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Nguyen LBL, Lemoine M, Ndow G, Ward ZJ, Hallet TB, D'Alessandro U, Thursz M, Nayagam S, Shimakawa Y. Treat All versus targeted strategies to select HBV-infected people for antiviral therapy in The Gambia, west Africa: a cost-effectiveness analysis. Lancet Glob Health 2024; 12:e66-e78. [PMID: 38097300 DOI: 10.1016/s2214-109x(23)00467-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 10/04/2023] [Accepted: 10/05/2023] [Indexed: 12/18/2023]
Abstract
BACKGROUND Global elimination of hepatitis B virus (HBV) requires expanded uptake of antiviral therapy, potentially by simplifying testing algorithms, especially in resource-limited countries. We evaluated the effectiveness, cost-effectiveness, and budget impact of three strategies that determine eligibility for anti-HBV treatment, as compared with the WHO 2015 treatment eligibility criteria, in The Gambia. METHODS We developed a microsimulation model of natural history using data from the Prevention of Liver Fibrosis and Cancer in Africa programme (known as PROLIFICA) in The Gambia, for an HBV-infected cohort of individuals aged 20 years. The algorithms included in the model were a conventional strategy using the European Association for the Study of the Liver (EASL) 2017 criteria, a simplified algorithm using hepatitis B e antigen and alanine aminotransferase (the Treatment Eligibility in Africa for the Hepatitis B Virus [TREAT-B] score), a Treat All approach for all HBV-infected individuals, and the WHO 2015 criteria. Outcomes to measure effectiveness were disability-adjusted life years (DALYs) and years of life saved (YLS), which were used to calculate incremental cost-effectiveness ratios (ICERs) with the WHO 2015 criteria as the base-case scenario. Costs were assessed from a modified social perspective. A budget impact analysis was also done. We tested the robustness of results with a range of sensitiviy analyses including probabilistic sensitivity analysis. FINDINGS Compared with the WHO criteria, TREAT-B resulted in 4877 DALYs averted and Treat All resulted in 9352 DALYs averted, whereas the EASL criteria led to an excess of 795 DALYs. TREAT-B was cost-saving, whereas the ICER for Treat All (US$2149 per DALY averted) was higher than the cost-effectiveness threshold for The Gambia (0·5 times the country's gross domestic product per capita: $352). These patterns did not change when YLS was the outcome. In a modelled cohort of 5000 adults (aged 20 years) with chronic HBV infection from The Gambia, the 5-year budget impact was $1·14 million for Treat All, $0·66 million for TREAT-B, $1·03 million for the WHO criteria, and $1·16 million for the EASL criteria. Probabilistic sensitivity analysis indicated that among the Treat All, EASL, and TREAT-B algorithms, Treat All would become the most preferred strategy only with a willingness-to-pay threshold exceeding approximately $72 000 per DALY averted or $110 000 per YLS. INTERPRETATION Although the Treat All strategy might be the most effective, it is unlikely to be cost-effective in The Gambia. A simplified strategy such as TREAT-B might be a cost-saving alternative. FUNDING UK Research and Innovation (Medical Research Council). TRANSLATION For the French translation of the abstract see Supplementary Materials section.
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Affiliation(s)
- Liem B Luong Nguyen
- Institut Pasteur, Université Paris Cité, Unité d'Épidémiologie des Maladies Émergentes, Paris, France; CIC Cochin Pasteur, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Maud Lemoine
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary's Hospital, Imperial College London, UK; Medical Research Council Unit, London School of Hygiene & Tropical Medicine, Fajara, The Gambia
| | - Gibril Ndow
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary's Hospital, Imperial College London, UK; Medical Research Council Unit, London School of Hygiene & Tropical Medicine, Fajara, The Gambia
| | - Zachary J Ward
- Center for Health Decision Science, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Timothy B Hallet
- Medical Research Council Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College London, London, UK
| | - Umberto D'Alessandro
- Medical Research Council Unit, London School of Hygiene & Tropical Medicine, Fajara, The Gambia
| | - Mark Thursz
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary's Hospital, Imperial College London, UK
| | - Shevanthi Nayagam
- Department of Metabolism, Digestion and Reproduction, Division of Digestive Disease, Liver Unit, St Mary's Hospital, Imperial College London, UK; Medical Research Council Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College London, London, UK
| | - Yusuke Shimakawa
- Institut Pasteur, Université Paris Cité, Unité d'Épidémiologie des Maladies Émergentes, Paris, France.
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Shah KK, Wyld M, Hedley JA, Waller KMJ, De La Mata N, Webster AC, Morton RL. Cost-effectiveness of Kidney Transplantation From Donors at Increased Risk of Blood-borne Virus Infection Transmission. Transplantation 2023; 107:2028-2042. [PMID: 37211651 DOI: 10.1097/tp.0000000000004632] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
BACKGROUND Demand for donor kidneys outstrips supply. Using kidneys from selected donors with an increased risk of blood-borne virus (BBV) transmission (hepatitis B virus and hepatitis C virus [HCV], human immunodeficiency virus) may expand the donor pool, but cost-effectiveness of this strategy is uncertain. METHODS A Markov model was developed using real-world evidence to compare healthcare costs and quality-adjusted life years (QALYs) of accepting kidneys from deceased donors with potential increased risk of BBV transmission, because of increased risk behaviors and/or history of HCV, versus declining these kidneys. Model simulations were run over a 20-y time horizon. Parameter uncertainty was assessed through deterministic and probabilistic sensitivity analyses. RESULTS Accepting kidneys from donors at increased risk of BBVs (2% from donors with increased-risk behaviors and 5% from donors with active or past HCV infection) incurred total costs of 311 303 Australian dollars with a gain of 8.53 QALYs. Foregoing kidneys from these donors incurred total costs of $330 517 and a gain of 8.44 QALYs. A cost-saving of $19 214 and additional 0.09 QALYs (~33 d in full health) per person would be generated compared with declining these donors. Increasing the availability of kidneys with increased risk by 15% led to further cost-savings of $57 425 and additional 0.23 QALY gains (~84 d in full health). Probabilistic sensitivity analysis using 10 000 iterations showed accepting kidneys from donors at increased risk led to lower costs and higher QALY gains. CONCLUSIONS Shifting clinical practice to accept increased BBV risk donors would likely produce lower costs and higher QALYs for health systems.
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Affiliation(s)
- Karan K Shah
- Health Economics and Health Technology Assessment, NHMRC Clinical Trials Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Melanie Wyld
- Collaborative Centre for Organ Donation Evidence, Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia
| | - James A Hedley
- Collaborative Centre for Organ Donation Evidence, Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Karen M J Waller
- Collaborative Centre for Organ Donation Evidence, Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Nicole De La Mata
- Collaborative Centre for Organ Donation Evidence, Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Angela C Webster
- Health Economics and Health Technology Assessment, NHMRC Clinical Trials Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Collaborative Centre for Organ Donation Evidence, Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Centre for Transplant and Renal Research, Westmead Hospital, Sydney, NSW, Australia
| | - Rachael L Morton
- Health Economics and Health Technology Assessment, NHMRC Clinical Trials Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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Controversies in Treating Chronic Hepatitis B virus: The Role of Hepatitis B Virus DNA and Surface Antigen Titer. Clin Liver Dis 2021; 25:763-784. [PMID: 34593152 DOI: 10.1016/j.cld.2021.06.005] [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] [Indexed: 01/31/2023]
Abstract
Controversial areas in chronic hepatitis B (CHB) are those where there is uncertainty, or differences of opinion in management, or where evidence may be insufficient. Areas of controversy include whether patients with high viral load but normal liver function tests should be treated to prevent hepatocellular carcinoma (HCC) or liver disease progression to cirrhosis. Another area is whether quantitative hepatitis B surface antigen (qHBsAg) can be used to better characterize phases of CHB and prognosticate. Finally, the utility of qHBsAg in the management of patients on antiviral therapy such as interferon and nucleoside analogues could improve management practices.
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Khoo T, Lam D, Olynyk JK. Impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes of liver disease. World J Gastroenterol 2021; 27:4831-4845. [PMID: 34447229 PMCID: PMC8371504 DOI: 10.3748/wjg.v27.i29.4831] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 05/14/2021] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections with the hepatitis B and C viruses have significant worldwide health and economic impacts. Previous treatments for hepatitis C such as interferon and ribavirin therapy were ineffective and poorly tolerated by patients. The introduction of directly acting curative antiviral therapy for hepatitis C and the wider use of nucleos(t)ide analogues for suppression of chronic Hepatitis B infection have resulted in many positive developments. Decreasing the prevalence of hepatitis B and C have concurrently reduced transmission rates and hence, the number of new infections. Antiviral treatments have decreased the rates of liver decompensation and as a result, lowered hospitalisation and mortality rates for both chronic hepatitis B and C infection. The quality of life of chronically infected patients has also been improved significantly by modern treatment. Antiviral therapy has stopped the progression of liver disease to cirrhosis in certain patient cohorts and prevented ongoing hepatocellular damage in patients with existing cirrhosis. Longer term benefits of antiviral therapy include a reduced risk of developing hepatocellular carcinoma and decreased number of patients requiring liver transplantation. This review article assesses the literature and summarises the impact of modern antiviral therapy of chronic hepatitis B and C on clinical outcomes from liver disease.
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Affiliation(s)
- Tiffany Khoo
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - Danielle Lam
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
| | - John K Olynyk
- Department of Gastroenterology and Hepatology, Fiona Stanley Hospital, Murdoch 6150, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup 6027, Australia
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Chen Q, Li F, Zhong C, Zou Y, Li Z, Gao Y, Zou Q, Xia Y, Wang K, Shen F. Inflammation Score System using Preoperative Inflammatory Markers to Predict Prognosis for Hepatocellular Carcinoma after Hepatectomy: A Cohort Study. J Cancer 2020; 11:4947-4956. [PMID: 32742442 PMCID: PMC7378936 DOI: 10.7150/jca.45274] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 05/29/2020] [Indexed: 02/07/2023] Open
Abstract
Background: This study developed a novel inflammation score system to predict survival outcomes using preoperational inflammatory markers in hepatocellular carcinoma (HCC) after surgery. Materials and Methods: An inflammation score system was developed using five preoperative inflammatory markers based on the clinical data of 455 HCC patients (training cohort) receiving radical resection in the Eastern Hepatobiliary Surgery Hospital. The system was validated using a cohort from a different hospital (external validation). Kaplan-Meier curves and log-rank test were used to compare the survival of patients with different inflammation scores. A nomogram including inflammation scores for survival prediction was created to exhibit the risk factors of overall survival (OS). Results: The patients in the low-score group showed better OS and recurrence-free survival (RFS) in the training and external validation cohorts than those from the high-score group. Subgroup analysis showed that compared with patients in the training cohort from the high-score group, stage I (eighth TNM stage) patients in the low-score group exhibited better prognosis results, whereas the findings for Stage II and III patients were different. Multivariate Cox analysis revealed that high inflammation score is an independent risk factor of OS and RFS. The nomogram established using the inflammation score with the C-index value of 0.661 (95% confidence interval=0.624-0.698) revealed a good three- and five-year calibration curves. Conclusions: The inflammation score system based on five preoperative inflammatory markers well predicted the survival of HCC patients after surgery, especially in those at the early stage (Stage I).
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Affiliation(s)
- Qinjunjie Chen
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Fengwei Li
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.,Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Chengqian Zhong
- Longyan First Hospital, Affiliated to Fujian Medical University, Longyan, China
| | - Yiran Zou
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Zheng Li
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yuzhen Gao
- Department of Molecular Diagnosis, Clinical Medical College, Yangzhou University, Jiangsu, China
| | - Qifei Zou
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Yong Xia
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Kui Wang
- Department of Hepatic Surgery II, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Department of Hepatic Surgery IV, the Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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Xiao Y, Howell J, van Gemert C, Thompson AJ, Seaman CP, McCulloch K, Scott N, Hellard ME. Enhancing the hepatitis B care cascade in Australia: A cost-effectiveness model. J Viral Hepat 2020; 27:526-536. [PMID: 31856377 DOI: 10.1111/jvh.13252] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 11/12/2019] [Accepted: 12/07/2019] [Indexed: 02/06/2023]
Abstract
If Australia is to successfully eliminate hepatitis B as a public health threat, it will need to enhance the chronic hepatitis B (CHB) care cascade. This study used a Markov model to assess the impact, cost and cost-effectiveness of scaling up CHB diagnosis, linkage to care and treatment to reach national and international elimination targets for hepatitis B in Australia. Compared to continued current trends, the model calculated the difference in care cascade projection, disability-adjusted life years (DALYs), costs and the incremental cost-effectiveness ratio (ICER), of scaling up CHB diagnosis, linkage to care and treatment to reach: (a) Australia's 2022 national targets and (b) the WHO's 2030 global targets. Achieving the national and WHO targets had ICERs of A$13 435 (A$10 236-A$21 165) and A$14 482 (A$13 031-A$25 641) per DALY averted between 2016 and 2030 in Australia, respectively. However, this excluded implementation and demand generation costs. The ICER for the National Strategy and WHO Strategy remained under A$50 000 per DALY averted if Australia spent up to A$328 or A$538 million, respectively, per annum (for 2016-2030) on implementation and demand generation activities. Sensitivity analysis showed that cost-effectiveness was predominately driven by the cost of CHB treatment and influenced by disease progression rates. Hence for Australia to reach the National Hepatitis B Strategy 2022 targets and WHO Strategy 2030 targets, it requires an improvement in the CHB care cascade. We estimated it is cost-effective to spend up to A$328 million or A$538 million per year to reach the National and WHO Strategy targets, respectively.
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Affiliation(s)
- Yinzong Xiao
- Burnet Institute, Melbourne, Vic, Australia.,Department of Gastroenterology, St Vicent's Hospital, Melbourne, Vic, Australia.,University of Melbourne, Melbourne, Vic, Australia
| | - Jessica Howell
- Burnet Institute, Melbourne, Vic, Australia.,Department of Gastroenterology, St Vicent's Hospital, Melbourne, Vic, Australia.,University of Melbourne, Melbourne, Vic, Australia.,Monash University, Melbourne, Vic, Australia
| | - Caroline van Gemert
- Burnet Institute, Melbourne, Vic, Australia.,University of Melbourne, Melbourne, Vic, Australia
| | - Alexander J Thompson
- Department of Gastroenterology, St Vicent's Hospital, Melbourne, Vic, Australia.,University of Melbourne, Melbourne, Vic, Australia
| | - Christopher P Seaman
- Burnet Institute, Melbourne, Vic, Australia.,Monash University, Melbourne, Vic, Australia
| | - Karen McCulloch
- University of Melbourne, Melbourne, Vic, Australia.,WHO Collaborating Centre for Viral Hepatitis, Melbourne, Vic, Australia.,Victorian Infectious Diseases Reference Laboratory, Melbourne, Vic, Australia.,The Peter Doherty Institute for Infection and Immunity, Melbourne, Vic, Australia
| | - Nick Scott
- Burnet Institute, Melbourne, Vic, Australia.,Monash University, Melbourne, Vic, Australia
| | - Margaret E Hellard
- Burnet Institute, Melbourne, Vic, Australia.,University of Melbourne, Melbourne, Vic, Australia.,Monash University, Melbourne, Vic, Australia.,The Peter Doherty Institute for Infection and Immunity, Melbourne, Vic, Australia.,School of Population Health, Monash University, Melbourne, Vic, Australia.,Department of Infectious Diseases, Alfred Hospital, Melbourne, Vic, Australia
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7
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Tong MJ, Pan CQ, Han SB, Lu DS, Raman S, Hu K, Lim JK, Hann HW, Min AD. An expert consensus for the management of chronic hepatitis B in Asian Americans. Aliment Pharmacol Ther 2018; 47:1181-1200. [PMID: 29479728 PMCID: PMC5900913 DOI: 10.1111/apt.14577] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/10/2017] [Accepted: 01/27/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide. AIM To generate recommendations for the management of Asian Americans infected with HBV. METHODS These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women. RESULTS Asian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti-viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3 , basal core promoter (BCP) mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life-long anti-viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life-long surveillance for HCC with alpha-fetoprotein (AFP) testing and abdominal ultrasound examination at 6-month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3-month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence. CONCLUSIONS Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.
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Affiliation(s)
- M. J. Tong
- Pfleger Liver InstituteDivision of Digestive DiseasesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
- Liver CenterHuntington Medical Research InstitutesPasadenaCAUSA
| | - C. Q. Pan
- Division of Gastroenterology and HepatologyNYU Langone Medical CenterNew York University School of MedicineNew YorkNYUSA
| | - S.‐H. B. Han
- Pfleger Liver InstituteDivision of Digestive DiseasesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - D. S.‐K. Lu
- Department of Radiological SciencesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - S. Raman
- Department of Radiological SciencesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - K.‐Q. Hu
- Division of GI/HepatologySchool of MedicineUniversity of California, IrvineOrangeCAUSA
| | - J. K. Lim
- Yale Liver Center and Section of Digestive DiseasesYale University School of MedicineNew HavenCTUSA
| | - H. W. Hann
- Liver Disease Prevention CenterDivision of Gastroenterology and HepatologySidney Kimmel Jefferson Medical College of Thomas Jefferson UniversityPhiladelphiaPAUSA
| | - A. D. Min
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNYUSA
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8
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Mittal S, Kramer JR, Omino R, Chayanupatkul M, Richardson PA, El-Serag HB, Kanwal F. Role of Age and Race in the Risk of Hepatocellular Carcinoma in Veterans With Hepatitis B Virus Infection. Clin Gastroenterol Hepatol 2018; 16:252-259. [PMID: 28870660 DOI: 10.1016/j.cgh.2017.08.042] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 08/20/2017] [Accepted: 08/28/2017] [Indexed: 01/30/2023]
Abstract
BACKGROUND & AIMS Hepatocellular (HCC) surveillance guidelines for patients with chronic hepatitis B virus (HBV) infection are based on race- and age-specific estimates of HCC risk, derived from studies conducted in areas in which HBV is endemic. METHODS We conducted a retrospective cohort study using the national Veterans Administration data to identify patients with chronic HBV infection from 2001 through 2013. We examined the effect of race and age on HCC risk while adjusting for baseline clinical characteristics. RESULTS The study cohort had 8329 patients; 3498 patients (42.0%) were white, 3248 (39%) were African Americans, and 659 (7.9%) were Asian Pacific Islanders. The annual HCC incidence was highest in Asian Pacific Islanders (0.65%), followed by whites (0.57%) and African Americans (0.40%). After adjusting for clinical and viral factors, the risk of HCC was significantly higher in Asian Pacific Islanders compared with whites (adjusted hazard ratio [HR] = 2.04; 95% CI, 1.31-3.17). There was no difference in HCC risk between African Americans and whites (adjusted HR, 0.77; 95% CI, 0.58-1.02). HCC risk increased with age: adjusted HR was 1.97 (95% CI, 0.99-3.87) for 40-49 years; adjusted HR was 3.00 (95% CI, 1.55-5.81) for 50-59 years; and adjusted HR was 4.02 (95% CI, 2.03-7.94) for more than 60 years vs less than 40 years. Patients with cirrhosis had higher risk of HCC than patients without cirrhosis (adjusted HR = 3.69; 95% CI, 2.82-4.83). However, even among patients without cirrhosis, the annual incidence of HCC was more than 0.2% for all patients older than 40 years with high levels of alanine aminotransferase-regardless of race. CONCLUSIONS In a sample of male veterans with chronic HBV infection, risk of HCC is highest among Asian Pacific Islanders, followed by whites and African Americans. Cirrhosis increased HCC risk. Among patients without cirrhosis, male patients who are older than 40 years and have increased levels of alanine aminotransferase might benefit from HCC surveillance, regardless of race.
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Affiliation(s)
- Sahil Mittal
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology, Houston, Texas; Baylor College of Medicine, Houston, Texas.
| | - Jennifer R Kramer
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology, Houston, Texas
| | | | | | - Peter A Richardson
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology, Houston, Texas
| | - Hashem B El-Serag
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology, Houston, Texas; Baylor College of Medicine, Houston, Texas; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Fasiha Kanwal
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology, Houston, Texas; Baylor College of Medicine, Houston, Texas; Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
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Taida T, Arai M, Kanda T, Hige S, Ueno Y, Imazeki F, Izumi N, Tanaka E, Shinkai N, Yoshioka K, Nakamoto Y, Nishiguchi S, Tsuge M, Abe M, Sata M, Yatsuhashi H, Ido A, Kita K, Azemoto R, Kitsukawa Y, Goto N, Yokosuka O. The prognosis of hepatitis B inactive carriers in Japan: a multicenter prospective study. J Gastroenterol 2017; 52:113-122. [PMID: 27306374 DOI: 10.1007/s00535-016-1229-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Accepted: 06/03/2016] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatitis B e antigen (HBeAg)-negative inactive carriers, the majority of hepatitis B virus (HBV) carriers, are considered to have a good prognosis. The definition of the inactive HBV carrier state has been based on HBV DNA and alanine aminotransferase (ALT) levels. Here we conducted a prospective study involving 18 hospitals to clarify the prognosis of HBeAg-negative inactive carriers. METHODS Three hundred eighty-eight HBeAg-negative inactive carriers at the baseline were observed prospectively from January 2011 to November 2015. We evaluated the primary end point, defined as the development of cirrhosis, hepatocellular carcinoma (HCC), or liver-related death. Also, we analyzed the factors associated with inactive carrier dropout and markedly increased levels of ALT or HBV DNA or both during the follow-up period. RESULTS At the baseline, the mean age was 57.5 ± 13.1 years and 42 % of patients were male. No individual developed cirrhosis, HCC, or liver-related death during the follow-up period (1035 ± 252 days). Loss of inactive carrier status was seen in 75 patients (19.3 %). Factors associated with failure to meet the inactive carrier criteria in the multivariate analysis were the levels of ALT (hazard ratio 1.13, 95 % confidence interval 1.07-1.19, p < 0.001), HBV DNA (hazard ratio 2.70, 95 % confidence interval 1.63-4.49, p < 0.001), and γ-glutamyl transpeptidase (hazard ratio 1.01, 95 % confidence interval 1.00-1.02, p = 0.003) at the baseline. CONCLUSIONS Most inactive carriers in Japan had a good prognosis. However, despite the short observation period, some patients had loss of IC status. The long-term prognosis of inactive carriers remains unclear; therefore, careful follow-up of inactive carriers is needed.
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Affiliation(s)
- Takashi Taida
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670, Japan
| | - Makoto Arai
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670, Japan.
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670, Japan
| | - Shuhei Hige
- Department of Gastroenterology, Sapporo-Kosei General Hospital, Sapporo, Hokkaido, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Fumio Imazeki
- Safety and Health Organization, Chiba University, Chiba, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Tokyo, Japan
| | - Eiji Tanaka
- Department of Internal Medicine, Division of Gastroenterology, Shinshu University School of Medicine, Matsumoto, Nagano, Japan
| | - Noboru Shinkai
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Kentaro Yoshioka
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Aichi, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Masanori Abe
- Departments of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama, Ehime, Japan
| | - Michio Sata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, National Hospital Organization (NHO) Nagasaki Medical Center, Omura, Nagasaki, Japan
| | - Akio Ido
- Digestive and Lifestyle Diseases, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
| | - Kazuhiko Kita
- Department of Gastroenterology, Chiba Kaihin Municipal Hospital, Chiba, Japan
| | - Ryousaku Azemoto
- Department of Gastroenterology, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan
| | - Yoshio Kitsukawa
- Department of Gastroenterology, Chiba Aoba Municipal Hospital, Chiba, Japan
| | - Nobuaki Goto
- Department of Gastroenterology, Numazu City Hospital, Numazu, Shizuoka, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Inohana 1-8-1, Chiba, 260-8670, Japan
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10
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Van Hees S, Michielsen P, Vanwolleghem T. Circulating predictive and diagnostic biomarkers for hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2016; 22:8271-8282. [PMID: 27729734 PMCID: PMC5055858 DOI: 10.3748/wjg.v22.i37.8271] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 07/18/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infected patients have an almost 100-fold increased risk to develop hepatocellular carcinoma (HCC). HCC is the fifth most common and third most deadly cancer worldwide. Up to 50% of newly diagnosed HCC cases are attributed to HBV infection. Early detection improves survival and can be achieved through regular screening. Six-monthly abdominal ultrasound, either alone or in combination with alpha-fetoprotein serum levels, has been widely endorsed for this purpose. Both techniques however yield limited diagnostic accuracy, which is not improved when they are combined. Alternative circulating or histological markers to predict or diagnose HCC are therefore urgently needed. Recent advances in systems biology technologies have enabled the identification of several new putative circulating biomarkers. Although results from studies assessing combinations of these biomarkers are promising, evidence for their clinical utility remains low. In addition, most of the studies conducted so far show limitations in design. Attention must be paid for instance to different ethnicities and different etiologies when studying biomarkers for hepatocellular carcinoma. This review provides an overview on the current understandings and recent progress in the field of diagnostic and predictive circulating biomarkers for hepatocellular carcinoma in chronically infected HBV patients and discusses the future prospects.
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11
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Raffetti E, Fattovich G, Donato F. Incidence of hepatocellular carcinoma in untreated subjects with chronic hepatitis B: a systematic review and meta-analysis. Liver Int 2016; 36:1239-51. [PMID: 27062182 DOI: 10.1111/liv.13142] [Citation(s) in RCA: 115] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 03/31/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS In the natural history of hepatitis B virus (HBV) chronic infection, the hepatocellular carcinoma (HCC) risk is unclear. We assessed incidence and predictors of HCC by a systematic review and meta-analysis. METHODS We included longitudinal studies and randomized controlled trials assessing HCC incidence in untreated patients with HBV chronic infection. Incidence rates and their 95% confidence intervals were extracted by each study and pooled together in random effects models. RESULTS Sixty-six studies were included with a total of 347 859 patients. According to liver disease status, the summary incidence rates were in Europe, North America and East Asia, respectively: (a) asymptomatic carriers: 0.07 (95% confidence interval: 0.05-0.09), 0.19 (0.07-0.31) and 0.42 (0.21-0.63) per 100 person-years, respectively; (b) inactive carriers: 0.03 (0.0-0.10), 0.17 (0.02-0.62) and 0.06 (0.02-0.10), respectively; (c) chronic hepatitis: 0.12 (0.0-0.27), 0.48 (0.22-0.91) and 0.49 (0.32-0.66), respectively; (d) compensated cirrhosis (Child-Pugh A): 2.03 (1.30-2.77), 2.89 (1.23-4.55) and 3.37 (2.48-4.26) respectively. Multivariate meta-regression showed a significant increase in incidence rates for age, and for status of a symptomatic carrier, chronic hepatitis and compensated cirrhosis compared to inactive carrier, but not for geographical area after adjusting for age. An increase in the incidence rates was also observed for alcohol intake ≥60 g/dl, HBV genotype C with respect to B and HBV-DNA serum levels >2000 IU/ml, in Asian studies. CONCLUSIONS Hepatocellular carcinoma risk in untreated subjects with HBV chronic infection is strongly related with age and liver disease status.
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Affiliation(s)
- Elena Raffetti
- Unit of Hygiene, Epidemiology and Public Health, University of Brescia, Brescia, Italy
| | | | - Francesco Donato
- Unit of Hygiene, Epidemiology and Public Health, University of Brescia, Brescia, Italy
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12
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Nayagam S, Conteh L, Sicuri E, Shimakawa Y, Suso P, Tamba S, Njie R, Njai H, Lemoine M, Hallett TB, Thursz M. Cost-effectiveness of community-based screening and treatment for chronic hepatitis B in The Gambia: an economic modelling analysis. Lancet Glob Health 2016; 4:e568-78. [PMID: 27443782 DOI: 10.1016/s2214-109x(16)30101-2] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 05/05/2016] [Accepted: 05/23/2016] [Indexed: 12/23/2022]
Abstract
BACKGROUND Despite the high burden of hepatitis B virus (HBV) infection in sub-Saharan Africa, absence of widespread screening and poor access to treatment leads to most people remaining undiagnosed until later stages of disease when prognosis is poor and treatment options are limited. We examined the cost-effectiveness of community-based screening and early treatment with antiviral therapy for HBV in The Gambia. METHODS In this economic evaluation, we combined a decision tree with a Markov state transition model to compare a screen and treat intervention consisting of adult community-based screening using a hepatitis B surface antigen (HBsAg) rapid test and subsequent HBV antiviral therapy versus current practice, in which there is an absence of publicly provided screening or treatment for HBV. We used data from the PROLIFICA study to parameterise epidemiological, primary screening, and cost information, and other model parameter inputs were obtained from a literature search. Outcome measures were cost per disability-adjusted life-year (DALY) averted; cost per life-year saved; and cost per quality-adjusted life-year (QALY) gained. We calculated the incremental cost-effectiveness ratios (ICERs) between current practice and the screen and treat intervention. Costs were assessed from a health provider perspective. Costs (expressed in 2013 US$) and health outcomes were discounted at 3% per year. FINDINGS In The Gambia, where the prevalence of HBsAg is 8·8% in people older than 30 years, adult screening and treatment for HBV has an incremental cost-effectiveness ratio (ICER) of $540 per DALY averted, $645 per life-year saved, and $511 per QALY gained, compared with current practice. These ICERs are in line with willingness-to-pay levels of one times the country's gross domestic product per capita ($487) per DALY averted, and remain robust over a wide range of epidemiological and cost parameter inputs. INTERPRETATION Adult community-based screening and treatment for HBV in The Gambia is likely to be a cost-effective intervention. Higher cost-effectiveness might be achievable with targeted facility-based screening, price reductions of drugs and diagnostics, and integration of HBV screening with other public health interventions. FUNDING European Commission.
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Affiliation(s)
- Shevanthi Nayagam
- Division of Digestive Diseases, St Mary's Hospital, Imperial College, London, UK; Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London, UK.
| | - Lesong Conteh
- Health Economics Group, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London, UK
| | - Elisa Sicuri
- Health Economics Group, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London, UK; ISGlobal, Barcelona Centre for International Health Research (CRESIB), Hospital Clinic, Universitat de Barcelona, Barcelona, Spain
| | - Yusuke Shimakawa
- Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia; Unité d'Épidémiologie des Maladies Émergentes, Institut Pasteur, Paris, France
| | - Penda Suso
- Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia
| | - Saydiba Tamba
- Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia
| | - Ramou Njie
- International Agency for Research on Cancer (IARC), Lyon, France
| | - Harr Njai
- Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia
| | - Maud Lemoine
- Division of Digestive Diseases, St Mary's Hospital, Imperial College, London, UK; Medical Research Council Laboratories, The Gambia Unit, Fajara, The Gambia
| | - Timothy B Hallett
- Department of Infectious Disease Epidemiology, School of Public Health, Imperial College, London, UK
| | - Mark Thursz
- Division of Digestive Diseases, St Mary's Hospital, Imperial College, London, UK
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13
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Tagaram HRS, Desai D, Li G, Liu D, Rountree CB, Gowda K, Berg A, Amin S, Staveley-O'Carroll KF, Kimchi ET. A Selenium Containing Inhibitor for the Treatment of Hepatocellular Cancer. Pharmaceuticals (Basel) 2016; 9:E18. [PMID: 27023566 PMCID: PMC4932536 DOI: 10.3390/ph9020018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 03/11/2016] [Accepted: 03/16/2016] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most deadly cancer in the world. New treatment strategies are desperately needed due to limited standard therapies. Activation of the Erk, Akt, and STAT3pathways is implicated in the prognosis of HCC. The Se,Se'-1,4-phenylenebis(1,2-ethanediyl) bisisoselenourea (PBISe), is a selenium-containing MAPK and PI3 kinase inhibitor, effectively inhibit tumorigenesis in a variety of experimental models. The aim of our study is to demonstrate the potential role of PBISe in the treatment of HCC. The anti-proliferative and pro-apoptotic ability of PBISe is studied in vitro in four human HCC cell lines and in vivo in a spontaneous murine HCC model. Inhibition of cancer growth was performed by cell viability assay and apoptosis by caspase 3/7, PARP cleavage, annexin-V, and TUNEL assays. Role of PBISe on PI3 kinase, MAPK and STAT3 signaling is determined by Western blotting. In vivo effects of PBISe on tumor sizes were monitored using MRI in a spontaneous murine HCC. Liver tissues from the PBISe-treated mice are analyzed for angiogenesis, proliferation, and signaling pathway markers. Overall, PBISe activated caspase-3/7 and increased DNA fragmentation, which is positively correlated with the increased PARP cleavage. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling with significant reduction in the tumor sizes (p < 0.007). PBISe-treated tumors reduced survival marker PCNA, and angiogenesis markers Vegf-A, Vegf-R3 and CD34. These results demonstrate the chemotherapeutic effects of PBISe, by inhibiting tumor growth and facilitating tumor apoptosis for HCC treatment.
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Affiliation(s)
| | - Dhimant Desai
- Department of Pharmacology, Pennsylvania State University, Hershey, PA 17033, USA.
| | - Guangfu Li
- Medical University of South Carolina, Charleston, SC 29425, USA.
| | - Dai Liu
- Medical University of South Carolina, Charleston, SC 29425, USA.
| | - C Bart Rountree
- Bon Secours Pediatric Associates, 5875 Bremo Road, Richmond, VA 23226, USA.
| | - Kavitha Gowda
- Department of Surgery, Pennsylvania State University, Hershey, PA 17033, USA.
| | - Arthur Berg
- Department of Public Health Sciences, Pennsylvania State University, Hershey, PA 17033, USA.
| | - Shantu Amin
- Department of Pharmacology, Pennsylvania State University, Hershey, PA 17033, USA
| | | | - Eric T Kimchi
- Medical University of South Carolina, Charleston, SC 29425, USA.
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14
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Lok ASF, McMahon BJ, Brown RS, Wong JB, Ahmed AT, Farah W, Almasri J, Alahdab F, Benkhadra K, Mouchli MA, Singh S, Mohamed EA, Abu Dabrh AM, Prokop LJ, Wang Z, Murad MH, Mohammed K. Antiviral therapy for chronic hepatitis B viral infection in adults: A systematic review and meta-analysis. Hepatology 2016; 63:284-306. [PMID: 26566246 DOI: 10.1002/hep.28280] [Citation(s) in RCA: 412] [Impact Index Per Article: 45.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 09/23/2015] [Indexed: 01/10/2023]
Abstract
UNLABELLED Chronic hepatitis B viral (HBV) infection remains a significant global health problem. Evidence-based guidelines are needed to help providers determine when treatment should be initiated, which medication is most appropriate, and when treatment can safely be stopped. The American Association for the Study of Liver Diseases HBV guideline methodology and writing committees developed a protocol a priori for this systematic review. We searched multiple databases for randomized controlled trials and controlled observational studies that enrolled adults ≥18 years old diagnosed with chronic HBV infection who received antiviral therapy. Data extraction was done by pairs of independent reviewers. We included 73 studies, of which 59 (15 randomized controlled trials and 44 observational studies) reported clinical outcomes. Moderate-quality evidence supported the effectiveness of antiviral therapy in patients with immune active chronic HBV infection in reducing the risk of cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In immune tolerant patients, moderate-quality evidence supports improved intermediate outcomes with antiviral therapy. Only very low-quality evidence informed the questions about discontinuing versus continuing antiviral therapy in hepatitis B e antigen-positive patients who seroconverted from hepatitis B e antigen to hepatitis B e antibody and about the safety of entecavir versus tenofovir. Noncomparative and indirect evidence was available for questions about stopping versus continuing antiviral therapy in hepatitis B e antigen-negative patients, monotherapy versus adding a second agent in patients with persistent viremia during treatment, and the effectiveness of antivirals in compensated cirrhosis with low-level viremia. CONCLUSION Most of the current literature focuses on the immune active phases of chronic HBV infection; decision-making in other commonly encountered and challenging clinical settings depends on indirect evidence.
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Affiliation(s)
- Anna S F Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Brian J McMahon
- Liver Diseases and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY
| | - John B Wong
- Division of Clinical Decision Making, Tufts Medical Center, Boston, MA
| | - Ahmed T Ahmed
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Wigdan Farah
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Jehad Almasri
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Fares Alahdab
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Khalid Benkhadra
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | | | - Siddharth Singh
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Essa A Mohamed
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | | | | | - Zhen Wang
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN
| | - Mohammad Hassan Murad
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.,Division of Preventive, Occupational and Aerospace Medicine, Mayo Clinic, Rochester, MN
| | - Khaled Mohammed
- Evidence-Based Practice Research Program, Mayo Clinic, Rochester, MN.,Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN.,Division of Preventive, Occupational and Aerospace Medicine, Mayo Clinic, Rochester, MN
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15
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Zhang C, Chen X, Liu H, Li H, Jiang W, Hou W, McNutt MA, Lu F, Li G. Alpha fetoprotein mediates HBx induced carcinogenesis in the hepatocyte cytoplasm. Int J Cancer 2015; 137:1818-1829. [PMID: 25846475 DOI: 10.1002/ijc.29548] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Revised: 03/17/2015] [Accepted: 03/24/2015] [Indexed: 12/14/2022]
Abstract
Although tumor-associated fetal protein AFP has demonstrated utility as a clinical tumor marker, the significance of intracellular AFP is still unclear. The aim of this study was to explore the role of cytoplasmic AFP during HBx induced carcinogenesis, which had not previously been recognized; 614 HCC patients were analyzed for correlation of HBV infection with AFP level, and much higher AFP levels were found in HBsAg positive patients. Tumor tissue specimens from 20 HCC patients were used for analysis of AFP and GADD45α. Analysis of HCC specimens showed that upregulation of cytoplasmic AFP is associated with down-regulation of GADD45α in neoplastic tissue. Transfected HBx promotes transcription of AFP by acting on the elements in the AFP gene regulatory region. HBx itself did not directly impact transcription of GADD45α. However, the obstruction of RAR signaling by HBx induced elevation of AFP, which led to down-regulation of GADD45α. Cytoplasmic AFP was able to interact with RAR, disrupting its entrance into the nucleus and binding to the elements in the regulatory region of the GADD45α gene. Knockdown of AFP in siRNA-transfected AFP positive cell lines was synchronously associated with an incremental increase of RAR binding to DNA, as well as upregulation of GADD45α and it was contrary in AFP gene-transfected AFP negative cell lines. These results indicate cytoplasmic AFP is not only a histochemical tumor biomarker for human hepatoma but is also an intracellular signal molecule and potential participant in HBx induced hepatocarcinogenesis.
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Affiliation(s)
- Chao Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xiangmei Chen
- Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Hui Liu
- Department of Pathology, Beijing You'an Hospital, Beijing, China
| | - Hui Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Wei Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Wenting Hou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Michael A McNutt
- Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Fengmin Lu
- Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Gang Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
- Shenzhen PKU-HKUST Medical Center, Shenzhen, Guangdong, China
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16
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Tong MJ, Huynh TT, Siripongsakun S, Chang PW, Tong LT, Ha YP, Mena EA, Weissman MF. Predicting clinical outcomes in patients with HBsAg-positive chronic hepatitis. Hepatol Int 2015. [PMID: 26219830 DOI: 10.1007/s12072-015-9651-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS The progression of HBsAg-positive chronic hepatitis is insidious and unpredictable. Identification of factors leading to either a benign or more serious clinical outcome may assist in decision making for antiviral therapy. METHODS From 1989 to 1998, 130 untreated patients with chronic hepatitis were enrolled in a prospective study and followed every 3-6 months with liver and virologic tests, platelet counts and alpha-fetoprotein (AFP) measurements. RESULTS During a mean follow-up of 107 ± 86 months, 16 (12.3 %) chronic hepatitis patients progressed to cirrhosis (annual rate 1.4 %), and 23 (17.7 %) reverted to being inactive carriers (annual rate 2.1 %). Compared to baseline values, chronic hepatitis patients who progressed to cirrhosis exhibited declines in mean platelet counts (225.7-195.2 mm(3), p = 0.008-0.04) during the first 4 years of follow-up, while those who reverted to being inactive carriers had substantial reductions in mean levels of AST (83.5-27.2 u/l, p < 0.001-0.002) and ALT (100.2-29.2 u/l, p < 0.001-0.007). In addition, during spontaneous alanine aminotransferase (ALT) flares, patients progressing to cirrhosis had concomitant elevations of AFP levels, while patients who became inactive carriers maintained normal AFP values during ALT flares (13.45 vs. 4.65 ng/ml, p = 0.001). These AFP differences during episodes of ALT flares were similarly observed when analyzed in two separate cohorts of cirrhosis and inactive carrier patients. CONCLUSION Patients with chronic hepatitis who progressed to cirrhosis exhibited declines in platelet counts and had AFP elevations during ALT flares. To prevent progression, serial measurements of these parameters during the chronic hepatitis stage will assist in identifying patients requiring antiviral therapy.
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Affiliation(s)
- Myron John Tong
- Liver Center, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA, 91105, USA.
- Division of Digestive Diseases, The Pfleger Liver Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
| | - Thatcher Thi Huynh
- Liver Center, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA, 91105, USA
| | - Surachate Siripongsakun
- Liver Center, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA, 91105, USA.
- Division of Digestive Diseases, The Pfleger Liver Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
- Chulabhorn Hospital, Bangkok, Thailand.
| | - Patrick Weijen Chang
- Liver Center, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA, 91105, USA
| | - Lori Terese Tong
- Liver Center, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA, 91105, USA
| | - Yen Phi Ha
- Liver Center, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA, 91105, USA
| | - Edward Alphonso Mena
- Liver Center, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA, 91105, USA
| | - Matthew Frank Weissman
- Liver Center, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, CA, 91105, USA
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17
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Thiele M, Gluud LL, Fialla AD, Dahl EK, Krag A. Large variations in risk of hepatocellular carcinoma and mortality in treatment naïve hepatitis B patients: systematic review with meta-analyses. PLoS One 2014; 9:e107177. [PMID: 25225801 PMCID: PMC4167336 DOI: 10.1371/journal.pone.0107177] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 08/14/2014] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The complications to chronic hepatitis B (HBV) include incidence of hepatocellular carcinoma (HCC) and mortality. The risk of these complications may vary in different patient groups. AIM To estimate the incidence and predictors of HCC and in untreated HBV patients. METHODS Systematic review with random effects meta-analyses of randomized controlled trials and observational studies. Results are expressed as annual incidence (events per 100 person-years) with 95% confidence intervals. Subgroup and sensitivity analyses of patient and study characteristics were performed to identify common risk factors. RESULTS We included 68 trials and studies with a total of 27,584 patients (264,919 person-years). In total, 1,285 of 26,687 (5%) patients developed HCC and 730 of 12,511 (6%) patients died. The annual incidence was 0.88 (95% CI, 0.76-0.99) for HCC and 1.26 (95% CI, 1.01-1.51) for mortality. Patients with cirrhosis had a higher risk of HCC (incidence 3.16; 95% CI, 2.58-3.74) than patients without cirrhosis (0.10; 95% CI, 0.02-0.18). The risk of dying was also higher for patients with than patients without cirrhosis (4.89; 95% CI, 3.16-6.63; and 0.11; 95% CI, 0.09-0.14). The risk of developing HCC increased with HCV coinfection, older age and inflammatory activity. The country of origin did not clearly predict HCC or mortality estimates. CONCLUSIONS Cirrhosis was the strongest predictor of HCC incidence and mortality. Patients with HBV cirrhosis have a 31-fold increased risk of HCC and a 44-fold increased mortality compared to non-cirrhotic patients. The low incidence rates should be taken into account when considering HCC screening in non-cirrhotic patients. TRIAL REGISTRATION Prospero CRD42013004764.
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Affiliation(s)
- Maja Thiele
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Lise Lotte Gluud
- Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Denmark
| | - Annette Dam Fialla
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Emilie Kirstine Dahl
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
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18
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Ma WJ, Wang HY, Teng LS. Correlation analysis of preoperative serum alpha-fetoprotein (AFP) level and prognosis of hepatocellular carcinoma (HCC) after hepatectomy. World J Surg Oncol 2013; 11:212. [PMID: 23981851 PMCID: PMC3844510 DOI: 10.1186/1477-7819-11-212] [Citation(s) in RCA: 139] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Accepted: 08/05/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND To investigate the prediction value of preoperative serum alpha-fetoprotein (AFP) level for the prognosis of hepatocellular carcinoma (HCC), by comparing pathological characteristics, recurrence rate and survival rate after hepatectomy. METHODS 108 cases of HCC patients who received liver resection in our hospital from 2005 to 2011 were enrolled in this study. According to preoperative serum AFP level, the patients were divided into AFP ≤ 20 ng/mL group, AFP 20 to 400 ng/mL group and AFP > 400 ng/mL group, and the clinicopathological and cytopathological features were compared. All the patients were followed up for 24 months, the postoperative recurrence rates and survival rates were compared and analyzed, and the risk factors for HCC postoperative survival rate were studied by multifactor regression analysis. RESULTS Of the 108 cases of HCC patients, there were 42 cases in AFP ≤20 ng/mL group, 28 cases in AFP 20-400 ng/mL group and 39 cases in AFP > 400 ng/mL group. It was shown that cell differentiation degrees (χ² = 20.198, P = 0.000) and microvascular invasion rates (χ² = 20.358, P = 0.000) were significantly different among the three groups. The AFP ≤ 20 ng/mL group showed higher cell differentiation degrees and significantly lower microvascular invasion rates compared to the other groups (P < 0.05). The follow-up data showed that postoperative 2-year recurrence rate (χ² = 6.164, P = 0.046), 18-month survival rate (χ² = 7.647, P = 0.022) and 24-month survival rate (χ² = 6.725, P = 0.035) of the three groups were significantly different, and we found that the AFP ≤ 20 ng/mL group had lower postoperative 2-year recurrence rate, and higher 18-month survival rate and 24-month survival rate than the other two groups (P <0.05). Multiple logistic regression analysis indicated that tumor diameter (≥ 5 cm) and preoperative serum AFP level (> 400 ng/mL) were closely correlated with HCC postoperative survival rate (P <0.05). CONCLUSIONS It is shown that preoperative serum AFP level has considerable predictive value for the malignant feature and prognosis of HCC. It is suggested that HCC patients with no contraindication of operation and serum AFP ≤ 20 ng/mL can benefit most from primary treatment of hepatectomy. While HCC patients with serum AFP higher than 20 ng/mL need comprehensive therapy besides surgical resection and close follow up.
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Affiliation(s)
- Wen-jun Ma
- Cancer Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310003, P,R, China.
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Thiele M, Gluud LL, Dahl EK, Krag A. Antiviral therapy for prevention of hepatocellular carcinoma and mortality in chronic hepatitis B: systematic review and meta-analysis. BMJ Open 2013; 3:bmjopen-2013-003265. [PMID: 23945731 PMCID: PMC3752055 DOI: 10.1136/bmjopen-2013-003265] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES The effect of antiviral therapy on clinical outcomes in chronic hepatitis B virus (HBV) is not established. We aimed to assess the effects of interferon and/or nucleos(t)ide analogues versus placebo or no intervention on prevention of hepatocellular carcinoma (HCC) and mortality in chronic HBV. DESIGN Random-effects pairwise meta-analysis of randomised trials and observational studies. SETTING Electronic and manual searches were combined. Randomised controlled trials (RCTs) were included in the primary analyses. Observational studies were included in sensitivity analyses. PRIMARY AND SECONDARY OUTCOME MEASURES The primary outcome measures were HCC incidence and mortality. The secondary outcome measure was HCC mortality. RESULTS We included 8 RCTs, 8 prospective cohort studies and 19 case-control studies with a total of 3433 patients allocated to antiviral therapy and 4625 controls. The maximum duration of follow-up was 23 years. Randomised trials found no effect of antiviral therapy on HCC or mortality. Cohort studies found that antiviral therapy increased the risk of HCC (risk ratio 1.43; 95% CI 1.06 to 1.95), whereas case-control studies found a decreased risk of HCC in the intervention group (risk ratio 0.69; 95% CI 0.54 to 0.88). There was a clear difference between the results of RCTs and observational studies (test for subgroup differences, p<0.001). Antiviral therapy did not affect mortality in cohort studies, but reduced mortality in case-control studies (relative risk 0.71; 95% CI 0.54 to 0.93; test for subgroup differences, p=0.406). CONCLUSIONS The effect of antiviral therapy on clinical outcomes in HBV remains to be established. Although there was a positive effect in the sensitivity analyses, the strength of the evidence does not allow for extrapolation to clinical practice as research design plays an essential role in the overall assessment. TRIAL REGISTRATION NUMBER Prospero number CRD42013003881.
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Affiliation(s)
- Maja Thiele
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Lise L Gluud
- Department of Medicine, Copenhagen University Hospital of Gentofte, Hellerup, Denmark
| | - Emilie K Dahl
- Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
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Abstract
OBJECTIVE Hepatitis B virus (HBV) inactive carriers are HBV e antigen (HBeAg)-negative patients with normal alanine aminotransferase (ALT) levels and HBV DNA of ≤ 10000 copies/mL. We aimed to determine the clinical impact of ALT and HBV DNA elevations during the course of HBV infection. METHODS From January 1989 to January 2012, 146 inactive carriers were prospectively followed every 6-12 months with ALT and HBV DNA measurements and with hepatocellular carcinoma (HCC) surveillance. RESULTS During the follow-up of 8 ± 6.3 years, 56 of the 146 patients maintained ALT ≤ 40 U/L and HBV DNA ≤ 10000 copies/mL. However, 39 had rises of ALT > 40-80 U/L and 4 had ALT > 80 U/L; all except one reverted to baseline values. Also, during follow up, 69 (47.3%) inactive carriers had increases in HBV DNA of > 10000-999999 copies/mL; 38 of these patients' HBV DNA returned to baseline levels, while the remaining 31 patients maintained elevated HBV DNA values but had corresponding ALT of ≤ 40 U/L. There were four liver-related outcomes: 129 (88.4%) remained "inactive carriers", 13 (8.9%) had loss of hepatitis B surface antigen (HBsAg), one (0.7%) had a spontaneous reactivation to HBeAg-negative chronic hepatitis, and two (1.4%) developed HCC. CONCLUSIONS Although the prognosis of inactive carrier is favorable, transient ALT and HBV DNA elevations may be observed but have minimal clinical significance. Moreover, continuous HCC surveillance remains necessary since the risk of development still exists.
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Affiliation(s)
- Myron J Tong
- Liver Center, Huntington Medical Research Institutes, Pasadena, California 91105, USA.
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Incidence of hepatocellular carcinoma among US patients with cirrhosis of viral or nonviral etiologies. Clin Gastroenterol Hepatol 2012; 10:1412-7. [PMID: 22902757 PMCID: PMC3511850 DOI: 10.1016/j.cgh.2012.08.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 08/01/2012] [Accepted: 08/06/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We aimed to identify risk factors for hepatocellular carcinoma (HCC) in patients with cirrhosis in the United States. We performed a prospective study to identify associations between etiologies of cirrhosis and ethnicity with HCC incidence. METHODS We used convenience sampling to select a cohort of 379 patients with cirrhosis who visited the liver clinic at the Stanford University Medical Center from 2001 to 2009 (65% male, 75% white or Hispanic, and 20% Asian). Study end points were HCC diagnosis by histology or noninvasive criteria, liver transplantation, or last screening without HCC. Patients were followed up, with ultrasound or computed tomographic imaging analyses and measurements of serum levels of α-fetoprotein, approximately every 6 months, for a median time of 34 months (range, 6-99 mo). RESULTS The etiologies of cirrhosis in the cohort were 68% hepatitis C, 7% hepatitis B, and 25% nonviral. Forty-four patients (12%) were diagnosed with HCC during the follow-up period. Patients with cirrhosis related to viral hepatitis had a statistically significantly higher incidence of HCC than those with nonviral diseases in Kaplan-Meier analysis (P = .04). There was no statistically significant difference in HCC incidence between Asian and non-Asian patients. In a multivariate Cox proportional hazards model that included age, sex, ethnicity, etiology, and Child-Pugh-Turcotte score, viral cirrhosis was associated significantly with HCC, compared with nonviral cirrhosis (hazard ratio, 3.6; 95% confidence interval, 1.3-10.1; P = .02) but Asian ethnicity was not. CONCLUSIONS In a diverse cohort of patients in the United States with cirrhosis, a viral etiology of cirrhosis was associated with increased incidence of HCC, but Asian ethnicity was not. These findings indicate the importance of cirrhosis etiology in determining risk for HCC.
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Li C, Wang S, Jiang W, Li H, Liu Z, Zhang C, McNutt MA, Li G. Impact of intracellular alpha fetoprotein on retinoic acid receptors-mediated expression of GADD153 in human hepatoma cell lines. Int J Cancer 2012; 130:754-764. [PMID: 21365646 DOI: 10.1002/ijc.26025] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Accepted: 02/17/2011] [Indexed: 12/13/2022]
Abstract
The aim of our study was to gain a better understanding of the molecular mechanism underlying the previously unrecognized role of cytoplasmic alpha fetoprotein (AFP) in retinoic acid receptors (RAR) mediated expression and biological effects of GADD153. Using microarray analysis, the expression of the GADD153 gene showed the greatest fold change among apoptosis/growth related genes in response to ATRA. AFP was able to interact with RAR in HepG2 cells, which was undetectable in HLE cells owing to absence of AFP. ATRA promoted nuclei entrance of RAR, expression of GADD153 and apoptosis, and these changes were reversed after transfection with the afp gene or addition of AGN193109. The level of GADD153 was gradually elevated as the effect of AFP was counteracted by increasing dose or prolonging treatment time with ATRA in HepG2 cells. Knockdown of AFP in siRNA-transfected HepG2 cells or over-expression of AFP in afp gene-transfected HLE cells was synchronously associated with up-regulation or down-regulation, respectively, of GADD153 expression. Both ATRA administration and AFP knockdown were each able to promote greater binding of RAR to its response element with consequent elevation of the proportion of apoptotic cells. Conversely, transfection of HLE cells with pcDNA3.1-afp resulted in apparent reduction of RAR binding to DNA and change of biological effect. These data taken together demonstrate the involvement of AFP in RAR-mediated expression and biological effects of GADD153. These findings provide a novel insight into the mechanism underlying the impact of AFP on the RAR signal network.
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Affiliation(s)
- Chaoying Li
- Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China
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Li P, Wang SS, Liu H, Li N, McNutt MA, Li G, Ding HG. Elevated serum alpha fetoprotein levels promote pathological progression of hepatocellular carcinoma. World J Gastroenterol 2011; 17:4563-4571. [PMID: 22147961 PMCID: PMC3226982 DOI: 10.3748/wjg.v17.i41.4563] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2011] [Revised: 07/28/2011] [Accepted: 08/04/2011] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the biological role of alpha fetoprotein (AFP) and its clinical significance in carcinogenesis of hepatocellular carcinoma (HCC). METHODS Clinical analysis of HCC patients and immunohistochemical examination were conducted to evaluate the relationship between serum AFP level and patient mortality. Confocal microscopy, Western blotting, dimethylthiahzolyl-2,5-diphenyl-tetrazolium bromide, Cell Counting Kit-8 assays and flow cytometry were performed to explore the possible mechanism. RESULTS Among the 160 HCC patients enrolled in this study, 130 patients survived 2 years (81.25%), with a survival rate of 86.8% in AFP < 2 0 μg/L group, 88.9% in AFP 20-250 μg/L group, and 69.6% in AFP > 250 μg/L group, demonstrating a higher mortality rate in HCC patients with higher AFP levels. Surgical treatment was beneficial only in patients with low AFP levels. The mortality rate of HCC patients with high AFP levels who were treated surgically was apparently higher than those treated with conservative management. The results of immunohistochemistry showed that AFP and AFP receptor were merely expressed in tissues of HCC patients with positive serum AFP. Consistently, in vitro analysis showed that AFP and AFPS were expressed in HepG2 but not in HLE cells. AFP showed a capability to promote cell growth, and this was more apparent in HepG2 cells, in which the proliferation was increased by 3.5 folds. Cell cycle analysis showed that the percentage of HepG2 cells in S phase after exposure to AFP was modestly increased. CONCLUSION HCC patients with higher AFP levels show a higher mortality rate, which appears to be attributable to the growth promoting properties of AFP.
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Tong MJ, Pan CQ, Hann HW, Kowdley KV, Han SHB, Min AD, Leduc TS. The management of chronic hepatitis B in Asian Americans. Dig Dis Sci 2011; 56:3143-3162. [PMID: 21935699 DOI: 10.1007/s10620-011-1841-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Accepted: 07/15/2011] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) infection is common with major clinical consequences worldwide. In Asian Americans, the HBsAg carrier rate ranges from 7 to 16%; HBV is the most important cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Patients are first diagnosed at different stages of clinical disease, which is categorized by biochemical and virologic tests. Patients at risk for liver complications should be identified and offered antiviral therapy. The two antiviral agents recommended for first-line treatment of chronic hepatitis B (CHB) are entecavir and tenofovir. The primary goal of therapy is sustained suppression of viral replication to achieve clinical remission, reverse fibrosis, and prevent and reduce progression to end-stage liver disease and HCC. Asian patients with chronic hepatitis, either HBeAg-positive or -negative, with HBV DNA levels >10(4) copies/mL (>2,000 IU/mL) and alanine aminotransferase (ALT) values above normal are candidates for antiviral therapy. HBeAg-negative patients with HBV DNA >10(4) copies/mL (>2,000 IU/mL) and normal ALT levels but who have either serum albumin ≤3.5 g/dL or platelet count ≤130,000 mm(3), basal core promoter mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive antiviral therapy. Considerations for treatment include pregnant women with high viremia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg-positive patients with risk factors, lifelong surveillance for HCC with alpha-fetoprotein testing and abdominal ultrasound examination at 6-month intervals is required. These recommendations are based on a review of relevant literature and the opinion of a panel of Asian American physicians with expertise in hepatitis B treatment.
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Affiliation(s)
- Myron J Tong
- Pfleger Liver Institute, Division of Digestive Diseases, University of California School of Medicine, Los Angeles, CA, USA.
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25
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Li CY, Li G. Biological functions of alpha-fetoprotein. Shijie Huaren Xiaohua Zazhi 2011; 19:1436-1440. [DOI: 10.11569/wcjd.v19.i14.1436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Alpha-fetoprotein (AFP) is a well-known biomarker for the diagnosis of hepatocellular carcinoma. Extracellular AFP can act as a carrier to transport a variety of ligands or as a growth regulator to control the growth of tumor cells, while intracellular AFP can bind to and interact with transcription factors or some key proteins and function as a signal molecule to regulate cell proliferation or apoptosis. This paper provides novel insights into the mechanisms underlying the role of AFP in carcinogenesis and tumor chemotherapy.
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Tong MJ, Hsu L, Chang PW, Blatt LM. Evaluation of current treatment recommendations for chronic hepatitis B: a 2011 update. J Gastroenterol Hepatol 2011; 26:829-35. [PMID: 21214888 DOI: 10.1111/j.1440-1746.2011.06623.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIM Guidelines for the treatment of chronic hepatitis B have been recently updated in the 2009 European Association for the Study of the Liver consensus statement, the 2008 US Panel, the 2008 Asian-Pacific consensus statement, and the 2009 American Association for the Study of Liver Disease practice guidelines. We sought to determine whether these guidelines identified patients who developed hepatocellular carcinoma (HCC) or who died of non-HCC liver-related deaths for antiviral therapy. METHODS The criteria described in the new treatment guidelines were matched to the database of 369 hepatitis B surface antigen-positive patients, in whom 30 developed HCC and 37 died of non-HCC liver-related deaths during a mean follow up of 84 months. RESULTS Using criteria for antiviral therapy as stated by the four current guidelines, 19-30% of patients who died of non-HCC liver-related complications, and 23-53% of patients who developed HCC, would have been excluded for antiviral therapy. If baseline serum albumin levels of ≤ 3.5 g/dL or platelet counts of ≤ 130,000 mm(3) were included into the treatment criteria, then 85-94% of patients who developed liver-related complications would have been recommended for antiviral therapy. Also, the addition of precore A1896 mutants and basal core promoter T1762/A1764 mutants would have identified 98.5-100% of these patients. CONCLUSION The updated treatment guidelines for hepatitis B still excluded patients who developed serious liver-related complications. The inclusion of baseline serum albumin and platelet counts to current criteria would have identified a majority of these patients for antiviral therapy. These tests should be included into hepatitis B treatment strategies.
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Affiliation(s)
- Myron John Tong
- Pfleger Liver Institute and the Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
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Thomas MB, Jaffe D, Choti MM, Belghiti J, Curley S, Fong Y, Gores G, Kerlan R, Merle P, O'Neil B, Poon R, Schwartz L, Tepper J, Yao F, Haller D, Mooney M, Venook A. Hepatocellular carcinoma: consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 2010; 28:3994-4005. [PMID: 20679622 DOI: 10.1200/jco.2010.28.7805] [Citation(s) in RCA: 315] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocelluar carcinoma (HCC) is the most common primary malignancy of the liver in adults and the third most common cause of cancer death worldwide. The incidence of HCC in the United States is rising steadily because of the prevalence of hepatitis C viral infection and other causes of hepatic cirrhosis. The majority of patients have underlying hepatic dysfunction, which complicates patient management and the search for safe and effective therapies. The Clinical Trials Planning Meeting (CTPM) in HCC was convened by the National Cancer Institute's Gastrointestinal Cancer Steering Committee to identify the key knowledge gaps in HCC and define clinical research priorities. The CTPM structured its review according to current evidence-based treatment modalities in HCC and prioritized the recommendations on the basis of the patient populations representing the greatest unmet medical need.
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Affiliation(s)
- Melanie B Thomas
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
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Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and the third leading cause of cancer-related deaths. More than 80% of HCC cases are from the Asian and African continents, and more than 50% of cases are from mainland China. Approximately 350 million to 400 million persons are chronically infected with hepatitis B virus (HBV), and this virus is the most common cause of HCC worldwide. It is estimated that more than 50% of liver cancers worldwide are attributable to HBV and up to 89% of HBV-related HCC are from developing countries. Recently, increasing trends in HCC incidence have been reported from several Western countries, including France, Australia, and the United States.
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Affiliation(s)
- Amy C McClune
- Dumont-UCLA Liver Transplant Center, David Geffen School of Medicine at UCLA, The Pfleger Liver Institute, Los Angeles, CA 90095-7302, USA.
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Tong MJ, Hsu L, Hsien C, Kao JH, Durazo FA, Saab S, Blatt LM. A comparison of hepatitis B viral markers of patients in different clinical stages of chronic infection. Hepatol Int 2010; 4:516-22. [PMID: 20827410 PMCID: PMC2896649 DOI: 10.1007/s12072-010-9179-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2009] [Accepted: 03/05/2010] [Indexed: 12/22/2022]
Abstract
Purpose Hepatitis B viral markers may be useful for predicting outcomes such as liver-related deaths or development of hepatocellular carcinoma. We determined the frequency of these markers in different clinical stages of chronic hepatitis B infection. Methods We compared baseline hepatitis B viral markers in 317 patients who were enrolled in a prospective study and identified the frequency of these tests in immune-tolerant (IT) patients, in inactive carriers, and in patients with either hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis or cirrhosis. Results IT patients were youngest (median age 27 years) and HBeAg-negative patients with cirrhosis were oldest (median age 58 years) (p = 0.03 to <0.0001). The male to female ratio was similar both in IT patients and in inactive carriers, but there was a male preponderance both in patients with chronic hepatitis and in patients with cirrhosis (p < 0.0001). The A1896 precore mutants were most prevalent in inactive carriers (36.4%) and HBeAg-negative patients with chronic hepatitis (38.8%; p < 0.0001), and the T1762/A1764 basal core promoter mutants were most often detected in HBeAg-negative patients with cirrhosis (65.1%; p = 0.02). Genotype A was detected only in 5.3% of IT patients, and genotype B was least often detected in both HBeAg-Positive patients with chronic hepatitis and cirrhosis (p = 0.03). The hepatitis B viral DNA levels were lowest in inactive carriers (2.69 log10 IU/mL) and highest in IT patients (6.80 log10 IU/mL; p = 0.02 to <0.0001). At follow-up, HBeAg-positive and HBeAg-negative patients with cirrhosis accounted for 57 of 64 (89.1%) liver-related deaths (p < 0.0001). Conclusion Differences in baseline hepatitis B viral markers were detected in patients in various clinical stages of hepatitis B virus infection. HBeAg-positive and HBeAg-negative patients with cirrhosis accounted for the majority of the liver-related fatalities.
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Affiliation(s)
- Myron John Tong
- Division of Digestive Diseases, The Pfleger Liver Institute, David Geffen School of Medicine, University of California in Los Angeles, Los Angeles, CA USA
- The Liver Center, Huntington Medical Research Institutes, 660 S. Fair Oaks Ave, Pasadena, CA 91105 USA
| | - Leeyen Hsu
- The Liver Center, Huntington Medical Research Institutes, 660 S. Fair Oaks Ave, Pasadena, CA 91105 USA
| | - Carlos Hsien
- The Liver Center, Huntington Medical Research Institutes, 660 S. Fair Oaks Ave, Pasadena, CA 91105 USA
| | - Jia-Horng Kao
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Francisco Antonio Durazo
- Division of Digestive Diseases, The Pfleger Liver Institute, David Geffen School of Medicine, University of California in Los Angeles, Los Angeles, CA USA
| | - Sammy Saab
- Division of Digestive Diseases, The Pfleger Liver Institute, David Geffen School of Medicine, University of California in Los Angeles, Los Angeles, CA USA
| | - Lawrence Mitchell Blatt
- Division of Digestive Diseases, The Pfleger Liver Institute, David Geffen School of Medicine, University of California in Los Angeles, Los Angeles, CA USA
- Alios Biopharma, South San Francisco, CA USA
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