|
1
|
Izumi T, Toshima T, Itoh S, Yoshiya S, Bekki Y, Iseda N, Tsutsui Y, Toshida K, Nakayama Y, Ishikawa T, Yoshizumi T. Novel protocol for prevention from hepatitis B reactivation following living-donor liver transplantation. Hepatol Res 2024. [PMID: 39276320 DOI: 10.1111/hepr.14110] [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: 10/19/2023] [Revised: 08/06/2024] [Accepted: 08/25/2024] [Indexed: 09/16/2024]
Abstract
AIM Reactivation of hepatitis B virus (HBV) after liver transplantation (LT) remains a problem; thus, development of more effective HBV reactivation prophylaxis is desirable. We evaluated the efficacy of a combination of a long-term nucleotide analog (NA), such as entecavir (ETV) or tenofovir alafenamide (TAF), and short-term hepatitis B immunoglobulin (HBIG) in preventing HBV reactivation and compared it with conventional HBV prophylaxis. METHODS Between February 1999 and August 2023, 135 patients underwent living-donor liver transplantation for liver cirrhosis or acute liver failure caused by HBV infection or received an LT from a hepatitis B core antibody-positive donor. Recipients who had undergone LT were classified as being in the first or second era (namely until September 2017 and from October 2017), respectively, and outcomes of prophylaxis against HBV reactivation were compared between the two eras. RESULTS In the second era, recipients with HBV-related disease or who had received hepatitis B core antibody-positive liver received combination therapy with short-term HBIG and an NA such as TAF and ETV long-term. The duration of HBIG treatment was markedly shorter than in the first era in both categories of patients and HBIG could be discontinued in all cases. Surprisingly, we observed HBV reactivation in the first era, but not in the second era, in both groups. CONCLUSIONS We have established a protocol for prophylaxis against HBV reactivation using a combination of short-term HBIG and long-term NA. This protocol was found to be sufficient to prevent HBV reactivation after LT.
Collapse
Affiliation(s)
- Takuma Izumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Bekki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Norifumi Iseda
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuriko Tsutsui
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsuya Toshida
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Nakayama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takuma Ishikawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
2
|
Beck H, Dalavaye N, Kengadaran K, Khatun MM, Patel RH, Al-Rubaye T, Alrubaiy L. Hepatitis B Management in the Middle East: A Narrative Review of Current Antiviral Treatments. GASTROINTESTINAL DISORDERS 2024; 6:784-795. [DOI: 10.3390/gidisord6030054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
Abstract
Introduction: Chronic hepatitis B (CHB) is a significant public health issue worldwide, especially in the Middle East region. Around 8% to 20% of patients with CHB develop cirrhosis, which may progress to hepatocellular carcinoma. The significant morbidity and mortality associated with CHB denote the importance of high-quality treatment. Methods: We searched the PubMed, Medline, and Cochrane databases from inception to January 2024 to identify relevant studies. Search terms were generated using established treatment guidelines for CHB. We also manually searched the bibliographies of relevant literature to obtain additional papers. Results: In this narrative review, we evaluated the seven currently licensed antiviral therapies for chronic Hepatitis B treatment, including nucleos(t)ide analogs (NAs) and pegylated interferon-alpha (PEG-IFNα). NAs can be divided into two categories: high barrier to resistance and low barrier to resistance. Tenofovir disoproxil fumarate, tenofovir alafenamide, and entecavir are NAs with a high barrier to resistance. Telbivudine has shown promise in providing high efficacy with low viral resistance rates; however, it is not recommended because of insufficient evidence and lack of cost-effectiveness. Lamivudine and adefovir dipivoxil, despite being efficacious, have a low barrier to resistance, the primary reason they are no longer recommended. PEG-IFNα has high efficacy and can be completed in 48 weeks. It is not associated with resistance; however, it has been reported to have several systemic adverse effects. Conclusions: Current first-line NA treatments in the Middle East include entecavir, tenofovir disoproxil fumarate, and tenofovir alafenamide. These drugs are favored over other NAs because of their low rates of resistance. PEG-IFNα has superiority over NAs in inducing a more durable antiviral response and having a finite treatment duration. The main drawback of PEG-IFNα is an unfavorable safety profile.
Collapse
Affiliation(s)
- Hannah Beck
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Nishaanth Dalavaye
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | | | | | - Ria Hitesh Patel
- Gastroenterology and Hepatology Department, Imperial College London, London SW7 2AZ, UK
| | - Taif Al-Rubaye
- Primary Care Services, National Health Service, Manchester M26 2SP, UK
| | - Laith Alrubaiy
- Healthpoint Hospital, Abu Dhabi 112308, United Arab Emirates
- International Section of the British Society of Gastroenterology, London NW1 4LB, UK
- Department of Medicine Health and Life Sciences, Singleton Bay Campus, Swansea University School of Medicine, Swansea SA2 8PP, UK
| |
Collapse
|
|
3
|
Çelik M, Arslan Y, Önder T, Alkan S, Şahin A, Akgül F. Possible drug-drug interactions among elderly patients receiving antiviral therapy for chronic hepatitis B. Croat Med J 2024; 65:305-312. [PMID: 39219194 PMCID: PMC11399722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Abstract
AIM To identify possible drug-drug interactions in patients taking medications for other comorbidities while on antiviral therapy for chronic hepatitis B. METHODS The study enrolled patients with chronic hepatitis B aged ≥60 years who were treated with antiviral therapy in five hospitals in Turkey between January 1 and March 1, 2023. The Lexicomp® Drug Interactions program was used to identify possible drug-drug interactions. RESULTS The study included 213 patients (119 [55.9%] men). The mean age was 68.5 years. A potential drug-drug interaction was identified in 112 patients (52.6%). The most common type of interaction was type C ("follow the treatment") (71.54%). The number of potential drug-drug interactions increased with an increase in the number of drugs used by the patients. A robust and affirmative correlation was observed between the number of medications used and the number of possible drug-drug interactions (r=0.791, P<0.001). Adverse interactions (interactions of types C and D, 3.7% of cases) were limited to patients receiving tenofovir disoproxil fumarate. CONCLUSION Nonsteroidal anti-inflammatory medications should be used cautiously in elderly patients with chronic hepatitis B treated with tenofovir disoproxil fumarate due to the increased risk of renal toxicity.
Collapse
Affiliation(s)
- Mehmet Çelik
- Mehmet Çelik, Karşiyaka neighborhood, 498th street Tema Yeşilvadi Buildings A-block, Floor:6, No:12, Haliliye/Sanliurfa, Turkey,
| | | | | | | | | | | |
Collapse
|
|
4
|
Liaw YF, Jeng WJ, Chien RN. Reply: Benefits of stopping therapy in patients with cirrhotic hepatitis B, true effect, or residual confounding? Hepatology 2024; 79:E97-E98. [PMID: 37862454 DOI: 10.1097/hep.0000000000000641] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/22/2023]
Affiliation(s)
- Yun-Fan Liaw
- Department of Medicine, College of Medicine, Chang Gung University, Taipei, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
| | - Wen-Juei Jeng
- Department of Medicine, College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Department of Medicine, College of Medicine, Chang Gung University, Taipei, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
| |
Collapse
|
|
5
|
Liu YC, Jeng WJ, Chien RN. Letter: Safety after cessation of nucleos(t)ide analogue therapy in patients with chronic hepatitis B infection. Aliment Pharmacol Ther 2023; 58:731-732. [PMID: 37702033 DOI: 10.1111/apt.17657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/14/2023]
Abstract
LINKED CONTENTThis article is linked to Hsu et al papers. To view these articles, visit https://doi.org/10.1111/apt.17614 and https://doi.org/10.1111/apt.17681
Collapse
Affiliation(s)
- Yen-Chun Liu
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wen-Juei Jeng
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- College of Medicine, Chang Gung University, Taipei, Taiwan
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Liver Research Unit, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| |
Collapse
|
|
6
|
Reddy KR, McLerran D, Marsh T, Parikh N, Roberts LR, Schwartz M, Nguyen MH, Befeler A, Page-Lester S, Tang R, Srivastava S, Rinaudo JA, Feng Z, Marrero JA. Incidence and Risk Factors for Hepatocellular Carcinoma in Cirrhosis: The Multicenter Hepatocellular Carcinoma Early Detection Strategy (HEDS) Study. Gastroenterology 2023; 165:1053-1063.e6. [PMID: 37429366 PMCID: PMC10529044 DOI: 10.1053/j.gastro.2023.06.027] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/18/2023] [Accepted: 06/17/2023] [Indexed: 07/12/2023]
Abstract
BACKGROUND & AIMS Worldwide, hepatocellular carcinoma (HCC) is a common malignancy. We aimed to prospectively determine the incidence and risk factors of HCC in a U.S. COHORT METHODS The multicenter Hepatocellular Carcinoma Early Detection Strategy study of the National Institutes of Health prospectively enrolled patients with cirrhosis who underwent standard surveillance for HCC. Demographics, medical and family history, etiology of liver disease, and clinical features were evaluated for associations with HCC. RESULTS Between April 10, 2013 and December 31, 2021, 1723 patients were enrolled and confirmed eligible. During median follow-up of 2.2 years (range, 0-8.7 years), there were 109 incident cases of HCC for an incidence rate of 2.4 per 100 person-years: 88 (81%) patients with very early/early Barcelona Clinic Liver Cancer stage (0, A), 20 (18%) intermediate stage (B), and 1 (1%) unknown stage. Risk factor analyses were restricted to 1325 patients, including 95 incident HCC, with at least 6 months of follow-up. The majority were men (53.2%), obese or severely obese (median body mass index, 30.2 kg/m2), and white (86.3%); 42.0% had history of hepatitis C virus infection, 20.7% had alcoholic liver disease, and 24.9% had nonalcoholic fatty liver disease. Fourteen risk factors for HCC were significant (P < .05) in univariate analyses, and a multivariate subset was selected using stepwise logistic regression. The multivariate subset contained gender (P < .001; male; odds ratio [OR], 2.47; 95% confidence interval [CI], 1.54-4.07), years with cirrhosis (P = .004; OR, 1.06; 95% CI, 1.02-1.1), family history of liver cancer (P = .02; yes; OR, 2.69; 95% CI, 1.11-5.86), age (per 5 years; P = .02; OR, 1.17; 95% CI, 1.03-1.33), obesity (P = .02; yes; OR, 1.7; 95% CI, 1.08-2.73), aspartate aminotransferase (log(1+AST); P = .06; OR, 1.54; 95% CI, 0.97-2.42), alpha-fetoprotein (log(1+AFP); P = .07; OR, 1.32; 95% CI, 0.97-1.77), and albumin (P = .10; OR, 0.7; 95% CI, 0.46-1.07). CONCLUSIONS Thus far, this is the largest prospective and geographically diverse study of a U.S. cohort of patients with cirrhosis that validates known risk factors for HCC (gender, age, obesity, years with cirrhosis, family history of liver cancer, baseline AFP, albumin, and AST). The incidence of HCC was 2.4% per 100 person-years.
Collapse
Affiliation(s)
| | - Dale McLerran
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Tracey Marsh
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | | | | | | | | | | | | | - Runlong Tang
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | | | | | - Ziding Feng
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | | |
Collapse
|
|
7
|
Broquetas T, Carrión JA. Past, present, and future of long-term treatment for hepatitis B virus. World J Gastroenterol 2023; 29:3964-3983. [PMID: 37476586 PMCID: PMC10354584 DOI: 10.3748/wjg.v29.i25.3964] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 05/22/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
The estimated world prevalence of hepatitis B virus (HBV) infection is 316 million. HBV infection was identified in 1963 and nowadays is a major cause of cirrhosis and hepatocellular carcinoma (HCC) despite universal vaccination programs, and effective antiviral therapy. Long-term administration of nucleos(t)ide analogues (NA) has been the treatment of choice for chronic hepatitis B during the last decades. The NA has shown a good safety profile and high efficacy in controlling viral replication, improving histology, and decreasing the HCC incidence, decompensation, and mortality. However, the low probability of HBV surface antigen seroclearance made necessary an indefinite treatment. The knowledge, in recent years, about the different phases of the viral cycle, and the new insights into the role of the immune system have yielded an increase in new therapeutic approaches. Consequently, several clinical trials evaluating combinations of new drugs with different mechanisms of action are ongoing with promising results. This integrative literature review aims to assess the knowledge and major advances from the past of hepatitis B, the present of NA treatment and withdrawal, and the future perspectives with combined molecules to achieve a functional cure.
Collapse
Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona 08003, Spain
- Institut Hospital del Mar D’Investigacions Mèdiques, PSMAR, Barcelona 08003, Spain
- Universitat Pompeu Fabra, Facultat de Ciències de la Salut i de la Vida, Barcelona 08003, Spain
| |
Collapse
|
|
8
|
Ito T, Nguyen MH. Perspectives on the Underlying Etiology of HCC and Its Effects on Treatment Outcomes. J Hepatocell Carcinoma 2023; 10:413-428. [PMID: 36926055 PMCID: PMC10013586 DOI: 10.2147/jhc.s347959] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 02/25/2023] [Indexed: 03/11/2023] Open
Abstract
Hepatocellular carcinoma (HCC) continues to be a serious medical problem with poor prognosis worldwide. The distribution of the major etiologies of HCC is changing due to the progress of anti-viral treatments, including hepatitis B virus (HBV) suppression by nucleoside/nucleotide analogues (NAs) and increased sustained virologic response (SVR) rates by direct-acting antivirals (DAAs) for hepatitis C virus (HCV), as well as the rising trend of nonviral liver disease. Although viral hepatitis remains the most common cause of HCC, non-alcoholic liver disease (NAFLD) with metabolic syndrome and alcohol-associated liver disease (ALD) are increasing. Effective and well-tolerated NAs treatment can slow the disease progression of chronic HBV infection to cirrhosis, end-stage liver disease, and reduce HCC risk. Treatment with NAs is also associated with significant improvement in the long-term survival of patients with HBV infection who already have HCC. DAAs have achieved viral elimination in almost all patients with HCV without significant adverse events, even in patients with decompensated liver cirrhosis and HCC. Similarly, DAA therapy can reduce disease progression, liver and non-liver complications, and improve the long-term survival of patients with chronic HCV infection with or without HCC. Meanwhile, NAFLD is a rapidly increasing cause of HCC along with the epidemics of obesity and type 2 diabetes globally. NAFLD-related HCC can occur in patients without cirrhosis and is known to have a lower survival rate than viral hepatitis-related HCC. Since there is currently no specific pharmacotherapy effective for NAFLD, lifestyle modification and prevention of complications are important to improve prognosis. Additionally, ALD is the second fastest-growing cause of HCC-related deaths, especially with an accelerated trend since the COVID-19 pandemic. This review provides an overview of the epidemiologic trends in the etiologies of HCC, and the progress of treatments for each etiology and the impact on outcome in the patients with HCC.
Collapse
Affiliation(s)
- Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, CA, USA.,Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, CA, USA
| |
Collapse
|
|
9
|
Aguilar JC, Aguiar JA, Akbar SMF. Action Mechanisms and Scientific Rationale of Using Nasal Vaccine (HeberNasvac) for the Treatment of Chronic Hepatitis B. Vaccines (Basel) 2022; 10:2087. [PMID: 36560498 PMCID: PMC9787858 DOI: 10.3390/vaccines10122087] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 11/29/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022] Open
Abstract
Nasvac (HeberNasvac®) is a novel therapeutic vaccine for chronic hepatitis B (CHB). This product is a formulation of the core (HBcAg) and surface (HBsAg) antigens of the hepatitis B virus (HBV), administered by nasal and subcutaneous routes, in a distinctive schedule of immunizations. In the present review article, we discuss the action mechanisms of HeberNasvac, considering the immunological properties of the product and their antigens. Specifically, we discuss the capacity of HBcAg to activate different pathways of innate immunity and the signal transduction after a multi-TLR agonist effect, and we review the results of recent clinical trials and in vitro studies. Aimed at understanding the clinical results of Nasvac and other therapeutic vaccines under development, we discuss the rationale of administering a therapeutic vaccine through the nasal route and also the current alternatives to combine therapeutic vaccines and antivirals (NUCs). We also disclose potential applications of this product in novel fields of immunotherapy.
Collapse
Affiliation(s)
- Julio Cesar Aguilar
- Hepatitis B Therapeutic Vaccine Project, Center for Genetic Engineering and Biotechnology, La Habana 10600, Cuba
| | - Jorge Agustin Aguiar
- Hepatitis B Therapeutic Vaccine Project, Center for Genetic Engineering and Biotechnology, La Habana 10600, Cuba
| | - Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Matsuyama 791-0295, Japan
| |
Collapse
|
|
10
|
Xu JH, Wang S, Zhang DZ, Yu YY, Si CW, Zeng Z, Xu ZN, Li J, Mao Q, Tang H, Sheng JF, Chen XY, Ning Q, Shi GF, Xie Q, Zhang XQ, Dai J. One hundred and ninety-two weeks treatment of entecavir maleate for Chinese chronic hepatitis B predominantly genotyped B or C. World J Clin Cases 2022; 10:10085-10096. [PMID: 36246814 PMCID: PMC9561570 DOI: 10.12998/wjcc.v10.i28.10085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/12/2022] [Accepted: 08/24/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Entecavir (ETV) is a potent and selective nucleotide analog with significant activity against hepatitis B virus (HBV). ETV maleate is a derivative compound of ETV and was reported to have an efficacy and safety profile that is comparable to ETV (Baraclude) when used in Chinese patients with chronic hepatitis B (CHB) in phase III clinical trials (Clinical Trials.gov number, NCT01926288) at weeks 48, 96, and 144. AIM To investigate the antiviral potency and safety of ETV maleate at week 192 in Chinese CHB patients predominantly genotyped B or C. METHODS In this double-blind study, we randomly assigned patients to receive 0.5 mg/d ETV (Group A) or ETV maleate (Group B) (ratio, 1:1), each with a placebo tablet for 48 wk. Then, all patients received open-label treatment with 0.5 mg/d ETV maleate starting at week 49. The primary efficacy endpoint was the reduction in HBV DNA levels from baseline. Secondary endpoints included the proportion of patients with undetectable HBV DNA (< 20 IU/mL), serologic response, serum alanine aminotransferase (ALT) normalization and development of resistance mutations. RESULTS Two hundred eighteen patients who were hepatitis B e antigen (HBeAg) positive and 57 who were HBeAg negative were analyzed and predominantly presented with genotype B (49.82%) or C (48.73%). For the HBeAg-positive CHB patients, the mean HBV DNA level decrease (6.61 Log10 IU/mL vs 6.69 Log10 IU/mL, P > 0.05), viral suppression with HBV DNA < 20 IU/mL (83.33% vs 79.17%, P > 0.05) and HBeAg seroconversion (28.77% vs 20.00%, P > 0.05) occurred similarly between Groups A and B at week 192. However, there was a significant difference in the proportion of patients with normal ALT levels (91.14% vs 78.38%, P < 0.05). For the HBeAg-negative CHB patients, no significant difference was found between Groups A and B at week 192 in terms of reductions in HBV DNA levels from baseline (6.05 Log10 IU/mL vs 6.03 Log10 IU/mL, P > 0.05), percentages of patients who achieved undetectable HBV DNA (100% vs 100%, P > 0.05) and rates of ALT normalization (95.65% vs 100.00%, P > 0.05). Safety and adverse event profiles were similar between Groups A and B. Two HBeAg-positive patients in Group A and 5 in Group B developed genotypic resistance to ETV. CONCLUSION Long-term ETV maleate treatment for up to 192 wk is effective and safe in Chinese CHB patients predominantly genotyped as B or C.
Collapse
Affiliation(s)
- Jing-Hang Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing 100094, China
| | - Sa Wang
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Da-Zhi Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital with Chongqing Medical University, Chongqing 400010, China
| | - Yan-Yan Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing 100094, China
| | - Chong-Wen Si
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing 100094, China
| | - Zheng Zeng
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing 100094, China
| | - Zhong-Nan Xu
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing 222006, Jiangsu Province, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Qing Mao
- Department of Infectious Diseases, Southwest China Hospital, Chongqing 400038, China
| | - Hong Tang
- Department of Infectious Diseases, West China Hospital, Chengdu 610041, Sichuan Province, China
| | - Ji-Fang Sheng
- Department of Infectious Diseases, The First Affiliated Hospital of Zhejiang University, Hangzhou 310010, Zhejiang Province, China
| | - Xin-Yue Chen
- Department of International Medicine, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Qin Ning
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Guang-Feng Shi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai 200040, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai 200025, China
| | - Xi-Quan Zhang
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing 222006, Jiangsu Province, China
| | - Jun Dai
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing 222006, Jiangsu Province, China
| |
Collapse
|
|
11
|
Chang ML, Chien RN, Liaw YF. Evidence-Based Management of Oral Nucleos(t)ide Analogue Withdrawal in Virally Suppressed Patients with Chronic HBV Infection. CURRENT HEPATOLOGY REPORTS 2022; 21:52-58. [DOI: 10.1007/s11901-022-00587-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/11/2022] [Indexed: 01/02/2025]
|
|
12
|
Pan CQ, Afdhal NH, Ankoma‐Sey V, Bae H, Curry MP, Dieterich D, Frazier L, Frick A, Hann H, Kim WR, Kwo P, Milligan S, Tong MJ, Reddy KR. First-line therapies for hepatitis B in the United States: A 3-year prospective and multicenter real-world study after approval of tenofovir alefenamide. Hepatol Commun 2022; 6:1881-1894. [PMID: 35445803 PMCID: PMC9315121 DOI: 10.1002/hep4.1964] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 03/01/2022] [Accepted: 03/04/2022] [Indexed: 12/28/2022] Open
Abstract
Real-world data are limited on tenofovir alafenamide (TAF). We aimed to study TAF real-world outcomes with other first-line regimens for chronic hepatitis B (CHB). We enrolled patients with CHB from 10 centers retrospectively and followed them for 36 months prospectively. We analyzed switching patterns of antiviral therapy and treatment outcomes of TAF, tenofovir disoproxil fumarate (TDF), and entecavir therapy. For efficacy and safety, we analyzed a subset of patients with complete data at 24 months after switching to TAF or remaining on TDF or entecavir. Among 1037 enrollees, 889 patients were analyzed. The mean age was 52%, and 72% were hepatitis B e antigen-negative. After enrollment, shifts in therapies were mostly in reduced use of TDF from 63% to 30% due to switching to TAF. Clinical parameters were compared at enrollment or initiation to measures at 24 months for patients remaining on TAF (187), TDF (229), or entecavir (181). At 24 months, a significantly higher portion of patients on TAF achieved hepatitis B virus (HBV) DNA ≤ 20 IU/ml (93% vs. 86%; p = 0.012) and normalized alanine aminotransferase (ALT) (66% vs. 56%; p = 0.031) with stable estimated glomerular filtration rates (eGFRs). However, a higher percentage of the patient with eGFR < 60 ml/mi/1.7 m2 was observed in the TDF-treated group (9% vs. 4%; p = 0.010). In patients who remained on entecavir or TDF for 24 months, ALT and HBV-DNA results did not differ significantly from baseline. Treatment of CHB in the United States has significantly shifted from TDF to TAF. Our data suggest that switching from TDF or entecavir to TAF may result in increased frequency of ALT normalization and potential clearance of viremia at the 24-month time point.
Collapse
Affiliation(s)
- Calvin Q. Pan
- Beijing Ditan HospitalCapital Medical UniversityBeijingChina
- NYU Langone HealthNYU Grossman School of MedicineNew YorkNew YorkUSA
| | | | | | - Ho Bae
- St. Vincent Medical CenterAsian Pacific Liver CenterLos AngelesCaliforniaUSA
| | | | | | | | | | - Hie‐Won Hann
- Thomas Jefferson University HospitalPhiladelphiaPennsylvaniaUSA
| | - W. Ray Kim
- Stanford University School of MedicineStanfordCaliforniaUSA
| | - Paul Kwo
- Stanford University School of MedicineStanfordCaliforniaUSA
| | | | - Myron J. Tong
- Huntington Medical Research InstitutesPasadenaCaliforniaUSA
| | | |
Collapse
|
|
13
|
Fung S, Choi HSJ, Gehring A, Janssen HLA. Getting to HBV cure: The promising paths forward. Hepatology 2022; 76:233-250. [PMID: 34990029 DOI: 10.1002/hep.32314] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 12/17/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
Chronic HBV infection is a global public health burden estimated to impact nearly 300 million persons worldwide. Despite the advent of potent antiviral agents that effectively suppress viral replication, HBV cure remains difficult to achieve because of the persistence of covalently closed circular DNA (cccDNA), HBV-DNA integration into the host genome, and impaired immune response. Indefinite treatment is necessary for most patients to maintain level of viral suppression. The success of direct-acting antivirals (DAAs) for hepatitis C treatment has rejuvenated the search for a cure for chronic hepatitis B (CHB), though an HBV cure likely requires an additional layer: immunomodulators for restoration of robust immune responses. DAAs such as entry inhibitors, capsid assembly modulators, inhibitors of subviral particle release, cccDNA silencers, and RNA interference molecules have reached clinical development. Immunomodulators, namely innate immunomodulators (Toll-like receptor agonists), therapeutic vaccines, checkpoint inhibitors, and monoclonal antibodies, are also progressing toward clinical development. The future of the HBV cure possibly lies in triple combination therapies with concerted action on replication inhibition, antigen reduction, and immune stimulation. Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates. This review gives an overview of the current therapies for CHB, HBV biomarkers used to evaluate treatment response, and development of DAAs and immune-targeting drugs and discusses the limitations and unanswered questions on the journey to an HBV cure.
Collapse
Affiliation(s)
- Scott Fung
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Hannah S J Choi
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Adam Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, Toronto General Hospital, Toronto, Ontario, Canada
| |
Collapse
|
|
14
|
Broquetas T, Carrión JA. Current Perspectives on Nucleos(t)ide Analogue Therapy for the Long-Term Treatment of Hepatitis B Virus. Hepat Med 2022; 14:87-100. [PMID: 35936810 PMCID: PMC9346298 DOI: 10.2147/hmer.s291976] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/12/2022] [Indexed: 01/27/2023] Open
Affiliation(s)
- Teresa Broquetas
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - José A Carrión
- Liver Section, Gastroenterology Department, Hospital del Mar, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| |
Collapse
|
|
15
|
Nagra N, Kozarek RA, Burman BE. Therapeutic Advances in Viral Hepatitis A-E. Adv Ther 2022; 39:1524-1552. [PMID: 35220557 DOI: 10.1007/s12325-022-02070-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/31/2022] [Indexed: 11/25/2022]
Abstract
Viral hepatitis remains a significant global health problem. All forms of viral hepatitis A through E (A-E) can lead to acute symptomatic infection, while hepatitis B and C can lead to chronic infection associated with significant morbidity and mortality related to progression to cirrhosis, end-stage-liver disease, and liver cancer. Viral hepatitis occurs worldwide, though certain regions are disproportionately affected. We now, remarkably, have highly effective curative regimens for hepatitis C, and safe and tolerable medications to suppress hepatitis B activity, and to prevent liver damage and slow disease progression. We have effective vaccines for hepatitis A and B which provide long-lasting immunity, while improved sanitation and awareness can curb outbreaks of hepatitis A and E. However, more effective and available preventive and curative strategies are needed to achieve global eradication of viral hepatitis. This review provides an overview of the epidemiology, transmission, diagnosis, and clinical features of each viral hepatitis with a primary focus on current and future therapeutic and curative options.
Collapse
Affiliation(s)
- Navroop Nagra
- Department of Gastroenterology, University of Louisville, Louisville, KY, 40202, USA
| | - Richard A Kozarek
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA
| | - Blaire E Burman
- Center for Digestive Health, Virginia Mason Franciscan Health, 1100 9th Ave., Seattle, WA, 98101, USA.
| |
Collapse
|
|
16
|
Current Trend in Antiviral Therapy for Chronic Hepatitis B. Viruses 2022; 14:v14020434. [PMID: 35216027 PMCID: PMC8877417 DOI: 10.3390/v14020434] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/13/2022] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
Since active hepatitis B virus (HBV) replication is the key driver of hepatic necroinflammation and disease progression, the treatment aim of chronic hepatitis B (CHB) is to suppress HBV replication permanently to prevent hepatic decompensation, liver cirrhosis and/or hepatocellular carcinoma and prolong survival. Currently, pegylated interferon (Peg-IFN), entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line drugs of choice. Peg-IFN therapy has been used rarely due to its subcutaneous injection and significant side effect profile. Once daily oral ETV, TDF and TAF can suppress HBV DNA profoundly but have no direct action on cccDNA of the HBV-infected hepatocytes, hence continuing long-term therapy is usually needed to maintain HBV suppression, but the ultimate goal of HBsAg loss was rarely achieved (10 year 2%). In addition, long-term NUC therapy comes with several concerns such as increasing cost, medication adherence and loss-to-follow-up. Studies, mainly from Taiwan, have shown that finite NUCs therapy of two to three years in HBeAg-negative patients is feasible, safe and has a great benefit of much increasing HBsAg loss rate up to 30%/5 year. These have led an emerging paradigm shift to finite NUC therapy in HBeAg-negative patients globally. However, off-NUC relapse with hepatitis B flares may occur and have a risk of decompensation or even life-threatening outcomes. Therefore, proper monitoring, assessment, and retreatment decisions are crucial to ensure safety. Ideally, retreatment should be not too late to ensure safety and also not too early to allow further immune response for further HBsAg decline toward HBsAg loss. Assessment using combined HBsAg/ALT kinetics during hepatitis flare is better than biochemical markers alone to make a right retreatment decision. The strategy of finite NUC therapy has set a benchmark of high HBsAg loss rate to be achieved by the new anti-HBV drugs which are under preclinical or early phase study.
Collapse
|
|
17
|
Leowattana W, Leowattana T. Chronic hepatitis B: New potential therapeutic drugs target. World J Virol 2022; 11:57-72. [PMID: 35117971 PMCID: PMC8788212 DOI: 10.5501/wjv.v11.i1.57] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/13/2021] [Accepted: 01/05/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) infection remains the most causative agent of liver-related morbidity and mortality worldwide. It impacts nearly 300 million people. The current treatment for chronic infection with the hepatitis B virus (HBV) is complex and lacks a durable treatment response, especially hepatitis B surface antigen (HBsAg) loss, necessitating indefinite treatment in most CHB patients due to the persistence of HBV covalently closed circular DNA (cccDNA). New drugs that target distinct steps of the HBV life cycle have been investigated, which comprise inhibiting the entry of HBV into hepatocytes, disrupting or silencing HBV cccDNA, modulating nucleocapsid assembly, interfering HBV transcription, and inhibiting HBsAg release. The achievement of a functional cure or sustained HBsAg loss in CHB patients represents the following approach towards HBV eradication. This review will explore the up-to-date advances in the development of new direct-acting anti-HBV drugs. Hopefully, with the combination of the current antiviral drugs and the newly developed direct-acting antiviral drugs targeting the different steps of the HBV life cycle, the ultimate eradication of CHB infection will soon be achieved.
Collapse
Affiliation(s)
- Wattana Leowattana
- Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Bangkok 10110, Thailand
| |
Collapse
|
|
18
|
Charatcharoenwitthaya P, Kaewdech A, Piratvisuth T. Controversies in Treating Chronic HBV: The Role of PEG-interferon-alfa. Clin Liver Dis 2021; 25:741-762. [PMID: 34593151 DOI: 10.1016/j.cld.2021.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pegylated interferon-alpha therapy is one of the first-line chronic hepatitis B treatment. Finite treatment duration, absence of drug resistance, delayed response, and higher hepatitis B surface antigen loss than nucleos(t)ides analog therapy are the advantages of pegylated interferon-alpha treatment. Common side effects and subcutaneous injections requirement limit its use. Identifying patients likely to respond to pegylated interferon-alpha and optimizing treatment is reasonable. Motivating patients to complete the 48-week treatment is necessary. Treatment is stopped or switched to other treatment strategies in patients with stopping rule criteria. Combination therapy with nucleos(t)ides analog may improve response, but remains controversial.
Collapse
Affiliation(s)
- Phunchai Charatcharoenwitthaya
- Gastroenterology Division, Department of Internal Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Wang-Lang Road, Bangkok 10700, Thailand
| | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand
| | - Teerha Piratvisuth
- Gastroenterology and Hepatology Unit, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand; NKC Institute of Gastroenterology and Hepatology, Songklanagarind Hospital, Prince of Songkla University, Kanchanawanich Road, Songkhla 90110, Thailand.
| |
Collapse
|
|
19
|
Buti M, Riveiro-Barciela M, Esteban R. Treatment of Chronic Hepatitis B Virus with Oral Anti-Viral Therapy. Clin Liver Dis 2021; 25:725-740. [PMID: 34593150 DOI: 10.1016/j.cld.2021.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nucleoside analogues are the drugs most commonly used in the treatment of chronic hepatitis B. They act by inhibiting viral replication and have minimal impact on HBsAg loss. Nucleoside analogues are indicated in patients with chronic hepatitis, cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and in those with extrahepatic manifestations. Real-world experience has been ongoing for more than 10 years, and the efficacy and safety results obtained are similar to those reported in clinical trials. Prolonged use is needed to maintain suppression of viral replication, prevent the development of liver cirrhosis and decompensated cirrhosis, and to decrease the risk of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Maria Buti
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129, General Hospital, 5th floor, Barcelona 08035, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129, General Hospital, 5th floor, Barcelona 08035, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Rafael Esteban
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Passeig Vall d'Hebron 119-129, General Hospital, 5th floor, Barcelona 08035, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
20
|
Kaewdech A, Sripongpun P. Challenges in the discontinuation of chronic hepatitis B antiviral agents. World J Hepatol 2021; 13:1042-1057. [PMID: 34630873 PMCID: PMC8473499 DOI: 10.4254/wjh.v13.i9.1042] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 05/07/2021] [Accepted: 07/28/2021] [Indexed: 02/06/2023] Open
Abstract
Long-term antiviral treatment of chronic hepatitis B patients has been proven to be beneficial in reducing liver-related complications. However, lengthy periods of daily administration of medication have some inevitable drawbacks, including decreased medication adherence, increased cost of treatment, and possible long-term side effects. Currently, discontinuation of antiviral agent has become the strategy of interest to many hepatologists, as it might alleviate the aforementioned drawbacks and increase the probability of achieving functional cure. This review focuses on the current evidence of the outcomes following stopping antiviral treatment and the factors associated with subsequent hepatitis B virus relapse, hepatitis B surface antigen clearance, and unmet needs.
Collapse
Affiliation(s)
- Apichat Kaewdech
- Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand
| | - Pimsiri Sripongpun
- Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand.
| |
Collapse
|
|
21
|
Abstract
Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.
Collapse
Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan.,Department of Gastroenterology and Hepatology, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Medical Center, Chang Gung University, Chang Gung Memorial Hospital, College of Medicine, Taoyuan, Taiwan
| |
Collapse
|
|
22
|
APASL guidance on stopping nucleos(t)ide analogues in chronic hepatitis B patients. Hepatol Int 2021; 15:833-851. [PMID: 34297329 DOI: 10.1007/s12072-021-10223-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 06/21/2021] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is currently incurable. Long-term treatment with potent and safe nucleos(t)ide analogs (NAs) can reduce hepatocellular carcinoma (HCC) and cirrhosis-related complications through profound viral suppression. However, indefinite therapy raises several crucial issues with pros and cons. Because seroclearance of hepatitis B surface (HBsAg) as functional cure is not easily achievable, a finite therapy including sequential 48-week pegylated interferon therapy may provide an opportunity to facilitate HBsAg seroclearance by the rejuvenation of exhausted immune cells. However, the cost of stopping NA is the high incidence of virological relapse and surge of alanine aminotransferase (ALT) levels, which may increase the risk of adverse outcomes (e.g., decompensation, fibrosis progression, HCC, or liver-related mortality). So far, the APASL criteria to stop NA treatment is undetectable HBV DNA levels with normalization of ALT; however, this criterion for cessation of treatment is associated with various incidence rates of virological/clinical relapse and more than 40% of NA-stoppers eventually receive retreatment. A very intensive follow-up strategy and identification of low-risk patients for virological/clinical relapse by different biomarkers are the keys to stop the NA treatment safely. Recent studies suggested that decreasing HBsAg level at the end-of-treatment to < 100-200 IU/mL seems to be a useful marker for deciding when to discontinue NAs therapy. In addition, several viral and host factors have been reviewed for their potential roles in predicting clinical relapse. Finally, the APASL guidance has proposed rules to stop NA and the subsequent follow-up strategy to achieve a better prognosis after stopping NA. In general, for both HBeAg-positive and HBeAg-negative patients who have stopped treatment, these measurements should be done every 1-3 months at the minimum until 12 months.
Collapse
|
|
23
|
Yeh H, Chiang CC, Yen TH. Hepatocellular carcinoma in patients with renal dysfunction: Pathophysiology, prognosis, and treatment challenges. World J Gastroenterol 2021; 27:4104-4142. [PMID: 34326614 PMCID: PMC8311541 DOI: 10.3748/wjg.v27.i26.4104] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 03/17/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
The population of patients with hepatocellular carcinoma (HCC) overlaps to a high degree with those for chronic kidney disease (CKD) and end-stage renal disease (ESRD). The degrees of renal dysfunction vary, from the various stages of CKD to dialysis-dependent ESRD, which often affects the prognosis and treatment choice of patients with HCC. In addition, renal dysfunction makes treatment more difficult and may negatively affect treatment outcomes. This study summarized the possible causes of the high comorbidity of HCC and renal dysfunction. The possible mechanisms of CKD causing HCC involve uremia itself, long-term dialysis status, immunosuppressive agents for postrenal transplant status, and miscellaneous factors such as hormone alterations and dysbiosis. The possible mechanisms of HCC affecting renal function include direct tumor invasion and hepatorenal syndrome. Finally, we categorized the risk factors that could lead to both HCC and CKD into four categories: Environmental toxins, viral hepatitis, metabolic syndrome, and vasoactive factors. Both CKD and ESRD have been reported to negatively affect HCC prognosis, but more research is warranted to confirm this. Furthermore, ESRD status itself ought not to prevent patients receiving aggressive treatments. This study then adopted the well-known Barcelona Clinic Liver Cancer guidelines as a framework to discuss the indicators for each stage of HCC treatment, treatment-related adverse renal effects, and concerns that are specific to patients with pre-existing renal dysfunction when undergoing aggressive treatments against CKD and ESRD. Such aggressive treatments include liver resection, simultaneous liver kidney transplantation, radiofrequency ablation, and transarterial chemoembolization. Finally, focusing on patients unable to receive active treatment, this study compiled information on the latest systemic pharmacological therapies, including targeted and immunotherapeutic drugs. Based on available clinical studies and Food and Drug Administration labels, this study details the drug indications, side effects, and dose adjustments for patients with renal dysfunction. It also provides a comprehensive review of information on HCC patients with renal dysfunction from disease onset to treatment.
Collapse
Affiliation(s)
- Hsuan Yeh
- Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taipei 105, Taiwan
| | - Chun-Cheng Chiang
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Tzung-Hai Yen
- Department of Nephrology, Chang Gung Memorial Hospital and Chang Gung University, Taipei 105, Taiwan
| |
Collapse
|
|
24
|
Nguyen MH, Atsukawa M, Ishikawa T, Yasuda S, Yokohama K, Trinh HN, Arai T, Fukunishi S, Ogawa E, Hsu YC, Maeda M, Dang H, Tseng CH, Takahashi H, Jun DW, Watanabe T, Chuma M, Nozaki A, Kawada N, Cheung R, Enomoto M, Takaguchi K, Toyoda H. Outcomes of Sequential Therapy With Tenofovir Alafenamide After Long-term Entecavir. Am J Gastroenterol 2021; 116:1264-1273. [PMID: 34074829 DOI: 10.14309/ajg.0000000000001157] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/29/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Entecavir (ETV) and tenofovir alafenamide (TAF) are both first-line hepatitis B virus (HBV) therapies, but ETV-to-TAF switch outcome data are limited. We aimed to assess outcomes up to 96 weeks after ETV-to-TAF switch. METHODS ETV-treated (≥12 months) chronic hepatitis B patients switched to TAF in routine practice at 15 centers (United States, Korea, Japan, and Taiwan) were included. Primary outcome was complete viral suppression (CVS) rate (HBV DNA <20 IU/mL). RESULTS We analyzed 425 eligible patients (mean age 60.7 ± 13.2 years, 60% men, 90.8% Asian, 20.7% with diabetes, 27% with hypertension, 14.8% with cirrhosis, 8.3% with hepatocellular carcinoma, and mean ETV duration before switch 6.16 ± 3.17 years). The mean baseline estimated glomerular filtration rate (eGFR) was 89 ± 19 (chronic kidney disease [CKD] stages: 55.6% stage 1, 35.7% stage 2, and 8.8% stages 3-5). CVS rate increased from 91.90% at switch (from 90.46% 24 weeks before switch) to 95.57% and 97.21% at 48 and 96 weeks after (P = 0.03 and 0.02, respectively). Over the 96 weeks after switch, mean HBV DNA (P < 0.001) but not alanine aminotransferase or CKD stage decreased. Between switch and 96-week follow-up, 11% (26/235) of CKD stage 1 patients migrated to stage 2 and 8% (12/151) of stage 2 patients to stages 3-5, whereas 18% (27/151) from stage 2 to 1, and 19% (7/37) from stages 3-5 to 2. On multivariable generalized estimated equation analysis adjusted for age, sex, hypertension, diabetes, and cirrhosis, baseline eGFR, age (P < 0.001), and CKD stages 2 and 3-5 (vs 1) (both P < 0.001) were associated with lower follow-up eGFR. DISCUSSION After an average of 6 years on ETV, CVS increased from 91.9% at TAF switch to 97.2% at 96 weeks later.
Collapse
Affiliation(s)
- Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Hospital, Niigata, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Keisuke Yokohama
- 2nd Department of Internal Medicine, Osaka Medical College, Osaka, Japan
| | - Huy N Trinh
- San Jose Gastroenterology, San Jose, California, USA
| | - Taeang Arai
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Shinya Fukunishi
- Premier Development Research of Medicine, Osaka Medical College, Osaka, Japan
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Mayumi Maeda
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Hansen Dang
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
| | - Cheng-Hao Tseng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
| | - Hirokazu Takahashi
- Liver Center, Saga University Hospital, Saga, Japan
- Division of Metabolism and Endocrinology, Saga University, Faculty of Medicine, Saga, Japan
| | - Dae Won Jun
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, South Korea
| | - Tsunamasa Watanabe
- Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Makoto Chuma
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Akito Nozaki
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Ramsey Cheung
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
- Division of Gastroenterology & Hepatology, The Palo Alto Veterans Affairs Health Care System, Palo Alto, California, USA
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Takaguchi
- Department of Hepatology, Kagawa Prefectural Central Hospital, Kagawa, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
| |
Collapse
|
|
25
|
Peng CW, Jeng WJ, Chien RN, Liaw YF. The impact of hepatitis flare on HBeAg loss was effective mainly in the first year of Nucleot(s)ide therapy in chronic hepatitis B. J Viral Hepat 2021; 28:475-483. [PMID: 33274536 DOI: 10.1111/jvh.13449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/16/2020] [Accepted: 11/09/2020] [Indexed: 12/28/2022]
Abstract
HBeAg loss during nucleos(t)ide analogue (Nuc) therapy is significantly higher in patients with hepatitis flare (ALT ≥ 5-times upper limited of normal). It is not clear whether ALT level higher above the hepatitis flare leads to greater HBeAg loss rate nor its durability. This study aimed to investigate the impact of pretherapy ALT level on HBeAg loss in each year of Nuc treatment. Entecavir or Tenofovir treated HBeAg-positive chronic hepatitis B (CHB) patients were recruited consecutively. Patients with prior treatment history that experienced HBeAg seroconversion and reversion were excluded. Pretherapy age, gender, cirrhosis, genotype, ALT, HBsAg and HBV DNA levels were analysed. The hazard function was calculated for the probability of HBeAg loss in each year. Of the 290 patients, the 3-year cumulative HBeAg loss rate was 58.1%, higher in patients with hepatitis flare than those without (67.6% vs. 39.6%, P < 0.001). The HBeAg loss rate in the first year correlated positively with higher ALT levels at a stepwise fashion. The hazard function in patients with hepatitis flare was 0.74 at half year, then dropped to 0.33 by the first year and was lower thereafter to a rate closer to that of the patients without hepatitis flare. In conclusion, the impact of pretherapy ALT levels on HBeAg loss rate was not long-lasting and was effective mainly in the first year of Nuc therapy. Strategies such as adding an immune-modulating agent may help enhance HBeAg loss rate after the first year of Nuc therapy for those who remained HBeAg positive. Word count: 249 (<250).
Collapse
Affiliation(s)
- Chien-Wei Peng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Rong-Nan Chien
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan.,Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| |
Collapse
|
|
26
|
Roade L, Riveiro-Barciela M, Esteban R, Buti M. Long-term efficacy and safety of nucleos(t)ides analogues in patients with chronic hepatitis B. Ther Adv Infect Dis 2021; 8:2049936120985954. [PMID: 33614029 PMCID: PMC7871062 DOI: 10.1177/2049936120985954] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
Nucleos(t)ide analogues with high barrier to resistance are regarded as the principal therapeutic option for chronic hepatitis B (CHB). Treatment with entecavir (ETV), tenofovir disoproxil (TDF) and the later released tenofovir alafenamide (TAF) is highly effective at controlling hepatitis B virus (HBV) infection and, in the vast majority of patients, is well tolerated. No significant differences in viral suppression have been described among the different regimens, although an earlier achievement in biochemical response has been suggested first under TDF and recently under TAF. High barrier to resistance NAs rarely achieve hepatitis B surface antigen sero-clearance, and therefore should be maintained life-long in most cases. This has increased concerns about treatment-related toxicity, especially in patients under TDF with additional risk factors for kidney and bone impairment. TAF has shown a better bone and kidney safety profile than TDF, although it is not yet available worldwide due to its higher cost. Emergence of adverse events should be monitored since treatment-switch to ETV/TAF seems to be effective and safe in HBV mono-infected subjects. Finally, although an effective antiviral treatment leads to a clear improvement in clinical outcome of CHB patients; the risk of developing hepatocellular carcinoma (HCC) is not completely avoided with viral suppression. Whether tenofovir-based regimens provide any additional benefit over ETV in HCC prevention remains unclear and requires further investigation.
Collapse
Affiliation(s)
- Luisa Roade
- Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebrón, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Madrid, Spain
| | - Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebrón, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Madrid, Spain
| | - Rafael Esteban
- Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebrón, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Madrid, Spain
| | - Maria Buti
- Liver Unit, Internal Medicine Department, Hospital Universitario Vall d'Hebrón, Vall d'Hebron Barcelona Hospital Campus, Barcelona, 119-129, Spain. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto Carlos III, Madrid, Spain
| |
Collapse
|
|
27
|
Liaw YF. Hepatitis B Flare After Cessation of Nucleos(t)ide Analogue Therapy in HBeAg-Negative Chronic Hepatitis B: To Retreat or Not to Retreat. Hepatology 2021; 73:843-852. [PMID: 32810321 DOI: 10.1002/hep.31525] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/14/2020] [Accepted: 08/03/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Yun-Fan Liaw
- Liver Research UnitChang Gung Memorial HospitalChang Gung University College of MedicineTaipeiTaiwan
| |
Collapse
|
|
28
|
Outcome and risk of de novo Hepatitis B after liver transplantation: Are all anti-HBc-positive grafts the same? Clin Res Hepatol Gastroenterol 2020; 44:791-793. [PMID: 32586783 DOI: 10.1016/j.clinre.2020.05.016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 02/04/2023]
|
|
29
|
Duraisamy GS, Bhosale D, Lipenská I, Huvarova I, Růžek D, Windisch MP, Miller AD. Advanced Therapeutics, Vaccinations, and Precision Medicine in the Treatment and Management of Chronic Hepatitis B Viral Infections; Where Are We and Where Are We Going? Viruses 2020; 12:v12090998. [PMID: 32906840 PMCID: PMC7552065 DOI: 10.3390/v12090998] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 08/31/2020] [Accepted: 09/02/2020] [Indexed: 02/06/2023] Open
Abstract
The management of chronic hepatitis B virus (CHB) infection is an area of massive unmet clinical need worldwide. In spite of the development of powerful nucleoside/nucleotide analogue (NUC) drugs, and the widespread use of immune stimulators such as interferon-alpha (IFNα) or PEGylated interferon-alpha (PEG-IFNα), substantial improvements in CHB standards of care are still required. We believe that the future for CHB treatment now rests with advanced therapeutics, vaccination, and precision medicine, if all are to bring under control this most resilient of virus infections. In spite of a plethora of active drug treatments, anti-viral vaccinations and diagnostic techniques, the management of CHB infection remains unresolved. The reason for this is the very complexity of the virus replication cycle itself, giving rise to multiple potential targets for therapeutic intervention some of which remain very intractable indeed. Our review is focused on discussing the potential impact that advanced therapeutics, vaccinations and precision medicine could have on the future management of CHB infection. We demonstrate that advanced therapeutic approaches for the treatment of CHB, in the form of gene and immune therapies, together with modern vaccination strategies, are now emerging rapidly to tackle the limitations of current therapeutic approaches to CHB treatment in clinic. In addition, precision medicine approaches are now gathering pace too, starting with personalized medicine. On the basis of this, we argue that the time has now come to accelerate the design and creation of precision therapeutic approaches (PTAs) for CHB treatment that are based on advanced diagnostic tools and nanomedicine, and which could maximize CHB disease detection, treatment, and monitoring in ways that could genuinely eliminate CHB infection altogether.
Collapse
Affiliation(s)
- Ganesh Selvaraj Duraisamy
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Dattatry Bhosale
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Ivana Lipenská
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Ivana Huvarova
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
| | - Daniel Růžek
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
- Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, CZ-37005 České Budějovice, Czech Republic
| | - Marc P. Windisch
- Applied Molecular Virology Laboratory, Institut Pasteur Korea, 696 Sampyeong-dong, Bundang-gu, Seongnam-si, Gyeonggi-do 463-400, Korea;
- Division of Bio-Medical Science and Technology, University of Science and Technology, Daejeon 305-350, Korea
| | - Andrew D. Miller
- Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; (G.S.D.); (D.B.); (I.L.); (I.H.); (D.R.)
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemědělská 1, Černá Pole, CZ-61300 Brno, Czech Republic
- KP Therapeutics (Europe) s.r.o., Purkyňova 649/127, CZ-61200 Brno, Czech Republic
- Correspondence:
| |
Collapse
|
|
30
|
Rodríguez M, Buti M, Esteban R, Lens S, Prieto M, Suárez E, García-Samaniego J. Consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B virus infection (2020). GASTROENTEROLOGIA Y HEPATOLOGIA 2020; 43:559-587. [PMID: 32778356 DOI: 10.1016/j.gastrohep.2020.03.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 03/31/2020] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) infection remains a global public health problem. HBV vaccination is the most effective tool to reduce the incidence of HBV disease. Despite there has not been new clinical developments for the treatment of chronic hepatitis B in the last few years, changing epidemiology and current insights on natural history, diagnostic tools and therapy indications make necessary an update of the former version of the consensus document of the Spanish Association for Study of the Liver on the treatment of hepatitis B infection published in 2012. The current document updates the management of chronic hepatitis B. The treatment of choice is the long-term administration of a nucleos(t)ide analogue with high barrier to resistance (entecavir, tenofovir or tenofovir alafenamide). Pegylated interferon may be an option in patients with non-advanced liver disease, but its applicability is limited due to the low efficacy and poor tolerability. All patients must be monitored for the risk of progression to advanced liver disease and development of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Manuel Rodríguez
- Sección de Hepatología, Servicio de Digestivo, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, España.
| | - María Buti
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Rafael Esteban
- Servicio de Hepatología-Medicina Interna, Hospital Universitario Valle Hebrón, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Barcelona, España
| | - Sabela Lens
- Servicio de Hepatología, Hospital Clínic, IDIBAPS, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Universidad de Barcelona, Barcelona, España
| | - Martín Prieto
- Sección de Hepatología, Servicio de Medicina Digestiva, Hospital Universitari ì Politècnic La Fe, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Valencia, España
| | - Emilio Suárez
- Unidad de Enfermedades Digestivas, Hospital Universitario Virgen de Valme, Sevilla, España
| | - Javier García-Samaniego
- Unidad de Hepatología, Hospital Universitario La Paz, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CiBERehd), Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, España.
| |
Collapse
|
|
31
|
Undesirable Long-Term Outcome of Entecavir Therapy in Chronic Hepatitis B With Cirrhosis. Clin Gastroenterol Hepatol 2020; 18:2146-2147. [PMID: 32088301 DOI: 10.1016/j.cgh.2020.02.028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 02/11/2020] [Indexed: 02/07/2023]
|
|
32
|
Shen S, Wong GLH, Kuang Z, van Campenhout MJH, Fan R, Wong VWS, Yip TCF, Chi H, Liang X, Hu X, Lin W, Wu Y, Liu X, Boonstra A, Hou J, Sun J, Chan HLY. Development and validation of a model for hepatitis B e antigen seroconversion in entecavir-treated patients with chronic hepatitis B. J Med Virol 2020; 92:1206-1213. [PMID: 31724212 DOI: 10.1002/jmv.25628] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 11/13/2019] [Indexed: 12/15/2022]
Abstract
Achieving hepatitis B e antigen (HBeAg) seroconversion is a satisfactory endpoint during antiviral treatment for chronic hepatitis B (CHB). This study aimed to develop and validate a novel scoring system to predict HBeAg seroconversion during entecavir (ETV) treatment. A total of 526 patients with HBeAg-positive CHB treated with ETV for at least 1 year were randomly assigned to the training and validation cohorts. Baseline parameters including hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), and alanine aminotransferase level were quantified. Patients who achieved HBeAg seroconversion were compared with those without HBeAg seroconversion. A prediction model was established to predict HBeAg seroconversion during ETV treatment. After a median follow up of 2.67 years, 93 (36.0%) and 87 (32.5%) patients in the training and validation cohorts developed HBeAg seroconversion. A prediction score composed of age, HBsAg and HBcAb quantification was derived. Areas under receiver operating characteristic curve at 5 years of this prediction score were 0.70 and 0.72 in the training and validation cohorts. By using the dual cutoff values of 0.28 and 0.58, the model was endowed with high sensitivity and specificity to exclude or identify patients developing HBeAg seroconversion (90.3% sensitivity and 90.2% specificity in the training cohort as well as 92.8% sensitivity and 84.4% specificity in the validation cohort, respectively). A novel prediction score that uses baseline clinical variables was developed and validated. The score accurately estimates the probabilities of developing HBeAg seroconversion at 5-years ETV therapy in patients with CHB.
Collapse
Affiliation(s)
- Sheng Shen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Grace L-H Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Zhe Kuang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Rong Fan
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Vincent W-S Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Terry C-F Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Heng Chi
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Xieer Liang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoyun Hu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Weiyin Lin
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yaobo Wu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoju Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - André Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Disease, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Sun
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Henry L-Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| |
Collapse
|
|
33
|
Ogawa E, Nomura H, Nakamuta M, Furusyo N, Koyanagi T, Dohmen K, Ooho A, Satoh T, Kawano A, Kajiwara E, Takahashi K, Azuma K, Kato M, Shimoda S, Hayashi J. Tenofovir alafenamide after switching from entecavir or nucleos(t)ide combination therapy for patients with chronic hepatitis B. Liver Int 2020; 40:1578-1589. [PMID: 32304611 DOI: 10.1111/liv.14482] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Revised: 03/14/2020] [Accepted: 04/13/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Tenofovir alafenamide (TAF) has been newly approved for the treatment of chronic hepatitis B (CHB). We aimed to assess the effectiveness and renal safety of switching from entecavir (ETV) or nucleos(t)ide analogue (NA) combination therapy to TAF. METHODS This multicentre, retrospective, cohort study included 313 consecutive CHB patients who switched to TAF monotherapy after treatment with ETV or a nucleos(t)ide analogue (NA) combination for over 2 years. Virological/laboratory responses were evaluated for 48 weeks after switchover. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . Differences in longitudinal parameters were compared by the generalized estimating equation method. RESULTS In the prior ETV group (n = 191), the HBV DNA suppression rate at week 48 was significantly increased, from 75.9% to 96.9% (P < .001). Additionally, mean changes in the HBsAg level at week 48 in HBsAg ≥ 3.0 logIU/mL and < 3.0 logIU/mL groups were -0.09 and -0.13 logIU/mL respectively. In the prior NA combination group (n = 122), the mean changes in HBsAg level at week 48 in the HBsAg ≥ 3.0 logIU/mL and <3.0 logIU/mL groups were -0.08 and -0.11 logIU/mL respectively. For patients with CKD, the eGFR at week 48 was significantly improved compared to those with non-CKD (adjusted slope coefficient difference: 2.75 mL/min/1.73 m2 /48 weeks; P = .001). CONCLUSIONS Switching from ETV or an NA combination to TAF was effective for HBV suppression and continued HBsAg reduction. Moreover, the renal glomerular function of patients in the prior NA combination group with CKD was significantly improved compared to those with non-CKD. LAY SUMMARY Nucleos(t)ide analogues, such as entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide, inhibit hepatitis B virus (HBV) replication and are recommended as first-line oral agents for chronic HBV infection. We evaluated the virological/biochemical effects and renal safety when patients are switched from entecavir or nucleoside-nucleotide analogue combination therapy to tenofovir alafenamide. Our findings suggest that switching to tenofovir alafenamide was effective for HBV suppression and the improvement in renal function for patients with chronic kidney disease.
Collapse
Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu, Japan.,Department of Medicine, Haradoi Hospital, Fukuoka, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, Kyushu Medical Center, National Hospital Organization, Fukuoka, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
| | | | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka, Japan
| | - Aritsune Ooho
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Takeaki Satoh
- Center for Liver Disease, Kokura Medical Center, Kitakyushu, Japan
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | | | | | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka, Japan
| | | |
Collapse
|
|
34
|
Su CW, Wu CY, Lin JT, Ho HJ, Wu JC. Nucleos(t)ide analogue continuous therapy associated with reduced adverse outcomes of chronic hepatitis B. J Chin Med Assoc 2020; 83:125-133. [PMID: 32015266 DOI: 10.1097/jcma.0000000000000247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Nucleos(t)ide analogue (NA) therapy reduces the risk of disease progression in chronic hepatitis B virus-infected patients. However, the risk of liver decompensation, hepatic failure, and mortality after discontinuation of NA therapy remains unknown. METHODS Among 51,574 chronic hepatitis B patients who received NAs in the Taiwan National Health Insurance Research Database, we identified 8,631 patients who continued NA therapy (treatment cohort) and 8,631 propensity-score matched patients who stopped NA therapy after their initial 1.5 years treatment (off-therapy cohort) between October 1, 2003 and December 31, 2011. All study subjects were followed up from the index date, that is, the date 1.5 years after the first prescription of NA, until development of liver decompensation and hepatic failure, death or end of 18-month follow-up period. RESULTS Treatment cohort had significantly lower risks of liver decompensation (1.05%; 95% confidence interval [CI], 0.81%-1.30% vs 2.13%; 95% CI, 1.82%-2.45%; p < 0.001), hepatic failure (0.35%; 95% CI, 0.21%-0.49% vs 0.63%; 95% CI, 0.46%-0.80%; p = 0.008) and overall mortality (1.67%; 1.37%-1.98% vs 2.44%; 95% CI, 2.10%-2.77%; p < 0.001) during the 18-month follow-up period. After adjusting for potential confounders, NA continuous therapy was associated with reduced risks of liver decompensation (hazard ratio [HR]: 0.47; 95% CI, 0.36-0.62, p < 0.001), hepatic failure (HR: 0.53; 95% CI, 0.33-0.86, p = 0.01) and overall mortality (HR: 0.67; 95% CI, 0.53-0.84, p = 0.001). The number needed to reduce one less disease progression and mortality was 47. The protective effect of NA continuous therapy was found in nearly all subgroups. CONCLUSION NA continuous therapy is associated with reduced risks of liver decompensation, hepatic failure, and overall mortality.
Collapse
Affiliation(s)
- Chien-Wei Su
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Chun-Ying Wu
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Public Health and Graduate Institute of Clinical Medical Sciences, China Medical University, Taichung, Taiwan, ROC
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC
- Department of Life Sciences and RongHsing Research Center for Translational Medicine, National Chung-Hsing University, Taichung, Taiwan, ROC
| | - Jaw-Town Lin
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan, ROC
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan, ROC
| | - Hsiu J Ho
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Jaw-Ching Wu
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| |
Collapse
|
|
35
|
Adverse events of nucleos(t)ide analogues for chronic hepatitis B: a systematic review. J Gastroenterol 2020; 55:496-514. [PMID: 32185517 PMCID: PMC7188775 DOI: 10.1007/s00535-020-01680-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 02/26/2020] [Indexed: 02/04/2023]
Abstract
Nucleos(t)ide analogues (NAs) are the main drug category used in chronic hepatitis B (CHB) treatment. Despite the fact that NAs have a favourable safety profile, undesired adverse events (AEs) may occur during the treatment of CHB. Given the eminent number of patients currently receiving NAs, even a small risk of any of these toxicities can represent a major medical issue. The main objective of this review was to analyse information available on AEs associated with the use of NAs in published studies. We choose the following MesH terms for this systematic review: chronic hepatitis B, side effects and treatment. All articles published from 1 January 1990 up to 19 February 2018 in MEDLINE of PubMed, EMBASE, the Cochrane Library and LILACS databases were searched. A total of 120 articles were selected for analysis, comprising 6419 patients treated with lamivudine (LAM), 5947 with entecavir (ETV), 3566 with tenofovir disoproxil fumarate (TDF), 3096 with telbivudine (LdT), 1178 with adefovir dipivoxil (ADV) and 876 with tenofovir alafenamide (TAF). The most common AEs in all NAs assessed were abdominal pain/discomfort, nasopharyngitis/upper respiratory tract infections, fatigue, and headache. TAF displays the highest density of AEs per patient treated among NAs (1.14 AE/treated patient). In conclusion, treatment of CHB with NAs is safe, with a low incidence of AEs. Despite the general understanding TAF being safer than TDF, the number of patients treated with TAF still is too small in comparison to other NAs to consolidate an accurate safety profile. PROSPERO Registration No. CRD42018086471.
Collapse
|
|
36
|
Temiz SA, Özer İ, Ataseven A, Fındık S. A case of entecavir-associated bullous fixed drug eruption and a review of literature. TURKISH JOURNAL OF GASTROENTEROLOGY 2019; 30:299-302. [PMID: 30459136 DOI: 10.5152/tjg.2018.17887] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Fixed drug eruption (FDE) is a type of drug reaction characterized by localized erythema, hyperpigmentation, and bullous at the same site(s), generally observed following every intake of a causative drug. Delayed-type cellular hypersensitivity (Type IVC) is considered to play a role in FDE etiology. Several antibiotics, barbiturates, oral contraceptives, nonsteroidal anti-inflammatory drugs, laxative-containing phenolphthalein, metronidazole, and quinine are known to be the primary drugs responsible for FDE. Bullous FDE, on the other hand, is a relatively rare form of FDE. Hepatitis B is a significant worldwide health problem, and entecavir is a common nucleoside (deoxyguanosine) analog used for treating hepatitis B; however, it has various side effects, such as lactic acidosis, myalgia, azotemia, hypophosphatemia, headache, diarrhea, pancreatitis, and neuropathy, and, in rare cases, cutaneous drug eruption. Our aim is to present a case of entecavir-associated bullous drug reaction, which has not been reported in the literature. Furthermore, we performed a review of literature to compile previously reported entecavir-associated drug reactions.
Collapse
Affiliation(s)
- Selami Aykut Temiz
- Department of Dermatology, Necmettin Erbakan University School of Medicine, Konya, Turkey
| | - İlkay Özer
- Department of Dermatology, Necmettin Erbakan University School of Medicine, Konya, Turkey
| | - Arzu Ataseven
- Department of Dermatology, Necmettin Erbakan University School of Medicine, Konya, Turkey
| | - Sıddıka Fındık
- Department of Pathology, Necmettin Erbakan University School of Medicine, Konya, Turkey
| |
Collapse
|
|
37
|
Marcellin P, Wong DK, Sievert W, Buggisch P, Petersen J, Flisiak R, Manns M, Kaita K, Krastev Z, Lee SS, Cathcart AL, Crans G, Op den Brouw M, Jump B, Gaggar A, Flaherty J, Buti M. Ten-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B virus infection. Liver Int 2019; 39:1868-1875. [PMID: 31136052 DOI: 10.1111/liv.14155] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Revised: 05/08/2019] [Accepted: 05/09/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) is a first-line treatment for chronic hepatitis B (CHB). We aimed to describe the efficacy and safety profiles of TDF treatment for up to 10 years in a well-described cohort of CHB patients. METHODS Hepatitis B e antigen (HBeAg)-negative and HBeAg-positive patients from two randomised, double-blind trials (ClinicalTrials.gov: NCT00117676 and NCT00116805) completed 48 weeks of randomised treatment with TDF or adefovir dipivoxil. A subset of these patients was then eligible to receive open-label TDF treatment for up to 10 years. At Year 10, patients were assessed for virological suppression, alanine aminotransferase (ALT) normalisation, serological response, safety and tolerability. RESULTS Of 641 randomised and treated patients, 585 (91%) entered the open-label extension phase with 203 (32%) patients completing Year 10 of the study. At Year 10, 118/118 (100%) of HBeAg-negative patients and 78/80 (98%) of HBeAg-positive patients with available data achieved hepatitis B virus (HBV) DNA < 69 IU/mL, while 88/106 (83%) and 60/77 (78%) patients achieved ALT normalisation, respectively. Of the 23 patients with HBeAg status available at Year 10, 12 (52%) and six (27%) experienced HBeAg loss and seroconversion, respectively. No resistance to TDF was documented up to Year 10. In the period between Year 8 and Year 10, the safety profile of TDF was similar to previous reports, with few patients experiencing renal- or bone-related adverse events. CONCLUSIONS Over 10 years, TDF had a favourable safety profile, was well tolerated, and resulted in continued maintenance of virological suppression with no documented resistance.
Collapse
Affiliation(s)
| | - David K Wong
- Toronto Centre for Liver Disease, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - William Sievert
- Gastroenterology and Hepatology Unit, Monash Health and Monash University, Melbourne, Australia
| | - Peter Buggisch
- Liver Unit, IFI-Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany
| | - Jörg Petersen
- Liver Unit, IFI-Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany
| | - Robert Flisiak
- Department of Infectious Diseases and Hepatology, Medical University Bialystok, Bialystok, Poland
| | - Michael Manns
- Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany.,Helmholtz Center for Infection Research (HZI), Hannover, Germany
| | - Kelly Kaita
- Viral Hepatitis Investigative Unit, University of Manitoba, Winnipeg, Canada
| | - Zahari Krastev
- Clinic of Gastroenterology, St Ivan Rilsky University Hospital, Medical University, Sofia, Bulgaria
| | - Samuel S Lee
- Liver Unit, University of Calgary, Calgary, Alberta, Canada
| | | | | | | | | | - Anuj Gaggar
- Gilead Sciences Inc, Foster City, California
| | | | - Maria Buti
- Liver Unit, Hospital Universitario Vall d'Hebron and CIBEREHD del Instituto Carlos III, Barcelona, Spain
| |
Collapse
|
|
38
|
Finite nucleos(t)ide analog therapy in HBeAg-negative chronic hepatitis B: an emerging paradigm shift. Hepatol Int 2019; 13:665-673. [PMID: 31559604 DOI: 10.1007/s12072-019-09989-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 09/03/2019] [Indexed: 12/14/2022]
Abstract
Potent nucleos(t)ide analogs (NUC), such as entecavir and tenofovir disoproxil fumarate, are able to suppress HBV DNA to undetectable level. These agents have no direct action on cccDNA, which is a very stable template for HBV production, hence long-term or even life-long NUC therapy is required in HBeAg-negative patients to maintain HBV suppression and to achieve the ultimate goal of HBsAg loss. However, there are concerns of indefinite or life-long NUC therapy, including drug resistance, financial burden, adherence and willingness for indefinite long-term NUC therapy. Patients lost to follow-up and hence, not monitored may risk severe relapse that may deteriorate to hepatic decompensation or even hepatic failure. This Review integrated the cumulated evidence and assessed the strategy of finite NUC therapy in HBeAg-negative patients which was first tried in early 2000s. Earlier Asian findings that 2-year NUC therapy is feasible and safe have founded APASL stopping rule for patients on NUC therapy over 2-3 years since 2008. Subsequent studies have supported the strategy of finite NUC therapy, which has finally been accepted as an option by American and European liver associations since 2016. More recent studies have further shown greatly increased HBsAg loss rate (up to 5-year 39%) after stopping NUC therapy. The cumulated evidence has shown that the paradigm shift from indefinite long-term therapy to finite NUC therapy in HBeAg-negative patients is emerging. More studies are needed to fine-tuning the strategy including research for the optimal duration of consolidation therapy, timing to stop and to start re-treatment.
Collapse
|
|
39
|
Viganò M, Loglio A, Labanca S, Zaltron S, Castelli F, Andreone P, Messina V, Ganga R, Coppola N, Marrone A, Russello M, Marzano A, Tucci A, Taliani G, Fasano M, Fagiuoli S, Villa E, Bronte F, Santantonio T, Brancaccio G, Occhipinti V, Facchetti F, Grossi G, Rumi M, Lampertico P. Effectiveness and safety of switching to entecavir hepatitis B patients developing kidney dysfunction during tenofovir. Liver Int 2019; 39:484-493. [PMID: 30525275 DOI: 10.1111/liv.14017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 11/15/2018] [Accepted: 11/25/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF-associated glomerular and/or tubular dysfunction. METHODS A total of 103 TDF-treated patients were included as follows: age 64 years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV-R) and 71% previously treated with adefovir. Twenty-nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFRMDRD ) was <60 mL/min, 37 (36%) because blood phosphate (P) levels were <2.5 mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4 months thereafter. RESULTS During 46 (4-115) months of ETV treatment, all patients' renal parameters significantly improved as follows: creatinine from 1.30 to 1.10 mg/dL (P < 0.0001), eGFRMDRD from 54 to 65 mL/min (P = 0.002), P from 2.2 to 2.6 mg/dL (P < 0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/L (P < 0.0001). Thirteen patients (52%) improved their eGFRMDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV-R. The 5-year cumulative probability of ETV-R was 0% in LMV-naïve patients, and 11% in LMV-R patients (P = 0.018). CONCLUSIONS Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long-term TDF treatment.
Collapse
Affiliation(s)
- Mauro Viganò
- U.O. Epatologia, Ospedale San Giuseppe, University of Milan, Milan, Italy
| | - Alessandro Loglio
- CRC "A. M. e A. Migliavacca", Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Sara Labanca
- U.O. Epatologia, Ospedale San Giuseppe, University of Milan, Milan, Italy
| | - Serena Zaltron
- Clinica Malattie Infettive e Tropicali. Spedali Civili Brescia, University of Brescia, Brescia, Italy
| | - Francesco Castelli
- Clinica Malattie Infettive e Tropicali. Spedali Civili Brescia, University of Brescia, Brescia, Italy
| | - Pietro Andreone
- Dipartimento di Scienze Mediche e Chirurgiche, University of Bologna, Bologna, Italy
| | - Vincenzo Messina
- U.O.C. Malattie Infettive, A.O. S. Anna e S. Sebastiano, Caserta, Italy
| | - Roberto Ganga
- S.C Medicina Interna, Ospedale S. Michele A.O. Brotzu, Cagliari, Italy
| | - Nicola Coppola
- Malattie Infettive, Second University of Naples, Dipartimento Salute Mentale e Medicina Preventiva, Naples, Italy
| | - Aldo Marrone
- Dipartimento di Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell'Invecchiamento, Luigi Vanvitelli University of Campania, Naples, Italy
| | - Maurizio Russello
- U.O.S. Epatologia e Malattie Gastroenteriche dell'A.R.N.A.S. Garibaldi-Nesima, Catania, Italy
| | - Alfredo Marzano
- U.O. Gastroenterologia Universitaria, Ospedale San Giovanni Battista, Città della Salute e della Scienza di Torino, Turin, Italy
| | - Alessandra Tucci
- U.O. Gastroenterologia Universitaria, Ospedale San Giovanni Battista, Città della Salute e della Scienza di Torino, Turin, Italy
| | - Gloria Taliani
- Unità di Malattie Infettive e Tropicali, Dipartimento di Medicina Clinica, Sapienza University, Rome, Italy
| | - Massimo Fasano
- UOC Malattie Infettive Ospedale F. Fallacara, Triggiano, Italy
| | - Stefano Fagiuoli
- Dipartimento di Gastroenterologia, Epatologia e Trapianto di Fegato, Ospedale Papa Giovanni XXIII, Bergamo, Italy
| | - Erica Villa
- Divisione di Gastroenterologia, AOU Policlinico di Modena, University of Modena e Reggio Emilia, Modena, Italy
| | - Fabrizio Bronte
- Unità di Gastroenterologia ed Epatologia, DiBiMIS, University of Palermo, Palermo, Italy
| | - Teresa Santantonio
- Dipartimento di Medicina Clinica e Sperimentale, University of Foggia, Foggia, Italy
| | | | | | - Floriana Facchetti
- CRC "A. M. e A. Migliavacca", Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Glenda Grossi
- CRC "A. M. e A. Migliavacca", Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| | - Mariagrazia Rumi
- U.O. Epatologia, Ospedale San Giuseppe, University of Milan, Milan, Italy
| | - Pietro Lampertico
- CRC "A. M. e A. Migliavacca", Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy
| |
Collapse
|
|
40
|
Lee HM, Ahn J, Kim WR, Lim JK, Nguyen M, Pan CQ, Kim D, Mannalithara A, Te H, Trinh H, Chu D, Tran T, Woog J, Lok AS. A Comparison Between Community and Academic Practices in the USA in the Management of Chronic Hepatitis B Patients Receiving Entecavir: Results of the ENUMERATE Study. Dig Dis Sci 2019; 64:358-366. [PMID: 30238203 DOI: 10.1007/s10620-018-5281-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/07/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS The management of chronic hepatitis B patients is not well characterized in real-world practice. We compared baseline characteristics of CHB patients on entecavir, the frequency of on-treatment monitoring, and the effectiveness of ETV treatment between academic and community practices. METHODS Treatment-naïve CHB patients ≥18 years old, treated with ETV for ≥12 months from 2005 to 2013, in 26 community and academic practices throughout the USA were retrospectively evaluated. RESULTS Of 841 patients enrolled, 658 (65% male, 83% Asian, median age 47, 9% with cirrhosis) met inclusion criteria. Half of the patients (52%) were from community practices. A lower percentage of patients in community practices had cirrhosis or liver cancer (5 vs. 14%). Community practices more often treated patients with baseline ALT < 2 × ULN. Over a median follow-up of 4 years, community practices were more likely to discontinue ETV with less frequent laboratory monitoring compared to academic practices. The 5-year cumulative probability of ALT normalization was greater among patients treated in community practices (70 vs. 50%, p < 0.001), but the 5-year cumulative probability of undetectable HBV DNA was lower (45 vs. 70%, p < 0.001) than those treated in academic practices. CONCLUSION Academic practices saw CHB patients with more advanced liver disease, more often followed AASLD guidelines, and monitored patients on ETV treatment more frequently than community practices. While patients in community practices were less likely to achieve undetectable HBV DNA and more likely to achieve ALT normalization, the rates of HBeAg loss and seroconversion as well as HBsAg loss were similar.
Collapse
Affiliation(s)
- Hannah M Lee
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University Medical Center, 1200 E. Broad St., 14th Floor, P.O. Box 980341, Richmond, VA, 23298, USA.
| | - Joseph Ahn
- Division of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, OR, USA
| | - W Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | | | - Mindie Nguyen
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Calvin Q Pan
- Division of Gastroenterology and Hepatology, NYU Langone Health, NYU School of Medicine, New York, USA
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Ajitha Mannalithara
- Division of Gastroenterology and Hepatology, Stanford University, Stanford, CA, USA
| | - Helen Te
- Digestive Disease Center, University of Chicago, Chicago, IL, USA
| | - Huy Trinh
- San Jose Gastroenterology, San Jose, CA, USA
| | - Danny Chu
- Albert Einstein College of Medicine, New York, NY, USA
| | - Tram Tran
- Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA, USA
| | | | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
| |
Collapse
|
|
41
|
Borges KA, Dai J, Parikh ND, Schwartz M, Nguyen MH, Roberts LR, Befeler AS, Srivastava S, Rinaudo JA, Feng Z, Marrero JA, Reddy KR. Rationale and design of the Hepatocellular carcinoma Early Detection Strategy study: A multi-center longitudinal initiative of the National Cancer Institute's Early Detection Research Network. Contemp Clin Trials 2019; 76:49-54. [PMID: 30439517 PMCID: PMC7086481 DOI: 10.1016/j.cct.2018.11.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/06/2018] [Accepted: 11/08/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a common malignancy with a steadily rising incidence and associated morbidity and mortality. Cirrhosis of the liver is presently the leading risk factor for developing HCC. Abdominal imaging, with or without alpha-fetoprotein (AFP) testing, every 6 months is the current surveillance strategy for patients at risk. The available biomarkers for detecting this cancer at an early stage have inadequate sensitivity and specificity. METHODS The Hepatocellular carcinoma Early Detection Strategy (HEDS) study, a multi-center initiative of the National Cancer Institutes' (NCI) Early Detection Research Network (EDRN), launched an effort to establish what has become the nation's largest comprehensive biorepository and database on patients at high risk of developing HCC. The cohort has been developed in seven clinical centers across the USA. Subjects are enrolled for a five-year period involving data and specimen collection every six months in accordance with standard surveillance for HCC. Extensive clinical data are collected and specimens are stored at a central repository. RESULTS The database and biorepository contain longitudinally collected clinical data and serum and plasma samples from 1482 participants with cirrhosis and without evidence of HCC at baseline. Fifty-six percent are male, 85% Caucasian, 30% have a history of chronic HCV and 71% have compensated cirrhosis. CONCLUSIONS The HEDS cohort provides opportunities for the continued study of the incidence and course of HCC in a comprehensively followed population of patients at high risk for this malignancy. Further, the EDRN biorepository provides a distinct opportunity for the development of novel biomarkers. Trial registry URL: https://edrn.nci.nih.gov/protocols/316-hepatocellular-carcinoma-early-detection-strategy.
Collapse
Affiliation(s)
- Kelly A Borges
- Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd 7S, Philadelphia, PA, 19104, USA.
| | - Jianliang Dai
- Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA.
| | - Neehar D Parikh
- University of Michigan, 1500 E Medical Center Dr. Taubman Center SPC 3912, Ann Arbor, MI 48109, USA.
| | - Myron Schwartz
- Mount Sinai Hospital, 1468 Madison Ave, New York, NY 10029, USA.
| | - Mindie H Nguyen
- Stanford University, Stanford, 750 Welch Road, #210, Palo Alto, CA 94304, USA.
| | | | - Alex S Befeler
- Saint Louis University, 1 N Grand Blvd, St. Louis, MO 63103, USA.
| | - Sudhir Srivastava
- National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
| | - Jo Ann Rinaudo
- National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
| | - Ziding Feng
- Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA.
| | - Jorge A Marrero
- University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA.
| | - K Rajender Reddy
- Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd 7S, Philadelphia, PA, 19104, USA.
| |
Collapse
|
|
42
|
Leowattana W. Antiviral Drugs and Acute Kidney Injury (AKI). Infect Disord Drug Targets 2019; 19:375-382. [PMID: 31288730 DOI: 10.2174/1871526519666190617154137] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 03/15/2019] [Accepted: 06/17/2019] [Indexed: 02/05/2023]
Abstract
The introduction of more efficient antiviral drugs are common cause drug-induced acute kidney injury (AKI). The true prevalence of antiviral drugs induced nephrotoxicity is hardly determined. It causes AKI by many mechanisms including acute tubular necrosis (ATN), allergic interstitial nephritis (AIN), and crystal nephropathy. ATN has been described with a few kinds of antiviral drugs such as cidofovir, adefovir and tenofovir with unique effects on transporter defects, apoptosis, and mitochondrial injury. AIN from atazanavir is a rapid onset of AKI and usually nonoliguric but dialytic therapy are needed because of severity. Additionally, crystal nephropathy from acyclovir, indinavir, and foscarnet can cause AKI due to intratubular obstruction. In this article, the mechanisms of antiviral drug-induced AKI were reviewed and strategies for preventing AKI were mentioned.
Collapse
Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Mahidol University, 420/6 Rajavithi Road, Rachatawee, Bangkok 10400, Thailand
| |
Collapse
|
|
43
|
van Campenhout MJH, Brouwer WP, Xie Q, Guo S, Chi H, Qi X, Tabak F, Streinu-Cercel A, Wang JY, Zhang NP, Idilman R, Reesink HW, Diculescu M, Simon K, Akdogan M, Mazur W, de Knegt RJ, Verhey E, Hansen BE, Janssen HLA. Long-term follow-up of patients treated with entecavir and peginterferon add-on therapy for HBeAg-positive chronic hepatitis B infection: ARES long-term follow-up. J Viral Hepat 2019; 26:109-117. [PMID: 30187612 DOI: 10.1111/jvh.12997] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 07/12/2018] [Accepted: 08/08/2018] [Indexed: 12/23/2022]
Abstract
Addition of peginterferon alpha (PEG-IFN add-on) to entecavir (ETV) treatment after a short lead-in phase results in more response than ETV monotherapy in HBeAg-positive chronic hepatitis B infection (CHB). This study is the first to assess long-term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG-IFN add-on in a global trial (ARES study) and completed follow-up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG-IFN add-on and 48 patients treated with ETV monotherapy were included. The median follow-up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non-responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG-IFN add-on and ETV monotherapy, respectively. In 41 initial non-responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG-IFN add-on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow-up, rates of serological response became comparable between PEG-IFN add-on and ETV monotherapy. Although in this LTFU study initial non-responders were overrepresented in the add-on arm, PEG-IFN add-on possibly leads rather to accelerated HBeAg loss than to increased long-term HBeAg loss rates.
Collapse
Affiliation(s)
- Margo J H van Campenhout
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Willem Pieter Brouwer
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Qing Xie
- Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China
| | - S Guo
- Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China
| | - Heng Chi
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Xun Qi
- Gastroenterology and Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China
| | - Fehmi Tabak
- Cerrahpasa Medical Faculty, Istanbul, Turkey
| | - Adrian Streinu-Cercel
- Carol Davila University of Medicine and Pharmacy, National Institute for Infectious Diseases "Prof. Dr. Matei Balș", Bucharest, Romania
| | - Ji-Yao Wang
- Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China
| | - Ning-Ping Zhang
- Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China
| | | | - Hendrik W Reesink
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Mircea Diculescu
- Department of Gastroenterology, Fundeni Clinical Institute, Bucharest, Romania
| | - Krzysztof Simon
- Division of Infectious Diseases and Hepatology, Wroclaw Medical University, Wroclaw, Poland
| | - Meral Akdogan
- Department of Gastroenterology, Yuksek Ihtisas Hospital, Ankara, Turkey.,Department of Infectious Diseases, Silesian Medical University, Katowice, Poland
| | - Włodzimierz Mazur
- Department of Infectious Diseases, Silesian Medical University, Katowice, Poland
| | - Rob J de Knegt
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Elke Verhey
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Bettina E Hansen
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada.,Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada
| | - Harry L A Janssen
- Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada
| | | |
Collapse
|
|
44
|
Cuenca-Gómez JÁ, Lozano-Serrano AB, Cabezas-Fernández MT, Soriano-Pérez MJ, Vázquez-Villegas J, Estévez-Escobar M, Cabeza-Barrera I, Salas-Coronas J. Chronic hepatitis B genotype E in African migrants: response to nucleos(t)ide treatment in real clinical practice. BMC Infect Dis 2018; 18:568. [PMID: 30428845 PMCID: PMC6236963 DOI: 10.1186/s12879-018-3469-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Accepted: 10/31/2018] [Indexed: 12/18/2022] Open
Abstract
Background Hepatitis B virus (HBV) genotype E is a poorly studied genotype that almost exclusively occurs in African people. It seems to harbour intrinsic potential oncogenic activity and virological characteristics of immune scape but a paucity of information is available on clinical and virological characteristic of HBV genotype E-infected patients as well as on the efficacy of anti-HBV drugs for such patients. The increasing flow of migrants from high endemic HBV sub-Saharan Africa, where genotype E is the predominant one, to Western countries makes improving such knowledge critical in order to deliver proper medical care. Methods Prospective observational study of naïve patients of sub-Saharan origin treated for chronic HBV genotype E infection at a Tropical Medicine clinic sited in Spain from February 2004 to January 2018. The aim of the study was to describe the response of chronic HBV genotype E infection to nucleos(t)ide analogues (NA), entecavir or tenofovir, in real clinical practice. Results During the study period, 2209 sub-Saharan patients were assisted at our Tropical Medicine Unit and 609 (27.6%) had chronic HBV (CHB) infection. Genotype information was available for 55 naïve patients initiating treatment with NA (entecavir or tenofovir), 43 (84.3%) of them being genotype E, although 15 were excluded because they did not meet study inclusion criteria. Thus, a total of 28 CHB genotype E patients were included and followed for 24 months at least. Twenty-one patients were in HBeAg-negative chronic hepatitis phase and 7 patients in HBeAg-positive chronic hepatitis phase. After one year of treatment, among those with good adherence, 89.4% (17/19) of the HBeAg-negative patients and 80% of the HBeAg-positive ones had undetectable viral loads. Response rates reached 100% in both groups after 15–18 months of follow-up. Out of the 7 HBeAg-positive patients, 6 (85.7%) presented HBeAg loss in a median time of 31.8 months. Neither serious adverse effects nor hepatocarcinoma cases happened during the study period. Conclusions HBV genotype may influence disease progression and antiviral response. Our study provides precious information on the efficacy and safety of NA treatment for CHB genotype E infection, a fairly unknown genotype with and increasing epidemiological impact.
Collapse
Affiliation(s)
- José Ángel Cuenca-Gómez
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain.
| | - Ana Belén Lozano-Serrano
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain
| | | | - Manuel Jesús Soriano-Pérez
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain
| | | | | | - Isabel Cabeza-Barrera
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain
| | - Joaquín Salas-Coronas
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain
| |
Collapse
|
|
45
|
Hsu YC, Jun T, Huang YT, Yeh ML, Lee CL, Ogawa S, Cho SH, Lin JT, Yu ML, Nguyen MH, Tanaka Y. Serum M2BPGi level and risk of hepatocellular carcinoma after oral anti-viral therapy in patients with chronic hepatitis B. Aliment Pharmacol Ther 2018; 48:1128-1137. [PMID: 30306612 DOI: 10.1111/apt.15006] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 06/26/2018] [Accepted: 09/10/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Mac-2 binding protein glycosylation isomer (M2BPGi) is an emerging biomarker for risk prediction of liver disease, but data remain sparse for patients with chronic hepatitis B (CHB) who are treated with nucleos(t)ide analogues (NA). AIM To clarify serial changes in M2BPGi and its association with subsequent hepatocellular carcinoma (HCC) development in NA-treated CHB patients. METHODS We enrolled 384 previously untreated CHB patients who received NAs. Among them, 195 had baseline cirrhosis (n = 142:48:5 for Child A:B:C). Sera were collected at NA initiation, and after 1 and 2 years. Serum M2BPGi levels were measured and expressed as cut-off index (COI) at different time points. The association between M2BPGi and HCC was evaluated by the Cox proportional hazard model. RESULTS The median M2BPGi levels significantly decreased from 1.68 COI at baseline, to 1.0 at year 1, and 0.88 at year 2. During median follow-up of 72.7 months, HCC occurred in 37 patients, 36 of whom had cirrhosis. In patients with cirrhosis, baseline M2BPGi level was associated with HCC risk (adjusted hazard ratio, 1.07 per COI; 95% CI, 1.01-1.14) on the multivariable Cox analysis, whereas levels at year 1 or 2 were not independently predictive. A risk score for HCC was developed using baseline M2BPGi, age and body mass index with c statistics of 0.77, 0.79 and 0.87 at 3, 5 and 10 years, respectively. CONCLUSIONS Serum M2BPGi level significantly decreases after NA treatment in CHB patients. Baseline level can be factored into the risk prediction of HCC in NA-treated patients with cirrhosis.
Collapse
Affiliation(s)
- Yao-Chun Hsu
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
- Division of Gastroenterology and Hepatology, E-Da Hospital, Kaohsiung, Taiwan
- Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
| | - Tomi Jun
- Department of Medicine, Stanford University Medical Center, Palo Alto, California
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Long Lee
- Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan
| | - Shintaro Ogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shu-Hsien Cho
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Jaw-Town Lin
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei, Taiwan
- School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| |
Collapse
|
|
46
|
Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology 2018; 68:425-434. [PMID: 29108132 DOI: 10.1002/hep.29640] [Citation(s) in RCA: 243] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 10/06/2017] [Accepted: 11/02/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatitis B surface antigen (HBsAg) loss is a rare event during nucleos(t)ide analogue (Nuc) therapy. Limited data suggest that stopping Nuc therapy may increase HBsAg loss rate in hepatitis B e antigen-negative patients. A large study was conducted to investigate this issue in more detail. Of the 1,075 hepatitis B e antigen-negative patients treated with Nuc for a median of 156 (61-430) weeks, 5 showed HBsAg seroclearance during treatment at an estimated annual incidence of 0.15%. Of the patients who remained HBsAg-seropositive, 691 (52.3 years old, 86% male, 44.6% cirrhosis) had stopped Nuc therapy by the Asian-Pacific Association for the Study of the Liver stopping rule and then were prospectively followed up. Baseline and on-treatment clinical and viral features, treatment duration, consolidation duration, time to undetectable hepatitis B virus DNA, time to normal alanine aminotransferase, end-of-treatment HBsAg, and HBsAg log reduction were compared between patients with and without HBsAg seroclearance after end of treatment. During a median off-therapy follow-up period of 155 (2-614) weeks, HBsAg seroclearance was confirmed in 42 patients. The 6-year cumulative incidence was 13% with an estimated annual incidence of 1.78%. Cox regression analysis showed that shorter time to undetectable hepatitis B virus DNA (<12 weeks), greater HBsAg reduction during therapy (>1 log10 ), lower end-of-treatment HBsAg level (<100 IU/mL), patients with sustained response, and relapsers not retreated were factors for off-therapy HBsAg seroclearance. CONCLUSION The incidence of HBsAg seroclearance after stopping Nuc was much higher than that during therapy and highest in patients without virologic and clinical relapse; patients with clinical relapse who remained untreated had a 7.34 times higher incidence of HBsAg clearance than those who received retreatment, suggesting that transient untreated clinical relapse may drive sufficient immune control to functional cure. (Hepatology 2017).
Collapse
Affiliation(s)
- Wen-Juei Jeng
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
| | - Yi-Cheng Chen
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
| | - Rong-Nan Chien
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
| | - I-Shyan Sheen
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.,Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| |
Collapse
|
|
47
|
Tong MJ, Pan CQ, Han SB, Lu DS, Raman S, Hu K, Lim JK, Hann HW, Min AD. An expert consensus for the management of chronic hepatitis B in Asian Americans. Aliment Pharmacol Ther 2018; 47:1181-1200. [PMID: 29479728 PMCID: PMC5900913 DOI: 10.1111/apt.14577] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/10/2017] [Accepted: 01/27/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide. AIM To generate recommendations for the management of Asian Americans infected with HBV. METHODS These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women. RESULTS Asian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti-viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3 , basal core promoter (BCP) mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life-long anti-viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life-long surveillance for HCC with alpha-fetoprotein (AFP) testing and abdominal ultrasound examination at 6-month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3-month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence. CONCLUSIONS Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.
Collapse
Affiliation(s)
- M. J. Tong
- Pfleger Liver InstituteDivision of Digestive DiseasesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
- Liver CenterHuntington Medical Research InstitutesPasadenaCAUSA
| | - C. Q. Pan
- Division of Gastroenterology and HepatologyNYU Langone Medical CenterNew York University School of MedicineNew YorkNYUSA
| | - S.‐H. B. Han
- Pfleger Liver InstituteDivision of Digestive DiseasesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - D. S.‐K. Lu
- Department of Radiological SciencesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - S. Raman
- Department of Radiological SciencesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - K.‐Q. Hu
- Division of GI/HepatologySchool of MedicineUniversity of California, IrvineOrangeCAUSA
| | - J. K. Lim
- Yale Liver Center and Section of Digestive DiseasesYale University School of MedicineNew HavenCTUSA
| | - H. W. Hann
- Liver Disease Prevention CenterDivision of Gastroenterology and HepatologySidney Kimmel Jefferson Medical College of Thomas Jefferson UniversityPhiladelphiaPAUSA
| | - A. D. Min
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| |
Collapse
|
|
48
|
Wong GLH, Seto WK, Wong VWS, Yuen MF, Chan HLY. Review article: long-term safety of oral anti-viral treatment for chronic hepatitis B. Aliment Pharmacol Ther 2018; 47:730-737. [PMID: 29359487 DOI: 10.1111/apt.14497] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 11/30/2017] [Accepted: 12/11/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Safety profile of nucleos(t)ide analogues is an important issue in view of its widespread use for decades in patients with chronic hepatitis B (CHB). AIM To review and evaluate the latest evidence on the safety profiles of the six approved nucleoside analogues. METHODS Relevant articles related to nucleoside analogue safety were selected for review following extensive language- and date-unrestricted, electronic searches of the literature. RESULTS Nephrotoxicity has been well reported in patients receiving older generations of nucleotide analogues, namely adefovir dipivoxil and tenofovir disoproxil fumarate (TDF). Yet risks of renal failure and renal replacement therapy were similar in patients treated with nucleoside analogues versus nucleotide analogues in real-life setting. Bone toxicity is closely related to nucleoside analogue effect on renal proximal tubular and phosphaturia. Real-life data demonstrated increased risk of hip fracture in patients receiving adefovir but not TDF. The newly approved tenofovir alafenamide (TAF) has improved renal and bone safety profiles compared to TDF. Long-term use of nucleoside analogues eg entecavir does not increase the risk of other cancers. Muscular toxicity may be seen in telbivudine-treated patients so regular monitoring is advised. Peripheral neuropathy and lactic acidosis are rare adverse events. Latest international guidelines support the use of TDF, telbivudine and lamivudine during pregnancy; breastfeeding is not contraindicated during TDF therapy. CONCLUSIONS Long-term safety profile of nucleoside analogues is now better defined with more data from large real-life cohorts and clinical trials with long-term follow-up. The new nucleotide analogue, TAF is now available with favourable renal and bone safety profiles.
Collapse
Affiliation(s)
- G L-H Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong, China
| | - W-K Seto
- Department of Medicine & State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - V W-S Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong, China
| | - M-F Yuen
- Department of Medicine & State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - H L-Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong, China.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong, China
| |
Collapse
|
|
49
|
Buti M, Riveiro-Barciela M, Esteban R. Long-term safety and efficacy of nucleo(t)side analogue therapy in hepatitis B. Liver Int 2018; 38 Suppl 1:84-89. [PMID: 29427500 DOI: 10.1111/liv.13641] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 11/21/2017] [Indexed: 12/11/2022]
Abstract
Long-term treatment of chronic hepatitis B (CHB) with nucleos(t)ide analogues is often necessary to achieve durable viral suppression. Therefore, current guidelines recommend the most potent drugs with optimal resistance profiles. Entecavir (ETV), tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) are the first-line monotherapies for CHB. All of these drugs are highly effective in suppressing viral replication but with slightly different safety profiles. This review provides an overview of the long-term efficacy and safety data that have become available over the 10 years since ETV and TDF were first approved for the treatment of chronic hepatitis, and recent data on TAF in patients with CHB.
Collapse
Affiliation(s)
- Maria Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain.,Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Mar Riveiro-Barciela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain.,Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Rafael Esteban
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain.,Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| |
Collapse
|
|
50
|
Lampertico P, Agarwal K, Berg T, Buti M, Janssen HL, Papatheodoridis G, Zoulim F, Tacke F. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2017; 67:370-398. [PMID: 28427875 DOI: 10.1016/j.jhep.2017.03.021] [Citation(s) in RCA: 3720] [Impact Index Per Article: 465.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2017] [Accepted: 03/23/2017] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection remains a global public health problem with changing epidemiology due to several factors including vaccination policies and migration. This Clinical Practice Guideline presents updated recommendations for the optimal management of HBV infection. Chronic HBV infection can be classified into five phases: (I) HBeAg-positive chronic infection, (II) HBeAg-positive chronic hepatitis, (III) HBeAg-negative chronic infection, (IV) HBeAg-negative chronic hepatitis and (V) HBsAg-negative phase. All patients with chronic HBV infection are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while HBsAg loss is an optimal endpoint. The typical indication for treatment requires HBV DNA >2,000IU/ml, elevated ALT and/or at least moderate histological lesions, while all cirrhotic patients with detectable HBV DNA should be treated. Additional indications include the prevention of mother to child transmission in pregnant women with high viremia and prevention of HBV reactivation in patients requiring immunosuppression or chemotherapy. The long-term administration of a potent nucleos(t)ide analogue with high barrier to resistance, i.e., entecavir, tenofovir disoproxil or tenofovir alafenamide, represents the treatment of choice. Pegylated interferon-alfa treatment can also be considered in mild to moderate chronic hepatitis B patients. Combination therapies are not generally recommended. All patients should be monitored for risk of disease progression and HCC. Treated patients should be monitored for therapy response and adherence. HCC remains the major concern for treated chronic hepatitis B patients. Several subgroups of patients with HBV infection require specific focus. Future treatment strategies to achieve 'cure' of disease and new biomarkers are discussed.
Collapse
|