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1
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Block PD, Lim JK. Chronic Hepatitis B Virus: What an Internist Needs to Know. Med Clin North Am 2023; 107:435-447. [PMID: 37001946 DOI: 10.1016/j.mcna.2022.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is a bloodborne infection which affects approximately 1.6 million persons in the U.S. and 292 million persons worldwide and is associated with significant morbidity and mortality due to cirrhosis and hepatocellular carcinoma. HBV disproportionately affects foreign-persons from endemic regions such as sub-Saharan Africa and the Asian-Pacific region. Chronic HBV is diagnosed with positive HBsAg and detectable HBV DNA. Patients with immunoactive disease (elevated HBV DNA and serum ALT) may require antiviral therapy with peg-interferon or oral nucleos(t)ide analogues which suppress viral replication, and are associated with a decreased risk for liver events.
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Affiliation(s)
- Peter D Block
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
| | - Joseph K Lim
- Section of Digestive Diseases and Yale Liver Center, Yale School of Medicine, 333 Cedar Street, LMP 1080, New Haven, CT 06520, USA.
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2
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HBsAg Loss as a Treatment Endpoint for Chronic HBV Infection: HBV Cure. Viruses 2022; 14:v14040657. [PMID: 35458387 PMCID: PMC9029793 DOI: 10.3390/v14040657] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/01/2022] [Accepted: 03/10/2022] [Indexed: 02/07/2023] Open
Abstract
Despite the availability of effective vaccines and antiviral therapy over the past two to three decades, chronic hepatitis B virus (HBV) infection remains a major global health threat as a leading cause of cirrhosis and liver cancer. Functional HBV cure defined as hepatitis B surface antigen (HBsAg) loss and undetectable serum HBV DNA is associated with improved clinical outcomes in patients with chronic HBV infection. However, spontaneous loss of HBsAg is rare and occurs in only 1% of all HBsAg-positive individuals annually. Furthermore, the rate of functional cure with currently available antiviral therapy is even lower, <1% patients on treatment per year. Nonetheless, HBsAg loss has become the new target or therapeutic endpoint for antiviral treatment. Recently, there has been much excitement surrounding the development of novel antiviral agents such as small interfering RNA (siRNA), core assembly modulators (CAMs), nucleic acid polymers (NAPs) among others, which may be used in combination with nucleos(t)ide analogs and possibly immunomodulatory therapies to achieve functional cure in a significant proportion of patients with chronic hepatitis B. Novel assays with improved sensitivity for detection of very low levels of HBsAg and to determine the source of HBsAg production will also be required to measure efficacy of newer antiviral treatments for HBV cure. In this narrative review, we will define HBV cure, discuss various sources of HBsAg production, evaluate rates of HBsAg loss with current and future antiviral agents, review clinical factors associated with spontaneous HBsAg loss, and explore clinical implications of functional cure.
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Immunopathogenesis of Acute Flare of Chronic Hepatitis B: With Emphasis on the Role of Cytokines and Chemokines. Int J Mol Sci 2022; 23:ijms23031407. [PMID: 35163330 PMCID: PMC8835919 DOI: 10.3390/ijms23031407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/22/2022] [Accepted: 01/25/2022] [Indexed: 11/17/2022] Open
Abstract
Acute flares (AFs) of chronic hepatitis B usually occur during the immune-active stage (both immune clearance phase and immune reactivation phase), as the host immune system tries to control the virus. Successful host immune control over viral replication is usually presented as hepatitis B surface antigen seroclearance; however, 20–30% individuals with chronic hepatitis B may encounter repeated AFs with accumulative liver injuries, finally leading to the development of cirrhosis and hepatocellular carcinoma. AF can also develop in other clinical situations such as organ transplantation, cancer chemotherapy, and under treatment for chronic hepatitis B or treatment for chronic hepatitis C in patients with co-infected hepatitis B/hepatitis C. Understanding the natural history and immunopathogenesis of AF would help develop effective strategies to eradicate the virus and improve the clinical outcomes of patients with chronic hepatitis B. In this review article, the immunopathogenesis of AF, and the involvement of innate and adaptive immune responses on the development of hepatitis B flare will be briefly reviewed, with the emphasis on the role of cytokines and chemokines.
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Jeng W. The unsolved issues in oral antiviral therapy in HBeAg positive chronic hepatitis B patients. ADVANCES IN DIGESTIVE MEDICINE 2021. [DOI: 10.1002/aid2.13276] [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: 11/07/2022]
Affiliation(s)
- Wen‐Juei Jeng
- College of Medicine Chang Gung University Taipei Taiwan
- Department of Gastroenterology and Hepatology Chang Gung Memorial Hospital, Linkou branch Taoyuan Taiwan
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5
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Wen S, Tsai C, Cheng L, Huang C, Kuo W. Predictors of HBeAg loss after nucleos(t)ide analogues treatment for chronic hepatitis B: A preliminary finding. ADVANCES IN DIGESTIVE MEDICINE 2020. [DOI: 10.1002/aid2.13190] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Shi‐Chi Wen
- Division of Gastroenterology, Department of Internal Medicine Pao‐Chien Hospital Pingtung Taiwan
| | - Chi‐Chang Tsai
- Division of Gastroenterology, Department of Internal Medicine Kaohsiung Armed Forces General Hospital Kaohsiung Taiwan
| | - Lung‐Chih Cheng
- Division of Gastroenterology, Department of Internal Medicine Pao‐Chien Hospital Pingtung Taiwan
| | - Chien‐Wei Huang
- Division of Gastroenterology, Department of Internal Medicine Kaohsiung Armed Forces General Hospital Kaohsiung Taiwan
| | - Wu‐Hsien Kuo
- Division of Gastroenterology, Department of Internal Medicine Yuan‐Sheng Hospital Changhua Taiwan
- Division of Gastroenterology, Department of Internal Medicine National Defense Medical Center Taipei Taiwan
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Wang CH, Chang KK, Lin RC, Kuo MJ, Yang CC, Tseng YT. Consolidation period of 18 months no better at promoting off-treatment durability in HBeAg-positive chronic hepatitis B patients with tenofovir disoproxil fumarate treatment than a 12-month period: A prospective randomized cohort study. Medicine (Baltimore) 2020; 99:e19907. [PMID: 32358357 PMCID: PMC7440314 DOI: 10.1097/md.0000000000019907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
There has been no clear consensus on the optimal consolidation periods following HBeAg seroconversion (SC) in HBeAg-positive chronic hepatitis B (CHB) patients. Our study aimed to prospectively compare relapse rates between 12 months' and 18 months' consolidation periods to see whether or not there is beneficial durability of tenofovir disoproxil fumarate (TDF) therapy with longer consolidation periods.We enrolled a total of 137 HBeAg-positive Asian CHB patients treated with TDF monotherapy. Forty-six patients achieved HBeAg SC. Then, they were randomly assigned to consolidation period of either 12 months (group A) or 18 months (group B). After stopping TDF therapy, all patients were followed up for 12 months.Thirteen patients (56.5%) relapsed in group A and 12 patients (52.2%) relapsed in group B after 12 months' follow-up (P = .958). Pretreatment HBsAg level is the only significant predictor for off-therapy recurrence by univariate analysis (P = .024). Baseline HBeAg >1000 S/CO in group B patients were significantly less likely to relapse than those of group A (P = .046). Baseline alanine aminotransferase (ALT) >133 U/L could significantly predict occurrence of HBeAg SC (P = .008; 95% CI: 0.545-0.763; AUC: 0.654).Overall, a prolonged consolidation period has no positive effect on TDF therapy on sustained viral suppression in HBeAg-positive Asian CHB patients. However, a prolonged consolidation period was beneficial to patients with high baseline semi-quantitative HBeAg levels in terms of off-treatment durability. Baseline ALT > 133 U/L could significantly predict the occurrence of HBeAg SC.
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Affiliation(s)
- Chun-Hsiang Wang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Kuo-Kuan Chang
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Ruey-Chang Lin
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Ming-Jeng Kuo
- Department of Hepatogastroenterology, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan
| | - Chi-Chieh Yang
- Department of Hepatogastroenterology, Show Chwan Memorial Hospital, Changhua
| | - Yuan-Tsung Tseng
- Committee of Medical Research, Tainan Municipal Hospital (Managed by Show Chwan Medical Care Corporation), Tainan, Taiwan
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Su CW, Wu CY, Lin JT, Ho HJ, Wu JC. Nucleos(t)ide analogue continuous therapy associated with reduced adverse outcomes of chronic hepatitis B. J Chin Med Assoc 2020; 83:125-133. [PMID: 32015266 DOI: 10.1097/jcma.0000000000000247] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Nucleos(t)ide analogue (NA) therapy reduces the risk of disease progression in chronic hepatitis B virus-infected patients. However, the risk of liver decompensation, hepatic failure, and mortality after discontinuation of NA therapy remains unknown. METHODS Among 51,574 chronic hepatitis B patients who received NAs in the Taiwan National Health Insurance Research Database, we identified 8,631 patients who continued NA therapy (treatment cohort) and 8,631 propensity-score matched patients who stopped NA therapy after their initial 1.5 years treatment (off-therapy cohort) between October 1, 2003 and December 31, 2011. All study subjects were followed up from the index date, that is, the date 1.5 years after the first prescription of NA, until development of liver decompensation and hepatic failure, death or end of 18-month follow-up period. RESULTS Treatment cohort had significantly lower risks of liver decompensation (1.05%; 95% confidence interval [CI], 0.81%-1.30% vs 2.13%; 95% CI, 1.82%-2.45%; p < 0.001), hepatic failure (0.35%; 95% CI, 0.21%-0.49% vs 0.63%; 95% CI, 0.46%-0.80%; p = 0.008) and overall mortality (1.67%; 1.37%-1.98% vs 2.44%; 95% CI, 2.10%-2.77%; p < 0.001) during the 18-month follow-up period. After adjusting for potential confounders, NA continuous therapy was associated with reduced risks of liver decompensation (hazard ratio [HR]: 0.47; 95% CI, 0.36-0.62, p < 0.001), hepatic failure (HR: 0.53; 95% CI, 0.33-0.86, p = 0.01) and overall mortality (HR: 0.67; 95% CI, 0.53-0.84, p = 0.001). The number needed to reduce one less disease progression and mortality was 47. The protective effect of NA continuous therapy was found in nearly all subgroups. CONCLUSION NA continuous therapy is associated with reduced risks of liver decompensation, hepatic failure, and overall mortality.
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Affiliation(s)
- Chien-Wei Su
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Chun-Ying Wu
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Public Health and Graduate Institute of Clinical Medical Sciences, China Medical University, Taichung, Taiwan, ROC
- National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan, ROC
- Department of Life Sciences and RongHsing Research Center for Translational Medicine, National Chung-Hsing University, Taichung, Taiwan, ROC
| | - Jaw-Town Lin
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan, ROC
- Institute of Population Health Sciences, National Health Research Institutes, Miaoli, Taiwan, ROC
| | - Hsiu J Ho
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Jaw-Ching Wu
- Division of Translational Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
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Chu CM, Liaw YF. Letter to the Editor: Age at Hepatitis B e Antigen Seroconversion and Other Factors for Outcomes of Chronic Hepatitis B. Hepatology 2019; 69:2711. [PMID: 30014494 DOI: 10.1002/hep.30179] [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: 12/07/2022]
Affiliation(s)
- Chia-Ming Chu
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Analysis of hepatitis B virus-mixed genotype infection by ultra deep pyrosequencing in Sudanese patients, 2015-2016. Infection 2019; 47:793-803. [PMID: 30963405 DOI: 10.1007/s15010-019-01306-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 04/03/2019] [Indexed: 12/15/2022]
Abstract
PURPOSE The frequency of detection of HBV co-infection with multiple HBV genotypes is influenced by the detection method; usually co-infections are detected by multiplex PCR or hybridization assays, and are rarely confirmed by sequencing and conventional cloning. The objective of this study was to confirm by ultra-deep pyrosequencing (UDPS) mixed HBV infections, previously detected by multiplex-nested PCR. METHODS Sixteen samples from HBV co-infected Sudanese patients detected by multiplex-nested PCR, were amplified targeting the P/S region and sequenced by UDPS. RESULTS The only genotypes identified using UDPS were D and E, while A, B, C and F genotypes, previously detected by multiplex-nested PCR, were not detected. Specifically, 10 samples were shown to be mono-infected (D or E); in 3 out of 10 mono-infected D patients, a subtype combination was observed: D1 + D7 in 2 cases and D2 + D6 in 1 case. The remaining 6 subjects were D + E co-infected (harboring different mixtures of D subtypes). CONCLUSIONS Overall, UDPS is more effective than multiplex-nested PCR for identifying multiple HBV genotypes and subtypes infections.
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10
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Genotype Matters in Patients with Acute-on-chronic Liver Failure Due to Reactivation of Chronic Hepatitis B. Clin Transl Gastroenterol 2018; 9:202. [PMID: 30416197 PMCID: PMC6230554 DOI: 10.1038/s41424-018-0071-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 08/20/2018] [Accepted: 10/09/2018] [Indexed: 12/30/2022] Open
Abstract
Background Acute-on-chronic liver failure (ACLF) can be caused by reactivation of chronic hepatitis B virus (HBV) infection (HBV-ACLF). It’s unclear whether HBV genotypes affect the clinical and therapeutical outcomes of patients with HBV-ACLF. This study was to investigate the short-term antiviral response and overall survival in HBV-ACLF patients treated by tenofovir or entecavir. Methods Seventy-three consecutive patients with HBV-ACLF were stratified into genotype B group (n = 33) and C group (n = 40). They were prospectively followed-up. Results At 2 weeks, the genotype B group had significantly lower HBV-DNA load (P = 0.005), greater HBV-DNA decline (P = 0.026), higher proportion of patients with HBV-DNA < 500 IU/ml (P = 0.007), improved Child-Turcotte-Pugh (CTP; P = 0.032) and model for end-stage liver disease (MELD; P = 0.039) scores compared to the genotype C group. At three months, survivors in both groups had undetectable HBV-DNA loads, comparable CTP (P = 0.850) and MELD (P = 0.861) scores; the genotype C group had markedly lower overall survival rate than the B group (P = 0.013). The genotype (hazard ratio [HR]: 2.138; 95% confidence interval [CI]: 1.034–4.143; P = 0.041), MELD score (HR:1.664, 95%CI: 1.077–2.571; P = 0.022) and HBV-DNA decline (HR: 0.225, 95% CI: 0.067–0.758; P = 0.016) at 2 weeks were significantly associated with mortality at 3 months. No severe adverse event was noted. Conclusions Genotype B was associated with better short-term antiviral response and clinical outcome compared to genotype C in patients with HBV-ACLF.
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Datta S, Dasgupta D, Ghosh A, Ghosh S, Manna A, Datta S, Chatterjee M, Chowdhury A, Banerjee S. Oncogenic potential of hepatitis B virus subgenotype D1 surpasses D3: significance in the development of hepatocellular carcinoma. Carcinogenesis 2018; 39:283-292. [PMID: 29228221 DOI: 10.1093/carcin/bgx145] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 12/06/2017] [Indexed: 12/15/2022] Open
Abstract
Despite widespread distribution of hepatitis B virus (HBV)-genotype D, the clinical implications of its ten subgenotypes (D1-D10) have not been well documented. Here, we have investigated the impact of two major circulating HBV/D subgenotypes, D1 and D3 in Eastern India towards pathogenesis of liver disease progression to hepatocellular carcinoma (HCC). HBV subgenotypes were determined using full-length genome sequences of HBV isolates from patients with chronic hepatitis B (CHB), liver cirrhosis (LC) and HCC. Impact of D1 and D3 on viral lifecycle and disease progression was assessed by several in vitro assays. Phylogenetic tree analysis revealed that HBV/D1 and HBV/D3 were the two predominating HBV subgenotypes circulating in Eastern India. Interestingly, the frequency of patients infected with HBV/D1 was noticed progressively rising from CHB to HCC through LC while the increasing frequency of HBV/D3 declined suddenly in HCC implicating HBV/D1 might have greater oncogenic potential than HBV/D3. Similar to higher viral load noted in HCC patients infected with HBV/D1 than HBV/D3, the larger amount of intracellular/extracellular viral DNA and secreted HBsAg levels in transfected cell lines also implicated that HBV/D1 might replicate faster than HBV/D3. Again, higher expression of marker genes related to endoplasmic reticulum stress, epithelial-mesenchymal transition, DNA double strand breaks, angiogenesis etc. and faster rate of cellular migration and anchorage independent growth cumulatively suggested that compared to HBV/D3, HBV/D1 generates more liver injuries which eventually culminates into HCC. Therefore, our results highlight the importance of determination of subgenotypes of HBV in CHB patients, so that high-risk individual can be monitor periodically that may help to detect HCC at early stages.
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Affiliation(s)
- Somenath Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Debanjali Dasgupta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Alip Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Suchandrima Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Alak Manna
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata,, India
| | - Simanti Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Mitali Chatterjee
- Department of Pharmacology, Institute of Post Graduate Medical Education and Research, Kolkata,, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
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Rajoriya N, Combet C, Zoulim F, Janssen HLA. How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach? J Hepatol 2017; 67:1281-1297. [PMID: 28736138 DOI: 10.1016/j.jhep.2017.07.011] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 06/27/2017] [Accepted: 07/12/2017] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B virus (HBV) infection remains a global problem. Several HBV genotypes exist with different biology and geographical prevalence. Whilst the future aim of HBV treatment remains viral eradication, current treatment strategies aim to suppress the virus and prevent the progression of liver disease. Current strategies also involve identification of patients for treatment, namely those at risk of progressive liver disease. Identification of HBV genotype, HBV mutants and other predictive factors allow for tailoured treatments, and risk-surveillance pathways, such as hepatocellular cancer screening. In the future, these factors may enable stratification not only of treatment decisions, but also of patients at risk of higher relapse rates when current therapies are discontinued. Newer technologies, such as next-generation sequencing, to assess drug-resistant or immune escape variants and quasi-species heterogeneity in patients, may allow for more information-based treatment decisions between the clinician and the patient. This article serves to discuss how HBV genotypes and genetic variants impact not only upon the disease course and outcomes, but also current treatment strategies. Adopting a personalised genotypic approach may play a role in future strategies to combat the disease. Herein, we discuss new technologies that may allow more informed decision-making for response guided therapy in the battle against HBV.
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Affiliation(s)
- Neil Rajoriya
- Toronto Centre for Liver Diseases, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada
| | - Christophe Combet
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon 69XXX, France
| | - Fabien Zoulim
- Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon 69XXX, France; Department of Hepatology, Groupement Hospitalier Nord, Hospices Civils de Lyon, Lyon, France
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario M5G 2C4, Canada.
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Hsieh AR, Fann CSJ, Yeh CT, Lin HC, Wan SY, Chen YC, Hsu CL, Tai J, Lin SM, Tai DI. Effects of sex and generation on hepatitis B viral load in families with hepatocellular carcinoma. World J Gastroenterol 2017; 23:876-884. [PMID: 28223732 PMCID: PMC5296204 DOI: 10.3748/wjg.v23.i5.876] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Revised: 12/15/2016] [Accepted: 01/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To explore factors associated with persistent hepatitis B virus (HBV) infection in a cohort of hepatocellular carcinoma (HCC)-affected families and then investigate factors that correlate with individual viral load among hepatitis B surface antigen (HBsAg)-positive relatives.
METHODS We evaluated non-genetic factors associated with HBV replication in relatives of patients with HCC. Relatives of 355 HCC cases were interviewed using a structured questionnaire. Demographics, relationship to index case, HBsAg status of mothers and index cases were evaluated for association with the HBV persistent infection or viral load by generalized estimating equation analysis.
RESULTS Among 729 relatives enrolled, parent generation (P = 0.0076), index generation (P = 0.0044), mothers positive for HBsAg (P = 0.0007), and HBsAg-positive index cases (P = 5.98 × 10-8) were associated with persistent HBV infection. Factors associated with HBV viral load were evaluated among 303 HBsAg-positive relatives. Parent generation (P = 0.0359) and sex (P = 0.0007) were independent factors associated with HBV viral load. The intra-family HBV viral load was evaluated in families clustered with HBsAg-positive siblings. An intra-family trend of similar HBV viral load was found for 27 of 46 (58.7%) families. Male offspring of HBsAg-positive mothers (P = 0.024) and older siblings were associated with high viral load.
CONCLUSION Sex and generation play important roles on HBV viral load. Maternal birth age and nutritional changes could be the reasons of viral load difference between generations.
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Jun BG, Lee SH, Kim HS, Kim SG, Kim YS, Kim BS, Jeong SW, Jang JY, Kim YD, Cheon GJ. Predictive Factors for Sustained Remission after Discontinuation of Antiviral Therapy in Patients with HBeAg-positive Chronic Hepatitis B. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2017; 67:28-34. [PMID: 26809629 DOI: 10.4166/kjg.2016.67.1.28] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND/AIMS The optimal timing for discontinuing oral antiviral therapy in patients with HBeAg-positive chronic hepatitis B (CHB) is unclear. The aim of our study was to investigate sustained remission after stopping antiviral therapy in patients with HBeAg-positive CHB. METHODS We analyzed the medical records of 58 patients who were HBeAg-positive and had discontinued antiviral therapy. Antiviral therapy was discontinued after HBeAg seroconversion and HBV DNA negativity for 6-12 months with consolidation therapy. Virologic relapse was defined as an increase in serum HBV DNA >2,000 IU/mL. RESULTS No difference was observed between the virologic non-relapse and virologic relapse groups in baseline HBV DNA level (p=0.441) or duration of seroconversion (p=0.070). Time-to-undetectable HBV DNA during treatment was shorter in the virologic non-relapse group (29 patients) compared to the relapse group (29 patients) (4.9±2.6 vs. 13.2±12.7 months; p<0.01). Cumulative relapse rates were 12.7 in month 3, 32.7 in month 6, 47.3 in month 12, and 52.7% in month 18. We determined by multivariate analysis that the consolidation period (≥18 months, p=0.020) and early virologic response (HBV DNA <20 IU/mL) at six months during antiviral therapy (p=0.017) were significant predictors for sustained remission. CONCLUSIONS A consolidation period of at least 18 months and early virological response at six months during antiviral therapy were associated with sustained remission in patients with HBeAg-positive CHB after treatment.
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Affiliation(s)
- Baek Gyu Jun
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sang Gyune Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young Seok Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Boo Sung Kim
- Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Soung Won Jeong
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Young Don Kim
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
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On-treatment and off-treatment efficacy of entecavir in a real-life cohort of chronic hepatitis B patients. Eur J Gastroenterol Hepatol 2016; 28:1179-87. [PMID: 27428552 DOI: 10.1097/meg.0000000000000691] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Entecavir (ETV) is a potent nucleoside analogue with high genetic barrier to resistance. In this study, real-life clinical experiences in the long-term use of ETV and the durability of its off-treatment effectiveness were analyzed. MATERIALS AND METHODS This study was based on a large real-life cohort of 2240 chronic hepatitis B patients treated with ETV between January 2006 and December 2012 using a centralized electronic data repository. RESULTS Among 2240 patients, 804 patients were treatment naive and underwent ETV monotherapy. Their mean treatment duration was 712±493 days, with a cumulative proportion of patients achieving HBV DNA less than 300 copies/ml in 85.8, 95.7, and 97.6% at years 1, 2, and 3, respectively. Predictors for earlier virologic response were female sex, lower HBV DNA, higher alanine transaminase, lower platelet count, and HBeAg negativity at baseline. In patients who achieved virologic response and HBeAg loss, the cumulative relapse rate was 91.3% in 2 years after the cessation of treatment. During the treatment, 34 patients developed hepatocellular carcinoma, among whom 30 patients had cirrhosis before treatment initiation. ETV treatment showed efficient virologic response as the treatment duration was extended, but off-treatment efficacy was not durable, and the antiviral treatment showed some limitation in preventing hepatocellular carcinoma among liver cirrhosis patients, implying that treatment cessation should be taken into consideration more carefully. CONCLUSION This study from a real-life cohort may provide data on treating chronic hepatitis B patients more close to everyday clinical practice.
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16
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Man Cho S, Choe BH. Treatment strategies according to genotype for chronic hepatitis B in children. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:336. [PMID: 27761440 DOI: 10.21037/atm.2016.09.06] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
This review article was requested by editor-in-chief of this journal as 'pediatric CHB treatment' for the upcoming special issue. The main objective of chronic hepatitis B (CHB) treatment is diminishing the risk of complications related to chronic liver disease. In Asia, there are already some reports about hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) infected children. The key points of treatment in children with CHB infections are selection of which patients to treat and conformation of the optimal therapy time that would reduce viral resistance. The choice of therapy is determined by the district (Western/Eastern), HBV genotype, medical accessibility, and economic state of the country. Newly developed nucleos(t)ide analogues (NAs) are potent in children with CHB. However, to improve therapeutic efficacy, physicians are recommended to follow treatment guidelines and determine the specific genotype in the CHB patient. In this article, the treatment of pediatric CHB is reviewed according to differences in genotype.
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Affiliation(s)
- Seung Man Cho
- Department of Pediatrics, Dongguk University School of Medicine, Gyeongju, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, Kyungpook National University School of Medicine, Daegu, Korea
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Nagata N, Kagawa T, Hirose S, Arase Y, Tsuruya K, Anzai K, Shiraishi K, Mine T. Off-treatment durability of antiviral response to nucleoside analogues in patients with chronic hepatitis B. BMC Gastroenterol 2016; 16:38. [PMID: 26987437 PMCID: PMC4794926 DOI: 10.1186/s12876-016-0454-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2015] [Accepted: 03/09/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Off-treatment durability of nucleoside analogue (NA) therapy in patients with chronic hepatitis B has not been well investigated. In this study we monitored antiviral effect of NA therapy and evaluated off-treatment durability after NA cessation in patients with chronic hepatitis B. PATIENTS AND METHODS A total of 94 consecutive patients (39 HBeAg-negative and 55 HBeAg-positive patients) who received NA therapy were followed up for approximately 9 years. We discontinued NA according to the following criteria; undetectable serum HBV-DNA by polymerase chain reaction (PCR) on three separate occasions at least 6 months apart in HBeAg-negative patients (APASL stopping recommendation), and seroconversion from HBeAg-positive to HBeAb-positive and undetectable serum HBV-DNA by PCR for at least 12 months in HBeAg-positive patients. RESULTS The cumulative rate of relapse after NA cessation was 48 % and 40 % in HBeAg-negative and -positive patients, respectively. Higher baseline serum alanine aminotransferase level was the only significant predictor for maintaining remission. No patients experienced decompensation after relapse. HBsAg loss occurred at an annual rate of 1.4 % and 0.4 % in HBeAg-negative and -positive patients, respectively. Hepatocellular carcinoma developed at an annual rate of 0.6 % in both HBeAg-negative and -positive patients. CONCLUSIONS Almost half of the patients did not relapse after cessation of NA therapy in both HBeAg-negative and -positive patients. Therefore, NA therapy could be discontinued with close monitoring if the APASL stopping recommendation is satisfied even in HBeAg-negative patients.
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Affiliation(s)
- Naruhiko Nagata
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, 259-1193, Japan
| | - Tatehiro Kagawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, 259-1193, Japan.
| | - Shunji Hirose
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, 259-1193, Japan
| | - Yoshitaka Arase
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, 259-1193, Japan
| | - Kota Tsuruya
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, 259-1193, Japan
| | - Kazuya Anzai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, 259-1193, Japan
| | - Koichi Shiraishi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, 259-1193, Japan
| | - Tetsuya Mine
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Shimokasuya 143, Isehara, 259-1193, Japan
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18
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Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63:261-83. [PMID: 26566064 PMCID: PMC5987259 DOI: 10.1002/hep.28156] [Citation(s) in RCA: 1555] [Impact Index Per Article: 172.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 08/25/2015] [Indexed: 12/11/2022]
Affiliation(s)
| | | | - Kyong-Mi Chang
- Corporal Michael J. Crescenz VA Medical Center & University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | - Jessica P Hwang
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Maureen M Jonas
- Boston Children's Hospital, Harvard Medical School, Boston, MA
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Lu J, Li J, Liu Y, Ren S, Cao Z, Jin Y, Ma L, Shen C, Chen X. Study on Post-Treatment Relapse in HBeAg Positive CHB Patients. PLoS One 2015; 10:e0141072. [PMID: 26524467 PMCID: PMC4629894 DOI: 10.1371/journal.pone.0141072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 10/05/2015] [Indexed: 11/20/2022] Open
Abstract
BACKGROUND Many factors are associated with post-treatment relapse in CHB patients, and there are no effective factors to predict relapse. In this study, we investigate the influence factors associated with post-treatment relapse and their predictive value in HBeAg positive CHB (eP-CHB). METHODS The factors associated with post-treatment relapse were analyzed firstly by a retrospective study in eP-CHB. Variables included age, sex, regimen, baseline HBeAg and HBV DNA level, total course of treatment as well as duration of consolidation therapy after HBeAg seroconversion. The predictive effects of the influence factors were evaluated in an eP-CHB prospective cohort. RESULTS 89 patients were enrolled in the retrospective study, 42(47.2%) relapsed after discontinuation of treatment. Factors related to post-treatment relapse were total course of treatment, duration of consolidation therapy and baseline HBV DNA level. Relapse rates in patients with total course >36 months, consolidation duration >12 months and baseline HBV DNA level < 1.0E+5IU/ml were lower than those of total course <24 months (P = 0.002), consolidation duration≤12 months (P = 0.011) and baseline HBV DNA level > 1.0E+7IU/ml (P = 0.01) respectively. Patients with HBV DNA≥1.0E+7IU/ml plus HBeAg<200COI at baseline had the highest relapse rate and cumulative relapse rate than the other three arms (P = 0.048 and 0.008 respectively). Logistic regression analysis demonstrated that baseline HBV DNA level, duration of consolidation therapy and combination of baseline HBV DNA and HBeAg (IgDNA/IgHBeAg) were independent factors to predict post-treatment relapse. The model based on baseline IgDNA/IgHBeAg and consolidation duration worked well in predicting post-treatment relapse in the prospective study and the accuracy, specificity, sensitivity, PPV and NPV for prediction were 80.3%, 81.1%, 79.2%, 73.1% and 85.7% respectively. CONCLUSIONS Virological factors including baseline HBV DNA, HBeAg and treatment course were major influence factors associated with post-treatment relapse in eP-CHB. Patients with higher HBV DNA and lower HBeAg levels at baseline, shorter total course as well as consolidation therapy were more likely to develop relapse after discontinuation of therapy. The antiviral therapy in eP-CHB patients should be individually managed at different levels. It is better to treat those with higher viral load and lower HBeAg levels at baseline for a longer course, especially longer consolidation duration so as to decrease the relapse rate.
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Affiliation(s)
- Junfeng Lu
- Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Jin’e Li
- Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Yali Liu
- Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Shan Ren
- Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Zhenhuan Cao
- Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Yi Jin
- Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Lina Ma
- Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Chengli Shen
- Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, United States of America
| | - Xinyue Chen
- Beijing You’an Hospital, Capital Medical University, Beijing, China
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20
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Fong TL, Tien A, Jo KJ, Chu D, Cheung E, Mena EA, Phan QQ, Yu AS, Mohammed W, Velasco A, LeDuc VH, Nguyen N, Han SB, Chang M, Bae HS, Cho YW, Tong MJ, Cooper SL. Durability of Hepatitis B e Antigen Seroconversion in Chronic Hepatitis B Patients Treated with Entecavir or Tenofovir. Dig Dis Sci 2015; 60:3465-72. [PMID: 26138653 PMCID: PMC4803449 DOI: 10.1007/s10620-015-3775-9] [Citation(s) in RCA: 17] [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: 04/23/2015] [Accepted: 06/17/2015] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Loss of HBeAg and development of anti-HBe (seroconversion) is seen as a milestone and endpoint in the treatment of HBeAg-positive patients with chronic hepatitis B (CHB). Among patients treated with nucleos(t)ide analogs (NA), recurrent viremia is common after discontinuation of therapy. Entecavir (ETV) and tenofovir (TDF) are highly potent NA. The durability of virological response and HBeAg seroconversion in patients treated with these agents is not well studied. METHODS We retrospectively studied the outcomes of 54 HBeAg-positive CHB patients who were treated with either ETV (n = 30) or TDF (23) or both (n = 1) that achieved virological response and underwent seroconversion and consolidation therapy before cessation of treatment. RESULTS Only 4 (7%) patients had sustained virological, serological, and biochemical remission. Thirteen patients (24%) continued to have HBV DNA levels below 2000 IU/mL and normal alanine aminotransferase activity (ALT). Thirty-seven patients (69%) developed HBV DNA >2000 IU/mL, with 20 having elevated ALT. Among these 37 patients, 23 (62%) remained HBeAg negative/anti-HBe positive, 12 (32%) became HBeAg positive, and 2 (5%) were HBeAg and anti-HBe negative. Duration of consolidation therapy did not correlate with low versus high level of virological relapse. CONCLUSIONS Durability of HBeAg seroconversion associated with ETV or TDF was not superior to that reported in patients treated with less potent NA. Our results, aggregated with others, suggest HBeAg seroconversion should not be considered as a treatment endpoint for most HBeAg-positive patients treated with NA. Future updates of treatment guidelines should reconsider HBeAg seroconversion as an endpoint to therapy.
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Affiliation(s)
- Tse-Ling Fong
- Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA, USA.
- Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, 1510 San Pablo Street, 2/F, Los Angeles, CA, 90033, USA.
| | - Andy Tien
- Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA, USA
| | - Kahee J Jo
- Liver Disease and Transplant Program, California Pacific Medical Center, San Francisco, CA, USA
| | | | - Eddie Cheung
- Division of Gastroenterology, University of California Davis, Davis, CA, USA
- Private Practice, Oakland, CA, USA
| | - Edward A Mena
- Liver Center, Huntington Research Institute, Pasadena, CA, USA
| | | | | | - Wafa Mohammed
- Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA, USA
| | - Andrew Velasco
- Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA, USA
| | - Vinh-Huy LeDuc
- Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA, USA
| | - Nickolas Nguyen
- Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA, USA
| | - Steven-Bui Han
- Division of Gastroenterology, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Mimi Chang
- Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA, USA
| | - Ho S Bae
- Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA, USA
| | - Yong-Won Cho
- Asian Pacific Liver Center, Saint Vincent Medical Center, Los Angeles, CA, USA
| | - Myron J Tong
- Liver Center, Huntington Research Institute, Pasadena, CA, USA
| | - Stewart L Cooper
- Liver Disease and Transplant Program, California Pacific Medical Center, San Francisco, CA, USA
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21
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Chen CH, Hung CH, Hu TH, Wang JH, Lu SN, Su PF, Lee CM. Association Between Level of Hepatitis B Surface Antigen and Relapse After Entecavir Therapy for Chronic Hepatitis B Virus Infection. Clin Gastroenterol Hepatol 2015; 13:1984-92.e1. [PMID: 26073492 DOI: 10.1016/j.cgh.2015.06.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Revised: 04/21/2015] [Accepted: 06/09/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS We investigated the rate of relapse of hepatitis B virus (HBV) infection after entecavir therapy for chronic hepatitis B and the association between level of hepatitis B surface antigen (HBsAg) and relapse. METHODS In a retrospective study, we analyzed data from 252 patients with chronic HBV infection who were treated with entecavir and met the Asian Pacific Association for the Study of the Liver treatment stopping rules (mean time, 164 ± 45 weeks) from January 2007 through June 2011 in Taiwan. Eighty-three were hepatitis B e antigen (HBeAg)-positive, and 169 were HBeAg-negative. Patients had regular post-treatment follow-up examinations for at least 12 months. Virologic relapse was defined on the basis of serum HBV DNA >2000 IU/mL after entecavir therapy. Clinical relapse was defined as a level of alanine aminotransferase > 2-fold the upper limit of normal and HBV DNA > 2000 IU/mL. RESULTS Two years after therapy ended, 42% of HBeAg-positive patients had a virologic relapse, and 37.6% had a clinical relapse; 3 years after therapy ended, these rates were 64.3% and 51.6% for HBeAg-negative patients, respectively. On the basis of Cox regression analysis, factors independently associated with virologic and clinical relapse included old age, HBV genotype C, and higher baseline levels of HBsAg for HBeAg-positive patients and old age and higher end-of-treatment levels of HBsAg for HBeAg-negative patients. In HBeAg-positive patients, risk of HBV relapse increased with age ≥ 40 years and HBsAg level ≥ 1000 IU/mL at baseline (P < .001). In HBeAg-negative patients, the combination of age (< 55 years) and HBsAg level (< 150 IU/mL) at the end of treatment was associated with a lower rate of virologic relapse (4.5% of HBeAg-negative patients had viral relapse at year 3). The decrease in level of HBsAg from month 12 of treatment until the end of treatment was greater in patients who did lose HBsAg after entecavir therapy compared with those who did not. CONCLUSIONS The combination of age and level of HBsAg is associated with relapse of HBV infection after treatment with entecavir. HBsAg levels might be used to guide the timing of cessation of entecavir treatment in patients with chronic HBV infection.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 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
| | - Jing-Houng Wang
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Pei-Fang Su
- Department of Statistics, National Cheng Kung University, Tainan, 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.
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22
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Murakami E, Tsuge M, Hiraga N, Kan H, Uchida T, Masaki K, Nakahara T, Ono A, Miki D, Kawaoka T, Abe H, Imamura M, Aikata H, Ochi H, Hayes CN, Akita T, Tanaka J, Chayama K. Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones. J Infect 2015; 72:91-102. [PMID: 26515673 DOI: 10.1016/j.jinf.2015.09.038] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2015] [Revised: 08/23/2015] [Accepted: 09/14/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF) has been approved for chronic hepatitis B treatment, and favorable susceptibility of hepatitis B virus (HBV) has been indicated. However, differences in TDF susceptibility among HBV genotypes and drug-resistant strains are unclear. In this study, TDF susceptibilities between genotypes A and C were evaluated in vitro and in vivo using several drug-resistant HBV clones. METHODS HBV expression plasmids were constructed from sera of HBV carriers, and drug-resistant substitutions were introduced by site-directed mutagenesis. TDF susceptibility was evaluated by changes of core-associated HBV replication intermediates in vitro or by change of serum HBV DNA in human hepatocyte chimeric mice carrying each HBV clone in vivo. RESULTS TDF susceptibilities of lamivudine-resistant clones (rtL180M/M204V) and lamivudine plus entecavir-resistant clones (rtL180M/S202G/M204V) were similar to wild type clones in vitro. However, lamivudine plus adefovir-resistant clones (rtA181T/N236T) acquired tolerance to TDF, and the rtN236T mutation was considered to be a causal substitution for TDF resistance. Furthermore, genotypic differences in TDF susceptibility were also observed between genotypes A and C in vitro, and the differences could be confirmed in vivo (p = 0.023). CONCLUSIONS The present study indicates that TDF susceptibility varies among HBV genotypes and drug-resistant HBV clones.
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Affiliation(s)
- Eisuke Murakami
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Kan
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Keiichi Masaki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Hidenori Ochi
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan
| | - C Nelson Hayes
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Disease Control and Prevention, Integrated Health Sciences, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Junko Tanaka
- Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Department of Epidemiology, Infectious Disease Control and Prevention, Integrated Health Sciences, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima, Japan; Liver Research Project Center, Hiroshima University, Hiroshima, Japan; Laboratory for Digestive Diseases, Center for Genomic Medicine, The Institute of Physical and Chemical Research (RIKEN), Hiroshima, Japan.
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23
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Gu L, Han Y, Li Y, Zhu T, Song X, Huang Y, Yang F, Guan S, Xie J, Gohda J, Hosoya N, Kawana-Tachikawa A, Liu W, Gao GF, Iwamoto A, Li T, Ishida T. Emergence of Lamivudine-Resistant HBV during Antiretroviral Therapy Including Lamivudine for Patients Coinfected with HIV and HBV in China. PLoS One 2015; 10:e0134539. [PMID: 26288093 PMCID: PMC4543549 DOI: 10.1371/journal.pone.0134539] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 07/11/2015] [Indexed: 02/06/2023] Open
Abstract
In China, HIV-1-infected patients typically receive antiretroviral therapy (ART) that includes lamivudine (3TC) as a reverse-transcriptase inhibitor (RTI) (ART-3TC). Previous studies from certain developed countries have shown that, in ART-3TC, 3TC-resistant HBV progressively emerges at an annual rate of 15–20% in patients coinfected with HIV-1 and HBV. This scenario in China warrants investigation because >10% of all HIV-infected patients in China are HBV carriers. We measured the occurrence of 3TC-resistant HBV during ART-3TC for HIV-HBV coinfection and also tested the effect of tenofovir disoproxil fumarate (TDF) used as an additional RTI (ART-3TC/TDF) in a cohort study in China. We obtained 200 plasma samples collected from 50 Chinese patients coinfected with HIV-1 and HBV (positive for hepatitis B surface antigen) and examined them for the prevalence of 3TC-resistant HBV by directly sequencing PCR products that covered the HBV reverse-transcriptase gene. We divided the patients into ART-3TC and ART-3TC/TDF groups and compared the efficacy of treatment and incidence of drug-resistance mutation between the groups. HIV RNA and HBV DNA loads drastically decreased in both ART-3TC and ART-3TC/TDF groups. In the ART-3TC group, HBV breakthrough or insufficient suppression of HBV DNA loads was observed in 20% (10/50) of the patients after 96-week treatment, and 8 of these patients harbored 3TC-resistant mutants. By contrast, neither HBV breakthrough nor treatment failure was recorded in the ART-3TC/TDF group. All of the 3TC-resistant HBV mutants emerged from the cases in which HBV DNA loads were high at baseline. Our results clearly demonstrated that ART-3TC is associated with the emergence of 3TC-resistant HBV in patients coinfected with HIV-1 and HBV and that ART-3TC/TDF reduces HBV DNA loads to an undetectable level. These findings support the use of TDF-based treatment regimens for patients coinfected with HIV-1 and HBV.
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Affiliation(s)
- Lijun Gu
- China-Japan Joint Laboratory of Molecular Immunology & Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
- Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Yang Han
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Yijia Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Ting Zhu
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Xiaojing Song
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Ying Huang
- China-Japan Joint Laboratory of Molecular Immunology & Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
| | - Feifei Yang
- China-Japan Joint Laboratory of Molecular Immunology & Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
| | - Shuo Guan
- China-Japan Joint Laboratory of Molecular Immunology & Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
| | - Jing Xie
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China
| | - Jin Gohda
- China-Japan Joint Laboratory of Molecular Immunology & Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
- Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Noriaki Hosoya
- Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Ai Kawana-Tachikawa
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Wenjun Liu
- China-Japan Joint Laboratory of Molecular Immunology & Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
| | - George Fu Gao
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
| | - Aikichi Iwamoto
- Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Taisheng Li
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, P.R. China
- * E-mail: (TI); (TL)
| | - Takaomi Ishida
- China-Japan Joint Laboratory of Molecular Immunology & Molecular Microbiology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, P.R. China
- Research Center for Asian Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- * E-mail: (TI); (TL)
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Yao CC, Lee CM, Hung CH, Wang JH, Hu TH, Lu SN, Changchien CS, Hsu MC, Chen CH. Combining age and HBsAg level predicts post-treatment durability of nucleos(t)ide analogue-induced HBeAg seroconversion. J Gastroenterol Hepatol 2015; 30:918-24. [PMID: 25532588 DOI: 10.1111/jgh.12874] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/01/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Previous studies have indicated that lamivudine-induced hepatitis B e antigen (HBeAg) seroconversion may not be durable in the Asian population. We investigated the useful predictors of post-treatment hepatitis B virus (HBV) relapse in patients with nucleos(t)ide analogue (NA)-induced HBeAg loss/seroconversion. METHODS A total of 157 non-cirrhotic patients with NA-induced HBeAg loss/seroconversion (78, lamivudine; 68, entecavir; 11, telbivudine) were retrospectively analyzed. All patients had at least 12 months of post-treatment follow-up and consolidation therapy duration. RESULTS The cumulative rate of post-treatment HBV relapse at 5 years was 57.1%. Multivariate analysis revealed that age and baseline hepatitis B surface antigen (HBsAg) levels independently predicted post-treatment HBV relapse. The post-treatment HBV relapse rate was significantly higher in patients aged > 40 years than in those < 40 years (P < 0.001). A baseline HBsAg level of 2000 IU/mL was the optimal cut-off value for predicting post-treatment HBV relapse (P = 0.002). The post-treatment HBV relapse risk further increased with the presence of both risk factors (age ≥ 40 years and baseline HBsAg level ≥ 2000 IU/mL; P < 0.001). A prolonged consolidation therapy period of ≥ 18 or 24 months had no positive effect on sustained viral suppression. There was no significant difference in post-treatment HBV relapse rates between patients with lamivudine- and entecavir-induced HBeAg loss/seroconversion during the off-treatment follow-up (P = 0.31). CONCLUSION The combination of an age of 40 years and a baseline HBsAg level of 2000 IU/mL was a useful marker for predicting post-treatment HBV relapse in patients with NA-induced HBeAg loss/seroconversion.
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Affiliation(s)
- Chih-Chien Yao
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
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Abstract
Aim of the study To identify distribution of HBV genotypes in particular regions of Poland. Material and methods The study included 270 treatment-naïve, HBV-infected individuals, enrolled in 7 centers of Poland. HBV genotyping was performed in 243 of them with the INNO-LiPA HBV Genotyping assay (Innogenetics). Results Genotype A present in 2/3 patients was demonstrated as the most predominant in Poland. It was followed by D (20%), H (5%) and mixed A + D (5%). Remaining patients were infected with genotype F, mixed D + G, A + C or D + F. Analysis of distribution demonstrated regional differences, with a higher rate of genotype D prevalence (about 30%) in the eastern (Białystok and Lublin) and south-western (Wrocław) parts compared to other regions, where the prevalence rate was below 15%. The highest prevalence of genotype A (exceeding 80%) was observed in central Poland (Bydgoszcz, Łódź). Conclusions The presented data reveal the current distribution of HBV genotypes across Poland, which is the first and the largest such epidemiological analysis.
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Abstract
Chronic hepatitis B virus (HBV) infection is a global health problem, leading to cirrhosis, hepatocellular carcinoma (HCC) and liver-related deaths. Universal hepatitis B vaccination is the most cost-effective way to eradicate HBV infection with the remarkable reduction of chronic carriage, neonatal fulminant hepatitis and childhood HCC. The introduction of highly effective antiviral agents, including lamivudine, adefovir dipivoxil, entecavir, telbivudine, tenofovir disoproxil fumarate and pegylated interferons further improve short-, medium- and long-term outcomes of chronic HBV infection, such as ALT normalization, HBV DNA suppression, HBeAg seroconversion, HBsAg seroclearance, fibrosis regression, reduction of cirrhosis, HCC, liver-related deaths and the need for liver transplantation. Above all, sustained and profound viral suppression is the key to improve the clinical outcomes of chronic hepatitis B.
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Affiliation(s)
- Tung-Hung Su
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te Street, Taipei 10002, Taiwan
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27
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Dienstag JL, Delemos AS. Viral Hepatitis. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1439-1468.e7. [DOI: 10.1016/b978-1-4557-4801-3.00119-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Chang ML, Liaw YF. Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management. J Hepatol 2014; 61:1407-17. [PMID: 25178562 DOI: 10.1016/j.jhep.2014.08.033] [Citation(s) in RCA: 211] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Revised: 08/22/2014] [Accepted: 08/24/2014] [Indexed: 02/06/2023]
Abstract
Hepatitis B flare, defined as an event with abrupt rise of alanine aminotransferase (ALT) levels to >5 times the upper limit of normal during chronic hepatitis B virus (HBV) infection, is considered to be the result of a human leukocyte antigen-I restricted, cytotoxic T lymphocyte mediated immune response against HBV and its downstream mechanisms. It may occur spontaneously, during or after antiviral therapy and in the setting of immunosuppression and/or chemotherapy. The clinical spectrum of hepatitis B flares varies from asymptomatic to symptomatic and typical overt acute hepatitis, even with hepatic decompensation or failure. Flares may also occur in viraemic patients with cirrhosis with higher incidence of decompensation/mortality, hence requiring immediate antiviral therapy. An upsurge of serum HBV DNA and hepatitis B surface antigen levels usually precedes the abrupt rise of ALT levels. Rising or stable and high HBV DNA during flares represent ineffective immune clearance and further hepatocytolysis, even hepatic decompensation, may occur. Such patients require immediate antiviral therapy. In contrast, bridging hepatic necrosis and/or alpha-fetoprotein levels >100 ng/ml or decreasing HBV DNA during flares represent a more effective immune clearance and frequently leads to seroclearance of HBV DNA and/or hepatitis B e antigen with remission. If patients are non-cirrhotic and there is no concern of developing decompensation, patients may be observed for 3-6 months before deciding on the need of antiviral therapy. Severe and repeated flares are prone to develop into decompensation or lead to the development of cirrhosis, thus a timely treatment to prevent the hepatitis B flare is better than to cope with the flare. Screening, monitoring and prophylactic or pre-emptive antiviral therapy is mandatory for patients who are going to receive immunosuppressants or chemotherapy.
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Affiliation(s)
- Ming-Ling Chang
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
| | - Yun-Fan Liaw
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
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29
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Chien RN. Toward personalized therapy of chronic hepatitis B. ADVANCES IN DIGESTIVE MEDICINE 2014. [DOI: 10.1016/j.aidm.2014.07.001] [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: 11/29/2022]
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Jackson V, Ferguson W, Kelleher TB, Lawless M, Eogan M, Nusgen U, Coughlan S, Connell J, Lambert JS. Lamivudine treatment and outcome in pregnant women with high hepatitis B viral loads. Eur J Clin Microbiol Infect Dis 2014; 34:619-23. [PMID: 25381607 DOI: 10.1007/s10096-014-2270-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 10/20/2014] [Indexed: 01/27/2023]
Abstract
Perinatal transmission is the most common mode of hepatitis B virus (HBV) transmission and is a leading cause of chronic infection worldwide. Maternal treatment with lamivudine (LAM) can result in a rapid and significant reduction in HBV viral load (VL) and, thus, mitigate the risk of mother-to-child transmission (MTCT). The aim of this study was to retrospectively evaluate the safety of LAM treatment administered in the third trimester of pregnancy and determine the influence, if any, on infant outcome. The medical charts of all HBV surface antigen (HBsAg)-positive women eligible for treatment with LAM and who registered for antenatal care between 2007 and 2012 were retrospectively reviewed. During the 6-year period, 45 women met the criteria for LAM treatment. Thirty-six women (80 %) accepted treatment; the remaining women declined treatment (5), defaulted from care (3) or transferred to another maternity unit (1). The median duration of treatment was 11.4 weeks (range 5.3-17.4) and the median baseline VL was 1.4 × 10(8) IU/mL (range 1.8 × 10(7)-1.7 × 10(8)). The median VL at delivery was 2.3 × 10(5) IU/mL and 60 % of women achieved a VL reduction >2 log10 IU/mL before delivery. No cases of perinatal transmission occurred in the infants born to mothers who received treatment; however, one infant, born to a mother who defaulted from care, was HBV-infected at 8 months. The results suggest that LAM therapy in highly viraemic HBV-infected pregnant women could lower the rate of vertical transmission.
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Affiliation(s)
- V Jackson
- Department of Infectious Diseases, The Rotunda Hospital, Dublin, Ireland
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Sun HY, Sheng WH, Tsai MS, Lee KY, Chang SY, Hung CC. Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: A review. World J Gastroenterol 2014; 20:14598-14614. [PMID: 25356024 PMCID: PMC4209527 DOI: 10.3748/wjg.v20.i40.14598] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 12/24/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Due to the shared modes of transmission, coinfection with HBV and human immunodeficiency virus (HIV) is not uncommon. It is estimated that 10% of HIV-infected patients worldwide are coinfected with HBV. In areas where an HBV vaccination program is implemented, the HBV seroprevalence has declined significantly. In HIV/HBV-coinfected patients, HBV coinfection accelerates immunologic and clinical progression of HIV infection and increases the risk of hepatotoxicity when combination antiretroviral therapy (cART) is initiated, while HIV infection increases the risk of hepatitis events, cirrhosis, and end-stage liver disease related to chronic HBV infection. With the advances in antiviral therapy, concurrent, successful long-term suppression of HIV and HBV replication can be achieved in the cART era. To reduce the disease burden of HBV infection among HIV-infected patients, adoption of safe sex practices, avoidance of sharing needles and diluent, HBV vaccination and use of cART containing tenofovir disoproxil fumarate plus emtricitabine or lamivudine are the most effective approaches. However, due to HIV-related immunosuppression, using increased doses of HBV vaccine and novel approaches to HBV vaccination are needed to improve the immunogenicity of HBV vaccine among HIV-infected patients.
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Kuo LF, Lee CM, Hung CH, Wang JH, Hu TH, Lu SN, Changchien CS, Chen CH. High risk of hepatitis B virus reactivation in nucleos(t)ide analogue-induced hepatitis B e antigen seroconverters older than 40 years. Dig Dis Sci 2014; 59:2580-7. [PMID: 24846794 DOI: 10.1007/s10620-014-3194-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 04/28/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND A recent study showed that chronic hepatitis B virus (HBV) carriers with nucleos(t)ide analogue (NA)-induced hepatitis B antigen (HBeAg) seroconversion occurring before the age of 30 years have a higher risk of HBV reactivation. AIM To compare the risk of HBV reactivation and HBeAg seroreversion between patients with spontaneous and NA-induced HBeAg seroconversion. METHODS A total of 135 and 251 non-cirrhotic patients with NA-induced and spontaneous HBeAg seroconversion, respectively, were analyzed. RESULTS NA-induced HBeAg seroconverters faced higher risks of HBV reactivation and HBeAg seroreversion than spontaneous HBeAg seroconverters (P < 0.001). In spontaneous HBeAg seroconverters, age at HBeAg seroconversion, sex, HBV DNA levels before HBeAg seroconversion, HBV genotype C, and pre-S deletions were independent predictors of HBV reactivation. In NA-induced HBeAg seroconverters, only age at baseline was an independent predictor of HBV reactivation. To determine whether the difference in the incidence of HBV reactivation or HBeAg seroreversion between two groups was age-specific, we analyzed these patients according to their age at HBeAg seroconversion (20-29, 30-39, and ≥40 years). Our data showed that NA-induced HBeAg seroconversion was an independent predictor of HBV reactivation and HBeAg seroreversion than spontaneous HBeAg seroconversion in patients older than 40 years at HBeAg seroconversion, but not in patients between 20-29 and 30-39 years of age. CONCLUSIONS NA-induced HBeAg seroconverters are associated with higher risks of HBV reactivation and HBeAg seroreversion compared to spontaneous HBeAg seroconverters, especially in patients who are older than 40 years at HBeAg seroconversion.
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Affiliation(s)
- Li-Fu Kuo
- Division of Hepatogastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung and School of Medicine, College of Medicine, Chang Gung University, Taoyuan, 123 Ta Pei Road, Kaohsiung, Taiwan
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Chen CH, Lu SN, Hung CH, Wang JH, Hu TH, Changchien CS, Lee CM. The role of hepatitis B surface antigen quantification in predicting HBsAg loss and HBV relapse after discontinuation of lamivudine treatment. J Hepatol 2014; 61:515-22. [PMID: 24798617 DOI: 10.1016/j.jhep.2014.04.029] [Citation(s) in RCA: 123] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Revised: 03/10/2014] [Accepted: 04/25/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS We investigated whether the quantification of hepatitis surface antigen (HBsAg) could predict HBsAg loss or hepatitis B virus (HBV) relapse after stopping lamivudine treatment. METHODS A total of 188 naive chronic hepatitis B patients (83 HBeAg-positive, 105 HBeAg-negative patients), who were previously treated with lamivudine (treatment duration: 89.3 ± 35.9 weeks, range: 52-243 weeks) but stopped the treatment for at least 12 months were recruited. RESULTS The cumulative incidence of HBsAg loss and HBV relapse at year 6 after stopping lamivudine treatment was 24% and 65.9% respectively. Cox regression analysis revealed that lower alanine aminotransferase (ALT) at baseline, lower HBsAg levels at the end of treatment, and longer treatment duration were independent predictors for HBsAg loss, and old age, male sex and higher HBsAg levels at the end of treatment were independent predictors for post-treatment HBV relapse. At the end of treatment, the HBsAg cut-off value of 300 IU/ml could predict 55.6% (5/9) HBsAg loss in HBeAg-positive patients. In HBeAg-negative patients, the HBsAg cut-off values of 120 and 200 IU/ml could predict 79.2% (19/24) HBsAg loss and 93.3% (28/30) post-treatment sustained response respectively. Further HBsAg reduction (>0.22 log IU/ml) at month 6 after stopping treatment was an independent predictor for HBsAg loss after adjusting for HBsAg level at the end of treatment. CONCLUSIONS Serum HBsAg level at the end of treatment is a useful predictor to guide the timing of stopping lamivudine treatment in chronic hepatitis B patients.
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Affiliation(s)
- Chien-Hung Chen
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Sheng-Nan Lu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Hung Hung
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jing-Houng Wang
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Tsung-Hui Hu
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chi-Sin Changchien
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chuan-Mo Lee
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
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Ridruejo E, Marciano S, Galdame O, Reggiardo MV, Muñoz AE, Adrover R, Cocozzella D, Fernandez N, Estepo C, Mendizábal M, Romero GA, Levi D, Schroder T, Paz S, Fainboim H, Mandó OG, Gadano AC, Silva MO. Relapse rates in chronic hepatitis B naïve patients after discontinuation of antiviral therapy with entecavir. J Viral Hepat 2014; 21:590-6. [PMID: 24188363 DOI: 10.1111/jvh.12200] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2013] [Accepted: 09/21/2013] [Indexed: 01/03/2023]
Abstract
Registration studies show entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B, but relapse rates after treatment discontinuation have not been well established. Relapse rates and predictors of relapse were evaluated in naïve HBeAg-positive and HBeAg-negative patients treated with ETV. Treatment duration was defined according to international guidelines. Virological relapse was defined as reappearance in serum of hepatitis B virus (HBV) DNA to >2000 IU/mL after discontinuation of treatment. A hundred and sixty-nine consecutive patients were treated for a median 181 weeks. 61% were HBeAg positive, 23% had cirrhosis, and mean HBV DNA level was 6.88 ± 1.74 log10 IU/mL. Ninety-two per cent became HBV DNA negative; 71% of HBeAg+ve patients became HBeAg negative and 68% anti-HBe positive; 14% became HBsAg negative and 13% anti-HBs positive. At the end of the study, 36 patients discontinued treatment: one due to breakthrough associated with resistant variants and 35 (20%) due to sustained virological response; 33 of these patients developed HBeAg seroconversion and 18 HBsAg seroconversion. Median off-treatment time was 69 weeks. Nine patients (26%), all HBeAg positive at baseline, developed virological relapse after a median 48 weeks off-treatment, 3 of them showed HBeAg reversion and 4 lost anti-HBe. No patient with HBsAg seroconversion relapsed. HBeAg clearance after week 48 of treatment was associated with an increase risk of relapse. After ETV discontinuation, HBsAg seroconversion was maintained in 100% of the patients, HBeAg seroconversion maintained in 90%, and virological relapse rate was 24%.
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Affiliation(s)
- E Ridruejo
- Hepatology Section, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno 'CEMIC', Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina; Hepatology and Liver Transplant Unit, Hospital Universitario Austral, Provincia de Buenos Aires, Pilar, Argentina
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Kim GA, Lim YS, An J, Lee D, Shim JH, Kim KM, Lee HC, Chung YH, Lee YS, Suh DJ. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic hepatitis B: clinical outcomes and durability. Gut 2014; 63:1325-32. [PMID: 24162593 DOI: 10.1136/gutjnl-2013-305517] [Citation(s) in RCA: 310] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Little is known about the long-term clinical outcome and durability of HBsAg seroclearance following nucleos(t)ide analogue (NUC) therapy in patients with chronic hepatitis B (CHB). DESIGN During a median follow-up period of 6 years (33 567 patient-years) of 5409 CHB patients who were initially treated with lamivudine or entecavir, a total of 110 achieved HBsAg seroclearance (0.33% annual seroclearance rate) and were included in this study. RESULTS Baseline alanine aminotransferase (ALT) level >5 times of upper limit of normal was associated with higher probability of HBsAg seroclearance (HR 1.80, p<0.01), while HBeAg positivity (HR 0.46, p<0.01), high HBV DNA level (log(10) IU/mL; HR 0.61, p<0.01), and cirrhosis (HR 0.48, p<0.01) were inversely associated with the probability of HBsAg seroclearance by multivariable analysis. During follow-up for 287 patient-years after HBsAg seroclearance, only two patients with baseline cirrhosis developed hepatocellular carcinoma (HCC) or died (0.7% annual risk), which was of a significantly lower rate compared with propensity score-matched patients without HBsAg seroclearance (HR 0.09, p<0.01). HBsAg reversion and/or HBV DNA reversion occurred in 18 patients, most of which were transient with extremely low serum levels of HBsAg (0.05-1.00 IU/mL) and HBV DNA (17-1818 IU/mL). None required retreatment. The cumulative probability of anti-HBs seroconversion (detection of anti-HBs) at 4 years was 67.4% by Kaplan-Meier analysis. Selection for lamivudine-resistance HBV mutants during treatment was not associated with composite reversion (p=0.66). CONCLUSIONS HBsAg seroclearance achieved after NUC treatment was associated with favourable clinical outcomes and was durable in most cases during long-term follow-up.
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Affiliation(s)
- Gi-Ae Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Suk Lim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jihyun An
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Danbi Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Ju Hyun Shim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kang Mo Kim
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han Chu Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Hwa Chung
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yung Sang Lee
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong Jin Suh
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Chen CH, Chiu YC, Lu SN, Lee CM, Wang JH, Hu TH, Hung CH. Serum hepatitis B surface antigen levels predict treatment response to nucleos(t)ide analogues. World J Gastroenterol 2014; 20:7686-7695. [PMID: 24976706 PMCID: PMC4069297 DOI: 10.3748/wjg.v20.i24.7686] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 12/13/2013] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
Quantification of hepatitis B surface antigen (HBsAg) has been suggested to be helpful in the management of chronic hepatitis B (CHB) patients. Nucleos(t)ide analogs (NAs) are the therapy of choice for CHB and are used in the majority of CHB patients. NAs are able to induce hepatitis B virus (HBV) viral suppression, normalization of alanine aminotransferase (ALT) levels, and improvement in liver histology. Automated quantitative assays for serum HBsAg have recently become available, facilitating standardized quantification of serum HBsAg. This has led to increased interest in the clinical application of quantitative serum HBsAg for predicting therapeutic response to NAs. Recent studies have shown that a decline in serum HBsAg levels in patients receiving peginterferon may signal successful induction of immune control over HBV, and can therefore be used to predict therapeutic response. NA treatment typically induces a less rapid decline in HBsAg than interferon treatment; it has been estimated that full HBsAg clearance can require decades of NA treatment. However, a rapid HBsAg decline during NA therapy may identify patients who will show clearance of HBsAg. Currently, there is no consensus on the clinical utility of serum HBsAg monitoring for evaluating patient responses to NA therapy. This review focuses on recent findings regarding the potential application of HBsAg quantification in the management of CHB patients receiving NA therapy.
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Kang W, Park JY. When to stop nucleos(t)ide analogues treatment for chronic hepatitis B? Durability of antiviral response. World J Gastroenterol 2014; 20:7207-7212. [PMID: 24966590 PMCID: PMC4064065 DOI: 10.3748/wjg.v20.i23.7207] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 12/13/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Introduction of nucleos(t)ide analogues (NAs) for oral antiviral therapy has dramatically improved the clinical outcome in patients with chronic hepatitis B (CHB). Although current international guidelines for the management of CHB provide information regarding when to begin the antiviral therapy with NAs, there is no clear consensus on when to stop the treatment, especially for those who respond to the therapy. Hepatitis B surface antigen loss has been regarded as an ideal endpoint of oral antiviral therapy with NAs, however since this is rarely achieved, practical endpoints have been suggested by the international guidelines. Despite the stopping rules recommended by the international guidelines, whether oral antiviral therapy with NAs can be safely discontinued is of major concern. While attention has been drawn to whether antiviral treatment with NAs can be a finite therapy, there is lack of sufficient data on off-treatment durability of highly potent NAs. Based on the available evidences, current guidelines for stopping NA therapy seems to be inadequate in terms of off-treatment durability, with relapse rates of more than 40% for both hepatitis Be antigen (HBeAg)-positive and HBeAg-negative patients. Therefore, further studies are required to accumulate data on off-treatment durability of highly potent NAs, and future studies are warranted to identify adequate predictive markers that could provide supplementary information to guide the timing of stopping NA therapy.
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Lee HW, Kang W, Ahn SH, Lee HJ, Hwang JS, Sohn JH, Jang JY, Han KJ, Kim JK, Kim DY, Paik YH, Lee CK, Choi IS, Lee KS, Han KH. Individual prediction model for lamivudine treatment response in hepatitis B virus e antigen-positive chronic hepatitis B patients. J Gastroenterol Hepatol 2014; 29:1049-55. [PMID: 24575848 DOI: 10.1111/jgh.12522] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/08/2013] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIMS Although prolonged lamivudine (LAM) therapy is associated with the emergence of LAM-resistant mutations, it is still a commonly used therapy in many Asian countries because of its established long-term safety and low cost. The aim of our study was to assess the predictors of long-term LAM treatment response and to establish an individual prediction model (IPM) for hepatitis B virus e antigen (HBeAg) seroconversion in HBeAg-positive chronic hepatitis B (CHB) patients. METHODS This was a multicenter analysis of 838 patients treated with LAM between January 1999 and August 2004. Of these, 748 patients were followed up for at least 24 months. RESULTS The median age was 43.0 years (range, 19-79 years) and the mean duration of LAM monotherapy was 34.2 ± 0.7 months. In the multivariate analysis, age (odds ratio [OR] = 0.974, P < 0.001), baseline alanine aminotransferase level (OR = 1.001, P = 0.014), and baseline hepatitis B virus DNA level (OR = 0.749, P < 0.001) were independent factors for HBeAg seroconversion. Based on the predictors, an IPM was established. Patients were classified into high (> 50%), intermediate (30-50%), or low (≤ 30%) response groups based on their probability of HBeAg seroconversion according to the IPM. The cumulative HBeAg seroconversion rate at 6 years for the high, intermediate, and low response groups was 66.0%, 48.5%, and 21.8%, respectively (P < 0.001). CONCLUSIONS An IPM was developed based on predictors of HBeAg seroconversion in HBeAg-positive CHB patients on LAM monotherapy. This model will allow screening of LAM responders prior to the commencement of antiviral treatment.
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Affiliation(s)
- Hyun Woong Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea; Liver Cirrhosis Clinical Research Center, Seoul, Korea
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Chen J, Yan L, Zhu FC, Liu JX, Li RC, Wang FZ, Li J, Zhuang H. Amino acid polymorphism in the reverse transcriptase region of hepatitis B virus and the relationship with nucleos(t)ide analogues treatment for preventing mother-to-infant transmission. J Med Virol 2014; 86:1288-95. [PMID: 24777553 DOI: 10.1002/jmv.23948] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/18/2014] [Indexed: 12/24/2022]
Abstract
A high maternal serum hepatitis B virus (HBV) DNA level is associated with vaccine failure. The administration of nucleos(t)ide analogues (NAs) in pregnancy for decreasing serum HBV is regarded as an effective and safe method to reduce HBV perinatal transmission. However, the effect of NAs treatment is closely related to amino acid polymorphisms in the HBV reverse transcriptase (RT) region. The full-length RT coding region of 334 HBV isolates from untreated Chinese women of childbearing age with persistent HBV infection were sequenced and amino acid polymorphic analysis was performed to evaluate its impact on NAs treatment for decreasing HBV perinatal transmission. Of the 334 isolates, 36 (10.8%) harbored NAs resistance (NAr) mutations which were mainly putative drug mutations related to lamivudine. The primary drug mutation rtA181T/V was detected in three HBeAg-negative women with an HBV DNA level of <4 log IU/ml. These NAr mutations were rarely detected in women with an HBV DNA level of ≥7 log IU/ml (P = 0.014) or in women younger than 35 years (P = 0.001). The NAr mutation rate among young women (<35 years) who had a high HBV DNA level (≥7 log IU/ml) was significantly lower than in women who had lower HBV DNA levels (<7 log IU/ml) or who were older (≥35 years; P = 0.017). These results suggest that younger women with a high HBV DNA level harbor fewer NAr mutations and that this population may respond to NAs treatment for the prevention of mother-to-infant transmission.
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Affiliation(s)
- Jie Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
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Prior exposure to lamivudine increases entecavir resistance risk in chronic hepatitis B Patients without detectable lamivudine resistance. Antimicrob Agents Chemother 2014; 58:1730-7. [PMID: 24395227 DOI: 10.1128/aac.02483-13] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The efficacy of entecavir (ETV) treatment in chronic hepatitis B (CHB) patients who were exposed to lamivudine (LAM) but had no detectable LAM resistance (LAM-R) is not well evaluated. In this study, we aimed to evaluate whether the probability of developing genotypic resistance to ETV in LAM-exposed patients with or without LAM-R is comparable to that in antiviral-naive patients. This retrospective cohort study included 500 consecutive patients with CHB who started ETV monotherapy at a single tertiary hospital in Korea. The patients were divided into three groups: nucleos(t)ide analogue (NA)-naive patients (group 1, n=142), patients who were previously exposed to LAM and had no currently or previously detected LAM-R (group 2, n=233), and patients with LAM-R when starting ETV (group 3, n=125). The overall median ETV treatment duration was 48.7 months. The probabilities of virologic breakthrough were significantly increased not only in group 3 (hazard ratio [HR]=14.4, P<0.001) but also in group 2 (HR=5.0, P<0.001) compared to group 1. Genotypic ETV resistance (ETV-R) developed more frequently in group 2 (HR=13.0, P=0.013) as well as group 3 (HR=43.9, P<0.001) than in group 1: the probabilities of developing ETV-R in groups 1, 2, and 3 were <1.0%, 8.0%, and 28.2%, respectively, at month 48. The results of this study indicate that ETV-R occurred more frequently in LAM-exposed patients, even though they had no detectable LAM-R, than in NA-naive patients. Therefore, LAM-exposed CHB patients, regardless of the presence or absence of LAM-R, should be monitored more cautiously for the development of ETV-R during ETV monotherapy.
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Durability of efficacy after telbivudine off-treatment in chronic hepatitis B patients. J Clin Virol 2014; 59:50-4. [DOI: 10.1016/j.jcv.2013.11.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2013] [Revised: 10/18/2013] [Accepted: 11/02/2013] [Indexed: 11/22/2022]
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HBV genotype B/C and response to lamivudine therapy: a systematic review. BIOMED RESEARCH INTERNATIONAL 2013; 2013:672614. [PMID: 24364035 PMCID: PMC3863712 DOI: 10.1155/2013/672614] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 10/11/2013] [Accepted: 10/22/2013] [Indexed: 12/14/2022]
Abstract
A number of nucleoside analogues such as lamivudine (LAM), actually used for the treatment of chronic hepatitis B, can suppress HBV DNA replication, improve transaminase level and liver histology, and enhance the rate of hepatitis B e antigen (HBeAg) clearance. The responses to LAM therapy involve HBeAg clearance and HBV DNA conversion of negative. However, the associations between HBV genotype B/C and response to LAM therapy remain ambiguous. The aim of this meta-analysis is to determine more precise estimations of the relationship. All the publications on the associations between HBV genotype B/C and response to LAM (HBeAg clearance and HBV DNA conversion of negative) through June 2013 were collected. Relative risk (RR) with 95% confidence intervals (95% CI) was calculated in fixed or random model, I2 was calculated to examine heterogeneity, and funnel plots were plotted to examine small study effects with Stata 11 software. Overall, for HBeAg clearance and genotype B/C, the RR (95% CI) was 1.27 (0.94–1.71), while for HBV DNA conversion of negative and genotype B/C, the RR (95% CI) was 1.07 (0.98–1.17). HBV genotype B/C shows no significance associations with response to lamivudine therapy (HBeAg clearance and HBV DNA conversion of negative).
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Peng CY. Nucleos(t)ide Analogues Therapy for Chronic Hepatitis B in Taiwan: Short-Term Versus Long-Term. CURRENT HEPATITIS REPORTS 2013; 12:181-187. [DOI: 10.1007/s11901-013-0173-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Pan X, Zhang K, Yang X, Liang J, Sun H, Li X, Zou Y, Xu Q, An G, Li G, Xu Q. Relapse rate and associated-factor of recurrence after stopping NUCs therapy with different prolonged consolidation therapy in HBeAg positive CHB patients. PLoS One 2013; 8:e68568. [PMID: 23844222 PMCID: PMC3701059 DOI: 10.1371/journal.pone.0068568] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 05/30/2013] [Indexed: 12/22/2022] Open
Abstract
Background Many chronic hepatitis B (CHB) patients recur after off-therapy and have to accept prolonged consolidation therapy with NUCs. We investigated the rate of HBV relapse after stopping NUCs therapy with different time period of prolonged consolidation therapy in HBeAg positive CHB patients, and analyzed the associated-factor of recurrence. Methods We recruited 162 HBeAg-positive CHB patients who met the standard of stopping NUCs therapy recommended by the 2005 APASL. Patients in group A, without the prolonged consolidation therapy, were as controls. Patients in group B were divided into 3 subgroups (group B1, 7 (range 3–11) months of the prolonged consolidation therapy; group B2, 17 (range 13–20) months of the prolonged consolidation therapy; group B3, 28 (range 25–34) months of the prolonged consolidation therapy). Virologic relapse was defined as an increase in serum HBV DNA to >103copies/ml after off-therapy. Results One hundred and thirty-six patients (group A, 40 patients; group B1, 54 patients; group B2, 23 patients; group B3, 19 patients) were eligible for this study. The cumulative rates of relapse in group B at 6 months and 48 months were 29.2%, 41.7% after off-therapy, respectively. The cumulative rates of relapse in group B were statistically lower than that in group A at the same time periods. The cumulative rate of relapse in group B3 or group B2 was statistically lower than that in group B1, respectively. On multivariate analysis by Cox’s proportional hazard model, age at off-therapy, baseline ALT and the different time period of the prolonged consolidation therapy were associated with the relapse of HBV after off-therapy. Conclusions Consolidation therapy with NUCs after HBeAg seroconversion should be further prolonged. Age at off-therapy, ALT at baseline and the time period of the prolonged consolidation therapy could provide information to direct anti-viral therapy.
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Affiliation(s)
- Xingfei Pan
- Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ka Zhang
- Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoan Yang
- Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiayi Liang
- Ultrasound Division, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Haixia Sun
- Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xuejun Li
- Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yong Zou
- Department of Blood Transfusion, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qingqiang Xu
- Department of Dermatology, Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Geng An
- Department of Reproductive Medicine Center, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The 3rd Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Gang Li
- Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Qihuan Xu
- Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- * E-mail:
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Dai CY, Tseng TC, Wong GLH, Huang JF, Wong VWS, Liu CJ, Yu ML, Chuang WL, Kao JH, Chan HLY, Chen DS. Consolidation therapy for HBeAg-positive Asian chronic hepatitis B patients receiving lamivudine treatment: a multicentre study. J Antimicrob Chemother 2013; 68:2332-8. [PMID: 23798667 DOI: 10.1093/jac/dkt193] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES For hepatitis B e antigen (HBeAg)-positive patients, continuing therapy (consolidation) for 6-12 months before cessation of nucleos(t)ide analogues (NAs) was recommended. This study aimed to investigate whether a longer period of lamivudine consolidation therapy leads to better outcomes and the clinical factors associated with response. METHODS Combined response [HBeAg seroconversion and undetectable serum hepatitis B virus (HBV) DNA by PCR assay] 6 months [end of follow-up (EOF)] after cessation of therapy was assessed in 101 HBeAg-positive chronically infected patients who received continued long-term lamivudine treatment and achieved a combined response at the end of treatment. RESULTS The rate of combined response at EOF was 40.6%. A lower pretreatment HBV DNA level, a longer duration of consolidation therapy, pretreatment hepatitis B surface antigen titre <1500 IU/mL and a higher proportion of consolidation duration of >18 months were significantly associated with combined response. A lower pretreatment HBV DNA level and a longer duration of consolidation therapy were independent factors associated with combined response at EOF by multivariate logistic regression analyses. The rate of combined response was 71.4%, 39.0% and 25.6% in patients with consolidation duration of >18 months, 12-18 months and <12 months, respectively (P = 0.001). Consolidation therapy for >18 months achieved a significantly higher rate of combined response at EOF in patients achieving combined response within or after 6 months. CONCLUSIONS Consolidation therapy for >18 months significantly improved the outcome of lamivudine therapy, particularly for patients who achieved a combined response after 6 months.
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Affiliation(s)
- Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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Wang GQ, Ding YP, Dong YH. Telbivudine treatment is associated with high hepatitis B e antigen seroconversion and immune modulatory effects in chronic hepatitis B patients. J Viral Hepat 2013; 20 Suppl 1:9-17. [PMID: 23458520 DOI: 10.1111/jvh.12059] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 12/05/2012] [Indexed: 01/10/2023]
Abstract
Chronic hepatitis B (CHB) is characterized by an impaired immune response to hepatitis B virus. Among the nucleos(t)ides used in CHB treatment, telbivudine is associated with the highest rates of hepatitis B e antigen (HBeAg) seroconversion rates, which are similar to those observed with pegylated interferon (PegIFN). Besides direct antiviral effect, modulation of the immune system may be an additional benefit for telbivudine-treated patients. Indeed, there is much clinical data indicating an IFN-like behaviour for telbivudine in contrast to other oral nucleos(t)ides, such as high HBeAg seroconversion, similar hepatitis B surface antigen (HBsAg) decline and biphasic viral kinetics. Clinical studies, animal models and in vitro studies suggest that both the innate and adaptive immune system responses contribute to high HBeAg seroconversion during telbivudine treatment through modulation of the function and/or expression of CD4+/CD8+ T cells, Th1/Th2, Treg, PD-1/PD-L1, Th17, IL-21 and TFH. The results described in this review suggest that the antiviral effect of telbivudine may be attributable not only to direct suppression of hepatitis B virus, but also to immunoregulatory effects. Hypothetically, telbivudine shares some common signal pathways with IFN.
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Affiliation(s)
- G-Q Wang
- Department of Infectious Diseases and Center for Liver Diseases, Peking University First Hospital, Beijing, China.
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Lin CL, Kao JH. Hepatitis B viral factors and treatment responses in chronic hepatitis B. J Formos Med Assoc 2013; 112:302-11. [PMID: 23787007 DOI: 10.1016/j.jfma.2013.02.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2012] [Revised: 12/07/2012] [Accepted: 02/05/2013] [Indexed: 12/13/2022] Open
Abstract
Baseline and on-treatment hepatitis B viral factors are reported to affect treatment responses. A lower baseline hepatitis B virus (HBV) DNA level is a strong predictor of the response to antiviral therapy. HBV genotype A/B patients have better responses to interferon-based therapy than those with genotypes C/D. Regarding the association of HBV mutants with responses to antiviral therapy, current evidence is limited. On-treatment viral suppression is the most important predictor of response to nucleoside analogs. On-treatment hepatitis B surface antigen decline is significantly associated with response to pegylated interferon. In the future, individualized therapy should be based on treatment efficacy, adverse effects, baseline and on-treatment predictors of antiviral therapy.
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Affiliation(s)
- Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
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Huang CC, Kuo TM, Yeh CT, Hu CP, Chen YL, Tsai YL, Chen ML, Chou YC, Chang C. One single nucleotide difference alters the differential expression of spliced RNAs between HBV genotypes A and D. Virus Res 2013; 174:18-26. [PMID: 23501362 DOI: 10.1016/j.virusres.2013.02.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 02/08/2013] [Accepted: 02/08/2013] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) is generally classified into eight genotypes (A to H) based on genomic sequence divergence. The sequence variation among the different HBV genotypes suggests that the spliced RNAs should be different from genotype to genotype. However, the cis-acting element involved in the modulation of the distinct expression profiles of spliced HBV RNAs remains unidentified. Moreover, the biological role of splicing in the life cycle of HBV is not yet understood. In this study, spliced RNAs generated from genotypes A and D were carefully characterized in transfected HepG2 cells. The species and frequency of the spliced RNAs were dramatically different in the two genotypes. Of note, a population of multiply spliced RNAs with intron 2067-2350 excision was identified in HBV genotype A-transfected HepG2 cells, but not in genotype D transfected HepG2 cells. Further, we found a single nucleotide difference (2335) located within the polypyrimidine tract of the splice acceptor site 2350 between the two genotypes, and a single base substitution at 2335 was able to convert the splicing pattern of genotype D (or genotype A) to that of genotype A (or genotype D). These findings suggest that different unique splice sites may be preferentially used in different HBV genotypes resulting in distinct populations of spliced RNAs. The possible significance of the distinct spliced RNAs generated from the different HBV genotypes in HBV infection is discussed.
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Affiliation(s)
- Chien-Chiao Huang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
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Song MJ, Song DS, Kim HY, Yoo SH, Bae SH, Choi JY, Yoon SK, Paik YH, Lee JS, Lee HW, Kim HJ. Durability of viral response after off-treatment in HBeAg positive chronic hepatitis B. World J Gastroenterol 2012; 18:6277-6283. [PMID: 23180949 PMCID: PMC3501777 DOI: 10.3748/wjg.v18.i43.6277] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the durability in hepatitis B e antigen (HBeAg) positive chronic hepatitis B patients who discontinued antiviral treatment.
METHODS: A total of 48 HBeAg positive chronic hepatitis B patients who were administered nucleoside analogues and maintained virological response for ≥ 6 mo [hepatitis B virus (HBV) DNA < 300 copies/mL and HBeAg seroconversion] before cessation of treatment were enrolled between February 2007 and January 2010. The criteria for the cessation of the antiviral treatment were defined as follows: (1) achievement of virological response; and (2) duration of consolidation therapy (≥ 6 mo). After treatment cessation, the patients were followed up at 3-6 mo intervals. The primary endpoint was serologic and virologic recurrence rates after withdrawal of antiviral treatment. Serologic recurrence was defined as reappearance of HBeAg positivity after HBeAg seroconversion. Virologic recurrence was defined as an increase in HBV-DNA level > 104 copies/mL after HBeAg seroconversion with previously undetectable HBV-DNA level.
RESULTS: During the median follow-up period of 18.2 mo (range: 5.1-47.5 mo) after cessation of antiviral treatment, the cumulative serological recurrence rate was 15 % at 12 mo. The median duration between the cessation of antiviral treatment and serologic recurrence was 7.2 mo (range: 1.2-10.9 mo). Of the 48 patients with HBeAg positive chronic hepatitis, 20 (41.6%) showed virological recurrence. The cumulative virologic recurrence rates at 12 mo after discontinuing the antiviral agent were 41%. The median duration between off-treatment and virologic recurrence was 7.6 mo (range: 4.3-27.1 mo). The mean age of the virological recurrence group was older than that of the non-recurrence group (46.7 ± 12.1 years vs 38.8 ± 12.7 years, respectively; P = 0.022). Age (> 40 years) and the duration of consolidation treatment (≥ 15 mo) were significant predictive factors for offtreatment durability in the multivariate analysis [P = 0.049, relative risk (RR) 0.31, 95% CI (0.096-0.998) and P = 0.005, RR 11.29, 95% CI (2.054-65.12), respectively]. Patients with age (≤ 40 years) who received consolidation treatment (≥ 15 mo) significantly showed durability in HBeAg positive chronic hepatitis B patients (P = 0.014). These results suggest that additional treatment for more than 15 mo after HBeAg seroconversion in patients who are ≤ 40 years old may be beneficial in providing a sustained virological response.
CONCLUSION: Our data suggest that HBeAg seroconversion is an imperfect end point in antiviral treatment. Long-term consolidation treatment (≥ 15 mo) in younger patients is important for producing better prognosis in HBeAg positive chronic hepatitis B.
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Jin YJ, Kim KM, Yoo DJ, Shim JH, Lee HC, Chung YH, Lee YS, Suh DJ. Clinical course of chronic hepatitis B patients who were off-treated after lamivudine treatment: analysis of 138 consecutive patients. Virol J 2012; 9:239. [PMID: 23078793 PMCID: PMC3495756 DOI: 10.1186/1743-422x-9-239] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2011] [Accepted: 09/18/2012] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND/AIMS Little is known about the long-term outcome of chronic hepatitis B (CHB) patients who discontinued antiviral therapy. We intended to analyze the long-term outcome of CHB patients who discontinued lamivudine therapy and to evaluate predictors for post-treatment outcome. MATERIAL/METHODS From 2007 to 2008, 138 lamivudine off-treated CHB patients with alanine aminotransferase normalization were consecutively enrolled. Post-treatment virologic relapse, biochemical breakthrough, hepatitis flare, and retreatment results were retrospectively analyzed. RESULTS Among 138 patients, 102 were initially HBeAg-positive at the start of lamivudine treatment. Virologic relapse, biochemical breakthrough, and hepatitis flare were observed in 45.2, 52.9, and 12.7% of HBeAg-positive and 29.4, 30.6, and 8.3% of HBeAg-negative patients during the median follow-up of 28 and 30 months, respectively. The cumulative virologic relapse and biochemical breakthrough rates were significantly lower in patients with HBV DNA <50 copies/mL than 50-104 copies/mL at lamivudine cessation. Hepatitis flare was observed in 4.8 and 11.8% of HBeAg-positive and HBeAg-negative patients with HBV DNA <50copies/mL, respectively. Thirty-eight among 138 patients received retreatment and most of them achieved biochemical (37/38) and virologic response (35/38) within 1 year of retreatment. Undetectable serum HBV DNA (<50 copies/mL) and young age at lamivudine cessation were inversely associated with virologic relapse. Undetectable HBV DNA at cessation, female, and initial HBeAg-negative were inversely associated with biochemical breakthrough. CONCLUSIONS Post-treatment virologic relapse and biochemical breakthrough incidence were low in patients who achieved undetectable viral titer at lamivudine cessation. Retreatment after biochemical breakthrough or virologic relapse was safe and effective. Intermittent antiviral therapy might be cautiously considered in appropriately selected CHB patients.
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Affiliation(s)
- Young-Joo Jin
- Department of Internal Medicine, Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, South Korea
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