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Chen CJ, Yu HC, Chang CW, Bair MJ, Lin CC, Lin YS, Cai ZS, Chen MJ. Efficacy of telbivudine and entecavir against virus reactivation in HBeAg-patients undergoing chemotherapy. Medicine (Baltimore) 2020; 99:e20330. [PMID: 32481407 DOI: 10.1097/md.0000000000020330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The renal protective effect of telbivudine (LdT) was verified by a previous meta-analysis. It was left unclear, however if this effect offsets the associated risk of virological breakthrough in hepatitis B e-antigen-negative (HBeAg-) patients receiving chemotherapy (C/T).Records of 260 HBeAg-, non-cirrhotic cancer patients undergoing systemic C/T with prophylactic LdT or entecavir (ETV) were retrospectively investigated. The investigation was conducted 6 months after completion of C/T, patient death from cancer, or antiviral modification. Treatment duration, outcome, change of renal function, and reason for antiviral modification were analyzed. The primary endpoint was the occurrence of virological breakthrough during prophylaxis C/T and the change in renal function.Of the 126 HBeAg- patients treated with LdT, 3 (2.38%) experienced HBV virological breakthroughs, whereas none of the patients treated with ETV (P = .07) did. The estimated glomerular filtration rate for the patients treated with LdT was essentially unaltered, decreasing only slightly from 87.5 ± 23.1 to 87.3 ± 21.3 ml/minute/1.73 m (P = .55), while the rate for the ETV-treated patients was significantly lowered from 95.7 ± 32.2 to 85.5 ± 85.7 ml/minute/1.73 m (P = .0009).The absolute risk reduction ARR is 27.8% - 21.2% = 6.6%, comparing ETV with LdT for reduction of renal function impairment and the absolute risk increase for virological breakthrough during C/T, the absolute risk increase (ARI) is 2.38% - 0% = 2.38%. The overall likelihood of being helped over being harmed was 2.77. With careful selection of patients with the criteria of HBeAg-status and non-hematologic cancer, it is feasible that telbivudine raise lower probability of virological breakthroughs during prophylaxis treatment.
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Affiliation(s)
- Chih-Jen Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei City
- Department of Medicine, MacKay Medical College, New Taipei City
- Department of Nursing, MacKay Junior College of Medicine, Nursing, and Management
| | - Hsien-Chung Yu
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung City
- Faculty of Medicine, School of Medicine, National Yang Ming University, Taipei
- Institute of Health Care Management, Department of Business Management, National Sun Yat-Sen University, Kaohsiung
| | - Chen-Wang Chang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei City
- Department of Medicine, MacKay Medical College, New Taipei City
- Department of Nursing, MacKay Junior College of Medicine, Nursing, and Management
| | - Ming-Jong Bair
- Department of Medicine, MacKay Medical College, New Taipei City
- Department of Nursing, MacKay Junior College of Medicine, Nursing, and Management
- Division of Gastroenterology, Department of Internal Medicine, Taitung MacKay Memorial Hospital, Taitung City, Taiwan
| | - Ching-Chung Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei City
- Department of Medicine, MacKay Medical College, New Taipei City
| | - Yang-Sheng Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei City
- Department of Medicine, MacKay Medical College, New Taipei City
- Department of Nursing, MacKay Junior College of Medicine, Nursing, and Management
| | - Zong-Sian Cai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei City
- Department of Medicine, MacKay Medical College, New Taipei City
- Department of Nursing, MacKay Junior College of Medicine, Nursing, and Management
| | - Ming-Jen Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, MacKay Memorial Hospital, Taipei City
- Department of Medicine, MacKay Medical College, New Taipei City
- Department of Nursing, MacKay Junior College of Medicine, Nursing, and Management
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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Kao JH, Asselah T, Dou XG, Hamed K. Telbivudine therapy for chronic hepatitis B: A journey to identify super-responders and to optimize treatment using the roadmap model. J Gastroenterol Hepatol 2017; 32:73-81. [PMID: 27515408 DOI: 10.1111/jgh.13512] [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] [Accepted: 08/03/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection is one of the most serious health problems worldwide with a high risk for cirrhosis and liver cancer. Several antiviral agents have been approved for the treatment of chronic hepatitis B, leading to a rapid reduction in HBV DNA and normalization of serum alanine aminotransferase levels. Telbivudine, a potent inhibitor of HBV replication, has been shown to be well tolerated. Because of the emergence of drug resistance, optimization strategies for telbivudine therapy have been shown to improve patient responses. Optimal baseline characteristics in so-called super-responders have been used to predict the virological response. Baseline HBV DNA levels < 9 log10 copies/mL (2 × 108 IU/mL) or alanine aminotransferase levels of more than or equal to twofold the upper limit of normal in HBeAg-positive patients and HBV DNA < 7 log10 copies/mL (2 × 106 IU/mL) in HBeAg-negative patients were strong predictors for virological response. In addition, the roadmap model, based on early virological response at week 24 of therapy, is considered as a powerful tool to identify patients at risk of treatment failure (HBV DNA ≥ 300 copies/mL, i.e. 60 IU/mL) and to reduce the risk of antiviral resistance. When considering pre-treatment characteristics and on-treatment responses, telbivudine may provide physicians with a wide choice of options to effectively treat patients with chronic hepatitis B, especially those with or at risk of renal impairment, or women of childbearing age.
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Affiliation(s)
- Jia-Horng Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Tarik Asselah
- Hepatology Department, AP-HP, Beaujon Hospital, University Paris Diderot and INSERM UMR1149, Centre de Recherche sur l'inflammation, Labex INFLAMEX, Clichy, France
| | - Xiao-Guang Dou
- Department of Infectious Disease, Shengjing Hospital, China Medical University, Shenyang, China
| | - Kamal Hamed
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA
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Krastev Z, Petrova D, Kotzev I, Celen MK, Mendelson M, Chandra R, Pandey P, Hamed K. Telbivudine vs tenofovir in hepatitis B e antigen-negative chronic hepatitis B patients: OPTIMA roadmap study. World J Hepatol 2016; 8:1402-1413. [PMID: 27917266 PMCID: PMC5114476 DOI: 10.4254/wjh.v8.i32.1402] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 05/06/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To make efficacy and safety comparison of telbivudine-raodmap and tenofovir-roadmap in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients.
METHODS This was the first prospective, randomised, two-arm, open-label, non-inferiority study in HBeAg-negative CHB patients that compared telbivudine and tenofovir administered as per roadmap concept. Patients were treated up to 24 wk and, depending on virologic response, continued the same therapy or received add-on therapy up to 104 wk. Eligible patients received an additional 52 wk of treatment in the extension period (i.e., up to 156 wk). Patients who developed virologic breakthrough (VB) while on monotherapy also received add-on therapy. The primary efficacy endpoint was the rate of patients achieving hepatitis B virus (HBV) DNA < 300 copies/mL at week 52. Secondary efficacy endpoints included the rates of HBV DNA < 300 and < 169 copies/mL, HBV DNA change from baseline, alanine aminotransferase normalisation, hepatitis B surface antigen (HBsAg) loss, HBsAg seroconversion, VB, and emergence of resistance at various timepoints throughout the study. Safety and estimated glomerular filtration rate (eGFR) were also analysed.
RESULTS A total of 241 patients were randomised. Non-inferiority of telbivudine arm to tenofovir arm was demonstrated at week 52 (± 7 d window), with over 91% of patients in each treatment arm achieving HBV DNA level < 300 copies/mL. Both arms were similar in terms of key secondary efficacy variables at weeks 104 and 156. The percentage of patients achieving HBV DNA < 300 copies/mL remained high and was similar in the telbivudine and tenofovir arms at both weeks 104 and 156. Over 82% of patients in both arms achieved alanine aminotransferase normalisation at week 52, and this percentage remained high at weeks 104 and 156. Telbivudine treatment progressively reduced serum HBsAg levels from baseline while no change was reported in quantitative HBsAg during therapy with tenofovir. Both treaments showed acceptable safety profiles. The telbivudine arm showed eGFR improvement unlike the tenofovir arm.
CONCLUSION Efficacy was shown for both telbivudine-roadmap and tenofovir-roadmap regimens in HBeAg-negative CHB patients over 156 wk. Telbivudine arm was associated with renal improvement.
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Wang CC, Lin CL, Hsieh TY, Tseng KC, Peng CY, Su TH, Yang SS, Hsu YC, Chen TM, Kao JH. Efficacy and resistance to telbivudine treatment in chronic hepatitis B patients with favorable predictors: a multicenter study in Taiwan. Hepatol Int 2016; 10:294-301. [PMID: 26399763 DOI: 10.1007/s12072-015-9662-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2015] [Accepted: 08/18/2015] [Indexed: 01/10/2023]
Abstract
BACKGROUND/PURPOSE A subgroup analysis of a GLOBE study identified subgroups of chronic hepatitis B (CHB) patients with excellent outcomes to telbivudine (LdT) treatment. The aim of this study was to validate this concept using a real-world clinical population. METHODS This prospective, retrospective, and multicenter study examined both HBeAg-positive and HBeAg-negative CHB patients treated with LdT for 2 years. RESULTS A total of 116 CHB patients were recruited. Of the 64 HBeAg-positive patients, 35 had favorable baseline characteristics [hepatitis B virus (HBV) DNA ≤ 9 log(10) copies/mL and alanine aminotransferase ≥ 2× the upper limit of normal (ULN)], but only 40% (14/35) achieved polymerase chain reaction (PCR) negativity at week 24. Among the 14 patients with favorable baseline characteristics and on-treatment response, the rates of virologic, biochemical, and serologic response and genotypic resistance were 78.6% (11/14), 64.3% (9/14), 50% (7/14), and 7.1% (1/14), respectively, at week 104 of therapy. Of the 52 HBeAg-negative patients, 34 met the criteria of a baseline serum HBV-DNA level less than 7 log(10) copies/mL, and 29 (85.3%) achieved PCR negativity at week 24. Among the 29 patients with favorable baseline characteristics and on-treatment response, the rates of virologic and biochemical response and genotypic resistance were 96.6% (28/29), 72.4% (21/29), and 6.9% (2/29), respectively. In addition, the PCR negativity at week 24 was the only factor associated with the virologic response and genotypic resistance to LdT treatment. CONCLUSION The efficacy and resistance to LdT treatment in CHB patients with favorable predictors were comparable between a real-world clinical population and the GLOBE study. In addition, PCR negativity at week 24 could predict virologic response and genotypic resistance to LdT treatment.
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Affiliation(s)
- Chia-Chi Wang
- Department of Gastroenterology, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Chih-Lin Lin
- Department of Gastroenterology, Taipei City Hospital, Ren-Ai Branch, Taipei, Taiwan.
| | - Tsai-Yuan Hsieh
- Department of Gastroenterology, Tri-service General Hospital, Taipei, Taiwan.
| | - Kuo-Chih Tseng
- Department of Hepatology, Da-Lin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan.
| | - Cheng-Yuan Peng
- Department of Gastroenterology, China Medical University Hospital, Shenyang, China.
| | - Tung-Hung Su
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
| | - Sheng-Shun Yang
- Division of Gastroenterology & Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
| | - Yu-Chun Hsu
- Department of Gastroenterology, Changhua Christian Hospital, Changhua, Taiwan.
| | - Tsung-Ming Chen
- Department of Gastroenterology and Hepatology, Tungs' Taichung MetroHarbor Hospital, Taichung, Taiwan.
| | - Jia-Horng Kao
- Graduate Institute of Clinical Medicine and Hepatitis Research Center, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan.
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te Street, Taipei, 100, Taiwan.
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Hermans LE, Svicher V, Pas SD, Salpini R, Alvarez M, Ben Ari Z, Boland G, Bruzzone B, Coppola N, Seguin-Devaux C, Dyda T, Garcia F, Kaiser R, Köse S, Krarup H, Lazarevic I, Lunar MM, Maylin S, Micheli V, Mor O, Paraschiv S, Paraskevis D, Poljak M, Puchhammer-Stöckl E, Simon F, Stanojevic M, Stene-Johansen K, Tihic N, Trimoulet P, Verheyen J, Vince A, Weis N, Yalcinkaya T, Lepej SZ, Perno C, Boucher CAB, Wensing AMJ. Combined Analysis of the Prevalence of Drug-Resistant Hepatitis B Virus in Antiviral Therapy-Experienced Patients in Europe (CAPRE). J Infect Dis 2015; 213:39-48. [PMID: 26136470 DOI: 10.1093/infdis/jiv363] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 06/23/2015] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND European guidelines recommend treatment of chronic hepatitis B virus infection (CHB) with the nucleos(t)ide analogs (NAs) entecavir or tenofovir. However, many European CHB patients have been exposed to other NAs, which are associated with therapy failure and resistance. The CAPRE study was performed to gain insight in prevalence and characteristics of NA resistance in Europe. METHODS A survey was performed on genotypic resistance testing results acquired during routine monitoring of CHB patients with detectable serum hepatitis B virus DNA in European tertiary referral centers. RESULTS Data from 1568 patients were included. The majority (73.8%) were exposed to lamivudine monotherapy. Drug-resistant strains were detected in 52.7%. The most frequently encountered primary mutation was M204V/I (48.7%), followed by A181T/V (3.8%) and N236T (2.6%). In patients exposed to entecavir (n = 102), full resistance was present in 35.3%. Independent risk factors for resistance were age, viral load, and lamivudine exposure (P < .001). CONCLUSIONS These findings support resistance testing in cases of apparent NA therapy failure. This survey highlights the impact of exposure to lamivudine and adefovir on development of drug resistance and cross-resistance. Continued use of these NAs needs to be reconsidered at a pan-European level.
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Affiliation(s)
- Lucas Etienne Hermans
- Department of Medical Microbiology, University Medical Centre Utrecht Department of Virology, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Valentina Svicher
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Italy
| | | | - Romina Salpini
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Italy
| | - Marta Alvarez
- Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs. GRANADA, Hospitales Universitarios de Granada, Spain
| | - Ziv Ben Ari
- Liver Disease Centre, Sheba Medical Centre, Ramat Gan, Israel
| | - Greet Boland
- Department of Medical Microbiology, University Medical Centre Utrecht
| | | | - Nicola Coppola
- Malattie Infettive, Seconda Università degli studi di Napoli, Naples, Italy
| | | | - Tomasz Dyda
- Molecular Diagnostics Laboratory, Hospital of Infectious Diseases, Warsaw, Poland
| | - Federico Garcia
- Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs. GRANADA, Hospitales Universitarios de Granada, Spain
| | - Rolf Kaiser
- Institute of Virology, University of Cologne, Germany
| | - Sukran Köse
- Clinic of Infectious Diseases and Clinical Microbiology, Izmir Tepecik Education and Research Hospital, Turkey
| | - Henrik Krarup
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Denmark
| | - Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Serbia
| | - Maja M Lunar
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia
| | - Sarah Maylin
- Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, France
| | | | - Orna Mor
- National HIV Reference Laboratory, Central Virology Laboratory, Ministry of Health, Tel Hashomer, Ramat Gan, Israel
| | - Simona Paraschiv
- Molecular Diagnostics Laboratory, National Institute for Infectious Diseases Matei Bals, Bucharest, Romania
| | - Dimitrios Paraskevis
- National Retrovirus Reference Centre, Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, National and Kapodistrian University of Athens, Greece
| | - Mario Poljak
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Slovenia
| | | | - François Simon
- Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, France
| | - Maja Stanojevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Serbia
| | | | - Nijaz Tihic
- Institute of Microbiology, Polyclinic for Laboratory Diagnostics, University Clinical Centre Tuzla, Bosnia and Herzegovina
| | - Pascale Trimoulet
- Virology Laboratory, Centre Hospitalier Régional et Université Victor Segalen, Bordeaux, France
| | - Jens Verheyen
- Institute of Virology, University-Hospital, University Duisburg-Essen, Germany
| | - Adriana Vince
- University of Zagreb School of Medicine and University Hospital for Infectious Diseases "Dr Fran Mihaljevic", Croatia
| | - Nina Weis
- Department of Infectious Diseases, Copenhagen University Hospital, Denmark
| | | | - Snjezana Zidovec Lepej
- University of Zagreb School of Medicine and University Hospital for Infectious Diseases "Dr Fran Mihaljevic", Croatia
| | - Carlo Perno
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Italy
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Yan LB, Chen EQ, Bai L, Du LY, Chen LL, Liao J, He M, Tang H. Efficacy of entecavir treatment for up to 96 weeks in nucleoside-naive HBeAg-positive chronic hepatitis B patients with high viral load. Clin Res Hepatol Gastroenterol 2015; 39:366-372. [PMID: 25468548 DOI: 10.1016/j.clinre.2014.09.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2013] [Revised: 06/15/2014] [Accepted: 09/04/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS To evaluate the antiviral response of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients who had baseline high viral load (HVL), defined as having hepatitis B virus (HBV) DNA>9log 10 copies/mL, after 96weeks of entecavir (ETV) treatment. METHODS A total of 99 HBeAg-positive CHB patients (50 with HVL and 49 with non-HVL) were treated with ETV monotherapy for 96weeks. RESULTS Virological response (VR) (HBVDNA<300copies/mL) was achieved in 42%, 62%, 68% of HVL patients and in 67.34%, 85.71%, 85.71% of non-HVL patients at weeks 48,72,96, respectively. The VR rates of the HVL group were lower than those of the non-HVL group (P=0.006, P=0.007, and P=0.037). In the HVL group, a total of 30 patients had HBV DNA<1000copies/mL at week 48 and those patients had a 93.3% chance of achieving VR at week 96, whereas the patients who had HBV DNA levels>1000copies/mL at week 48 only had a 30% chance to achieve VR at week 96. Among the 96weeks of treatment, one patient had virological breakthrough in the HVL group and this patient had HBVDNA>1000copies/mL at week48. The rates of biochemical responses (BR) and HBeAg seroconversion (SR) were similar between the HVL group and non-HVL group at weeks 48 and 96. CONCLUSION The baseline HVL was a negative predictor of virological response in CHB patients with ETV monotherapy. For those HVL patients treated by ETV with poor VR, which defined as HBVDNA>1000copies/mL at week48, the treatment strategies need to be adjusted.
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Affiliation(s)
- Li-Bo Yan
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Ling-Yao Du
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Lan-Lan Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Juan Liao
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Min He
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu 610041, People's Republic of China.
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Wang Y, Liu S, Chen Y, Zheng S, Zhou L, Lu F, Duan Z. Delayed Reduction of Hepatitis B Viral Load and Dynamics of Adefovir-Resistant Variants during Adefovir plus Entecavir Combination Rescue Therapy. Int J Med Sci 2015; 12:416-422. [PMID: 26005376 PMCID: PMC4441066 DOI: 10.7150/ijms.11687] [Citation(s) in RCA: 3] [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: 01/25/2015] [Accepted: 04/20/2015] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE Entecavir (ETV) added to adefovir (ADV) is recommended in the consensus for management of patients with ADV resistance. However, little attention has been focused on the delayed reduction of HBV DNA and dynamics of ADV-resistant variants during ADV-ETV combination rescue therapy in the clinical setting. We characterized the dynamics of viral load and resistant variants in nucleos(t)ide analogues (NAs)-naïve chronic hepatitis B (CHB) patients during antiviral treatment with ADV monotherapy followed by ADV-ETV combination therapy. METHODS A cohort of 55 CHB patients was enrolled in this study. Three NAs-naïve patients developed ADV-resistant variants during 24-33 months of ADV monotherapy, and then switched to ADV-ETV combination therapy. Thirty-five serial serum samples from these three patients were regularly collected during treatment. Ten mutants associated with commonly used antiviral drugs were detected by pyrosequencing. RESULTS HBV DNA decreased to the lowest level during ADV monotherapy at 6-18 months, with a decrease of 0.95-5.51 log10 copies/mL, whereas rtA181V or rtN236T gradually increased with extended therapy. HBV DNA decreased to below the detectable level during ADV-ETV combination therapy at 21-24 months, with a decrease of 4.19-4.65 log10 copies/mL. Resistant rtA181V and rtN236T were undetectable after 21-24 months of combination therapy. Moreover, no LAM-resistant rtM204I/V or ETV-resistant variants were detected during the 27-36 months of combination therapy. CONCLUSION Although ADV-resistant variants were suppressed, viral load reduction was delayed during ADV-ETV combination rescue therapy in patients with ADV-resistant HBV. The quantification of resistant variants by pyrosequencing may facilitate monitoring of antiviral therapy.
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Affiliation(s)
- Yang Wang
- 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Shuang Liu
- 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Yu Chen
- 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Sujun Zheng
- 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Li Zhou
- 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
| | - Fengmin Lu
- 2. Department of Microbiology & Infectious Disease Center, Peking University Health Science Center, Beijing, China
| | - Zhongping Duan
- 1. Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing 100069, China
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Wang J, Du LY, Zhu X, Chen EQ, Tang H. The predictive value of early indicators for HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients with Telbivudine treatment for 104 weeks. Indian J Med Microbiol 2015; 33 Suppl:20-25. [PMID: 25657151 DOI: 10.4103/0255-0857.148827] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE Through an observation on HBeAg-positive chronic hepatits B (CHB) patients in Telbivudine (LDT) treatment for 104 weeks, we tried to explore valuable early predictors for HBeAg seroconversion during the treatment. MATERIALS AND METHODS A prospective study lasting for 104 weeks was conducted, and the patients enrolled were administered with LDT 600 mg daily. The medical evaluation went every 12 weeks, then the age distribution, baseline ALT level, early HBVDNA, HBsAg and HBeAg levels at baseline, week 12 and 24 as well as the decrease of the three indicators at week 12 and 24 were analyzed for their predictive values for HBeAg seroconversion at week 104. RESULT Thirty-three patients finished the observation. All patients got ALT normalisation and 28 patients (84.84%) got complete virological response (HBV DNA<291 copies/ml) at week 104. Poor virological response and virologic breakthrough was observed in two (6.06%) and three patients (9.09%), respectively. Nine patients (27.27%) got HBeAg seroconversion. HBeAg levels and its decrease levels at week 12 and 24 showed significant differences between patients with and without HBeAg seroconversion. And the HBsAg levels at week 12 and 24 showed tendencies of significant differences in two groups. HBeAg level at week 24 was confirmed related to its longer term seroconversion in regression analysis. The patients with HBeAg level<2.1 S/CO at week 24 would be more possible to get HBeAg seroconversion at week 104, with sensitivity, specificity, positive and negative predictive value of 95.83%, 88.89%, 95.8% and 88.9%, respectively. CONCLUSION Good efficacy of long-term LDT treatment in biological and virological response and its advantage in serological response was confirmed again in our study. The HBeAg level at week 24 showed significant value in prediction for HBeAg seroconversion at week 104 compared to other serological markers in the early period.
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Affiliation(s)
| | | | | | | | - Hong Tang
- Center of Infectious Diseases,West China Hospital of Sichuan University; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China
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10
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Zheng Q, Zhu YY, Chen J, Liu YR, You J, Dong J, Zeng DW, Gao LY, Chen LH, Jiang JJ. Decline in intrahepatic cccDNA and increase in immune cell reactivity after 12 weeks of antiviral treatment were associated with HBeAg loss. J Viral Hepat 2014; 21:909-916. [PMID: 24888640 DOI: 10.1111/jvh.12261] [Citation(s) in RCA: 15] [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: 11/13/2013] [Accepted: 02/25/2014] [Indexed: 12/12/2022]
Abstract
Viral load reduction facilitates recovery of antiviral T-cell responses. Dynamic alterations in intrahepatic viraemia clearance and immune cell reactivity during the early phase of nucleoside analogue (NA) therapy and the impact of these changes on HBeAg seroconversion are unknown. Fifteen HBeAg-positive chronic hepatitis B (CHB) patients were treated with adefovir dipivoxil. T-cell reactivity to HBV core and surface antigens were tested using ELISPOT assay from baseline to week 48 post-treatment (at 4-week intervals). Before and at week 12 of treatment, paired liver biopsies were analysed for intrahepatic HBV-DNA and cccDNA via real-time fluorescent PCR. In situ detection of CD4(+) , CD8(+) T cells and NK cells was analysed by immunohistochemistry. With viral load reduction, HBV-specific IFN-γ-producing CD4(+) T cells in patients with HBeAg loss were greatly enhanced and reached the highest level at week 12, with further increase observed between week 36 and week 48. After 12 weeks of treatment, total intrahepatic HBV-DNA and cccDNA had significantly decreased; however, there was no difference in the viral loads or extent of reduction between patients with and without HBeAg loss. Paralleling reduction in viral load, intrahepatic CD8(+) T lymphocytes increased in patients with HBeAg loss compared with baseline values. Only one patient without HBeAg loss exhibited similar results. Increased immune cells were observed in certain patients along with reduced hepatic viral loads during the second phase of HBV-DNA decline, which could promote the recovery of antiviral immunity and facilitate HBeAg loss.
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Affiliation(s)
- Q Zheng
- Center of Liver Diseases, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
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11
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Chen EQ, Tang H. Optimization therapy for the treatment of chronic hepatitis B. World J Gastroenterol 2014; 20:5730-5736. [PMID: 24914334 PMCID: PMC4024783 DOI: 10.3748/wjg.v20.i19.5730] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/07/2014] [Accepted: 03/04/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B (CHB) is currently medically managed with either interferon-alpha or one of the five nucleos(t)ide analogs. However, there are still a large number of CHB patients whose response to the above therapies remains less than satisfactory, and their incomplete or non-response to antiviral therapies has plagued clinicians worldwide. In recent years, a newly proposed optimization therapy has provided us with a new approach to solve this problem. The key points in this optimization therapy are to initiate antiviral therapy with an appropriate agent at the correct time point, and to adjust treatments in patients with poor early responses by adding a second agent or switching to another more potent agent. In this review, we summarize recent developments in optimization therapy for the treatment of CHB, and provide an outlook for future research in this field.
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12
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Tsai MC, Yu HC, Hung CH, Lee CM, Chiu KW, Lin MT, Tseng PL, Chang KC, Yen YH, Chen CH, Hu TH. Comparing the efficacy and clinical outcome of telbivudine and entecavir naïve patients with hepatitis B virus-related compensated cirrhosis. J Gastroenterol Hepatol 2014; 29:568-575. [PMID: 24716215 DOI: 10.1111/jgh.12436] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/05/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM There is limited data on the efficacy and outcome of telbivudine (LdT) therapy in patients with chronic hepatitis B and compensated cirrhosis. We evaluated LdT as first-line therapy in these patients and compared with those treated with entecavir (ETV). METHODS We consecutively enrolled 88 chronic hepatitis B patients with compensated cirrhosis primarily treated with LdT at least for 2 years or less than 2 years but developed resistance, and evaluated the efficacy and clinical outcomes. Meanwhile, we matched a control group who treated with ETV for comparison. RESULTS In LdT group, alanine aminotransferase normalization (65.8%), hepatitis B e antigen seroconversion (39.8%), hepatitis B virus (HBV) DNA undetectablility (71.6%), and virologic resistance (23.9%) were noted after 2 years treatment. Compared with ETV group, there were significant difference in HBV DNA undetectablility (P < 0.001) and virologic resistance (P < 0.001). In addition, the decline of serum hepatitis B surface antigen levels, hepatocellular carcinoma development, mortality, disease progression, and the change of renal function were similar. Cox regression analysis showed that pretreatment low albumin level and high model for end-stage liver disease scores were risk factors for disease progression. CONCLUSIONS These results indicated that although LdT and ETV are similar in clinical outcomes for patients with HBV-related compensated cirrhosis, LdT still had lower HBV undetectablility and higher resistant rate after 2 years treatment, which was a challenge for being as first-line therapy in these patients who need lifelong therapy.
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13
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Soriano V, McMahon B. Strategic use of lamivudine in the management of chronic hepatitis B. Antiviral Res 2013; 100:435-8. [PMID: 24050850 DOI: 10.1016/j.antiviral.2013.08.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 08/29/2013] [Accepted: 08/30/2013] [Indexed: 02/08/2023]
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Chao DC, Hu KQ. Update on rescue therapies in patients with lamivudine-resistant chronic hepatitis B. Drug Des Devel Ther 2013; 7:777-788. [PMID: 23990707 PMCID: PMC3753145 DOI: 10.2147/dddt.s33947] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Chronic hepatitis B continues to be a global problem, with an estimated 240 million cases according to the World Health Organization. Chronic infection with the hepatitis B virus (HBV) is associated with cirrhosis, hepatic decompensation, and hepatocellular carcinoma. There are currently several US Food and Drug Administration-approved medications for treating chronic hepatitis B, with Lamivudine (LAM) being the first oral agent made available. The major problem with LAM is significantly decreased effectiveness over time due to the development of anti-HBV resistance that can lead to virologic and biochemical breakthrough as well as hepatitis B flare, progression of liver disease, and decompensation of pre-existing cirrhosis. Despite its high anti-HBV resistant rate, LAM remains widely used in underdeveloped countries due to its wide availability and low cost compared to other antiviral medications, including those that are more effective. Therefore, it is still clinically important to learn how to prevent and treat LAM resistant strains of HBV. Several regimens with the other available antiviral agents have been studied, including switching to monotherapy with either Adefovir, Entecavir, or Tenofovir, adding Adefovir to LAM, and switching to a combination of Adefovir and Entecavir. This review article will examine molecular mechanisms and diagnosis of LAM anti-HBV resistance, risks for and approaches to reduce LAM anti-HBV resistance, and currently available rescue therapy regimens for LAM resistance.
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Affiliation(s)
- Daniel C Chao
- Division of Gastroenterology and Hepatology, University of California, Irvine Medical Center, Orange, CA, USA
| | - Ke-Qin Hu
- Division of Gastroenterology and Hepatology, University of California, Irvine Medical Center, Orange, CA, USA
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15
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Wang Y, Thongsawat S, Gane EJ, Liaw YF, Jia J, Hou J, Chan HLY, Papatheodoridis G, Wan M, Niu J, Bao W, Trylesinski A, Naoumov NV. Efficacy and safety of continuous 4-year telbivudine treatment in patients with chronic hepatitis B. J Viral Hepat 2013; 20:e37-46. [PMID: 23490388 PMCID: PMC3618368 DOI: 10.1111/jvh.12025] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Accepted: 10/01/2012] [Indexed: 12/16/2022]
Abstract
In the phase-III GLOBE/015 studies, telbivudine demonstrated superior efficacy vs lamivudine during 2-year treatment in HBeAg-positive and HBeAg-negative chronic hepatitis B (CHB). After completion, 847 patients had an option to continue telbivudine treatment for further 2 years. A total of 596 (70%) of telbivudine-treated patients, who were serum HBV DNA positive or negative and without genotypic resistance to telbivudine at the end of the GLOBE/015 trials, were enrolled into a further 2-year extension study. A group of 502 patients completed 4 years of continuous telbivudine treatment and were included in the telbivudine per-protocol population. Amongst 293 HBeAg-positive patients, 76.2% had undetectable serum HBV DNA and 86.0% had normal serum ALT at the end of 4 years. Notably, the cumulative rate of HBeAg seroconversion was 53.2%. Amongst 209 HBeAg-negative patients, 86.4% had undetectable HBV DNA and 89.6% had normal serum ALT. In patients who had discontinued telbivudine treatment due to HBeAg seroconversion, the HBeAg response was durable in 82% of patients (median 111 weeks of off-treatment follow-up). The cumulative 4-year resistance rate was 10.6% for HBeAg-positive and 10.0% for HBeAg-negative patients. Most adverse events were mild or moderate in severity and transient. Renal function measured by estimated glomerular filtration rate (eGFR) increased by 14.9 mL/min/1.73 m(2) (16.6%) from baseline to 4 years (P < 0.0001). In conclusion, in HBeAg-positive and HBeAg-negative CHB patients without resistance after 2 years, two additional years of telbivudine treatment continued to provide effective viral suppression with a favourable safety profile. Moreover, telbivudine achieved 53% of HBeAg seroconversion in HBeAg-positive patients.
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Affiliation(s)
- Y Wang
- Institute of Infectious Diseases, Southwest Hospital, Third Military Medical UniversityChongqing, China
| | - S Thongsawat
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai UniversityChiang Mai, Thailand
| | - E J Gane
- New Zealand Liver Unit, Auckland City HospitalAuckland, New Zealand
| | - Y-F Liaw
- Liver Research Unit, Chang Gung Memorial Hospital & UniversityTaipei, Taiwan
| | - J Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical UniversityBeijing, China
| | - J Hou
- Hepatology Unit and Department of Infectious Diseases, Nanfang HospitalGuangzhou, China
| | - H L Y Chan
- Medicine and Therapeutics, Chinese University of Hong KongHong Kong, China
| | - G Papatheodoridis
- Academic Department of Medicine, Hippokration General HospitalAthens, Greece
| | - M Wan
- Department of Infectious Diseases, ChangHai Hospital of the Second Military Medical UniversityShanghai, China
| | - J Niu
- Department of Hepatology, First hospital of Jilin UniversityJilin, China
| | - W Bao
- Novartis Pharma CorporationEast Hanover, NJ, USA
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16
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Wang YX, Zheng SM, Zhang Y, Qin JP, Lin H, Liu XC, Shen CF, Jiang MD. Sustained efficacy of adefovir add-on therapy in chronic hepatitis B patient with a poor virological response to peginterferon alfa. Scand J Gastroenterol 2013; 48:213-7. [PMID: 23234601 DOI: 10.3109/00365521.2012.749513] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Currently, there is no consensus on the recommendation of peginterferon alfa (pegIFNα) to chronic hepatitis B (CHB) patients with poor viral response (EVR). This study aimed to assess the sustained curative efficacy of adefovir (ADV) add-on therapy in optimizing pegIFNα monotherapy. METHODS A total of 85 hepatitis B e antigen (HBeAg)-positive CHB patients with poor virological response at month 6 after starting pegIFNα-2a were enrolled, and received either pegIFNα-2a continuing monotherapy (group A, n = 51) or add-on therapy with ADV (group B, n = 34). The treatment duration for all patients was 6 months, and the sustained responses after the end of treatment were evaluated between two groups. RESULTS The baseline characteristics were comparable between two groups. At months 6 after treatment completion, the sustained virological response (SVR) rates were 31.4% and 73.5%, the sustained biochemical response (SBR) rates were 39.2% and 85.3% in group A and group B respectively, and the difference in either SVR or SBR was statistically significant (both p < 0.001). As compared to patients in group A, significantly more patients in group B obtained HBeAg loss (19.6% vs. 55.9%, p = 0.001) and seroconversion (13.7% vs. 41.2%, p = 0.004). CONCLUSION ADV add-on therapy could significantly improve and sustain the curative efficacy of CHB patient with poor virological response to pegIFNα-2a monotherapy, but further large well-designed randomized controlled trials are needed to confirm our findings.
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Affiliation(s)
- Yun-Xia Wang
- Department of Digestion, Chengdu Military General Hospital, Chengdu, China
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17
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Hsu CW, Chao YC, Lee CM, Chang TT, Chen YC. Efficacy of telbivudine in Taiwanese chronic hepatitis B patients compared with GLOBE extension study and predicting treatment outcome by HBV DNA kinetics at week 24. BMC Gastroenterol 2012; 12:178. [PMID: 23234302 PMCID: PMC3563525 DOI: 10.1186/1471-230x-12-178] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 12/10/2012] [Indexed: 12/19/2022] Open
Abstract
Background The aims of this study were to compare results from a Taiwanese sub-study of the GLOBE 2303 telbivudine study and evaluate the HBV DNA kinetics. Methods Forty-one Taiwanese patients were treated for an additional 2 years with telbivudine. Efficacy endpoints were the same as the GLOBE study. The correlations of reductions in HBV DNA levels at Week 24 were evaluated. Results All 7 HBeAg-positive patients with undetectable HBV DNA levels at Week 24 sustained this response at Year 4 with rates of ALT normalization 71%, HBeAg seroconversion 57%, and cumulative resistance 0%. Out of 16 HBeAg-negative patients with undetectable HBV DNA levels at Week 24, 11 (78%) sustained this response at Year 4 with rates of ALT normalization 83% and cumulative resistance 8.7%. There were significant correlations between reductions of DNA of ≥5 log10 copies/mL at Week 24 with maintained PCR negativity at Years 2–4 and a lack of resistance at Year 2. Conclusions Long-term telbivudine efficacy in Taiwanese patients was comparable to the GLOBE 2303 study. A reduction in HBV DNA levels by ≥5 log10 copies/mL at Week 24 represented the optimal cut-off point, which may predict favourable outcomes in patients with high baseline HBV DNA levels. Trial registration ClinicalTrials.gov Identifier: NCT00142298 (http://clinicaltrials.gov/).
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Affiliation(s)
- Chao Wei Hsu
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, 199 Tung Hwa North Road, Taipei 105, Taiwan.
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Wang C, Fan R, Sun J, Hou J. Prevention and management of drug resistant hepatitis B virus infections. J Gastroenterol Hepatol 2012; 27:1432-40. [PMID: 22694205 DOI: 10.1111/j.1440-1746.2012.07198.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In the past decade, broadened therapeutic options of oral direct antiviral agents for the treatment of chronic hepatitis B infection include: Lamivudine, Adefovir Dipivoxil, Telbivudine, Entecavir and Tenofovir Disoproxil Fumarate. These direct oral antiviral agents effectively suppress the replication of the virus and reduce the risk of potential liver-related complications. However, prolonged use of these nucleos(t)ide analogues has been associated with drug resistance that compromises the initial clinical benefits. Moreover, the oncogenic risk of mutations due to prolonged nucleos(t)ide analogue therapy needs to be further investigated by in vitro and in vivo studies. In the current era of potent nucleotide analogues, new data are emerging, we are still facing the pool of patients who have developed resistance to the prior generation of nucleos(t)ide analogues. This paper aims to focus on incidence of antiviral drug resistance and virological breakthrough, prudent selection of initial therapy, on-treatment monitoring for drug resistance and revise treatment strategies for patients with resistant virus.
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Affiliation(s)
- Cheng Wang
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
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19
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Abstract
Large volume of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2008. These include further studies in asymptomatic subjects with chronic HBV infection and community-based cohorts, the role of HBV genotype/naturally occurring HBV mutations, the application of non-invasive assessment of hepatic fibrosis and quantitation of HBV surface antigen and new drug or new strategies towards more effective therapy. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings was discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new 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, patients receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.
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Gish R, Jia JD, Locarnini S, Zoulim F. Selection of chronic hepatitis B therapy with high barrier to resistance. THE LANCET. INFECTIOUS DISEASES 2012; 12:341-53. [PMID: 22326017 DOI: 10.1016/s1473-3099(11)70314-0] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Antiviral drug resistance is a crucial factor that frequently determines the success of long-term therapy for chronic hepatitis B. The development of resistance to nucleos(t)ide analogues has been associated with exacerbations in liver disease and increased risk of emergence of multidrug resistance. The selection of a potent nucleos(t)ide analogue with a high barrier to resistance as a first-line therapy, such as entecavir or tenofovir, provides the best chance of achieving long-term treatment goals and should be used wherever possible. The barrier to resistance of a given nucleos(t)ide analogue is influenced by genetic barrier, drug potency, patient adherence, pharmacological barrier, viral fitness, mechanism of action, and cross-resistance. In countries with limited health-care resources, the selection of a therapy with a high barrier to resistance is not always possible and alternative strategies for preventing resistance might be needed, although limited data are available to support these strategies.
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Affiliation(s)
- Robert Gish
- Center for Hepatobiliary Disease and Abdominal Transplantation, UC San Diego Health System, San Diego, CA, USA
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21
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Zhu XF, Lu LX, Wang Y, Xu KW, Li DJ, Zhu X, Liu L, Liu C, Wang JR, Tang H, Wang LC. Effect and Predictive Elements for 52 Weeks' Telbivudine Treatment on Naïve HBeAg positive Chronic Hepatitis B. HEPATITIS MONTHLY 2011; 11:980-5. [PMID: 22368682 PMCID: PMC3282031 DOI: 10.5812/kowsar.1735143x.4203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Revised: 09/03/2011] [Accepted: 12/07/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND Antiviral treatment with nucleoside analogs has been used for chronic hepatitis B (CHB). Each kind of nucleoside analog has its own characteristics and suitability for patients. Telbivudine (LdT, brand name: Sebivo, Beijing Novartis Pharma Ltd) is the newest nucleoside analog, with strong and rapid viral suppression. However, its resistance rate is relatively high during long-term application, due to low genetic barriers to resistance. So, it is necessary to increase the effect and reduce resistance with effective management, according to baseline factors and early on-treatment responses. OBJECTIVES To reveal possible predictive factors of the effect of telbivudine (LdT) treatment on naïve HBeAg-positive chronic hepatitis B (CHB) patients to optimize treatment. PATIENTS AND METHODS A total 71 naïve chronic hepatitis B (CHB) patients who met the inclusion criteria were enrolled. All patients were treated with LdT 600 mg Qd for at least 52 weeks. Multiple logistic regression analyses were done to investigate the predictive values of baseline factors and responses at Week 24. RESULTS The reduction in hepatitis virus B (HBV) DNA level was 6.44 ± 2.38 lg copies/mL at Week 52 compared with baseline. The complete virus response (CVR), biochemical response (BR), serological response (SR), and drug resistance (DR) were 61.99%, 77.46%, 35.21%, and 8.45% respectively. By multiple regression analysis, baseline alanine aminotransferase (ALT) levels significantly affected CVR (P = 0.024, OR = 1.008), and baseline ALT and baseline HBV DNA levels were independent compact factors of SR (P = 0.012, OR = 1.007; P = 0.001, OR = 0.423). The differences in CVR, SR, and DR in patients with ALT > 120 Iu/mL compared with patients with ALT ≤ 120 Iu/mL were statistically significant. The differences in SR in patients with HBV DNA > 107 copies/mL compared with patients with HBV DNA ≤ 107 copies/mL were statistically significant. Additionally, CVR, BR, and SR were differed significantly between patients with HBV DNA lower than 300 copies/mL at Week 24 and patients with HBV DNA higher than 300 copies/mL (P = 0.000, P = 0.0016, and P = 0.000, respectively). CONCLUSIONS There were more responders among naïve HBeAg-positive chronic hepatitis B patients with lower HBV DNA levels (especially lower than 107 copies/mL) and higher ALT values (especially higher than 120 Iu/mL at baseline) to LdT treatment. Adjustments for treatment strategy should be considered if HBV DNA > 300 copies/mL at Week 24 is observed.
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Affiliation(s)
- Xiao-Feng Zhu
- Epidemiology Department,West China School of public Health, Sichuan University, Chengdu, China
| | - Li-Xia Lu
- Center of Infectious Diseases,West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases,State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Ying Wang
- Center of Infectious Diseases,West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases,State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Kong-wen Xu
- Center of Infectious Diseases,West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases,State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Da-jiang Li
- Center of Infectious Diseases,West China Hospital, Sichuan University, Chengdu, China
| | - Xia Zhu
- Center of Infectious Diseases,West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases,State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Li Liu
- Center of Infectious Diseases,West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases,State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Cong Liu
- Center of Infectious Diseases,West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases,State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Jin-Rong Wang
- Center of Infectious Diseases,West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases,State Key Laboratory of Biotherapy, Sichuan University, Chengdu, 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, China
| | - Li-Chun Wang
- Center of Infectious Diseases,West China Hospital, Sichuan University, Chengdu, China
- Division of Infectious Diseases,State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
- Corresponding author: Li-Chun Wang, Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan province, people’s Republic of China. Tel.: +86-2885422650, Fax: +86-2885423052, E-mail:
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Abstract
The management of hepatitis B in liver transplantation has evolved significantly over the past 2 decades. Introduction of hepatitis B immune globulin and subsequently nucleos(t)ide analogues has revolutionized transplantation for hepatitis B virus (HBV), increasing survival for patients transplanted for this indication. With the availability of new and potent antivirals for HBV, the need for liver transplant should continue to decrease in the coming years. Moreover, the newer antivirals with high resistance barriers will allow effective long-term viral prophylaxis and therefore, prevention of recurrence.
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Affiliation(s)
- Corinne Buchanan
- Center for Liver Transplantation, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Ong A, Wong VWS, Wong GLH, Chan HY, Tse CH, Chan HLY. Management options for lamivudine-resistant chronic hepatitis B patients with suboptimal virological suppression by adefovir. Aliment Pharmacol Ther 2011; 34:972-81. [PMID: 21883327 DOI: 10.1111/j.1365-2036.2011.04833.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND In chronic hepatitis B (CHB) patients, adefovir is commonly used as a rescue therapy for lamivudine resistance, but often results in incomplete virological suppression. AIM To study the factors predicting response to adefovir rescue, and the treatment response of tenofovir and entecavir in suboptimal responders to adefovir in CHB patients. METHODS Chronic hepatitis B patients who took adefovir for at least 6 months for lamivudine resistance were studied. Early virological response was defined as undetectable HBV DNA at month 6. Maintained virological response was defined as undetectable HBV DNA till the last follow-up. RESULTS Among 136 patients on adefovir for 39 (5-117) months, 30 (22%) had early virological response. The 3-year cumulative probability of maintained virological response was similar between patients on adefovir monotherapy (n = 53, 57.9%) and those on combination of lamivudine and adefovir treatment (n = 83, 56.5%). The month 6 HBV DNA was the only independent factor associated with maintained virological response (adjusted hazard ratio 0.49, 95% confidence interval 0.37-0.65, P < 0.001). Twenty-six of 30 (87%) early responders and 36 of 106 (34%) non-early responders had maintained virological response on adefovir (P < 0.001). Among 106 non-early responders, 18 and 11 were switched to tenofovir and entecavir, respectively. The 1-year cumulative probability of maintained virological response was higher in patients switched to tenofovir (87.5%) than those switched to entecavir (37.5%; P = 0.048) or continued with adefovir (8.7%; P < 0.001). CONCLUSIONS In adefovir rescue for lamivudine resistance, month 6 HBV DNA predicts maintained virological response in CHB patients. Switching to tenofovir achieved best viral suppression among suboptimal responders to adefovir.
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Affiliation(s)
- A Ong
- Institute of Digestive Disease, The Chinese University of Hong Kong; Hong Kong SAR, China
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Joukar F, Besharati S, Mirpour H, Mansour-Ghanaei F. Hepatitis C and hepatitis B seroprevalence and associated risk factors in hemodialysis patients in Guilan province, north of Iran: HCV and HBV seroprevalence in hemodialysis patients. HEPATITIS MONTHLY 2011; 11:178-181. [PMID: 22087139 PMCID: PMC3206684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/07/2010] [Revised: 10/10/2010] [Accepted: 11/22/2010] [Indexed: 11/28/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV) and hepatitis B virus (HBV) infection are especially problematic in patients with end-stage renal disease who are undergoing hemodialysis (HD). OBJECTIVES To determine the prevalence of HCV and HBV infection in HD population in Guilan, north of Iran. PATIENTS AND METHODS In a cross-sectional study, from May to September 2009, in 11 different hemodialysis units in Guilan province, North of Iran, clinical data such as age, gender, duration of dialysis, HBsAg and anti-HCV antibody of 514 HD patients were recorded. Patients with positive antibodies against HCV were tested for HCV RNA. RESULTS From 514 patients, 286 (55.64%) were male. 61 (11.9%) patients were anti-HCV-positive and 31 (50.8%) were HCV PCR-positive. There was significant relationship between HCV Ab-positivity with gender and HD duration (p < 0.05). There was significant difference between the mean HD duration in anti-HCV-positive and anti-HCV-negative patients (p < 0.05). Also, significant relationship was found between HCV RNA-positivity with gender and HD duration (p < 0.05). Seven (1.4%) patients were positive for HBsAg. Two (0.38 %) were found positive for both HBsAg and anti-HCV antibody. CONCLUSIONS There is low a prevalence of HCV and HBV in HD patients in our region. The rate can be decreased by HBV vaccination of end-stage renal disease patients before setting chronic HD, antiviral treatment and isolation of infected individuals.
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Affiliation(s)
- Farahnaz Joukar
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, IR Iran
| | - Sepiedeh Besharati
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, IR Iran
| | - Hasan Mirpour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, IR Iran
| | - Fariborz Mansour-Ghanaei
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, IR Iran
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Abstract
IMPORTANCE OF THE FIELD Successful treatment of chronic hepatitis B (CHB) often requires long-term oral nucleoside/nucleotide agents which can be associated with viral resistance, patient non-compliance and adverse effects. Telbivudine is one of the more potent options available, with a 6.5- to 6.6-log copies/ml hepatitis B DNA reduction at 12 weeks in an early viral kinetic study, a potency comparable to entecavir. It is also one of the few drugs in the treatment of CHB under FDA pregnancy Category B. AREAS COVERED IN THIS REVIEW The efficacy and safety profile of telbivudine in compensated and decompensated CHB patients compared to other agents are discussed. Viral resistance, characteristic adverse effects including elevation in creatine kinase and peripheral neuropathy in telbivudine treatment are reviewed. Infrequent but significant adverse effects of other nucleoside/nucleotide analogs are highlighted. WHAT THE READER WILL GAIN Readers are provided the latest update on the clinical profile of long-term use of telbivudine. TAKE HOME MESSAGE Long-term telbivudine treatment offers effective viral suppression to CHB patients with certain baseline characteristics and on-treatment virologic response. Creatine kinase elevation is not a good predictor of muscle-related adverse effects with nucleoside/nucleotide analogs. But significant myopathy and neuropathy have been reported in a small number of patients receiving telbivudine.
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Affiliation(s)
- David Yiu-Kuen But
- University of Hong Kong, Queen Mary Hospital, Department of Medicine, Pokfulam Road, Hong Kong SAR, China
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26
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Abstract
Telbivudine (Sebivo®; Tyzeka®) is a synthetic nucleoside analogue that inhibits replication of hepatitis B virus (HBV). It is used in the treatment of adults with chronic hepatitis B (CHB) with evidence of viral replication and persistently elevated serum ALT and/or AST levels, and/or histological evidence of active disease. Telbivudine is a potent antiviral that provides effective and sustained viral suppression in patients with compensated CHB. In clinical trials, treatment outcomes were improved significantly more with telbivudine 600 mg once daily than with lamivudine 100 mg or adefovir 10 mg once daily, and telbivudine-treated patients had significantly less viral resistance than lamivudine-treated patients. Increasing rates of hepatitis B e antigen (HBeAg) seroconversion were achieved in HBeAg-positive patients during periods of up to 4 years continuous telbivudine treatment, and seroconversion was durable in most patients throughout a 2-year, off-treatment follow-up, indicating the potential for a finite treatment period in this group of patients. Telbivudine is associated with a medium genetic barrier to resistance and, as patients with undetectable HBV DNA levels have significantly improved outcomes, it is recommended that HBV DNA levels are monitored at week 24 (and 6 monthly thereafter), with the addition of a nucleoside/nucleotide analogue without cross resistance (such as adefovir dipivoxil) if viraemia is present to reduce the risk of resistance (Roadmap concept). Telbivudine was generally well tolerated in clinical trials for periods of up to 4 years, and has a similar tolerability profile to that of lamivudine. A minority of telbivudine-treated patients experience creatinine kinase elevation, usually transient, and myopathy occurs rarely. In modelled cost effectiveness studies in several Asian countries, treatment with telbivudine Roadmap was cost effective in HBeAg-positive patients. Thus, telbivudine provides a valuable treatment option in CHB, particularly when administered using the Roadmap concept in HbeAg-positive patients.
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27
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Sung JJY, Amarapurkar D, Chan HLY, Cheng J, Kao JH, Han KH, Piratvisuth T. Treatment of chronic hepatitis B in Asia-Pacific countries: is the Asia-Pacific consensus statement being followed? Antivir Ther 2010; 15:607-16. [PMID: 20587854 DOI: 10.3851/imp1561] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND The Asia-Pacific consensus guidelines for the management of chronic hepatitis B state that the principal indicators for starting therapy are increased HBV DNA levels (> or =20,000 IU/ml for hepatitis B e antigen [HBeAg]-positive status and >2,000 IU/ml for HBeAg-negative status) and alanine aminotransferase (ALT) levels >2x the upper limit of normal. We aimed to determine whether clinicians in the Asia-Pacific region are treating patients with chronic hepatitis B according to the Asia-Pacific consensus statement on the management of chronic hepatitis B. METHODS An online survey of chronic hepatitis B treatment practices was prepared, consisting of 14 questions grouped into seven categories: patient statistics, treatment statistics, treatment decision, first-choice treatment, treatment duration, future directions and patient preference. RESULTS In total, 124 respondents from 12 countries completed the survey. Most respondents indicated that detectable HBV DNA was either the first or second most important factor when deciding whether to initiate therapy. Many physicians were unsure about initiation of treatment in patients >40 years of age when ALT levels were within the normal range. Oral antiviral drugs were the most frequently used medication because of their effectiveness, safety and ability to provide sustained viral suppression. Conversely, the most important reasons for selecting interferon therapy were effectiveness, fixed duration of treatment and lack of drug resistance. Criteria for stopping treatment generally followed the recommendations included in the guidelines. CONCLUSIONS These data suggest that clinicians from the Asia-Pacific region use criteria beyond those advocated in treatment guidelines when deciding whether to initiate treatment in HBV-infected patients.
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Affiliation(s)
- Joseph J Y Sung
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
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Marcellin P, Sung J, Piratvisuth T. Avoiding and managing lamivudine resistance in chronic hepatitis B: current approaches and potential strategies including pegylated interferon. Liver Int 2010; 30:657-68. [PMID: 20158610 DOI: 10.1111/j.1478-3231.2010.02207.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
Since its approval for the treatment of chronic hepatitis B in 1998, lamivudine (LAM) has been used extensively throughout the world, because of its relatively low costs and favourable tolerability. However, clinical trials and cohort studies have demonstrated that a high rate of resistance to this drug develops and, as a result, it is no longer included as a first-line therapy in most current treatment guidelines. Nevertheless, because of its low cost, this drug continues to be used in many countries and the pool of patients who have developed resistance to LAM continues to increase. Thus, there is a clear need to develop coherent management strategies to treat such patients as well as limit the emergence of resistance in the first instance. The purpose of this review is to highlight the need to aim for long-term treatment success while limiting the emergence of drug resistance and its consequences for the future. In addition to add-on/switch strategies with other nucleos(t)ide analogs, currently available data suggest that interferon-based therapies, with their potential to induce a sustained response, are worthy of consideration not only for reducing de novo resistance but as an option for the management of those patients in whom drug resistance has already developed.
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Affiliation(s)
- Patrick Marcellin
- Service d'Hépatologie, INSERM-CRB3, Hôpital Beaujon, APHP University of Paris 7, Clichy, France.
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Lu HY, Zhuang LW, Yu YY, Si CW. Virological response to antiviral therapy at week 12 indicates a great reduction of intrahepatic hepatitis B virus DNA and cccDNA in HBeAg-positive chronic hepatitis B patients. J Viral Hepat 2010; 17 Suppl 1:59-65. [PMID: 20586935 DOI: 10.1111/j.1365-2893.2010.01272.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Early virological response is considered to be a predictor for the outcome of anti-hepatitis B virus (HBV) therapy. To analyze its correlation to intrahepatic HBV DNA and covalently closed circular DNA (ccc)DNA, 71 hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B patients were recruited: 34 patients were treated with lamivudine; 13 with interferon-alpha2b; and 24 with sequential therapy of lamivudine-interferon-alpha2b for 48 weeks. Intrahepatic HBV DNA and cccDNA load were measured at the baseline and at Week 48. Fifty-seven patients had virological response at Week 12. Median decreases of serum HBV DNA in patients with or without virological response at Week 12 were 4.0 log(10) (max. 6.2, min. 2.2) and 1.1 log(10) (max. 2.1, min. 0) (Z = -5.766, P = 0.0000), respectively. At Week 48 they were 4.1 log(10) (max. 7.4, min. 1.0) and 2.3 log(10) (max. 7.5, min. 0.3) (Z = -2.760, P = 0.006), respectively. For intrahepatic HBV DNA load they were 1.3 log(10) (max. 4.3, min. -1.2) and 0.6 log(10) (max. 3.5, min. -0.8), respectively, and for HBV cccDNA load they were 1.1 log(10) (max. 4.8, min. -0.5) and 0.5 log(10) (max. 3.0, min. -0.8) (Z = -2.097, P = 0.036), respectively at Week 48. Step-wise logistic regression analysis indicated that the baseline intrahepatic HBV DNA load effected virological response at Week 12 [odds ratio (OR) 0.405; 95% confidence interval (CI) 0.174-0.944; P = 0.036] and HBeAg seroconversion at Week 48 (OR 0.292; 95% CI 0.131-0.649; P = 0.003). In conclusion, virological response at Week 12 indicated a great reduction of intrahepatic DNA and cccDNA load in HBeAg-positive CHB patients. The baseline intrahepatic HBV DNA load affected virological response at Week 12 and HBeAg seroconversion at Week 48.
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Affiliation(s)
- H Y Lu
- Department of Infectious Disease, Peking University First Hospital, Beijing, China
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Hann HW, Gregory VL, Dixon JS, Barker KF. A review of the one-year incidence of resistance to lamivudine in the treatment of chronic hepatitis B : Lamivudine resistance. Hepatol Int 2008; 2:440-456. [PMID: 19669319 PMCID: PMC2716910 DOI: 10.1007/s12072-008-9105-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2008] [Accepted: 09/14/2008] [Indexed: 02/06/2023]
Abstract
PURPOSE The development of antiviral resistance is a recognized challenge to successful treatment of chronic hepatitis B (CHB), but it has been difficult to establish an accurate estimate of its incidence due to a number of factors: (a) lack of an accepted definition of antiviral resistance; (b) lack of a standardized assay to assess resistance; and (c) lack of consensus on patient selection criteria for resistance testing. Lamivudine, an effective and well-established antiviral agent, has been reported to show one-year resistance rates in CHB ranging from 6% to 32%, but methodologies used to calculate these rates vary considerably. This article reviews the clinical, statistical, and laboratory methodologies of clinical studies reporting one-year rates of antiviral resistance to lamivudine in CHB. METHODS Studies reporting one-year resistance rates to lamivudine in CHB were analyzed for methodologic differences and their influence on reported resistance rates. RESULTS Studies using only a genotypic definition of resistance reported one-year rates ranging from 14% to 32%. Studies assessing genotypic resistance in patients with evidence of virologic breakthrough reported much lower one-year resistance rates of 6.4-15.4%. CONCLUSIONS It is important when comparing resistance rates to antiviral drugs in CHB to consider the methodology and definition of resistance used because this can dramatically influence the results.
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Affiliation(s)
- Hie-Won Hann
- Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College, 1025 Walnut Street, Philadelphia, PA 19107 USA
| | | | - Jonathan S. Dixon
- GlaxoSmithKline, 980 Great West Road, Brentford, Middlesex, TW8 9GS UK
| | - Keith F. Barker
- GlaxoSmithKline, 980 Great West Road, Brentford, Middlesex, TW8 9GS UK
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31
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A review of the one-year incidence of resistance to lamivudine in the treatment of chronic hepatitis B : Lamivudine resistance. Hepatol Int 2008. [PMID: 19669319 DOI: 10.1007/s12072-008-9105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE The development of antiviral resistance is a recognized challenge to successful treatment of chronic hepatitis B (CHB), but it has been difficult to establish an accurate estimate of its incidence due to a number of factors: (a) lack of an accepted definition of antiviral resistance; (b) lack of a standardized assay to assess resistance; and (c) lack of consensus on patient selection criteria for resistance testing. Lamivudine, an effective and well-established antiviral agent, has been reported to show one-year resistance rates in CHB ranging from 6% to 32%, but methodologies used to calculate these rates vary considerably. This article reviews the clinical, statistical, and laboratory methodologies of clinical studies reporting one-year rates of antiviral resistance to lamivudine in CHB. METHODS Studies reporting one-year resistance rates to lamivudine in CHB were analyzed for methodologic differences and their influence on reported resistance rates. RESULTS Studies using only a genotypic definition of resistance reported one-year rates ranging from 14% to 32%. Studies assessing genotypic resistance in patients with evidence of virologic breakthrough reported much lower one-year resistance rates of 6.4-15.4%. CONCLUSIONS It is important when comparing resistance rates to antiviral drugs in CHB to consider the methodology and definition of resistance used because this can dramatically influence the results.
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32
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Abstract
Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon alpha2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, 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, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included.
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Liaw YF, Leung N, Kao JH, Piratvisuth T, Gane E, Han KH, Guan R, Lau GKK, Locarnini S. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2008; 2:263-83. [PMID: 19669255 PMCID: PMC2716890 DOI: 10.1007/s12072-008-9080-3] [Citation(s) in RCA: 743] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2008] [Accepted: 04/09/2008] [Indexed: 12/13/2022]
Abstract
Large amounts of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2005. These include long-term follow-up studies in large community-based cohorts or asymptomatic subjects with chronic HBV infection, further studies on the role of HBV genotype/naturally occurring HBV mutations, treatment of drug resistance and new therapies. In addition, Pegylated interferon alpha2a, entecavir and telbivudine have been approved globally. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings were discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, special indications for liver biopsy in patients with persistently normal alanine aminotransferase, 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, patients receiving immune-suppressive medications or chemotherapy and patients in the setting of liver transplantation, are also included.
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Affiliation(s)
- Yun-Fan Liaw
- Liver Research Unit, Chang Gung University and Memorial Hospital, 199, Tung Hwa North Road, Taipei, Taiwan,
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