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Wu J, Xie S, Ma Y, He X, Dong X, Shi Q, Wang Q, Li M, Yao N, Yao L. Entecavir for children and adults with chronic hepatitis B. Cochrane Database Syst Rev 2025; 4:CD015536. [PMID: 40260837 PMCID: PMC12012880 DOI: 10.1002/14651858.cd015536.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
RATIONALE Chronic hepatitis B is a major worldwide public health concern. Entecavir, one nucleos(t)ide analogue antiviral therapy option, is recommended as the first-line drug for chronic hepatitis B in many clinical guidelines. However, none of the guideline recommendations are based on the findings of a systematic review with meta-analysis, where entecavir versus no treatment or placebo are compared directly. OBJECTIVES To evaluate the benefits and harms of entecavir versus no treatment or placebo in children and adults with chronic hepatitis B, who are either hepatitis B e-antigen (HBeAg)-positive or HBeAg-negative. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE Ovid, Embase Ovid, three other databases, online trial registries, and reference lists, and contacted authors. The latest search was on 19 July 2024. ELIGIBILITY CRITERIA We included randomised clinical trials comparing entecavir versus no treatment or placebo in children or adults, or both, with chronic hepatitis B, and irrespective of treatment history with other antiviral drugs and other viral co-infections. We allowed co-interventions when administered equally to all intervention groups. OUTCOMES The outcomes reported in this abstract and in the summary of findings table are all-cause mortality, health-related quality of life, and proportion of people with serious adverse events at the longest follow-up. RISK OF BIAS We used the Cochrane RoB 2 tool to assess risk of bias in the included trials. SYNTHESIS METHODS We used a random-effects model to meta-analyse outcome results, where possible, and presented the results as a risk ratio (RR) with 95% confidence interval (CI). Where there was considerable heterogeneity, we performed a narrative analysis. We used a fixed-effect model for sensitivity analysis. We used GRADE to evaluate the certainty of evidence. INCLUDED STUDIES We included 22 randomised clinical trials (published from 2005 to 2022) with 2940 participants diagnosed with chronic hepatitis B. All trials had a parallel-group design. The experimental intervention was oral entecavir, with a follow-up duration of 5 weeks to 228 weeks. The comparator in 12 trials was no treatment, and in 10 trials was placebo. Fourteen trials equally administered co-interventions to the trial participants in the entecavir and no treatment and placebo groups. One trial included participants between 14 years and 55 years of age, one trial included only children, 19 trials included only adults, and one trial did not provide the age of participants. SYNTHESIS OF RESULTS Twenty trials contributed data to the quantitative analysis. Ten trials (1379 participants) reported all-cause mortality with a mean follow-up duration of 48.9 weeks (range 5 to 100 weeks). The result was not estimable because no deaths occurred in any of the entecavir and no treatment or placebo groups. None of the trials provided data on health-related quality of life. We are very uncertain about the effect of entecavir versus no treatment or placebo on the proportion of people with serious adverse events (RR 0.66, 95% CI 0.33 to 1.32; absolute risk difference 22 fewer per 1000 (from 44 fewer to 21 more); 15 trials, 1676 participants; very low-certainty evidence). The mean follow-up duration was 58.4 weeks (range 5 weeks to 228 weeks). We downgraded the certainty of evidence for these outcomes to very low, mainly because the overall risk of bias in most trials was with some concerns or high, and serious imprecision (no events or few events). AUTHORS' CONCLUSIONS Given the issues of risk of bias and insufficient power of the included trials and the very low certainty of the available evidence, we could not determine the effect of entecavir versus no treatment or placebo on critical outcomes such as all-cause mortality and serious adverse events. There is a lack of data on health-related quality of life. Given the first-line recommendation and wide usage of entecavir in people with chronic hepatitis B, further evidence on clinically important outcomes, analysed in this review, is needed. FUNDING This Cochrane review had no dedicated funding. REGISTRATION Registration: Entecavir for children and adults with chronic hepatitis B, CD015536 via DOI 10.1002/14651858.CD015536.
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Affiliation(s)
- Jing Wu
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Shitong Xie
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Yanfang Ma
- Chinese EQUATOR Centre, Hong Kong Baptist University, Hong Kong, China
| | - Xiaoning He
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Xinyue Dong
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Qianling Shi
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Qi Wang
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Meixuan Li
- Evidence-based Medicine Center, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China
| | - Naijuan Yao
- The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Liang Yao
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
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Lumley SF, Mokaya J, Maponga TG, Kramvis A, Dusheiko G, Irving W, Delphin M, Said Mohammed K, Downs LO, Waddilove E, Anderson M, Iwuji C, Msomi N, Ocama P, Hamid S, Adda D, Halford R, Kabagambe K, Benschop KSM, Inzaule S, Chan P, Paul MAS, Izumi K, Nisa T, De Dieu Iragena J, Girón-Callejas A, Kpossou AR, Jamiyu G, Emmanuel O, Balkissa M, Keita M, Prabdial-Sing N, Martinez A, Magongo EN, Shao Y, Sued O, Sereno LS, Shafer RW, Lesi O, Faini D, Easterbrook P, Duncombe C, Jordan MR, Matthews PC. Hepatitis B virus resistance to nucleos(t)ide analogue therapy: WHO consultation on questions, challenges, and a roadmap for the field. THE LANCET. MICROBE 2025:101076. [PMID: 40220768 DOI: 10.1016/j.lanmic.2025.101076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 12/19/2024] [Accepted: 01/14/2025] [Indexed: 04/14/2025]
Abstract
In this Review, we summarise outputs from a multidisciplinary consultation convened by WHO between July 11 and 13, 2023, to discuss hepatitis B virus (HBV) drug resistance (HBVDR). Treatment of chronic HBV infection with highly effective nucleos(t)ide analogue agents, tenofovir and entecavir, is a crucial intervention that supports the global goal of elimination of HBV infection as a public health threat. The risk of HBVDR as a threat to treatment outcomes is currently considered low from a public health perspective; however, drug resistance can influence individual outcomes, particularly among those who are treatment-experienced. We highlight the need to develop appropriate prevention, monitoring, and surveillance approaches for HBVDR, to support investment in the global scale-up of HBV diagnosis and treatment. Recommendations for the HBVDR field will ultimately be incorporated into a WHO integrated Global Action Plan for drug-resistant HIV, viral hepatitis, and priority sexually transmitted infections.
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Affiliation(s)
- Sheila F Lumley
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals, Oxford, UK
| | - Jolynne Mokaya
- Parasites and Microbes, Wellcome Sanger Institute, Cambridge, UK
| | - Tongai G Maponga
- Division of Medical Virology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa; National Health Laboratory Service, Tygerberg Business Unit, Cape Town, South Africa
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
| | - Geoffrey Dusheiko
- University of the Witwatersrand, Johannesburg, South Africa; Institute of Liver Studies, King's College Hospital, London, UK
| | - William Irving
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust, University of Nottingham, Nottingham, UK
| | | | | | - Louise O Downs
- Nuffield Department of Medicine, University of Oxford, Oxford, UK; Department of Infectious Diseases and Microbiology, Oxford University Hospitals, Oxford, UK; Kenya Medical Research Institute Wellcome Trust, Kilifi, Kenya
| | | | - Motswedi Anderson
- The Francis Crick Institute, London, UK; Africa Health Research Institute, Durban, South Africa; Botswana Harvard Health Partnership, Gaborone, Botswana
| | - Collins Iwuji
- Africa Health Research Institute, Durban, South Africa; Department of Global Health and Infection, Brighton and Sussex Medical School, University of Sussex, Brighton, UK
| | - Nokukhanya Msomi
- Discipline of Virology, University of KwaZulu-Natal and National Health Laboratory Service, Durban, South Africa
| | - Ponsiano Ocama
- Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | - Saeed Hamid
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Danjuma Adda
- World Hepatitis Alliance, Geneva, Switzerland; Center for Initiative and Development and Chagro-Care Trust, Jalingo, Nigeria
| | | | - Kenneth Kabagambe
- The National Organisation for People Living with Hepatitis B, Kampala, Uganda
| | | | - Seth Inzaule
- Amsterdam Institute for Global Health and Development and Department of Global Health, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Polin Chan
- Department of Communicable Diseases, WHO South-East Asia Regional Office, New Delhi, India
| | | | - Kiyohiko Izumi
- Division of Programmes for Disease Control, WHO Western Pacific Regional Office, Manila, Philippines
| | - Tiara Nisa
- Division of Programmes for Disease Control, WHO Western Pacific Regional Office, Manila, Philippines
| | - Jean De Dieu Iragena
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | - Amalia Girón-Callejas
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | | | - Ganiyu Jamiyu
- National AIDS, Viral Hepatitis and STIs Control Programme, Abuja, Nigeria
| | - Omolara Emmanuel
- National AIDS, Viral Hepatitis and STIs Control Programme, Abuja, Nigeria
| | - Mahamadou Balkissa
- Programme National de Lutte contre le Sida et les Hépatites (PNLSH), Ministère de la Santé Publique, de la Population et des Affaires Sociales, Niamey, Niger
| | - Mamadou Keita
- The Sectoral Unit for the Fight against HIV, Tuberculosis and Viral Hepatitis, Ministry of Health, Bamako, Mali
| | - Nishi Prabdial-Sing
- National Institute for Communicable Diseases and National Health Laboratory Service and the Faculty of Health Sciences, Witwatersrand University, Johannesburg, South Africa; National Institute for Communicable Diseases, National Health Laboratory Service, Johannesburg, South Africa
| | - Alexander Martinez
- Gorgas Memorial Institute for Health Studies, Panama City, Panama; Department of Microbiology and Immunology, University of Panama, Panama City, Panama
| | | | - Yiming Shao
- National Centre for AIDS/STD Control and Prevention A, Chinese Center for Disease Control and Prevention, Changping Laboratory, Beijing, China
| | - Omar Sued
- HIV, STI, Viral Hepatitis and TB Unit, Department of Communicable Disease Prevention, Control, and Elimination, Pan American Health Organization, Washington, DC, USA
| | - Leandro Soares Sereno
- HIV, STI, Viral Hepatitis and TB Unit, Department of Communicable Disease Prevention, Control, and Elimination, Pan American Health Organization, Washington, DC, USA
| | - Robert W Shafer
- Department of Medicine, Division of Infectious Diseases, Stanford University, Stanford, CA, USA
| | - Olufunmilayo Lesi
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland; University of Lagos, Lagos, Nigeria
| | - Diana Faini
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | - Philippa Easterbrook
- Department of Global HIV, Hepatitis and Sexually Transmitted Infections, WHO, Geneva, Switzerland
| | - Chris Duncombe
- International Association of Providers of AIDS Care, Washington DC, USA
| | - Michael R Jordan
- Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, MA, USA; Collaboratory for Emerging Infectious Diseases and Response, Tufts University, Medford, MA, USA
| | - Philippa C Matthews
- Kenya Medical Research Institute Wellcome Trust, Kilifi, Kenya; Division of Infection and Immunity, University College London, London, UK; Department of Infectious Diseases, University College London Hospital, London, UK.
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Kim HR, Kang SH, Yim HJ, Suh SJ, Jung YK, Kim JH, Seo YS, Yeon JE, Byun KS. Need of Treatment Modification During Entecavir Therapy in Patients with Chronic Hepatitis B: Long-Term Follow-Up Results for 120 Months. Microorganisms 2025; 13:218. [PMID: 40005585 PMCID: PMC11857378 DOI: 10.3390/microorganisms13020218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 02/27/2025] Open
Abstract
Entecavir (ETV) may have limited antiviral efficacy in chronic hepatitis B (CHB) patients with a high baseline viral load, especially in cases of partial virologic response (PVR). This study evaluated the outcomes of prolonged ETV monotherapy, given the lack of clear evidence favoring continuation or combination therapy in such scenarios. We included 188 treatment-naïve patients on ETV 0.5 mg and compared antiviral responses between high viral load (HVL, ≥7 log10 IU/mL) and non-HVL groups for over up to 120 months in this study. Compared to the non-HVL group, the HVL group exhibited a lower cumulative virologic response (VR, <20 IU/mL) during the 10-year therapy period (p < 0.01). Antiviral resistance to entecavir (rtS202G + rtM204V + rtL180M) developed in three out of 90 patients in the HVL group. Patients with complete response at 6 months had a 100% likelihood of achieving VR, while 83.9% of patients with PVR at 6 months achieved VR by month 120 (p < 0.01). Multivariate analysis revealed that baseline HVL was a significant predictor of long-term VR at 120 months. In conclusion, CHB patients with baseline HVL and PVR at 6 months are prone to ETV resistance and inadequate response, warranting a modification in treatment strategy.
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Affiliation(s)
| | | | - Hyung Joon Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, Republic of Korea; (H.R.K.); (S.H.K.); (S.J.S.); (Y.K.J.); (J.H.K.); (Y.S.S.); (J.E.Y.); (K.S.B.)
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Peng W, Yi M, Qi X, Qi W, Li C, Wen T. The effect of switch therapy to tenofovir versus entecavir maintenance on recurrence of hepatocellular carcinoma after surgery (SWITE): study protocol for a randomized controlled trial. Trials 2023; 24:781. [PMID: 38042834 PMCID: PMC10693690 DOI: 10.1186/s13063-023-07822-y] [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: 04/03/2023] [Accepted: 11/22/2023] [Indexed: 12/04/2023] Open
Abstract
BACKGROUND Antiviral therapy has been reported to be associated with lower recurrence rate of hepatocellular carcinoma (HCC) for patients with hepatitis B virus (HBV) infection. While entecavir (ETV) and tenofovir disoproxil fumarate (TDF) were both recommended as first-line therapies for HBV patients, recent retrospective studies proposed a lower incidence rate of HCC occurrence or recurrence in those receiving TDF compared ETV. However, the survival benefits of switching to TDF therapy after prolonged ETV treatment before surgery remain uncertain. We delineate the rationale and design of SWITE, a randomized, open-label, phase III trial contrasting TDF switch therapy versus ETV maintenance in HBV-related HCC patients. METHODS AND ANALYSIS This is a prospective, randomized, controlled, single-center study with two parallel groups of patients with HBV-related HCC who have received long-term ETV therapy before surgery. West China Hospital will enroll 238 patients, randomized in a 1:1 ratio to TDF switch therapy or ETV maintenance after surgery. The primary endpoint of this study is 3-year recurrence free survival (RFS), with the secondary endpoint being 3-year overall survival (OS) after curative surgery of HCC. Safety events will be diligently recorded. ETHICS AND DISSEMINATION The study protocol aligns with the ethical guidelines of the 1975 Declaration of Helsinki. It was approved by ethics committee of West China Hospital (approval number: 2022-074) and was registered with chictr.org.cn (chiCTR2200057867). Informed consent will be obtained from all participants. The results of this trial will be published in peer-reviewed journals and presentations at national and international conferences relevant to this topic. TRIAL REGISTRATION chiCTR2200057867 . Date of registration is March 20 2022.
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Affiliation(s)
- Wei Peng
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
- Chinese Evidence-based Medicine Center, West China Hospital, Sichuan University, Chengdu, China
| | - Mengshi Yi
- Deparment of Hepatobiliary Surgery, the First Affiliated Hospital of Army Medical University, Chongqing, China
| | - Xin Qi
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Weili Qi
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chuan Li
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Tianfu Wen
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
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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.
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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
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Martin P, Nguyen MH, Dieterich DT, Lau DTY, Janssen HLA, Peters MG, Jacobson IM. Treatment Algorithm for Managing Chronic Hepatitis B Virus Infection in the United States: 2021 Update. Clin Gastroenterol Hepatol 2022; 20:1766-1775. [PMID: 34329775 DOI: 10.1016/j.cgh.2021.07.036] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 07/15/2021] [Accepted: 07/21/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Chronic hepatitis B (CHB) infection remains the most frequent etiology of hepatocellular carcinoma globally as well as a major cause of cirrhosis. Despite vaccination, substantial numbers of persons have already been infected with hepatitis B virus and remain at risk of progressive liver disease. METHODS In 2004, a CHB management algorithm was developed by a panel of North American hepatologists, which was subsequently updated in 2006, 2008, and 2015. Since the most recent version, several developments have altered the management of CHB. Tenofovir alafenamide, with a more favorable safety profile than tenofovir disoproxil fumarate, has been introduced as an initial antiviral choice as well as an alternative for long-term therapy. Quantitation of hepatitis B surface antigen is becoming more widely available in clinical practice, with implications for monitoring response to treatment. Additionally, there has been a shift in how the natural history of CHB is perceived, as newer evidence has challenged the concept that during the immunotolerant phase of infection disease progression is not a concern. Finally, recent analyses indicate that in the United States, the average age of patients with CHB has increased, implying that the presence of comorbidities, including metabolic liver disease, increasing use of biologics associated with aging will increasingly affect disease management. RESULTS This updated algorithm is intended to serve as a guide to manage CHB while new antiviral strategies are developed. CONCLUSIONS Recommendations have been based on evidence from the scientific literature, when possible, as well as clinical experience and consensus expert opinion. Points of continued debate and areas of research need are also described.
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Affiliation(s)
- Paul Martin
- Division of Digestive Health and Liver Diseases, University of Miami School of Medicine, Miami, Florida.
| | - Mindie H Nguyen
- Department of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California; Department of Epidemiology and Population Health, Stanford University Medical Center, Palo Alto, California
| | | | - Daryl T-Y Lau
- Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, University Health Network, Toronto, Canada
| | - Marion G Peters
- Division of Gastroenterology, University of California, San Francisco, San Francisco, California
| | - Ira M Jacobson
- Division of Gastroenterology, NYU Langone Health, New York, New York
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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: 76] [Impact Index Per Article: 25.3] [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.
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Cheng K, Chen Y, Wang X, Xu M, Liao W, Duan X, Zhao X, Sun Y, Duan Z, Wang L. Entecavir combined with interferon-α Is superior to entecavir monotherapy in reducing hepatic and extrahepatic cancer in patients with chronic hepatitis B. Cancer 2022; 128:558-569. [PMID: 34623636 DOI: 10.1002/cncr.33949] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 08/30/2021] [Accepted: 09/07/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND The objective of this study was to assess whether entecavir (ETV) in combination with interferon-α (IFN-α) could reduce hepatocellular cancer (HCC) and extrahepatic cancers (EHCs) in patients with chronic hepatitis B (CHB). METHODS The cohort consisted of 4194 patients with CHB treated with ETV combined with IFN-α or ETV monotherapy at a tertiary hospital in Beijing, China, from January 2009 to December 2017. The risks, hazard ratios (HRs), and 95% confidence intervals (CIs) of HCC and EHCs were compared in the 2 groups. RESULTS In a multivariate Cox regression analysis, a significantly lower risk of HCC (HR, 0.6; 95% CI, 0.3-0.9; P = .0310) and a marginally significantly lower risk of EHCs (HR, 0.2; 95% CI, 0.02-1.3; P = .0854) were observed in the group receiving ETV combined with IFN-α in comparison with the ETV monotherapy group. The annual virological response rates were significantly higher in the combination therapy group versus the monotherapy group (33.8% vs 21.2%; P < .0001), but the hepatitis B surface antigen (HBsAg) seroclearance rates were not (1.2% vs 0.9%; P = .8537). The HRs were consistent with propensity score-based matching, inverse probability weighting adjustments, and adjustments for virological response and HBsAg seroclearance. CONCLUSIONS ETV combined with IFN-α therapy is superior to ETV monotherapy in reducing the risk of HCC and EHCs for patients with CHB. People who can tolerate and benefit from IFN-α therapy could consider combination therapy.
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Affiliation(s)
- Kailiang Cheng
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yu Chen
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Xiaomo Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Manman Xu
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Wei Liao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | | | - Xinyu Zhao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yuanyuan Sun
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Zhongping Duan
- Fourth Department of Liver Disease (Difficult and Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital, Capital Medical University, Beijing, China
- Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Li Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences/School of Basic Medicine, Peking Union Medical College, Beijing, China
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Wang X, Chen Y, Xu M, Cheng K, Duan X, Liao W, Wang Y, Lu Y, Duan Z, Wang L. Virologic response maintenance and hepatocellular carcinoma in chronic hepatitis B patients treated with entecavir. Expert Rev Gastroenterol Hepatol 2021; 15:1337-1344. [PMID: 34511012 DOI: 10.1080/17474124.2021.1980385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 09/10/2021] [Indexed: 01/27/2023]
Abstract
INTRODUCTION The treatment evidence for entecavir-treated chronic hepatitis B (CHB) patients without maintaining of virologic response (MVR, defined as persistent HBV DNA <20 IU/mL during therapy) remains uncertain. We aimed to determine the relationship between non-MVR and hepatocellular carcinoma (HCC) risk in entecavir-treated CHB patients. METHODS A cohort of 1447 entecavir-treated CHB patients were enrolled. Multivariate and propensity score-based inverse probability weighting (IPW) model was performed to estimate the effect of MVR on HCC. RESULTS During a median follow-up of 5 years, 214 (14.8%) patients occurred with non-MVR. Non-MVR patients had a higher risk of HCC [the IPW model: hazard ratio (HR) = 3.59, 95% confidence interval (CI): 2.23-5.75] than MVR patients, especially in those with cirrhosis (HR = 4.60, 95% CI: 2.81-7.56) and the high HCC score by the Chinese University of Hong Kong (HR = 4.35, 95% CI: 2.58-7.32). MVR patients with transient (HR = 4.72, 95% CI: 1.98-11.24) or persistent (HR = 12.16, 95% CI: 3.58-41.31) abnormal ALT after virologic response had higher HCC hazard. CONCLUSIONS Our study indicated an elevated HCC probability for entecavir-treated CHB patients with Non-MVR, especially for those with cirrhosis or a high predicted score at baseline. For MVR patients, the trajectories of ALT after virologic response suggested different HCC risks.
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Affiliation(s)
- Xiaomo Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences; School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Yu Chen
- Fourth Department of Liver Disease (Difficult & Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital Affiliated to Capital Medical University, Beijing, China
- Fourth Department of Liver Disease (Difficult & Complicated Liver Diseases and Artificial Liver Center), Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Manman Xu
- Fourth Department of Liver Disease (Difficult & Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital Affiliated to Capital Medical University, Beijing, China
- Fourth Department of Liver Disease (Difficult & Complicated Liver Diseases and Artificial Liver Center), Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Kailiang Cheng
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences; School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Xiaoman Duan
- Department of General Business and Finance, Sam Houston State University, Huntsville, Texas, USA
| | - Wei Liao
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences; School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Yanhong Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences; School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Ying Lu
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences; School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Zhongping Duan
- Fourth Department of Liver Disease (Difficult & Complicated Liver Diseases and Artificial Liver Center), Beijing You'an Hospital Affiliated to Capital Medical University, Beijing, China
- Fourth Department of Liver Disease (Difficult & Complicated Liver Diseases and Artificial Liver Center), Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Li Wang
- Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences; School of Basic Medicine Peking Union Medical College, Beijing, China
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Marlet J, Lier C, Roch E, Moreau A, Combe B, Handala L, Lefeuvre S, Maugey M, Elkrief L, d'Alteroche L, Potier P, Brand D, Gaudy-Graffin C. Evolution and phenotypic characterization of whole HBV genome in compliant patients experiencing unexplained entecavir treatment failure. Antiviral Res 2021; 192:105106. [PMID: 34214504 DOI: 10.1016/j.antiviral.2021.105106] [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] [Received: 11/02/2020] [Revised: 04/29/2021] [Accepted: 05/31/2021] [Indexed: 12/20/2022]
Abstract
Entecavir treatment failure can be observed in compliant patients despite an absence of detectable resistance mutations by Pol/RT Sanger sequencing. We hypothesized that these unexplained treatment failures could rely on other mechanisms of viral resistance, especially on mutations selected outside of the Pol/RT domain. Partial virological response to entecavir was observed in three patients treated with immunosuppressive drugs, without selection of Pol/RT resistance mutations. Mutations selected in the whole HBV genome during entecavir treatment and potentially associated with resistance were searched for using deep sequencing and characterized using a phenotypic resistance assay. Mutations Q206K (pre-core/core), Q120K (pre-S1/pre-S2, T-cell epitope) and A300E (spacer domain) were selected during entecavir treatment in patient #1 but were not associated with an increased level of resistance to entecavir or an increase in HBV replication capacity. Core promoter mutations T1753G, A1762T and G1764A were present as major mutations before and after treatment in patient #1. HBs Ag immune escape mutations were present as major mutations before and after treatment in patients #2 (sK122R, sT126I, sP127S and sG145R) and #3 (sM133I). We demonstrated that PVR to entecavir does not require selection of any resistance mutation in the whole HBV genome. Our results demonstrate that major mutations can be selected outside of the Pol/RT domain before or during entecavir treatment. These mutations could contribute to entecavir treatment failure by other mechanisms than an increased level of resistance.
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Affiliation(s)
- Julien Marlet
- INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France.
| | - Clément Lier
- INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France
| | | | - Alain Moreau
- INSERM U1259, Université de Tours et CHRU de Tours, France
| | - Benjamin Combe
- INSERM U1259, Université de Tours et CHRU de Tours, France
| | - Lynda Handala
- INSERM U1259, Université de Tours et CHRU de Tours, France
| | | | - Morgan Maugey
- INSERM U1259, Université de Tours et CHRU de Tours, France
| | - Laure Elkrief
- Service D'Hépato-gastroentérologie, CHRU de Tours, France
| | | | - Pascal Potier
- Service D'Hépato-gastroentérologie, CHR D'Orléans, France
| | - Denys Brand
- INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France
| | - Catherine Gaudy-Graffin
- INSERM U1259, Université de Tours et CHRU de Tours, France; Service de Bactériologie-Virologie-Hygiène, CHRU de Tours, France
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11
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Yin GQ, Li J, Zhong B, Yang YF, Wang MR. New therapeutic options for persistent low-level viremia in patients with chronic hepatitis B virus infection: Increase of entecavir dosage. World J Gastroenterol 2021; 27:666-676. [PMID: 33716446 PMCID: PMC7934007 DOI: 10.3748/wjg.v27.i8.666] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 12/25/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection (CHB) is a public health concern worldwide. Current therapies utilizing nucleos(t)ide analogs (NA) have not resulted in a complete cure for CHB. Furthermore, patients on long-term NA treatment often develop low-level viremia (LLV). Persistent LLV, in addition to causing the progression of liver disease or hepatocellular carcinoma, may shed light on the current plight of NA therapy. Here, we review the literature on LLV, NA treatment, and various doses of entecavir to find a strategy for improving the efficacy of this antiviral agent. For LLV patients, three therapeutic options are available, switching to another antiviral monotherapy, interferon-α switching therapy, and continuing monotherapy. In real-world clinical practice, entecavir overdose has been used in antiviral therapy for CHB patients with NA refractory and persistent LLV, which encouraged us to conduct further in-depth literature survey on dosage and duration related entecavir studies. The studies of pharmacodynamics and pharmacokinetics show that entecavir has the maximal selected index for safety, and has great potential in inhibiting HBV replication, in all of the NAs. In the particular section of the drug approval package published by the United States Food and Drug Administration, entecavir doses 2.5-20 mg/d do not increase adverse events, and entecavir doses higher than 1.0 mg/d might improve the antiviral efficacy. The literature survey led us to two suggestions: (1) Increasing entecavir dose to 1.0 mg/d for the treatment of NA naïve patients with HBV DNA >2 × 106 IU/mL is feasible and would provide better prognosis; and (2) Further research is needed to assess the long-term toxic effects of higher entecavir doses (2.5 and 5.0 mg/d), which may prove beneficial in treating patients with prior NA treatment, partial virological response, or LLV state.
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Affiliation(s)
- Guo-Qing Yin
- Department of Infectious Diseases, Nanjing Zhong-Da Hospital, Southeast University School of Medicine, Nanjing 210009, Jiangsu Province, China
| | - Jun Li
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Bei Zhong
- The Sixth Affiliated Hospital, Guangzhou Medical University/Qingyuan People’s Hospital, Qingyuan 511518, Guangdong Province, China
| | - Yong-Fong Yang
- Department of Liver Disease, The Second Hospital of Nanjing, Nanjing University of Chinese Medicine, Nanjing 210003, Jiangsu Province, China
| | - Mao-Rong Wang
- Department of Infectious Diseases and Liver Disease Center, The Affiliated Nanjing Jinling Hospital, Nanjing University, Nanjing 210002, Jiangsu Province, China
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12
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Sonneveld MJ, van Meer S. Management of Patients With Chronic Hepatitis B (Hepadnaviridae) and Chronic Hepatitis D Infection (Deltavirus). ENCYCLOPEDIA OF VIROLOGY 2021:217-226. [DOI: 10.1016/b978-0-12-814515-9.00104-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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13
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Li X, Zhou D, Chi X, Li Q, Wang L, Lu B, Mao D, Wu Q, Wang X, Zhang M, Xue J, Li Y, Lu W, Guo J, Jiang F, Zhang X, Li Z, Yang X, Guo H, Gan D, He L, Luo L, Zhang L, Du H, Ye Y. Entecavir combining Chinese herbal medicine for HBeAg-positive chronic hepatitis B patients: a randomized, controlled trial. Hepatol Int 2020; 14:985-996. [PMID: 33128206 DOI: 10.1007/s12072-020-10097-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 09/30/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM Traditional Chinese medicine (TCM) is widely accepted and prescribed in China alongside Nucleoside analogs (NAs). In this double-blind, placebo-controlled, randomized, multi-center trial, we evaluated whether entecavir (ETV) plus TCM formulas Tiao-Gan-Yi-Pi granule (TGYP) and Tiao-Gan-Jian-Pi-Jie-Du granule (TGJPJD) increase the rate of hepatitis B e antigen (HBeAg) loss in Chinese patients. METHODS 596 eligible participants were randomly assigned, in a 1:1 ratio, to two study groups in this 108-week trial: The experiment group was assigned ETV plus the TCM formula. The control group was assigned ETV plus a TCM placebo. We compared the rate of HBeAg loss by the end of week 108 between the two arms as the primary outcome. Secondary outcomes included hepatitis B surface antigen (HBsAg) level, proportion of undetectable HBV-DNA, and liver enzymes (ALT, AST, GGT) at week 108. RESULTS The combination therapy achieved superior HBeAg loss at 108 weeks, without additional adverse events. The rate of HBeAg loss at week 108 was 37.54% (95% CI 31.9-43.2%) in the experiment group and 27.21% (95% CI 22.0-32.4%) in the control group. There was a statistically significant difference between the two arms of 10.33% (95% CI 8.4-12.3%, p = 0.008). The DNA loss rate, serum HBsAg level, and liver enzymes were similar between the groups by the end of 108th week. CONCLUSION Combining the Chinese herbal formula with ETV therapy demonstrated superior HBeAg clearance compared with ETV monotherapy. This finding indicates that this combined therapy could produce an improved therapeutic effect and safety profile. CLINICAL TRIAL NUMBER ChiCTR-TRC-12002784 (Chinese Clinical Trial Registry).
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Affiliation(s)
- Xiaoke Li
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Daqiao Zhou
- Department of Hepatology, Shenzhen TCM Hospital, No. 1 Fuhua Road, Futian District, Shenzhen, 518033, China
| | - Xiaoling Chi
- Department of Hepatology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Dade Road 111, Guangzhou, 510120, Guangdong, China
| | - Qin Li
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, No. 312 Xihong road, Gulou District, Fujian, 350025, Fuzhou, China
| | - Li Wang
- Department of Hepatology, Public Health Clinical Center of Chengdu, No. 377 Jingming Road, Jinjiang District, Chengdu, 610066, Sichuan, China
| | - Bingjiu Lu
- Department of Hepatology, Liaoning Hospital of TCM, Huanggu District, No. 33, Beiling Street, Shenyang, 110032, Liaoning, China
| | - Dewen Mao
- Department of Hepatology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No. 89-9, Dongge road, Nanning, 530023, Guangxi, China
| | - Qikai Wu
- Department of Hepatology, The Third People's Hospital of Shenzhen, No. 29 Bujibulan Road, Longgang District, Shenzhen, 518112, China
| | - Xianbo Wang
- Department of Hepatology, Beijing Ditan Hospital, No. 8 Jingshun East Road, Chaoyang District, Beijing, 100015, China
| | - Mingxiang Zhang
- Department of Hepatology, The Sixth People's Hospital of Shenyang, No. 85 Heping south road, Heping District, Shenyang, 110006, Liaoning, China
| | - Jingdong Xue
- Department of Hepatology, Shaanxi Hospital of TCM, No. 4 Xihuamen, Lianhu District, Xi'an, 710003, Shaanxi, China
| | - Yong Li
- Department of Hepatology, The Affiliated Hospital of Shandong University of TCM, No. 42 Wenhua West Road, Jinan, 250011, Shandong, China
| | - Wei Lu
- Department of Hepatology, Tianjin Second People's Hospital, No.7 Sudi South Road, Nankai District, Tianjin, 300192, China
| | - Jianchun Guo
- Department of Hepatology, Xixi Hospital of Hangzhou, No. 2 Hengbu road, Liuxiazhen, Xihu District, Hangzhou, 310023, Zhejiang, China
| | - Feng Jiang
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Xinwei Zhang
- Department of Liver Disease, Fifth Medical Center of Chinese PLA General Hospital, No.100 West Fourth Ring Road, Beijing, 100039, China
| | - Zhiguo Li
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Xianzhao Yang
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Hui Guo
- Department of Hepatology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No. 314 An Shan Xi Road, Nan Kai District, Tianjin, 300193, China
| | - Danan Gan
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Liyun He
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medicine Sciences, No. 16, Dongzhimen South Street, Dongcheng District, Beijing, 100700, China
| | - Lin Luo
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medicine Sciences, No. 16, Dongzhimen South Street, Dongcheng District, Beijing, 100700, China
| | - Ludan Zhang
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China
| | - Hongbo Du
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China.
| | - Yong'an Ye
- Department of Gastroenterology, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine (BUCM), Institute of Liver Diseases, BUCM, No. 5 Haiyuncang road, Dongcheng District, Beijing, 100700, China.
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14
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Tao YC, Wang ML, Zhang DM, Wu DB, Wang YH, Liao J, Tang H, Chen EQ. Optimal drug administration manner would rescue partial virological response in chronic hepatitis B patients with entecavir or tenofovir treatment. J Viral Hepat 2020; 27:731-738. [PMID: 32048386 DOI: 10.1111/jvh.13275] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/03/2020] [Accepted: 01/21/2020] [Indexed: 02/05/2023]
Abstract
Not all treatment-naïve patients receiving entecavir (ETV) or tenofovir disoproxil fumarate (TDF) therapy can achieve complete virological response, and many factors may be related with the outcome of partial virological response. This study aimed to determine whether the manner of drug administration affects the antiviral efficacy of ETV/TDF monotherapy. All eligible patients were divided into complete or partial response cohorts based on their virological response following 24-week therapy. Factors related with partial response were evaluated. Patients with partial response were further grouped depending on whether they later adjusted the manner of drug administration, and the antiviral efficacy was compared between the two groups during prolonged treatment. A total of 518 patients were enrolled. Suboptimal drug administration (OR 77.511, P = .000), positive-HBeAg (OR 3.191, P = .000) and ETV treatment (OR 2.537, P = .001) were identified as independent risk factors for partial response. Among patients with partial response, 213 were in the adjusted group and 76 were in the unadjusted group. The percentages of patients with undetectable serum HBV DNA (78.9% vs 31.6%, P < .001) and with normal alanine aminotransferase (ALT) (88.7% vs 68.4%, P < .001) were both higher in the adjusted group than that in unadjusted group following a further 6-month therapy. In conclusion, the manner of drug administration is an important factor influencing the efficacy of ETV/TDF therapy, and optimal drug administration manner can help to increase antiviral efficacy and rescue patients with partial response.
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Affiliation(s)
- Ya-Chao Tao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Meng-Lan Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Dong-Mei Zhang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Dong-Bo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Juan Liao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
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15
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Kim JH, Sinn DH. Low-level viremia in patients undergoing antiviral therapy: Does it indicate time for a change? Clin Mol Hepatol 2020; 26:315-317. [PMID: 32570301 PMCID: PMC7364347 DOI: 10.3350/cmh.2020.0084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 05/31/2020] [Indexed: 11/27/2022] Open
Affiliation(s)
- Jung Hee Kim
- Division of Gastroenterology, Department of Internal Medicine, Hallym University Dongtan Sacred Heart Hospital, Dongtan, Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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16
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Wang YH, Liao J, Zhang DM, Wu DB, Tao YC, Wang ML, Chen EQ, Tang H. Tenofovir monotherapy versus tenofovir plus entecavir combination therapy in HBeAg-positive chronic hepatitis patients with partial virological response to entecavir. J Med Virol 2020; 92:302-308. [PMID: 31609007 DOI: 10.1002/jmv.25608] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 09/24/2019] [Accepted: 10/08/2019] [Indexed: 02/05/2023]
Abstract
AIMS The aim of this retrospective study was to compare the efficacy and safety of tenofovir disoproxil fumarate (TDF) monotherapy and TDF + entecavir (ETV) combination therapy for chronic hepatitis B (CHB) patients with the partial virological response (PVR) to ETV. METHODS CHB patients with PVR to ETV were switched to TDF monotherapy or TDF + ETV combination therapy. The primary efficacy outcome was a virological response (VR), and the secondary efficacy outcomes were hepatitis B e antigen (HBeAg) seroconversion and alanine aminotransferase (ALT) normalization. The primary safety outcomes were changes in serum creatinine and serum phosphorus levels. RESULTS A total of 143 patients were investigated, including 63 patients in the TDF monotherapy group and 80 patients in the TDF + ETV combination therapy group. Baseline demographics and clinical characteristics were comparable between groups. The median age of patients was 44.5 years, and 76.2% of them were male. The VR rate in TDF + ETV group was higher than that of the TDF group at 48 weeks (88.8% vs 71.4%; P = .009). At 48 weeks, the HBeAg seroconversion rate of TDF + ETV group was higher than that of the TDF group (30% vs 15.9%; P = .049). There was no significant difference in the proportion of patients with elevated ALT in the TDF group and TDF + ETV group at 48 weeks (9.5% vs 7.5%; P = .665). After adjusting the treatment regimen, serum creatinine levels increased slightly and serum phosphorus level decreased slightly in both groups. CONCLUSIONS TDF + ETV combination therapy for 48 weeks had a higher VR rate than TDF monotherapy in CHB patients with PVR to ETV.
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Affiliation(s)
- Yong-Hong Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Juan Liao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Dong-Mei Zhang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Dong-Bo Wu
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Ya-Chao Tao
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Meng-Lan Wang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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Hamdi M, Abdel-Bar HM, Elmowafy E, Al-Jamal KT, Awad GAS. An integrated vitamin E-coated polymer hybrid nanoplatform: A lucrative option for an enhanced in vitro macrophage retention for an anti-hepatitis B therapeutic prospect. PLoS One 2020; 15:e0227231. [PMID: 31923260 PMCID: PMC6953793 DOI: 10.1371/journal.pone.0227231] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 12/13/2019] [Indexed: 01/19/2023] Open
Abstract
A platform capable of specifically delivering an antiviral drug to the liver infected with hepatitis B is a major concern in hepatology. Vaccination has had a major effect on decreasing the emerging numbers of new cases of infection. However, the total elimination of the hepatitis B virus from the body requires prolonged therapy. In this work, we aimed to target the liver macrophages with lipid polymer hybrid nanoparticles (LPH), combining the merit of polymeric nanoparticles and lipid vesicles. The hydrophilic antiviral drug, entecavir (E), loaded LPH nanoparticles were optimized and physicochemically characterized. A modulated lipidic corona, as well as, an additional coat with vitamin E were used to extend the drug release enhance the macrophage uptake. The selected vitamin E coated LPH nanoparticles enriched with lecithin-glyceryl monostearate lipid shell exhibited high entrapment for E (80.47%), a size ≤ 200 nm for liver passive targeting, extended release over one week, proven serum stability, retained stability after refrigeration storage for 6 months. Upon macrophage uptake in vitro assessment, the presented formulation displayed promising traits, enhancing the cellular retention in J774 macrophages cells. In vivo and antiviral activity futuristic studies would help in the potential application of the ELPH in hepatitis B control.
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Affiliation(s)
- Mohamed Hamdi
- Department of Pharmaceutics, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt
| | - Hend Mohamed Abdel-Bar
- Department of Pharmaceutics, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt
| | - Enas Elmowafy
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Sadat City, Egypt
| | - Khuloud T. Al-Jamal
- Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King’s College London, England, United Kingdom
| | - Gehanne A. S. Awad
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Sadat City, Egypt
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18
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Song JE, Lee CH, Kim BS. Efficacy of long-term tenofovir disoproxil fumarate therapy in chronic hepatitis B patients with partial virologic response in real practice. Korean J Intern Med 2019; 34:802-810. [PMID: 30959583 PMCID: PMC6610193 DOI: 10.3904/kjim.2019.037] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 02/18/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS The optimal management of chronic hepatitis B (CHB) patients with partial virologic response (PVR) to tenofovir disoproxil fumarate (TDF) remains unclear. We aimed to evaluate the long-term efficacy of prolonged TDF therapy in treatment-naïve CHB patients with PVR to TDF therapy in real practice. METHODS We retrospectively investigated the efficacy of prolonged TDF therapy in treatment-naïve CHB patients with PVR to TDF. PVR was defined as a decrease in serum hepatitis B virus (HBV) DNA over 2 log10 IU/mL from baseline, with detectable HBV DNA by real-time polymerase chain reaction at week 48. RESULTS We included 232 patients who underwent TDF therapy for over 48 weeks. Forty-two patients (18.1%) showed PVR. In multivariate analysis, hepatitis B e antigen (HBeAg) positivity, and high levels of serum HBV DNA at baseline and week 12 were independent predictive factors for PVR during TDF therapy. Out of 42 patients with PVR, 39 (92.9%) achieved virologic response (VR) during continuous TDF treatment; the cumulative VR rates at 24, 36, and 48 months were 79.8%, 88.2%, and 95.6%, respectively. With an additional 12 months of therapy, VR was achieved in 28/31 (90.3%) patients with HBV DNA < 100 IU/mL, compared to 5/11 (45.5%) patients with HBV DNA ≥ 100 IU/mL, at week 48. CONCLUSION The vast majority of patients achieved VR through prolonged TDF therapy, thus TDF treatment can be maintained in nucleos(t)ide-naïve patients with PVR at week 48, especially in those with low viremia.
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Affiliation(s)
- Jeong Eun Song
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
| | - Chang Hyeong Lee
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
| | - Byung Seok Kim
- Department of Internal Medicine, Daegu Catholic University School of Medicine, Daegu, Korea
- Correspondence to Byung Seok Kim, M.D. Department of Internal Medicine, Daegu Catholic University School of Medicine, 33 Duryugongwon-ro 17- gil, Nam-gu, Daegu 42472, Korea Tel: +82-53-650-4090 Fax: +82-53-656-3281 E-mail:
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19
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Luo J, You X, Chong Y, Wu Y, Gong J, Jie Y, Li X, Xi S, Zhang Z, Zhang Y, Xie D, Li Z, Li X. Efficacy of long-term treatment with tenofovir in Chinese nucleos(t)ide-naïve chronic hepatitis B patients regardless of baseline viral load. Exp Ther Med 2019; 18:260-268. [PMID: 31258661 DOI: 10.3892/etm.2019.7547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Accepted: 03/26/2019] [Indexed: 01/10/2023] Open
Abstract
The aim of the present study was to analyze the efficacy and safety of tenofovir (TDF) treatment for up to 5 years in nucleos(t)ide-naïve chronic hepatitis B (CHB) patients, particularly those with a high viral load, a in real-life scenario. A total of 144 nucleos(t)ide-naïve CHB patients who received TDF monotherapy for at least 3 months were retrospectively analyzed. The primary endpoint measure was the achievement of virological response (VR; undetectable serum HBV DNA, <100 IU/ml). The secondary endpoints were alanine aminotransferase (ALT) normalization (ALT < upper limit of normal), hepatitis B e antigen (HBeAg) seroconversion and safety. The median follow-up period was 120 weeks (range, 12-264 weeks). In total, 144, 130, 114, 78, 67, 40 and 13 patients were followed up for at least 12, 24, 48, 96, 144, 192 and 240 weeks, respectively. An incremental trend was observed in the rate of VR: 73.1, 91.3, 98.1, 100, 100 and 100% of the patients exhibited VR at 24, 48, 96, 144, 192 and 240 weeks, respectively. Furthermore, 29 patients with hepatitis B virus (HBV) DNA ≥8 log10 IU/ml at baseline achieved VR during the follow-up period. The proportions of patients achieving normal ALT levels were 72.1, 78.6, 91.2, 95, 96 and 100%, at 24, 48, 96, 144, 192 and 240 weeks, respectively. The rate of HBeAg loss reached 35.6% at week 240. Among the 130 patients, HBV DNA was detectable [partial VR (PVR)] in 35 patients at 24 weeks of follow-up, and 30 of those 35 patients (85.7%) required >24 weeks of further TDF therapy to achieve VR. No serious adverse events were reported. In conclusion, long-term TDF treatment of nucleos(t)ide-naïve chronic hepatitis B patients, regardless of high viral load at baseline, was effective and safe in a real-life scenario. Adjustment of TDF monotherapy may be unnecessary in nucleos(t)ide-naïve patients with PVR at 24 weeks.
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Affiliation(s)
- Jie Luo
- Department of Hepatology, The Third Affiliated Hospital of Shenzhen University, Shenzhen Luohu People's Hospital, Shenzhen, Guangdong 518000, P.R. China
| | - Xu You
- Department of Clinical Laboratory, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, P.R. China
| | - Yutian Chong
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yuankai Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Jiao Gong
- Department of Clinical Laboratory, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yusheng Jie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xinhua Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Sujuan Xi
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhiwei Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Yufeng Zhang
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Dongying Xie
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Zhanyi Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
| | - Xiangyong Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510630, P.R. China
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Xu M, Zhou Z, Xu R, Zhang H, Lin N, Zhong Y. Antiviral therapy predicts the outcomes following resection of hepatocellular carcinoma in patients negative for HBV DNA: a propensity score matching analysis. World J Surg Oncol 2019; 17:45. [PMID: 30823932 PMCID: PMC6397498 DOI: 10.1186/s12957-019-1577-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 02/11/2019] [Indexed: 02/07/2023] Open
Abstract
Background The effect of antiviral therapy (AVT) on clinical outcomes in patients with hepatocellular carcinoma (HCC) who are seronegative for hepatitis B virus (HBV), defined as HBV DNA < 100 IU/ml prior to surgical resection, is unknown. The main purpose of this study was to evaluate the possible value of AVT in this cohort of patients. Methods From January 2006 to January 2013, 161 HCC patients with positive serum tests for HBV surface antigen (HBsAg) but negative tests for HBV DNA who had undergone hepatectomy were included and analyzed. Propensity score matching (PSM) was used to balance the heterogeneity in baseline characteristics. Results All patients were divided into the following two groups: the AVT group (n = 73, 45.34%) and the non-AVT group (n = 88, 54.66%). HBV reactivation occurred in 20 patients in the non-AVT group (22.73%) but in only 2 patients in the AVT group (2.74%, p < 0.001). After PSM, the 1-, 2-, and 3-year recurrence-free survival (RFS) rates in the AVT group and the non-AVT group were 78.38%, 72.97%, and 62.16% and 81.08%, 72.97%, and 72.97%, respectively (p = 0.564); the 1-, 2-, and 3-year overall survival (OS) rates were 97.30%, 97.3%, and 91.89% and 94.59%, 94.59%, and 86.49% in the AVT group and non-AVT group, respectively (p = 0.447). Conclusions Antiviral therapy can reduce HBV reactivation but is not correlated with a significant increase in postoperative RFS and OS in HCC patients with HBV DNA levels < 100 IU/ml. Electronic supplementary material The online version of this article (10.1186/s12957-019-1577-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mingxing Xu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Zheng Zhou
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Ruiyun Xu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Huiling Zhang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China
| | - Nan Lin
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China.
| | - Yuesi Zhong
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, China.
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Chien RN, Kao JH, Peng CY, Chen CH, Liu CJ, Huang YH, Hu TH, Yang HI, Lu SN, Ni YH, Chuang WL, Lee CM, Wu JC, Chen PJ, Liaw YF. Taiwan consensus statement on the management of chronic hepatitis B. J Formos Med Assoc 2019; 118:7-38. [PMID: 30527436 DOI: 10.1016/j.jfma.2018.11.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 11/06/2018] [Accepted: 11/15/2018] [Indexed: 01/10/2023] Open
Abstract
The experts of Taiwan Association for the Study of Liver (TASL) have actively participated and led the guidelines on hepatitis B virus (HBV) management by Asian Pacific Association for the Study of Liver (APASL) which is the first international association for the study of liver to publish the statement on HBV management before. However, there are more and more new data on the natural history and treatment of HBV infection in the past decade. These include new application of an old biomarker (quantitative HBsAg), clinical significance of HBV genotype and naturally occurring mutations, the role of non-invasive examination in evaluating severity of hepatic fibrosis, clinical significance of outcome calculators, new drug or new combination strategies towards more effective therapy and organ transplantation including liver and non-liver transplantation. It is time to publish the guidelines on HBV management of Taiwan. Hence, TASL have conducted an expert meeting to review, to discuss and to debate the relevant literatures, followed by draft the manuscript of HBV management guidelines and recommendations. The guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patient receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.
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Affiliation(s)
- Rong-Nan Chien
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan.
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Cheng-Yuan Peng
- Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chun-Jen Liu
- Graduate Institute of Clinical Medicine, Department of Internal Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Tsung-Hui Hu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hwa-I Yang
- Department of Genomic Research Center, Sinica Academia, Taipei, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University College of Medicine and Children's Hospital, Taipei, Taiwan
| | - Won-Long Chuang
- Division of Hepatobiliary and Pancreas, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jaw-Chin Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Linkou Chang Gung Memorial Hospital and University College of Medicine, Taoyuan, Taiwan
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Is Low Level Viremia Acceptable During Antiviral Therapy of Patients With HBV Infection and Decompensated Cirrhosis? Clin Gastroenterol Hepatol 2018; 16:1876-1878. [PMID: 30213586 DOI: 10.1016/j.cgh.2018.09.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 09/04/2018] [Accepted: 09/05/2018] [Indexed: 02/07/2023]
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23
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Yim HJ, Kim IH, Suh SJ, Jung YK, Kim JH, Seo YS, Yeon JE, Kim CW, Kwon SY, Park SH, Lee MS, Um SH, Byun KS. Switching to tenofovir vs continuing entecavir for hepatitis B virus with partial virologic response to entecavir: a randomized controlled trial. J Viral Hepat 2018; 25:1321-1330. [PMID: 29772084 DOI: 10.1111/jvh.12934] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 04/16/2018] [Indexed: 12/19/2022]
Abstract
Entecavir 0.5 mg (ETV) is widely used among treatment-naïve chronic hepatitis B (CHB) patients. However, 10%-30% of patients show partial virologic response (PVR) to the drug. If the hepatitis B virus (HBV) continues to replicate, the underlying liver disease may progress. Herein, we compared the efficacy of switching to tenofovir disoproxil fumarate (TDF) with that of continuing ETV in CHB patients with PVR to ETV. This was an open-label randomized controlled trial including CHB patients who had been receiving 0.5 mg of ETV for >12 months, but who still had detectable HBV DNA levels of >60 IU/mL without known resistance to ETV. Sixty patients were enrolled and 45 qualified for the study: Twenty-two patients were randomly assigned into the TDF group and 23 into the ETV group. After 12 months of treatment, the virologic response rate (HBV DNA <20 IU/mL) was significantly higher in the TDF group than in the ETV group, as measured using per-protocol analysis (55% vs 20%; P = .022) and intention-to-treat analysis (50% vs 17.4%; P = .020). The reduction in HBV DNA was greater (-1.13 vs -0.67 log10 IU/mL; P = .024), and the mean HBV DNA level was lower (1.54 vs 2.01 log10 IU/mL; P = .011) in the TDF group than in the ETV group. In conclusion, to achieve optimal response in CHB patients with PVR to ETV, switching to TDF would be a better strategy than continuing ETV. Appropriate modification of therapy would further improve the outcome of chronic HBV infection.
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Affiliation(s)
- H J Yim
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, South Korea
| | - I H Kim
- Department of Internal Medicine, Chonbuk National University Hospital, Jeonju, South Korea
| | - S J Suh
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, South Korea
| | - Y K Jung
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan, South Korea
- Department of Internal Medicine, Gachon University Gil Hospital, Incheon, South Korea
| | - J H Kim
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, South Korea
| | - Y S Seo
- Department of Internal Medicine, Korea University Anam Hospital, Seoul, South Korea
| | - J E Yeon
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, South Korea
| | - C W Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea
| | - S Y Kwon
- Department of Internal Medicine, Konkuk University Hospital, Seoul, South Korea
| | - S H Park
- Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Seoul, South Korea
| | - M S Lee
- Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Seoul, South Korea
| | - S H Um
- Department of Internal Medicine, Korea University Anam Hospital, Seoul, South Korea
| | - K S Byun
- Department of Internal Medicine, Korea University Guro Hospital, Seoul, South Korea
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Ye YA, Li XK, Zhou DQ, Chi XL, Li Q, Wang L, Lu BJ, Mao DW, Wu QK, Wang XB, Zhang MX, Xue JD, Li Y, Lu W, Guo JC, Jiang F, Zhang XW, Du HB, Yang XZ, Guo H, Gan DN, Li ZG. Chinese Herbal Medicine Combined with Entecavir for HBeAg Positive Chronic Hepatitis B: Study Protocol for a Multi-Center, Double-Blind Randomized-Controlled Trial. Chin J Integr Med 2018; 24:653-660. [PMID: 30209792 DOI: 10.1007/s11655-018-3011-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/11/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND The domestic prevalence of chronic hepatitis B (CHB) in China is 7.18% in 2006, imposing great societal healthcare burdens. Nucleot(s)ide analogues (NUCs) anti-hepatitis B virus (HBV) therapies are widely applied despite the relatively low rate of seroconversion and high risk of drug-resistant mutation. More effective treatments for CHB deserve further explorations. Combined therapy of NUCs plus Chinese herbal medicine (CHM) is widely accepted in China, which is recognized as a prospective alternative approach. The study was primarily designed to confirm the hypothesis that Tiaogan-Yipi Granule (, TGYP) or Tiaogan-Jianpi-Jiedu Granule (, TGJPJD) plus entecavir tablet (ETV) was superior over ETV monotherapy in enhancing HBeAg loss rate. METHODS The study was a nationwide, large-scale, multi-center, double-blind, randomized, placebo-controlled trial with a designed duration of 108 weeks. A total of 16 hospitals and 596 eligible Chinese HBeAg positive CHB patients were enrolled from November 2012 to September 2013 and randomly allocated into 2 groups in 1:1 ratio via central randomization system: experimental group (EG) and control group (CG). Subjects in EG received CM formulae (TGYP or TGJPJD, 50 g per dose, twice daily) plus ETV tablet (or ETV placebo) 0.5 mg per day in the first 24 weeks (stage 1), and CHM granule plus ETV tablet (0.5 mg per day) from week 25 to 108 (stage 2). Subjects in CG received CHM Granule placebo plus ETV tablet (0.5 mg per day) for 108 weeks throughout the trial. The assessments of primary outcomes (HBV serum markers and HBV-DNA) were conducted by a third-party College of American Pathologists (CAP) qualified laboratory. Adverse effects were observed in the hospitals of recruitment. DISCUSSION The study was designed to compare the curative effect of CM plus ETV and ETV monotherapy in respect of HBeAg loss, which is recognized by the European Association for the Study of the Liver as "a valuable endpoint". We believe this trial could provide a reliable status for patients' "journey" towards durable responses after treatment discontinuation. The trial was registered before recruitment on Chinese Clinical trial registry (No. ChiCTR-TRC-12002784, Version 1.0, 2015/12/23).
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Affiliation(s)
- Yong-An Ye
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Xiao-Ke Li
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Da-Qiao Zhou
- Department of Hepatology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong Province, 518033, China
| | - Xiao-Ling Chi
- Department of Hepatology, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, 510006, China
| | - Qin Li
- Department of Hepatology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
| | - Li Wang
- Department of Hepatology, Public Health Clinical Center of Chengdu, Chengdu, 610066, China
| | - Bing-Jiu Lu
- Department of Hepatology, Liaoning Hospital of Traditional Chinese Medicine, Shenyang, 110032, China
| | - De-Wen Mao
- Department of Hepatology, the First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, 530023, China
| | - Qi-Kai Wu
- Department of Hepatology, the Third People's Hospital of Shenzhen, Shenzhen, Guangdong Province, 518112, China
| | - Xian-Bo Wang
- Department of Hepatology, Beijing Ditan Hospital, Beijing, 100015, China
| | - Ming-Xiang Zhang
- Department of Hepatology, the Sixth People's Hospital of Shenyang, Shenyang, 110006, China
| | - Jing-Dong Xue
- Department of Hepatology, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an, 710003, China
| | - Yong Li
- Department of Hepatology, Shandong Hospital of Traditional Chinese Medicine, Jinan, 250011, China
| | - Wei Lu
- Department of Hepatology, the Second People's Hospital of Tianjin, Tianjin, 300000, China
| | - Jian-Chun Guo
- Department of Hepatology, Xixi Hospital of Hangzhou, Hangzhou, 310023, China
| | - Feng Jiang
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xin-Wei Zhang
- Department of Hepatology, 302 Military Hospital of China, Beijing, 100039, China
| | - Hong-Bo Du
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Xian-Zhao Yang
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Hui Guo
- Department of Hepatology, the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300000, China
| | - Da-Nan Gan
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Zhi-Guo Li
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Dongzhimen Hospital affiliated to Beijing University of Chinese Medicine, Beijing, 100700, China
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Singh L, Indermun S, Govender M, Kumar P, du Toit LC, Choonara YE, Pillay V. Drug Delivery Strategies for Antivirals against Hepatitis B Virus. Viruses 2018; 10:E267. [PMID: 29772748 PMCID: PMC5977260 DOI: 10.3390/v10050267] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2018] [Revised: 05/04/2018] [Accepted: 05/08/2018] [Indexed: 12/16/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection poses a significant health challenge due to associated morbidity and mortality from cirrhosis and hepatocellular cancer that eventually results in the breakdown of liver functionality. Nanotechnology has the potential to play a pivotal role in reducing viral load levels and drug-resistant HBV through drug targeting, thus reducing the rate of evolution of the disease. Apart from tissue targeting, intracellular delivery of a wide range of drugs is necessary to exert a therapeutic action in the affected organelles. This review encompasses the strategies and techniques that have been utilized to target the HBV-infected nuclei in liver hepatocytes, with a significant look at the new insights and most recent advances in drug carriers and their role in anti-HBV therapy.
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Affiliation(s)
- Latavia Singh
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Sunaina Indermun
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Mershen Govender
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Pradeep Kumar
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Lisa C du Toit
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Yahya E Choonara
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
| | - Viness Pillay
- Wits Advanced Drug Delivery Platform Research Unit, Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2193, South Africa.
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Xie YD, Ma H, Feng B, Wei L. Efficacy of Real-world Entecavir Therapy in Treatment-naïve Chronic Hepatitis B Patients. Chin Med J (Engl) 2018; 130:2190-2197. [PMID: 28875955 PMCID: PMC5598331 DOI: 10.4103/0366-6999.213969] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: Entecavir (ETV) has been shown to be effective in randomized controlled trials in highly selected patients with hepatitis B virus (HBV) infection. This study aimed to evaluate the efficacy of ETV in chronic hepatitis B (CHB) patients in the real-world setting. Methods: A total of 233 treatment-naïve, CHB patients who received at least 12 months of ETV treatment were included in this retrospective study. Rates of virological response (VR), hepatitis B s antigen (HBsAg) loss, hepatitis B e antigen (HBeAg) clearance/seroconversion, virological breakthrough, cirrhosis, and hepatocellular carcinoma were evaluated. Results: Of 233 patients, 175 patients were male, with mean age of 43 years old, and 135 patients were HBeAg positive. The mean baseline levels of serum alanine aminotransferase and HBV DNA in all patients were 230 U/L and 6.6 log 10 IU/ml, respectively. The mean follow-up period was 28 months. The cumulative rates of achieving VR increased from 3.4% at 3 months to 94.4% at 60 months. Primary nonresponse occurred in 3 (1.3%) patients. Partial VR (PVR) occurred in 61 (26.2%) patients at 12 months. The baseline serum HBV DNA level (hazard ratio [HR], 2.054; P < 0.001) was an independent risk factor for PVR. HBsAg loss did not occur. The cumulative rates of HBeAg clearance increased from 2.2% at 3 months to 28.2% at 60 months. PVR was the significant determinant of HBeAg clearance (HR, 0.341; P = 0.026). Age (HR, 1.072; P = 0.013) and PVR (HR, 5.131; P = 0.017) were the significant determinants of cirrhosis. Conclusions: ETV treatment was effective for HBV DNA suppression in this study, but HBsAg loss and HBeAg clearance/seroconversion rates were lower compared with previous clinical trials. PVR was associated with HBeAg clearance and cirrhosis.
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Affiliation(s)
- Yan-Di Xie
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Beijing 100044, China
| | - Hui Ma
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Beijing 100044, China
| | - Bo Feng
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Beijing 100044, China
| | - Lai Wei
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People's Hospital, Beijing 100044, China
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Choi JW, Kim SH, Seo JH, Cho YS, Won SY, Park BK, Jeon HH, Lee YK, Lee CK. Real World Experience of Telbivudine Versus Entecavir in Patients with Chronic Hepatitis B, Including Long-Term Outcomes after Treatment Modification. Yonsei Med J 2018; 59:383-388. [PMID: 29611400 PMCID: PMC5889990 DOI: 10.3349/ymj.2018.59.3.383] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 01/09/2018] [Accepted: 02/14/2018] [Indexed: 12/26/2022] Open
Abstract
PURPOSE To estimate long-term outcomes after treatment modification in patients with chronic hepatitis B (CHB) treated with entecavir (ETV) and telbivudine (LdT). MATERIALS AND METHODS The study enrolled 131 nucleos(t)ide analogue (NA)-naïve CHB patients treated with ETV or LdT. During the 3-year study, NA treatment history including the incidence, the type of treatment modification, reasons for the modification, and overall complete virologic response (CVR) rate were retrospectively evaluated using the patients' medical records. RESULTS Among the 131 patients, 84 and 47 were initially treated with ETV and LdT, respectively. During the course of 3-year study, 82 patients in the ETV group (97.6%) maintained initial treatment whereas only 19 in the LdT group (40.4%). In the LdT group, 26 patients (92.9%) switched to another NA and another NA was added in 2 (7.1%) patients. An assessment of the CVR rate at 3 years, including treatment modification, showed that 89.3% and 95.7% of patients in the ETV and LdT groups, respectively, had undetectable serum hepatitis B virus DNA levels (p=0.329). Among LdT patients with treatment modification, the cumulative incidence rate of a CVR for rescue therapy was significantly higher in the tenofovir than in the ETV group (p=0.009). CONCLUSION During the 3-year study, there were no significant differences in the CVR between the ETV and LdT groups if appropriate rescue therapy was considered.
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Affiliation(s)
- Jong Won Choi
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Se Hyun Kim
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Jeong Hun Seo
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Yong Suk Cho
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Sun Young Won
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Byung Kyu Park
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Han Ho Jeon
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Yong Kang Lee
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Chun Kyon Lee
- Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea.
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Nam JY, Chang Y, Cho H, Kang SH, Cho YY, Cho EJ, Lee JH, Yu SJ, Yoon JH, Kim YJ. Delayed viral suppression during antiviral therapy is associated with increased hepatocellular carcinoma rates in HBeAg-positive high viral load chronic hepatitis B. J Viral Hepat 2018; 25:552-560. [PMID: 29194870 DOI: 10.1111/jvh.12838] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 10/26/2017] [Indexed: 12/26/2022]
Abstract
The treatment option in chronic hepatitis B (CHB) patients with persistent low-level viremia despite entecavir or tenofovir monotherapy is unclear. This study investigated the development of hepatocellular carcinoma (HCC) or cirrhosis in hepatitis B e antigen (HBeAg)-positive high viral load CHB patients, according to the time needed to achieve complete viral suppression. A total of 325 HBeAg-positive CHB patients with high viral load who were recently started on antiviral therapy with entecavir or tenofovir were included. The enrolled patients were divided into 2 groups with 4 separate criteria based on the time needed to achieve complete viral suppression: within 1, 2, 3 or 4 years of therapy initiation. The outcomes were development of HCC and cirrhosis. The cumulative incidence of HCC was significantly higher in patients failing complete viral suppression within 1 year (hazard ratio (HR), 4.54; 95% confidence interval (CI), 1.03-19.93; P = .045) or 2 years (HR, 3.38; 95% CI, 1.24-9.23; P = .018), than patients who achieved complete viral suppression within 1 or 2 years, respectively. Cumulative incidence of cirrhosis was also significantly higher in patients failing suppression within 1 year (HR, 1.95; 95% CI, 1.04-3.66; P = .037) or 2 years (HR, 2.44; 95% CI, 1.41-4.22; P = .001). When the time for achieving viral suppression exceeded 2 years, the cumulative incidence of HCC or cirrhosis was not different regardless of viral suppression. Complete hepatitis B virus suppression within 2 years of antiviral therapy initiation is associated with risk reduction in HCC or cirrhosis development.
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Affiliation(s)
- J Y Nam
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y Chang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - H Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - S H Kang
- Department of Internal Medicine, Wonju Severance Christian Hospital, Yonsei University, Wonju College of Medicine, Wonju-si, Korea
| | - Y Y Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - E J Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J-H Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - S J Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - J-H Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Y J Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Arora A, Singh SP, Kumar A, Saraswat VA, Aggarwal R, Bangar M, Bhaumik P, Devarbhavi H, Dhiman RK, Dixit VK, Goel A, Goswami B, Kapoor D, Madan K, Narayan J, Nijhawan S, Pandey G, Rai RR, Sahu MK, Saraf N, Shalimar, Shenoy T, Thomas V, Wadhawan M. INASL Position Statements on Prevention, Diagnosis and Management of Hepatitis B Virus Infection in India: The Andaman Statements. J Clin Exp Hepatol 2018; 8:58-80. [PMID: 29743798 PMCID: PMC5938334 DOI: 10.1016/j.jceh.2017.12.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 12/09/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B Virus (HBV) infection is one of the major causes of morbidity, mortality and healthcare expenditure in India. There are no Indian consensus guidelines on prevention, diagnosis and management of HBV infection. The Indian National Association for Study of the Liver (INASL) set up a taskforce on HBV in 2016, with a mandate to develop consensus guidelines for diagnosis and management of HBV infection, relevant to disease patterns and clinical practices in India. The taskforce first identified contentious issues on various aspects of HBV management, which were allotted to individual members of the taskforce who reviewed them in detail. A 2-day round table discussion was held on 11th and 12th February 2017 at Port Blair, Andaman & Nicobar Islands, to discuss, debate, and finalize the consensus statements. The members of the taskforce reviewed and discussed the existing literature threadbare at this meeting and formulated the 'INASL position statements' on each of the issues. The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system with minor modifications. The strength of recommendations (strong: 1, weak: 2) thus reflects the quality (grade) of underlying evidence (A, B, C, D). We present here the INASL position statements on prevention, diagnosis and management of HBV in India.
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Key Words
- AASLD, American Association for the Study of Liver Diseases
- ADV, adefovir dipivoxil
- ALT, alanine aminotransferase
- APASL, Asian Pacific Association for the Study of the Liver
- ART, antiretroviral therapy
- AST, aspartate aminotransferase
- Anti-HBe, antibodies to hepatitis B envelope antigen
- CBC, complete blood count
- CDC, Center for Disease Control
- CHB, chronic hepatitis B
- CU-HCC, Chinese University-Hepatocellular Carcinoma
- DAA, direct-acting antiviral
- DILI, drug induced liver injury
- DNA, deoxyribonucleic acid
- EASL, European Association for the Study of the Liver
- ETV, entecavir
- GAG-HCC, Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-Hepatocellular Carcinoma
- GGT, gamma-glutamyl transferase
- GRADE, Grading of Recommendations Assessment Development and Evaluation
- HBIG, hepatitis B immune globulin
- HBV, hepatitis B virus
- HBeAg, hepatitis B envelope antigen
- HCC, hepatocellular carcinoma
- HCV, hepatitis C virus
- HDV, hepatitis D virus
- HIV, human immunodeficiency virus
- IFN-α, interferon alpha
- INASL, Indian National Association for Study of the Liver
- INR, international normalized ratio
- KASL, Korean Association for the Study of the Liver
- LAM, lamivudine
- NA, nucleos(t)ide analogue
- PAGE-B, platelets, age, gender—hepatitis B
- PVNR, primary virological non-response
- PVR, partial virological response
- PegIFN-α, pegylated interferon alpha
- RCT, randomized controlled trial
- REACH-B, risk estimation for hepatocellular carcinoma in chronic hepatitis B
- SOVR, sustained off-therapy virological response
- TAF, tenofovir alafenamide
- TDF, tenofovir disoproxil fumarate
- TDV, telbivudine
- TSH, thyroid-stimulating hormone
- VR, virologic response
- WHO, World Health Organization
- anti-HBs, antibody to hepatitis B surface antigen
- cccDNA, covalently closed circular DNA
- chronic hepatitis
- cirrhosis
- eGFR, estimated glomerular filtration rate
- hepatitis B
- jaundice
- liver failure
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Affiliation(s)
- Anil Arora
- Director, Institute of Liver, Gastroenterology, and Pancreatico-Biliary Sciences, Ganga Ram Institute for Postgraduate Medical Education & Research (GRIPMER), Sir Ganga Ram Hospital, New Delhi, India
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Huang M, Liu J, Chow M, Zhou X, Han Z, He Z, Xue J, Zhu Z, Li X, Xia J. Negative HBcAg in immunohistochemistry assay of liver biopsy is a predictive factor for the treatment of patients with nucleos(t)ide analogue therapy. J Cell Mol Med 2018; 22:1675-1683. [PMID: 29193766 PMCID: PMC5824392 DOI: 10.1111/jcmm.13444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 09/18/2017] [Indexed: 02/05/2023] Open
Abstract
The hepatitis B core antigen (HBcAg) is an important target for antiviral response in chronic hepatitis B (CHB) patients. However, the correlation between HBcAg in the hepatocyte nucleus and nucleos(t)ide analogue (NA) therapeutic response is unclear. We sought to evaluate the role of HBcAg by analysing liver biopsies for viral response in NA-naïve hepatitis B e antigen (HBeAg) positive (+) CHB patients via immunohistochemistry (IHC). A total of 48 HBcAg-negative (-) patients and 48 HBcAg (+) patients with matching baseline characteristics were retrospectively analysed for up to 288 weeks. Virological response (VR) rates of patients in the HBcAg (-) group were significantly higher at week 48 and 96 than the HBcAg (+) group (77.1% versus 45.8% at week 48, respectively, P = 0.002 and 95.3% versus 83.3% at week 96, respectively, P = 0.045). The serological negative conversion rate of HBeAg was significantly higher in the HBcAg (-) than in the HBcAg (+) group from week 96 to 288 (35.4 % versus 14.6% at week 96, respectively, P = 0.018; 60.4% versus 14.6%, respectively, P < 0.001 at week 144; 72.9% versus 35.4%, respectively, P < 0.001 at week 288). The cumulative frequencies of VR and lack of HBeAg were higher in the HBcAg (-) group (both P < 0.05). Binary logistic regression analysis showed that HBcAg (-) was the predictor for the lack of HBeAg (OR 4.482, 95% CI: 1.58-12.68). In summary, the absence of HBcAg in the hepatocyte nucleus could be an independent predictor for HBeAg seroconversion rates during NA-naïve treatment in HBeAg (+) CHB patients.
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Affiliation(s)
- Mingxing Huang
- Department of Infectious DiseasesThe Fifth Affiliated Hospital of Sun Yat‐Sen University (SYSU)ZhuhaiGuangdongChina
| | - Jian Liu
- Department of Infectious DiseasesThe Fifth Affiliated Hospital of Sun Yat‐Sen University (SYSU)ZhuhaiGuangdongChina
| | - Monica Chow
- PGY IVDepartment of General Surgery RutgersRobert Wood Johnson Medical SchoolPiscatawayNJUSA
| | - Xuan Zhou
- Department of Infectious DiseasesThe Fifth Affiliated Hospital of Sun Yat‐Sen University (SYSU)ZhuhaiGuangdongChina
| | - Zongping Han
- Department of Infectious DiseasesThe Fifth Affiliated Hospital of Sun Yat‐Sen University (SYSU)ZhuhaiGuangdongChina
| | - Zhenjian He
- School of Public HealthSun Yat‐sen UniversityGuangzhouChina
| | - Jinfang Xue
- Department of Infectious DiseasesThe Fifth Affiliated Hospital of Sun Yat‐Sen University (SYSU)ZhuhaiGuangdongChina
| | - Zhe Zhu
- Department of MedicineDivision of Regenerative MedicineUniversity of CaliforniaSan DiegoSchool of MedicineLa JollaCAUSA
- Department of Stem Cell Biology and Regenerative MedicineCleveland ClinicLerner Research InstituteClevelandOHUSA
| | - Xinhua Li
- Department of Infectious DiseasesThe Third Affiliated HospitalSun Yat‐Sen UniversityGuangzhouGuangdongChina
| | - Jinyu Xia
- Department of Infectious DiseasesThe Fifth Affiliated Hospital of Sun Yat‐Sen University (SYSU)ZhuhaiGuangdongChina
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Kim CW, Kim CS, Kim HY, Lee CD, Yu K, Llamoso C, Lee HJ. Large-scale surveillance study of the safety and effectiveness of entecavir in Korean patients with chronic hepatitis B. Korean J Intern Med 2018; 33:91-101. [PMID: 29228519 PMCID: PMC5768541 DOI: 10.3904/kjim.2016.111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 09/03/2016] [Accepted: 10/15/2016] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND/AIMS Entecavir (ETV) is effective and safe antiviral agent against hepatitis B virus (HBV) in clinical and real-world setting but, most studies were performed in single institute or have limitation in patient's number. A large-scale nation-wide real-world surveillance study was carried out to investigate safety, efficacy and clinical effectiveness of ETV in Korean patients with chronic hepatitis B (CHB). METHODS Between 2006 and 2012, 3,444 patients were enrolled from 132 Korean institutions. For the safety assessment, investigators recorded the occurrence of observed and patient-reported adverse events (AEs), as well as laboratory abnormalities. Efficacy, which consisted of change in HBV DNA and alanine aminotransferase (ALT), was evaluated in patients who had received at least 16 weeks of ETV treatment. Overall clinical effectiveness, based on improvement of ALT, HBV DNA and patient's symptoms, was evaluated by physicians. RESULTS Of the patients, 3,367 were evaluated for safety and 3,115 for efficacy and clinical effectiveness. Three hundred and eighty AEs were reported in 255 cases (7.57%), and 67 adverse drug reactions in 54 cases (1.6%). Serious AEs (SAE) were 19 events in nine cases (0.27%). Serious adverse drug reactions (SADR) were three events in two cases (0.06%), and unexpected SAE/SADR were three events in two cases (0.06%). Medical history and concomitant medications were factors inf luencing incidence rates of AEs. Overall clinical effectiveness rate was 96.53%, which was clinically assessed as marked improved or improved state. CONCLUSIONS This study showed that ETV was well tolerated and clinically effective in Korean patients with CHB in a real-world nation-wide setting.
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Affiliation(s)
- Chang Wook Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | | | - Hee Yeon Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chang Don Lee
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | | | | | - Heon Ju Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
- Correspondence to Heon Ju Lee, M.D. Department of Internal Medicine, Yeungnam University College of Medicine, 170 Hyeonchung-ro, Nam-gu, Daegu 42415, Korea Tel: +82-53-623-8000 Fax: +82-53-654-8386 E-mail:
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Kim HJ, Cho YK, Jeon WK, Kim BI. Clinical characteristics of patients with chronic hepatitis B who developed genotypic resistance to entecavir: Real-life experience. Clin Mol Hepatol 2017; 23:323-330. [PMID: 28870025 PMCID: PMC5760008 DOI: 10.3350/cmh.2017.0005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 06/28/2017] [Accepted: 07/26/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND/AIMS Clinical characteristics of patients with chronic hepatitis B (CHB) who developed genotypic resistance to entecavir (ETV) were compared to those without resistance. METHODS Two hundred fifty eight CHB patients who underwent ETV treatment in our institution from July 2007 to May 2013 were included. RESULTS Eight (3.1%) patients developed genotypic resistance to ETV during the follow-up period. The patterns of genotypic resistance to ETV were as follows: L180M + M204V + S202G (n=3); M204I + V173M (n=1); I169V + V173M (n=1); L180M + M204V + V173L (n=1); L180M + M204V + V173L + M250V (n=1); M204I + V214A + P237H (n=1). The cumulative occurrence rates of genotypic resistance to ETV were not significantly different between CHB patients with prior nucleos(t)tide analogues (NA) exposure (NA experienced, n=56) and NA naïve patients (n=202, P=0.823 by log rank comparison). Older age, higher baseline log10hepatitis B virus-deoxynucleic acid (log10HBV-DNA), higher log10HBV-DNA at 3, 6, 12 and 24 months after baseline, and complete virologic response (CVR, undetectable serum HBV-DNA by polymerase chain reaction 6 months after ETV treatment) were significant contributors to the development of genotypic resistance to ETV. Multivariate analyses showed higher log10HBV-DNA 6 months after baseline and absence of CVR were independent and significant contributors to the development of ETV resistance. CONCLUSIONS Clinical characteristics of patients who developed ETV resistance were higher log10HBV-DNA 6 months after baseline and absence of CVR during the ETV treatment.
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Affiliation(s)
- Hong Joo Kim
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong Kyun Cho
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Woo Kyu Jeon
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung Ik Kim
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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Xu JH, Wang S, Xu ZN, Yu YY, Si CW, Zeng Z, Li J, Mao Q, Zhang DZ, Tang H, Sheng JF, Chen XY, Ning Q, Shi GF, Xie Q, Zhang XQ, Dai J. Entecavir maleate versus entecavir in Chinese chronic hepatitis B predominantly genotype B or C: Results at week 144. J Viral Hepat 2017; 24:877-884. [DOI: https:/doi.org/10.1111/jvh.12710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
Affiliation(s)
- J.-H. Xu
- Department of Infectious Diseases; Center for Liver Diseases; Peking University First Hospital; Beijing China
| | - S. Wang
- Department of Infectious Diseases; Center for Liver Diseases; Peking University First Hospital; Beijing China
| | - Z.-N. Xu
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd; Nanjing China
| | - Y.-Y. Yu
- Department of Infectious Diseases; Center for Liver Diseases; Peking University First Hospital; Beijing China
| | - C.-W. Si
- Department of Infectious Diseases; Center for Liver Diseases; Peking University First Hospital; Beijing China
| | - Z. Zeng
- Department of Infectious Diseases; Center for Liver Diseases; Peking University First Hospital; Beijing China
| | - J. Li
- Department of Infectious Diseases; The First Affiliated Hospital with Nanjing Medical University; Nanjing China
| | - Q. Mao
- Department of Infectious Diseases; Southwest China Hospital; Chongqing China
| | - D.-Z. Zhang
- Department of Infectious Diseases; The Second Affiliated Hospital with Chongqing Medical University; Chongqing China
| | - H. Tang
- Department of Infectious Diseases; West China Hospital; Chengdu China
| | - J.-F. Sheng
- Department of Infectious Diseases; The First Affiliated Hospital; Zhejiang University; Hangzhou China
| | - X.-Y. Chen
- Department of International Medicine; Beijing Youan Hospital; Capital Medical University; Beijing China
| | - Q. Ning
- Department and Institute of Infectious Diseases; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan China
| | - G.-F. Shi
- Department of Infectious Diseases; Huashan Hospital; Fudan University; Shanghai China
| | - Q. Xie
- Department of Infectious Diseases; Ruijin Hospital; Jiaotong University School of Medicine; Shanghai China
| | - X.-Q. Zhang
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd; Nanjing China
| | - J. Dai
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd; Nanjing China
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Xu JH, Wang S, Xu ZN, Yu YY, Si CW, Zeng Z, Li J, Mao Q, Zhang DZ, Tang H, Sheng JF, Chen XY, Ning Q, Shi GF, Xie Q, Zhang XQ, Dai J. Entecavir maleate versus entecavir in Chinese chronic hepatitis B predominantly genotype B or C: Results at week 144. J Viral Hepat 2017; 24:877-884. [PMID: 28345157 DOI: 10.1111/jvh.12710] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 02/22/2017] [Indexed: 02/05/2023]
Abstract
Reports on the efficacy and safety of long-term entecavir treatment in chronic hepatitis B (CHB) predominantly genotype B or C are insufficient. This study presents the efficacy and safety of entecavir maleate in Chinese CHB patients. Patients were randomly assigned to receive 48-week treatment with either 0.5 mg/day entecavir (group A) or 0.5 mg/day entecavir maleate (group B), and then all patients received treatment with 0.5 mg/day entecavir maleate from week 49. Two hundred and seventy-five patients with CHB (HBeAg-positive: 218) were analysed, predominantly (98.5%) with genotype B or C. Baseline characteristics were balanced. For the HBeAg-positive CHB patients, the mean HBV DNA level decreased similarly (A: by 6.36 log10 IU/mL vs B: by 6.31 log10 IU/mL) between groups at week 144. The percentages of patients who achieved undetectable HBV DNA were similar (A: 70.59% vs B: 66.67%) between groups. Similar HBeAg loss rates (A: 43.53% vs B: 40.23%; P>.05) and HBeAg seroconversion rates (A: 21.52% vs B: 21.18%) were achieved. For the HBeAg-negative CHB patients, similar reductions in HBV DNA levels from baseline (A: by 6.13 log10 IU/mL vs B: by 5.65 log10 IU/mL) and percentages of patients who achieved undetectable HBV DNA (A: 100% vs B: 100%) were achieved. The overall incidence of adverse events was comparable between groups. In conclusions, 48-week administration of entecavir maleate and entecavir showed similar efficacy and safety in Chinese patients with CHB. Long-term entecavir maleate treatment was effective and safe in CHB patients.
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Affiliation(s)
- J-H Xu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - S Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - Z-N Xu
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing, China
| | - Y-Y Yu
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - C-W Si
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - Z Zeng
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China
| | - J Li
- Department of Infectious Diseases, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Q Mao
- Department of Infectious Diseases, Southwest China Hospital, Chongqing, China
| | - D-Z Zhang
- Department of Infectious Diseases, The Second Affiliated Hospital with Chongqing Medical University, Chongqing, China
| | - H Tang
- Department of Infectious Diseases, West China Hospital, Chengdu, China
| | - J-F Sheng
- Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - X-Y Chen
- Department of International Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Q Ning
- Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - G-F Shi
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Q Xie
- Department of Infectious Diseases, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, China
| | - X-Q Zhang
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing, China
| | - J Dai
- Jiangsu Chia-tai Tianqing Pharmaceutical Co., Ltd, Nanjing, China
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Clinical Course of Partial Virologic Response with Prolonged Tenofovir Therapy in Nuclos(t)ides-Naïve Patients with Chronic Hepatitis B. Dig Dis Sci 2017; 62:2908-2914. [PMID: 28871337 DOI: 10.1007/s10620-017-4737-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Accepted: 08/24/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS The clinical course of chronic hepatitis B (CHB) patients with partial virologic response (PVR) during tenofovir disoproxil fumarate (TDF) therapy remains unclear. METHODS We retrospectively investigated the long-term clinical outcomes of TDF treatment in nucleos(t)ides-naïve CHB patients, particularly in those with PVR. RESULTS A total of 391 patients treated with TDF therapy for more than 12 months were included. Virologic response (VR) was achieved in 341 patients (87.2%). PVR was evident in 127 (45.3%) of the 391 patients. Multivariate logistic regression analysis using selected baseline factors identified absolute HBV DNA levels at baseline (OR 0.496; 95% CI 1.369-1.969) and HBeAg positivity (OR 0.622; 95% CI 1.096-3.167) as factors significantly associated with PVR. During continuous prolonged TDF therapy, 127 (71.8%) of 177 patients with PVR achieved VR. The cumulative rates of VR in patients with PVR at 12, 24, and 36 months were 42.4, 79.7, and 90.2%, respectively. Serum HBV DNA level at week 24 was significantly associated with VR in patients with PVR. CONCLUSIONS The vast majority of CHB patients with PVR achieved VR through prolonged TDF therapy, although the time to achieve VR was delayed in those with PVR. This suggests that adjustment of TDF therapy in patients with PVR is unnecessary.
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Kim JH, Sinn DH, Kang W, Gwak GY, Paik YH, Choi MS, Lee JH, Koh KC, Paik SW. Low-level viremia and the increased risk of hepatocellular carcinoma in patients receiving entecavir treatment. Hepatology 2017; 66:335-343. [PMID: 28012257 DOI: 10.1002/hep.28916] [Citation(s) in RCA: 138] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 09/20/2016] [Accepted: 10/13/2016] [Indexed: 01/05/2023]
Abstract
UNLABELLED The long-term clinical impact of low-level viremia (LLV; <2,000 IU/mL) is not well understood. As a result, it is unclear whether the development of LLV during entecavir monotherapy requires a change in therapy. A retrospective cohort of 875 treatment-naive chronic hepatitis B virus (HBV) monoinfected patients (mean age 47.7 years, male = 564 [65.5%], cirrhosis = 443 [50.6%]) who received entecavir monotherapy were analyzed for the development of hepatocellular carcinoma (HCC). The HCC risk was compared between patients who maintained virological response (MVR), defined by persistently undetectable HBV DNA (<12 IU/mL), and patients who experienced LLV, defined by either persistent or intermittent episodes of <2,000 IU/mL detectable HBV DNA. During a median 4.5 years of follow-up (range 1.0-8.7 years), HCC was diagnosed in 85 patients (9.7%). HCC developed more frequently in patients who experienced LLV than MVR (14.3% versus 7.5% at 5 years, P = 0.015). The hazard ratio comparing those with LLV to MVR was 1.98 (95% confidence interval = 1.28-3.06, P = 0.002, adjusted for age, sex, hepatitis B e antigen, baseline HBV DNA levels, and cirrhosis). Among patients with cirrhosis, those with LLV exhibited a significantly higher HCC risk than those with MVR (HCC incidence rate at 5 years 23.4% versus 10.3%, adjusted hazard ratio = 2.20, 95% confidence interval 1.34-3.60; P = 0.002). However, for patients without cirrhosis, there was no significant difference in the HCC risk between LLV and MVR. CONCLUSION LLV observed during entecavir monotherapy was associated with a higher risk of HCC, especially for those with cirrhosis, indicating that LLV during potent antiviral therapy is consequential. (Hepatology 2017;66:335-343).
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Affiliation(s)
- Jung Hee Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Min AD. Low-level viremia in hepatitis b patients on antiviral treatment: Can we ignore it? Hepatology 2017; 66:312-314. [PMID: 28437872 DOI: 10.1002/hep.29235] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/10/2017] [Accepted: 04/19/2017] [Indexed: 12/26/2022]
Affiliation(s)
- Albert D Min
- Division of Digestive Diseases, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY
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Ruggeri M, Basile M, Coretti S, Drago C, Cicchetti A. Economic Analysis and Budget Impact of Tenofovir and Entecavir in the First-Line Treatment of Hepatitis B Virus in Italy. APPLIED HEALTH ECONOMICS AND HEALTH POLICY 2017; 15:479-490. [PMID: 28197805 DOI: 10.1007/s40258-017-0311-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
BACKGROUND Chronic hepatitis B is a common, progressive disease, particularly when viral replication is detected. Oral antivirals can suppress viral replication and prevent or delay the development of cirrhosis and liver-related complications. The treatments of chronic hepatitis B cannot totally cure the disease but can prevent its progression to hepatocellular carcinoma, decreasing the levels of both morbidity and mortality. To date, there are several therapies indicated by the international guidelines as first-line treatments for the management of hepatitis B; two of the most effective are those based on either tenofovir or entecavir. OBJECTIVE The aim of this study is to evaluate the cost-effectiveness of tenofovir and entecavir in the treatment of naïve patients with chronic hepatitis B. The two treatments are compared with the "no treatment" and to one another. METHODS The cost-effectiveness analysis was conducted using a Markov model; patients entered one of the following health states: chronic hepatitis, cirrhosis (compensated or decompensated), hepatocellular carcinoma, liver transplantation or death. The analysis was carried out from the perspective of the Italian National Health Service by considering a life-time horizon with cycles lasting 1 year and with costs and QALYs (quality-adjusted life years) discounted at a rate of 3.5%. The results of the model were analysed in terms of incremental cost-effectiveness ratio (ICER). RESULTS ICERs for tenofovir and entecavir emerging from the comparison versus "no treatment" were equal to €10,274.73 and €16,300.44 per QALY gained, respectively, on the life-time horizon. Tenofovir was dominant in the direct comparison with entecavir, indicating more QALYs and a lower consumption of resources. The Monte Carlo simulation demonstrated that in 97% (tenofovir) and in 85% (entecavir) of the scenarios performed, the cost per QALY fell below the threshold of €30,000/QALY. The budget impact analysis showed savings for tenofovir amounting to 33% compared to entecavir in the first year on treatment and to 31% in following years. CONCLUSIONS Entecavir and tenofovir are recommended for the treatment of patients with chronic Hepatitis B in the Italian Health System. In particular, tenofovir appeared to be the more cost-effective drug for the management of chronic hepatitis B virus (HBV) infections. These results could help decision makers and clinicians to address their decision when choosing a first-line treatment for the management of people affected by chronic HBV.
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Affiliation(s)
- M Ruggeri
- Catholic University of Sacred Heart, Rome, Italy
| | - M Basile
- Catholic University of Sacred Heart, Rome, Italy.
| | - S Coretti
- Catholic University of Sacred Heart, Rome, Italy
| | - C Drago
- "Nicolò Cusano" University, Rome, Italy
| | - A Cicchetti
- Catholic University of Sacred Heart, Rome, Italy
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Cho JY, Sohn W, Sinn DH, Gwak GY, Paik YH, Choi MS, Koh KC, Paik SW, Yoo BC, Lee JH. Long-term real-world entecavir therapy in treatment-naïve hepatitis B patients: base-line hepatitis B virus DNA and hepatitis B surface antigen levels predict virologic response. Korean J Intern Med 2017; 32:636-646. [PMID: 27809454 PMCID: PMC5511938 DOI: 10.3904/kjim.2016.096] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/22/2016] [Accepted: 06/04/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS Entecavir is a potent nucleoside analogue with high efficacy and barrier for resistance. We aimed to investigate the long-term efficacy and viral resistance rate of entecavir and explore the factors associated with virologic response, including quantitative hepatitis B surface antigen (qHBsAg) levels. METHODS One thousand and nine treatment-naïve chronic hepatitis B (CHB) patients were evaluated for cumulative rates of virologic response, biochemical response, and entecavir mutations. The role of baseline qHBsAg for virologic response was assessed in 271 patients with qHBsAg prior to entecavir treatment. RESULTS The median duration of entecavir treatment was 26.5 months. The cumulative rate of virologic response at years 1, 3, and 5 were 79.0%, 95.6%, and 99.4%, respectively. The cumulative rate of entecavir resistance was 1.0% and 2.1% in years 3 and 5. Multivariate analysis identified baseline hepatitis B e antigen (HBeAg) negative status (p < 0.001) and lower hepatitis B virus (HBV) DNA (p < 0.001) as predictors of virologic response. Lower qHBsAg was an independent predictor of virologic response in patients with baseline qHBsAg. There were no serious adverse events during treatment. CONCLUSIONS Long-term entecavir treatment of nucleos(t)ide-naïve CHB patients was associated with an excellent virologic response and a low rate of entecavir-resistant mutations at 5 years. Baseline HBV DNA load, qHBsAg levels, and HBeAg status were predictors of virologic response during entecavir treatment.
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Affiliation(s)
- Ju-Yeon Cho
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Medicine, Chosun University Hospital, Gwangju, Korea
| | - Won Sohn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Department of Hepatology, Daejin Medical Center, Bundang Jesaeng Hospital, Seongnam, Korea
| | - Dong-Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung Chul Yoo
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
- Correspondence to Joon Hyeok Lee, M.D. Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-3409 Fax: +82-2-3410-6983 E-mail:
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Jeon HJ, Jung SW, Park NH, Yang Y, Noh JH, Ahn JS, Kim HR, Lee JH, Shin JW. Efficacy of tenofovir-based rescue therapy for chronic hepatitis B patients with resistance to lamivudine and entecavir. Clin Mol Hepatol 2017; 23:230-238. [PMID: 28669175 PMCID: PMC5628011 DOI: 10.3350/cmh.2017.0003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 03/28/2017] [Accepted: 04/05/2017] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND/AIMS Tenofovir disoproxil fumarate (TDF) monotherapy for 48 weeks provided a virological response comparable to that of TDF and entecavir (ETV) combination therapy in patients infected with ETV-resistant hepatitis B virus (HBV). Little long-term data in routine clinical practice are available regarding the optimal treatment of patients with ETV-resistant HBV. METHODS We investigated the long-term antiviral efficacy of combination therapy of TDF+lamivudine (LAM) or TDF+ETV compared to that of TDF monotherapy in 73 patients with resistance to both LAM and ETV. RESULTS Patients were treated with TDF monotherapy (n=12), TDF+LAM (n=19), or TDF+ETV (n=42) for more than 6 months. The median duration of TDF-based rescue therapy was 37 months. Virologic response (VR) was found in 63 patients (86.3%). The rates of VR among the three groups (TDF monotherapy, TDF+LAM, and TDF+ETV) were not statistically different (log-rank P=0.200) at 12 months (59.3%, 78.9%, and 51.8%, respectively) or at 24 months (88.4%, 94.7%, and 84.2%). In addition, treatment efficacy of TDF-based combination or TDF monotherapy was not statistically different with ETV-resistant strains or exposure to other antiviral agents. In multivariate analysis, only lower baseline HBV DNA level was an independent predictor for VR (hazard ratio, 0.723; 95% confidence interval, 0.627-0.834; P<0.001). CONCLUSIONS TDF monotherapy was as effective as combination therapy of TDF+LAM or TDF+ETV in maintaining long-term viral suppression in chronic hepatitis B patients with resistance to both LAM and ETV. HBV DNA level at the start of TDF rescue therapy was the only independent predictor of subsequent VR.
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Affiliation(s)
- Hee-Jeong Jeon
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Seok Won Jung
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea.,Department of Biomedical Research Center, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Yujin Yang
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jin-Hee Noh
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jae-Sung Ahn
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Hyung Rae Kim
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jae Ho Lee
- Department of Anesthesiology and Pain Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jung Woo Shin
- Department of Internal Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
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Gao Y, Zhang TY, Yuan Q, Xia NS. Antibody-mediated immunotherapy against chronic hepatitis B virus infection. Hum Vaccin Immunother 2017; 13:1768-1773. [PMID: 28521640 DOI: 10.1080/21645515.2017.1319021] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The currently available drugs to treat hepatitis B virus (HBV) infection include interferons and nucleos(t)ide analogs, which can only induce disease remission and are inefficient for the functional cure of patients with chronic HBV infection (CHB). Since high titers of circulating hepatitis B surface antigen (HBsAg) may be essential to exhaust the host anti-HBV immune response and they cannot be significantly reduced by current drugs, new antiviral strategies aiming to suppress serum hepatitis B surface antigen (HBsAg) could help restore virus-specific immune responses and promote the eradication of the virus. As an alternative strategy, immunotherapy with HBsAg-specific antibodies has shown some direct HBsAg suppression effects in several preclinical and clinical trial studies. However, most described previously HBsAg-specific antibodies only had very short-term HBsAg suppression effects in CHB patients and animal models mimicking persistent HBV infection. More-potent antibodies with long-lasting HBsAg clearance effects are required for the development of the clinical application of antibody-mediated immunotherapy for CHB treatment. Our recent study described a novel mAb E6F6 that targets a unique epitope on HBsAg. It could durably suppress the levels of HBsAg and HBV DNA via Fcγ receptor-dependent phagocytosis in vivo. In this commentary, we summarize the current research progress, including the therapeutic roles and mechanisms of antibody-mediated HBV clearance as well as the epitope-determined therapeutic potency of the antibody. These insights may provide some clues and guidance to facilitate the development of therapeutic antibodies against persistent viral infection.
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Affiliation(s)
- Ying Gao
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics , School of Public Health, Xiamen University , Xiamen , China.,b National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science , Xiamen University , Xiamen , China
| | - Tian-Ying Zhang
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics , School of Public Health, Xiamen University , Xiamen , China.,b National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science , Xiamen University , Xiamen , China
| | - Quan Yuan
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics , School of Public Health, Xiamen University , Xiamen , China.,b National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science , Xiamen University , Xiamen , China
| | - Ning-Shao Xia
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics , School of Public Health, Xiamen University , Xiamen , China.,b National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Science , Xiamen University , Xiamen , China
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Predictors of HBeAg seroconversion after long-term nucleos(t)ide analogues treatment for chronic hepatitis B: a multicenter study in real clinical setting. Braz J Infect Dis 2017; 21:213-218. [PMID: 28351603 PMCID: PMC9427966 DOI: 10.1016/j.bjid.2017.03.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 03/10/2017] [Accepted: 03/10/2017] [Indexed: 12/26/2022] Open
Abstract
Aims To evaluate the HBeAg seroconversion rate in real clinical setting and explore its predictors in long-term nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B (CHB). Methods 251 patients were recruited from January 2001 to September 2009 in four hospitals in Hebei province, China, for this retrospective study. Clinical and laboratory data before and after treatment with lamivudine (LAM, 100 mg daily), adefovir (ADV, 10 mg daily), telbivudine (LDT, 600 mg daily), entecavir (ETV, 0.5 mg daily), and LAM/ADV combination were compared among three groups according to treatment outcomes: synchronous HBeAg loss and HBeAg seroconversion, anti-HBe development after treatment, and no anti-HBe. Adherence was also evaluated. Results In real clinical setting, cumulative HBeAg seroconversion rates were 14.3%, 32.7%, 43.0%, 46.9%, and 50.5% after 1, 2, 3, 5, and 8 years, respectively. 45 patients (17.9%) were non-adherent. Adherence (p < 0.001, Hazard Ratio (HR) = 2.203), elevated alanine aminotransferase (ALT) levels (p < 0.001, HR = 2.049), and non-vertical transmission (p = 0.006, HR = 1.656) were predictors of HBeAg seroconversion. Conclusion Adherence, elevated ALT, and non-vertical transmission are predictors of HBeAg seroconversion in CHB patients treated with NAs.
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Yamada N, Sugiyama R, Nitta S, Murayama A, Kobayashi M, Okuse C, Suzuki M, Yasuda K, Yotsuyanagi H, Moriya K, Koike K, Wakita T, Kato T. Resistance mutations of hepatitis B virus in entecavir-refractory patients. Hepatol Commun 2017; 1:110-121. [PMID: 29404449 PMCID: PMC5721430 DOI: 10.1002/hep4.1022] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 12/28/2016] [Accepted: 02/08/2017] [Indexed: 12/17/2022] Open
Abstract
The emergence of resistance mutations in the reverse transcriptase gene of hepatitis B virus (HBV) is associated with treatment failure. Entecavir (ETV) is one of the most potent anti‐HBV reagents; it has a very low resistance rate and is used as the first‐line treatment for chronic hepatitis B. In this study, we isolated HBVs in 4 ETV‐refractory patients (2 with viral breakthrough, 1 with partial virological response, and 1 with flare‐up) and assessed ETV resistance using replication‐competent 1.38‐fold HBV genome‐length molecular clones. The full genome sequences of infected HBVs in ETV‐refractory patients were determined. The HBV molecular clones were generated with the patient‐derived sequences. After transfection of these molecular clones into HepG2 cells, viral replications and ETV susceptibilities were evaluated by measuring the amount of intracellular core‐particle‐associated HBV DNA using Southern blotting and real‐time polymerase chain reaction. Among these cases, ETV‐resistant variants were detected in 2 patients with viral breakthrough and responsible amino acid mutations in reverse transcriptase were successfully identified in these variants. No ETV‐resistant mutation was detected in the other cases. The identified ETV‐resistant mutations did not confer resistance to tenofovir disoproxil fumarate. Conclusion: The HBV replication model with patient‐derived sequences is useful for assessing replication efficiency, susceptibility to anti‐HBV reagents, and responsible resistance mutations and can aid in choosing the appropriate treatment strategy for treatment‐failure cases of chronic hepatitis B. (Hepatology Communications 2017;1:110‐121)
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Affiliation(s)
- Norie Yamada
- Department of Virology II National Institute of Infectious Diseases Tokyo Japan.,Department of Internal Medicine Center for Liver Diseases, Seizankai Kiyokawa Hospital Tokyo Japan
| | - Ryuichi Sugiyama
- Department of Virology II National Institute of Infectious Diseases Tokyo Japan
| | - Sayuri Nitta
- Department of Virology II National Institute of Infectious Diseases Tokyo Japan.,Department of Gastroenterology and Hepatology Tokyo Medical and Dental University Tokyo Japan
| | - Asako Murayama
- Department of Virology II National Institute of Infectious Diseases Tokyo Japan
| | - Minoru Kobayashi
- Department of Internal Medicine Center for Liver Diseases, Seizankai Kiyokawa Hospital Tokyo Japan
| | - Chiaki Okuse
- Department of Internal Medicine Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine Kanagawa Japan
| | - Michihiro Suzuki
- Department of Internal Medicine Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine Kanagawa Japan
| | - Kiyomi Yasuda
- Department of Internal Medicine Center for Liver Diseases, Seizankai Kiyokawa Hospital Tokyo Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases Advanced Clinical Research Center, Institute of Medical Science
| | - Kyoji Moriya
- Department of Infection Control and Prevention Graduate School of Medicine
| | - Kazuhiko Koike
- Department of Gastroenterology Graduate School of Medicine, The University of Tokyo Tokyo Japan
| | - Takaji Wakita
- Department of Virology II National Institute of Infectious Diseases Tokyo Japan
| | - Takanobu Kato
- Department of Virology II National Institute of Infectious Diseases Tokyo Japan
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Grossi G, Viganò M, Loglio A, Lampertico P. Hepatitis B virus long-term impact of antiviral therapy nucleot(s)ide analogues (NUCs). Liver Int 2017; 37 Suppl 1:45-51. [PMID: 28052621 DOI: 10.1111/liv.13291] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 10/25/2016] [Indexed: 02/13/2023]
Abstract
The goal of antiviral therapy is to improve the quality of life and survival of patients with chronic hepatitis B (CHB) by halting the progression to cirrhosis, end-stage liver disease or hepatocellular carcinoma (HCC), thus preventing anticipated liver-related death. Oral administration of potent and less resistance-prone nucleot(s)ide analogues (NUCs), such as entecavir (ETV) and tenofovir disoproxil fumarate (TDF) has become the most popular treatment strategy worldwide because of their excellent efficacy and safety profile as well as easy management confirmed in both registration trials and in clinical practice studies. Long-term administration of ETV or TDF suppresses HBV replication in >95% of patients, resulting in biochemical remission, histological improvement including the regression of cirrhosis and prevention or reversal of clinical decompensation but not the development of HCC, particularly in patients with cirrhosis. Moreover, NUCs can be administered to all patients including those with severe liver disease, the elderly and in those who do not respond, are unwilling to take or have contraindications to interferon. The need for long-term, perhaps indefinite, treatment is the main limitation of NUCs therapy with the associated costs, unknown long-term safety and the low rates of hepatitis B surface antigen (HBsAg) seroclearance, which is still the best stopping rule for NUCs-treated patients with cirrhosis.
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Affiliation(s)
- Glenda Grossi
- "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Mauro Viganò
- Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - Alessandro Loglio
- "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - Pietro Lampertico
- "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
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Mohanty A, Lim JK. Current Management of Hepatitis B in 2016. CURRENT HEPATOLOGY REPORTS 2016; 15:266-270. [DOI: 10.1007/s11901-016-0323-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2025]
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Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection. J Gastroenterol 2016; 51:1073-1080. [PMID: 26943168 DOI: 10.1007/s00535-016-1189-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 02/16/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Interferon and nucleotide/nucleoside analogues are the main treatments for chronic hepatitis B. These drugs effectively reduce serum hepatitis B virus (HBV) DNA titers but fail to sufficiently reduce hepatitis B surface antigen (HBsAg) levels. Following the recent identification of sodium taurocholate cotransporting polypeptide as a receptor for HBV entry, inhibition of HBV entry has become an attractive therapeutic target for chronic hepatitis B treatment. We therefore evaluated the antiviral effects of antibody to HBsAg (anti-HBs) immunoglobulin (HBIG), which can inhibit HBV entry, by in an vivo study and a clinical trial. METHODS In the in vivo study, HBV-infected mice were generated from human hepatocyte chimeric mice and treated with HBIG. A clinical trial evaluating HBIG therapy in patients was also performed. RESULTS In the mouse study, HBV DNA titers were reduced and serum HBsAg titers decreased to undetectable levels following high-dose HBIG injection. On the basis of this result, eight chronic hepatitis B patients, who had received long-term nucleotide analogue treatment, were treated with monthly HBIG injections as an additional treatment. After 1 year of treatment, an HBsAg level reduction of more than 1 log IU/mL was observed in four patients, and three patients became anti-HBs positive. No adverse events occurred during HBIG therapy. CONCLUSION These results suggest that monthly HBIG injection might benefit patients with chronic hepatitis B whose HBsAg titer becomes lower following long-term nucleotide/nucleoside analogue treatment.
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Pawłowska M, Domagalski K, Smok B, Rajewski P, Wietlicka-Piszcz M, Halota W, Tretyn A. Continuous up to 4 Years Entecavir Treatment of HBV-Infected Adolescents - A Longitudinal Study in Real Life. PLoS One 2016; 11:e0163691. [PMID: 27685782 PMCID: PMC5042476 DOI: 10.1371/journal.pone.0163691] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 09/13/2016] [Indexed: 12/27/2022] Open
Abstract
This study evaluated the long-term (up to 4 years) efficacy and safety of entecavir ETV treatment and analysed the significance of baseline and on-treatment factors in long-term ETV outcomes in adolescents with chronic hepatitis B (CHB). We determined the cumulative virological and serological outcomes of 44 adolescents with CHB receiving ETV for up to 4 years. To investigate the dynamics of HBV DNA, ALT activity and hepatitis B e antigen (HBeAg) seroconversion over time and their associations with the considered factors, generalized estimating equation (GEE) models were used. The cumulative rates of undetectable HBV DNA (<20 IU/ml) and HBeAg seroconversion after 4 years were 89.7% and 55.4%, respectively. In the study group, we showed that having undetectable HBV DNA at the 6th or 12th month of therapy predicted the achievement of a sustained response rate (SRR, defined as the loss of HBV DNA, loss of HBeAg and ALT normalization) at year 3 of ETV therapy (P = 0.048, OR = 5.83; P = 0.012; OR = 14.57, respectively). The GEE analysis indicated that of the different factors, the duration of ETV therapy had a strong impact on the achievement of virological suppression, HBeAg seroconversion and SRR in adolescents. Each month after the initiation of therapy, the odds of loss of HBV DNA increased by approximately 5% (OR = 1.05, P<0.0001), on average. Additionally, the GEE analysis revealed that adolescents with an age at infection of ≥10 years had 3 times higher odds of achieving undetectable HBV DNA than patients with a younger infection age (OR = 3.67, P = 0.028). None of the ETV-treated patients reported significant adverse effects. ETV is an effective and safe treatment option for adolescents with CHB. Undetectable HBV DNA in the 6th and/or 12th month of ETV treatment and older age at infection could predict maintained virological suppression.
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Affiliation(s)
- Małgorzata Pawłowska
- Department of Paediatric Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Krzysztof Domagalski
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Toruń, Poland
- * E-mail:
| | - Beata Smok
- Department of Paediatric Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Paweł Rajewski
- Provincial Infectious Diseases Hospital, Bydgoszcz, Poland
| | - Magdalena Wietlicka-Piszcz
- Department of Theoretical Foundations of Biomedical Sciences and Medical Information Technology, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Waldemar Halota
- Department of Infectious Diseases and Hepatology, Faculty of Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Andrzej Tretyn
- Department of Plant Physiology and Biotechnology, Nicolaus Copernicus University, Toruń, Poland
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Zoulim F, Białkowska-Warzecha J, Diculescu MM, Goldis AE, Heyne R, Mach T, Marcellin P, Petersen J, Simon K, Bendahmane S, Klauck I, Wasiak W, Janssen HLA. Entecavir plus tenofovir combination therapy for chronic hepatitis B in patients with previous nucleos(t)ide treatment failure. Hepatol Int 2016; 10:779-788. [PMID: 27206517 DOI: 10.1007/s12072-016-9737-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 04/24/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS In patients with chronic hepatitis B (CHB) who have failed on other nucleos(t)ide analogs (NUCs), the combination of entecavir (ETV) plus tenofovir disoproxil fumarate (TDF), two potent agents with non-overlapping resistance profiles, may provide a single rescue regimen. METHODS In this single-arm, open-label study, 92 CHB patients with a primary non-response, partial response, or virologic breakthrough on their current NUC were switched to ETV (1 mg) plus TDF (300 mg) and treated for 96 weeks. RESULTS At baseline, 62 % of patients were HBeAg(+) and mean HBV DNA was 4.4 log10IU/mL. Patients had received ≥1 line of prior NUC therapy, with the latest regimen consisting of monotherapy with ETV (53 %), lamivudine (LVD 22 %), TDF (12 %), adefovir (ADV 4 %), or telbivudine (2 %), or combinations of these agents (7 %); 58 % had evidence of single- or multidrug resistance mutations (LVD 52 %, ETV 26 %; ADV 7 %). Response rates for HBV DNA <50 IU/mL were 76 % (70/92) at week 48 (primary endpoint), and 85 % (78/92) at week 96, including 80 % (16/20) in prior LVD failures, 100 % (4/4) in ADV failures, 82 % (9/11) in TDF failures, and 88 % (42/48) in ETV failures. No treatment-emergent resistance to ETV or ADV was observed. ETV/TDF was well tolerated, with no significant renal or additive toxicities observed. CONCLUSIONS In NUC-experienced patients who have failed prior NUC therapy, ETV/TDF was well tolerated and effective, achieving virologic suppression through 96 weeks in the majority (85 %), irrespective of prior NUC exposure, without occurrence of treatment-emergent resistance to either agent.
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Affiliation(s)
- Fabien Zoulim
- Hepatology Department, Hospices Civils de Lyon, INSERM U1052, INSERM, Lyon University, 151 Cours Albert Thomas, 69424, Lyon Cedex 03, France.
| | | | - Mircea Mihai Diculescu
- Centre of Gastroenterology and Hepatology, Fundeni Clinical Institute, Bucharest, Romania
| | | | | | - Tomasz Mach
- Department of Gastroenterology and Hepatology, Jagiellonian University, Krakow, Poland
| | - Patrick Marcellin
- Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, University of Paris 7, Paris, France
- INSERM Unité 773, Centre de Recherches Claude Bernard sur les Hépatites Virales, Clichy, France
| | - Jörg Petersen
- IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St Georg, Hamburg, Germany
| | - Krzysztof Simon
- Division of Infectious Diseases and Hepatology, Wrocław Medical University, Wrocław, Poland
| | | | | | | | - Harry L A Janssen
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Liver Clinic, Toronto Western and General Hospital, University Health Network, Toronto, Canada
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Liu K, Xiang X, Bao R, Chen R, Liu Y, Xie J, Guo Q, Bao S, Xie Q, Wang H. A five years study of antiviral effect of entecavir in Chinese chronic hepatitis B patients. Sci Rep 2016; 6:28779. [PMID: 27364728 PMCID: PMC4929461 DOI: 10.1038/srep28779] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/08/2016] [Indexed: 01/10/2023] Open
Abstract
Entecavir (ETV) is a potent viral replication inhibitor for chronic hepatitis B (CHB) patients. To investigate the efficacy of ETV in Chinese nucleos(t)ide(NA)-experienced CHB patients. Among 89 CHB patients with ETV monotherapy for ≥6 months, 33/89 (37%) or 56/89 (73%) were NA-naïve or NA-experienced. During a median follow-up of 5.75 years, all NA-naïve CHB patients achieved VR without genotypic ETV-resistance. However, VR was observed in 50/56 (~90%) of NA-experienced CHB patients during a median follow-up of 4.75 years. Antiviral efficacy was not reduced in patients with previous lamivudine (LAM) with/without LAM-resistance (HR 0.465; 95% CI 0.196–1.100; p > 0.05) (HR 0.472; 95% CI 0.205–1.091; p > 0.05). Patients with a primary treatment failure to adefovir (ADV) had a reduced probability of achieving VR compared to NA-naïve (HR 0.496; 95% CI 0.287–0.857; p < 0.01). Previous ADV-experienced patients with a partial VR (HR 1.253; 95% CI 0.429–3.665; p > 0.05) did not influence antiviral response to ETV. The antiviral efficacy of ETV is not influenced by previous treatment LAM with/without LAM-resistance. ETV may still be an option in ADV-experienced patients with a partial VR, but not advised in patients with a primary treatment failure to ADV.
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Affiliation(s)
- Kehui Liu
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaogang Xiang
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Rebecca Bao
- Discipline of Anatomy and Histology, School of Medical Sciences and The Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Rong Chen
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yunye Liu
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jingdong Xie
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qing Guo
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shisan Bao
- Discipline of Pathology, School of Medical Sciences and The Bosch Institute, The University of Sydney, Sydney, NSW 2006, Australia
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Wang
- Department of Infectious Diseases, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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50
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Resultados en la práctica clínica del tratamiento de la hepatitis crónica por virus B con tenofovir y entecavir. INFECTIO 2016. [DOI: 10.1016/j.infect.2015.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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