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Salfi AB, Hussain M, Majeed MI, Nawaz H, Rashid N, Albekairi NA, Alshammari A, Yousaf A, Ullah MH, Fatima E, Mehmood S, Hakeem M, Amin I, Javed M. Surface-enhanced Raman spectroscopy for the characterization of filtrate portions of hepatitis B blood serum samples using 100 kDa ultra filtration devices. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2025; 333:125883. [PMID: 39978181 DOI: 10.1016/j.saa.2025.125883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 12/30/2024] [Accepted: 02/08/2025] [Indexed: 02/22/2025]
Abstract
The blood serum of patients infected by the Hepatitis B virus contains high molecular weight fractions and low molecular weight fractions (LMWF) of biomarker proteins of the disease. The LMWF including the associated peptidome and metabolome, is recognized as a critical molecular population with high potential for research on disease-associated biomarkers. This fraction of biomarkers can be suppressed by HMWF, proteins such as albumin, and immunoglobulins hence difficult to be detected. The purpose of this study is to separate HMWF) and LMWF using 100 kDa centrifugal filtration devices resulting in two parts including residue (HMWF) and filtrate parts (LMWF) of blood serum followed by the analysis of the later part employing surface-enhanced Raman spectroscopy (SERS). This strategy can enhance this optical technique's capability to characterize the biochemical changes caused by the infection of HBV and the diagnosis of the disease. The silver nanoparticles (Ag-NPs) were employed as a SERS substrate to distinguish between filtrate parts of the blood serum of HBV patients and healthy individuals based on their specific SERS peaks. The SERS spectral features associated with the filtrate parts of HBV patients' blood serum are well differentiated from the healthy volunteers. Principle component analysis (PCA) was applied on the SERS spectral data sets of HBV patients and healthy individuals and found extremely beneficial for the classification of their SERS spectral groups. Moreover, partial least square regression analysis (PLSR) has shown excellent performance in the quantitative analysis of the viral load values of the HBV patients using their SERS spectral data sets.
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Affiliation(s)
- Abu Bakar Salfi
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Munawar Hussain
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Muhammad Irfan Majeed
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan.
| | - Haq Nawaz
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan.
| | - Nosheen Rashid
- Department of Chemistry, University of Education, Faisalabad Campus, Faisalabad 38000 Pakistan
| | - Norah A Albekairi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2455, Riyadh 11451 Saudi Arabia
| | - Abdulrahman Alshammari
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Post Box 2455, Riyadh 11451 Saudi Arabia
| | - Arslan Yousaf
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Muhammad Hafeez Ullah
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Eman Fatima
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Sana Mehmood
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Munazza Hakeem
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad 38000 Pakistan
| | - Imran Amin
- PCR Laboratory, PINUM Hospital, Faisalabad 38000 Pakistan
| | - Mahrosh Javed
- Nacionalinis Fizinių ir technologijos mokslų centras (NFTMC), Department of Environmental Research, Lithuania
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Nwude VN, Lesi OA, Onyekwere C, Charpentier E, Hübschen JM. Clinical Characteristics of Hepatitis B Virus-Associated Hepatocellular Carcinoma Patients in Southwest Nigeria. Pathogens 2025; 14:169. [PMID: 40005544 PMCID: PMC11858220 DOI: 10.3390/pathogens14020169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/03/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) is a major cause of morbidity and mortality in West Africa, but its presentation is poorly understood. In this study, we describe the clinical characteristics of HBV-associated HCC patients in Lagos, Nigeria. Data for all cases were collected at the emergency and gastroenterology units (2017-2019), considering chronic carriers as controls. Clinical data and routine biochemical and radiologic test results were extracted from the files. The serum biomarkers (Osteopontin, AFP-L3, DCP) were investigated. For some cases, the hepatitis B viral load was determined. The mean age of the cases (n = 92) was 41.4 years, compared to 39.9 years for the controls (n = 100). Clinically, 69.5% of cases presented with ascites, 66.3% had nodules occupying >50% of the liver, and 67.4% had moderate hepatic encephalopathy. The mean viral load and the median values of Osteopontin, AFP-L3, and DCP for the cases were significantly higher than for the controls (p < 0.001). The area under the curve, sensitivity, and specificity were significantly higher for Osteopontin, compared with DCP and AFP-L3 (p < 0.001). Most HCC patients presented at a late disease stage, when the prognosis is usually poor. Especially Osteopontin seems to have potential for early HCC detection and could possibly complement AFP and abdominal ultrasound scan for risk-group screening.
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Affiliation(s)
- Vivian N. Nwude
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA
| | - Olufunmilayo A. Lesi
- Department of Internal Medicine, College of Medicine, University of Lagos, Lagos 12003, Lagos State, Nigeria
| | - Charles Onyekwere
- Lagos State University Teaching Hospital, 1-5 Oba Akinjobi Way, Ikeja 101233, Lagos State, Nigeria;
| | - Emilie Charpentier
- Clinical and Applied Virology, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg;
| | - Judith M. Hübschen
- Clinical and Applied Virology, Department of Infection and Immunity, Luxembourg Institute of Health, 4354 Esch-sur-Alzette, Luxembourg;
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Tan ECH, Yehoshua A, Jeyakumar S, Peng P, Lin A, Smith NJ, Kachru N. The Cost-Effectiveness of Tenofovir Alafenamide for Chronic Hepatitis B Virus in Taiwan. MDM Policy Pract 2025; 10:23814683251328659. [PMID: 40162197 PMCID: PMC11954167 DOI: 10.1177/23814683251328659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 02/14/2025] [Indexed: 04/02/2025] Open
Abstract
Background. Chronic hepatitis B (CHB) is a lifelong disease requiring long-term or indefinite therapy, resulting in substantial economic burden. Thus, careful consideration must be used in the selection of therapies. Aim. This analysis assessed the cost-effectiveness of tenofovir alafenamide (TAF) compared with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) from the perspective of the Taiwan National Health Insurance Administration Healthcare payer for the management of CHB over a lifetime horizon. Methods. An individual patient simulation model assessed the impact of treatment on CHB infection for liver- and safety-related outcomes. Patients could achieve spontaneous or treatment-induced responses, experience a reactivation of the disease, develop long-term liver complications, or experience treatment-related renal or bone complications. Patient population profiles were based on clinical trial and real-world data. Data on clinical parameters (safety, mortality, resistance risk, and flare), health utilities, and costs were sourced from the published literature. Results. TAF was associated with fewer liver disease events and fewer cases of bone and renal complications per 100 person-years. TAF also had higher eAg and sAg seroconversion compared with TDF and ETV. As compared with both treatments, TAF was both more effective and more costly, resulting in incremental cost-effectiveness ratios of USD 3,348 and USD 3,940 per quality-adjusted life-year gained versus TDF and ETV, respectively. Conclusion. TAF leads to better health outcomes at acceptable incremental costs compared with the most commonly used therapies in the management of CHB, thus making it a cost-effective option for the treatment of CHB in Taiwan. Highlights The cost-effectiveness of tenofovir alafenamide (TAF) versus tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was assessed in patients with chronic hepatitis B in Taiwan.TAF was associated with fewer liver disease events, fewer cases of bone and renal complications, and higher eAG and sAG seroconversion compared with TDF and ETV; TAF was found to be cost-effective compared with both treatments.
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Affiliation(s)
- Elise Chia-Hui Tan
- Department of Health Service Administration, China Medical University, Taichung, Taiwan
| | | | | | - Pongo Peng
- Gilead Sciences Inc., Foster City, CA, USA
| | - Amy Lin
- Gilead Sciences Inc., Foster City, CA, USA
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Shuaib BI, Momodu A, Ohenhen JE, Umeche IE, Muhibi MA. Prevalence of overt and occult hepatitis B viral infection among pregnant women attending antenatal clinics in Edo state university teaching hospital Auchi, Nigeria. BMC Infect Dis 2024; 24:1468. [PMID: 39731052 DOI: 10.1186/s12879-024-10376-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 12/19/2024] [Indexed: 12/29/2024] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection remains a major health challenge in Nigeria, with high prevalence rates among pregnant women. The prevalence of overt and occult hepatitis B infection (HBIOV and HBIOC) among pregnant women was investigated to understand the burden and associated risk factors in this population. METHODS A cross-sectional study was conducted among 200 pregnant women. Socio-demographic and clinical data were collected, and blood samples were screened for hepatitis B surface antigen (HBsAg) and hepatitis B virus DNA (HBV-DNA) using Enzyme-Linked Immunosorbent Assay (ELISA) and real time Polymerase Chain Reaction max Eco 48 system. Data were analyzed using GraphPad Prism software (v6) and Statistical Package for the Social Sciences (IBM SPSS 23.0). A significance level of P ≤ 0.05 was considered statistically significant. RESULTS The overall prevalence of hepatitis B infection was 6.0% (12/200), comprising 2.5% HBIOC and 3.5% HBIOV. The participants, aged 19 to 43 years, were predominantly married (89.5%) and urban-dwelling (69.0%), with diverse educational levels and occupations. There were no statistically significant differences in demographic factors such as age, marital status, or education between HBIOC and HBIOV groups. However, significant associations were observed between HBV infection and risk factors including blood transfusion (p = 0.01), cigarette exposure (p = 0.03), and alcohol consumption (p = 0.01). Viral load was significantly higher in the HBIov group [4.84 log IU/mL (IQR: 4.00-9.14)] compared to the HBIoc group [2.30 log IU/mL (IQR: 2.19-3.00)] (p = 0.001). CONCLUSION The findings reveal a 6.0% prevalence of hepatitis B infection among pregnant women, with 3.5% overt and 2.5% occult infections. The results emphasize the need for HBV DNA testing in screening protocols to detect occult and overt HB infections and address key risk factors to improve antenatal care and prevention strategies.
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Affiliation(s)
- Bukhari Isah Shuaib
- Department of Medical Laboratory Science, Faculty of Applied Health Sciences, Edo State University, Uzairue, Edo State, Nigeria.
| | - Amina Momodu
- Department of Medical Laboratory Science, Faculty of Applied Health Sciences, Edo State University, Uzairue, Edo State, Nigeria
| | - Johnsolomon Eghosa Ohenhen
- Department of Medical Laboratory Science, Faculty of Applied Health Sciences, Edo State University, Uzairue, Edo State, Nigeria
| | - Ijeoma Evangeline Umeche
- Department of Medical Laboratory Science, Faculty of Applied Health Sciences, Edo State University, Uzairue, Edo State, Nigeria
| | - Musa Abidemi Muhibi
- Department of Medical Laboratory Science, Faculty of Applied Health Sciences, Edo State University, Uzairue, Edo State, Nigeria
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Lai JCT, Wong GLH, Tse YK, Hui VWK, Lai MSM, Chan HLY, Wong VWS, Yip TCF. Histological severity, clinical outcomes and impact of antiviral treatment in indeterminate phase of chronic hepatitis B: A systematic review and meta-analysis. J Hepatol 2024:S0168-8278(24)02718-1. [PMID: 39577468 DOI: 10.1016/j.jhep.2024.11.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 11/10/2024] [Accepted: 11/13/2024] [Indexed: 11/24/2024]
Abstract
BACKGROUND & AIMS Current international guidelines recommend close monitoring and evaluation of patients with chronic hepatitis B (CHB) in the indeterminate phase, and treatment of patients at high risk of adverse outcomes. Clinical outcomes and the effect of antiviral therapy on the indeterminate phase remain unclear. We performed a systematic review and meta-analysis to study the incidence of adverse clinical outcomes including hepatocellular carcinoma (HCC), cirrhosis, and hepatic decompensation, and the effect of antiviral therapy, in the indeterminate phase. METHODS Two investigators independently searched Embase, MEDLINE, Web of Science and China National Knowledge Infrastructure from 1/1/2007 to 31/12/2023. Three investigators independently assessed study eligibility and quality. We included cohort studies and a randomised-controlled trial, allowing for calculation of the incidence rate of adverse clinical outcomes, and cross-sectional studies that reported the prevalence of moderate-to-severe inflammation and different degrees of fibrosis. Incidence rates and prevalence were pooled using generalised linear mixed-effects models and random-effects models, respectively. RESULTS One hundred and three studies (70 case-control studies [18,739 patients], 32 cohort studies [15,118 patients], and one RCT [160 patients]) were included. The annual incidence rate of HCC in patients in the indeterminate phase was 0.32% (95% CI 0.21-0.48%, I2 = 85.7%), and those of cirrhosis and hepatic decompensation were 0.67% (95% CI 0.30-1.49%, I2 = 94.3%) and 0.34% (95% CI 0.17-0.69%, I2 = 51.8%), respectively. The pooled prevalence of moderate-to-severe liver inflammation, significant fibrosis, advanced fibrosis, and cirrhosis was 40.7%, 39.7%, 17.9%, and 7.2%, respectively. Use of antiviral therapy was associated with a lower risk of HCC in patients in the indeterminate phase (adjusted incidence rate ratio 0.38, 95% CI 0.18-0.79, p = 0.009). CONCLUSIONS Patients in the indeterminate phase are at risk of developing advanced liver disease and HCC. Although inherent heterogeneity across studies limited the evidence to support expanding treatment to all patients in the indeterminate phase, antiviral therapy may reduce the risk of HCC development in high-risk subgroups. IMPACT AND IMPLICATIONS Current international guidelines recommend close monitoring and evaluation of patients with chronic hepatitis B (CHB) in the indeterminate phase, in whom antiviral treatment is not always indicated. Based on the systematic review and meta-analysis with significant heterogeneity across studies, patients in the indeterminate phase are at risk of developing hepatocellular carcinoma, cirrhosis, and hepatic decompensation. Meta-regression findings on platelet count, positive HBeAg, and age highlighted the importance of liver fibrosis assessment, accurate phase classification, and timely detection of phase transition to identify antiviral treatment indications, supporting current guideline recommendations. Antiviral treatment may reduce the risk of hepatocellular carcinoma in the high-risk subgroups of patients in the indeterminate phase. PROSPERO REGISTRATION NUMBER CRD42024537095.
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Affiliation(s)
- Jimmy Che-To Lai
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Grace Lai-Hung Wong
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Yee-Kit Tse
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Vicki Wing-Ki Hui
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Mandy Sze-Man Lai
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Henry Lik-Yuen Chan
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Department of Internal Medicine, Union Hospital, Hong Kong Special Administrative Region of China
| | - Vincent Wai-Sun Wong
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China
| | - Terry Cheuk-Fung Yip
- Medical Data Analytics Centre, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region of China.
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Pawlotsky JM. Virological markers for clinical trials in chronic viral hepatitis. JHEP Rep 2024; 6:101214. [PMID: 39524203 PMCID: PMC11550202 DOI: 10.1016/j.jhepr.2024.101214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/30/2024] [Accepted: 09/02/2024] [Indexed: 11/16/2024] Open
Abstract
Chronic hepatitis virus infections remain a major public health problem, despite significant therapeutic advances over the past two decades. Considerable progress has been made in the treatment of chronic viral hepatitis, but continued efforts are needed to develop and bring to market new drugs to fill the gaps in the current therapeutic armamentarium. Thus, clinical trials to assess the safety and efficacy of these new therapeutic approaches, including the selection of reliable and objective treatment endpoints, are still needed. Virological biomarkers play an important role in the diagnosis, monitoring, and evaluation of antiviral treatment efficacy. They are often used as primary or secondary endpoints in the evaluation of new treatments for chronic viral hepatitis. However, these markers are not all equally informative. The aim of this review article is to provide a comprehensive overview of the available virological tests for chronic viral hepatitis due to hepatitis B, D, C and E viruses, the information they provide and lack, the specific challenges associated with each, and their use in clinical trials of new treatments.
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Affiliation(s)
- Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor (AP-HP), Université Paris-Est, Créteil, France
- Team “Viruses, Hepatology, Cancer”, Institut Mondor de Recherche Biomédicale, INSERM U955, Université Paris-Est, Créteil, France
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Mak LY, Boettler T, Gill US. HBV Biomarkers and Their Role in Guiding Treatment Decisions. Semin Liver Dis 2024; 44:474-491. [PMID: 39442530 DOI: 10.1055/a-2448-4157] [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: 10/25/2024]
Abstract
Over 300 million individuals worldwide are chronically infected with hepatitis B virus and at risk for progressive liver disease. Due to the lack of a therapy that reliably achieves viral elimination and the variability of liver disease progression, treatment decisions are guided by the degree of liver disease and viral biomarkers as the viral life-cycle is well characterized and largely conserved between individuals. In contrast, the immunological landscape is much more heterogeneous and diverse and the measurement of its components is less well standardized. Due to the lack of a universal and easily measurable set of biomarkers, clinical practice guidelines remain controversial, aiming for a balance between simplifying treatment decisions by reducing biomarker requirements and using all available biomarkers to avoid overtreatment of patients with low risk for disease progression. While approved therapies such as nucleos(t)ide analogs improve patient outcomes, the inability to achieve a complete cure highlights the need for novel therapies. Since no treatment candidate has demonstrated universal efficacy, biomarkers will remain important for treatment stratification. Here, we summarize the current knowledge on virological and immunological biomarkers with a specific focus on how they might be beneficial in guiding treatment decisions in chronic hepatitis B.
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Affiliation(s)
- Lung-Yi Mak
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
- Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, The Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Tobias Boettler
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Upkar S Gill
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
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Zhao J, Fang L, Pu R, Liu W, Cai S, Wang R, Shi Y, Li Z, Zhang Z, Li Z, Cao G. Androgen receptor-induced molecules and androgen contribute synergistically to male-predominance of hepatocellular carcinoma. iScience 2024; 27:110519. [PMID: 39156638 PMCID: PMC11326917 DOI: 10.1016/j.isci.2024.110519] [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: 02/12/2024] [Revised: 05/30/2024] [Accepted: 07/12/2024] [Indexed: 08/20/2024] Open
Abstract
We aimed to clarify the mechanisms of male predominance of hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC). Androgen receptor (AR) facilitates HCC cell growth, which was augmented by androgen (dihydrotestosterone [DHT]) and attenuated by anti-androgen (flutamide). AR upregulated the expressions of BIRC7, IGFBP3, and NTSR1 via increasing their promoter activities, which were enhanced by DHT. Wild-type HBV X (WT-HBx) upregulated AR transcription, which depended on DHT; whereas the effect of C-terminal carboxy-truncated HBx on AR transcription was independent of DHT. BIRC7, IGFBP3, and NTSR1 increased the growth of HCC. High expression of BIRC7 and NTSR1 contributes to poor HCC outcomes in male patients, but not in female patients. Downregulation of NTSR1 inhibits tumor growth in male mice rather than in female mice. Conclusively, AR promotes HCC at least partially via upregulating BIRC7, IGFBP3, and NTSR1, which is enhanced by androgen and HBx. BIRC7 and NTSR1 facilitate HCC progression in a male-predominant manner.
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Affiliation(s)
- Jiayi Zhao
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
| | - Letian Fang
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
| | - Rui Pu
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
| | - Wenbin Liu
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
| | - Shiliang Cai
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
| | - Ruihua Wang
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
| | - Yiwei Shi
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
| | - Zheng Li
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
| | - Zihan Zhang
- Tongji University School of Medicine, Tongji University, Shanghai 200120, China
| | - Zishuai Li
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
- Key Laboratory of Biological Defense, Ministry of Education, Second Military Medical University, Shanghai 200433, China
- Shanghai Key Laboratory of Medical Bioprotection, Second Military Medical University, Shanghai 200433, China
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Chaiwiriyawong S, Assawasuwannakit S, Feuangwattana P, Sripongpun P, Chamroonkul N, Piratvisuth T, Kaewdech A. Clinical Utility of the aMAP Score for Predicting Hepatocellular Carcinoma Development in Patients with Chronic Hepatitis B. Diagnostics (Basel) 2024; 14:1325. [PMID: 39001216 PMCID: PMC11240693 DOI: 10.3390/diagnostics14131325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 06/16/2024] [Accepted: 06/20/2024] [Indexed: 07/16/2024] Open
Abstract
This study aimed to evaluate the efficacy of the aMAP score and compare it with other risk scores for predicting hepatocellular carcinoma (HCC) development in Thai patients with chronic hepatitis B (CHB). We retrospectively analyzed patients with CHB between 1 January 2008 and 31 December 2019. Data on demographics, clinical parameters, cirrhosis status, HCC imaging, and alpha fetoprotein surveillance were collected to calculate the aMAP score (0-100) based on age, sex, albumin-bilirubin level, and platelet count. Of the 1060 patients analyzed, 789 were eligible, of whom 51 developed HCC. The cumulative HCC incidences in the low-, moderate-, and high-risk groups at 3, 5, and 10 years were significantly different (log-rank, p < 0.0001). The area under the receiver operating characteristic curves (AUROCs) of the aMAP scores for predicting HCC at 3, 5, and 10 years were 0.748, 0.777, and 0.784, respectively. Among the risk scores, the CU-HCC score had the highest AUROCs (0.823) for predicting 5-year HCC development. The aMAP score is a valuable tool for predicting HCC risk in Thai patients with CHB and can enhance surveillance strategies. However, its performance is inferior to that of the CU-HCC score, suggesting the need for new predictive tools for HCC surveillance.
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Affiliation(s)
- Supakorn Chaiwiriyawong
- Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Suraphon Assawasuwannakit
- Department of Medicine, Panyananthaphikkhu Chonprathan Medical Center, Srinakharinwirot University, Nonthaburi 11120, Thailand
| | - Poorikorn Feuangwattana
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Pimsiri Sripongpun
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Naichaya Chamroonkul
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Teerha Piratvisuth
- NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Songkhla 90110, Thailand
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
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10
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Su L, Luo H, Yan Y, Yang Z, Lu J, Xu D, Du L, Liu J, Yang G, Chi H. Exploiting gender-based biomarkers and drug targets: advancing personalized therapeutic strategies in hepatocellular carcinoma. Front Pharmacol 2024; 15:1433540. [PMID: 38966543 PMCID: PMC11222576 DOI: 10.3389/fphar.2024.1433540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 06/04/2024] [Indexed: 07/06/2024] Open
Abstract
This review systematically examines gender differences in hepatocellular carcinoma (HCC), identifying the influence of sex hormones, genetic variance, and environmental factors on the disease's epidemiology and treatment outcomes. Recognizing the liver as a sexually dimorphic organ, we highlight how gender-specific risk factors, such as alcohol consumption and obesity, contribute differently to hepatocarcinogenesis in men and women. We explore molecular mechanisms, including the differential expression of androgen and estrogen receptors, which mediate diverse pathways in tumor biology such as cell proliferation, apoptosis, and DNA repair. Our analysis underscores the critical need for gender-specific research in liver cancer, from molecular studies to clinical trials, to improve diagnostic accuracy and therapeutic effectiveness. By incorporating a gender perspective into all facets of liver cancer research, we advocate for a more precise and personalized approach to cancer treatment that acknowledges gender as a significant factor in both the progression of HCC and its response to treatment. This review aims to foster a deeper understanding of the biological and molecular bases of gender differences in HCC and to promote the development of tailored interventions that enhance outcomes for all patients.
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Affiliation(s)
- Lanqian Su
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Huanyu Luo
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Yalan Yan
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Zhongqiu Yang
- Department of General Surgery, Dazhou Central Hospital, Dazhou, China
| | - Jiaan Lu
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Danqi Xu
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Linjuan Du
- Department of Oncology, Dazhou Central Hospital, Dazhou, China
| | - Jie Liu
- Department of General Surgery, Dazhou Central Hospital, Dazhou, China
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH, United States
| | - Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China
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11
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Yaow CYL, Hong ASY, Chong NZY, Chong RIH, Mai AS, Tan EK. Risk of Parkinson's disease in hepatitis B and C populations: a systematic review and meta-analysis. J Neural Transm (Vienna) 2024; 131:609-616. [PMID: 37899363 DOI: 10.1007/s00702-023-02705-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 09/27/2023] [Indexed: 10/31/2023]
Abstract
Parkinson's disease (PD) is a common neurodegenerative disorder, and its association with viral hepatitis has been debated. We performed a meta-analysis to examine the association between PD risk and viral hepatitis. Medline, EMBASE, and the Cochrane library were searched from inception till July 2022. Meta-analysis was conducted using a fixed-effect model with the inverse variance method. Three groups were compared to controls: infection with either hepatitis B or C virus (HBV and HCV, respectively), or coinfection with both viruses. We found 551 records, and six studies comprising of 2,566,947 patients were included in the analysis. PD risk was increased in HCV-infected population (OR 1.10, 95% CI 1.03-1.17, p = 0.005) and (HR 1.37, 95% CI 1.26-1.49, p < 0.001). This increase was not observed for the HBV-infected and HBV-HCV-coinfected coinfection populations. For pooled OR, the risk was significantly lower in HBV-infected (OR 0.79, 95% CI 0.76-0.83, p < 0.001) but not significantly different in HBV-HCV-coinfected populations (OR 0.96, 95% CI 0.82-1.12, p = 0.57). For pooled HR, the risk was significantly higher in both HBV-infected (HR 1.22, 95% CI 1.14-1.31, p < 0.001) and HBV-HCV-coinfected populations (HR 1.29, 95% CI 1.05-1.58, p = 0.013). We found that the risk of PD was increased in the HCV-infected population, but results were inconsistent in those with HBV and HBV-HCV infections. Our findings provide impetus for further clinical and functional studies to unravel the role of the adaptive immune system in PD.
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Affiliation(s)
- Clyve Yu Leon Yaow
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | | | | | - Ryan Ian Houe Chong
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Aaron Shengting Mai
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Eng-King Tan
- Department of Neurology, Singapore General Hospital Campus, National Neuroscience Institute, Duke NUS Medical School, Outram Road, Singapore, 169608, Singapore.
- Neuroscience and Behavioural Disorders, Duke-NUS Medical School, Singapore, Singapore.
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12
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Toniutto P, Shalaby S, Mameli L, Morisco F, Gambato M, Cossiga V, Guarino M, Marra F, Brunetto MR, Burra P, Villa E. Role of sex in liver tumor occurrence and clinical outcomes: A comprehensive review. Hepatology 2024; 79:1141-1157. [PMID: 37013373 DOI: 10.1097/hep.0000000000000277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 12/06/2022] [Indexed: 04/05/2023]
Abstract
Clinical research on sex-based differences in the manifestations, pathophysiology, and prevalence of several diseases, including those affecting the liver, has expanded considerably in recent years. Increasing evidence suggests that liver diseases develop, progress, and respond to treatment differently depending on the sex. These observations support the concept that the liver is a sexually dimorphic organ in which estrogen and androgen receptors are present, which results in disparities between men and women in liver gene expression patterns, immune responses, and the progression of liver damage, including the propensity to develop liver malignancies. Sex hormones play protective or deleterious roles depending on the patient's sex, the severity of the underlying disease, and the nature of precipitating factors. Moreover, obesity, alcohol consumption, and active smoking, as well as social determinants of liver diseases leading to sex-related inequalities, may interact strongly with hormone-related mechanisms of liver damage. Drug-induced liver injury, viral hepatitis, and metabolic liver diseases are influenced by the status of sex hormones. Available data on the roles of sex hormones and gender differences in liver tumor occurrence and clinical outcomes are conflicting. Here, we critically review the main gender-based differences in the molecular mechanisms associated with liver carcinogenesis and the prevalence, prognosis, and treatment of primary and metastatic liver tumors.
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Affiliation(s)
- Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Azienda Sanitaria Universitaria Integrata, Department of Medical Area, University of Udine, Udine, Italy
| | - Sarah Shalaby
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Laura Mameli
- Liver and Pancreas Transplant Center, Azienda Ospedaliera Brotzu Piazzale Ricchi 1, Cagliari, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Martina Gambato
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Valentina Cossiga
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Erica Villa
- Gastroenterology Department, University of Modena and Reggio Emilia, Modena, Italy
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13
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Sinakos E, Kachru N, Tsoulas C, Jeyakumar S, Smith NJ, Yehoshua A, Cholongitas E. Cost-effectiveness of switching from tenofovir disoproxil fumarate to tenofovir alafenamide versus entecavir for chronic hepatitis B patients in Greece. J Comp Eff Res 2024; 13:e230090. [PMID: 38317634 PMCID: PMC11044955 DOI: 10.57264/cer-2023-0090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 01/18/2024] [Indexed: 02/07/2024] Open
Abstract
Aim: This study assessed the clinical impact and cost-effectiveness of switching from tenofovir disoproxil fumarate (TDF) to either tenofovir alafenamide (TAF) or entecavir (ETV) in a Greek chronic hepatitis B (CHB) population. Patients & methods: A Markov model from the perspective of a third-party payer in Greece quantified the health and economic benefits of switching from TDF to either TAF or ETV over a lifetime horizon. Results: Over a lifetime, patients who switch from TDF to TAF versus patients who switch from TDF to ETV had an overall lower incidence of compensated cirrhosis (0.4% lower), decompensated cirrhosis (0.04% lower) and hepatocellular carcinoma (0.25% lower). Chronic kidney disease and end-stage renal disease were also lower in patients who switch to TAF; major osteoporotic fractures were similar for both groups. While total costs were higher for switching from TDF to TAF versus TDF to ETV due to the higher cost of TAF, switching from TDF to TAF versus ETV was cost effective with an incremental cost-effectiveness ratio of €17,113 per quality-adjusted life year. Conclusion: Switching from TDF to TAF in patients living with CHB is a cost effective strategy to reduce adverse liver disease outcomes, while improving bone- and renal-related safety outcomes.
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Affiliation(s)
- Emmanouil Sinakos
- 4th Department of Internal Medicine, Hippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | | | | | | | | | | | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School of National & Kapodistrian University of Athens, Athens, Greece
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14
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Contreras-Mancilla J, Cerapio JP, Ruiz E, Fernández R, Casavilca-Zambrano S, Machicado C, Fournié JJ, Pineau P, Bertani S. Hepatocellular carcinoma in Peru: A molecular description of an unconventional clinical presentation. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2024; 89:194-204. [PMID: 37164797 DOI: 10.1016/j.rgmxen.2023.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 01/17/2023] [Indexed: 05/12/2023]
Abstract
INTRODUCTION AND AIM Hepatocellular carcinoma (HCC) is the third most frequent cancer of digestive tract tumors in Peru, with a high mortality rate of 17.7 per 100,000 inhabitants. A significant number of HCC cases in Peru do not follow the classic clinical epidemiology of the disease described in other parts of the world. Those patients present with a distinct transcriptome profile and a singular tumor process, suggesting a particular type of hepatocarcinogenesis in a portion of the Peruvian population. Our aim was to understand the clinical and biologic involvement of the epigenetic profile (methylation) and gene expression (transcriptome) of HCC in Peruvian patients. METHODS HCC and liver transcriptome and DNA methylation profiles were evaluated in 74 Peruvian patients. RESULTS When grouped by age, there was greater DNA methylation in younger patients with HCC but no differences with respect to the transcriptomic profile. A high prevalence of the hepatitis B virus (HBV) (>90%) was also observed in the younger patients with HCC. Enrichment analyses in both molecular profiles pinpointed PRC2 as an important molecular effector of that liver tumor process in Peruvian patients. CONCLUSION HCC in Peruvian patients has a unique molecular profile, associated with the presence of HBV, as well as overall DNA hypermethylation related to undifferentiated liver cells or cellular reprogramming.
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Affiliation(s)
- J Contreras-Mancilla
- Laboratorio de Investigación Traslacional y Biología Computacional, Facultad de Ciencias y Filosofía - LID, Universidad Peruana Cayetano Heredia, Lima, Peru; Laboratorio Mixto Internacional de Oncología Antropológica Molecular (LOAM), IRD, INEN, Lima, Peru
| | - J P Cerapio
- Laboratorio Mixto Internacional de Oncología Antropológica Molecular (LOAM), IRD, INEN, Lima, Peru; Université de Toulouse, UMR 1037 CRCT, INSERM, CNRS, UPS, Toulouse, France; Laboratorio de Excelencia Toulouse-Cáncer (TOUCAN), Toulouse, France
| | - E Ruiz
- Laboratorio Mixto Internacional de Oncología Antropológica Molecular (LOAM), IRD, INEN, Lima, Peru; Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
| | - R Fernández
- Laboratorio Mixto Internacional de Oncología Antropológica Molecular (LOAM), IRD, INEN, Lima, Peru; Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
| | - S Casavilca-Zambrano
- Laboratorio Mixto Internacional de Oncología Antropológica Molecular (LOAM), IRD, INEN, Lima, Peru; Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru
| | - C Machicado
- Laboratorio de Investigación Traslacional y Biología Computacional, Facultad de Ciencias y Filosofía - LID, Universidad Peruana Cayetano Heredia, Lima, Peru; Instituto de Biocomputación y Sistemas Complejos (BIFI), Universidad de Zaragoza, Zaragoza, Spain
| | - J J Fournié
- Laboratorio Mixto Internacional de Oncología Antropológica Molecular (LOAM), IRD, INEN, Lima, Peru; Université de Toulouse, UMR 1037 CRCT, INSERM, CNRS, UPS, Toulouse, France; Laboratorio de Excelencia Toulouse-Cáncer (TOUCAN), Toulouse, France
| | - P Pineau
- Laboratorio Mixto Internacional de Oncología Antropológica Molecular (LOAM), IRD, INEN, Lima, Peru; Institut Pasteur, U 993, INSERM, Paris, France
| | - S Bertani
- Laboratorio Mixto Internacional de Oncología Antropológica Molecular (LOAM), IRD, INEN, Lima, Peru; Université de Toulouse, UMR 152 PHARMADEV, IRD, UPS, Toulouse, France.
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15
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Tai AS, Lin SH. Multiply robust estimation of natural indirect effects with multiple ordered mediators. Stat Med 2024; 43:656-673. [PMID: 38081593 DOI: 10.1002/sim.9977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 08/06/2023] [Accepted: 11/20/2023] [Indexed: 01/13/2024]
Abstract
Multiple mediation analysis is a powerful methodology to assess causal effects in the presence of multiple mediators. Several methodologies, such as G-computation and inverse-probability-weighting, have been widely used to draw inferences about natural indirect effects (NIEs). However, a limitation of these methods is their potential for model misspecification. Although powerful semiparametric methods with high robustness and consistency have been developed for inferring average causal effects and for analyzing the effects of a single mediator, a comparably robust method for multiple mediation analysis is still lacking. Therefore, this theoretical study proposes a method of using multiply robust estimators of NIEs in the presence of multiple ordered mediators. We show that the proposed estimators not only enjoy the multiply robustness to model misspecification, they are also consistent and asymptotically normal under regular conditions. We also performed simulations for empirical comparisons of the finite-sample properties between our multiply robust estimators and existing methods. In an illustrative example, a dataset for liver disease patients in Taiwan is used to examine the mediating roles of liver damage and liver cancer in the pathway from hepatitis B/C virus infection to mortality. The model is implemented in the open-source R package "MedMR."
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Affiliation(s)
- An-Shun Tai
- Department of Statistics, National Cheng Kung University, Tainan, Taiwan
| | - Sheng-Hsuan Lin
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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16
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Cooke GS. Viral Hepatitis. MANSON'S TROPICAL DISEASES 2024:152-166. [DOI: 10.1016/b978-0-7020-7959-7.00018-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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17
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Shiha G, Soliman R, Hassan A, Farahat A, Salem A, Taha A, Sabry R, Geith A, Elshawaf A, Mikhail N. Management of patients with CHB outside the guidelines: Insights from Egyptian cohort with long-term follow-up. Clin Liver Dis (Hoboken) 2024; 23:e0183. [PMID: 38881725 PMCID: PMC11177830 DOI: 10.1097/cld.0000000000000183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 03/18/2024] [Indexed: 06/18/2024] Open
Abstract
It is alarming that globally, only 2.2% (6.6 million) of patients with chronic hepatitis B (CHB) received treatment in 2019. One contributing factor to this low treatment rate is the complexity and restrictive nature of clinical practice guidelines. Since 1998, we have adopted a "treat-all" approach to patients with CHB. A retrospective study was conducted involving patients with CHB who received treatment from 1998 to 2020 at 2 institutions in Egypt. These patients underwent evaluation through various clinical and laboratory methods, which included testing for liver enzymes and HBV DNA. The study analyzed 1825 patients with HBV, finding that 27.4% had viremia levels under 2000 IU/mL. Most (88%) were HBeAg-negative, with 12% positive. A large portion (77.6%) had normal alanine aminotransferase levels, though 5.6% exceeded twice the upper limit of normal. About 14.2% were diagnosed with liver cirrhosis, and 9.6% with F3 stage fibrosis at enrollment. Notably, 2% (25 cases) lost HBsAg over a median of 52 months. Patients with HBV DNA <2000 IU/mL had a higher HBsAg loss rate (4.2%) compared to those with levels >2000 IU/mL (1.3%). During follow-up, 9.5% (117 patients) experienced decompensation, with a higher incidence in those with HBV DNA <2000 IU/mL (16.8%) than those >2000 IU/mL (7.1%). HCC developed in 5.2% of patients with lower HBV DNA and 2.6% with higher levels, showing significant differences. Liver-related deaths occurred in 2.8% of the cohort, with a slightly higher rate in those with lower initial HBV DNA levels (3.5% vs. 2.5%). The findings suggest a paradigm shift in CHB management toward early and broader eligibility for antiviral therapy. This could improve patient outcomes and address the global treatment gap in CHB management, especially in regions with high CHB prevalence.
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Affiliation(s)
- Gamal Shiha
- Hepatology and Gastroenterology Unit, Internal Medicine Department, Faculty of Medicine, Mansoura University, El Mansoura, Egypt
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Riham Soliman
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
- Tropical Medicine Department, Faculty of Medicine, Port Said University, Port Said, Egypt
| | - Ayman Hassan
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
- Higher Institute of Applied Medical Sciences, Sherbin, El Mansoura, Egypt
| | - Ahmed Farahat
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Ahmed Salem
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Amr Taha
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Ramy Sabry
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Ahmed Geith
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Ahmed Elshawaf
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
| | - Nabiel Mikhail
- Egyptian Liver Research Institute and Hospital (ELRIAH), Sherbin, El Mansoura, Egypt
- Biostatistics and Cancer Epidemiology Department, South Egypt Cancer Institute, Assuit University, Assuit, El Fateh, Egypt
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18
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Sanai FM, Aljawad M, Alghamdi AS, Yehoshua A, Khathlan A, Alghamdi M, Kozma S, Smith N, El-Moustaid F, Jeyakumar S, Kachru N. Long-term health and economic benefits of switching to tenofovir alafenamide versus continuing on entecavir in chronic hepatitis B patients with low-level viremia in Saudi Arabia. Saudi J Gastroenterol 2024; 30:23-29. [PMID: 37417192 PMCID: PMC10852144 DOI: 10.4103/sjg.sjg_170_23] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2023] [Accepted: 06/12/2023] [Indexed: 07/08/2023] Open
Abstract
BACKGROUND Despite the success of current treatments, many chronic hepatitis B (CHB) patients still live with low-level viremia [LLV] resulting in liver disease progression. This study evaluated the long-term health and economic impact of switching to tenofovir alafenamide (TAF) from entecavir (ETV) in Saudi Arabia (SA) in chronic hepatitis B (CHB) LLV patients. METHODS A hybrid decision tree Markov state-transition model was developed to simulate a cohort of patients with CHB LLV treated with ETV and switched to TAF over a lifetime horizon in SA. While on treatment, patients either achieved complete virologic response (CVR) or maintained LLV. CVR patients experienced slower progression to advanced liver disease stages as compared to LLV patients. Demographic data, transition probabilities, treatment efficacy, health state costs, and utilities were sourced from published literature. Treatment costs were sourced from publicly available databases. RESULTS Base case analysis found that over a lifetime horizon, switching to TAF versus remaining on ETV increased the proportion of patients achieving CVR (76% versus 14%, respectively). Switching to TAF versus remaining on ETV resulted in a reduction in cases of compensated cirrhosis (-52%), decompensated cirrhosis (-5%), hepatocellular carcinoma (-22%), liver transplants (-12%), and a 37% reduction in liver-related deaths. Switching to TAF was cost-effective with an incremental cost-effectiveness ratio of $57,222, assuming a willingness-to-pay threshold of three times gross national income per capita [$65,790/QALY]. CONCLUSIONS This model found that switching to TAF versus remaining on ETV in SA CHB LLV patients substantially reduced long-term CHB-related morbidity and mortality and was a cost-effective treatment strategy.
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Affiliation(s)
- Faisal M. Sanai
- Gastroenterology Section, Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Mohammed Aljawad
- Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | | | - Alon Yehoshua
- HEOR - Global Value and Access, Gilead Sciences, Foster City, CA, USA
| | - Abdullah Khathlan
- Gastroenterology and Hepatology Department, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Mohammed Alghamdi
- Department of Medicine, King Fahad Military Medical Complex, Dhahran, Saudi Arabia
| | - Sam Kozma
- Formerly Gilead Sciences Inc., Dubai, United Arab Emirates
| | | | | | | | - Nandita Kachru
- HEOR - Global Value and Access, Gilead Sciences, Foster City, CA, USA
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19
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Nuermaimaiti A, Chang L, Yan Y, Sun H, Xiao Y, Song S, Feng K, Lu Z, Ji H, Wang L. The role of sex hormones and receptors in HBV infection and development of HBV-related HCC. J Med Virol 2023; 95:e29298. [PMID: 38087447 DOI: 10.1002/jmv.29298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/02/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023]
Abstract
Gender disparity in hepatitis B virus (HBV)-related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone-related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV-specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV-related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone-related HCC treatment.
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Affiliation(s)
- Abudulimutailipu Nuermaimaiti
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Le Chang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Ying Yan
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huizhen Sun
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yingzi Xiao
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shi Song
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kaihao Feng
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhuoqun Lu
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huimin Ji
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Lunan Wang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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20
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Zhao B, Qiao H, Zhao Y, Gao Z, Wang W, Cui Y, Li J, Guo Z, Chuai X, Chiu S. HBV precore G1896A mutation promotes growth of hepatocellular carcinoma cells by activating ERK/MAPK pathway. Virol Sin 2023; 38:680-689. [PMID: 37331658 PMCID: PMC10590694 DOI: 10.1016/j.virs.2023.06.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the leading causes of hepatocellular carcinoma (HCC). The HBV genome is prone to mutate and several variants are closely related to the malignant transformation of liver disease. G1896A mutation (G to A mutation at nucleotide 1896) is one of the most frequently observed mutations in the precore region of HBV, which prevents HBeAg expression and is strongly associated with HCC. However, the mechanisms by which this mutation causes HCC are unclear. Here, we explored the function and molecular mechanisms of the G1896A mutation during HBV-associated HCC. G1896A mutation remarkably enhanced the HBV replication in vitro. Moreover, it increased tumor formation and inhibited apoptosis of hepatoma cells, and decreased the sensitivity of HCC to sorafenib. Mechanistically, the G1896A mutation could activate ERK/MAPK pathway to enhanced sorafenib resistance in HCC cells and augmented cell survival and growth. Collectively, our study demonstrates for the first time that the G1896A mutation has a dual regulatory role in exacerbating HCC severity and sheds some light on the treatment of G1896A mutation-associated HCC patients.
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Affiliation(s)
- Baoxin Zhao
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Hongxiu Qiao
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Yan Zhao
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Zhiyun Gao
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Weijie Wang
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Yan Cui
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Jian Li
- Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China
| | - Zhanjun Guo
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
| | - Xia Chuai
- Department of Pathogen Biology, Hebei Medical University, Shijiazhuang, 050017, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega Science, Chinese Academy of Sciences, Wuhan, 430207, China.
| | - Sandra Chiu
- Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, 050017, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China.
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21
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Ghany MG, Saraswat VA. Patients With Compensated Hepatitis B Virus-Related Cirrhosis and Low-Level Viremia: Treat or Not to Treat? Am J Gastroenterol 2023; 118:970-971. [PMID: 36940387 PMCID: PMC10238665 DOI: 10.14309/ajg.0000000000002224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 01/31/2023] [Indexed: 03/22/2023]
Abstract
ABSTRACT Patients with hepatitis B virus-related cirrhosis and low-level viremia represent a special group that might benefit from treatment because of their higher risk of complications. Evidence for the benefit of treatment in this population is lacking. The current study, which analyzed data of a historical cohort of 627 patients from a single Korean center with hepatitis B virus-related compensated cirrhosis, reported a 2.4-fold increased hepatocellular carcinoma risk among patients with low-level viremia compared with those with undetectable viremia provides indirect evidence in support of treatment for this population. The study underscores the importance of treating patients before the development of cirrhosis and the need for finite duration curative therapy.
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Affiliation(s)
- Marc G Ghany
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Vivek A Saraswat
- Department of Hepatology and Liver Transplantation, Mahatma Gandhi Medical College, Sitapura, Jaipur, India
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22
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Relevance of HBx for Hepatitis B Virus-Associated Pathogenesis. Int J Mol Sci 2023; 24:ijms24054964. [PMID: 36902395 PMCID: PMC10003785 DOI: 10.3390/ijms24054964] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/20/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
The hepatitis B virus (HBV) counts as a major global health problem, as it presents a significant causative factor for liver-related morbidity and mortality. The development of hepatocellular carcinomas (HCC) as a characteristic of a persistent, chronic infection could be caused, among others, by the pleiotropic function of the viral regulatory protein HBx. The latter is known to modulate an onset of cellular and viral signaling processes with emerging influence in liver pathogenesis. However, the flexible and multifunctional nature of HBx impedes the fundamental understanding of related mechanisms and the development of associated diseases, and has even led to partial controversial results in the past. Based on the cellular distribution of HBx-nuclear-, cytoplasmic- or mitochondria-associated-this review encompasses the current knowledge and previous investigations of HBx in context of cellular signaling pathways and HBV-associated pathogenesis. In addition, particular focus is set on the clinical relevance and potential novel therapeutic applications in the context of HBx.
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23
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New hepatitis B drug development disillusions: time to reset? Lancet Gastroenterol Hepatol 2023; 8:192-197. [PMID: 36343654 DOI: 10.1016/s2468-1253(22)00341-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 10/03/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022]
Abstract
After more than 5 years of intense preclinical and clinical research, the development of new hepatitis B virus (HBV) drugs appears to be stalling. The main reasons for this are the major limitations of the developmental path, including the use of inappropriate endpoints for clinical development, the standards for efficacy and approval being too strict (functional cure after short finite treatment duration), expecting compounds to do what they cannot do because of their known targets and mechanisms of action, and hoping that one size will fit all, despite the fact that HBV infection is heterogeneous. A functional HBV cure cannot be easily attained with only a few weeks or months of treatment with the classes of compounds that are currently in development. Therefore, researchers, drug developers, and regulators need to establish a new consensus about endpoints that are both clinically relevant and achievable, and redefine the objectives, timelines, and pathways of new HBV drug development.
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24
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Lin JH, Tai AS, Lin SH. Population attributable fraction based on marginal sufficient component cause model for mediation settings. Ann Epidemiol 2022; 75:57-66. [PMID: 36084802 DOI: 10.1016/j.annepidem.2022.08.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 07/28/2022] [Accepted: 08/24/2022] [Indexed: 11/19/2022]
Abstract
PURPOSE Population attributable fraction (PAF), defined as the proportion of the occurrence of a disease which will be reduced by eliminating risk factors in a population, is one of the most common measurements for evaluating the benefit of a health-related policy in epidemiologic study. In this article, we propose an alternative PAF defined based on sufficient cause framework, which decompose the occurrence of a disease into several pathways including mediation and mechanistic interaction. METHODS We propose a formal statistical definition and regression-based estimator for PAF based on sufficient cause framework within mediation settings. Under monotonicity assumption, the proposed method can decompose the occurrence of a disease into nine PAFs corresponding to all types of mechanisms attributing to exposure and the mediator, including the portion attributing to exposure directly, to mediator, to indirect effect through mediator, to the mechanistic interaction, to both of mediation and interaction, and to none of exposure or mediator. RESULTS We apply the proposed method to explore the mechanism of a hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) mediated by and/or interacted with alanine aminotransferase (ALT) and hepatitis B virus (HBV). When treating ALT as mediator, 56.77% of diseased subjects can be attributable to either HCV or abnormal ALT. When treating HBV as mediator, HCC is mainly induced by an exogenous high HBV viral load directly. CONCLUSIONS The proposed method can identify the impact of exposure and pathway effects, and benefit to allocate the resources on intervention strategies.
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Affiliation(s)
- Jui-Hsiang Lin
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - An-Shun Tai
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan; Department of Statistics, National Cheng Kung University, Tainan
| | - Sheng-Hsuan Lin
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan.
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25
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Lim YS, Ahn SH, Shim JJ, Razavi H, Razavi-Shearer D, Sinn DH. Impact of expanding hepatitis B treatment guidelines: A modelling and economic impact analysis. Aliment Pharmacol Ther 2022; 56:519-528. [PMID: 35614532 DOI: 10.1111/apt.17052] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/31/2021] [Accepted: 05/14/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Antiviral treatment in patients with chronic hepatitis B (CHB) may decrease the risk of hepatocellular carcinoma (HCC) and death. However, only 2.2% of CHB patients receive antiviral treatment globally. The complexity and strictness of the current clinical practice guidelines may limit expanding the treatment coverage for CHB. AIMS To examine the impact of expanding treatment criteria on future disease burden in Korea, a hepatitis B virus (HBV) endemic country with high diagnostic rates. MATERIALS Dynamic country-level data were used to estimate the HCC incidence, overall mortality and economic impact of three incremental scenarios compared to the base case in Korea through 2035. RESULTS In 2020, 1,409,000 CHB cases were estimated, with the majority born before 1995. All scenarios assumed treating 70% of eligible individuals. The first scenario removed viral load restrictions in cirrhotic patients, which would avert 13,000 cases of HCC and save 11,800 lives. The second scenario, lowering the alanine aminotransferase (ALT) level restriction to the upper limit of the normal in non-cirrhotic patients, would avert 26,700 cases of HCC and save 23,300 lives. The last scenario removed the restriction by ALT and HBeAg in treating non-cirrhotic individuals with a viral load of ≥2000 IU/ml, which would avert 43,300 cases of HCC and save 37,000 lives. All scenarios were highly cost-effective. CONCLUSIONS Simplifying and expanding treatment eligibility for CHB would save many lives and be highly cost-effective when combined with high diagnostic rates. These dynamic country-level data may provide new insights for their global application.
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Affiliation(s)
- Young-Suk Lim
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang Hoon Ahn
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Jun Shim
- Kyung Hee University Hospital, Seoul, Republic of Korea
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26
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Li J, Xu J, Wang Y, Li Q, Sun X, Fu W, Zhang B. Association of Nucleostemin Polymorphisms with Chronic Hepatitis B Virus Infection in Chinese Han Population. Genet Test Mol Biomarkers 2022; 26:255-262. [PMID: 35638911 PMCID: PMC9150128 DOI: 10.1089/gtmb.2021.0181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Chronic hepatitis B virus infection (CHB) is a common infectious disease that poses a global economic and health burden due to its high morbidity and mortality. Studies have demonstrated that host genetic factors play critical roles in the susceptibility and outcome of CHB. Aims: In this study, we aimed to assess the potential role of genetic variants of the nucleostemin (NS) gene with respect to CHB susceptibility. Materials and Methods: Four single nucleotide polymorphisms (SNPs) in the NS gene were genotyped in 446 patients with CHB and 399 healthy controls all of Chinese Han origin using the polymerase chain reaction-ligation detection reaction method. Results: The results showed that the three SNPs, rs3733039, rs1866268, and rs11177, were significantly associated with CHB. After a Bonferroni correction, the positive association of the rs3733039 SNP with CHB remained significant. Further analyses based on gender demonstrated that these SNPs are associated with CHB in both the female and male subgroups. After correction for multiple comparisons, all three SNPs in the female group were associated with CHB, whereas only the rs1866268 SNP in the male group was associated with CHB. Haplotype analysis showed that the C-C-G and T-T-T haplotypes in the block consisting of rs3733039-rs1866268-rs11177 were significantly associated with CHB. Conclusion: Our study demonstrated a genetic association between SNPs in the NS gene and the risk of CHB in the Chinese Han population for the first time. Thus, variations in the NS gene might serve as potential genetic biomarkers of CHB.
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Affiliation(s)
- Jixia Li
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai, China
| | - Jinya Xu
- Department of Clinical Laboratory, Yantai Qishan Hospital, Yantai, China
| | - Yangui Wang
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai, China
| | - Qin Li
- Department of Clinical Laboratory, Yantai Yuhuangding Hospital, Yantai, China
| | - Xilian Sun
- Department of Nursing, Yantaishan Hospital, Yantai, China
| | - Wen Fu
- Department of Clinical Laboratory, Yantaishan Hospital, Yantai, China
| | - Bo Zhang
- Department of Gastroenterology, Yantai Yuhuangding Hospital, Yantai, China
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27
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Brown R, Goulder P, Matthews PC. Sexual Dimorphism in Chronic Hepatitis B Virus (HBV) Infection: Evidence to Inform Elimination Efforts. Wellcome Open Res 2022; 7:32. [PMID: 36212217 PMCID: PMC9520633 DOI: 10.12688/wellcomeopenres.17601.3] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2022] [Indexed: 11/20/2022] Open
Abstract
Sexual dimorphism in infectious diseases refers to the different infection susceptibilities and outcomes between males and females, and has been described for many pathogens, including hepatitis B virus (HBV). HBV is a substantial global health problem, with close to 300 million people chronically infected, and accounting for a million deaths each year, with an urgent need for enhanced interventions to support progress towards elimination goals. Sexual dimorphism has a strong influence in HBV infection, with males more likely to be exposed, to develop chronic infection, and to suffer from complications including cirrhosis and hepatocellular carcinoma (HCC) compared to females. Different outcomes are driven by differential immune responses, sexual dimorphism of the liver, and androgen response elements in the HBV genome. The impact of sex may also vary with age, with changes at puberty and influences of menarche, pregnancy and menopause in females. In addition, gender has complex influences on education, beliefs, behaviour and access to / engagement with healthcare services, which may contribute to differences in diagnosis and treatment. Interplay between these complex factors, alongside other attributes of host, virus and the environment, accounts for different outcomes of infection. However, gaps remain in our understanding of sexual dimorphism in HBV, and little effort has previously been made to harness this knowledge for translational gains. In this review, we assimilate human and animal data to consider the mechanism, outcomes and impact of sexual dimorphism, and consider how these insights can be used to inform advances in surveillance, treatment and prevention for HBV infection.
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Affiliation(s)
- Robin Brown
- Harris Manchester College, University of Oxford, Oxford, Oxon, OX1 3TD, UK
| | - Philip Goulder
- Department of Paediatrics, University of Oxford, Oxford, Oxon, OX1 3SY, UK
| | - Philippa C. Matthews
- Harris Manchester College, University of Oxford, Oxford, Oxon, OX1 3TD, UK
- The Francis Crick Institute, London, London, NW1 1AT, UK
- Division of Infection and Immunity, University College London, London, WC1E 6BT, UK
- Department of Infectious Diseases, University College London Hospital, London, NW1 2BU, UK
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28
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Brown R, Goulder P, Matthews PC. Sexual Dimorphism in Chronic Hepatitis B Virus (HBV) Infection: Evidence to Inform Elimination Efforts. Wellcome Open Res 2022; 7:32. [PMID: 36212217 PMCID: PMC9520633 DOI: 10.12688/wellcomeopenres.17601.2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2022] [Indexed: 08/27/2024] Open
Abstract
Sexual dimorphism in infectious diseases refers to the different infection susceptibilities and outcomes between males and females, and has been described for many pathogens, including hepatitis B virus (HBV). HBV is a substantial global health problem, with close to 300 million people chronically infected, and accounting for a million deaths each year, with an urgent need for enhanced interventions to support progress towards elimination goals. Sexual dimorphism has a strong influence in HBV infection, with males more likely to be exposed, to develop chronic infection, and to suffer from complications including cirrhosis and hepatocellular carcinoma (HCC) compared to females. Different outcomes are driven by differential immune responses, sexual dimorphism of the liver, and androgen response elements in the HBV genome. The impact of sex may also vary with age, with changes at puberty and influences of menarche, pregnancy and menopause in females. In addition, gender has complex influences on education, beliefs, behaviour and access to / engagement with healthcare services, which may contribute to differences in diagnosis and treatment. Interplay between these complex factors, alongside other attributes of host, virus and the environment, accounts for different outcomes of infection. However, gaps remain in our understanding of sexual dimorphism in HBV, and little effort has previously been made to harness this knowledge for translational gains. In this review, we assimilate human and animal data to consider the mechanism, outcomes and impact of sexual dimorphism, and consider how these insights can be used to inform advances in surveillance, treatment and prevention for HBV infection.
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Affiliation(s)
- Robin Brown
- Harris Manchester College, University of Oxford, Oxford, Oxon, OX1 3TD, UK
| | - Philip Goulder
- Department of Paediatrics, University of Oxford, Oxford, Oxon, OX1 3SY, UK
| | - Philippa C. Matthews
- Harris Manchester College, University of Oxford, Oxford, Oxon, OX1 3TD, UK
- The Francis Crick Institute, London, London, NW1 1AT, UK
- Division of Infection and Immunity, University College London, London, WC1E 6BT, UK
- Department of Infectious Diseases, University College London Hospital, London, NW1 2BU, UK
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29
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Hepatitis B Virus Chronic Infection in Blood Donors from Asian and African High or Medium Prevalence Areas: Comparison According to Sex. Viruses 2022; 14:v14040673. [PMID: 35458403 PMCID: PMC9029447 DOI: 10.3390/v14040673] [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: 02/09/2022] [Revised: 03/16/2022] [Accepted: 03/21/2022] [Indexed: 02/07/2023] Open
Abstract
Immune control of various infectious diseases, particularly viral, was shown to be more efficient for females than males. Response to viral vaccines (HAV, HBV) was higher in females. Data on hepatitis B virus (HBV) markers accumulated over 15 years in blood donors was stratified according to sex, including HBsAg, HBV viral load and levels of anti-HBs in areas where genotypes B and C (China), genotype D (Iran, Lebanon, Tunisia) and genotype E (Ghana, Burkina Faso, Gabon) were prevalent. HBsAg was screened by either ELISA or rapid tests, anti-HBc and anti-HBs by ELISA, HBV DNA load by a standardized method across sites. In Ghanaian children less than 5 years, HBV DNA load was significantly lower in females than in males (p = 0.035). In China, Ghana, Burkina Faso and Gabon blood donors, median HBsAg prevalence was ~5% and 3% in China, ~8.5% and 4.5% in Gabon, ~16% and 11% in Burkina Faso and ~11% and 7% in Ghana for male and female donors, respectively (p < 0.001). In HBsAg+ Ghanaian blood donors, distribution and median viral load were not significantly different between sexes; occult hepatitis B infections (OBI) were significantly more frequent in males. In Chinese blood donor anti-HBc+ and anti-HBs+, anti-HBs levels tended to be higher in males but vaccinated donors’ anti-HBs+ only, while anti-HBs levels were females > males. In areas where genotypes B-E are dominant, the prevalence of chronic HBV infection (HBsAg+) seems better controlled before age 16−18 by females infected vertically or horizontally. OBIs appear considerably more frequent in men, suggesting lower efficacy of HBV infection control. Female blood donors appear significantly safer from HBV than males, and their donation should be encouraged.
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30
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Bari RZA, Nawaz H, Majeed MI, Rashid N, Iqbal M, Akram M, Yaqoob N, Yousaf S, Mushtaq A, Almas F, Shahzadi A, Amin I. Surface-enhanced Raman spectroscopic analysis of centrifugally filtered HBV serum samples. Photodiagnosis Photodyn Ther 2022; 38:102808. [PMID: 35301153 DOI: 10.1016/j.pdpdt.2022.102808] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 03/04/2022] [Accepted: 03/10/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND Raman spectroscopy is an effective tool for detecting and discriminating centrifugally filtered hepatitis B virus serum and centrifugally filtered control serum. OBJECTIVES The purpose of current study is to separate high molecular weight fractions from low molecular weight fractions present hepatitis B serum to increase the disease diagnostic ability of surface enhanced Raman spectroscopy (SERS). METHODS Clinically diagnosed centrifugally filtered serum samples of hepatitis B patients are subjected for surface enhanced Raman spectroscopy (SERS) in comparison with centrifugally filtered serum samples of healthy individuals by using silver nanoparticles (Ag-NPs) as SERS substrates. Some SERS spectral features are solely observed in centrifugally filtered serum samples of hepatitis B and some SERS spectral are solely observed in centrifugally filtered serum samples of healthy individuals. The diagnostic ability of SERS is further enhanced with different statistical techniques like principal component analysis (PCA), partial least square discriminant analysis (PLS-DA) and partial least square regression analysis (PLSR) have applied. RESULTS The disease biomarkers of hepatitis B are more pronounced after their centrifugation as compared with uncentrifuged form. Statistical tools like principal component analysis (PCA) and partial least square discriminant analysis (PLS-DA) clearly differentiated centrifugally filtered serum samples of hepatitis B from centrifugally filtered serum samples of healthy individuals. Furthermore, partial least square regression analysis (PLSR) has been applied for predicting unknown viral load of centrifugally filtered serum sample of hepatitis B. CONCLUSION SERS technique along with chemometric tools have successfully differentiated centrifugally filtered serum samples of hepatitis B from centrifugally filtered serum samples of healthy individuals. The centrifugal filtration process has increased the differentiation accuracy of PLS-DA in terms of percentage 98% and regression accuracy of PLSR regression analysis in terms of RMSEP (0.30 IU/mL) of this diagnostic method as compared with that of uncentrifuged method.
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Affiliation(s)
- Rana Zaki Abdul Bari
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan
| | - Haq Nawaz
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan.
| | - Muhammad Irfan Majeed
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan.
| | - Nosheen Rashid
- Department of Chemistry, University of Education, Faisalabad Campus, Faisalabad (38000), Pakistan.
| | - Maham Iqbal
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan
| | - Maria Akram
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan
| | - Nimra Yaqoob
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan
| | - Sadia Yousaf
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan
| | - Aqsa Mushtaq
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan
| | - Farakh Almas
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan
| | - Anam Shahzadi
- Department of Chemistry, University of Agriculture Faisalabad, Faisalabad (38000), Pakistan
| | - Imran Amin
- PCR Laboratory, PINUM Hospital, Faisalabad (38000), Pakistan
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31
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Brown R, Goulder P, Matthews PC. Sexual Dimorphism in Chronic Hepatitis B Virus (HBV) Infection: Evidence to Inform Elimination Efforts. Wellcome Open Res 2022; 7:32. [PMID: 36212217 PMCID: PMC9520633 DOI: 10.12688/wellcomeopenres.17601.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2022] [Indexed: 09/06/2024] Open
Abstract
Sexual dimorphism in infectious diseases refers to the different infection susceptibilities and outcomes between males and females, and has been described for many pathogens, including hepatitis B virus (HBV) infection. HBV is a substantial global health problem, with close to 300 million people infected, and accounting for a million deaths each year, with an urgent need for enhanced interventions to support progress towards elimination goals. Sexual dimorphism has a strong influence in HBV infection, with males more likely to be exposed, to develop chronic infection, and to suffer from complications including cirrhosis and hepatocellular carcinoma (HCC) compared to females. Different outcomes are driven by differential immune responses, sexual dimorphism of the liver, and androgen response elements in the HBV genome. The impact of sex may also vary with age, with changes at puberty and influences of menarche, pregnancy and menopause in females. In addition, gender has complex influences on education, beliefs, behaviour and access to / engagement with healthcare services, which may contribute to differences in diagnosis and treatment. Interplay between these complex factors, alongside other attributes of host, virus and the environment, accounts for different outcomes of infection. However, gaps remain in our understanding of sexual dimorphism in HBV, and little effort has previously been made to harness this knowledge for translational gains. In this review, we assimilate human and animal data to consider the mechanism, outcomes and impact of sexual dimorphism, considering how these insights can be used to inform advances in surveillance, treatment and prevention for HBV infection.
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Affiliation(s)
- Robin Brown
- Harris Manchester College, University of Oxford, Oxford, Oxon, OX1 3TD, UK
| | - Philip Goulder
- Department of Paediatrics, University of Oxford, Oxford, Oxon, OX1 3SY, UK
| | - Philippa C. Matthews
- Harris Manchester College, University of Oxford, Oxford, Oxon, OX1 3TD, UK
- The Francis Crick Institute, London, London, NW1 1AT, UK
- Division of Infection and Immunity, University College London, London, WC1E 6BT, UK
- Department of Infectious Diseases, University College London Hospital, London, NW1 2BU, UK
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32
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Dezanet LNC, Miailhes P, Lascoux-Combe C, Chas J, Maylin S, Gabassi A, Rougier H, Delaugerre C, Lacombe K, Boyd A. Profiles of liver fibrosis evolution during long-term tenofovir treatment in HIV-positive patients coinfected with hepatitis B. Liver Int 2021; 41:2874-2884. [PMID: 34297463 DOI: 10.1111/liv.15019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 07/11/2021] [Accepted: 07/19/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND & AIMS Data on liver fibrosis evolution and its involvement in liver-related morbidity are scarce in individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) co-infection during treatment. We identified profiles of liver fibrosis evolution in coinfected patients undergoing tenofovir (TDF). METHODS We included 169 HIV-HBV-coinfected patients on TDF-based antiretroviral therapy. Virological and clinical data were obtained at TDF-initiation and every 6-12 months. From data on non-invasive liver fibrosis assessments collected yearly (FibroTest®), we established clusters of individuals with similar liver fibrosis evolution using group-based trajectory models. RESULTS Four profiles of liver fibrosis evolution were established from a median follow-up of 7.6 years (IQR = 3.1-13.1): low fibrosis with no progression (29.6%, profile A), low fibrosis with progression (22.5%, profile B), moderate fibrosis with high fluctuation (39.6%, profile C), and cirrhosis with no regression (8.3%, profile D). When compared to profile A, baseline HBeAg-positive status was associated with profiles B (P = .007) and C (P = .004), older age with profiles C (P < .001) and D (P = .001), exposure to second-generation protease inhibitors with profile C (P = .004), and CD4+ <500/mm3 at the last visit with profiles C (P = .02) and D (P = .002). Incident liver-related events occurred in profiles other than A (B, n = 1/38; C, n = 6/67; D, n = 3/14) and all five cases of hepatocellular carcinoma occurred in profiles C (n = 2) and D (n = 3). CONCLUSIONS TDF-treated HIV-HBV coinfected individuals do not seem to benefit from comparable levels of liver fibrosis regression as in HBV mono-infection. Liver-related morbidity occurs mainly in those with fluctuating or consistently high fibrosis levels.
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Affiliation(s)
- Lorenza N C Dezanet
- INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, IPLESP, Sorbonne Université, Paris, France
| | - Patrick Miailhes
- Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Service de Maladies Infectieuses et Tropicales, Lyon, France
| | | | - Julie Chas
- APHP, Hôpital Tenon, Service de Maladies Infectieuses, Paris, France
| | - Sarah Maylin
- APHP, Hôpital Saint-Louis, Laboratoire de Virologie, Paris, France
| | - Audrey Gabassi
- APHP, Hôpital Saint-Louis, Laboratoire de Virologie, Paris, France.,INSERM U944, Institut de Recherche Saint-Louis, Université de Paris, Paris, France
| | - Hayette Rougier
- Institut de Médecine et d'Épidémiologie Appliquée, Paris, France
| | - Constance Delaugerre
- APHP, Hôpital Saint-Louis, Laboratoire de Virologie, Paris, France.,INSERM U944, Institut de Recherche Saint-Louis, Université de Paris, Paris, France
| | - Karine Lacombe
- INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, IPLESP, Sorbonne Université, Paris, France.,APHP, Hôpital Saint-Antoine, Service de Maladies Infectieuses et Tropicales, Paris, France
| | - Anders Boyd
- INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, IPLESP, Sorbonne Université, Paris, France.,APHP, Hôpital Saint-Antoine, Service de Maladies Infectieuses et Tropicales, Paris, France
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Abstract
Hepatitis B virus (HBV) is the one of most common causes of the hepatocellular carcinoma (HCC), especially in eastern world. The aim of this review is to try to understand the relationship between HBV and HCC and to reveal the role of prevention and treatment of HBV infection in reducing the incidence of HCC. Strategies to prevent HCC due to HBV can be classified into three categories. These are primary, secondary, and tertiary preventions. Hepatitis B vaccine is now in the most vital position in preventing HBV-associated HCC. In patients with chronic hepatitis B infection, suppressing viral load with potent antivirals such as tenofovir disoproxil fumarate (TDF) and entecavir (ETV) prevents the development of HCC and improves prognosis by reducing recurrence after HCC treatments. There is currently no clear consensus on which of these drugs should be preferred. Although data on tenofovir alafenamide (TAF) are scarce, available data with TDF suggest that TAF therapy will also be a strong actor for HCC.
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de Almeida NAA, de Paula VS. Occult Hepatitis B virus (HBV) infection and challenges for hepatitis elimination: A literature review. J Appl Microbiol 2021; 132:1616-1635. [PMID: 34724308 DOI: 10.1111/jam.15351] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/08/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Occult hepatitis B infection (OBI) is characterized by the detection of hepatitis B virus (HBV) DNA in serum or liver but negativity for hepatitis B surface antigen. OBI, which is thought to be maintained by host, immunological, viral and/or epigenetic factors, is one of the most challenging clinical features in the study of viral hepatitis. Currently, there is no validated detection test for OBI. It is believed that OBI is widely distributed throughout the world, with a higher prevalence in populations at high-risk HBV, but the detailed worldwide prevalence patterns are unknown. We conducted a survey of recently published studies on OBI rates across all continents. High prevalence rates of OBI are observed in some specific groups, including patients with hepatitis C virus, human immunodeficiency virus co-infection or hepatocellular carcinoma. In 2016, the World Health Organization adopted strategies to eliminate viral hepatitis by 2030, but the difficulties in detecting and treating OBI currently challenge this goal. Subjects with OBI can transmit HBV, and episodes of reactivation can occur. Further studies to understanding the mechanisms that drive the development of OBI are needed and can contribute to efforts at eliminating viral hepatitis.
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Galle PR, Kudo M, Llovet JM, Finn RS, Karwal M, Pezet D, Kim TY, Yang TS, Lonardi S, Tomasek J, Phelip JM, Touchefeu Y, Koh SJ, Stirnimann G, Liang K, Ogburn KD, Wang C, Abada P, Widau RC, Zhu AX. Ramucirumab in patients with previously treated advanced hepatocellular carcinoma: Impact of liver disease aetiology. Liver Int 2021; 41:2759-2767. [PMID: 34173317 DOI: 10.1111/liv.14994] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying aetiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease aetiology and baseline serum viral load. METHODS Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N = 542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by aetiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pre-treatment serum HBV DNA and HCV RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study). RESULTS Baseline characteristics were generally balanced between arms in each subgroup (HBV: N = 225, HCV: N = 127, Other: N = 190). No significant difference in treatment effect by aetiology subgroup was detected (OS interaction P-value = .23). Median OS (ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74, 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82, 95% CI 0.55-1.23) for HCV and 8.5 versus 5.4 (HR 0.56, 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function and liver-specific adverse events. CONCLUSIONS Ramucirumab improved survival across aetiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.
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Affiliation(s)
- Peter R Galle
- Department of Internal Medicine, Mainz University Medical Center, Mainz, Germany
| | - Masatoshi Kudo
- Departments of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, Spain
- Institució Catalana d'Estudis Avançats (ICREA), Barcelona, Spain
| | | | - Mark Karwal
- University of Iowa Hospitals and Clinics, University of Iowa Health Care, Iowa City, IA, USA
| | - Denis Pezet
- Estaing Hospital, Aubrac, Clermont-Ferrand, France
| | - Tae-You Kim
- Seoul National University Hospital, Seoul, Korea
| | | | - Sara Lonardi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Jiri Tomasek
- Masaryk Memorial Cancer Institute, Masaryk University, Brno, Czech Republic
| | | | | | - Su-Jin Koh
- Division of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Guido Stirnimann
- University Hospital Inselspital and University of Bern, Bern, Switzerland
| | - Kun Liang
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | | | - Paolo Abada
- Eli Lilly and Company, Indianapolis, IN, USA
| | | | - Andrew X Zhu
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
- Jiahui International Cancer Center, Jiahui Health, Shanghai, China
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Coffin CS, Schreiber RA. Hepatitis B in Children-The Pursuit of a Hepatitis Free Future Generation. J Pediatr 2021; 237:9-11. [PMID: 34273356 DOI: 10.1016/j.jpeds.2021.07.017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 07/09/2021] [Indexed: 10/20/2022]
Affiliation(s)
- Carla S Coffin
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Richard A Schreiber
- University of British Columbia, Vancouver, British Columbia, Canada; McGill University, Montreal, Quebec, Canada; Division of Gastroenterology, Hepatology and Nutrition, BC Children's Hospital, Vancouver, British Columbia, Canada
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Cost-effectiveness analysis of first-line treatment for chronic hepatitis B in China. Clin Microbiol Infect 2021; 28:300.e1-300.e8. [PMID: 34197929 DOI: 10.1016/j.cmi.2021.06.024] [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: 12/04/2020] [Revised: 06/07/2021] [Accepted: 06/12/2021] [Indexed: 11/21/2022]
Abstract
OBJECTIVES Hepatitis B virus infection is an important public health problem. We analysed the cost-effectiveness of the first-line therapies, including nucleotide analogues (namely tenofovir alafenamide fumarate (TAF), tenofovir disoproxil fumarate (TDF) and entecavir) and pegylated interferon (Peg-IFN) for patients with chronic hepatitis B (CHB) in China. METHODS A Markov model describing CHB disease progression was constructed to compare the cost-effectiveness of the first-line therapies, considering both satisfactory (HBeAg seroconversion) and optimal (HBsAg seroclearance) treatment goals. We examined the main outcomes, including cumulative lifetime cost per patient, incremental quality-adjusted life years (QALYs), incremental cost-effectiveness ratio and net monetary benefit. Uncertainty analysis was conducted to identify key influential parameters. RESULTS Compared with the baseline strategy, Peg-IFN had the highest QALY gain for HBeAg-positive (HBeAg+) CHB patients achieving a satisfactory goal and an optimal goal (3.19 and 6.32 respectively), and TDF was the most cost-effective therapy for HBeAg-negative CHB patients ($1418/QALY) achieving a satisfactory goal. Among nucleotide analogues, TAF was the most-effective strategy and had higher acceptability to achieve an optimal goal in the Eastern region of China (under 1 x GDP per capita threshold). CONCLUSIONS Among nucleotide analogues, TDF was the most cost-effective treatment in China for CHB patients to achieve satisfactory and optimal treatment goals, whereas TAF was cost-effective and more effective in the wealthier region. Peg-IFN was most cost-effective among HBeAg+ CHB patients to achieve both goals, with better clinical outcomes. Our findings also indicate the importance of regular monitoring during and after CHB treatment, and could inform treatment strategies in China and other countries.
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Tai AS, Lin SH. Integrated multiple mediation analysis: A robustness-specificity trade-off in causal structure. Stat Med 2021; 40:4541-4567. [PMID: 34114676 DOI: 10.1002/sim.9079] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 05/10/2021] [Accepted: 05/18/2021] [Indexed: 01/17/2023]
Abstract
Recent methodological developments in causal mediation analysis have addressed several issues regarding multiple mediators. However, these developed methods differ in their definitions of causal parameters, assumptions for identification, and interpretations of causal effects, making it unclear which method ought to be selected when investigating a given causal effect. Thus, in this study, we construct an integrated framework, which unifies all existing methodologies, as a standard for mediation analysis with multiple mediators. To clarify the relationship between existing methods, we propose four strategies for effect decomposition: two-way, partially forward, partially backward, and complete decompositions. This study reveals how the direct and indirect effects of each strategy are explicitly and correctly interpreted as path-specific effects under different causal mediation structures. In the integrated framework, we further verify the utility of the interventional analogues of direct and indirect effects, especially when natural direct and indirect effects cannot be identified or when crossworld exchangeability is invalid. Consequently, this study yields a robustness-specificity trade-off in the choice of strategies. Inverse probability weighting is considered for estimation. The four strategies are further applied to a simulation study for performance evaluation and for analyzing the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer dataset from Taiwan to investigate the causal effect of hepatitis C virus infection on mortality.
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Affiliation(s)
- An-Shun Tai
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Sheng-Hsuan Lin
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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Tai AS, Tsai CA, Lin SH. Survival mediation analysis with the death-truncated mediator: The completeness of the survival mediation parameter. Stat Med 2021; 40:3953-3974. [PMID: 34111901 DOI: 10.1002/sim.9008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 03/31/2021] [Accepted: 04/11/2021] [Indexed: 11/07/2022]
Abstract
In medical research, the development of mediation analysis with a survival outcome has facilitated investigation into causal mechanisms. However, studies have not discussed the death-truncation problem for mediators, the problem being that conventional mediation parameters cannot be well defined in the presence of a truncated mediator. In the present study, we systematically defined the completeness of causal effects to uncover the gap, in conventional causal definitions, between the survival and nonsurvival settings. We propose a novel approach to redefining natural direct and indirect effects, which are generalized forms of conventional causal effects for survival outcomes. Furthermore, we developed three statistical methods for the binary outcome of survival status and formulated a Cox model for survival time. We performed simulations to demonstrate that the proposed methods are unbiased and robust. We also applied the proposed method to explore the effect of hepatitis C virus infection on mortality, as mediated through hepatitis B viral load.
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Affiliation(s)
- An-Shun Tai
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Chun-An Tsai
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
| | - Sheng-Hsuan Lin
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu, Taiwan
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Characterization and prediction of viral loads of Hepatitis B serum samples by using surface-enhanced Raman spectroscopy (SERS). Photodiagnosis Photodyn Ther 2021; 35:102386. [PMID: 34116250 DOI: 10.1016/j.pdpdt.2021.102386] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 05/27/2021] [Accepted: 06/03/2021] [Indexed: 12/31/2022]
Abstract
BACKGROUND Raman spectroscopy is a promising technique to analyze the body fluids for the purpose of non-invasive disease diagnosis. OBJECTIVES To develop a surface-enhanced Raman spectroscopy (SERS) based method for qualitative and quantitative analysis of hepatitis B viral (HBV) infection from blood serum samples. METHODS Clinically diagnosed hepatitis B virus (HBV) infected serum samples of patients of different levels of viral loads have been subjected for SERS analysis in comparison with the healthy ones by using silver nanoparticles (Ag NPs) based SERS substrates. The SERS measurements were performed on blood serum samples of 11 healthy and 32 clinically diagnosed HBV patients of different viral load levels of different exponentials including (101, 102 called as low level), (103, 104 called as medium level) and (105, 108 called as high level). Furthermore, multivariate data analysis techniques, Principal Component Analysis (PCA) and Partial Least Square Regression (PLSR) were also performed on SERS spectral data. RESULTS The SERS spectral features due to biochemical changes in HBV positive serum samples associated with the increasing viral loads were established which could be employed for HBV diagnostic purpose. PCA was found helpful for the differentiation between SERS spectral data of serum samples of different levels of HBV infection and healthy individuals. PLSR model developed with standard samples of known viral loads for predicting the viral loads of blind/unknown samples with 99% predicted accuracy. CONCLUSION SERS can be employed for qualitative and quantitative analysis of HBV infection from blood serum samples.
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Unique Features of Hepatitis B Virus-Related Hepatocellular Carcinoma in Pathogenesis and Clinical Significance. Cancers (Basel) 2021; 13:cancers13102454. [PMID: 34070067 PMCID: PMC8158142 DOI: 10.3390/cancers13102454] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/12/2021] [Accepted: 05/14/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatitis B virus (HBV) infection is the major risk factor for hepatocellular carcinoma (HCC). Understanding the unique features for HBV-induced HCC can shed new light on the unmet needs in its early diagnosis and effective therapy. During decades of chronic hepatitis B, hepatocytes undergoing repeated damage and regeneration accumulate genetic changes predisposing to HCC development. In addition to traditional mutations in viral and cellular oncogenes, HBV integration into the cell chromosomes is an alternative genetic change contributing to hepatocarcinogenesis. A striking male dominance in HBV-related HCC further highlights an interaction between androgen sex hormone and viral factors, which contributes to the gender difference via stimulating viral replication and activation of oncogenes preferentially in male patients. Meanwhile, a novel circulating tumor biomarker generated by HBV integration shows great potential for the early diagnosis of HCC. These unique HBV-induced hepatocarcinogenic mechanisms provide new insights for the future development of superior diagnosis and treatment strategies. Abstract Hepatitis B virus (HBV) infection is one of the important risk factors for hepatocellular carcinoma (HCC) worldwide, accounting for around 50% of cases. Chronic hepatitis B infection generates an inflammatory microenvironment, in which hepatocytes undergoing repeated cycles of damage and regeneration accumulate genetic mutations predisposing them to cancer. A striking male dominance in HBV-related HCC highlights the influence of sex hormones which interact with viral factors to influence carcinogenesis. HBV is also considered an oncogenic virus since its X and surface mutant proteins showed tumorigenic activity in mouse models. The other unique mechanism is the insertional mutagenesis by integration of HBV genome into hepatocyte chromosomes to activate oncogenes. HCC survival largely depends on tumor stages at diagnosis and effective treatment. However, early diagnosis by the conventional protein biomarkers achieves limited success. A new biomarker, the circulating virus–host chimera DNA from HBV integration sites in HCC, provides a liquid biopsy approach for monitoring the tumor load in the majority of HBV–HCC patients. To maximize the efficacy of new immunotherapies or molecular target therapies, it requires better classification of HCC based on the tumor microenvironment and specific carcinogenic pathways. An in-depth study may benefit both the diagnosis and treatment of HBV-related HCC.
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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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Güzelbulut F, Gökçen P, Can G, Adalı G, Değirmenci Saltürk AG, Bahadır Ö, Özdil K, Doğanay HL. Validation of the HCC-RESCUE score to predict hepatocellular carcinoma risk in Caucasian chronic hepatitis B patients under entecavir or tenofovir therapy. J Viral Hepat 2021; 28:826-836. [PMID: 33586270 DOI: 10.1111/jvh.13485] [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] [Received: 12/09/2020] [Revised: 01/12/2021] [Accepted: 01/29/2021] [Indexed: 02/06/2023]
Abstract
The HCC-RESCUE score was developed to predict hepatocellular carcinoma (HCC) risk in Korean chronic hepatitis B (CHB) patients under entecavir therapy. We aimed to validate the HCC-RESCUE score to predict HCC risk in Caucasian CHB patients under entecavir or tenofovir therapy and to compare the predictive performance of the HCC-RESCUE score with those of the CAMD, PAGE-B and modified PAGE-B (mPAGE-B) scores. The study included 647 nucleos(t)ide analogue-naive noncirrhotic and compensated/decompensated cirrhotic patients who had received entecavir or tenofovir for ≥6 months and did not develop HCC during the first 6 months of therapy. Patients with HCC-RESCUE scores ≤64, 65-84 and ≥85 points were classified into low-, intermediate- and high-risk groups, respectively. The AUROCs of the HCC-RESCUE, CAMD, PAGE-B and mPAGE-B scores to predict HCC risk at 5 years were 0.875, 0.870, 0.866 and 0.880, and those at 10 years were 0.862, 0.845, 0.841 and 0.862, respectively (both p > .05). Cumulative HCC incidences at 5 years were 0.0%, 10.5% and 15.8%, and those at 10 years were 1.4%, 15.5% and 24.9%, respectively, in the low-, intermediate- and high-risk groups based on the HCC-RESCUE score (both log rank p < .001). In the entecavir versus tenofovir cohorts, the AUROCs of the HCC-RESCUE score to predict HCC risk at 5 and 10 years were 0.831 versus 0.898 and 0.803 versus 0.910, respectively (both p > .05). The HCC-RESCUE score accurately predicted HCC risk in Caucasian CHB patients under entecavir or tenofovir therapy. A substantial proportion of patients can be dropped from HCC surveillance by using the HCC-RESCUE score.
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Affiliation(s)
- Fatih Güzelbulut
- Department of Gastroenterology, Haydarpaşa Numune Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Pınar Gökçen
- Department of Gastroenterology, Ümraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Güray Can
- Faculty of Medicine, Department of Gastroenterology, Abant Izzet Baysal University, Bolu, Turkey
| | - Gupse Adalı
- Department of Gastroenterology, Ümraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Ayça Gökçen Değirmenci Saltürk
- Department of Gastroenterology, Haydarpaşa Numune Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Özgür Bahadır
- Department of Gastroenterology, Haydarpaşa Numune Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Kamil Özdil
- Department of Gastroenterology, Ümraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
| | - Hamdi Levent Doğanay
- Department of Gastroenterology, Ümraniye Training and Research Hospital, University of Health Sciences Turkey, Istanbul, Turkey
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Boyd A, Dezanet LNC, Kassime R, Miailhes P, Lascoux-Combe C, Chas J, Girard PM, Gozlan J, Zoulim F, Delaugerre C, Rougier H, Lacombe K. Subclinical and Clinical Outcomes in Patients Coinfected With HIV and Chronic Hepatitis B Virus From Clinical Outpatient Centers in France: Protocol for an Ambispective, Longitudinal Cohort Study. JMIR Res Protoc 2021; 10:e24731. [PMID: 33821807 PMCID: PMC8058690 DOI: 10.2196/24731] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/25/2022] Open
Abstract
Background Previous large-scale studies have examined the effect of chronic hepatitis B virus (HBV) infection on overall and cause-specific mortality in individuals with HIV. However, few studies have collected data on the subclinical indicators of HBV that lead to these severe outcomes in the coinfected population. Objective In this study, we aim to describe the procedures of a cohort study extension aimed at assessing HBV-DNA replication, serological markers of HBV (hepatitis B e antigen [HBeAg] and hepatitis B surface antigen), and liver fibrosis and how these subclinical outcomes relate to mortality in predominately tenofovir-treated, coinfected patients with HIV-HBV. We assessed the characteristics at cohort inclusion of those who participated in the cohort extension, as well as those who did not participate due to being lost to follow-up or death. Methods Patients with HIV and chronic HBV who completed follow-up in a prospective cohort study conducted in 4 outpatient centers (Paris and Lyon, France; 2002-2011) were invited to participate in a cross-sectional visit from November 2016 to March 2018, during which a comprehensive evaluation of HIV- and HBV-related disease was undertaken. Virological and clinical data since the previous study visit were retrospectively collected. Results Of the 308 individuals enrolled in the cohort, 147 (47.7%) participated in the cross-sectional study. At this visit, most participants were HBeAg negative (111/134, 82.8% with available data), had undetectable HBV DNA (124/132, 93.9% with available data), and were undergoing antiretroviral therapy containing tenofovir disoproxil fumarate or tenofovir alafenamide (114/147, 77.6%). There were no significant differences in characteristics at cohort inclusion between those who did and did not complete the cross-sectional visit, except for a lower proportion with an AIDS-defining illness (30/147, 20.5% vs 49/161, 30.4%, respectively; P=.04). Of the 161 nonparticipating individuals, 42 (26.1%) died, 41 (25.4%) were lost to follow-up and known to be alive, and 78 (48.4%) were lost to follow-up with unknown vital status. Most differences in characteristics at cohort inclusion were observed between deceased individuals and those participating in the cross-sectional visit or those lost to follow-up. With this extension, the median follow-up time of the overall cohort is presently 9.2 years (IQR 3.4-14.6). Conclusions Extended follow-up of the French HIV-HBV cohort will provide important long-term data on the subclinical trajectory of HBV disease in the coinfected population. The biases due to the relatively high rate of those lost to follow-up need to be assessed in future studies of this cohort. International Registered Report Identifier (IRRID) DERR1-10.2196/24731
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Affiliation(s)
- Anders Boyd
- Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France
| | - Lorenza N C Dezanet
- Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France
| | - Raisha Kassime
- Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France
| | - Patrick Miailhes
- Service de Maladies Infectieuses et Tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | | | - Julie Chas
- Service de Maladies Infectieuses, Hôpital Tenon, APHP, Paris, France
| | - Pierre-Marie Girard
- Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France.,Service de Maladies Infectieuses, Hôpital Saint-Antoine, APHP, Paris, France
| | - Joël Gozlan
- Service de Maladies Infectieuses, Hôpital Saint-Antoine, APHP, Paris, France.,Centre de Recherche Saint-Antoine, Paris, France
| | - Fabien Zoulim
- Centre de Recherche sur le Cancer de Lyon, Unité 1052, INSERM, UMR 5286, CNRS, Lyon, France
| | - Constance Delaugerre
- Laboratoire de Virologie, Hôpital Saint-Louis, APHP; Université de Paris, INSERM U944, Institut de Recherche Saint-Louis, Paris, France
| | - Hayette Rougier
- Institut de Médecine et d'Epidémiologie Appliquée (IMEA), Paris, France
| | - Karine Lacombe
- Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France.,Service de Maladies Infectieuses, Hôpital Saint-Antoine, APHP, Paris, France
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Pan Q, Qin F, Yuan H, He B, Yang N, Zhang Y, Ren H, Zeng Y. Normal tissue adjacent to tumor expression profile analysis developed and validated a prognostic model based on Hippo-related genes in hepatocellular carcinoma. Cancer Med 2021; 10:3139-3152. [PMID: 33818013 PMCID: PMC8085948 DOI: 10.1002/cam4.3890] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 12/25/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the most common malignant disease worldwide. Although the diagnosis and treatment of HCC have greatly improved in the recent years, there is still a lack of accurate methods to predict the prognosis of patients. Evidence has shown that Hippo signaling in tissues adjacent to HCC plays a significant role in HCC development. In the present study, we aimed to construct a model based on the expression of Hippo‐related genes (HRGs) in tissues adjacent to HCC to predict the prognosis of HCC patients. Methods Gene expression data of paired normal tissues adjacent to HCC (PNTAH) and clinical information were obtained from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The HRG signature was constructed using four canonical Hippo‐related pathways. Univariate Cox regression analysis was used to screen survival‐related HRGs. LASSO and multivariate Cox regression analyses were used to construct the prognostic model. The true and false positive rates of the model were confirmed using receiver operating characteristic (ROC) analysis. Results The prognostic model was constructed based on the expression levels of five HRGs (NF2, MYC, BIRC3, CSNK1E, and MINK1) in PNTAH. The mortality rate of HCC patients increased as the risk score determined by the model increased. Furthermore, the risk score was found to be an independent risk factor for the survival of patients. ROC analysis showed that the prognostic model had a better predictive value than the other conventional clinical parameters. Moreover, the reliability of the prognostic model was confirmed in TCGA‐LIHC cohort. A nomogram was generated to predict patient survival. An exploration of the predictive value of the model in HCC tissues indicated that the model is PNTAH‐specific. Conclusions We developed and validated a prognostic model based on the expression levels of five HRGs in PNTAH, and this model should be helpful in predicting the prognosis of patients with HCC.
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Affiliation(s)
- Qingbo Pan
- Department of Infectious Diseases, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fanbo Qin
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hanyu Yuan
- Caojie Community Medical Service Centre Hechuan, Chongqing, China
| | - Baoning He
- Chongqing YuCai Secondary School, Chongqing, China
| | - Ni Yang
- Chongqing YuCai Secondary School, Chongqing, China
| | - Yitong Zhang
- Chongqing YuCai Secondary School, Chongqing, China
| | - Hong Ren
- Department of Infectious Diseases, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yi Zeng
- Department of Infectious Diseases, The Key Laboratory of Molecular Biology for Infectious Diseases, Chinese Ministry of Education, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Anugwom CM, Allaire M, Akbar SMF, Sultan A, Bollipo S, Mattos AZ, Debes JD. Hepatitis B-related hepatocellular carcinoma: surveillance strategy directed by immune-epidemiology. HEPATOMA RESEARCH 2021; 7. [PMID: 33884303 PMCID: PMC8057710 DOI: 10.20517/2394-5079.2021.06] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatitis B infection (HBV) is one of the most common causes of hepatocellular carcinoma (HCC) worldwide. The age of occurrence, prognosis and incidence vary dramatically depending on the region of the world. This geographic variation is largely dependent on the contrasting incidence of HBV, age of transmission of the virus, the timing of integration into the human genome, and different HBV genotypes, as well as environmental factors. It results in a wide difference in viral interaction with the immune system, genomic modulation and the consequent development of HCC in an individual. In this review, we describe many factors implicated in HCC development, provide insight regarding at-risk populations and explain societal recommendations for HCC surveillance in persons living with HBV in different continents of the world.
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Affiliation(s)
- Chimaobi M Anugwom
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis 55455, USA
| | - Manon Allaire
- Sorbonne Université, Service d'Hépatologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Paris 75103, France.,Inserm U1149, Centre de Recherche sur l'Inflammation, France Faculté de Médecine, Xavier Bichat, Université Paris Diderot, Paris 75108, France
| | - Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan
| | - Amir Sultan
- College of Health Sciences, Addis Ababa University, Tikur Anbessa Specialized Hospital, Addis Ababa 5657, Ethiopia
| | - Steven Bollipo
- Department of Gastroenterology, John Hunter Hospital, Newcastle, Australia & School of Medicine & Public Health, University of Newcastle, New South Wales 2310, Australia
| | - Angelo Z Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre 90050-170, Brazil.,Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre 90020-090, Brazil
| | - Jose D Debes
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis 55455, USA.,Department of Medicine, Division of Infectious Diseases, University of Minnesota, Minneapolis, MN 55455, USA.,Department of Gastroenterology & Hepatology, Erasmus MC, Rotterdam 3015-CE, Netherlands
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Wang XH, Liu QB, Xiang CL, Mao XH, Yang B, Li Q, Zhou QF, Li SQ, Zhou ZG, Chen MS. Multi-institutional validation of novel models for predicting the prognosis of patients with huge hepatocellular carcinoma. Int J Cancer 2021; 149:127-138. [PMID: 33586134 DOI: 10.1002/ijc.33516] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/25/2021] [Accepted: 01/29/2021] [Indexed: 01/06/2023]
Abstract
The population of patients with huge hepatocellular carcinoma (H-HCC diameter > 10.0 cm) is an odd group that is not well adjudicated in the current staging systems, whose prognosis after curative resection varies. We aimed to develop novel models to predict the long-term outcomes of patients with H-HCC without portal vein tumor thrombus after hepatectomy. There were 1076 H-HCC patients enrolled who underwent curative liver resection in five institutions in China. In total, 670 patients were recruited from our center and randomly divided into the training cohort (n = 502) and internal validation (n = 168) cohorts. Additionally, 406 patients selected from other four centers as the external validation cohort. Novel models were constructed based on independent preoperative and postoperative predictors of postsurgical recurrence (PSR) and postsurgical mortality (PSM) determined in multivariable cox regression analysis. The predictive accuracy and discriminative ability of the model were measured using Harrell's concordance index (C index) and calibration curve and compared with five conventional HCC staging systems. PSR model and PSM model were constructed based on tumor number, microscopic vascular invasion, tumor differentiation, preoperative alpha-fetoprotein level, albumin-bilirubin grade, liver segment invasion, neutrophil-to-lymphocyte ratio or platelet-to-neutrophil ratio, and surgical margin or intraoperative blood transfusion. The C-indexes were 0.84 (95% CI, 0.78-0.90) and 0.85 (95% CI, 0.78-0.91) for the PSR and PSM models, respectively, which were substantially higher than those of the five conventional HCC staging systems (0.63-0.75 for PSR; 0.66-0.77 for PSM). The two novel models achieved more accurate prognostic predictions of PSR and PSM for H-HCC patients after curative liver resection.
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Affiliation(s)
- Xiao-Hui Wang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Qing-Bo Liu
- Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, Guangdong Province, China
| | - Cai-Ling Xiang
- Department of General Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, China
| | - Xian-Hai Mao
- Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan Province, China
| | - Bing Yang
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Qiang Li
- Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Qun-Fang Zhou
- Department of Minimally Invasive Interventional Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, China
| | - Shao-Qiang Li
- Department of Liver Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zhong-Guo Zhou
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Min-Shan Chen
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China.,Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
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Hepatitis B Virus DNA Integration and Clonal Expansion of Hepatocytes in the Chronically Infected Liver. Viruses 2021; 13:v13020210. [PMID: 33573130 PMCID: PMC7911963 DOI: 10.3390/v13020210] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 02/07/2023] Open
Abstract
Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. This immune response results in elevated rates of killing of virus-infected hepatocytes, which may extend over many years or decades, lead to fibrosis and cirrhosis, and play a role in the high incidence of hepatocellular carcinoma (HCC) in HBV carriers. Immune-mediated inflammation appears to cause oxidative DNA damage to hepatocytes, which may also play a major role in hepatocarcinogenesis. An additional DNA damaging feature of chronic infections is random integration of HBV DNA into the chromosomal DNA of hepatocytes. While HBV DNA integration does not have a role in virus replication it may alter gene expression of the host cell. Indeed, most HCCs that arise in HBV carriers contain integrated HBV DNA and, in many, the integrant appears to have played a role in hepatocarcinogenesis. Clonal expansion of hepatocytes, which is a natural feature of liver biology, occurs because the hepatocyte population is self-renewing and therefore loses complexity due to random hepatocyte death and replacement by proliferation of surviving hepatocytes. This process may also represent a risk factor for the development of HCC. Interestingly, during chronic HBV infection, hepatocyte clones detected using integrated HBV DNA as lineage-specific markers, emerge that are larger than those expected to occur by random death and proliferation of hepatocytes. The emergence of these larger hepatocyte clones may reflect a survival advantage that could be explained by an ability to avoid the host immune response. While most of these larger hepatocyte clones are probably not preneoplastic, some may have already acquired preneoplastic changes. Thus, chronic inflammation in the HBV-infected liver may be responsible, at least in part, for both initiation of HCC via oxidative DNA damage and promotion of HCC via stimulation of hepatocyte proliferation through immune-mediated killing and compensatory division.
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Shih WL, Fang CT, Chen PJ. Chapter XX Antiviral Treatment and Cancer Control. Recent Results Cancer Res 2021; 217:325-354. [PMID: 33200371 DOI: 10.1007/978-3-030-57362-1_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
Abstract
Hepatitis B virus (HBV), hepatitis C virus (HCV), human papilloma virus (HPV), Epstein-Barr virus (EBV), human T-cell lymphotropic virus type 1 (HTLV-1), Kaposi's sarcoma-associated herpesvirus (KSHV), and Merkel cell polyomavirus (MCV) contribute to about 10-15% global burden of human cancers. Conventional chemotherapy or molecular target therapies have been used to treat virus-associated cancers. However, a more proactive approach would be the use of antiviral treatment to suppress or eliminate viral infections to prevent the occurrence of cancer in the first place. Antiviral treatments against chronic HBV and HCV infection have achieved this goal, with significant reduction in the incidence of hepatocellular carcinoma in treated patients. Antiviral treatments for EBV, KSHV, and HTLV-1 had limited success in treating refractory EBV-associated lymphoma and post-transplant lymphoproliferative disorder, KSHV-associated Kaposi's sarcoma in AIDS patients, and HTLV-1-associated acute, chronic, and smoldering subtypes of adult T-cell lymphoma, respectively. Therapeutic HPV vaccine and RNA interference-based therapies for treating HPV-associated infection or cervical cancers also showed some encouraging results. Taken together, antiviral therapies have yielded promising results in cancer prevention and treatment. More large-scale studies in a real-world setting are necessary to confirm the efficacy of antiviral therapy. Further investigation for more effective and convenient antiviral regimens warrants more attention.
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Affiliation(s)
- Wei-Liang Shih
- Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-Tai Fang
- Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
| | - Pei-Jer Chen
- Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan.
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50
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Chen CJ, You SL, Hsu WL, Yang HI, Lee MH, Chen HC, Chen YY, Liu J, Hu HH, Lin YJ, Chu YJ, Huang YT, Chiang CJ, Chien YC. Epidemiology of Virus Infection and Human Cancer. Recent Results Cancer Res 2021; 217:13-45. [PMID: 33200360 DOI: 10.1007/978-3-030-57362-1_2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Seven viruses including the Epstein-Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), Kaposi's sarcoma herpes virus (KSHV), human immunodeficiency virus, type-1 (HIV-1), human T cell lymphotrophic virus, type-1 (HTLV-1), and human papillomavirus (HPV) have been classified as Group 1 human carcinogens by the International Agency for Research on Cancer (IARC). The conclusions are based on the findings of epidemiological and mechanistic studies. EBV, HPV, HTLV-1, and KSHV are direct carcinogens; HBV and HCV are indirect carcinogens through chronic inflammation; and HIV-1 is an indirect carcinogen through immune suppression. Some viruses may cause more than one cancer, while some cancers may be caused by more than one virus. However, only a proportion of persons infected by these oncogenic viruses will develop specific cancers. A series of studies have been carried out to assess the viral, host, and environmental cofactors of EBV-associated nasopharyngeal carcinoma, HBV/HCV-associated hepatocellular carcinoma, and HPV-associated cervical carcinoma. Persistent infection, high viral load, and viral genotype are important risk predictors of these virus-caused cancers. Risk calculators incorporating host and viral risk predictors have been developed for the prediction of long-term risk of hepatocellular carcinoma, nasopharyngeal carcinoma and cervical cancer. These risk calculators are useful for the triage and clinical management of infected patients. Both clinical trials and national programs of immunization, antiviral therapy and screening have demonstrated a significant reduction in the incidence of cancers caused by HBV, HCV, and HPV. Future research on gene-gene and gene-environment interactions of oncogenic viruses and the human host using large-scale longitudinal studies with serial measurements of biosignatures are in urgent need.
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Affiliation(s)
- Chien-Jen Chen
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sect. 2, Taipei, 115, Taiwan.
| | - San-Lin You
- School of Medicine and Big Data Research Centre, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Wan-Lun Hsu
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sect. 2, Taipei, 115, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sect. 2, Taipei, 115, Taiwan
| | - Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hui-Chi Chen
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sect. 2, Taipei, 115, Taiwan
| | | | - Jessica Liu
- Department of Pediatrics, Perinatal Epidemiology and Health Outcomes Research Unit, Stanford University School of Medicine and Lucile Packard Children's Hospital, Palo Alto, CA, USA
- California Perinatal Quality Care Collaborative, Palo Alto, CA, USA
| | - Hui-Han Hu
- Department of Translational Science, Preclinical Research, PharmaEngine Inc., Taipei, Taiwan
| | - Yu-Ju Lin
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yu-Ju Chu
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | - Yen-Tsung Huang
- Institute of Statistical Sciences, Academia Sinica, Taipei, Taiwan
| | - Chun-Ju Chiang
- Graduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
| | - Yin-Chu Chien
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sect. 2, Taipei, 115, Taiwan
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