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1
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Hu Y, Zhang Y, Jiang W. Targeting hepatitis B virus-associated nephropathy: efficacy and challenges of current antiviral treatments. Clin Exp Med 2025; 25:57. [PMID: 39954162 PMCID: PMC11829913 DOI: 10.1007/s10238-025-01584-4] [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: 01/07/2025] [Accepted: 02/02/2025] [Indexed: 02/17/2025]
Abstract
Hepatitis B virus (HBV) infection remains a major global health challenge, affecting approximately 296 million people and causing significant mortality annually. Despite vaccination efforts, HBV prevalence persists, particularly in low- and middle-income regions and endemic areas like China. HBV is closely associated with various kidney diseases, including acute kidney injury, chronic kidney disease, and glomerulonephritis, through mechanisms such as immune complex deposition, direct viral invasion, and chronic inflammation. Patients undergoing hemodialysis or kidney transplantation are at increased risk of HBV infection and reactivation, highlighting the need for effective preventive and therapeutic measures. This review examines the classification and clinical features of HBV-associated nephropathy, focusing on membranous nephropathy and membranoproliferative glomerulonephritis. It explores the pathogenesis, emphasizing immune complex deposition and podocyte apoptosis. Antiviral therapy, particularly with nucleos(t)ide analogs like entecavir and tenofovir (including TAF and TMF), demonstrates superior efficacy and safety compared to older agents such as lamivudine and adefovir. While interferon therapy offers benefits, its use is limited by adverse effects. Additionally, individualized treatment strategies for specific populations, including pregnant women and HIV co-infected patients, are crucial. Addressing HBV-associated nephropathy requires enhanced surveillance, timely antiviral intervention, and tailored therapeutic approaches to improve patient outcomes.
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Affiliation(s)
- Yongzheng Hu
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Yue Zhang
- Department of Stomatology, Qingdao Municipal Hospital, University of Health and Rehabilitation Sciences, Qingdao, Shandong, China
| | - Wei Jiang
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China.
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2
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He W, Zheng Z, Zhao Q, Zhang R, Zheng H. Targeting HBV cccDNA Levels: Key to Achieving Complete Cure of Chronic Hepatitis B. Pathogens 2024; 13:1100. [PMID: 39770359 PMCID: PMC11728772 DOI: 10.3390/pathogens13121100] [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: 11/14/2024] [Revised: 12/07/2024] [Accepted: 12/11/2024] [Indexed: 01/16/2025] Open
Abstract
Chronic hepatitis B (CHB) caused by HBV infection has brought suffering to numerous people. Due to the stable existence of HBV cccDNA, the original template for HBV replication, chronic hepatitis B (CHB) is difficult to cure completely. Despite current antiviral strategies being able to effectively limit the progression of CHB, complete CHB cure requires directly targeting HBV cccDNA. In this review, we discuss strategies that may achieve a complete cure of CHB, including inhibition of cccDNA de novo synthesis, targeting cccDNA degradation through host factors and small molecules, CRISP-Cas9-based cccDNA editing, and silencing cccDNA epigenetically.
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Affiliation(s)
- Wei He
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China; (W.H.); (Z.Z.)
- MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China
| | - Zhijin Zheng
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China; (W.H.); (Z.Z.)
- MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China
| | - Qian Zhao
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China; (W.H.); (Z.Z.)
- MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China
| | - Renxia Zhang
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China; (W.H.); (Z.Z.)
- MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China
| | - Hui Zheng
- Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, Jiangsu, China; (W.H.); (Z.Z.)
- MOE Key Laboratory of Geriatric Disease and Immunology of Ministry of Education of China, Collaborative Innovation Center of Hematology, International Institute of Infection and Immunity, Institutes of Biology and Medical Sciences (IBMS), School of Medicine, Soochow University, Suzhou 215123, Jiangsu, China
- Department of Laboratory Medicine, Institute of Laboratory Medicine, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 611731, Sichuan, China
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3
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Ohlendorf V, Bremer B, Sandmann L, Mix C, Tergast T, Cornberg M, Wedemeyer H, Deterding K, Maasoumy B. Limited stability of Hepatitis B virus RNA in plasma and serum. Sci Rep 2024; 14:27128. [PMID: 39511219 PMCID: PMC11543676 DOI: 10.1038/s41598-024-77329-2] [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: 03/16/2024] [Accepted: 10/22/2024] [Indexed: 11/15/2024] Open
Abstract
Pregenomic hepatitis B virus RNA (HBV pgRNA) is a potential biomarker in the management of HBV infected patients. However, prior to the use in routine clinical practice potential confounders of test results need to be identified. This study investigates the stability of HBV pgRNA under various storage conditions. HBV-RNA level of 26 HBV patients were determined using the Roche cobas® 6800/8800 investigational HBV-RNA assay. Plasma and serum were stored for 6,48,169 h at 4,25 and 42 °C, respectively. Additionally, 10 serum and plasma samples underwent 4 or 11 cycles of freezing (-80 °C) and thawing (25 °C). A significant decline in mean pgRNA concentration compared to baseline was observed after storage for 48 h at 25 °C as well as after 6 h of storage at 42 °C. Accordingly, sub-analyses of predefined pgRNA baseline concentrations (≤ 10 cp/mL, > 10-100 cp/ml, > 100 cp/mL) revealed significant changes in pgRNA level after storage at 25 and 42 °C. No effect of freezing and thawing on pgRNA level was observed. A qualitative detection of HBV pgRNA is feasible in samples with > 100 cp/mL up to 48 h under storage temperatures of 4-42 °C. For most stable quantitative HBV pgRNA values storage at 4 °C should be preferred.
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Affiliation(s)
- Valerie Ohlendorf
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Birgit Bremer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Lisa Sandmann
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Carola Mix
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Tammo Tergast
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
- Centre for Individualised Infection Medicine (CiiM), A Joint Venture of Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany
- Centre for Experimental and Clinical Infection Research, A Joint Venture between the Hanover Medical School and the Helmholtz Centre for Infection Research, TWINCORE, Braunschweig, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Katja Deterding
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
- German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany.
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Hige S, Aoki K, Nakamoto D, Flaherty JF, Botros I, Mizutani H, Ishizaki A, Konishi H, Yuan J, Jinushi M, Ng LJ. Real-world safety and effectiveness of tenofovir alafenamide for 144 weeks in Japanese patients with chronic hepatitis B. J Viral Hepat 2024; 31:165-175. [PMID: 38163911 DOI: 10.1111/jvh.13912] [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: 08/17/2023] [Revised: 11/17/2023] [Accepted: 12/13/2023] [Indexed: 01/03/2024]
Abstract
Tenofovir alafenamide (TAF), a prodrug of tenofovir, delivers high levels of active drug to hepatocytes and is given in a lower dose than tenofovir disoproxil fumarate (TDF). TAF reduces viral replication in patients with chronic hepatitis B (CHB) similar to TDF and has shown a lower risk of the renal and bone toxicities associated with TDF use. This post-marketing surveillance study examined the safety and effectiveness of TAF in treatment-naïve and -experienced CHB patients who received TAF for 144 weeks at real-world clinical sites in Japan. Safety assessments included the incidence of adverse drug reactions (ADRs), renal and bone events, and changes in selected laboratory parameters. Effectiveness was based on the proportion of patients with HBV DNA levels below the lower limit of quantitation or <29 IU/mL. This analysis included 580 patients; 18.4% of whom were treatment-naïve. The cumulative incidence of ADRs was 0.21 per 100 person-months, and the incidence of serious ADRs was 0.01 (95% CI, 0.00-0.04) per 100 person-months. There were no ADRs of declines in estimated glomerular filtration rates, renal failure or proximal tubulopathy. The most common ADR was hypophosphataemia in seven (1.2%) patients. Two (0.4%) patients each had decreased blood phosphorus, bone mineral density decreased, dizziness and alopecia. Overall, the proportion of virologically suppressed patients increased from 68.8% at baseline to 97.5% at Week 144. These results confirm the real-world safety and effectiveness of TAF in Japanese patients with CHB and are consistent with the findings of other evaluations of the safety and efficacy of TAF in CHB.
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Affiliation(s)
- Shuhei Hige
- Department of Gastroenterology, Sapporo-Kosei General Hospital, Sapporo, Japan
| | - Kouji Aoki
- Gilead Sciences K.K., Chiyoda-Ku, Tokyo, Japan
| | | | | | - Irina Botros
- Gilead Sciences, Inc., Foster City, California, USA
| | | | | | | | - Jason Yuan
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Leslie J Ng
- Gilead Sciences, Inc., Foster City, California, USA
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Zeleke TK, Bazezew ZA, Abebe RB. The Burden of Inappropriate Prescriptions and Predictors for Hospitalized Patients with Liver Cirrhosis in Ethiopia. Hepat Med 2023; 15:129-140. [PMID: 37790886 PMCID: PMC10542506 DOI: 10.2147/hmer.s423351] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 09/14/2023] [Indexed: 10/05/2023] Open
Abstract
Background Pathophysiological alterations in liver cirrhosis affect how medications are metabolized and eliminated. Therefore, when prescribing medicines for patients with cirrhosis, appropriate prescription of medication is an accepted standard of practice. Since patients with cirrhosis require a complex therapy plan, it necessitates regular reviews of medication utilization. However, no research was conducted in Ethiopia. The aim of this study was to figure out the predictors of inappropriate prescriptions and the pattern of prescription in patients with cirrhosis. Patients and methods A cross-sectional study design was carried out at Felege-Hiwot, a specialized and comprehensive referral hospital, from June 30, 2022, to November 30, 2022, in 123 hospitalized patients with cirrhosis. Patients were recruited using a simple random sampling procedure, and data were collected using an interviewer-administered questionnaire. For the purpose of identifying determinants of inappropriate prescription, logistic regression analyses have been carried out and statistical significance was defined by a p-value of less than 0.05 and a 95% confidence range. Results The burden of inappropriate prescriptions among patients with cirrhosis was 35.8%. An increased number of medications prescribed (AOR = 4.88 (1.05-22.68)), prescription by a general practitioner (AOR = 3.57 (95% CI 1.07-11.44)), increased level of bilirubin (AOR = 3.54 (95% CI 1.95-6.45)), and decreased level of albumin (AOR = 0.18 (95% CI 0.04-0.72)) were predictors for an inappropriate prescription. Conclusion It has been found that there were inappropriate prescriptions among patients with liver cirrhosis. Prescribers should pay close attention to patients who have prescribed with higher number of medications, increased level of bilirubin and decreased level of albumin. Moreover, educational level of prescribers needs to be upgraded in order to adopt evidence-based medication prescriptions and adhere to recommended practices.
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Affiliation(s)
- Tirsit Ketsela Zeleke
- Department of Pharmacy, College of Medicine and Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Zegaye Agmassie Bazezew
- Department of Pharmacy, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
| | - Rahel Belete Abebe
- Department of Clinical Pharmacy, School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Ward JW, Wanlapakorn N, Poovorawan Y, Shouval D. Hepatitis B Vaccines. PLOTKIN'S VACCINES 2023:389-432.e21. [DOI: 10.1016/b978-0-323-79058-1.00027-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Ohlendorf V, Wübbolding M, Gineste P, Höner Zu Siederdissen C, Bremer B, Wedemeyer H, Cornberg M, Maasoumy B. Low anti-HBc levels are associated with lower risk of virological relapse after nucleos(t)ide analogue cessation in HBe antigen-negative patients. Liver Int 2022; 42:2674-2682. [PMID: 36152268 DOI: 10.1111/liv.15433] [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: 05/20/2022] [Revised: 07/25/2022] [Accepted: 09/06/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Low anti-HBc serum levels at the time of therapy cessation were linked to a higher relapse risk in predominantly HBeAg-positive cohorts. We investigated the association of anti-HBc levels with relapse in HBeAg-negative patients. METHODS Serum levels of anti-HBc, HBsAg and HBcrAg were determined in 136 HBeAg-negative patients, participating in a vaccination trial (ABX-203, NCT02249988), before treatment cessation or vaccination. Importantly, vaccination showed no impact on relapse. The correlation between the biomarkers and their predictive value for relapse (HBV DNA >2000 IU/ml ± ALT >2xULN) was investigated. RESULTS After therapy cessation 50% (N = 68) of patients relapsed. Median anti-HBc prior to treatment stop was significantly higher among relapsers compared to off-treatment responders (520 IU/ml vs. 330 IU/mL, p = .0098). The optimal anti-HBc cut-off to predict relapse was 325 IU/ml according to the Youden-Index. About 35% of patients with anti-HBc level < 325 IU/ml versus 60% of those with values ≥325 IU/mL relapsed (p = .0103; sensitivity 50%, specificity 75%). Combining the optimal cut-offs of HBsAg (>3008 IU/mL) or HBcrAg (≥1790 U/ml) with anti-HBc increased the proportion of patients with relapse to 80% (p < .0001) and 74% (p = .0006), respectively. CONCLUSION In contrast to predominantly HBeAg-positive cohorts, in our cohort of HBeAg-negative patients lower anti-HBc levels are associated with a significantly lower relapse risk after nucleos(t)ide analogue cessation. The vast majority of included patients were either genotype B or C and the applicability to other genotypes has to be further evaluated. However, anti-HBc level as an indicator of the host response might be prospectively further explored for prediction models.
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Affiliation(s)
- Valerie Ohlendorf
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Maximilian Wübbolding
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Centre for Individualized Infection Medicine (CiiM), a joint venture of Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, Hannover, Germany
| | | | | | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, Hannover, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Centre for Individualized Infection Medicine (CiiM), a joint venture of Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, Hannover, Germany
| | - Benjamin Maasoumy
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.,Centre for Individualized Infection Medicine (CiiM), a joint venture of Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany.,German Center for Infection Research (DZIF), Partner-Site Hannover-Braunschweig, Hannover, Germany
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8
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Tian F, Feld JJ, Feng Z, Sander B, Wong WWL. Feasibility of hepatitis B elimination in high-income countries with ongoing immigration. J Hepatol 2022; 77:947-956. [PMID: 35483535 DOI: 10.1016/j.jhep.2022.04.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 04/11/2022] [Accepted: 04/13/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Addressing HBV is vital to meeting the World Health Organization (WHO)'s viral hepatitis elimination goals, as 47% of viral hepatitis complications can be attributed to HBV. The objective of this study is to develop an agent-based model determining which integrated strategies involving vaccination, screening, and treatment would achieve the WHO's goals. METHODS We developed an agent-based model to characterize the HBV epidemic in a high-income country with ongoing immigration. The spread of HBV was simulated through sexual networks and perinatal transmission. Model parameters were estimated from the literature and calibrated against historical HBV data. Sensitivity analyses were performed to assess the uncertainty. RESULTS We predict that under the current strategies, the incidence of acute hepatitis B, and HBV-attributable decompensated cirrhosis and hepatocellular carcinoma would decrease by 64.5%, 9.4%, and 10.5% between 2015-2030, respectively. However, the incidence of chronic hepatitis B and liver-related deaths would increase by 26.6% and 1.0% between 2015-2030, respectively. Results were sensitive to the number of immigrants and HBV prevalence in immigrants. CONCLUSIONS The results suggest that the current vaccination, screening, and treatment strategies will be inadequate to achieve WHO elimination goals. Even with extensive integrated scale-up in vaccination, screening, and treatment, the morbidity and mortality targets may not be reachable, highlighting the need for a re-evaluation of the global strategy for HBV, the importance of developing curative therapy for HBV, and of establishing tailored strategies to prevent long-term sequelae and improve health in immigrants. LAY SUMMARY We have developed a model that reflects the dynamics of hepatitis B virus (HBV) transmission in a high-income country with ongoing immigration, which enabled us to forecast the epidemiology of HBV for policy-level decision making. Our analysis suggests that current vaccination, screening, and treatment strategies are inadequate to achieve the WHO goals of eliminating chronic hepatitis B. Even with extensive integrated scale-up in vaccination, screening, and treatment, the morbidity and mortality targets may not be reachable.
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Affiliation(s)
- Feng Tian
- School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Zeny Feng
- Department of Mathematics and Statistics, University of Guelph, Guelph, Ontario, Canada
| | - Beate Sander
- Toronto Health Economics and Technology Assessment Collaborative (THETA), University Health Network, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; ICES, Toronto, Ontario, Canada; Public Health Ontario, Toronto, Ontario, Canada
| | - William W L Wong
- School of Pharmacy, University of Waterloo, Kitchener, Ontario, Canada; Toronto Health Economics and Technology Assessment Collaborative (THETA), University Health Network, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; ICES, Toronto, Ontario, Canada.
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Abstract
The last few years have seen a resurgence of activity in the hepatitis B drug pipeline, with many compounds in various stages of development. This review aims to provide a comprehensive overview of the latest advances in therapeutics for chronic hepatitis B (CHB). We will discuss the broad spectrum of direct-acting antivirals in clinical development, including capsids inhibitors, siRNA, HBsAg and polymerase inhibitors. In addition, host-targeted therapies (HTT) will be extensively reviewed, focusing on the latest progress in immunotherapeutics such as toll-like receptors and RIG-1 agonists, therapeutic vaccines and immune checkpoints modulators. A growing number of HTT in pre-clinical development directly target the key to HBV persistence, namely the covalently closed circular DNA (cccDNA) and hold great promise for HBV cure. This exciting area of HBV research will be highlighted, and molecules such as cyclophilins inhibitors, APOBEC3 deaminases and epigenetic modifiers will be discussed.
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Affiliation(s)
- Sandra Phillips
- Institute of Hepatology Foundation for Liver Research London UK, School of Immunology and Microbial Sciences King's College London, UK
| | - Ravi Jagatia
- Institute of Hepatology Foundation for Liver Research London UK, School of Immunology and Microbial Sciences King's College London, UK
| | - Shilpa Chokshi
- Institute of Hepatology Foundation for Liver Research London UK, School of Immunology and Microbial Sciences King's College London, UK
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10
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Novel Neplanocin A Derivatives as Selective Inhibitors of Hepatitis B Virus with a Unique Mechanism of Action. Antimicrob Agents Chemother 2022; 66:e0207321. [PMID: 35604213 DOI: 10.1128/aac.02073-21] [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: 11/20/2022] Open
Abstract
Novel neplanocin A derivatives have been identified as potent and selective inhibitors of hepatitis B virus (HBV) replication in vitro. These include (1S,2R,5R)-5-(5-bromo-4-methyl-7H-pyrrolo[2,3-d]-pyrimidin-7-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol (AR-II-04-26) and (1S,2R,5R)-5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-(hydroxylmethyl)cyclopent-3-ene-1,2-diol (MK-III-02-03). The 50% effective concentrations of AR-II-04-26 and MK-III-02-03 were 0.77 ± 0.23 and 0.83 ± 0.36 μM in HepG2.2.15.7 cells, respectively. These compounds reduced intracellular HBV RNA levels in HepG2.2.15.7 cells and infected primary human hepatocytes. Accordingly, they could reduce HBs and HBe antigen production in the culture supernatants, which was not observed with clinically approved anti-HBV nucleosides and nucleotides (reverse transcriptase inhibitors). The neplanocin A derivatives also inhibited HBV RNA derived from cccDNA. In addition, unlike neplanocin A itself, the compounds did not inhibit S-adenosyl-l-homocysteine hydrolase activity. Thus, it appears that the mechanism of action of AR-II-04-26 and MK-III-02-03 differs from that of the clinically approved anti-HBV agents. Although their exact mechanism (target molecule) remains to be elucidated, the novel neplanocin A derivatives are considered promising candidate drugs for inhibition of HBV replication.
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11
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Burdette DL, Lazerwith S, Yang J, Chan HLY, Delaney IV WE, Fletcher SP, Cihlar T, Feierbach B. Ongoing viral replication and production of infectious virus in patients with chronic hepatitis B virus suppressed below the limit of quantitation on long-term nucleos(t)ide therapy. PLoS One 2022; 17:e0262516. [PMID: 35363817 PMCID: PMC8974970 DOI: 10.1371/journal.pone.0262516] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 12/28/2021] [Indexed: 01/05/2023] Open
Abstract
Nucleos(t)ide analogs are standard-of-care for the treatment of chronic hepatitis B and can effectively reduce hepatitis B virus (HBV) replication but rarely leads to cure. Nucleos(t)ide analogs do not directly eliminate the viral episome, therefore treatment cessation typically leads to rapid viral rebound. While treatment is effective, HBV DNA is still detectable (although not quantifiable) in the periphery of the majority of nucleos(t)ide analog treated HBV patients, even after prolonged treatment. Addressing whether the detectable HBV DNA represents infectious virus is a key unknown and has important implications for the development of a curative treatment for HBV. The minimum HBV genome equivalents required to establish infection in human liver chimeric mice was determined by titration of HBV patient sera and the infectivity in chimeric mice of serum from patients (n = 7) suppressed to the limit of detection on nucleos(t)ide analog therapy was evaluated. A minimum of 5 HBV genome equivalents were required to establish infection in the chimeric mice, confirming this model has sufficient sensitivity to determine whether serum from virally suppressed patients contains infectious virus. Strikingly, serum from 75% (n = 3 out of 4) of nucleos(t)ide-treated HBV patients with DNA that was detectable, but below the lower limit of quantitation, also established infection in the chimeric mice. These results demonstrate that infectious virus is still present in some HBV patients on suppressive nucleos(t)ide therapy. This residual virus may support viral persistence via continuous infection and explain the ongoing risk for HBV-related complications despite long-term suppression on therapy. Thus, additional treatment intensification may facilitate HBV cure.
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Affiliation(s)
- Dara L Burdette
- Discovery Virology, Gilead Sciences, Foster City, CA, United States of America
| | - Scott Lazerwith
- Medicinal Chemistry, Gilead Sciences, Foster City, CA, United States of America
| | - Jenny Yang
- Clinical Research, Gilead Sciences, Foster City, CA, United States of America
| | | | | | - Simon P. Fletcher
- Discovery Virology, Gilead Sciences, Foster City, CA, United States of America
| | - Tomas Cihlar
- Discovery Virology, Gilead Sciences, Foster City, CA, United States of America
| | - Becket Feierbach
- Clinical Virology, Gilead Sciences, Foster City, CA, United States of America
- * E-mail:
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Yamashige D, Hosaka T, Suzuki F, Fujiyama S, Kawamura Y, Sezaki H, Akuta N, Kobayashi M, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kobayashi M, Kumada H. Effectiveness of tenofovir alafenamide for chronic hepatitis B patients with a poor response to the previously used nucleos(t)ide analogs. J Gastroenterol 2021; 56:1008-1021. [PMID: 34596753 DOI: 10.1007/s00535-021-01826-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Accepted: 09/10/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Few studies have demonstrated the potency of tenofovir alafenamide (TAF) in patients with poor response to other nucleos(t)ide analogs (NAs). METHODS We conducted a retrospective study comprising consecutive 40 patients exhibiting a poor response to other NAs, who subsequently received TAF-containing regimens. The primary outcome was the prevalence of virological response (VR) at each time and maintained virological response (MVR) under TAF-containing regimens until week 96. RESULTS In the entire cohort, the prevalence of MVR was 71.1% (27/38). Further, poor tenofovir disoproxil fumarate (TDF) response was significantly associated with a lower prevalence of MVR (p = 0.014). In TDF-naïve patients, the prevalence of MVR was 92.3% (12/13) and 62.5% (5/8) in patients with lamivudine resistance (LAM-r) and entecavir resistance (ETV-r), respectively. Further, viral load and HBeAg status at baseline were associated with a lower prevalence of MVR (p = 0.013). Among the seven patients with prior TDF exposure, 2 patients achieved MVR. Among them, one patient with development of viral breakthrough during TDF/LAM achieved MVR after switching to TAF/ETV. In contrast, one of the five patients with non-MVR had three substitutions (rtS106C, rtD134N/S, and rtL269I) of quadruple mutations in addition to ETV-r. Other patients with rtA181T + rtN236T also could not achieve MVR. CONCLUSION TAF exhibited high antiviral potency in patients with LAM-r and ETV-r. However, TAF potency was associated with previous TDF response, viral load, and HBeAg status at baseline. Additionally, a quadruple mutation may impact tenofovir resistance; however, further studies are needed to verify this.
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Affiliation(s)
- Daiki Yamashige
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Tetsuya Hosaka
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan.
| | - Fumitaka Suzuki
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Shunichiro Fujiyama
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yusuke Kawamura
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Hitomi Sezaki
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Norio Akuta
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Masahiro Kobayashi
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yoshiyuki Suzuki
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Satoshi Saitoh
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Yasuji Arase
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Kenji Ikeda
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
| | - Mariko Kobayashi
- Research Institute for Hepatology, Toranomon Hospital, Kawasaki, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital, 2-2-2, Toranomon, Minato-ku, Tokyo, 105-8470, Japan
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13
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Li X. Emergent liver transplantation for patients with acute-on-chronic liver failure. Dig Liver Dis 2021; 53:1360. [PMID: 34108095 DOI: 10.1016/j.dld.2021.05.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Xiaofei Li
- Department of Infectious Diseases, YiWu Central Hospital, Zhejiang 322000, China.
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14
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Higuera-de-la-Tijera F, Castro-Narro GE, Velarde-Ruiz Velasco JA, Cerda-Reyes E, Moreno-Alcántar R, Aiza-Haddad I, Castillo-Barradas M, Cisneros-Garza LE, Dehesa-Violante M, Flores-Calderón J, González-Huezo MS, Márquez-Guillén E, Muñóz-Espinosa LE, Pérez-Hernández JL, Ramos-Gómez MV, Sierra-Madero J, Sánchez-Ávila JF, Torre-Delgadillo A, Torres R, Marín-López ER, Kershenobich D, Wolpert-Barraza E. Asociación Mexicana de Hepatología A.C. Clinical guideline on hepatitis B. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:403-432. [PMID: 34483073 DOI: 10.1016/j.rgmxen.2021.04.002] [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: 01/12/2021] [Accepted: 04/14/2021] [Indexed: 12/24/2022]
Abstract
Hepatitis B virus (HBV) infection continues to be a worldwide public health problem. In Mexico, at least three million adults are estimated to have acquired hepatitis B (total hepatitis B core antibody [anti-HBc]-positive), and of those, 300,000 active carriers (hepatitis B surface antigen [HBsAg]-positive) could require treatment. Because HBV is preventable through vaccination, its universal application should be emphasized. HBV infection is a major risk factor for developing hepatocellular carcinoma. Semi-annual liver ultrasound and serum alpha-fetoprotein testing favor early detection of that cancer and should be carried out in all patients with chronic HBV infection, regardless of the presence of advanced fibrosis or cirrhosis. Currently, nucleoside/nucleotide analogues that have a high barrier to resistance are the first-line therapies.
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Affiliation(s)
- F Higuera-de-la-Tijera
- Departamento de Gastroenterología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - G E Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico.
| | - J A Velarde-Ruiz Velasco
- Departamento de Gastroenterología, Hospital Civil de Guadalajara "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
| | - E Cerda-Reyes
- Departamento de Gastroenterología, Hospital Central Militar, Mexico City, Mexico
| | - R Moreno-Alcántar
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - I Aiza-Haddad
- Clínica de Enfermedades Hepáticas, Hospital Ángeles Lomas, Mexico City, Mexico
| | - M Castillo-Barradas
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional "La Raza", IMSS, Mexico City, Mexico
| | - L E Cisneros-Garza
- Centro de Enfermedades Hepáticas, Hospital San José, Nuevo León, Monterrey, Mexico
| | - M Dehesa-Violante
- Fundación Mexicana para la Salud Hepática A.C. (FUNDHEPA), Mexico City, Mexico
| | - J Flores-Calderón
- Departamento de Gastroenterología, Hospital de Pediatría del Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico
| | - M S González-Huezo
- Servicio de Gastroenterología y Endoscopia Gastrointestinal, ISSSEMYM, Metepec, Estado de México, Mexico
| | - E Márquez-Guillén
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - L E Muñóz-Espinosa
- Clínica de Hígado, Departamento de Medicina Interna, Hospital Universitario "Dr. José E. González", Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
| | - J L Pérez-Hernández
- Departamento de Gastroenterología, Hospital General de México "Dr. Eduardo Liceaga", Mexico City, Mexico
| | - M V Ramos-Gómez
- Departamento de Gastroenterología, Centro Médico Nacional "20 de Noviembre", ISSSTE, Mexico City, Mexico
| | - J Sierra-Madero
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - J F Sánchez-Ávila
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Mexico City, Mexico
| | - A Torre-Delgadillo
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
| | - R Torres
- Hospital de Infectología del Centro Médico Nacional "La Raza", IMSS, Mexico City, Mexico
| | | | - D Kershenobich
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición "Salvador Zubirán", Mexico City, Mexico
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15
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Martinez MG, Boyd A, Combe E, Testoni B, Zoulim F. Covalently closed circular DNA: The ultimate therapeutic target for curing HBV infections. J Hepatol 2021; 75:706-717. [PMID: 34051332 DOI: 10.1016/j.jhep.2021.05.013] [Citation(s) in RCA: 99] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/03/2021] [Accepted: 05/07/2021] [Indexed: 12/16/2022]
Abstract
Current antiviral therapies, such as pegylated interferon-α and nucleos(t)ide analogues, effectively improve the quality of life of patients with chronic hepatitis B. However, they can only control the infection rather than curing infected hepatocytes. Complete HBV cure is hampered by the lack of therapies that can directly affect the viral minichromosome (in the form of covalently closed circular DNA [cccDNA]). Approaches currently under investigation in early clinical trials are aimed at achieving a functional cure, defined as the loss of HBsAg and undetectable HBV DNA levels in serum. However, achieving a complete HBV cure requires therapies that can directly target the cccDNA pool, either via degradation, lethal mutations or functional silencing. In this review, we discuss cutting-edge technologies that could lead to non-cytolytic direct cccDNA targeting and cure of infected hepatocytes.
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Affiliation(s)
| | - Anders Boyd
- Stichting HIV Monitoring, Amsterdam, the Netherlands; Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, Amsterdam, the Netherlands
| | - Emmanuel Combe
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France
| | - Fabien Zoulim
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France; University of Lyon, Université Claude- Bernard (UCBL), 69008 Lyon, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France.
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16
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Higuera-de-la-Tijera F, Castro-Narro GE, Velarde-Ruiz Velasco JA, Cerda-Reyes E, Moreno-Alcántar R, Aiza-Haddad I, Castillo-Barradas M, Cisneros-Garza LE, Dehesa-Violante M, Flores-Calderón J, González-Huezo MS, Márquez-Guillén E, Muñóz-Espinosa LE, Pérez-Hernández JL, Ramos-Gómez MV, Sierra-Madero J, Sánchez-Ávila JF, Torre-Delgadillo A, Torres R, Marín-López ER, Kershenobich D, Wolpert-Barraza E. Asociación Mexicana de Hepatología A.C. Clinical guideline on hepatitis B. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2021; 86:S0375-0906(21)00061-6. [PMID: 34384668 DOI: 10.1016/j.rgmx.2021.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/11/2021] [Accepted: 04/14/2021] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection continues to be a worldwide public health problem. In Mexico, at least three million adults are estimated to have acquired hepatitis B (total hepatitis B core antibody [anti-HBc]-positive), and of those, 300,000 active carriers (hepatitis B surface antigen [HBsAg]-positive) could require treatment. Because HBV is preventable through vaccination, its universal application should be emphasized. HBV infection is a major risk factor for developing hepatocellular carcinoma. Semi-annual liver ultrasound and serum alpha-fetoprotein testing favor early detection of that cancer and should be carried out in all patients with chronic HBV infection, regardless of the presence of advanced fibrosis or cirrhosis. Currently, nucleoside/nucleotide analogues that have a high barrier to resistance are the first-line therapies.
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Affiliation(s)
- F Higuera-de-la-Tijera
- Departamento de Gastroenterología, Hospital General de México «Dr. Eduardo Liceaga», Ciudad de México, México
| | - G E Castro-Narro
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México.
| | - J A Velarde-Ruiz Velasco
- Departamento de Gastroenterología, Hospital Civil de Guadalajara «Fray Antonio Alcalde», Guadalajara, Jalisco, México
| | - E Cerda-Reyes
- Departamento de Gastroenterología, Hospital Central Militar, Ciudad de México, México
| | - R Moreno-Alcántar
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México
| | - I Aiza-Haddad
- Clínica de Enfermedades Hepáticas, Hospital Ángeles Lomas, Ciudad de México, México
| | - M Castillo-Barradas
- Departamento de Gastroenterología, Hospital de Especialidades del Centro Médico Nacional «La Raza», IMSS, Ciudad de México, México
| | - L E Cisneros-Garza
- Centro de Enfermedades Hepáticas, Hospital San José, Nuevo León, Monterrey, México
| | - M Dehesa-Violante
- Fundación Mexicana para la Salud Hepática A.C. (FUNDHEPA), Ciudad de México, México
| | - J Flores-Calderón
- Departamento de Gastroenterología, Hospital de Pediatría del Centro Médico Nacional Siglo XXI, IMSS, Ciudad de México, México
| | - M S González-Huezo
- Servicio de Gastroenterología y Endoscopia Gastrointestinal, ISSSEMYM, Metepec, Estado de México, México
| | - E Márquez-Guillén
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | - L E Muñóz-Espinosa
- Clínica de Hígado, Departamento de Medicina Interna, Hospital Universitario «Dr. José E. González», Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México
| | - J L Pérez-Hernández
- Departamento de Gastroenterología, Hospital General de México «Dr. Eduardo Liceaga», Ciudad de México, México
| | - M V Ramos-Gómez
- Departamento de Gastroenterología, Centro Médico Nacional «20 de Noviembre», ISSSTE, Ciudad de México, México
| | - J Sierra-Madero
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | - J F Sánchez-Ávila
- Tecnológico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ciudad de México, México
| | - A Torre-Delgadillo
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
| | - R Torres
- Hospital de Infectología del Centro Médico Nacional «La Raza», IMSS, Ciudad de México, México
| | | | - D Kershenobich
- Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Ciudad de México, México
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17
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Lee S, Goyal A, Perelson AS, Ishida Y, Saito T, Gale M. Suppression of hepatitis B virus through therapeutic activation of RIG-I and IRF3 signaling in hepatocytes. iScience 2021; 24:101969. [PMID: 33458618 PMCID: PMC7797372 DOI: 10.1016/j.isci.2020.101969] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 10/29/2020] [Accepted: 12/16/2020] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) mediates persistent infection, chronic hepatitis, and liver disease. HBV covalently closed circular (ccc)DNA is central to viral persistence such that its elimination is considered the cornerstone for HBV cure. Inefficient detection by pathogen recognition receptors (PRRs) in the infected hepatocyte facilitates HBV persistence via avoidance of innate immune activation and interferon regulatory factor (IRF)3 induction of antiviral gene expression. We evaluated a small molecule compound, F7, and 5'-triphosphate-poly-U/UC pathogen-associated-molecular-pattern (PAMP) RNA agonists of RIG-I, a PRR that signals innate immunity, for ability to suppress cccDNA. F7 and poly-U/UC PAMP treatment of HBV-infected cells induced RIG-I signaling of IRF3 activation to induce antiviral genes for suppression of cccDNA formation and accelerated decay of established cccDNA, and were additive to the actions of entecavir. Our study shows that activation of the RIG-I pathway and IRF3 to induce innate immune actions offers therapeutic benefit toward elimination of cccDNA.
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Affiliation(s)
- Sooyoung Lee
- Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, WA 98109, USA
| | - Ashish Goyal
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Alan S. Perelson
- Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM, USA
| | - Yuji Ishida
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- PhoenixBio Co., Ltd., Research and Development Unit, Higashi-Hiroshima, Japan
| | - Takeshi Saito
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Michael Gale
- Center for Innate Immunity and Immune Disease, Department of Immunology, University of Washington, Seattle, WA 98109, USA
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18
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Hong B, Wang L, Huang C, Hong X, Liu A, Li Q, Liu Q, Su L, Wang L, Wang C, Ying T. Decrease of Clone Diversity in IgM Repertoires of HBV Chronically Infected Individuals With High Level of Viral Replication. Front Microbiol 2021; 11:615669. [PMID: 33519772 PMCID: PMC7843509 DOI: 10.3389/fmicb.2020.615669] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/22/2020] [Indexed: 01/05/2023] Open
Abstract
High-throughput antibody sequencing allows in-depth insights into human antibody repertoires. To investigate the characteristics of antibody repertoires in patients with chronic HBV infection, we performed Illumina sequencing and IMGT/HighV-QUEST analysis of B lymphocytes from healthy adults and the HBV carriers with high or low level of viral replication. The comparative study revealed high levels of similarity between the IgM and IgG repertoires of the HBV carriers and the healthy adults, including the somatic mutations in V regions, the average CDR3 length, and the occurrence of junctional modifications. Nevertheless, the diversity of the unique clones decreased and some clusters of unique clones expanded in the IgM repertoire of chronic HBV carriers (CHB) compared with healthy adults (HH) and inactive HBV carriers (IHB). Such difference in clone diversity and expansion was not observed in the IgG repertoires of the three populations. More shared antibody clones were found between the IgM repertoires of IHB and HH than that found between CHB and HH (7079 clones vs. 2304 clones). Besides, the biased used IGHD genes were IGHD2-2 and IGHD3-3 in CHB library but were IGHD3-10 and IGHD3-22 in IHB and HH library. In contrast, for IgG repertories, the preferred used VDJ genes were similar in all the three populations. These results indicated that low level of serum HBV might not induce significant changes in BCR repertoires, and high level of HBV replication could have more impacts on IgM repertories than IgG repertoires. Taken together, our findings provide a better understanding of the antibody repertoires of HBV chronically infected individuals.
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Affiliation(s)
- Binbin Hong
- Central Laboratory, Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - Lizhi Wang
- Traditional Chinese Medicine Department, Rehabilitation Hospital, Quanzhou, China
| | - Chunlan Huang
- Traditional Chinese Medicine Department, Rehabilitation Hospital, Quanzhou, China
| | - Xiaoju Hong
- Traditional Chinese Medicine Department, Rehabilitation Hospital, Quanzhou, China
| | - Alan Liu
- Traditional Chinese Medicine Department, Rehabilitation Hospital, Quanzhou, China
| | - Qiulan Li
- Central Laboratory, Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - Qiaoling Liu
- Central Laboratory, Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - Lili Su
- Central Laboratory, Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - Lixing Wang
- Central Laboratory, Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - Chunyu Wang
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Tianlei Ying
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai, China
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19
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Mohebbi A, Azadi F, Hashemi MM, Askari FS, Razzaghi N. Havachoobe (Onosma dichroanthum Boiss) Root Extract Decreases the Hepatitis B Virus Surface Antigen Secretion in the PLC/PRF/5 Cell Line. Intervirology 2020; 64:1-5. [PMID: 33321500 DOI: 10.1159/000512140] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 10/03/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Many efforts are currently focused on functional treatment of the hepatitis B virus (HBV). This can be done by suppressing the secretion of HBV surface antigen (HBsAg). Scientific communities are very interested in natural products in that respect. OBJECTIVE Use of root extract of Havachoobe (Onosma dichroanthum BoissI), a Northern Iranian native medical herb, for assessment of its anti-HBsAg secretion activity. METHODS Havachoobe had been bought at a nearby apothecary store. Plant root extract was obtained using a hydroalcoholic process. Cytotoxic activity of the extract was examined on PLC/PRF/5 cells using MTT assay. ELISA has been used to measure HBsAg in the treated cell line supernatants. In addition, real-time PCR analysis was performed to evaluate the expression of HBsAg before and after treatment of Onosma in vitro. RESULTS The results showed very low root extract cytotoxicity at concentrations under 8 μg/mL. Tissue culture infectious dose 50 was obtained at 63.78 μg/mL. In a dose-dependent and time-dependent manner, a significantly reduced HBsAg secretion was observed at a concentration of 8 ppm at 12 h post-treatment. The real-time PCR result showed relative decreased HBsAg expression at all doses at 12 h post-treatment time. DISCUSSION In this study, we first reported anti-HBsAg activity on an Iranian herbal medicine. Havachoobe root extract was shown to be able to inhibit HBsAg in a dose-dependent and time-dependent manner. We find the extract exerts its inhibitory effect of HBsAg by targeting transcription of HBsAg.
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Affiliation(s)
- Alireza Mohebbi
- Student Research Committee, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran,
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran,
- Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran,
| | - Fahimeh Azadi
- Student Research Committee, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | | | - Fatemeh Sana Askari
- Student Research Committee, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Nazanin Razzaghi
- Laboratory Sciences Research Center, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
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20
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Yang SS, Cai CW, Ma XQ, Xu J, Yu CB. Efficacy and cost-effectiveness of antiviral regimens for entecavir-resistant hepatitis B: A systematic review and network meta-analysis. Hepatobiliary Pancreat Dis Int 2020; 19:507-514. [PMID: 33051132 DOI: 10.1016/j.hbpd.2020.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 09/15/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic hepatitis B (CHB) patients who had exposed to lamivudine (LAM) and telbivudine (LdT) had high risk of developing entecavir (ETV)-resistance after long-term treatment. We aimed to conduct a systematic review and a network meta-analysis on the efficacy and cost-effectiveness on antiviral regimens in CHB patients with ETV-resistance. DATA SOURCES We searched PubMed, EMBASE and Web of Science for studies on nucleos(t)ide analogues (NAs) treatment [including tenofovir disoproxil fumarate (TDF)-based rescue therapies, adefovir (ADV)-based rescue therapies and double-dose ETV therapy] in CHB patients with ETV-resistance. The network meta-analysis was conducted for 1-year complete virological response (CVR) and biological response (BR) rates using GeMTC and ADDIS. A cost-effective analysis was conducted to select an economic and effective treatment regimen based on the 1-year CVR rate. RESULTS A total of 6 studies were finally included in this analysis. The antiviral efficacy was estimated. On network meta-analysis, the 1-year CVR rate in ETV-TDF [odds ratio (OR) = 22.30; 95 % confidence interval (CI): 2.78-241.93], LAM-TDF (OR = 70.67; 95 % CI: 5.16-1307.45) and TDF (OR = 16.90; 95 % CI: 2.28-186.30) groups were significantly higher than that in the ETV double-dose group; the 1-year CVR rate in the LAM-TDF group (OR = 14.82; 95 % CI: 1.03-220.31) was significantly higher than that in the LAM/LdT-ADV group. The 1-year BR rate of ETV-TDF (OR = 28.68; 95 % CI: 1.70-1505.08) and TDF (OR = 21.79; 95 % CI: 1.43-1070.09) therapies were significantly higher than that of ETV double-dose therapy. TDF-based therapies had the highest possibility to achieve the CVR and BR at 1 year, in which LAM-TDF combined therapy was the most effective regimen. The ratio of cost/effectiveness for 1-year treatment was 8 526, 17 649, 20 651 Yuan in the TDF group, TDF-ETV group, and ETV-ADV group, respectively. CONCLUSIONS TDF-based combined therapies such as ETV-TDF and LAM-TDF therapies were the first-line treatment if financial condition is allowed.
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Affiliation(s)
- Si-Si Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Cheng-Wei Cai
- Department of Neurosurgery, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xue-Qing Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jia Xu
- Kidney Disease Center, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Cheng-Bo Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
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21
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Wang Y, Wang M, Zhang G, Ou X, Ma H, You H, Jia J. Control of Chronic Hepatitis B in China: Perspective of Diagnosis and Treatment. China CDC Wkly 2020; 2:596-600. [PMID: 34594716 PMCID: PMC8428426 DOI: 10.46234/ccdcw2020.159] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 07/18/2020] [Indexed: 01/01/2023] Open
Affiliation(s)
- Yu Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Min Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Guanhua Zhang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Xiaojuan Ou
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Hong Ma
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University; Beijing Key Laboratory of Translational Medicine on Liver Cirrhosis; National Clinical Research Center for Digestive Diseases, Beijing, China
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22
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Herrscher C, Roingeard P, Blanchard E. Hepatitis B Virus Entry into Cells. Cells 2020; 9:cells9061486. [PMID: 32570893 PMCID: PMC7349259 DOI: 10.3390/cells9061486] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 06/15/2020] [Accepted: 06/16/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV), an enveloped partially double-stranded DNA virus, is a widespread human pathogen responsible for more than 250 million chronic infections worldwide. Current therapeutic strategies cannot eradicate HBV due to the persistence of the viral genome in a special DNA structure (covalently closed circular DNA, cccDNA). The identification of sodium taurocholate co-transporting polypeptide (NTCP) as an entry receptor for both HBV and its satellite virus hepatitis delta virus (HDV) has led to great advances in our understanding of the life cycle of HBV, including the early steps of infection in particular. However, the mechanisms of HBV internalization and the host factors involved in this uptake remain unclear. Improvements in our understanding of HBV entry would facilitate the design of new therapeutic approaches targeting this stage and preventing the de novo infection of naïve hepatocytes. In this review, we provide an overview of current knowledge about the process of HBV internalization into cells.
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Affiliation(s)
- Charline Herrscher
- Inserm U1259, Morphogénèse et Antigénicité du VIH et des Virus des Hépatites (MAVIVH), Université de Tours and CHRU de Tours, 37032 Tours, France;
| | - Philippe Roingeard
- Inserm U1259, Morphogénèse et Antigénicité du VIH et des Virus des Hépatites (MAVIVH), Université de Tours and CHRU de Tours, 37032 Tours, France;
- Plate-Forme IBiSA des Microscopies, PPF ASB, Université de Tours and CHRU de Tours, 37032 Tours, France
- Correspondence: (P.R.); (E.B.); Tel.: +33-2-3437-9646 (E.B.)
| | - Emmanuelle Blanchard
- Inserm U1259, Morphogénèse et Antigénicité du VIH et des Virus des Hépatites (MAVIVH), Université de Tours and CHRU de Tours, 37032 Tours, France;
- Plate-Forme IBiSA des Microscopies, PPF ASB, Université de Tours and CHRU de Tours, 37032 Tours, France
- Correspondence: (P.R.); (E.B.); Tel.: +33-2-3437-9646 (E.B.)
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23
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Hu Q, Zhang F, Duan L, Wang B, Ye Y, Li P, Li D, Yang S, Zhou L, Chen W. E-cadherin Plays a Role in Hepatitis B Virus Entry Through Affecting Glycosylated Sodium-Taurocholate Cotransporting Polypeptide Distribution. Front Cell Infect Microbiol 2020; 10:74. [PMID: 32175289 PMCID: PMC7056903 DOI: 10.3389/fcimb.2020.00074] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 02/13/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major cause of chronic liver disease and hepatocellular carcinoma. Current antiviral therapy does not effectively eradicate HBV and further investigations into the mechanisms of viral infection are needed to enable the development of new therapeutic agents. The sodium-taurocholate cotransporting polypeptide (NTCP) has been identified as a functional receptor for HBV entry in liver cells. However, the NTCP receptor is not sufficient for entry and other membrane proteins contribute to modulate HBV entry. This study seeks to understand how the NTCP functions in HBV entry. Herein we show that knockdown of the cell-cell adhesion molecule, E-cadherin significantly reduced infection by HBV particles and entry by HBV pseudoparticles in infected liver cells and cell lines. The glycosylated NTCP localizes to the plasma membrane through interaction with E- cadherin, which increases interaction with the preS1 portion of the Large HBV surface antigen. Our study contributes novel insights that advance knowledge of HBV infection at the level of host cell binding and viral entry.
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Affiliation(s)
- Qin Hu
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Key Laboratory of Laboratory Medical Diagnostics of Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Feifei Zhang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liang Duan
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bo Wang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuanyuan Ye
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Pu Li
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dandan Li
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Shengjun Yang
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Lan Zhou
- Key Laboratory of Laboratory Medical Diagnostics of Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Weixian Chen
- Department of Laboratory Medicine, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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24
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Hong B, Wen Y, Ying T. Recent Progress on Neutralizing Antibodies against Hepatitis B Virus and its Implications. Infect Disord Drug Targets 2020; 19:213-223. [PMID: 29952267 DOI: 10.2174/1871526518666180628122400] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 05/13/2018] [Accepted: 06/22/2018] [Indexed: 01/22/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection remains a global health problem. As "cure" for chronic hepatitis B is of current priority, hepatitis B immunoglobulin (HBIG) has been utilized for several decades to provide post-exposure prophylaxis. In recent years, a number of monoclonal antibodies (mAbs) targeting HBV have been developed and demonstrated with high affinity, specificity, and neutralizing potency. OBJECTIVE HBV neutralizing antibodies may play a potentially significant role in the search for an HBV cure. In this review, we will summarize the recent progress in developing HBV-neutralizing antibodies, describing their characteristics and potential clinical applications. RESULTS AND CONCLUSION HBV neutralizing antibodies could be a promising alternative in the prevention and treatment of HBV infection. More importantly, global collaboration and coordinated approaches are thus needed to facilitate the development of novel therapies for HBV infection.
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Affiliation(s)
- Binbin Hong
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.,Central Laboratory, the Second Affiliated Hospital of Fujian Medical University, Quanzhou 362000, China
| | - Yumei Wen
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Tianlei Ying
- Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
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25
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Tian F, Houle SKD, Alsabbagh MW, Wong WWL. Cost-Effectiveness of Tenofovir Alafenamide for Treatment of Chronic Hepatitis B in Canada. PHARMACOECONOMICS 2020; 38:181-192. [PMID: 31691902 DOI: 10.1007/s40273-019-00852-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
BACKGROUND/AIM Tenofovir alafenamide (TAF) has been approved for treating chronic hepatitis B (CHB) due to a proposed better safety profile in comparison with current therapies. We evaluated the cost effectiveness of TAF and other available treatment options for hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative CHB patients from a Canadian provincial Ministry of Health perspective. METHODS A state-transition model based on the published literature was developed to compare treatment strategies involving entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF. It adopted a lifetime time horizon. Outcomes measured were predicted number of liver-related deaths, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS For HBeAg-positive patients, TAF followed by ETV generated an additional 0.16 QALYs/person at an additional cost of Can$14,836.18 with an ICER of Can$94,142.71/QALY compared with TDF followed by ETV. Of the iterations, 28.7% showed that it is the optimal strategy with a Can$50,000 willingness-to-pay threshold. For HBeAg-negative patients, ETV followed by TAF would prevent an additional 13 liver-related deaths per 1000 CHB patients compared with TDF, followed by ETV. It generated an additional 0.13 QALYs/person at an additional cost of Can$59,776.53 with an ICER of Can$461,162.21/QALY compared with TDF, followed by ETV. TAF-containing strategies are unlikely to be a rational choice in either case. The results were sensitive to the HBeAg seroconversion rates and viral suppression rates of the treatments. CONCLUSIONS Our analysis suggests that TAF is not cost effective at its current cost. A 33.4% reduction in price would be required to make it cost effective for HBeAg-positive patients with a Can$50,000 willingness-to-pay threshold.
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Affiliation(s)
- Feng Tian
- School of Pharmacy, Faculty of Science, University of Waterloo, 10A Victoria Street S, Kitchener, ON, N2G1C5, Canada
| | - Sherilyn K D Houle
- School of Pharmacy, Faculty of Science, University of Waterloo, 10A Victoria Street S, Kitchener, ON, N2G1C5, Canada
| | - Mhd Wasem Alsabbagh
- School of Pharmacy, Faculty of Science, University of Waterloo, 10A Victoria Street S, Kitchener, ON, N2G1C5, Canada
| | - William W L Wong
- School of Pharmacy, Faculty of Science, University of Waterloo, 10A Victoria Street S, Kitchener, ON, N2G1C5, Canada.
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26
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Teppa E, Nadalin F, Combet C, Zea DJ, David L, Carbone A. Coevolution analysis of amino-acids reveals diversified drug-resistance solutions in viral sequences: a case study of hepatitis B virus. Virus Evol 2020; 6:veaa006. [PMID: 32158552 PMCID: PMC7050494 DOI: 10.1093/ve/veaa006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The study of mutational landscapes of viral proteins is fundamental for the understanding of the mechanisms of cross-resistance to drugs and the design of effective therapeutic strategies based on several drugs. Antiviral therapy with nucleos(t)ide analogues targeting the hepatitis B virus (HBV) polymerase protein (Pol) can inhibit disease progression by suppression of HBV replication and makes it an important case study. In HBV, treatment may fail due to the emergence of drug-resistant mutants. Primary and compensatory mutations have been associated with lamivudine resistance, whereas more complex mutational patterns are responsible for resistance to other HBV antiviral drugs. So far, all known drug-resistance mutations are located in one of the four Pol domains, called reverse transcriptase. We demonstrate that sequence covariation identifies drug-resistance mutations in viral sequences. A new algorithmic strategy, BIS2TreeAnalyzer, is designed to apply the coevolution analysis method BIS2, successfully used in the past on small sets of conserved sequences, to large sets of evolutionary related sequences. When applied to HBV, BIS2TreeAnalyzer highlights diversified viral solutions by discovering thirty-seven positions coevolving with residues known to be associated with drug resistance and located on the four Pol domains. These results suggest a sequential mechanism of emergence for some mutational patterns. They reveal complex combinations of positions involved in HBV drug resistance and contribute with new information to the landscape of HBV evolutionary solutions. The computational approach is general and can be applied to other viral sequences when compensatory mutations are presumed.
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Affiliation(s)
- Elin Teppa
- Sorbonne Université, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France
- Sorbonne Université, Institut des Sciences du Calcul et des Données (ISCD), 4 Place Jussieu, 75005 Paris, France
| | - Francesca Nadalin
- Sorbonne Université, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France
- Institute Curie, PSL Research University, INSERM U932, Immunity and Cancer Department, 26 rue d’Ulm, 75248 Paris, France
| | - Christophe Combet
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, 151 Cours Albert Thomas, 69424 Lyon, France
| | - Diego Javier Zea
- Sorbonne Université, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France
| | - Laurent David
- Sorbonne Université, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France
| | - Alessandra Carbone
- Sorbonne Université, Univ P6, CNRS, IBPS, Laboratoire de Biologie Computationnelle et Quantitative (LCQB) - UMR 7238, 4 Place Jussieu, 75005 Paris, France
- Institut Universitaire de France, 1 rue Descartes, 75231 Paris, France
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27
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Choe WH, Kim K, Lee SY, Choi YM, Kwon SY, Kim JH, Kim BJ. Tenofovir is a more suitable treatment than entecavir for chronic hepatitis B patients carrying naturally occurring rtM204I mutations. World J Gastroenterol 2019; 25:4985-4998. [PMID: 31543688 PMCID: PMC6737324 DOI: 10.3748/wjg.v25.i33.4985] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 07/30/2019] [Accepted: 08/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) DNA polymerase mutations usually occur to long term use of nucleos(t)ide analogues (NAs), but they can occur spontaneously in treatment-naïve chronic hepatitis B (CHB) patients. The naturally occurring HBV DNA polymerase mutations might complicate antiviral therapy with NAs, leading to the generation of drug-resistant viral mutants and disease progression. The most common substitutions are known to be YMDD-motif mutations, but their prevalence and the influence on antiviral therapy is unclear. AIM To investigate prevalence of the naturally occurring rtM204I mutations in treatment-naïve CHB genotype C2 patients and their influence on antiviral therapy. METHODS A total of 410 treatment-naïve CHB patients infected with HBV genotype C2 strains were enrolled in this retrospective study. Among the 410 patients, 232 were treated with NAs for at least 12 mo. Significant fibrosis was defined as fibrosis-4 index > 3.25 or aspartate aminotransferase to platelet ratio index > 1.5. Complete viral response (CVR) during NAs was defined as undetectable serum HBV DNA (< 24 IU/mL). The rtM204I variants were analyzed by a newly developed locked nucleotide probe (LNA probe) based real-time PCR (LNA-RT-PCR) method. RESULTS The LNA-RT-PCR could discriminate rtM204I mutant-type (17 patients, 4.2%) from rtM204 wild-type (386 patients, 95.8%) in 403 of 410 patients (98.3% sensitivity). Multivariate analysis showed that naturally occurring rtM204I variants were more frequently detected in patients with significant fibrosis [odd-ratio (OR) 3.397, 95% confidence-interval (CI) 1.119-10.319, P = 0.031]. Of 232 patients receiving NAs, multivariate analysis revealed that achievement of CVR was reversely associated with naturally occurring rtM204I variants prior to NAs treatment (OR 0.014, 95%CI 0.002-0.096, P < 0.001). Almost patients receiving tenofovir achieved CVR at 12 mo of tenofovir, irrespective of pre-existence of naturally occurring rtM204I mutations (CVR rates: patients with rtM204I, 100%; patients without rtM204I, 96.6%), whereas, pre-existence of naturally-occurring rtM204I-mutations prior to NAs significantly affects CVR rates in patients receiving entecavir (at 12 mo: Patients with rtM204I, 16.7%; patients without rtM204I, 95.6%, P < 0.001). CONCLUSION The newly developed LNA-RT-PCR method could detect naturally occurring rtM204I mutations with high-sensitivity. Theses mutations were more frequent in patients with liver fibrosis. Tenofovir is a more suitable treatment than entecavir for CHB patients carrying the naturally occurring rtM204I mutations.
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Affiliation(s)
- Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul 05030, South Korea
| | - Kijeong Kim
- Department of Microbiology, College of Medicine, Chung-Ang University, Seoul 06974, South Korea
| | - So-Young Lee
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul 03080, South Korea
| | - Yu-Min Choi
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul 03080, South Korea
| | - So Young Kwon
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul 05030, South Korea
| | - Jeong Han Kim
- Department of Internal Medicine, Konkuk University School of Medicine, Seoul 05030, South Korea
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute, Cancer Research Institute and SNUMRC, College of Medicine, Seoul National University, Seoul 03080, South Korea
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Toyama M, Sakakibara N, Takeda M, Okamoto M, Watashi K, Wakita T, Sugiyama M, Mizokami M, Ikeda M, Baba M. Pyrimidotriazine derivatives as selective inhibitors of HBV capsid assembly. Virus Res 2019; 271:197677. [PMID: 31376401 DOI: 10.1016/j.virusres.2019.197677] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 07/31/2019] [Accepted: 07/31/2019] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is currently treated with nucleoside/nucleotides analogs. They are potent inhibitors of HBV DNA polymerase, which also functions as reverse transcriptase. Although nucleoside/nucleotide analogs efficiently suppress HBV replication in liver cells, they cannot eradicate HBV DNA from liver cells and cure the disease. Therefore, it is still mandatory to identify and develop effective inhibitors that target a step other than reverse transcription in the viral replication cycle. HBV capsid assembly is a critical step for viral replication and an attractive target for inhibition of HBV replication. We conducted in silico screening of compounds expected to bind to the HBV capsid dimer-dimer interaction site. The selected compounds were further examined for their anti-HBV activity in vitro. Among the test compounds, novel pyrimidotriazine derivatives were found to be selective inhibitors of HBV replication in HepG2.2.15.7 cells. Among the compounds, 2-[(2,3-dichlorophenyl)amino]-4-(4-tert-butylphenyl)-8-methyl-4H,9H-pyrimido[1,2-a][1,3,5]triazin-6-one was the most active against HBV replication. Studies on its mechanism of action revealed that the compound interfered with HBV capsid assembly determined by a cell-free capsid assembly system. Thus, the pyrimidotriazine derivatives are considered to be potential leads for novel HBV capsid assembly inhibitors.
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Affiliation(s)
- Masaaki Toyama
- Division of Antiviral Chemotherapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, Japan
| | - Norikazu Sakakibara
- Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Sanuki, Japan
| | - Midori Takeda
- Division of Biological Information Technology, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, Japan
| | - Mika Okamoto
- Division of Antiviral Chemotherapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, Japan
| | - Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masaya Sugiyama
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masanori Ikeda
- Division of Biological Information Technology, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, Japan
| | - Masanori Baba
- Division of Antiviral Chemotherapy, Joint Research Center for Human Retrovirus Infection, Kagoshima University, Kagoshima, Japan.
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29
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Park ES, Lee AR, Kim DH, Lee JH, Yoo JJ, Ahn SH, Sim H, Park S, Kang HS, Won J, Ha YN, Shin GC, Kwon SY, Park YK, Choi BS, Lee YB, Jeong N, An Y, Ju YS, Yu SJ, Chae HB, Yu KS, Kim YJ, Yoon JH, Zoulim F, Kim KH. Identification of a quadruple mutation that confers tenofovir resistance in chronic hepatitis B patients. J Hepatol 2019; 70:1093-1102. [PMID: 30794889 DOI: 10.1016/j.jhep.2019.02.006] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 02/02/2019] [Accepted: 02/06/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) is one the most potent nucleot(s)ide analogues for treating chronic hepatitis B virus (HBV) infection. Phenotypic resistance caused by genotypic resistance to TDF has not been reported. This study aimed to characterize HBV mutations that confer tenofovir resistance. METHODS Two patients with viral breakthrough during treatment with TDF-containing regimens were prospectively enrolled. The gene encoding HBV reverse transcriptase was sequenced. Eleven HBV clones harboring a series of mutations in the reverse transcriptase gene were constructed by site-directed mutagenesis. Drug susceptibility of each clone was determined by Southern blot analysis and real-time PCR. The relative frequency of mutants was evaluated by ultra-deep sequencing and clonal analysis. RESULTS Five mutations (rtS106C [C], rtH126Y [Y], rtD134E [E], rtM204I/V, and rtL269I [I]) were commonly found in viral isolates from 2 patients. The novel mutations C, Y, and E were associated with drug resistance. In assays for drug susceptibility, the IC50 value for wild-type HBV was 3.8 ± 0.6 µM, whereas the IC50 values for CYE and CYEI mutants were 14.1 ± 1.8 and 58.1 ± 0.9 µM, respectively. The IC90 value for wild-type HBV was 30 ± 0.5 µM, whereas the IC90 values for CYE and CYEI mutants were 185 ± 0.5 and 790 ± 0.2 µM, respectively. Both tenofovir-resistant mutants and wild-type HBV had similar susceptibility to the capsid assembly modulator NVR 3-778 (IC50 <0.4 µM vs. IC50 = 0.4 µM, respectively). CONCLUSIONS Our study reveals that the quadruple (CYEI) mutation increases the amount of tenofovir required to inhibit HBV by 15.3-fold in IC50 and 26.3-fold in IC90. These results demonstrate that tenofovir-resistant HBV mutants can emerge, although the genetic barrier is high. LAY SUMMARY Tenofovir is the most potent nucleotide analogue for the treatment of chronic hepatitis B virus infection and there has been no hepatitis B virus mutation that confers >10-fold resistance to tenofovir up to 8 years. Herein, we identified, for the first time, a quadruple mutation that conferred 15.3-fold (IC50) and 26.3-fold (IC90) resistance to tenofovir in 2 patients who experienced viral breakthrough during tenofovir treatment.
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Affiliation(s)
- Eun-Sook Park
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Ah Ram Lee
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Doo Hyun Kim
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Jeong-Ju Yoo
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Gastroenterology and Hepatology, Soonchunhyang University Bucheon Hospital, Gyeonggido, Republic of Korea
| | - Sung Hyun Ahn
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Heewoo Sim
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Soree Park
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Hong Seok Kang
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Juhee Won
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Yea Na Ha
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Gu-Choul Shin
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - So Young Kwon
- Department of Internal Medicine, School of Medicine, Konkuk University, Seoul, Republic of Korea
| | - Yong Kwang Park
- Division of AIDS, Center for Immunology and Pathology, Korea National Institute of Health, Korea Center for Disease Control and Prevention, Osong, Chungbuk, Republic of Korea
| | - Byeong-Sun Choi
- Division of AIDS, Center for Immunology and Pathology, Korea National Institute of Health, Korea Center for Disease Control and Prevention, Osong, Chungbuk, Republic of Korea
| | - Yun Bin Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggido, Republic of Korea
| | - Nakcheol Jeong
- Department of Chemistry, Korea University, Seoul, Republic of Korea
| | - Yohan An
- Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejon, Republic of Korea
| | - Young Seok Ju
- Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejon, Republic of Korea; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejon, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hee Bok Chae
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Republic of Korea
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Fabien Zoulim
- INSERM Unité 1052, Cancer Research Center of Lyon, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Kyun-Hwan Kim
- Department of Pharmacology and Center for Cancer Research and Diagnostic Medicine, IBST, School of Medicine, Konkuk University, Seoul, Republic of Korea; KU Open Innovation Center, Konkuk University, Seoul, Republic of Korea; Research Institute of Medical Sciences, Konkuk University, Seoul, Republic of Korea.
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Jourdain G, Ngo-Giang-Huong N, Khamduang W. Current progress in the prevention of mother-to-child transmission of hepatitis B and resulting clinical and programmatic implications. Infect Drug Resist 2019; 12:977-987. [PMID: 31118703 PMCID: PMC6499137 DOI: 10.2147/idr.s171695] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 03/25/2019] [Indexed: 12/14/2022] Open
Abstract
There is currently no cure for hepatitis B chronic infections. Because new hepatitis B infections result mainly from perinatal transmission, preventing mother-to-child transmission is essential to reach by 2030 the goal of hepatitis B elimination set by the World Health Organization. The universal administration of hepatitis B vaccine to all infants, regardless of maternal status, starting with the birth dose, is the cornerstone of the strategy for elimination. Additional interventions, such as hepatitis B immune globulin administered to newborns and antiviral prophylaxis administered to hepatitis B infected pregnant women, may contribute to reaching the goal earlier. Hepatitis B immune globulin may remain out for reach of many pregnant women in low- and middle-income countries due to cost and logistic issues, but antivirals are cheap and do not require a cold chain for distribution. However, it has been observed that some viruses harbor mutations associated with escape from vaccine-elicited antibodies following immunization or administration of hepatitis B immune globulin. Also, resistance associated mutations have been described for several drugs used for treatment of hepatitis B infected patients as well as for the prevention of mother-to-child transmission. Whether these mutations have the potential to compromise the prevention of mother-to-child transmission or future treatment of the mother is a question of importance. We propose a review of important recent studies assessing tenofovir disoproxil fumarate for the prevention of mother-to-child transmission, and provides detailed information on the mutations possibly relevant in this setting.
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Affiliation(s)
- Gonzague Jourdain
- Unit 174-PHPT, Institut de recherche pour le développement (IRD), Marseille, France
- Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Nicole Ngo-Giang-Huong
- Unit 174-PHPT, Institut de recherche pour le développement (IRD), Marseille, France
- Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
- Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, MA, USA
| | - Woottichai Khamduang
- Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand
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31
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Zhang Y, Zhang H, Zhang J, Zhang J, Guo H. Naturally occurring core protein mutations compensate for the reduced replication fitness of a lamivudine-resistant HBV isolate. Antiviral Res 2019; 165:47-54. [PMID: 30902704 DOI: 10.1016/j.antiviral.2019.03.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 02/05/2019] [Accepted: 03/14/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) replicates its DNA genome through reverse transcription of an RNA intermediate. The lack of proofreading capacity of the viral DNA polymerase results in a high mutation rate of HBV genome. Under the selective pressure created by the nucleos(t)ide analogue (NA) antiviral drugs, viruses with resistance mutations are selected. However, the replication fitness of NA-resistant mutants is markedly reduced compared to wild-type. Compensatory mutations in HBV polymerase, which restore the viral replication capacity, have been reported to arise under continuous treatment with lamivudine (LMV). We have previously identified a highly replicative LMV-resistant HBV isolate from a chronic hepatitis B patient experiencing acute disease exacerbation. Besides the common YMDD drug-resistant mutations, this isolate possesses multiple additional mutations in polymerase and core regions. The transcomplementation assay demonstrated that the enhanced viral replication is due to the mutations of core protein. Further mutagenesis study revealed that the P5T mutation of core protein plays an important role in the enhanced viral replication through increasing the levels of capsid formation and pregenomic RNA encapsidation. However, the LMV-resistant virus harboring compensatory core mutations remains sensitive to capsid assembly modulators (CpAMs). Taken together, our study suggests that the enhanced HBV nucleocapsid formation resulting from core mutations represents an important viral strategy to surmount the antiviral drug pressure and contribute to viral pathogenesis, and CpAMs hold promise for developing the combinational antiviral therapy for hepatitis B.
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Affiliation(s)
- Yongmei Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Hu Zhang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Junjie Zhang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China; Key Laboratory of Medical Molecular Virology (MOH & MOE), Fudan University, Shanghai, China.
| | - Haitao Guo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
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32
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Kim DY, Park JY. Step-down strategy in antiviral resistant chronic hepatitis B patients who achieved viral suppression with rescue combination therapy. Future Virol 2018. [DOI: 10.2217/fvl-2018-0078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
In the treatment of chronic hepatitis B (CHB) patients with drug resistance, rescue combination therapy leads to viral suppression in almost all patients. However, once it is achieved, lifelong maintenance especially, by using combination therapy is not always possible in a significant proportion of patients. At present, there is no consensus on whether it is possible to switch to monotherapy from combination therapy. However, there is robust evidence to support step-down therapy, which involves switching from combination therapy to monotherapy in antiviral resistant CHB patients who achieve complete viral response from combination therapy. We review the evidence in favor of switching to monotherapy in antiviral resistant CHB patients who achieve complete viral response by combination therapy.
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Affiliation(s)
- Dong Yun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Liver Center, Severance Hospital, Seoul, Korea
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33
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Boyd A, Moh R, Maylin S, Abdou Chekaraou M, Mahjoub N, Gabillard D, Anglaret X, Eholié SP, Delaugerre C, Danel C, Zoulim F, Lacombe K. Precore G1896A mutation is associated with reduced rates of HBsAg seroclearance in treated HIV hepatitis B virus co-infected patients from Western Africa. J Viral Hepat 2018; 25:1121-1131. [PMID: 29660214 DOI: 10.1111/jvh.12914] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Accepted: 03/20/2018] [Indexed: 12/22/2022]
Abstract
The nucleotide substitution G1896A on the precore (pc) region has been implicated in virological and serological responses during treatment in hepatitis B virus (HBV)-infected patients. Whether this mutation affects the therapeutic course of HIV-HBV co-infected patients, especially from Western Africa, is unknown. In this prospective cohort study, 86 antiretroviral (ARV)-naïve HIV-HBV co-infected patients from Côte d'Ivoire, initiating ARV-treatment containing lamivudine (n = 53) or tenofovir (n = 33), had available baseline pc sequences. Association of the pcG1896A mutation with time to undetectable HBV-DNA, hepatitis B "e" antigen (HBeAg) seroclearance (in HBeAg-positive patients), and hepatitis B surface antigen (HBsAg) seroclearance was evaluated using Cox proportional hazards regression. At ARV-initiation, median HBV-DNA was 6.04 log10 copies/mL (IQR = 3.70-7.93) with 97.7% harbouring HBV genotype E. Baseline pcG1896A mutation was identified in 51 (59.3%) patients, who were more commonly HBeAg-negative (P < .001) and had basal core promotor A1762T/G1764A mutations (P < .001). Patients were followed for a median 36 months (IQR = 24-36). Cumulative proportion of undetectable HBV-DNA was significantly higher in patients with baseline mutation (pcG1896A = 86.6% vs no pcG1896A = 66.9%, P = .04), but not after adjusting for baseline HBV-DNA levels and anti-HBV agent (P = .2). No difference in cumulative proportion of HBeAg seroclearance was observed between mutation groups (pcG1896A = 57.1% vs no pcG1896A = 54.3%, P = .7). Significantly higher cumulative proportion of HBsAg seroclearance was observed in patients without this mutation (pcG1896A = 0% vs no pcG1896A = 36.9%, P < .001), even after adjusting for baseline HBsAg quantification and anti-HBV agent (P < .001). In conclusion, lacking the pcG1896A mutation before ARV initiation appeared to increase HBsAg seroclearance rates during treatment. The therapeutic implications of this mutation need further exploration in this setting.
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Affiliation(s)
- A Boyd
- INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Sorbonne Université, Paris, France
| | - R Moh
- Programme PAC-CI, ANRS Research Site, Treichville University Hospital, Abidjan, Côte d'Ivoire.,Department of Infectious and Tropical Diseases, Treichville University Teaching Hospital, Abidjan, Côte d'Ivoire.,Medical School, University Felix Houphouet Boigny, Abidjan, Côte d'Ivoire
| | - S Maylin
- Laboratoire de Virologie, Hôpital Saint-Louis, AP-HP, Paris, France.,Université Paris-Diderot, Paris, France
| | | | - N Mahjoub
- Laboratoire de Virologie, Hôpital Saint-Louis, AP-HP, Paris, France
| | - D Gabillard
- INSERM, U1219, Bordeaux, France.,University of Bordeaux, ISPED, Bordeaux, France
| | - X Anglaret
- Programme PAC-CI, ANRS Research Site, Treichville University Hospital, Abidjan, Côte d'Ivoire.,INSERM, U1219, Bordeaux, France.,University of Bordeaux, ISPED, Bordeaux, France
| | - S P Eholié
- Programme PAC-CI, ANRS Research Site, Treichville University Hospital, Abidjan, Côte d'Ivoire.,Department of Infectious and Tropical Diseases, Treichville University Teaching Hospital, Abidjan, Côte d'Ivoire.,Medical School, University Felix Houphouet Boigny, Abidjan, Côte d'Ivoire
| | - C Delaugerre
- Laboratoire de Virologie, Hôpital Saint-Louis, AP-HP, Paris, France.,Université Paris-Diderot, Paris, France.,INSERM U941, Paris, France
| | - C Danel
- Programme PAC-CI, ANRS Research Site, Treichville University Hospital, Abidjan, Côte d'Ivoire.,INSERM, U1219, Bordeaux, France.,University of Bordeaux, ISPED, Bordeaux, France
| | - F Zoulim
- INSERM U1052- Cancer Research Center of Lyon (CRCL), Lyon, France.,University of Lyon, UMR_S1052, CRCL, Lyon, France.,Department of Hepatology, Hospices Civils de Lyon, Lyon, France
| | - K Lacombe
- Department of Infectious and Tropical Diseases, Saint-Antoine Hospital, AP-HP, Paris, France.,INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Hôpital Saint Antoine, AP-HP, Sorbonne Université, Paris, France
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Chihab H, Jadid FZ, Foka P, Zaidane I, El Fihry R, Georgopoulou U, Marchio A, Elhabazi A, Chair M, Pineau P, Ezzikouri S, Benjelloun S. Programmed cell death-1 3'-untranslated region polymorphism is associated with spontaneous clearance of hepatitis B virus infection. J Med Virol 2018; 90:1730-1738. [PMID: 30016557 DOI: 10.1002/jmv.25265] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 06/18/2018] [Indexed: 12/29/2022]
Abstract
Hepatitis B virus (HBV)-specific CD8+ T cells play an important role in the clearance of HBV infection. Programmed cell death-1 (PD-1), an immunosuppressive molecule that regulates T-cell activation and peripheral immune tolerance, is increasingly shown to influence the outcome of HBV infection. rs10204525, a single-nucleotide polymorphism in the 3'-untranslated region (3'-UTR) of PD-1, has been associated with susceptibility and disease progression of chronic HBV infection in far-eastern patients. The aim of our study was to assess the impact of rs10204525 variation on HBV infection in Moroccan patients. A total of 236 patients with chronic HBV infection and 134 individuals with spontaneous HBV resolution were genotyped using a Taqman assay. In addition, PD-1 mRNA expression in peripheral blood nuclear cells was determined by quantitative reverse-transcription polymerase chain reaction. We found that the AA genotype is protective (odds ratio, 0.43; 95% confidence interval, 0.19 to 0.97; P = 0.038) against HBV infection. Interestingly, PD-1 messenger RNA (mRNA) expression analysis has revealed that chronic HBV carriers with GG and GA displayed higher levels of PD-1 mRNA compared with corresponding genotypes in resolved subjects (P = 0.031 and 0.014, respectively). Our data suggest that Mediterranean HBV-infected patients carrying PD-1 GG and GA genotypes at rs10204525 have high PD-1 mRNA expression and may be more prone to installation of chronicity.
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Affiliation(s)
- Hajar Chihab
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco.,Laboratoire de Biotechnologie, Biochimie et Nutrition, Faculté des Sciences d'El Jadida, Université Chouaib Doukkali, El Jadida, Morocco
| | - Fatima-Zahra Jadid
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Pelagia Foka
- Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece
| | - Imane Zaidane
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Raouia El Fihry
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | | | - Agnes Marchio
- Unité Organisation Nucléaire et Oncogenèse, INSERM U2993, Institut Pasteur, Paris, France
| | - Abdellah Elhabazi
- Laboratoire de Biotechnologie, Biochimie et Nutrition, Faculté des Sciences d'El Jadida, Université Chouaib Doukkali, El Jadida, Morocco
| | - Mohammed Chair
- Laboratoire de Biotechnologie, Biochimie et Nutrition, Faculté des Sciences d'El Jadida, Université Chouaib Doukkali, El Jadida, Morocco
| | - Pascal Pineau
- Unité Organisation Nucléaire et Oncogenèse, INSERM U2993, Institut Pasteur, Paris, France
| | - Sayeh Ezzikouri
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
| | - Soumaya Benjelloun
- Virology Unit, Viral Hepatitis Laboratory, Institut Pasteur du Maroc, Casablanca, Morocco
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Moreno-Cubero E, Arco RTSD, Peña-Asensio J, Villalobos ESD, Míquel J, Larrubia JR. Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients? World J Gastroenterol 2018; 24:1825-1838. [PMID: 29740199 PMCID: PMC5937201 DOI: 10.3748/wjg.v24.i17.1825] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 04/21/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) remains a challenging global health problem, with nearly one million related deaths per year. Nucleos(t)ide analogue (NA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus (HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen (HBsAg), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated NA therapy discontinuation after several years of NA treatment and before HBsAg loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBsAg seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure a close follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host’s immune system. Viral parameters that have been described as good predictors of response in HBeAg(+) cases, have proven useless in HBeAg(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe NA discontinuation in both groups.
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Affiliation(s)
| | - Robert T Sánchez del Arco
- Internal Medicine Service, Guadalajara University Hospital, University of Alcalá, Guadalajara 19002, Spain
| | - Julia Peña-Asensio
- Department of Biology of Systems, University of Alcalá, Alcalá de Henares (Madrid) 28805, Spain
| | | | | | - Juan Ramón Larrubia
- Department of Medicine and Medical Specialties, University of Alcalá, Alcalá de Henares (Madrid) 28805, Spain
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Guo X, Wu J, Wei F, Ouyang Y, Li Q, Liu K, Wang Y, Zhang Y, Chen D. Trends in hepatitis B virus resistance to nucleoside/nucleotide analogues in North China from 2009-2016: A retrospective study. Int J Antimicrob Agents 2018; 52:201-209. [PMID: 29654894 DOI: 10.1016/j.ijantimicag.2018.04.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 03/29/2018] [Accepted: 04/04/2018] [Indexed: 12/13/2022]
Abstract
Nucleos(t)ide analogues (NAs) are widely used in anti-hepatitis B virus (anti-HBV) therapy for effective inhibition of HBV replication. However, HBV resistance to NAs has emerged, resulting in virus reactivation and disease recurrence. Data on the current dynamics of HBV resistance are still rare in China. This study analysed 4491 plasma samples with HBV primary genotypic resistance mutations representative of the general HBV resistance situation in northern China from 2009-2016. We found that entecavir (ETV), representing 57.6% (12 713/22 060) of NA users in North China in 2016, has become the major NA for treating Chinese patients infected with HBV. Despite >50% of M204I/V±L180M among all HBV resistance cases annually and extensive exposure of patients to lamivudine (LAM), telbivudine (LdT) and adefovir dipivoxil (ADV), ETV resistance also showed a dramatically increased incidence, which rose to 17.1% in 2016. Moreover, A181T/V, ETV resistance mutations and multidrug resistance mutations were found more frequently in HBV genotype C compared with genotype B (21.2% vs. 8.5%, 12.4% vs. 7.9% and 5.9% vs. 3.0%, respectively), whereas M204I and N236T were more predominant in genotype B than genotype C (40.3% vs. 20.8% and 11.3% vs. 1.8%, respectively). In conclusion, we report the dynamic changes of HBV NA resistance mutation patterns and the current NA usage profile for anti-HBV treatment in North China over the past 8 years. These data provide valuable information on HBV NA resistance that is an important reference for clinicians to devise more effective treatment regimens for individual patients.
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Affiliation(s)
- Xianghua Guo
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Jushan Wu
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Feili Wei
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yabo Ouyang
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Qing Li
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Kai Liu
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yanjun Wang
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yulin Zhang
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
| | - Dexi Chen
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China; Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao City, Shandong Province 266003, China.
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Kim DY, Lee HW, Song JE, Kim BK, Kim SU, Kim DY, Ahn SH, Han KH, Park JY. Switching from tenofovir and nucleoside analogue therapy to tenofovir monotherapy in virologically suppressed chronic hepatitis B patients with antiviral resistance. J Med Virol 2018; 90:497-502. [PMID: 29077211 DOI: 10.1002/jmv.24986] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 09/27/2017] [Indexed: 12/30/2022]
Abstract
It is unclear whether chronic hepatitis B (CHB) patients with antiviral resistance, who achieve a complete virologic response (CVR) with tenofovir disoproxil fumarate (TDF) and nucleoside analogue (NUC) combination therapy, maintain CVR if switched to TDF monotherapy. We investigated the persistence of CVR after cessation of NUC in virologically suppressed antiviral resistant CHB patients using TDF+NUC combination therapy. This study recruited 76 antiviral-resistant CHB patients showing CVR on TDF+entecavir (ETV) (n = 52), TDF+lamivudine (LAM; n = 14), and TDF+telbivudine (LdT; n = 10) combination therapy, who were switched to TDF monotherapy as step-down therapy. At baseline, 47 patients were male and the median age was 53.0 years (range: 30-78 years); 72.3% cases were hepatitis B e antigen-positive (HBeAg+) and 23.7% were of liver cirrhosis. The median duration of TDF+NUC combination therapy was 20.8 months (range: 3-46 months). At a median follow-up of 24.7 months (range: 12-48 months) after switching to TDF monotherapy, all 76 patients maintained CVR, regardless of the duration of combination therapy and the type of prior NUC and antiviral resistance. Renal dysfunction was not observed during the treatment period. The step-down strategy of switching from TDF+NUC combination therapy to TDF monotherapy in virologically suppressed CHB patients with antiviral resistance should be considered.
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Affiliation(s)
- Dong Yun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Jeong Eun Song
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
- Yonsei Liver Center, Severance Hospital, Seoul, South Korea
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Wei W, Wang SF, Yu B, Ni M. Inhibition of HBV replication by delivering the dual-gene expression vector pHsa-miR16-siRNA in HepG2.2.15 cells. Curr Med Sci 2017; 37:828-832. [PMID: 29270739 DOI: 10.1007/s11596-017-1810-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Revised: 09/13/2017] [Indexed: 10/18/2022]
Abstract
This study aimed to construct the dual-gene expression vector pHsa-miR16-siRNA which can express human miR-16 and HBV X siRNA, and examine its regulatory effect on HBV gene expression in the HepG2.2.15 cell line. The expression vectors siR-1583 and pHsa-miR16-siRNA were designed and constructed. HepG2.2.15 cells were transfected with the empty vector, siR-1583, pmiR-16 and pHsa-miR16-siRNA, respectively. ELISA was performed to measure the expression of HBsAg and HBeAg in the culture supernatant 48 and72 h post transfection. Fluorescence quantitative PCR was used to measure the HBV mRNA degradation efficiency and HBV DNA copy number. The results showed that the expression of HBV genes was significantly inhibited in HepG2.2.15 cells transfected with siR-1583, pmiR-16 and pHsa-miR16-siRNA, respectively, when compared with that in cells transfected with the empty vectors, with the inhibitory effect of pHsa-miR16-siRNA being the most significant. ELISA showed that the inhibitory rates of HBsAg and HBeAg in pHsa-miR16-siRNA transfected cells were correspondingly 87.3% and 85.0% at 48 h, and 88.6% and 86.5% at 72 h post transfection (P<0.01 vs. control group). RT-PCR showed that the level of HBV mRNA decreased by 80.2% (t=-99.22, P<0.01), the genomic HBV DNA by 92.8% (t=-73.06, P<0.01), and the supernatant of HBV DNA copy number by 89.8% (t=-47.13, P<0.01) in pHsa-miR16-siRNA transfected group. It was suggested that the dual-gene expression vector pHsa-miR16-siRNA can inhibit the replication of HBV more efficiently than a single-gene expression vector.
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Affiliation(s)
- Wei Wei
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Su-Fei Wang
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Bing Yu
- Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Ming Ni
- Department of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Li X, Zhou K, He H, Zhou Q, Sun Y, Hou L, Shen L, Wang X, Zhou Y, Gong Z, He S, Jin H, Gu Z, Zhao S, Zhang L, Sun C, Zheng S, Cheng Z, Zhu Y, Zhang M, Li J, Chen S. Design, Synthesis, and Evaluation of Tetrahydropyrrolo[1,2- c]pyrimidines as Capsid Assembly Inhibitors for HBV Treatment. ACS Med Chem Lett 2017; 8:969-974. [PMID: 28947946 PMCID: PMC5601373 DOI: 10.1021/acsmedchemlett.7b00288] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 08/24/2017] [Indexed: 02/08/2023] Open
Abstract
The discovery of novel tetrahydropyrrolo[1,2-c]pyrimidines derivatives from Bay41_4109 as hepatitis B virus (HBV) inhibitors is herein reported. The structure-activity relationship optimization led to one highly efficacious compound 28a (IC50 = 10 nM) with good PK profiles and the favorite L/P ratio. The hydrodynamic injection model in mice clearly demonstrated the efficacy of 28a against HBV replication.
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Affiliation(s)
- Xiaolin Li
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Kai Zhou
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Haiying He
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Qiong Zhou
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Ya Sun
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Lijuan Hou
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Liang Shen
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Xiaofei Wang
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Yuedong Zhou
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Zhen Gong
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Shibo He
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Huangtao Jin
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Zhengxian Gu
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Shuyong Zhao
- Shandong
Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd., No. 243 Gong Ye Bei Road, Jinan, Shandong Province 250100, P. R. China
| | - Long Zhang
- Shandong
Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd., No. 243 Gong Ye Bei Road, Jinan, Shandong Province 250100, P. R. China
| | - Chunyan Sun
- Shandong
Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd., No. 243 Gong Ye Bei Road, Jinan, Shandong Province 250100, P. R. China
| | - Shansong Zheng
- Shandong
Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd., No. 243 Gong Ye Bei Road, Jinan, Shandong Province 250100, P. R. China
| | - Zhe Cheng
- Shandong
Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd., No. 243 Gong Ye Bei Road, Jinan, Shandong Province 250100, P. R. China
| | - Yidong Zhu
- Shandong
Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd., No. 243 Gong Ye Bei Road, Jinan, Shandong Province 250100, P. R. China
| | - Minghui Zhang
- Shandong
Provincial Key Laboratory of Small Molecular Targeted Drugs, Qilu Pharmaceutical Co., Ltd., No. 243 Gong Ye Bei Road, Jinan, Shandong Province 250100, P. R. China
| | - Jian Li
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
| | - Shuhui Chen
- WuXi
AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong Road, Shanghai 200131, P. R. China
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Zhou J, Liu YY, Lian JS, Pan LF, Yang JL, Huang JR. Efficacy and Safety of Tenofovir Disoproxil Treatment for Chronic Hepatitis B Patients with Genotypic Resistance to Other Nucleoside Analogues: A Prospective Study. Chin Med J (Engl) 2017; 130:914-919. [PMID: 28397720 PMCID: PMC5407037 DOI: 10.4103/0366-6999.204107] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: Tenofovir disoproxil (TDF) is a promising salvage therapy for patients with chronic hepatitis B (CHB) who failed regimens of other nucleoside analogues (NAs). In this study, we aimed to investigate the clinical efficacy and safety of TDF monotherapy in Chinese CHB patients with genotypic resistance. Methods: A total of 33 CHB patients who had failed treatment with other NAs and had genotypic resistance were switched to TDF monotherapy for 48 weeks. Patients’ demographic data (age, sex, history of hepatitis B virus [HBV] therapy), laboratory testing results (hepatitis B e antigen [HBeAg] status, HBV DNA levels, alanine aminotransferase [ALT] levels, serum creatinine, urinary protein, genotypic assay), clinical symptoms, and liver color ultrasound examinations were collected for evaluation at day 0 (baseline) and the 12th, 24th, 36th, and 48th weeks after initiating treatment. Statistical analyses were carried out using rank sum test or rank correlation. Results: With regard to efficacy, the study found that all patients who switched to TDF monotherapy had undetectable HBV DNA levels after 48 weeks. In addition, patients with lower baseline HBV DNA levels realized earlier virological undetectability (rs = 0.39, P = 0.030). ALT levels were normal in 30 of 33 patients (91%). HBeAg negative conversion occurred in 7 of 25 patients (28%), among whom HBeAg seroconversion (12%) and HBeAg seroclearance (16%) occurred. The time of complete virological response was significantly affected by the number of resistance loci (rs = 0.36, P = 0.040). Concerning safety, the study found that no adverse events were observed during the 48 weeks. Conclusion: TDF monotherapy is an effective and safe salvage treatment for CHB patients who are resistant to other NAs.
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Affiliation(s)
- Jing Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003; Department of Infectious Disease, The First People's Hospital of Yongkang, Jinhua, Zhejiang 321300, China
| | - Yue-Ying Liu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
| | - Jiang-Shan Lian
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
| | - Li-Fang Pan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
| | - Jian-Le Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
| | - Jian-Rong Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang 310003, China
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Inhibitory effects of metachromin A on hepatitis B virus production via impairment of the viral promoter activity. Antiviral Res 2017; 145:136-145. [PMID: 28827084 DOI: 10.1016/j.antiviral.2017.08.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 07/14/2017] [Accepted: 08/02/2017] [Indexed: 01/12/2023]
Abstract
The currently available antiviral agents for chronic infection with hepatitis B virus (HBV) are pegylated interferon-α and nucleoside/nucleotide analogues, although it has been difficult to completely eliminate covalently closed circular DNA (cccDNA) from patients. To identify an antiviral compound targeting HBV core promoter, 15 terpenes originating from marine organisms were screened using a cell line expressing firefly luciferase under the control of the HBV core promoter. Metachromin A, which is a merosesquiterpene isolated from the marine sponge Dactylospongia metachromia, inhibited the viral promoter activity at the highest level among the tested compounds, and suppressed HBV production with an EC50 value of 0.8 μM regardless of interferon signaling and cytotoxicity. The analysis on the structure-activity relationship revealed that the hydroquinone moiety, and the double bonds at carbon numbers-5 and -9 in metachromin A are crucial for anti-HBV activity. Furthermore, metachromin A reduced the protein level but not the RNA level of hepatic nuclear factor 4α, which mainly upregulates the activities of enhancer I/X promoter and enhancer II/core promoter. These results suggest that metachromin A can inhibit HBV production via impairment of the viral promoter activity. Antiviral agents targeting the viral promoter may ameliorate HBV-related disorders regardless of remaining cccDNA.
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Kim SY, Kim H, Kim SW, Lee NR, Yi CM, Heo J, Kim BJ, Kim NJ, Inn KS. An Effective Antiviral Approach Targeting Hepatitis B Virus with NJK14047, a Novel and Selective Biphenyl Amide p38 Mitogen-Activated Protein Kinase Inhibitor. Antimicrob Agents Chemother 2017; 61:e00214-17. [PMID: 28559272 PMCID: PMC5527585 DOI: 10.1128/aac.00214-17] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 05/16/2017] [Indexed: 12/17/2022] Open
Abstract
Despite recent advances in therapeutic strategies against hepatitis B virus (HBV) infection, chronic hepatitis B remains a major global health burden. Recent studies have shown that targeting host factors instead of viral factors can be an effective antiviral strategy with low risk of the development of resistance. Efforts to identify host factors affecting viral replication have identified p38 mitogen-activated protein kinase (MAPK) as a possible target for antiviral strategies against various viruses, including HBV. Here, a series of biphenyl amides were synthesized as novel p38 MAPK selective inhibitors and assessed for their anti-HBV activities. The suppression of HBV surface antigen (HBsAg) production by these compounds was positively correlated with p38 MAPK-inhibitory activity. The selected compound NJK14047 displayed significant anti-HBV activity, as determined by HBsAg production, HBeAg secretion, and HBV production. NJK14047 efficiently suppressed the secretion of HBV antigens and HBV particles from HBV genome-transfected cells and HBV-infected sodium taurocholate cotransporting polypeptide-expressing human hepatoma cells. Furthermore, NJK14047 treatment resulted in a significant decrease of pregenomic RNA and covalently closed circular DNA (cccDNA) of HBV in HBV-harboring cells, indicating its ability to inhibit HBV replication. Considering that suppression of HBsAg secretion and elimination of cccDNA of HBV are the major aims of anti-HBV therapeutic strategies, the results suggested the potential use of these compounds as a novel class of anti-HBV agents targeting host factors critical for viral infection.
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Affiliation(s)
- So-Young Kim
- Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Hong Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Sang-Won Kim
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Na-Rae Lee
- Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Chae-Min Yi
- Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Jinyuk Heo
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Nam-Jung Kim
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Kyung-Soo Inn
- Department of Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
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Yuan G, Hu C, Zhou Y, Liu J, Huang H, Li Y, Yang D, Zhou F, Zhang YY, Zhou Y. A different inhibitor is required for overcoming entecavir resistance: a comparison of four rescue therapies in a retrospective study. Br J Clin Pharmacol 2017; 83:2259-2265. [PMID: 28511283 DOI: 10.1111/bcp.13330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Revised: 05/03/2017] [Accepted: 05/14/2017] [Indexed: 01/02/2023] Open
Abstract
AIMS Little clinical data are available regarding re-establishing the effective inhibition of entecavir (ETV)-resistant mutants. In this retrospective study, we aimed to compare the efficacies of four treatment regimens as rescue therapy for those chronic hepatitis B (CHB) patients with ETV resistance. METHODS A total of 65 patients with ETV resistance were assigned either with tenofovir disoproxil fumarate (TDF) monotherapy (n = 21), ETV (0.5 mg) plus adefovir (ADV) combination therapy (n = 19), ETV (1.0 mg) monotherapy (n = 11) or ETV (0.5 mg) plus TDF combination therapy (n = 14). The efficacy and safety of four treatment regimens were compared. RESULTS There were no significant differences among the four study groups in baseline characteristics, including HBV DNA levels (χ2 = 0.749, P = 0.862) and hepatitis B e antigen-positivity (χ2 = 0.099, P = 0.992). The median reduction in serum HBV DNA level from baseline at week 48 was -2.37 ± 1.07 log10 IU ml-1 , -2.16 ± 0.81 log10 IU ml-1 , -1.17 ± 1.23 log10 IU ml-1 and -2.49 ± 1.10 log10 IU ml-1 , respectively (F = 4.078, P = 0.011). The TDF group and ETV (0.5 mg) + TDF group have the highest undetectable HBV DNA rate (76.19% vs. 78.57%) compared to the ETV (0.5 mg) + ADV group and the ETV (1.0 mg) group (63.16% vs. 18.18%, respectively). Two patients in the ETV (1.0 mg) group experienced virological breakthrough at week 48 and was attributed to poor drug adherence. CONCLUSIONS TDF monotherapy appeared to deliver the highest undetectable HBV DNA rate in patients with ETV resistance, and ADV plus ETV combination therapy could be another choice for patients with financial restraint.
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Affiliation(s)
- Guosheng Yuan
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chengguang Hu
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuchen Zhou
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junwei Liu
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huaping Huang
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Li
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Dinghua Yang
- Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fuyuan Zhou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | | | - Yuanping Zhou
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Schreiner S, Nassal M. A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation-and Beyond? Viruses 2017; 9:v9050125. [PMID: 28531167 PMCID: PMC5454437 DOI: 10.3390/v9050125] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 05/16/2017] [Accepted: 05/18/2017] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular (RC) DNA as genome in infectious particles. Upon infection, RC-DNA is converted into nuclear covalently closed circular (ccc) DNA. Associating with cellular proteins into an episomal minichromosome, cccDNA acts as template for new viral RNAs, ensuring formation of progeny virions. Hence, cccDNA represents the viral persistence reservoir that is not directly targeted by current anti-HBV therapeutics. Eliminating cccDNA will thus be at the heart of a cure for chronic hepatitis B. The low production of HBV cccDNA in most experimental models and the associated problems in reliable cccDNA quantitation have long hampered a deeper understanding of cccDNA molecular biology. Recent advancements including cccDNA-dependent cell culture systems have begun to identify select host DNA repair enzymes that HBV usurps for RC-DNA to cccDNA conversion. While this list is bound to grow, it may represent just one facet of a broader interaction with the cellular DNA damage response (DDR), a network of pathways that sense and repair aberrant DNA structures and in the process profoundly affect the cell cycle, up to inducing cell death if repair fails. Given the divergent interactions between other viruses and the DDR it will be intriguing to see how HBV copes with this multipronged host system.
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Affiliation(s)
- Sabrina Schreiner
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg, D-85764 Munich, Germany.
| | - Michael Nassal
- Dept. of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Hugstetter Str. 55, D-79106 Freiburg, Germany.
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Cost-Effectiveness Comparison Between the Response-Guided Therapies and Monotherapies of Nucleos(t)ide Analogues for Chronic Hepatitis B Patients in China. Clin Drug Investig 2017; 37:233-247. [PMID: 27928739 DOI: 10.1007/s40261-016-0486-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVE Nucleos(t)ide analogue (NA) monotherapies are typically used as the primary treatment for chronic hepatitis B (CHB) patients, including lamivudine (LAM), telbivudine (TBV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF). For high-resistance NAs (LAM, TBV, ADV), they can generate excellent clinical outcomes by using response-guided therapy; however, their pharmacoeconomic profiles remain unclear in China. We aimed to evaluate the cost effectiveness between response-guided therapies and monotherapies of NAs for Chinese hepatitis B e-antigen (HBeAg)-positive and -negative CHB patients. METHODS We constructed a Markov model to simulate CHB progression associated with 12 treatment strategies using effectiveness and cost data from the published literature. We measured the lifetime costs, quality adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). One-way sensitivity (especially to extend the range of the TDF price) and probabilistic sensitivity analyses were used to explore the uncertainties of the model. RESULTS For both HBeAg-positive and -negative patients, no treatment strategy generated the lowest lifetime costs (US$31,185-US$31,338) and QALYs (7.54-7.58). ETV and TDF monotherapies were not dominated by other treatments, whereas, the ICER of ETV monotherapy was the lowest (US$6112/QALY-US$8533/QALY). For each high-resistance NA, compared with its monotherapy, the ICERs of its response-guided therapies were below the willingness-to-pay threshold of US$22,833/QALY. Additionally, TDF monotherapy was the preferred treatment when its price dropped to US$1820/year or lower. CONCLUSION Among 12 treatment strategies evaluated, ETV monotherapy is the most cost-effective treatment for treatment-naive CHB patients in China. The response-guided therapies of high-resistance NAs are more cost-effective than their monotherapies.
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Wei L, Kao JH. Benefits of long-term therapy with nucleos(t)ide analogues in treatment-naïve patients with chronic hepatitis B. Curr Med Res Opin 2017; 33:495-504. [PMID: 27882776 DOI: 10.1080/03007995.2016.1264932] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE To assess the benefits of long-term nucleos(t)ide analogue (NA) therapy in reducing the severity and progression of liver disease in treatment-naïve patients with chronic hepatitis B (CHB). SCOPE As complications of CHB, such as hepatic decompensation and hepatocellular carcinoma (HCC), take a long time to develop in patients with less advanced disease, the long-term benefits of NA therapy in such patients are more difficult to prove than short- or medium-term benefits. Thus, the recent literature was reviewed to evaluate the impact of NA therapy on the long-term outcomes of treatment-naïve CHB patients. METHODS A literature search of the MEDLINE/PubMed database was undertaken to identify studies published since 2010 of the long-term use of NAs with high potency and low drug resistance profiles in treatment-naïve CHB patients. A total of 22 studies were identified, many of which were retrospective analyses or case-control studies, as well as three meta-analyses and one systematic review. RESULTS Analysis of the retrieved studies showed that long-term NA therapy in treatment-naïve CHB patients did prevent or delay the occurrence of complications, including hepatic decompensation, HCC, and liver-related death, in comparison with no treatment. However, it did not completely eliminate the risk of these complications, particularly in those with cirrhosis. Although long-term NA therapy improved the clinical status of patients with decompensated cirrhosis, the risk of cirrhotic complications including HCC, liver transplantation, and liver-related mortality remained significant in comparison with those with compensated cirrhosis. CONCLUSIONS Long-term administration is generally advised in all CHB patients treated with NAs because of the high rates of virological and clinical relapse after stopping therapy. The findings of this analysis lend support to the choice of highly potent agents with a low drug resistance profile to maximize viral suppression in CHB patients and halt or delay progression to end-stage liver disease.
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Affiliation(s)
- Lai Wei
- a Peking University People's Hospital, Peking Hepatology Institute , Beijing
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Decay of ccc-DNA marks persistence of intrahepatic viral DNA synthesis under tenofovir in HIV-HBV co-infected patients. J Hepatol 2016; 65:683-691. [PMID: 27210429 DOI: 10.1016/j.jhep.2016.05.014] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Revised: 05/11/2016] [Accepted: 05/12/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS In the presence of highly-potent antivirals, persistence of hepatitis B virus (HBV) is most well-characterized by covalently-closed circular DNA (cccDNA) and total intrahepatic DNA (IH-DNA). We sought to determine how antiviral therapy could affect their levels during human immunodeficiency virus (HIV)-HBV co-infection. METHODS Sixty co-infected patients from a well-defined cohort with ⩾1 liver biopsy were studied. HBV cccDNA and total IH-DNA were extracted from biopsies and quantified by real-time PCR. Factors associated with intrahepatic viral load were determined using mixed-effect linear regression and half-life viral kinetics during reconstructed follow-up using non-linear exponential decay models. RESULTS At biopsy, 35 (58.3%) patients were hepatitis B "e" antigen (HBeAg)-positive and 33 (55.0%) had detectable plasma HBV-DNA (median=4.58log10IU/ml, IQR=2.95-7.43). Overall, median cccDNA was -0.95log10copies/cell (IQR=-1.70, -0.17) and total IH-DNA was 0.27log10copies/cell (IQR=-0.39, 2.00). In multivariable analysis, significantly lower levels of cccDNA and total IH-DNA were observed in patients with HBeAg-negative serology, nadir CD4(+) cell counts >250/mm(3), and longer cumulative TDF-duration, but not lamivudine- or adefovir-duration. In post-hoc analysis using reconstructed TDF-duration (median 29.6months, IQR=15.0-36.1, n=31), average half-life of cccDNA was estimated at 9.2months (HBeAg-positive=8.6, HBeAg-negative=26.2) and total IH DNA at 5.8months (HBeAg-positive=1.3, HBeAg-negative=13.6). Intrahepatic viral loads remained detectable for all patients, even with prolonged TDF-exposure. CONCLUSIONS In co-infection, TDF-use is associated with lower levels of HBV replication intermediates and cccDNA. Slow decay of intrahepatic viral loads underscores that TDF is unable to completely block intracellular viral DNA synthesis, which possibly accounts for continuous replenishment of the cccDNA pool. LAY SUMMARY Chronic hepatitis B virus (HBV) is a persistent infection, while the only real way of knowing the extent of this persistence is through measuring levels of virus in the liver. In this study, we examine levels of HBV in the liver among patients with both HBV and human immunodeficiency virus, or HIV, infection. It would appear that the currently available medication, namely "tenofovir", works well to decrease virus levels in the liver, but it remains at low levels despite long periods of treatment.
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Tenofovir and kidney transplantation: case report. Clin Nephrol Case Stud 2016; 4:18-23. [PMID: 29043137 PMCID: PMC5438008 DOI: 10.5414/cncs108929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 06/29/2016] [Indexed: 12/15/2022] Open
Abstract
Background: Hepatitis B viral infection (HBV) has been regarded as a contraindication for kidney transplantation because of the high risk of viral activation induced by immunosuppressive therapy. Anti-retroviral drugs have changed the prognosis of patients with hepatitis B viral infection (HBV+) who are candidates for renal transplant; indeed, therapy with antiretroviral drugs may ensure lower rates of morbidity and mortality compared to traditional therapies. Entecavir is the first-line antiviral therapy recommended for the treatment of HBV+ kidney-transplanted patients. In case of resistance to entecavir, tenofovir may be an alternative drug, either alone or in combination with entecavir. However, the best strategy of treatment is still unknown. In this case-report, a HBV+ kidney-transplanted patient who presented resistance to entecavir was initially treated by associating tenofovir to entecavir and with tenofovir alone afterward. This strategy induced complete remission of viral replication. Case presentation: In a HBV+ kidney-transplanted patient under monotherapy with entecavir, HBV flare (HBV DNA > 170.000 × 103 UI/mL, HBeAg+, HbeAb–) occurred 9 months after transplantation; at that time, blood chemistry highlighted: creatinine 1.46 mg/dL, blood urea 65 mg/dL, e-GFR 50 mL/min, proteinuria 300 mg/24 h, calciuria 2,12 mmol/24 h, phosphaturia 0.56 g/24 h, vitamin D 11.5 ng/mL, PTH 130 pg/mL, calcemia 2.3 mmol/L, and phosphoremia 2 mg/dL. Liver elastometry (FibroScan) showed moderate fibrosis. Tenofovir was associated to entecavir. Three months after the combination therapy, reduction in HBV DNA replication (351 × 103 UI/mL) was obtained. Creatinine and e-GFR were 1.48 mg/dL and 52 mL/min, respectively. At this point, entecavir was discontinued. After 13 months of tenofovir monotherapy, complete remission of viral replication was achieved but renal function deteriorated and proteinuria increased. Conclusion: This case-report indicates that tenofovir is effective in reducing viral replication of hepatitis B virus in a kidney-transplanted patient who presented resistance to previous treatment with entecavir. However, it should be taken into account that tenofovir could affect renal function.
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Keshavarz K, Kebriaeezadeh A, Alavian SM, Akbari Sari A, Rezaei Hemami M, Lotfi F, Hashemi Meshkini A, Javanbakht M, Keshvari M, Nikfar S. A Cost-Utility and Cost-Effectiveness Analysis of Different Oral Antiviral Medications in Patients With HBeAg-Negative Chronic Hepatitis B in Iran: An Economic Microsimulation Decision Model. HEPATITIS MONTHLY 2016; 16:e37435. [PMID: 27822262 PMCID: PMC5091008 DOI: 10.5812/hepatmon.37435] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2016] [Revised: 07/02/2016] [Accepted: 08/07/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although hepatitis B infection is the major cause of chronic liver disease in Iran, no studies have employed economic evaluations of the medications used to treat Iranian patients with chronic hepatitis B (CHB). Therefore, the cost-effectiveness of the different treatment options for this disease in Iran is unknown. OBJECTIVES The aim of this study was to compare the cost utility and cost-effectiveness of medication strategies tailored to local conditions in patients with HB e antigen (HBeAg)-negative CHB infection in Iran. METHODS An economic evaluation of the cost utility of the following five oral medication strategies was conducted: adefovir (ADV), lamivudine (LAM), ADV + LAM, entecavir (ETV), and tenofovir (TDF). A Markov microsimulation model was used to estimate the clinical and economic outcomes over the course of the patient's lifetime and based on a societal perspective. Medical and nonmedical direct costs and indirect costs were included in the study and life-years gained (LYG) and quality-adjusted life-years (QALY) were determined as measures of effectiveness. The results are presented in terms of the incremental cost-effectiveness ratio (ICER) per QALY or LYG. The model consisted of nine stages of the disease. The transition probabilities for the movement between the different stages were based on clinical evidence and international expert opinion. A probabilistic sensitivity analysis (PSA) was used to measure the effects of uncertainty in the model parameters. RESULTS The results revealed that the TDF treatment strategy was more effective and less costly than the other options. In addition, TDF had the highest QALY and LYG in the HBeAg-negative CHB patients, with 13.58 and 21.26 (discounted) in all comparisons. The PSA proved the robustness of the model results. The cost-effectiveness acceptability curves showed that TDF was the most cost-effective treatment in 59% - 78% of the simulations of HBeAg-negative patients, with WTP thresholds less than $14010 (maximum WTP per QALY). CONCLUSIONS The use of TDF in patients with HBeAg-negative CHB seemed to be a highly cost-effective strategy. Compared with the other available medication options, TDF was the most cost-saving strategy. Thus, TDF may be the best option as a first-line medication. Patients can also be switched from other medications to TDF.
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Affiliation(s)
- Khosro Keshavarz
- Health Human Resource Research Center, School of Management and Information Sciences, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Abbas Kebriaeezadeh
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Ali Akbari Sari
- Department of Health Management and Economics, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Mohsen Rezaei Hemami
- Institute of Health & Wellbeing, Health Economics & Health Technology Assessment, University of Glasgow, Glasgow, United Kingdom
| | - Farhad Lotfi
- Health Human Resource Research Center, School of Management and Information Sciences, Shiraz University of Medical Sciences, Shiraz, IR Iran
| | - Amir Hashemi Meshkini
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Mehdi Javanbakht
- Health Economics Research Unit, Institute of Applied Health Sciences, University of Aberdeen, Aberdeen, UK
| | - Maryam Keshvari
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, IR Iran
| | - Shekoufeh Nikfar
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran
- Corresponding Author: Shekoufeh Nikfar, Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, IR Iran. Tel: +98-09123271200, Fax: +98-2188611883, E-mail:
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