence in hepatitis C virus associated cirrhosis: A real-world study. World J Hepatol 2024; 16:41-53. [PMID: 38313240 PMCID: PMC10835484 DOI: 10.4254/wjh.v16.i1.41] [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: 11/21/2023] [Revised: 12/18/2023] [Accepted: 01/09/2024] [Indexed: 01/23/2024] Open
Abstract
BACKGROUND Direct-acting antivirals (DAAs) revolutionized the treatment of chronic hepatitis C virus (HCV)-associated disease achieving high rates of sustained virological response (SVR). However, whether DAAs can reduce the occurrence of hepatocellular carcinoma (HCC) in patients with HCV-associated cirrhosis who are at high risk have not been concluded. AIM To investigate the effect of DAAs on the occurrence of HCC in patients with HCV-associated cirrhosis after achieving SVR. METHODS Of 427 inpatients with HCV-associated cirrhosis were enrolled in Tianjin Second People's Hospital from January 2014 to April 2020. 118 patients weren't received antiviral treatment with any reasons named non-antiviral treatment group, and 236 patients obtained from the 309 DAAs treatment patients according to the propensity score matching named DAAs treatment group. Demographic information and laboratory data were collected from baseline and the following up. Kaplan-Meier curve and Log-Rank test were used to compare the incidence and cumulative incidence of HCC between the two groups. Cox proportional risk regression was used to re-evaluate the risk factors for HCC. RESULTS HCC incidence was 4.68/100PY (95%CI, 3.09-6.81) in the DAAs treatment group, while it was 3.00/100PY (95%CI, 1.50-5.37) in the non-antiviral treatment group, and the relative risk was 1.82 (95%CI, 0.93-3.53, P > 0.05). The incidence of HCC at 12, 24, 36 and 48 months was 3.39%, 6.36%, 8.47% and 10.17% in the DAAs treatment group, and it was 0%, 0%, 3.39% and 9.32% in the non-antiviral treatment group, respectively. Age > 58 [hazard ratio (HR) = 1.089; 95%CI, 1.033-1.147; P = 0.002] and liver stiffness measurement > 27.85 kPa (HR = 1.043; 95%CI, 1.022-1.065; P = 0.000) were risk factors for HCC in all patients (n = 427), and DAAs treatment didn't show protective efficacy. CONCLUSION DAAs treatment seems failed to reduce the incidence of HCC occurrence in HCV-associated cirrhosis in 48 months, and even increased the incidence of HCC in 36 months.
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Affiliation(s)
- Xue-Mei Tao
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Ming-Hui Zeng
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - You-Fei Zhao
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Jia-Xin Han
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Yu-Qiang Mi
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
| | - Liang Xu
- Clinical School of the Second People's Hospital, Tianjin Medical University, Tianjin 300192, China
- Department of Hepatology, Tianjin Second People's Hospital, Tianjin 300192, China
- Department of Hepatology, Tianjin Research Institute of Liver Diseases, Tianjin 300192, China.
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Luan CH, Su PS, Chu CJ, Lin CC, Su CW, Lee SD, Wang YJ, Lee FY, Huang YH, Hou MC. Residual risk of hepatocellular carcinoma development for chronic hepatitis C patients treated by all oral direct-acting antivirals with sustained virological response. J Chin Med Assoc 2023; 86:795-805. [PMID: 37466658 DOI: 10.1097/jcma.0000000000000965] [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] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND The treatment of chronic hepatitis C (CHC) infection underwent a significant transformation with the introduction of all-oral direct-acting anti-virals (DAAs). These medications offered a high success rate in treatment, shorter duration, good tolerability, and expanded treatment options. However, a residual risk of hepatocellular carcinoma (HCC) development remained for a few patients even after achieving sustained virological response (SVR). To date, there is a lack of real-world data on evaluating risk factors associated with de novo HCC in CHC patients post-SVR, particularly in Taiwan. METHODS Between January 2017 and December 2019, a total of 671 consecutive CHC patients who achieved SVR after receiving DAAs were included for analysis. Patients with a history of HCC or liver transplantation prior to DAAs, a short follow-up period (<1 year), or treatment failure with DAAs were excluded. The primary outcome was the development of HCC following the initiation of DAAs. Variables associated with the primary outcome were assessed using multivariate Cox proportional hazards models. RESULTS The mean age of the enrolled patients was 65.1 ± 12.8 years, with 39.6% of them being male. Among the patients, 30.6% had advanced (F3-4) fibrosis, and the median follow-up period was 2.90 years. The cumulative incidence of HCC in CHC patients post-SVR12 was 1.6% at 1 year, 4.4% at 2 years, 4.8% at 3 years, 5.3% at 4 years, and 6.1% at 4.8 years, respectively. Variables independently associated with de novo HCC were advanced liver fibrosis (hazard ratio [HR] = 6.745; 95% CI = 1.960-23.218; p = 0.002), end-of-treatment 12 weeks (EOT 12 ) alpha-fetoprotein (AFP) >7 ng/mL (HR = 3.059; 95% CI = 1.215-7.669; p = 0.018), EOT 12 albumin-bilirubin (ALBI) grade ≥ 2 (HR = 2.664; 95% CI = 1.158-6.128; p = 0.021), and body mass index (BMI) ≥ 25 kg/m 2 (HR = 2.214; 95% CI = 1.011-4.852; p = 0.047). CONCLUSION Despite achieving viral clearance with DAAs, CHC patients still face a residual risk of de novo HCC. Establishing a risk stratification model based on independent variables could facilitate the prediction of future HCC development and enhance screening strategies.
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Affiliation(s)
- Chih-Hsuan Luan
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Pin-Shuo Su
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chi-Jen Chu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chung-Chi Lin
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chien-Wei Su
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Shou-Dong Lee
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
| | - Yuan-Jen Wang
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Healthcare and Services Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Fa-Yauh Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Ming-Chih Hou
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
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Kim NJ, Vutien P, Cleveland E, Cravero A, Ioannou GN. Fibrosis Stage-specific Incidence of Hepatocellular Cancer After Hepatitis C Cure With Direct-acting Antivirals: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2023; 21:1723-1738.e5. [PMID: 35525392 PMCID: PMC9636072 DOI: 10.1016/j.cgh.2022.04.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) eradication with direct-acting antivirals reduces hepatocellular carcinoma (HCC) risk. Pooled HCC incidence rates by cirrhosis status and fibrosis stage have not been estimated using meta-analysis. METHODS We searched PubMed, Web of Science, Embase, and Cochrane Library from January 1, 2014 to December 31, 2020 to identify studies assessing HCC incidence or outcomes by cirrhosis status, in adults with HCV who achieved sustained virologic response (SVR) after direct-acting antivirals. Pooled estimates were obtained using random-effects modeling. Subgroup, sensitivity, and meta-regression analyses were performed to evaluate heterogeneity. RESULTS We included 31 studies involving 27,711 patients with cirrhosis (mean follow-up, 2.1 years) and 11 studies involving 32,123 patients without cirrhosis (mean follow-up, 2.6 years). HCC incidence was 2.99/100 person-years (95% confidence interval [CI], 2.52-3.54; I2 = 75%) in patients with cirrhosis, 0.47/100 person-years (95% CI, 0.32-0.70, I2 = 71%) in patients without cirrhosis, and 0.63/100 person-years (95% CI: 0.34-1.20, I2 = 0%) in stage 3 (F3) fibrosis. Among patients with cirrhosis, HCC incidence was highest in studies with <1 year of follow-up (6.17/100 person-years [95% CI, 3.73-10.19]) and progressively lower in studies with longer follow-up (1-2 years: 2.75/100 person-years [95% CI, 2.48-3.06]; 2-3 years: 2.90/100 person-years [95% CI, 1.90-4.44]; ≥3 years: 1.83/100 person-years [95% CI, 0.88-3.80]). CONCLUSION Pooled HCC incidence after SVR in patients with cirrhosis was very high (2.99/100 person-years) but may be declining as longer time accrues after SVR. In patients without cirrhosis, including F3 fibrosis, HCC incidence was lower than thresholds associated with cost-effective HCC screening. In patients with F3 fibrosis, the lack of between-study heterogeneity provides strong evidence that HCC screening may not be warranted.
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Affiliation(s)
- Nicole J Kim
- Division of Gastroenterology, University of Washington, Seattle, Washington.
| | - Philip Vutien
- Division of Gastroenterology, University of Washington, Seattle, Washington
| | - Erin Cleveland
- Division of Gastroenterology, University of Washington, Seattle, Washington
| | - Anne Cravero
- Department of Medicine, University of Washington, Seattle, Washington
| | - George N Ioannou
- Division of Gastroenterology, University of Washington, Seattle, Washington; Division of Gastroenterology, Veterans Affairs Puget Sound Health Care System, Seattle, Washington
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Yamagiwa Y, Tanaka K, Matsuo K, Wada K, Lin Y, Sugawara Y, Mizoue T, Sawada N, Takimoto H, Ito H, Kitamura T, Sakata R, Kimura T, Tanaka S, Inoue M. Response to antiviral therapy for chronic hepatitis C and risk of hepatocellular carcinoma occurrence in Japan: a systematic review and meta-analysis of observational studies. Sci Rep 2023; 13:3445. [PMID: 36859564 PMCID: PMC9977913 DOI: 10.1038/s41598-023-30467-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/23/2023] [Indexed: 03/03/2023] Open
Abstract
In Japan, hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and hepatitis C virus infection is a major cause of HCC. We conducted a systematic review and meta-analysis of published studies evaluating patient response to antiviral therapy for chronic hepatitis C on the risk of HCC occurrence in Japan. Articles were searched using terms determined a priori through PubMed, screened by title and abstract, and selected by full-text assessment according to criteria determined a priori, including HCC occurrence in response to interferon (IFN)-based or IFN-free therapy, Japanese study, and 2 or more years of follow-up. We excluded studies on HCC recurrence. We calculated the pooled estimate of the crude incidence rate ratio with data from the selected studies using the person-years method with Poisson regression model and pooled estimate of the hazard ratio adjusted for potential confounders reported by the studies using a random effects model. A total of 26 studies were identified, all of which examined only IFN-based therapy as a result of the selection process. The pooled estimate (95% confidence interval [CI]) of 25 studies was 0.37 (0.33-0.43) for sustained virologic response (SVR) and 1.70 (1.61-1.80) for non-SVR for the HCC incidence rate per 100 person-years, and 0.22 (0.19-0.26) for the incidence rate ratio (SVR vs. non-SVR). The pooled estimate of the hazard ratio (95% CI) of HCC incidence adjusted for potential confounders of 8 studies was 0.25 (0.19-0.34). SVR to interferon therapy for chronic hepatitis C reduces the risk of HCC occurrence.
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Affiliation(s)
- Yoko Yamagiwa
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
- Clinical Research Centers for Medicine, International University of Health and Welfare, Tokyo, Japan
| | - Keitaro Tanaka
- Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan
| | - Keitaro Matsuo
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Keiko Wada
- Department of Epidemiology and Preventive Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yingsong Lin
- Department of Public Health, Aichi Medical University School of Medicine, Aichi, Japan
| | - Yumi Sugawara
- Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tetsuya Mizoue
- Department of Epidemiology and Prevention, Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Norie Sawada
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan
| | - Hidemi Takimoto
- Department of Nutritional Epidemiology, National Institute of Health and Nutrition, National Institute of Biomedical Innovation, Health and Nutrition, Tokyo, Japan
| | - Hidemi Ito
- Division of Cancer Information and Control, Department of Preventive Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Tetsuhisa Kitamura
- Department of Social Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Ritsu Sakata
- Department of Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan
| | - Takashi Kimura
- Department of Public Health, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Shiori Tanaka
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Manami Inoue
- Division of Prevention, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
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Impact of eradication of hepatitis C virus on liver-related and -unrelated diseases: morbidity and mortality of chronic hepatitis C after SVR. J Gastroenterol 2022; 58:299-310. [PMID: 36585501 DOI: 10.1007/s00535-022-01940-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 12/05/2022] [Indexed: 12/31/2022]
Abstract
Hepatitis C virus infection is characterized by chronic liver inflammation and fibrogenesis, leading to end-stage liver failure and hepatocellular carcinoma over the course of 20 to 30 years. It seems not only the chronicity of hepatitis C but also the presence of the virus in non-hepatic tissues creates a favorable environment for the potential development of pathogenic impacts on extrahepatic systems and organs. Numerous extra-hepatic manifestations have been reported in association with HCV infection, all of which can substantially affect morbidity, mortality, and quality of life. With the recent development of DAAs, antiviral treatment can cure almost all patients with HCV infection, even those intolerant of or unresponsive to IFN treatment, and several large multicenter studies have confirmed the association of DAA-induced SVR with reductions in liver-related and liver-unrelated complications, such as cardiovascular events, end stage renal disease, and so on. Because, in addition to liver-related diseases, extrahepatic lesions are threatening for patients, it is important to eradicate the virus before these progress and affect life prognosis; in other words, patients should be treated before reaching the point of no return. Tailored surveillance with biomarkers such as M2BPGi and Ang-2, which can be used to identify patients with an elevated risk of EHM, and early prevention or treatment for these patients could improve the morbidity, mortality and QOL. Advancement of both basic and clinical research in this field including the development of more precise biomarkers is highly anticipated.
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Alzahrani N. Hepatitis C Virus, Insulin Resistance, and Diabetes: A Review. Microbiol Immunol 2022; 66:453-459. [PMID: 35941761 DOI: 10.1111/1348-0421.13023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 07/19/2022] [Accepted: 08/03/2022] [Indexed: 12/15/2022]
Abstract
Hepatitis C virus (HCV) infection and diabetes mellitus (DM) are two chronic diseases that are a cause of significant health and economic burdens worldwide. HCV is associated with the development of insulin resistance (IR) and diabetes mellitus (DM). The mechanisms through which HCV induces IR and DM include direct viral effects, pro-inflammatory cytokines and other immune-mediated processes. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are both chronic diseases that involve impaired glucose homeostasis, albeit through different mechanisms. T1DM is an autoimmune disease that leads to the destruction of pancreatic beta cells resulting in insulin deficiency. In T2DM, a combination of peripheral insulin resistance and irregular production of insulin eventually lead to beta cell destruction and insulin insufficiency. Both type 1 and type 2 DM etiologies involve a combination of genetic and environmental factors. The data on HCV and T1DM association is limited, unlike T2DM, where a large body of evidence linking HCV to T2DM is available. Here, we intend to outline the current state of knowledge on HCV, IR, and DM. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Nabeel Alzahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud bin Abdulaziz University for Health Sciences, Riyadh, 14611, Saudi Arabia
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10
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Lockart I, Yeo MGH, Hajarizadeh B, Dore G, Danta M, Abe K, Carrat F, Lusivika‐Nzinga C, Degasperi E, Di Marco V, Hou J, Howell J, Janjua NZ, Wong S, Kumada T, Lleo A, Persico M, Lok AS, Wei L, Yang M, Nabatchikova E, Nguyen MH, Antonio Pineda J, Reig M, Shiha G, Yu M, Tsai P. HCC incidence after hepatitis C cure among patients with advanced fibrosis or cirrhosis: A meta-analysis. Hepatology 2022; 76:139-154. [PMID: 35030279 PMCID: PMC9303770 DOI: 10.1002/hep.32341] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/28/2021] [Accepted: 01/04/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS HCV cure reduces but does not eliminate the risk of HCC. HCC surveillance is recommended in populations where the incidence exceeds 1.5% per year. In cirrhosis, HCC surveillance should continue after HCV cure, although it is uncertain if this should be indefinite. For patients with advanced fibrosis (F3), guidelines are inconsistent in their recommendations. We evaluated the incidence of HCC after HCV cure among patients with F3 fibrosis or cirrhosis. APPROACH AND RESULTS This systematic review and meta-analysis identified 44 studies (107,548 person-years of follow-up) assessing the incidence of HCC after HCV cure among patients with F3 fibrosis or cirrhosis. The incidence of HCC was 2.1 per 100 person-years (95% CI, 1.9-2.4) among patients with cirrhosis and 0.5 per 100 person-years (95% CI, 0.3-0.7) among patients with F3 fibrosis. In a meta-regression analysis among patients with cirrhosis, older age (adjusted rate ratio [aRR] per 10-year increase in mean/median age, 1.32; 95% CI, 1.00-1.73) and prior decompensation (aRR per 10% increase in the proportion of patients with prior decompensation, 1.06; 95% CI, 1.01-1.12) were associated with an increased incidence of HCC. Longer follow-up after HCV cure was associated with a decreased incidence of HCC (aRR per year increase in mean/median follow-up, 0.87; 95% CI, 0.79-0.96). CONCLUSIONS Among patients with cirrhosis, the incidence of HCC decreases over time after HCV cure and is lowest in patients with younger age and compensated cirrhosis. The substantially lower incidence in F3 fibrosis is below the recommended threshold for cost-effective screening. The results should encourage the development of validated predictive models that better identify at-risk individuals, especially among patients with F3 fibrosis.
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Affiliation(s)
- Ian Lockart
- Faculty of MedicineSt. Vincent's Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia,St. Vincent’s HospitalSydneyNew South WalesAustralia
| | - Malcolm G. H. Yeo
- Faculty of MedicineSt. Vincent's Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia
| | - Behzad Hajarizadeh
- The Kirby InstituteUniversity of New South WalesSydneyNew South WalesAustralia
| | - Gregory J. Dore
- St. Vincent’s HospitalSydneyNew South WalesAustralia,The Kirby InstituteUniversity of New South WalesSydneyNew South WalesAustralia
| | - Mark Danta
- Faculty of MedicineSt. Vincent's Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia,St. Vincent’s HospitalSydneyNew South WalesAustralia
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11
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Perumalswami PV, Wyatt B, Bowman CA, Patel K, Mageras A, Lewis SC, Branch AD. Hepatocellular carcinoma surveillance, incidence, and tumor doubling times in patients cured of hepatitis C. Cancer Med 2022; 11:1995-2005. [PMID: 35261196 PMCID: PMC9089228 DOI: 10.1002/cam4.4508] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 11/24/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) incidence and mortality vary by race/ethnicity and both are higher in Black patients than in Whites. For HCC surveillance, all cirrhotic patients are advised to undergo lifelong twice‐annual abdominal imaging. We investigated factors associated with surveillance and HCC incidence in a diverse HCC risk group, cirrhotic patients recently cured of hepatitis C virus (HCV) infection. Methods In this observational cohort study, all participants (n = 357) had advanced fibrosis/cirrhosis and were cured of HCV with antiviral treatment. None had Liver Imaging Reporting and Data System (LI‐RADS) 2–5 lesions prior to HCV cure. Ultrasound, computed tomography, and/or magnetic resonance imaging were used for surveillance. Results At a median follow‐up of 40 months [interquartile range (IQR) = 28–48], the median percentage of time up‐to‐date with surveillance was 49% (IQR) = 30%–71%. The likelihood of receiving a first surveillance examination was not significantly associated with race/ethnicity, but was higher for patients with more advanced cirrhosis, for example, bilirubin [odds ratio (OR) = 3.8/mg/dL, p = 0.002], private insurance (OR = 3.4, p = 0.006), and women (OR = 2.3, p = 0.008). The likelihood of receiving two or three examinations was significantly lower for non‐Hispanic Blacks and Hispanics versus non‐Hispanic Whites (OR = 0.39, and OR = 0.40, respectively, p < 0.005 for both) and for patients with higher platelet counts (OR = 0.99/10,000 cells/µl, p = 0.01), but higher for patients with private insurance (OR = 2.8, p < 0.001). Incident HCC was associated with higher bilirubin (OR = 1.7, p = 0.02) and lower lymphocyte counts (OR = 0.16, p = 0.01). Conclusions Contrary to best practices, HCC surveillance was associated with sociodemographic factors (insurance status and race/ethnicity) among patients cured of HCV. Guideline‐concordant surveillance is needed to address healthcare disparities.
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Affiliation(s)
- Ponni V Perumalswami
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Brooke Wyatt
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Chip A Bowman
- Division of Hospital Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Krupa Patel
- Division of Hospital Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Anna Mageras
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Sara C Lewis
- Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Andrea D Branch
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Kamal A, Elsheaita A, Abdelnabi M. Association between direct-acting antiviral agents in hepatitis C virus treatment and hepatocellular carcinoma occurrence and recurrence: The endless debate. World J Clin Cases 2022; 10:1764-1774. [PMID: 35317156 PMCID: PMC8891795 DOI: 10.12998/wjcc.v10.i6.1764] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 08/05/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
Since direct-acting antiviral agents (DAAs) have been introduced into hepatitis C virus treatment, the sustained viral response (SVR) rate has significantly increased to more than 95%. Scientific evidence supports the idea that SVR after interferon therapy has beneficial effects related to cirrhosis progression, resulting in a reduction in the incidence of hepatocellular carcinoma (HCC). However, a significant debate exists related to DAA impact on HCC development. We reviewed the current literature highlighting the controversial data related to DAA association with de novo HCC occurrence or recurrence and possible pathophysiology of HCC related to DAAs. After a review of the published literature, we believe that the current evidence does not confirm or repudiate a higher rate of de novo HCC occurrence or recurrence related to DAA therapy. More trials are needed to determine if there is an association between HCC occurrence or recurrence and DAA or if it is related to preexisting liver cirrhosis.
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Affiliation(s)
- Ahmed Kamal
- Internal Medicine Department, Faculty of Medicine Alexandria University, Alexandria 21131, Egypt
| | - Ahmed Elsheaita
- Clinical and Experimental Internal Medicine Department, Medical Research Institute Alexandria University, Alexandria 21561, Egypt
| | - Mahmoud Abdelnabi
- Clinical and Experimental Internal Medicine Department, Medical Research Institute Alexandria University, Alexandria 21561, Egypt
- Internal Medicine Department, Texas Tech University Health Science Center, Lubbock, TX 79430, United States
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13
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Isfordink CJ, Maan R, de Man RA, van Erpecum KJ, van der Meer AJ. Should we continue surveillance for hepatocellular carcinoma and gastroesophageal varices in patients with cirrhosis and cured HCV infection? Eur J Intern Med 2021; 94:6-14. [PMID: 34563447 DOI: 10.1016/j.ejim.2021.08.023] [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: 05/17/2021] [Revised: 08/02/2021] [Accepted: 08/27/2021] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) and variceal bleeding are among the most common causes of liver-related mortality in patients with hepatitis C virus (HCV)-induced cirrhosis. Current guidelines recommend HCC and gastroesophageal varices (GEV) surveillance in patients with HCV infection and cirrhosis. However, since the recent introduction of direct-acting antivirals, most patients with cirrhosis are now cured of their chronic HCV infection. As virological cure is considered to substantially reduce the risk of cirrhosis-related complications, this review discusses the current literature concerning the surveillance of HCC and GEV in patients with HCV-induced cirrhosis with a focus on the setting following sustained virological response.
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Affiliation(s)
- Cas J Isfordink
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands; Division of Infectious Diseases, Amsterdam Infection & Immunity Institute Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Raoel Maan
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Robert A de Man
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Karel J van Erpecum
- Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, the Netherlands
| | - Adriaan J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.
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Alqahtani SA, Colombo M. Treatment for Viral Hepatitis as Secondary Prevention for Hepatocellular Carcinoma. Cells 2021; 10:3091. [PMID: 34831314 PMCID: PMC8619578 DOI: 10.3390/cells10113091] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/05/2021] [Accepted: 11/07/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with either hepatitis B or C virus (HBV or HCV) are among the most common risk factors for developing hepatocellular carcinoma (HCC). The hepatocarcinogenic potential of these viruses is mediated through a wide range of mechanisms, including the induction of chronic inflammation and oxidative stress and the deregulation of cellular pathways by viral proteins. Over the last decade, effective anti-viral agents have made sustained viral suppression or cure a feasible treatment objective for most chronic HBV/HCV patients. Given the tumorigenic potential of HBV/HCV, it is no surprise that obtaining sustained viral suppression or eradication proves to be effective in preventing HCC. This review summarizes the mechanisms by which HCV and HBV exert their hepatocarcinogenic activity and describes in detail the efficacy of anti-HBV and anti-HCV therapies in terms of HCC prevention. Although these treatments significantly reduce the risk for HCC in patients with chronic viral hepatitis, this risk is not eliminated. Therefore, we evaluate potential strategies to improve these outcomes further and address some of the remaining controversies.
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Affiliation(s)
- Saleh A. Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD 21287, USA
- Liver Transplant Center, and Biostatistics, Epidemiology, and Scientific Computing Department, King Faisal Specialist Hospital & Research Center, Riyadh 11564, Saudi Arabia
| | - Massimo Colombo
- Liver Center, IRCCS San Raffaele Hospital, 20132 Milan, Italy;
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15
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Váncsa S, Németh D, Hegyi P, Szakács Z, Farkas Á, Kiss S, Hegyi PJ, Kanjo A, Sarlós P, Erőss B, Pár G. Diabetes Mellitus Increases the Risk of Hepatocellular Carcinoma After Direct-Acting Antiviral Therapy: Systematic Review and Meta-Analysis. Front Med (Lausanne) 2021; 8:744512. [PMID: 34733865 PMCID: PMC8558240 DOI: 10.3389/fmed.2021.744512] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 09/23/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Hepatitis C virus (HCV)-infected patients treated with direct-acting antivirals (DAAs) are still at risk of developing hepatocellular carcinoma (HCC) after sustained virologic response (SVR). This study aimed to investigate the role of diabetes mellitus (DM) as a potential predictive risk factor in developing de novo HCC in HCV-infected patients after DAA treatment. Methods: This study was registered on PROSPERO under registration number CRD42021230457. We performed a systematic search in four medical databases from inception through November 3rd, 2020. Studies were eligible if they reported on HCV-infected patients treated with DAAs and compared the frequency of de novo HCC in patients with and without DM. We calculated pooled odds ratios, unadjusted (UHR), and adjusted hazard ratios (AHR) with 95% confidence intervals (CIs) in meta-analysis. Results: We included 30 articles in our systematic review and meta-analysis. DM proved to be a significant risk factor of HCC in DAA-treated HCV patients in unadjusted (UHR = 1.44, CI: 1.15-1.79) and adjusted analyses (AHR = 1.31, CI: 1.06-1.62). In the group of patients achieving SVR after DAA therapy, DM increased the risk of HCC in unadjusted (UHR = 1.3, CI: 1.09-1.51) analysis; however, in adjusted results, the risk was non-significant (AHR = 1.07, CI: 0.89-1.28). In patients with advanced liver fibrosis, DM was a risk factor for HCC in adjusted (AHR = 1.36, CI: 1.03-1.8), but not in unadjusted analysis (UHR = 1.11, CI: 0.8-1.42). Conclusions: DM is an independent risk factor of de novo HCC after DAA treatment in HCV-infected patients. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=230457, identifier: CRD42021230457.
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Affiliation(s)
- Szilárd Váncsa
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
| | - Dávid Németh
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- János Szentágothai Research Centre, University of Pécs, Pécs, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Zsolt Szakács
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Ádám Farkas
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Szabolcs Kiss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
| | - Péter Jenő Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Anna Kanjo
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Doctoral School of Clinical Medicine, University of Szeged, Szeged, Hungary
- Heim Pál National Pediatric Institute, Budapest, Hungary
| | - Patrícia Sarlós
- Department of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
| | - Bálint Erőss
- Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary
- Centre for Translational Medicine, Semmelweis University, Budapest, Hungary
| | - Gabriella Pár
- Department of Gastroenterology, First Department of Medicine, Medical School, University of Pécs, Pécs, Hungary
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16
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Long-term Risk of Hepatocellular Carcinoma Following Direct-Acting Antiviral Therapy in Compensated Liver Cirrhosis Induced by Hepatitis C Virus Infection. HEPATITIS MONTHLY 2021. [DOI: 10.5812/hepatmon.115910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Background: Considering the excellent safety profile and the high efficacy rates, great benefits were expected with the availability of the new direct-acting antivirals (DAAs) in treating hepatitis C virus (HCV) infection. Following the publication of two articles in 2016 on the high incidence rates of hepatocelullar carcinoma (HCC) following DAAs, several papers revealed contradictory results, thereby casting shadows on the role of DAAs in hepatocarcinogenesis. Objectives: The present study aimed to assess the incidence and risk factors of HCC in patients with HCV genotype 1b infection and compensated cirrhosis with the sustained virological response (SVR) following DAAs. Methods: This multicentric prospective study encompassed 479 patients with HCV genotype 1b compensated cirrhosis treated with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD) +/- ribavirin (RBV) for 12 weeks in two tertiary centers in Northeastern Romania. The patients were prospectively followed up in the Institute of Gastroenterology Iasi, Romania, from November 2015 to December 2020. Results: During the follow-up period (mean 60.11 ± 3.87 months), 23 patients (4.8%) developed HCC. The 1-, 3-, and 5-year cumulative incidence rates of HCC were 1.1, 1.9, and 2.6%, respectively. At the time of the diagnosis, 15 patients (65%) had a single tumor, 12 patients (52.2%) were within the Milan criteria, and nine persons (39%) had Barcelona liver cancer stage 0-A. In this regard, the mean AFP level was 35.3 ± 93.1 ng/mL. A multivariate analysis, age above 65 years, and a cutoff point of AFP ≥ 10 ng/mL at the end of treatment were independent factors associated with HCC. A majority of the patients (n = 11, 47.8%) received curative treatment by surgical resection. In this study, histopathological examination identified a moderately differentiated tumor (G2) in 5 patients, five patients had a poorly differentiated tumor (G3), and only one patient had a well-differentiated tumor (G1). Conclusions: Our study revealed no evidence of the high incidence rate of HCC after the long-term follow-up of patients with HCV-related liver cirrhosis and SVR following DAA treatment. However, the cumulative 5-year risk remained above the cutoff point, and this makes the HCC screening cost-effective. The HCC occurrence appears to be associated with aging and a moderately increased AFP level at EOT (≥ 10 ng/mL).
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Kilany S, Ata L, Gomaa A, Sabry A, Nada A, Tharwa ES, Badra G, Abogabal A, Elwaraky M, Moaz E, Ezzat S, Elsharawy A, Waked I. Decreased Incidence of Hepatocellular Carcinoma after Directly Acting Antiviral Therapy in Patients with Hepatitis C-Related Advanced Fibrosis and Cirrhosis. J Hepatocell Carcinoma 2021; 8:925-935. [PMID: 34408991 PMCID: PMC8367200 DOI: 10.2147/jhc.s295330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 05/06/2021] [Indexed: 01/03/2023] Open
Abstract
Background and Aim Existing data are controversial regarding the incidence of hepatitis C (HCV)-related hepatocellular carcinoma (HCC) following directly acting antiviral (DAA) therapy. This prospective study aimed to assess incidence, and risk factorss of HCC following DAA therapy in patients with HCV-related advanced fibrosis (F3) and cirrhosis (F4). Methods Incidence of HCC was calculated in 1,630 patients with HCV-related F3 and F4 treated with DAA prospectively followed for up to 43 months in a single tertiary referral center and compared to historical controls. Risk factors of incident HCC were also determined. Results The crude outcome rate was 2.15/100 person-years, significantly lower than a similar historical cohort (5.57/100 person-years). Risk of developing HCC was higher with the presence of cirrhosis (F4 vs F3, AHR 3.59) and treatment failure (vs achieving SVR, AHR 3.37). Presence of decompensated cirrhosis, platelet count <100×103/mL, and high AFP were independent risk factors of developing HCC. Conclusion Incidence of HCC was significantly lower in patients with HCV-related advanced fibrosis and cirrhosis treated with DAAs than in a historical cohort of untreated patients. Decompensated cirrhosis, baseline AFP ≥10 ng/mL, diabetes, and nonresponse to DAA were independent risk factors of incident HCC.
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Affiliation(s)
- Shimaa Kilany
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Lmyaa Ata
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Asmaa Gomaa
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Aliaa Sabry
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Ali Nada
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - El-Sayed Tharwa
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Gamal Badra
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Ashraf Abogabal
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Mohamed Elwaraky
- Radiology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Enas Moaz
- Epidemiology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Sameera Ezzat
- Epidemiology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Ahmed Elsharawy
- Clinical Pathology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
| | - Imam Waked
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Menoufia, Egypt
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Khoo T, Lam D, Olynyk JK. Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease. World J Gastroenterol 2021; 27:4831-4845. [PMID: 34447229 PMCID: PMC8371504 DOI: 10.3748/wjg.v27.i29.4831] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/14/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts. Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients. The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments. Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence, the number of new infections. Antiviral treatments have decreased the rates of liver decompensation and as a result, lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection. The quality of life of chronically infected patients has also been improved significantly by modern treatment. Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis. Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation. This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease.
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Affiliation(s)
- Tiffany Khoo
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - Danielle Lam
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - John K Olynyk
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
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Nevola R, Rinaldi L, Zeni L, Romano C, Marrone A, Galiero R, Pafundi PC, Acierno C, Vetrano E, Adinolfi LE. Changes in clinical scenarios, management, and perspectives of patients with chronic hepatitis C after viral clearance by direct-acting antivirals. Expert Rev Gastroenterol Hepatol 2021; 15:643-656. [PMID: 33445990 DOI: 10.1080/17474124.2021.1877136] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) causes a systemic infection inducing hepatic and extrahepatic diseases. These latter involve cardiovascular system, kidney, brain, endocrine, glucose, and lipid metabolism, and the immune system. HCV infection is associated with an increased risk of morbidity and mortality for both hepatic and extrahepatic events. Direct-acting antivirals (DAA), introduced in the most recent years for HCV treatment, are effective in up to 99% of cases and have changed the clinical scenarios and management of these patients. AREAS COVERED The literature on the impact of HCV clearance by DAA on both hepatic and extrahepatic disease outcomes has been analyzed and discussed in this review in order to summarize the full therapeutic potential and its weaknesses. EXPERT OPINION Patients achieving HCV clearance have improved hepatic and extrahepatic diseases, quality of life and survival. They have lower incidence of cardiovascular disease, type 2 diabetes, kidney damage, and immuno-mediated manifestations. However, the improvements are related to the degree of pre-treatment organ damage. Therefore, a significant percentage of patients with advanced disease remains at risk of morbidity and mortality and must be monitored in the post-treatment. In addition, data emphasize the importance of starting treatment during the early stages of HCV infection.
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Affiliation(s)
- Riccardo Nevola
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luca Rinaldi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Letizia Zeni
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Ciro Romano
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Aldo Marrone
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Raffaele Galiero
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Pia Clara Pafundi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Carlo Acierno
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Erica Vetrano
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Luigi Elio Adinolfi
- Internal Medicine, Department of Advanced Medical and Surgery Sciences, University of Campania Luigi Vanvitelli, Naples, Italy
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20
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Reig M, Forner A, Ávila MA, Ayuso C, Mínguez B, Varela M, Bilbao I, Bilbao JI, Burrel M, Bustamante J, Ferrer J, Gómez MÁ, Llovet JM, De la Mata M, Matilla A, Pardo F, Pastrana MA, Rodríguez-Perálvarez M, Tabernero J, Urbano J, Vera R, Sangro B, Bruix J. Diagnosis and treatment of hepatocellular carcinoma. Update of the consensus document of the AEEH, AEC, SEOM, SERAM, SERVEI, and SETH. Med Clin (Barc) 2021; 156:463.e1-463.e30. [PMID: 33461840 DOI: 10.1016/j.medcli.2020.09.022] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver neoplasm and one of the most common causes of death in patients with cirrhosis of the liver. In parallel, with recognition of the clinical relevance of this cancer, major new developments have recently appeared in its diagnosis, prognostic assessment and in particular, in its treatment. Therefore, the Spanish Association for the Study of the Liver (AEEH) has driven the need to update the clinical practice guidelines, once again inviting all the societies involved in the diagnosis and treatment of this disease to participate in the drafting and approval of the document: Spanish Society for Liver Transplantation (SETH), Spanish Society of Diagnostic Radiology (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Association of Surgeons (AEC) and Spanish Society of Medical Oncology (SEOM). The clinical practice guidelines published in 2016 and accepted as National Health System Clinical Practice Guidelines were taken as the reference documents, incorporating the most important recent advances. The scientific evidence and the strength of the recommendation is based on the GRADE system.
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Affiliation(s)
- María Reig
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Alejandro Forner
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España
| | - Matías A Ávila
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Programa de Hepatología, Centro de Investigación Médica Aplicada, Universidad de Navarra-IDISNA, Pamplona, España
| | - Carmen Ayuso
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Beatriz Mínguez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Hepatología, Hospital Universitario Vall d́Hebron, Grupo de Investigación en Enfermedades Hepáticas (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universidad Autónoma de Barcelona. Barcelona, España
| | - María Varela
- Sección de Hepatología, Servicio de Aparato Digestivo, Hospital Universitario Central de Asturias. Oviedo, España
| | - Itxarone Bilbao
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Servicio de Cirugía Hepatobiliopancreática y Trasplantes Digestivos, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona. Barcelona, España
| | - José Ignacio Bilbao
- Unidad de Radiología Vascular e Intervencionista, Departamento de Radiodiagnóstico, Clínica Universidad de Navarra, Pamplona, España
| | - Marta Burrel
- Servicio de Radiodiagnóstico, Hospital Clínic Barcelona, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Javier Bustamante
- Servicio de Gastroenterología y Hepatología, Sección de Hepatología y Trasplante, Hospital Universitario de Cruces, Baracaldo, España
| | - Joana Ferrer
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Cirugía Hepatobiliopancreática, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Miguel Ángel Gómez
- Unidad de Cirugía Hepatobiliopancreática y Trasplantes, Hospital Universitario Virgen del Rocío, Sevilla, España
| | - Josep María Llovet
- Grupo de Investigación Traslacional en Oncología Hepática, Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, Barcelona, España
| | - Manuel De la Mata
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Ana Matilla
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Sección de Hepatología, Servicio de Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, España
| | - Fernando Pardo
- Servicio de Cirugía Hepatobiliopancreática y Trasplante, Clínica Universidad de Navarra, Pamplona, España
| | - Miguel A Pastrana
- Servicio de Radiodiagnóstico, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, Madrid, España
| | - Manuel Rodríguez-Perálvarez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad Clínica de Aparato Digestivo, Hospital Universitario Reina Sofía, Córdoba, España
| | - Josep Tabernero
- Servicio de Oncología Médica, Hospital Universitario Vall d'Hebron, Universidad Autónoma de Barcelona, Barcelona, España
| | - José Urbano
- Unidad de Radiología Vascular e Intervencionista, Servicio de Radiodiagnóstico, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Madrid, España
| | - Ruth Vera
- Servicio de Oncología Médica, Complejo hospitalario de Navarra, Navarrabiomed-IDISNA, Pamplona, España
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España; Unidad de Hepatología y Área de Oncología HBP, Clínica Universidad de Navarra-IDISNA, Pamplona, España.
| | - Jordi Bruix
- Unidad de Oncología Hepática (Barcelona Clinic Liver Cancer), Servicio de Hepatología, Hospital Clínic, IDIBAPS, Universidad de Barcelona, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, España.
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21
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Sahakyan Y, Lee-Kim V, Bremner KE, Bielecki JM, Krahn MD. Impact of direct-acting antiviral regimens on mortality and morbidity outcomes in patients with chronic hepatitis c: Systematic review and meta-analysis. J Viral Hepat 2021; 28:739-754. [PMID: 33556225 DOI: 10.1111/jvh.13482] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 01/23/2021] [Indexed: 02/06/2023]
Abstract
The long-term effects of direct-acting antiviral therapies (DAAs) for chronic hepatitis C (CHC) remain uncertain. The objective of this systematic review and meta-analysis was to assess the impact of DAAs on CHC progression and mortality. We searched Ovid MEDLINE, Ovid EMBASE and PubMed databases (January 2011 to March 2020) for studies that compared the efficacy of DAAs to a non-DAA control in patients with CHC. Main outcomes were the adjusted hazard ratios (HRs) for mortality, liver decompensation, HCC occurrence and recurrence. Pooled estimates of HRs were determined using random-effects meta-analyses with inverse variance weighting, with sensitivity analyses and meta-regression to explore the effects of clinical factors. We identified 39 articles for the primary analysis. Compared with unexposed individuals, patients treated with DAA had a reduced risk of death (HR; CI = 0.44; 0.38-0.52), decompensation (HR; CI = 0.54; 0.38- 0.76) and HCC occurrence (HR; CI = 0.72; 0.61- 0.86). The protective effect of DAA on HCC recurrence was less clear (HR; CI = 0.72; 0.44-1.16). Sustained virologic response (SVR) attainment was a significant predictor of reduced mortality (HR; CI = 0.33; 0.23-0.46), decompensation (HR; CI = 0.11; 0.05-0.24), HCC occurrence (HR; CI = 0.31; 0.27-0.37) and HCC recurrence (HR; CI = 0.32; 0.20-0.51). Meta-regression showed no evidence of effect modification by patient age, sex, presence of cirrhosis or length of follow-up. In conclusion, our findings show protective effects of DAA treatment and DAA-related SVR on CHC progression and mortality.
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Affiliation(s)
- Yeva Sahakyan
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Victoria Lee-Kim
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.,School of Medicine, Queens University, Kingston, ON, Canada
| | - Karen E Bremner
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Joanna M Bielecki
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Murray D Krahn
- Toronto Health Economics and Technology Assessment (THETA) Collaborative, Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada.,Institute of Health Policy, Management and Evaluation (IHPME), University of Toronto, Toronto, ON, Canada.,Department of Medicine, University of Toronto and University Health Network, Toronto, ON, Canada.,Institute for Clinical Evaluative Sciences (ICES), Toronto, ON, Canada
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22
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Tada T, Toyoda H, Kumada T, Kurisu A, Sugiyama A, Akita T, Ohisa M, Aikata H, Miki D, Chayama K, Tanaka J. Comparison of liver disease state progression in patients with eradication of versus persistent infection with hepatitis C virus: Markov chain analysis. J Viral Hepat 2021; 28:538-547. [PMID: 33215790 DOI: 10.1111/jvh.13444] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/11/2020] [Accepted: 11/11/2020] [Indexed: 12/30/2022]
Abstract
To investigate the long-term prognosis of liver disease in patients with hepatitis C virus (HCV) eradication after antiviral therapy versus those with persistent HCV infection. Four hundred and eighty patients (5259 person-years [PYs]) who received interferon-based therapy and achieved sustained virologic response and 848 patients (3853 PYs) with persistent HCV infection were included. In the analysis of 1-year liver disease state transition probability matrices using Markov chain models, progression to cirrhosis from the chronic hepatitis state was observed (0.00%-0.63%) in patients with HCV eradication. Among patients with chronic hepatitis or cirrhosis and HCV eradication, hepatocellular carcinoma (HCC) development was observed in males aged ≥ 50 years (0.97%-1.96%) and females aged ≥ 60 years (0.26%-5.00%). Additionally, in patients with cirrhosis and HCV eradication, improvement to chronic hepatitis was also observed (4.94%-10.64%). Conversely, in patients with chronic hepatitis and persistent HCV infection, progression to cirrhosis was observed in males aged ≥ 30 years and female aged ≥ 40 years (0.44%-1.99%). In males aged ≥ 40 years and female aged ≥ 50 years with cirrhosis, the transition probability for HCC was relatively high (4.17%-14.02%). Under the assumption of either chronic hepatitis or cirrhosis at age 40 or 60 years as the starting condition for simulation over the next 30 or 40 years, respectively, the probability of HCC was higher in patients with persistent HCV infection than those with HCV eradication. In conclusion, HCV eradication can reduce the risk of developing cirrhosis or HCC in patients with chronic HCV infection.
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Affiliation(s)
- Toshifumi Tada
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Department of Internal Medicine, Japanese Red Cross Society Himeji Hospital, Himeji, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Takashi Kumada
- Faculty of Nursing, Gifu Kyoritsu University, Ogaki, Japan
| | - Akemi Kurisu
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Project Research Center for Epidemiology and Prevention of Viral Hepatitis and Hepatocellular Carcinoma, Hiroshima University, Hiroshima, Japan
| | - Aya Sugiyama
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Project Research Center for Epidemiology and Prevention of Viral Hepatitis and Hepatocellular Carcinoma, Hiroshima University, Hiroshima, Japan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Project Research Center for Epidemiology and Prevention of Viral Hepatitis and Hepatocellular Carcinoma, Hiroshima University, Hiroshima, Japan
| | - Masayuki Ohisa
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Project Research Center for Epidemiology and Prevention of Viral Hepatitis and Hepatocellular Carcinoma, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Disease Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Project Research Center for Epidemiology and Prevention of Viral Hepatitis and Hepatocellular Carcinoma, Hiroshima University, Hiroshima, Japan
- Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
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23
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Ceausu M, Socea B, Serban D, Smarandache CG, Predescu D, Bacalbaşa N, Slavu I, Tulin A, Alecu L, Ceauşu Z. Heterogeneity of antigenic constellation in human hepatocellular carcinoma. Exp Ther Med 2021; 21:270. [PMID: 33603877 PMCID: PMC7851646 DOI: 10.3892/etm.2021.9701] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 11/24/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma is one of the primary liver malignancies responsible for over a million deaths per year worldwide (approximately 10% of all deaths in the adult age range). The diagnosis of HCC can be difficult and often requires the use of more than one microscopic technique. A retrospective study was performed on a study batch of 42 cases that died of HCC due to metastasis or other secondary complications. Tissue samples were taken in order to investigate the tumour antigenic constellation by means of IHC method using a large variety of antibodies. In situ hybridization was also performed for albumin mRNA to assess the albumin expression in some selected cases. Telomerase activity was investigated using IHC method for the hTERT catalytic subunit. A cocktail of hepatic cytokeratins (CK8, 18) combined with Hep Par-1 and associated to albumin proved to be more powerful than albumin alone in differentiating HCC and increased the value of tumour diagnosis. hTERT expression was proportionally reverse to the tumour degree of differentiation, but was independent from the expression of tumour-proliferating indexes. The heterogeneity of the antigenic constellation in hepatocellular carcinoma suggests an antigenic mosaicism, which can be expressed a synchronous or metachronous manner, depending on the tumour degree of differentiation.
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Affiliation(s)
- Mihai Ceausu
- Department of Pathology, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Bogdan Socea
- Department of Surgery, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Surgery, ‘Sf. Pantelimon’ Emergency Hospital, 021659 Bucharest, Romania
| | - Dragos Serban
- Department of Surgery, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- IVth Department of Surgery, University Emergency Hospital, 050098 Bucharest, Romania
| | - Cătălin Gabriel Smarandache
- Department of Surgery, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- IVth Department of Surgery, University Emergency Hospital, 050098 Bucharest, Romania
| | - Dragoş Predescu
- Department of Surgery, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Surgery, ‘Sf. Maria’ Hospital, 011172 Bucharest, Romania
| | - Nicolae Bacalbaşa
- Department of Obstetrics and Gynecology, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Obstetrics and Gynecology, ‘Dr. I. Cantacuzino’ Clinical Hospital, 030167 Bucharest, Romania
| | - Iulian Slavu
- Department of Surgery, ‘Prof. Dr. Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania
| | - Adrian Tulin
- Department of Surgery, ‘Prof. Dr. Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania
- Department of Anatomy, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Lucian Alecu
- Department of Surgery, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Surgery, ‘Prof. Dr. Agrippa Ionescu’ Clinical Emergency Hospital, 011356 Bucharest, Romania
| | - Zenaida Ceauşu
- Pathology Department, ‘Sf. Pantelimon’ Emergency Hospital, 021659 Bucharest, Romania
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24
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Suceveanu AI, Micu IS, Baltatescu GI, Petcu LC, Dobrin N, Brinzan C, Nitipir C, Mazilu L, Botea F, Herlea V, Voinea F, Suceveanu AP. Overexpression of Survivin-1, TAG-72 and HERC5 in patients diagnosed with hepatocellular carcinoma in the Black Sea coast geographical area. Exp Ther Med 2021; 21:284. [PMID: 33603891 PMCID: PMC7851649 DOI: 10.3892/etm.2021.9715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 11/26/2020] [Indexed: 11/06/2022] Open
Abstract
Epidemiological data regarding hepatocellular carcinoma (HCC) report unsatisfactory morbimortality rates despite the global efforts to decrease the incidence and prolong patient survival. Current guidelines lack diagnostic biomarkers to better characterize patients with HCC. We aimed to validate the overexpression of Survivin-1, tumor-associated glyocoprotein 72 (Tag-72), and HECT and RLD domain containing E3 ubiquitin protein ligase 5 (HERC5) as tissue biomarkers for HCC characterization in patients from our geographical area and to standardize a local biomarker panel to be introduced in the current management guideline. Thirty samples of histologically confirmed HCC were compared to an equal number of samples of benign tumors in terms of Survivin-1, TAG-72, and HERC5 overexpression. Student's t-test, Mann-Whitney U test and Chi-square test were used to find differences between the two studied groups and to compare the categorical variables. The discriminative power of Survivin-1, Tag-72, and HERC5 overexpression was assessed using ROC curves. The multivariate linear regression analysis revealed that Survivin, Tag-72, and HERC5 were significantly overexpressed in older male patients, with α-fetoprotein (AFP) >200 ng/dl, low serum albumin, as well as in patients with imaging features of portal thrombosis and ascites. The diagnostic performance of Survivin-1, Tag-72 and HERC5 tissue biomarkers for HCC characterization was superior to that of the gold-standard AFP. Our study results validate the overexpression of Survivin-1, Tag-72, and HERC5 as tissue biomarkers for HCC characterization in patients from our geographical region and could be standardized in the current HCC management guideline.
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Affiliation(s)
| | - Ioan Sergiu Micu
- Department of Gastroenterology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Gabriela-Izabela Baltatescu
- Research and Development Centre for The Morphologic and Genetic Study of Malignant Pathology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Lucian Cristian Petcu
- Dentistry Faculty, Biophysics and Biostatistics Disciplines, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Nicolae Dobrin
- Research and Development Centre for The Morphologic and Genetic Study of Malignant Pathology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Costel Brinzan
- Doctoral School of Medicine, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Cornelia Nitipir
- Department of Oncology, ‘Carol Davila’ University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Laura Mazilu
- Department of Oncology, ‘Ovidius’ University, 900527 Constanta, Romania
| | - Florin Botea
- Liver Transplant and General Surgery Centre, ‘Fundeni’ Institute, 022328 Bucharest, Romania
| | - Vlad Herlea
- Department of Pathology, ‘Fundeni’ Institute, 022328 Bucharest, Romania
| | - Felix Voinea
- Department of Urology, ‘Ovidius’ University, 900527 Constanta, Romania
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25
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Owusu Sekyere S, Port K, Deterding K, Cornberg M, Wedemeyer H. Inflammatory patterns in plasma associate with hepatocellular carcinoma development in cured hepatitis C cirrhotic patients. United European Gastroenterol J 2021; 9:486-496. [PMID: 33349201 PMCID: PMC8259286 DOI: 10.1177/2050640620976991] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/31/2020] [Indexed: 01/10/2023] Open
Abstract
Introduction The risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon‐free direct‐acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance. Objective Here, we aimed at evaluating the effects of direct‐acting antiviral therapy‐induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct‐acting antiviral‐mediated hepatitis C clearance in cirrhosis patients was investigated. Methods Employing multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct‐acting antiviral treatment. Results Elevated pretherapy concentrations of specific soluble immune mediators including MCP‐3, GDNF, CDCP1, IL‐17C, IL‐17A, signalling lymphocytic activation family 1, CCL11, FGF‐5, LIF‐R, interleukin 10 (IL‐10), IL‐10RA, IL‐15RA, beta NGF, CCL28, CCL25 and NT‐3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF‐5 and IL‐15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma‐free patients experienced significant ameliorations. Conclusions These results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct‐acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct‐acting antiviral therapies would be superior to the risk of developing carcinoma.
Established knowledge on this subject
Current interferon (IFN)‐free direct‐acting antivirals (DAAs) are effective at eliminating hepatitis C virus (HCV), but risks of residual liver disease and development of hepatocellular carcinoma persists. The hepatic inflammation that occurs during chronic hepatitis C causes systemic changes in blood soluble immune mediators (SIMs) that impact carcinogenetic processes involved in the growth, invasion and metastasis of hepatocellular carcinoma (HCC). DAA‐induced HCV cure does not lead to a complete immunological restitution of the altered soluble inflammatory compartment in chronic hepatitis C.
Significant and/or new findings of this study
An elevated pre‐therapy plasma profile of an extended repertoire of SIMs in cirrhosis was associated with HCC development post‐DAA therapy. Successful DAA therapy did not alter the baseline elevated plasma SIM profile of cirrhosis patients that developed post‐therapy HCC contrary to its effect in those that remained HCC‐free.
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Affiliation(s)
- Solomon Owusu Sekyere
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany.,German Center for Infection Research (DZIF), Partner-site Hannover-Braunschweig, Braunschweig, Germany.,Integrated Research and Treatment Centre Transplantation (IFB-Tx), Hannover Medical School, Hannover, Germany
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26
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Muzica CM, Stanciu C, Huiban L, Singeap AM, Sfarti C, Zenovia S, Cojocariu C, Trifan A. Hepatocellular carcinoma after direct-acting antiviral hepatitis C virus therapy: A debate near the end. World J Gastroenterol 2020; 26:6770-6781. [PMID: 33268960 PMCID: PMC7684455 DOI: 10.3748/wjg.v26.i43.6770] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/27/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Direct acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection, achieving high rates (≥ 95%) of sustained virological response, with a good safety profile and high compliance rates. Consequently, it had been expected that viral clearance will reduce morbidity and mortality rates, as well as the risk of hepatocellular carcinoma (HCC). However, since 2016, concerns have been raised over an unexpected high rate of HCC occurrence and recurrence after DAA therapy, which led to an avalanche of studies with contradictory results. We aimed to review the most recent and relevant articles regarding the risk of HCC after DAA treatment and identify the associated risk factors.
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Affiliation(s)
- Cristina Maria Muzica
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Carol Stanciu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Laura Huiban
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Catalin Sfarti
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Sebastian Zenovia
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Camelia Cojocariu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
| | - Anca Trifan
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, St. Spiridon Emergency Hospital, Iasi 700115, Romania
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27
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Pawlotsky JM, Negro F, Aghemo A, Berenguer M, Dalgard O, Dusheiko G, Marra F, Puoti M, Wedemeyer H. EASL recommendations on treatment of hepatitis C: Final update of the series ☆. J Hepatol 2020; 73:1170-1218. [PMID: 32956768 DOI: 10.1016/j.jhep.2020.08.018] [Citation(s) in RCA: 732] [Impact Index Per Article: 146.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 02/08/2023]
Abstract
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Clinical care for patients with HCV-related liver disease has advanced considerably thanks to an enhanced understanding of the pathophysiology of the disease, as well as developments in diagnostic procedures and improvements in therapy and prevention. These therapies make it possible to eliminate hepatitis C as a major public health threat, as per the World Health Organization target, although the timeline and feasibility vary from region to region. These European Association for the Study of the Liver recommendations on treatment of hepatitis C describe the optimal management of patients with recently acquired and chronic HCV infections in 2020 and onwards.
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28
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Wedemeyer H, Khera T, Strunz B, Björkström NK. Reversal of Immunity After Clearance of Chronic HCV Infection-All Reset? Front Immunol 2020; 11:571166. [PMID: 33133084 PMCID: PMC7578424 DOI: 10.3389/fimmu.2020.571166] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic viral infections cause deterioration of our immune system. However, since persistent infections rarely can be eliminated, the reinvigoration capacity of an exhausted immune system has remained largely elusive. Chronic hepatitis C virus (HCV) infection can since some years be effectively cured with novel direct acting antiviral agents. Thus, it is now possible to study reversal of immunity in patients that are cured from a long-lasting chronic infection. We here highlight recent developments in the analysis of various immune cell populations during and after clearance of HCV infection. Surprisingly, whereas reinvigoration of certain immune traits clearly can be seen, many features of immune exhaustion persist over time after viral elimination. Thus, a long-term chronic insult might result in irreversible damage to our immune system. This will be important to consider in therapeutic vaccination efforts against chronic infection and in the development of immunotherapy based strategies against cancer.
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Affiliation(s)
- Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.,German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Tanvi Khera
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Benedikt Strunz
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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29
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Japan Society of Hepatology guidelines for the management of hepatitis C virus infection: 2019 update. Hepatol Res 2020; 50:791-816. [PMID: 32343477 DOI: 10.1111/hepr.13503] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/03/2020] [Accepted: 03/22/2020] [Indexed: 12/12/2022]
Abstract
The Drafting Committee for Hepatitis Management Guidelines established by the Japan Society of Hepatology (JSH) drafted the first version of the clinical practice guidelines for the management of hepatitis C virus (HCV) infection in 2012. Since then, we have been publishing updates as new drugs for hepatitis C become available and new indications for existing drugs are added. The new approval of sofosbuvir/velpatasvir prompted us to publish the seventh version of the guidelines in Japanese in March 2019. We also published the first English-language version of the JSH guidelines in 2013 and English versions of updates made to the Japanese-language guidelines in 2014 and 2016. In 2020, the Committee has decided to publish a new English version, covering general information about treatment for hepatitis C, drugs used, recommended treatments for chronic hepatitis and cirrhosis, and special populations, such as patients who have renal impairment, are on dialysis, or have developed recurrence of hepatitis C after liver transplantation. Furthermore, the Committee has released a separate publication covering the protective effect of antiviral therapy against hepatocarcinogenesis.
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30
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Rinaldi L, Nevola R, Franci G, Perrella A, Corvino G, Marrone A, Berretta M, Morone MV, Galdiero M, Giordano M, Adinolfi LE, Sasso FC. Risk of Hepatocellular Carcinoma after HCV Clearance by Direct-Acting Antivirals Treatment Predictive Factors and Role of Epigenetics. Cancers (Basel) 2020; 12:1351. [PMID: 32466400 PMCID: PMC7352473 DOI: 10.3390/cancers12061351] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/18/2020] [Accepted: 05/20/2020] [Indexed: 02/05/2023] Open
Abstract
Direct-acting antivirals (DAAs) induce a rapid virologic response (SVR) in up to 99% of chronic hepatitis C patients. The role of SVR by DAAs on the incidence or recurrence of hepatocellular carcinoma (HCC) is still a matter of debate, although it is known that SVR does not eliminate the risk of HCC. In this review, we made an updated analysis of the literature data on the impact of SVR by DAAs on the risk of HCC as well as an assessment of risk factors and the role of epigenetics. Data showed that SVR has no impact on the occurrence of HCC in the short-medium term but reduces the risk of HCC in the medium-long term. A direct role of DAAs in the development of HCC has not been demonstrated, while the hypothesis of a reduction in immune surveillance in response to the rapid clearance of HCV and changes in the cytokine pattern influencing early carcinogenesis remains to be further elucidated. HCV induces epigenetic alterations such as modifications of the histone tail and DNA methylation, which are risk factors for HCC, and such changes are maintained after HCV clearance. Future epigenetic studies could lead to identify useful biomarkers and therapeutic targets. Cirrhosis has been identified as a risk factor for HCC, particularly if associated with high liver stiffness and α-fetoprotein values, diabetes and the male sex. Currently, considering the high number and health cost to follow subjects' post-HCV clearance by DAAs, it is mandatory to identify those at high risk of HCC to optimize management.
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Affiliation(s)
- Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Riccardo Nevola
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Gianluigi Franci
- Department of Medicine, Surgery, Dentistry, University of Salerno “Scuola Medica Salernitana”, 84100 Salerno, Italy;
| | - Alessandro Perrella
- Immunological and Neurological Infectious Diseases, Cotugno Hospital, 80100 Naples, Italy;
| | - Giusy Corvino
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.C.); (M.V.M.); (M.G.)
| | - Aldo Marrone
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Massimiliano Berretta
- Department of Medical Oncology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, 33081 Aviano, Italy;
| | - Maria Vittoria Morone
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.C.); (M.V.M.); (M.G.)
| | - Marilena Galdiero
- Department of Experimental Medicine, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (G.C.); (M.V.M.); (M.G.)
| | - Mauro Giordano
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Luigi Elio Adinolfi
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80100 Naples, Italy; (R.N.); (A.M.); (M.G.); (L.E.A.); (F.C.S.)
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31
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Ma L, Liu J, Wang W, Yang F, Li P, Cai S, Zhou X, Chen X, Zhuang X, Zhang H, Cao G. Direct-acting antivirals and interferon-based therapy on hepatocellular carcinoma risk in chronic hepatitis-C patients. Future Oncol 2020; 16:675-686. [PMID: 32223423 DOI: 10.2217/fon-2019-0845] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Aim: It was controversial whether direct-acting antiviral (DAA) is better than interferon-based therapy (IBT) in preventing HCV-related hepatocellular carcinoma (HCC). Therefore, we accomplished this large, stepwise meta-analysis. Materials & methods: The PubMed, Cochrane and ScienceDirect were searched for studies published during January 2009-March 2019. Antiviral type, number of chronic hepatitis C (CHC) patients, number of HCC cases from CHC patients, sustained virological response (SVR) status and important covariate data were extracted from each study. Results & conclusion: It is demonstrated that antiviral treatment reduces the occurrence of HCC in patients with CHC; achieving SVR to antiviral treatment reduces HCC; DAA treatment is not better than IBT in the prophylaxis of HCC; DAA treatment and cirrhosis are independently associated with a higher incidence of HCC than IBT in middle-aged CHC patients who achieve SVR.
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Affiliation(s)
- Longteng Ma
- Department of Epidemiology, Navy Medical University, Shanghai, PR China
| | - Jiluo Liu
- Department of Epidemiology, Navy Medical University, Shanghai, PR China
| | - Wei Wang
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, PR China
| | - Fan Yang
- Department of Epidemiology, Navy Medical University, Shanghai, PR China
| | - Ping Li
- Department of Epidemiology, Navy Medical University, Shanghai, PR China
| | - Shiliang Cai
- Department of Epidemiology, Navy Medical University, Shanghai, PR China
| | - Xinyu Zhou
- Department of Epidemiology, Navy Medical University, Shanghai, PR China
| | - Xi Chen
- Department of Epidemiology, Navy Medical University, Shanghai, PR China
| | - Xun Zhuang
- Department of Epidemiology, School of Public Health, Nantong University, Nantong, PR China
| | - Hongwei Zhang
- Department of Epidemiology, Navy Medical University, Shanghai, PR China
| | - Guangwen Cao
- Department of Epidemiology, Navy Medical University, Shanghai, PR China
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32
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Ozeki I, Nakajima T, Suii H, Tatsumi R, Yamaguchi M, Arakawa T, Kuwata Y. Predictors of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting antiviral treatment: relationship with serum zinc. J Clin Biochem Nutr 2020; 66:245-252. [PMID: 32523252 DOI: 10.3164/jcbn.19-98] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Accepted: 12/04/2019] [Indexed: 12/20/2022] Open
Abstract
The recently approved direct-acting antivirals (DAA) agents are effective in terms of sustained virologic response (SVR) rates and are well tolerated in most hepatitis C virus (HCV) patients. This study aimed to analyze the association between serum zinc levels in patients who developed hepatocellular carcinoma (HCC) following HCV eradication after DAA treatment. The retrospective study included 769 HCV-infected patients who achieved SVR after DAA treatment. We calculated the annual incidence rate of HCC and identified risk factors associated with HCC development. We also assessed serum zinc and clinical factors at both baseline and end of treatment (EOT). During follow-up (median duration 35 months), HCC occurred in 18/769 (2.3%) patients. From the multivariate analysis, serum zinc <60 µg/dl [hazard ratio (HR) 5.936] and AFP ≥6.0 ng/dl (HR 5.862) at baseline, baseline-zinc <60 µg/dl (HR 6.283), EOT-serum zinc <63 µg/dl (HR 6.011), baseline-AFP ≥6.0 ng/dl (HR 8.163), and EOT-M2BPGi ≥2.5 (HR 12.194) at baseline and EOT were independently associated with increased HCC risk. In patients who achieved HCV eradication following DAA treatment, serum zinc levels before and at EOT could be a risk factor for developing HCC.
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Affiliation(s)
- Itaru Ozeki
- Department of Hepatology, Sapporo Kosei General Hospital, Kita 3 Higashi 8, Chuo-ku, Sapporo 060-0033, Japan
| | - Tomoaki Nakajima
- Department of Hepatology, Sapporo Kosei General Hospital, Kita 3 Higashi 8, Chuo-ku, Sapporo 060-0033, Japan
| | - Hirokazu Suii
- Department of Hepatology, Sapporo Kosei General Hospital, Kita 3 Higashi 8, Chuo-ku, Sapporo 060-0033, Japan
| | - Ryoji Tatsumi
- Department of Hepatology, Sapporo Kosei General Hospital, Kita 3 Higashi 8, Chuo-ku, Sapporo 060-0033, Japan
| | - Masakatsu Yamaguchi
- Department of Hepatology, Sapporo Kosei General Hospital, Kita 3 Higashi 8, Chuo-ku, Sapporo 060-0033, Japan
| | - Tomohiro Arakawa
- Department of Hepatology, Sapporo Kosei General Hospital, Kita 3 Higashi 8, Chuo-ku, Sapporo 060-0033, Japan
| | - Yasuaki Kuwata
- Department of Hepatology, Sapporo Kosei General Hospital, Kita 3 Higashi 8, Chuo-ku, Sapporo 060-0033, Japan
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33
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Branch AD. Escape from planned obsolescence: Hepatitis C, the cirrhotic liver, and clonal expansions. J Exp Med 2020; 217:133817. [PMID: 33002101 PMCID: PMC7062522 DOI: 10.1084/jem.20191070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Accepted: 01/29/2020] [Indexed: 11/04/2022] Open
Abstract
Eliminating the burden of disease caused by hepatitis C virus infection is proving difficult, despite the availability of curative drug treatments. Progress will require innovations in healthcare delivery and a deeper understanding of how the liver and other vital organs survive damage caused by chronic injury.
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34
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Ebel F, Deterding K, Port K, Schlevogt B, Manns MP, Maasoumy B, Cornberg M, Wedemeyer H. Letter: a 5-year long-term follow-up study after DAA treatment confirms a reduced HCC risk in a central European cohort of HCV patients with liver cirrhosis. Aliment Pharmacol Ther 2020; 51:194-195. [PMID: 31850589 DOI: 10.1111/apt.15597] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Friederike Ebel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology & Hepatology, Essen University Hospital, Essen, Germany
| | - Kerstin Port
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bernhard Schlevogt
- Department of Transplantation Medicine, University of Muenster, Muenster, Germany
| | - Michael P Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover, Germany.,German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology & Hepatology, Essen University Hospital, Essen, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hannover, Germany.,German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany
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Direct-acting antivirals for patients with chronic hepatitis C and hepatocellular carcinoma in Taiwan. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2019; 54:385-395. [PMID: 31771822 DOI: 10.1016/j.jmii.2019.09.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND/PURPOSE The treatment of chronic hepatitis C (CHC) has evolved from interferon (IFN)-based therapy to direct acting antivirals (DAAs). The effect of antiviral treatment on outcome of hepatocellular carcinoma (HCC) patients with CHC has not been well analyzed in Taiwan. METHODS From April 2015 to May 2018, 199 HCC patients with CHC undergoing DAAs treatment, including 127 having prospectively longitudinal observation, were enrolled. Among them, 107 BCLC 0/A patients achieving curative treatment of HCC were further compared with a historical cohort of 42 HCC patients experienced pegylated interferon (Peg-IFN) plus ribavirin for CHC after curative treatment. RESULTS The sustained virological response (SVR) rates were 95.0% in BCLC stage 0/A (114/120), 97.1% in BCLC B (68/70), and 77.8% in BCLC C (7/9). The median recurrence-free survivals (RFS) between the DAA and IFN arms were of no difference by counting either from antiviral treatment (29.3 mo vs 39.2 mo, p = 0.764) or from curative treatment (65.8 mo vs 44.0 mo, p = 0.130), respectively. Achievement of SVR was the key independent factor associated with RFS and overall survival. The pattern of recurrence was also similar between the DAA and IFN arms. For intermediate stage HCC patients, the median time to tumor progression was 9.2 months from the initiation of DAA therapy, and 90% of patients maintained in BCLC B till 12 months after the DAA treatment. CONCLUSIONS The SVR is high within BCLC B HCV-HCC patients by DAAs treatment. The risk of HCC recurrence and progression is not increased by DAAs.
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36
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Pascut D, Cavalletto L, Pratama MY, Bresolin S, Trentin L, Basso G, Bedogni G, Tiribelli C, Chemello L. Serum miRNA Are Promising Biomarkers for the Detection of Early Hepatocellular Carcinoma after Treatment with Direct-Acting Antivirals. Cancers (Basel) 2019; 11:cancers11111773. [PMID: 31717959 PMCID: PMC6895878 DOI: 10.3390/cancers11111773] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/01/2019] [Accepted: 11/08/2019] [Indexed: 02/07/2023] Open
Abstract
Direct antiviral agents (DAAs) have excellent efficacy against chronic hepatitis C virus (HCV) infection. Despite this strength, recent studies raised concerns about an unexpected hepatocellular carcinoma (HCC) occurrence rate after DAA therapy. In this exploratory case-control study, we evaluated the potential use of miRNAs as serum biomarkers for the detection of early HCC in DAA-treated patients. In the discovery phase, the circulating miRNome was assessed in 10 matched patients with (HCC+) or without HCC (HCC-) occurrence. Microarray analysis was performed before (T0) and after one month of the DAA therapy (T1). MiRNAs discriminating HCC+ and HCC- patients were validated in 60 samples by means of RT-qPCR. We estimated the time-averaged difference of a given miRNA between HCC+ and HCC- patients using a bootstrapped random-effect generalized least square regression model (RE-GLS). At T0, miR-1207-5p, miR-1275, miR-3197, miR-4443, miR-3178, miR-483-5p, miR-4706, miR-4793-3p and miR-1246 discriminated HCC+ from HCC- patients (p < 0.05). At T1, only miR-1180-3p, miR-1228-3p, miR-4329 and miR-4484 (p < 0.05) discriminated HCC+ from HCC- patients. The subsequent validation phase identified miR-3197 as changing with both disease and time. Our results suggest that patients might be already committed to HCC occurrence before DAA therapy. MiR-3197 shows some potential for the identification of patients at risk of HCC during DAA treatments.
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Affiliation(s)
- Devis Pascut
- Liver Research Center, Fondazione Italiana Fegato—ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy; (M.Y.P.); (G.B.); (C.T.)
- Correspondence: ; Tel.: +39-040-375-7924
| | - Luisa Cavalletto
- Department of Internal Medicine—DIMED, University-Hospital of Padova, 35128 Padova, Italy; (L.C.); (L.C.)
| | - Muhammad Yogi Pratama
- Liver Research Center, Fondazione Italiana Fegato—ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy; (M.Y.P.); (G.B.); (C.T.)
- Faculty of Medicine, Universitas Hasanuddin, Makassar 90245, Indonesia
| | - Silvia Bresolin
- Laboratory of Onco-Haematology, Department of Women’s and Children’s Health, University of Padova, 35128 Padova, Italy; (S.B.)
- Istituto di Ricerca Pediatrica—Città della Speranza, 35127 Padova, Italy
| | - Luca Trentin
- Laboratory of Onco-Haematology, Department of Women’s and Children’s Health, University of Padova, 35128 Padova, Italy; (S.B.)
| | - Giuseppe Basso
- IIGM Torino and Pediatric Hemato-Oncology, 10126 Torino, Italy;
| | - Giorgio Bedogni
- Liver Research Center, Fondazione Italiana Fegato—ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy; (M.Y.P.); (G.B.); (C.T.)
| | - Claudio Tiribelli
- Liver Research Center, Fondazione Italiana Fegato—ONLUS, AREA Science Park, Basovizza, 34149 Trieste, Italy; (M.Y.P.); (G.B.); (C.T.)
| | - Liliana Chemello
- Department of Internal Medicine—DIMED, University-Hospital of Padova, 35128 Padova, Italy; (L.C.); (L.C.)
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Pereira Guedes T, Fragoso P, Lemos C, Garrido M, Silva J, Falcão D, Maia L, Moreira T, Manuel Ferreira J, Pedroto I. Long-Term Follow-Up of Advanced Liver Disease after Sustained Virological Response to Treatment of Hepatitis C with Direct-Acting Antivirals: Outcomes from a Real-World Portuguese Cohort. GE-PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2019; 27:149-159. [PMID: 32509920 DOI: 10.1159/000503074] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 09/01/2019] [Indexed: 12/12/2022]
Abstract
Background Direct-acting antivirals (DAA) have revolutionized hepatitis C treatment, with high sustained virological response (SVR) rates reported, even in historically difficult-to-treat groups. SVR is associated with a decreased risk of hepatocellular carcinoma (HCC), need for transplantation, and overall and liver-related mortality. Data from real-life cohorts on the medium- to long-term outcomes of patients with advanced liver disease and DAA-induced SVR are still missing. Objectives To report and analyze the long-term outcomes of DAA-induced SVR in a real-life cohort of patients with advanced liver disease. Method In this retrospective, longitudinal, single-center study, we collected data from patients with chronic hepatitis C infection and advanced liver disease (cirrhosis or advanced fibrosis) that had initiated DAA treatment between February 2015 and January 2017. Results A total of 237 patients were included. A treatment completion rate of 98.7% and an SVR rate of 97.8% (intention to treat: 96.6%) were found. Of the 229 patients with SVR, 67.2% were cirrhotic (64.2% Child-Pugh class A; 3.1% Child-Pugh class B) and 32.8% had stage F3 fibrosis, with an average follow-up of 28 months. The overall mortality rate was 19/1,000 person-years and the liver-related mortality rate was 9.5/1,000 person-years. The hepatic decompensation incidence rate was 25/1,000 person-years and the HCC incidence rate was 11.6/1,000 person-years. There was a sustained increase in serum platelet values during up to 2 years of follow-up. A history of pretreatment decompensation and baseline platelet and albumin values were significantly associated with the occurrence of adverse liver events after the end of treatment. Conclusions A DAA-induced SVR remains durable and is associated with an excellent clinical prognosis in patients with compensated advanced liver disease and with improvement or disease stabilization in decompensated patients. SVR is associated with a low risk of - yet does not prevent - HCC occurrence or disease progression, especially in the presence of other causes of liver injury. It is recommended that these patients be kept under surveillance.
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Affiliation(s)
- Tiago Pereira Guedes
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Pedro Fragoso
- Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Carolina Lemos
- UnIGENe, Instituto de Biologia Molecular e Celular (IBMC) and Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Porto, Portugal.,Department of Population Studies, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Mónica Garrido
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Joana Silva
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Daniela Falcão
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Luís Maia
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Teresa Moreira
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - José Manuel Ferreira
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Isabel Pedroto
- Department of Gastroenterology, Centro Hospitalar Universitário do Porto, Porto, Portugal
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38
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Kanda T, Lau GKK, Wei L, Moriyama M, Yu ML, Chuang WL, Ibrahim A, Lesmana CRA, Sollano J, Kumar M, Jindal A, Sharma BC, Hamid SS, Kadir Dokmeci A, Mamun-Al-Mahtab, McCaughan GW, Wasim J, Crawford DHG, Kao JH, Ooka Y, Yokosuka O, Sarin SK, Omata M. APASL HCV guidelines of virus-eradicated patients by DAA on how to monitor HCC occurrence and HBV reactivation. Hepatol Int 2019; 13:649-661. [PMID: 31541423 PMCID: PMC6861433 DOI: 10.1007/s12072-019-09988-7] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 08/30/2019] [Indexed: 12/13/2022]
Abstract
In the direct-acting antiviral (DAA) era for hepatitis C virus (HCV) infection, sustained virological response (SVR) is very high, but close attention must be paid to the possible occurrence of hepatocellular carcinoma (HCC) and reactivation of hepatitis B virus (HBV) in patients with co-infection who achieved SVR in short term. HCC occurrence was more often observed in patients with previous HCC history. We found occurrence of HCC in 178 (29.6%) of 602 patients with previous HCC history (15.4 months mean follow-up post-DAA initiation) but, in contrast, in only 604 (1.3%) of 45,870 patients without previous HCC history (18.2 months mean follow-up). Thus, in these guidelines, we recommend the following: in patients with previous HCC history, surveillance at 4-month intervals for HCC by ultrasonography (US) and tumor markers should be performed. In patients without previous HCC history, surveillance at 6- to 12-month intervals for HCC including US is recommended until the long-term DAA treatment effects, especially for the resolution of liver fibrosis, are confirmed. This guideline also includes recommendations on how to follow-up patients who have been infected with both HCV and HBV. When HCV was eradicated in these HBsAg-positive patients or patients with previous HBV infection (anti-HBc and/or anti-HBs-positive), it was shown that HBV reactivation or HBV DNA reappearance was observed in 67 (41.4%) of 162 or 12 (0.9%) of 1317, respectively. For these co-infected patients, careful attention should be paid to HBV reactivation for 24 weeks post-treatment.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - George K K Lau
- Humanity and Health Medical Center, Hong Kong SAR, China
| | - Lai Wei
- Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Ming-Lung Yu
- College of Biological Science and Technology, National Chiao Tung University, Hsin-Chu, Taiwan.,Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wang-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Alaaeldin Ibrahim
- GI/Liver Division, Department of Internal Medicine, University of Benha, Banha, Egypt
| | - Cosmas Rinaldi Adithya Lesmana
- Digestive Disease and GI Oncology Centre, Medistra Hospital, Jakarta, Indonesia.,Hepatobiliary Division, Department of Internal Medicine, Dr. Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Jose Sollano
- University Santo Tomas Hospital, Manila, Philippines
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | | | - Saeed S Hamid
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - A Kadir Dokmeci
- Department of Gastroenterology, Ankara University School of Medicine, Ankara, Turkey
| | - Mamun-Al-Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, 1000, Bangladesh
| | - Geoffrey W McCaughan
- Royal Prince Alfred Hospital, Centenary Institute, University of Sydney, Sydney, Australia
| | - Jafri Wasim
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Darrell H G Crawford
- University of Queensland, School of Medicine, Woolloongabba, QLD, 4102, Australia
| | - Jia-Horng Kao
- National Taiwan University College of Medicine, and National Taiwan University Hospital, Taipei, Taiwan
| | - Yoshihiko Ooka
- Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Osamu Yokosuka
- Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Masao Omata
- Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi, 400-8506, Japan. .,The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
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39
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Deterding K, Manns MP, Wedemeyer H. [Current drug treatment of hepatitis C : Useful therapy algorithms taking into consideration economical aspects]. Internist (Berl) 2019; 59:401-409. [PMID: 29497776 DOI: 10.1007/s00108-018-0390-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Treatment of chronic hepatitis C (HCV) has changed dramatically since the approval of the direct-acting antivirals (DAA). Depending on the HCV genotype and the stage of liver disease, sustained HCV clearance can be achieved in more than 95% of patients with a treatment duration of 8-12 weeks in most of the cases. The selection and combination of the drugs depends on previous antivirals therapies, the stage of liver fibrosis, HCV genotype and subtype, viral load at baseline, and renal function. Nowadays, potent antiviral therapy with minimal side effects can be offered to almost every patient. In the real-world setting, a high quality of HCV therapy considering economic aspects has been documented in the German Hepatitis C Registry. A reduction of clinical complications of chronic liver disease by clearance of HCV has already been documented.
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Affiliation(s)
- K Deterding
- Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland. .,Universitätsklinikum Essen, Hufelandstr. 55, 45147, Essen, Deutschland.
| | - M P Manns
- Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland
| | - H Wedemeyer
- Universitätsklinikum Essen, Hufelandstr. 55, 45147, Essen, Deutschland
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40
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Oberhofer E. [Not Available]. MMW Fortschr Med 2019; 161:12-13. [PMID: 31175596 DOI: 10.1007/s15006-019-0572-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
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41
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El Kassas M, Elbaz T, Salaheldin M, Abdelsalam L, Kaseb A, Esmat G. Impact of treating chronic hepatitis C infection with direct-acting antivirals on the risk of hepatocellular carcinoma: The debate continues - A mini-review. J Adv Res 2019; 17:43-48. [PMID: 31193326 PMCID: PMC6526204 DOI: 10.1016/j.jare.2019.03.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 01/26/2019] [Accepted: 03/03/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus clearance is expected in more than 95% of patients treated with direct-acting antivirals (DAAs). However, an extensive debate about the impact of DAAs on the development of hepatocellular carcinoma (HCC) is currently ongoing. This review aimed to explore currently available evidence about the relationship between DAAs and HCC development. The American studies and some European studies clearly showed no relation, while the Japanese and Egyptian studies and the other European studies showed an increased risk of developing HCC after DAA exposure. These conflicting results may be due to geographical and ethnic variations and differences in the design and inclusion criteria among the studies. After reviewing the data from these different studies, it seems that some patients are at increased risk of developing HCC after DAA exposure. Identifying those at increased risk is very important for the management of HCC in light of the potentially major consequences of HCC for the patients' quality of life and the subsequent major burden imposed on healthcare resources.
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Affiliation(s)
- Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Tamer Elbaz
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed Salaheldin
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Lobna Abdelsalam
- Genome Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Ahmed Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Texas, USA
| | - Gamal Esmat
- Endemic Medicine and Hepatogastroenterology Department, Faculty of Medicine, Cairo University, Cairo, Egypt
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42
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Owusu Sekyere S, Schlevogt B, Mettke F, Kabbani M, Deterding K, Wirth TC, Vogel A, Manns MP, Falk CS, Cornberg M, Wedemeyer H. HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection. Liver Cancer 2019; 8:41-65. [PMID: 30815394 PMCID: PMC6388568 DOI: 10.1159/000490360] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 05/19/2018] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE HCV clearance by current antiviral therapies improves clinical outcomes but falls short in eliminating the risk for hepatocellular carcinoma (HCC) emergence. As the HCC immune surveillance establishment is vital for the control of neoplastic development and growth, we investigated its correlation with on-/post-treatment HCC emergence, and further analyzed the influence of viral eradication on this setup in patients with HCV-related liver cirrhosis. DESIGN PBMC isolated at baseline and longitudinally during therapy were analyzed for tumor-associated antigen (TAA)-specific CD8+ T cell responses against glypican-3 overlapping peptides in vitro using high-definition flow cytometry. Multianalyte profiling of fifty soluble inflammatory mediators (SIM) in the plasma was also performed using Luminex-based multiplex technology. RESULTS Cirrhosis patients were characterized by an altered profile of distinct SIMs at baseline. At this time point, immune-surveilling T cells targeting specific HCC-associated antigens were readily detectable in HCV-free cirrhosis patients whilst being rather weak in such patients who further developed HCC upon virus eradication. Therapy-induced cure of HCV infection analogously reduced the strength of the prevailing HCC immune surveillance machinery, particularly by CD8+ T cells in cirrhosis patients. These results were further validated by T cell reactivities to six immuno-dominant HCC-associated HLA-A2-restricted epi-topes. Further, we demonstrated that this phenomenon was likely orchestrated by alterations in SIMs - with evidence of IL-12 being a major culprit. CONCLUSION Given the relationship between the baseline HCC-specific immune surveilling T cell responses and therapy-associated HCC emergence, and the impact of HCV clearance on its strength and magnitude, we recommend a continued HCC screening in cirrhotic HCV patients despite HCV resolution.
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Affiliation(s)
- Solomon Owusu Sekyere
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Bernhard Schlevogt
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,Department of Medicine B, Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - Friederike Mettke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Mohammad Kabbani
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Thomas Christian Wirth
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Peter Manns
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TTU-IICH, German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover-Braunschweig, Germany,Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hanover, Germany
| | - Christine Susanne Falk
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,Institute of Transplantation Immunology (IFB-Tx), Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TTU-IICH, German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover-Braunschweig, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany,TTU-IICH, German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover-Braunschweig, Germany,Department of General, Abdominal, and Transplant Surgery, Hannover Medical School, Hanover, Germany,Department of Gastroenterology and Hepatology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany,*Prof. Dr. med. Heiner Wedemeyer, Klinik für Gastroenterologie und Hepatologie, Universitätsklinikum Essen, Hufelandstrasse 55, DE–45147 Essen (Germany), E-Mail
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43
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Na SK, Song BC. Development and surveillance of hepatocellular carcinoma in patients with sustained virologic response after antiviral therapy for chronic hepatitis C. Clin Mol Hepatol 2019; 25:234-244. [PMID: 30661334 PMCID: PMC6759435 DOI: 10.3350/cmh.2018.0108] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 12/17/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC), and is a leading cause of liver-related deaths worldwide. Recently available direct-acting antiviral agent is very safe and highly effective (>95% sustained virologic response, SVR) against all genotypes of HCV. Achievement of SVR has been associated with a significant reduction of hepatic decompensation, development of HCC, and liver-related mortality. However, HCC risk is not eliminated even after SVR. The annual incidences of HCC in advanced fibrosis or cirrhosis have been estimated to be up to 2.5-4.5% even in patients with SVR. Therefore, surveillance for HCC is recommended in this high-risk patients. In this review, we will describe the clinical outcomes and the risk of HCC in patients with SVR and suggest who should receive surveillance for HCC.
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Affiliation(s)
- Seong Kyun Na
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
| | - Byung-Cheol Song
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
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44
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Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Oncogenic Signaling Induced by HCV Infection. Viruses 2018; 10:v10100538. [PMID: 30279347 PMCID: PMC6212953 DOI: 10.3390/v10100538] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 09/29/2018] [Accepted: 09/30/2018] [Indexed: 02/07/2023] Open
Abstract
The liver is frequently exposed to toxins, metabolites, and oxidative stress, which can challenge organ function and genomic stability. Liver regeneration is therefore a highly regulated process involving several sequential signaling events. It is thus not surprising that individual oncogenic mutations in hepatocytes do not necessarily lead to cancer and that the genetic profiles of hepatocellular carcinomas (HCCs) are highly heterogeneous. Long-term infection with hepatitis C virus (HCV) creates an oncogenic environment by a combination of viral protein expression, persistent liver inflammation, oxidative stress, and chronically deregulated signaling events that cumulate as a tipping point for genetic stability. Although novel direct-acting antivirals (DAA)-based treatments efficiently eradicate HCV, the associated HCC risk cannot be fully eliminated by viral cure in patients with advanced liver disease. This suggests that HCV may persistently deregulate signaling pathways beyond viral cure and thereby continue to perturb cancer-relevant gene function. In this review, we summarize the current knowledge about oncogenic signaling pathways derailed by chronic HCV infection. This will not only help to understand the mechanisms of hepatocarcinogenesis but will also highlight potential chemopreventive strategies to help patients with a high-risk profile of developing HCC.
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Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
- Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
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45
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Cheng ML, Abdel-Hakeem MS, Cousineau SE, Grebely J, Marshall AD, Saeed S, Sagan SM, Shoukry NH, Feld JJ, MacParland SA. The 7th Canadian Symposium on Hepatitis C Virus: “Toward Elimination of HCV: How to Get There”. CANADIAN LIVER JOURNAL 2018; 1:139-152. [DOI: 10.3138/canlivj.2018-0018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 06/06/2018] [Indexed: 12/11/2022]
Abstract
Hepatitis C virus (HCV) affects more than 268,000 people in Canada. Both the Canadian Institutes of Health Research and the Public Health Agency of Canada recognize the significant impact of HCV-related liver diseases and supported the establishment of a national hepatitis C research network, the Canadian Network on Hepatitis C (CanHepC). Interferon-free direct-acting antiviral regimens lead to more than 95% cure rates in almost all patients with well-tolerated short-course therapy. However, the goal of eliminating HCV in Canada cannot be fully realized until we overcome the financial, geographical, cultural, and social barriers that affect the entire continuum of care from diagnosis and linkage to care through treatment and prevention of new and reinfections. Current practices face difficulties in reversing HCV-induced immunological defects, expanding treatment to neglected communities, combating reinfections and co-infections, and expediting and simplifying the processes of diagnosis and treatment. As part of its knowledge translation mandate, CanHepC has organized the annual Canadian symposium on hepatitis C since 2012. The theme of this year’s symposium, “Toward Elimination of HCV: How to Get There?” focused on identifying the requirements of our therapeutic strategies and health policies for the elimination of HCV in Canada.
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Affiliation(s)
- Michael L Cheng
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario
| | - Mohamed S Abdel-Hakeem
- Penn Institute for Immunology, Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Sophie E Cousineau
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec
| | - Jason Grebely
- Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - Alison D Marshall
- Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - Sahar Saeed
- Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec
| | - Selena M Sagan
- Department of Microbiology and Immunology, McGill University, Montreal, Quebec
- Department of Biochemistry, McGill University, Montreal, Quebec
| | - Naglaa H Shoukry
- Centre de Recherche du Centre hospitalier de l’Université de Montréal, Montreal, Quebec
| | - Jordan J Feld
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario
| | - Sonya A MacParland
- Multi-Organ Transplant Program, University Health Network, Toronto, Ontario
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario
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Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses 2018; 10:v10100531. [PMID: 30274202 PMCID: PMC6212901 DOI: 10.3390/v10100531] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/25/2018] [Accepted: 09/27/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.
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47
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Pawlotsky JM, Negro F, Aghemo A, Berenguer M, Dalgard O, Dusheiko G, Marra F, Puoti M, Wedemeyer H. EASL Recommendations on Treatment of Hepatitis C 2018. J Hepatol 2018; 69:461-511. [PMID: 29650333 DOI: 10.1016/j.jhep.2018.03.026] [Citation(s) in RCA: 1200] [Impact Index Per Article: 171.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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48
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Guarino M, Sessa A, Cossiga V, Morando F, Caporaso N, Morisco F. Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows. World J Gastroenterol 2018; 24:2582-2595. [PMID: 29962815 PMCID: PMC6021774 DOI: 10.3748/wjg.v24.i24.2582] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2018] [Revised: 05/18/2018] [Accepted: 06/12/2018] [Indexed: 02/06/2023] Open
Abstract
With the introduction of direct-acting antiviral agents (DAA), the rate of sustained virological response (SVR) in the treatment of hepatitis C virus (HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma (HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4% (maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4% (maximum “not well-defined” follow-up: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection.
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MESH Headings
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/virology
- Disease Progression
- Hepacivirus/drug effects
- Hepacivirus/physiology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/pathology
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Liver/drug effects
- Liver/pathology
- Liver/virology
- Liver Neoplasms/epidemiology
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Liver Neoplasms/virology
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/virology
- Risk Factors
- Sustained Virologic Response
- Treatment Outcome
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Affiliation(s)
- Maria Guarino
- Filomena Morisco, Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Anna Sessa
- Filomena Morisco, Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Valentina Cossiga
- Filomena Morisco, Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Federica Morando
- Filomena Morisco, Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
| | - Nicola Caporaso
- Filomena Morisco, Gastroenterology Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples 80131, Italy
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Persico M, Aglitti A, Aghemo A, Rendina M, Lleo A, Ciancio A, Di Marco V, Lampertico P, Brunetto MR, Zuin M, Andreone P, Villa E, Troshina G, Calvaruso V, Degasperi E, Coco B, Giorgini A, Conti F, Di Leo A, Marzi L, Boccaccio V, Bollani S, Maisonneuve P, Bruno S. High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma. Aliment Pharmacol Ther 2018; 47:1705-1712. [PMID: 29722439 DOI: 10.1111/apt.14685] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/17/2018] [Accepted: 04/03/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. AIM We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. METHODS From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 ± 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. RESULTS The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. CONCLUSION This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC.
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Singer AW, Reddy KR, Telep LE, Osinusi AO, Brainard DM, Buti M, Chokkalingam AP. Direct-acting antiviral treatment for hepatitis C virus infection and risk of incident liver cancer: a retrospective cohort study. Aliment Pharmacol Ther 2018. [PMID: 29516535 DOI: 10.1111/apt.14593] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Eradication of hepatitis C virus (HCV) infection via interferon-based treatment lowers hepatocellular carcinoma risk; some research suggests this effect extends to interferon-free treatment. AIMS The objective of this retrospective cohort study was to examine the association of direct-acting antiviral (DAA) exposure with risk of incident liver cancer in real-world data. METHODS From United States administrative claims data through March 31, 2017, we identified 30 183 adult HCV patients exposed to DAAs. For comparison, we identified contemporary adult HCV patients without evidence of HCV treatment (N = 137 502), and historical HCV patients treated with interferon prior to the introduction of DAAs (N = 12 948). Included patients had at least 12 months of prior enrolment and no evidence of prior liver cancer at baseline. Hazard ratios (HRs) estimating risk of incident liver cancer associated with DAA treatment were calculated using Cox proportional hazards methods. RESULTS Relative to untreated HCV patients, DAA-treated patients were older, more likely to be male, and more likely to have cirrhosis at baseline. After adjustment, DAA treatment was associated with a significantly reduced risk of liver cancer relative to no treatment (adjusted HR = 0.84, 95% CI: 0.73-0.96), and relative to interferon-based treatment in the pre-DAA era (HR = 0.69, 95% CI: 0.59-0.81). CONCLUSIONS In this large, population-based study, DAA-based treatment was associated with a reduced risk of incident liver cancer relative to both no HCV treatment and to interferon-based treatment in the pre-DAA era. As additional follow-up time of DAA-treated patients accrues, we anticipate that the long-term benefits of DAA treatment will become more apparent.
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Affiliation(s)
- A W Singer
- Gilead Sciences Inc., Foster City, CA, USA
| | - K R Reddy
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - L E Telep
- Gilead Sciences Inc., Foster City, CA, USA
| | | | | | - M Buti
- Hospital General Universitari Vall d'Hebron, Barcelona, Spain
| | - A P Chokkalingam
- Gilead Sciences Inc., Foster City, CA, USA.,School of Public Health, University of California, Berkeley, CA, USA
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