|
1
|
Wei S, Hu M, Chen H, Xie Q, Wang P, Li H, Peng J. Effectiveness of antiviral treatment in HBeAg-negative chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase: a retrospective study. BMC Gastroenterol 2022; 22:387. [PMID: 35978283 PMCID: PMC9387004 DOI: 10.1186/s12876-022-02471-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 08/09/2022] [Indexed: 11/29/2022] Open
Abstract
Background There are inadequate data and no histological evidence regarding the effects of antiviral treatment for hepatitis B e-antigen (HBeAg)-negative chronic hepatitis B (CHB) patients with normal or mildly elevated alanine aminotransferase (ALT). This study investigated the effects of antiviral treatment on these patients. Methods We retrospectively analysed the outcomes of antiviral treatment for HBeAg-negative CHB patients with normal or mildly elevated ALT who were treated with nucleoside/nucleotide analogues (NAs) for up to 96 weeks. Results A total of 128 patients were enrolled; 74 patients had normal ALT and 54 patients had mildly elevated ALT. The total cumulative rates of viral suppression were 64.06%, 81.97%, and 96.39%, at weeks 24, 48, and 96, respectively. The cumulative rates of viral suppression for the normal and mildly elevated ALT groups were 67.85% and 58.97%, 86.39% and 76.31%, and 93.13% and 97.04% at weeks 24, 48, and 96, respectively. The serum HBV DNA levels at week 12 and hepatitis B surface antigen (HBsAg) levels at week 24 were significant predictors of the 96-week virological response. Of the 128 patients, 54 with normal ALT and 33 with mildly elevated ALT underwent FibroScan at baseline. Significant fibrosis (F ≥ 2) was found in 44.4% (n = 24) and 51.5% (n = 17) of the patients in the normal ALT group and mildly elevated ALT group, respectively. Compared with the values at baseline, liver stiffness values significantly decreased at week 48 (8.12 kPa vs. 6.57 kPa; p < 0.001) and week 96 (8.87 kPa vs. 6.43 kPa; p < 0.001), respectively. Conclusions HBeAg-negative CHB patients with normal ALT could benefit from antiviral therapy with NAs, similar to patients with mildly elevated ALT. Antiviral treatment is strongly recommended for HBeAg-negative CHB patients with normal ALT. Additionally, significant liver fibrosis is not rare in HBeAg-negative CHB patients with ALT less than two-times the upper limit of normal, and FibroScan should be performed regularly for these patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02471-y.
Collapse
Affiliation(s)
- Sufang Wei
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Meixin Hu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Hongjie Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China
| | - Qiuli Xie
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, 528300, China
| | - Peng Wang
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, 528300, China
| | - Hong Li
- Department of Infectious Diseases, Shunde Hospital, Southern Medical University, Foshan, 528300, China
| | - Jie Peng
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510080, China.
| |
Collapse
|
|
2
|
Nicastro E, Norsa L, Di Giorgio A, Indolfi G, D'Antiga L. Breakthroughs and challenges in the management of pediatric viral hepatitis. World J Gastroenterol 2021; 27:2474-2494. [PMID: 34092970 PMCID: PMC8160618 DOI: 10.3748/wjg.v27.i20.2474] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/04/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic infections by hepatitis B virus (HBV) and hepatitis C virus (HCV) major causes of advanced liver disease and mortality worldwide. Although regarded as benign infections in children, their persistence through adulthood is undoubtedly of concern. Recent advances in HCV treatment have restored the visibility of these conditions and raised expectations for HBV treatment, which is currently far from being curative. Herein we describe direct-acting antivirals available for pediatric HCV (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir, glecaprevir/pibrentasvir) and their real-world use. A critical review of the HBV pediatric classification is provided. Anti-HBV investigational compounds are reviewed in light of the pathophysiology in the pediatric population, including capsid assembly modulators, antigen secretion inhibitors, silencing RNAs, and immune modifiers. Recommendations for screening and management of immunosuppressed children or those with other risk factors or comorbidities are also summarized.
Collapse
Affiliation(s)
- Emanuele Nicastro
- Department of Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
| | - Lorenzo Norsa
- Department of Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
| | - Angelo Di Giorgio
- Department of Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
| | - Giuseppe Indolfi
- Department of Neurofarba, Meyer Children's University Hospital of Florence, Florence 50137, Italy
| | - Lorenzo D'Antiga
- Department of Pediatric Gastroenterology Hepatology and Transplantation, ASST Papa Giovanni XXIII, Bergamo 24127, Italy
| |
Collapse
|
|
3
|
Pfefferkorn M, Böhm S, Schott T, Deichsel D, Bremer CM, Schröder K, Gerlich WH, Glebe D, Berg T, van Bömmel F. Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers. Gut 2018; 67:2045-2053. [PMID: 28951526 DOI: 10.1136/gutjnl-2017-313811] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 07/19/2017] [Accepted: 08/07/2017] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Among individuals with chronic hepatitis B, those with hepatitis B e-antigen (HBeAg)-negative chronic hepatitis (CHB) can be difficult to distinguish from those with HBeAg-negative chronic HBV infection, also referred to as inactive HBV carriers (ICs), but both require different medical management. The level of HBV surface antigen (HBsAg) has been proposed as a marker to discriminate between chronic infection and hepatitis stages. HBsAg consists of large, middle and small HBs. The aim of this study was to determine whether the composition of HBsAg improved the identification of ICs among HBsAg-positive subjects with different phases of HBV infections. DESIGN HBV large surface proteins (LHBs) and HBV middle surface proteins (MHBs) were quantified in serum samples from 183 clinically well-characterised untreated patients with acute (n=14) HBV infection, ICs (n=44), CHBs (n=46), chronic HBeAg-positive phase (n=68) and hepatitis delta coinfection (n=11) using an ELISA, with well-defined monoclonal antibodies against the preS1 domain (LHBs) and the preS2-domain (MHBs). A Western blot analysis was used to verify the quantitation of the components of HBsAg. Total HBsAg was quantified using a modified commercially available assay (HBsAg V.6.0, Enzygnost, Siemens, Erlangen). RESULTS The composition of HBsAg showed specific patterns across different phases of hepatitis B. Individuals in the IC phase had significantly lower proportions of LHBs and MHBs than patients in acute or chronic phases irrespective of their HBV e-antigen status (p<0.0001) or HBsAg level. Both LHBs and MHBs ratios better predicted the IC phase than total HBsAg levels. CONCLUSION Quantification of MHBs, particularly LHBs represents a novel tool for the identification of the IC stage.
Collapse
Affiliation(s)
- Maria Pfefferkorn
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Stephan Böhm
- Max von Pettenkofer-Institute for Hygiene and Clinical Microbiology, Ludwig-Maximilians-Universität, Munich, Germany
| | - Tina Schott
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Danilo Deichsel
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Corinna M Bremer
- National Reference Center for Hepatitis B and D Viruses, Institute for Medical Virology, German Centre for Infection Research (DZIF), Justus Liebig University Giessen, Giessen, Germany
| | - Kathrin Schröder
- National Reference Center for Hepatitis B and D Viruses, Institute for Medical Virology, German Centre for Infection Research (DZIF), Justus Liebig University Giessen, Giessen, Germany
| | - Wolfram H Gerlich
- National Reference Center for Hepatitis B and D Viruses, Institute for Medical Virology, German Centre for Infection Research (DZIF), Justus Liebig University Giessen, Giessen, Germany
| | - Dieter Glebe
- National Reference Center for Hepatitis B and D Viruses, Institute for Medical Virology, German Centre for Infection Research (DZIF), Justus Liebig University Giessen, Giessen, Germany
| | - Thomas Berg
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Florian van Bömmel
- Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| |
Collapse
|
|
4
|
Colombatto P, Barbera C, Bortolotti F, Maina AM, Moriconi F, Cavallone D, Calvo P, Oliveri F, Bonino F, Brunetto MR. HBV pre-core mutant in genotype-D infected children is selected during HBeAg/anti-HBe seroconversion and leads to HBeAg negative chronic hepatitis B in adulthood. J Med Virol 2018; 90:1232-1239. [PMID: 29488227 DOI: 10.1002/jmv.25068] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 02/23/2018] [Indexed: 12/26/2022]
Abstract
Selection of HBeAg defective HBV mutants (mt) during childhood might influence infection outcome in adults. Aim of this study was to correlate the dynamics of pre-core HBV mutant (pre-C mt) selection with virological/clinical outcomes in children followed-up until adulthood. Eighty subjects (50-M/30-F), 70 HBeAg-positive (87.5%), and 10 (12.5%) HBeAg-negative/anti-HBe-positive at the admission, mostly genotype D infected (91.2%), with median age of 6.5 (range: 0.2-17) years, were followed-up for 14.3 years (range: 1.1-24.5); 46 (57.5%) received IFN treatment. HBV-DNA and q-HBsAg were tested by commercial assays, Pre-Core 1896 mt by direct-sequence, oligo-hybridization-assay, and allele-specific-PCR (sensitivity: 30%, 10%, and 0.1% of total viremia). HBeAg/anti-HBe seroconversion (SC) occurred in 55/70 (78.6%) children. After SC, 8 (14.6%) developed HBeAg-negative chronic hepatitis (CHB), 41 (74.5%) remain with HBeAg-negative chronic infection, and 6 (10.9%) lost HBsAg. Baseline HBV-DNA and HBsAg were lower in SC than in no-SC children (median: 7.35 vs 8.95 Log IU/mL, P = 0.005, and 4.72 vs 5.04 Log IU/mL, P = 0.015). The prevalence of pre-C mt increased rapidly (10-40%) around SC. Eventually, pre-C mt was detected in 100% of CHB, in 33% of chronic infections without disease, and in 16% of subjects who cleared HBsAg (P < 0.001). HBV-DNA levels remained slightly higher in carriers of HBeAg negative infection with dominant/mixed pre-C mt populations, than in those with dominant pre-C wt (mean Log IU/mL: 3.83 and 3.42 vs 2.67, P = 0.007). In conclusion, pre-C-mt is selected during HBeAg/anti-HBe SC in children with poor control of HBV replication, leading to HBeAg-negative chronic-active-hepatitis during adulthood.
Collapse
Affiliation(s)
- Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Cristiana Barbera
- Paediatric Gastroenterology Unit, Regina Margherita Children Hospital, Torino, Italy
| | | | - Anna M Maina
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Francesco Moriconi
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Daniela Cavallone
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Pierluigi Calvo
- Paediatric Gastroenterology Unit, Regina Margherita Children Hospital, Torino, Italy
| | - Filippo Oliveri
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
| | - Ferruccio Bonino
- University of Pittsburgh Medical Center Institute for Health, Chianciano Terme, Siena, Italy
- Fondazione Italiana Fegato, AREA Science Park, Campus Basovizza, Trieste, Italy
| | - Maurizia R Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Centre of the Tuscany Region for Chronic Liver Disease and Cancer, University Hospital of Pisa, Pisa, Italy
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| |
Collapse
|
|
5
|
Yu Y, Wan P, Cao Y, Zhang W, Chen J, Tan L, Wang Y, Sun Z, Zhang Q, Wan Y, Zhu Y, Liu F, Wu K, Liu Y, Wu J. Hepatitis B Virus e Antigen Activates the Suppressor of Cytokine Signaling 2 to Repress Interferon Action. Sci Rep 2017; 7:1729. [PMID: 28496097 PMCID: PMC5431827 DOI: 10.1038/s41598-017-01773-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 03/31/2017] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) infection causes acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), and eventually hepatocellular carcinoma (HCC). The presence of hepatitis B e antigen (HBeAg) in the serum generally indicates ongoing viral replication and disease progression. However, the mechanism by which HBeAg regulates HBV infection remains unclear. Interferons (IFNs) are pleiotropic cytokines that participate in host innate immunity. After binding to receptors, IFNs activate the JAK/STAT pathway to stimulate expression of IFN-stimulated genes (ISGs), leading to induction of antiviral responses. Here, we revealed that HBeAg represses IFN/JAK/STAT signaling to facilitate HBV replication. Initially, HBeAg stimulates the expression of suppressor of cytokine signaling 2 (SOCS2). Subsequently, SOCS2 impairs IFN/JAK/STAT signaling through reducing the stability of tyrosine kinase 2 (TYK2), downregulating the expression of type I and III IFN receptors, attenuating the phosphorylation and nucleus translocation of STAT1. Finally, SOCS2 inhibits the expression of ISGs, which leads to the repression of IFN action and facilitation of viral replication. These results demonstrate an important role of HBeAg in the regulation of IFN action, and provide a possible molecular mechanism by which HBV resists the IFN therapy and maintains persistent infection.
Collapse
Affiliation(s)
- Yi Yu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.,Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Pin Wan
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Yanhua Cao
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Wei Zhang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Junbo Chen
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Li Tan
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Yan Wang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Zhichen Sun
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Qi Zhang
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Yushun Wan
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Ying Zhu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Fang Liu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China
| | - Kailang Wu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.
| | - Yingle Liu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.
| | - Jianguo Wu
- State Key Laboratory of Virology and College of Life Sciences, Wuhan University, Wuhan, 430071, China.
| |
Collapse
|
|
6
|
Ieluzzi D, Covolo L, Donato F, Fattovich G. Progression to cirrhosis, hepatocellular carcinoma and liver-related mortality in chronic hepatitis B patients in Italy. Dig Liver Dis 2014; 46:427-32. [PMID: 24548819 DOI: 10.1016/j.dld.2014.01.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 12/17/2013] [Accepted: 01/10/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND The natural history of chronic hepatitis B is variable. We evaluated some of the risk factors for cirrhosis, hepatocellular carcinoma and liver-related mortality in Italian patients with chronic hepatitis B. METHODS A cohort of 105 untreated patients with chronic hepatitis B without cirrhosis at diagnosis was followed prospectively for a mean period of 23 years. Clinical, histological and ultrasound examinations, biochemical and virological tests, and causes of death were analyzed. RESULTS Forty-two (40%) patients became inactive carriers and 63 (60%) showed persistent alanine aminotransferase elevation: 13 (13%) associated with HBeAg persistence, 35 (33%) with detectable serum HBV-DNA but HBeAg-negative, 11 (10%) with concurrent virus infection and 4 (4%) with non-alcoholic fatty liver disease. Cirrhosis incidence was 1.56/100 person-years. Older age and sustained HBV replication predicted cirrhosis occurrence independently. Hepatocellular carcinoma incidence was 2.1/100 person-years in patients who developed cirrhosis and 0.06 in those who did not. Cirrhosis occurrence was associated with an increased risk of hepatocellular carcinoma (hazard ratio 20.4, 95% confidence interval 2.54-167.5) and liver-related death (16.5, 2.0-138.8). CONCLUSIONS In Italian patients with chronic hepatitis B cirrhosis strongly predicts hepatocellular carcinoma occurrence and disease-related mortality, thus indicating that early antiviral treatment should be instituted before cirrhosis occurrence.
Collapse
Affiliation(s)
- Donatella Ieluzzi
- Division of Gastroenterology and Endoscopy, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Department of Surgery, University of Verona, Verona, Italy
| | - Loredana Covolo
- Institute of Hygiene, Epidemiology and Public Health, University of Brescia, Brescia, Italy
| | - Francesco Donato
- Institute of Hygiene, Epidemiology and Public Health, University of Brescia, Brescia, Italy
| | - Giovanna Fattovich
- Division of Gastroenterology and Endoscopy, Azienda Ospedaliera Universitaria Integrata, Verona, Italy; Department of Medicine, University of Verona, Verona, Italy.
| |
Collapse
|
|
7
|
Martinot-Peignoux M, Asselah T, Marcellin P. HBsAg quantification to predict natural history and treatment outcome in chronic hepatitis B patients. Clin Liver Dis 2013; 17:399-412. [PMID: 23905812 DOI: 10.1016/j.cld.2013.05.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
There is a growing interest in serum HBsAg quantification (qHbsAg). HBsAg titers are negatively correlated with liver fibrosis in HBeAg(+) patients. In HBeAg(-) HBsAg level <1000 IU/ml and HBV-DNA titer <2000 IU/ml accurately identify inactive carriers. During PEG-IFN treatment qHBsAg identifies patients with no benefit from therapy at week 12, allowing stopping or switched- "week 12 stopping rule". During nucleos(t)ide analogues the role of qHBsAg need to be clarified. In clinical practice qHBsAg is a simple and reproducible tool that may be used in association with HBV-DNA to classify patients during the natural history of HBV and to monitor therapy.
Collapse
|
|
8
|
Sali S, Alavian SM, Foster GR, Keyvani H, Mehrnoosh L, Mohammadi N. Influencing Factors on the Outcome and Prognosis of Patients With HBV Infction: Seven Years Follow-up. HEPATITIS MONTHLY 2013; 13:e8743. [PMID: 24066002 PMCID: PMC3776148 DOI: 10.5812/hepatmon.8743] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Revised: 05/12/2013] [Accepted: 06/08/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) is one of the most common chronic viral infections in the world. Iran has a low to intermediate HBV prevalence and approximately 1.5 million people are living with HBV infection. The impact of HBV in Iran is unknown and given the very low levels of alcohol consumption, this region provides an opportunity to examine the impact of isolated chronic HBV infection. OBJECTIVES To examine and evaluate outcome and prognosis of HBV in Iran. PATIENTS AND METHODS A longitudinal cohort study dating from 2003-2010 was performed. The patients were assessed six months after their first visit and then during periodic visits for the subsequent seven years. The patients' medical history, route of diagnosis of infection, family history, and liver diseases status including: carrier state of HBV, chronic HBV, cirrhosis, and HCC were recorded. Descriptive and analytic statistics were performed, using SPSS software version 18. RESULTS 275 HBsAg positive patients, who had completed a 7 year follow up period, were selected. The annual incidence rate for chronic hepatitis B in inactive carrier states and cirrhosis were 0.46% and 0.2% respectively. Over seven years, the rate of inactive carriers decreased by eight percent (They turned into chronic HBV or became HBSAg negative). No significant association was found between HBSAg seroclearance, HBeAg seroconversion and the outcome in the end of each year of follow up. Different treatment regimens did not have any statistically significant difference regarding HBeAg seroconversion. There was no significant association between the outcome and different habitual characteristics, especially smoking, as well as family history on HBsAg, HBsAb, HBeAg, and Anti-HBeAg. Values of platelets and ALT showed a significant change during the follow ups. Annual incidence rate of HCC in the present study was in the range of other studies. CONCLUSIONS These data confirm and extend data from other populations showing a low incidence of significant change in chronic HBV infection in short term with good responses to currently available therapeutics.
Collapse
Affiliation(s)
- Shahnaz Sali
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
- Corresponding author: Shahnaz Sali, Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran. Tel: +98-9123067784, Fax: +98-2122546026, E-mail:
| | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Tehran, IR Iran
| | - Graham R Foster
- Queen Mary, University of London, the Liver Unit, London, UK
| | - Hossein Keyvani
- Department of Virology, Tehran University of Medical Science, Tehran, IR Iran
| | - Leila Mehrnoosh
- Baqiyatallah Research Center for Gastroenterology and Liver Disease, Tehran, IR Iran
| | - Navid Mohammadi
- Department of Community Medicine, Faculty of medicine, Tehran University of Medical Sciences, Tehran, IR Iran
| |
Collapse
|
|
9
|
Niro GA, Ippolito AM, Fontana R, Valvano MR, Gioffreda D, Iacobellis A, Merla A, Durazzo M, Lotti G, Di Mauro L, Andriulli A. Long-term outcome of hepatitis B virus-related Chronic Hepatitis under protracted nucleos(t)ide analogues. J Viral Hepat 2013; 20:502-9. [PMID: 23730844 DOI: 10.1111/jvh.12054] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2012] [Accepted: 11/01/2012] [Indexed: 12/11/2022]
Abstract
Long-term outcome of patients with chronic hepatitis B virus (HBV) infection under continuous nucleos(t)ide analogues (NUCs) has been poorly elucidated. We enrolled 121 anti-HBe-positive patients into a prospective surveillance programme while on (>36 months) NUCs therapy. HBV-DNA clearance, add-on therapy and safety were evaluated. Development of cirrhosis, events of liver decompensation and hepatocellular carcinoma (HCC) during the follow-up were the main endpoints, as the complication-free survival. At baseline, 74 patients (61%) had chronic hepatitis, the remainders a cirrhotic liver. HBV-DNA levels >38 000 IU/mL were discovered in 103 patients. At enrolment, 79 patients were naïve to NUCs treatment. Lamivudine monotherapy (n = 70) or a different NUC (n = 51) was administered. At month 6 of therapy, HBV-DNA clearance was documented in 88 patients (73%). Treatment schedule was modified in 52 patients due to breakthrough or suboptimal response. During a mean follow-up of 6 ± 3 years, viral clearance was achieved in the majority of patients. Ten of 74 patients (13.5%) with chronic hepatitis progressed to cirrhosis, 1 patient developed a HCC. In the 47 patients with cirrhosis at presentation, HCC occurred in 14 (30%) and liver decompensation in 5 (11%). The 5 and 10-year event-free survivals were, respectively, 89.3% (95% CI, 81.7 -96.9) and 75.6% (95% CI, 61.5 -89.7) for patients with chronic hepatitis, and 70.2% (95% CI, 56.3 -84.1) and 40.4% (95% CI, 16.9 -63.9) for those with cirrhosis. Protracted, effective treatment with oral NUCs affects the natural history of chronic HBV infection by reducing the incidence of cirrhosis and risk of complications, but does not guarantee against the development of HCC in cirrhosis at presentation.
Collapse
Affiliation(s)
- G A Niro
- Division of Gastroenterology, "Casa Sollievo Sofferenza" Hospital, IRCCS, San Giovanni Rotondo, Italy.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Lampertico P, Viganò M, Cheroni C, Facchetti F, Invernizzi F, Valveri V, Soffredini R, Abrignani S, De Francesco R, Colombo M. IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B. Hepatology 2013; 57:890-6. [PMID: 22473858 DOI: 10.1002/hep.25749] [Citation(s) in RCA: 121] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2011] [Accepted: 03/22/2012] [Indexed: 12/12/2022]
Abstract
UNLABELLED Interleukin (IL)28B polymorphisms have been associated with interferon (IFN)-induced viral clearance in patients with chronic hepatitis C. Whether this is also true for patients with the difficult-to-cure hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is unknown. One hundred and one HBeAg-negative patients (92% genotype D) with compensated CHB (84% males, 46 years; hepatitis B virus [HBV] DNA: 6.0 log cp/mL; alanine aminotransferase [ALT]: 136 IU/L; 42% with cirrhosis) were followed up for a median of 11 years (range, 1-17) after a median of 23 months (range, 10-48) of either standard or pegylated (Peg)-IFN-alpha therapy. A post-treatment response was defined as hepatitis B surface antigen (HBsAg) clearance with or without antibody to hepatitis B surface antigen (anti-HBs) seroconversion. The rs12979860 (C>T) genotype in the IL28B locus was assessed in serum samples by using Custom TaqMan SNP Genotyping Assays (Applied Biosystems, Carlsbad, CA). During a median of 11 years of post-treatment follow-up, 21 patients (21%) cleared serum HBsAg, including 15 who developed>10 IU/mL of anti-HBs titers. Forty-eight patients (47%) had CC genotype, 42 (42%) had CT, and 11 (11%) had TT, with the allelic frequency being 68% for C allele and 32% for T allele. The rate of serum HBsAg clearance was 29% (n=14) in CC compared to 13% (n=7) in non-CC, genotype carriers (P=0.039). Baseline HBV DNA levels<6 log cp/mL (odds ratio [OR], 11.9; 95% confidence interval [CI]: 2.8-50.6; P=0.001), ALT levels>136 IU/L (OR, 6.5; 95% CI: 1.8-22.5; P=0.003), duration of IFN (OR, 1.16; 95% CI: 1.02-1.31; P=0.021), and genotype CC (OR, 3.9; 95% CI: 1.1-13.2; P=0.025) independently predicted HBsAg clearance. CONCLUSIONS IL28B polymorphism is an additional predictor of off-therapy IFN-related HBsAg seroclearance to be used in the pretreatment stratification of HBeAg-negative patients chronically infected by genotype D of HBV.
Collapse
Affiliation(s)
- Pietro Lampertico
- Migliavacca Center for the Study of Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
Martinot-Peignoux M, Lapalus M, Asselah T, Marcellin P. The role of HBsAg quantification for monitoring natural history and treatment outcome. Liver Int 2013; 33 Suppl 1:125-32. [PMID: 23286856 DOI: 10.1111/liv.12075] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Since its discovery by Blumberg in 1965, the hepatitis B virus antigen (HBsAg) is used as the fingerprint of hepatitis B infection. The HBsAg level is a reflection of the transcriptional activity of cccDNA. It is an important marker that not only indicates active hepatitis B infection but can also predict clinical and treatment outcomes. Assays for HBsAg quantification are fully automated and have high output. HBsAg titres are higher in HBe antigen (HBeAg)(+) than in HBeAg(-) patients and are negatively correlated with liver fibrosis in HBeAg(+) patients. In HBeAg(-) chronic hepatitis B, an HBsAg level <1000 IU/ml and an HBV DNA titre <2000 IU/ml accurately identify inactive carriers. During PEG-IFN treatment, HBsAg quantification is used to identify patients who will not benefit from therapy as early as week 12 on therapy, so that treatment may be stopped or switched- 'week 12 stopping rule'. With nucleos(t)ide analogues (NA), the role of HBsAg quantification must be clarified. Several studies show that baseline and on-treatment HBsAg levels might identify patients that can be treated with no subsequent risk of reactivation. In clinical practice, HBsAg quantification is a simple and reproducible tool that can be used in association with HBV DNA to classify patients during the natural history of HBV and to monitor therapy.
Collapse
Affiliation(s)
- Michelle Martinot-Peignoux
- INSERM, U-773, CRB3, Université Paris-Diderot, Hôpital Beaujon, Clichy, France. michelle.martinot@.inserm.fr
| | | | | | | |
Collapse
|
|
12
|
|
|
13
|
Kim BK, Revill PA, Ahn SH. HBV genotypes: relevance to natural history, pathogenesis and treatment of chronic hepatitis B. Antivir Ther 2012; 16:1169-86. [PMID: 22155900 DOI: 10.3851/imp1982] [Citation(s) in RCA: 115] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Although chronic HBV infection is the leading cause of chronic liver disease and death worldwide, there are substantial differences in its clinical courses regarding prevalence, mode of transmission, characteristics of each phase, responses to antiviral therapy, and development of cirrhosis and hepatocellular carcinoma, according to geographical areas (Asia versus Western Europe and North America versus Africa). Furthermore, the clinical course in infected individuals depends on a complex interplay among various factors including viral, host, environmental and other factors. Recently, understanding of molecular characteristics of the prevailing HBV genotypes, frequently accompanied mutations and their clinical implications might explain these geographical differences more pertinently. Hence, in this article, we review the global epidemiology and the natural history of HBV infection, with emphasis on summarizing the different HBV genotypes according to regions.
Collapse
Affiliation(s)
- Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
| | | | | |
Collapse
|
|
14
|
Lam YF, Yuen MF, Seto WK, Lai CL. Current Antiviral Therapy of Chronic Hepatitis B: Efficacy and Safety. CURRENT HEPATITIS REPORTS 2011; 10:235-243. [PMID: 22131901 PMCID: PMC3210946 DOI: 10.1007/s11901-011-0109-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The treatment of chronic hepatitis B is in constant evolution. Interferon, the first agent licensed for chronic hepatitis B treatment, has been superseded by the growing popularity of nucleoside/nucleotide analogues (NA). However, resistance to these agents is a major challenge. Newer NAs, such as entecavir and tenofovir dipivoxil fumarate, have very low resistance rates and favorable safety profiles. Long-term use of these agents can effectively suppress hepatitis B virus DNA, leading to decrease in incidence of hepatitic flares, as well as in the development of cirrhosis and hepatocellular carcinoma. The efficacy and safety of various antiviral agents is discussed in this review.
Collapse
Affiliation(s)
- Yuk-Fai Lam
- Department of Medicine, The University of Hong Kong Queen Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong Queen Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong Queen Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong
| | - Ching-Lung Lai
- Department of Medicine, The University of Hong Kong Queen Mary Hospital, Pokfulam Road, Hong Kong, Hong Kong
| |
Collapse
|
|
15
|
Chan HLY, Thompson A, Martinot-Peignoux M, Piratvisuth T, Cornberg M, Brunetto MR, Tillmann HL, Kao JH, Jia JD, Wedemeyer H, Locarnini S, Janssen HLA, Marcellin P. Hepatitis B surface antigen quantification: why and how to use it in 2011 - a core group report. J Hepatol 2011; 55:1121-31. [PMID: 21718667 DOI: 10.1016/j.jhep.2011.06.006] [Citation(s) in RCA: 245] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2011] [Revised: 05/27/2011] [Accepted: 06/09/2011] [Indexed: 12/22/2022]
Abstract
Quantitative HBsAg had been suggested to be helpful in management of HBV, but assays were cumbersome. The recent availability of commercial quantitative assays has restarted the interest in quantitative serum hepatitis B surface antigen (HBsAg) as a biomarker for prognosis and treatment response in chronic hepatitis B. HBsAg level reflects the transcriptional activity of cccDNA rather than the absolute amount of cccDNA copies. Serum HBsAg level tends to be higher in hepatitis B e antigen (HBeAg)-positive than HBeAg-negative patients. Among patients with a low HBV DNA (<2000IU/ml), HBsAg <1000IU/ml in genotype D HBV infection and HBsAg <100IU/ml in genotype B/C HBV infection is associated with inactive carrier state in HBeAg-negative patients. The HBsAg reduction by nucleos(t)ide analogues (NA) is not as pronounced as by interferon treatment. On peginterferon treatment, sustained responders tend to show greater HBsAg decline than the non-responders. The optimal on-treatment HBsAg cutoff to predict response needs further evaluation in HBeAg-positive patients, but an absence of HBsAg decline together with a <2 log reduction in HBV DNA at week 12 can serve as stopping rule in HBeAg-negative patients with genotype D HBV infection. A rapid serum HBsAg decline during NA therapy may identify patients who will clear HBsAg in the long-term. There are early reports among Asian patients that an HBsAg level of <100IU/ml might predict lower risk of relapse after stopping NA treatment. In clinical practice, serum HBsAg level should be used together with, but not as a substitute for, HBV DNA.
Collapse
Affiliation(s)
- Henry Lik-Yuen Chan
- Department of Medicine and Therapeutics and Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Lu H, Geng DY, Shen F, Zhang JY, Lu B, Ma LX. Optimization of adefovir therapy in chronic hepatitis B according to baseline predictors and on-treatment HBV DNA: a 5-year prospective study. Virol J 2011; 8:444. [PMID: 21936898 PMCID: PMC3205069 DOI: 10.1186/1743-422x-8-444] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 09/21/2011] [Indexed: 02/07/2023] Open
Abstract
Background Adefovir Dipivoxil (ADV) is an important agent to suppress hepatitis B virus (HBV) replication with suboptimal effect on virological and serological response. To optimize Adefovir therapy in chronic hepatitis B (CHB) patients with hepatitis B e antigen (HBeAg) positive, we studied the baseline parameters and on-treatment HBV DNA for favorable outcomes. Methods 48 patients were enrolled in the study and followed up for 5 years prospectively. Baseline characteristics, virological, serological and biochemical parameters as well as on treatment HBV DNA were assessed in prediction of favorable outcomes. Results 1. The patients with baseline alanine aminotransferase (ALT) ≥5 × the upper limit of normal (ULN, 40 IU/L) had higher rates of viral response (VR), HBeAg loss and HBeAg seroconversion at year 5 compared to the patients with ALT < 5 × ULN (VR: 75% vs 43.8%, p = 0.035; HBeAg loss: 43.9% vs 13.8%, p = 0.017; HBeAg seroconversion: 37.9% vs 13.8%, p = 0.035); Patients with baseline HBV DNA < 109 copies/ml and ALT ≥3 × ULN had more chance of HBeAg seroconversion (40.9% vs 8.7%, p = 0.012), while in patients with HBeAg < 800 s/co or HBsAg < 5000 IU/ml higher rates of HBeAg loss were achieved. 2. HBV DNA level < 104 copies/ml at week 24 was predictive for VR (96.0% vs 40.9%, P < 0.001), HBeAg loss (84.0% vs 36.3%, P = 0.001) and HBeAg seroconversion (36.0% vs 9.1%, P = 0.030). Conclusions ADV treatment should be started for patients with baseline ALT≥5 × ULN or patients with ALT≥3 × ULN and HBV DNA < 109 copies/ml. Lower level of HBeAg(< 800 s/co) and HBsAg(< 5000 IU/ml) may be regarded as referenced factors. In patients with serum HBV DNA < 104 copies/ml at week 24 the therapy should continue, and a favorable outcome may be achieved in 5 years or longer.
Collapse
Affiliation(s)
- Hui Lu
- Jinan Infectious Disease Hospital, affiliated to Shandong University, Jinan, China
| | | | | | | | | | | |
Collapse
|
|
17
|
Lee JS, Kim JH, Park BL, Cheong HS, Koh I, Kim JYH, Park TJ, Pasaje CF, Bae JS, Lee HS, Kim YJ, Shin HD. No associations of polymorphisms in ADPRT with hepatitis B virus clearance and hepatocellular carcinoma occurrence in a Korean population. Hepatol Res 2011; 41:250-7. [PMID: 21276153 DOI: 10.1111/j.1872-034x.2010.00772.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
AIM The human adenosine diphosphate ribosyl transferase (ADPRT) gene might significantly affect cancer by encoding poly(ADP-ribose) polymerase 1 enzyme (PARP-1) and promoting an important role in cellular responses to DNA damage, genomic stabilization and regulation of tumor suppressor genes. We explored whether polymorphisms of ADPRT affect clearance of hepatitis B virus (HBV) infection or risk of hepatocellular carcinoma (HCC) occurrence in a Korean HBV cohort. METHODS Genotyping was performed in a total of 1066 subjects composed of 434 spontaneously recovered (SR) subjects as normal controls and 632 chronic carriers (CC) of HBV who were further classified into 325 patients with liver cirrhosis (LC)/chronic hepatitis (CH) and 307 patients with HCC. RESULTS Logistic analyses of six common single nucleotide polymorphisms (SNP) and their haplotypes revealed that none of the polymorphisms were significantly associated with clearance of HBV infection and HCC occurrence, except for nominal evidence of association between haplotype 2 (ht2) with HBV clearance (P = 0.05). In the analysis of age of HCC occurrence which is an important factor in disease progression to HCC, results from Cox proportional hazards showed that none of the variants were significantly associated with onset age of HCC occurrence, although a nominal signal in ht4 (P = 0.03, but P(corr) > 0.05) was initially detected. CONCLUSION Although ADPRT is an important gene for cellular responses and tumor regulations, our study provides evidence that ADPRT variations do not affect HBV clearance and HCC occurrence.
Collapse
Affiliation(s)
- Jin Sol Lee
- Department of Life Science, Sogang University Department of Genetic Epidemiology, SNP Genetics Department of Physiology, College of Medicine, Hanyang University Department of Internal Medicine and Liver Research Institute, Seoul National University, Seoul, Korea
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Abstract
There have been numerous research milestones since the discovery of the hepatitis B virus (HBV) in the 1960s. These mark major advances in the serology and epidemiology of HBV infection, in identifying the wide clinical spectrum of acute and chronic hepatic diseases as well as the extrahepatic conditions induced by this virus, the molecular biology of the virus including its variants and mutants, its molecular diagnosis and monitoring, the host immune responses to the infecting virus, the pathogenesis and immunopathogenesis of liver disease as well as its natural course and outcome. These landmark discoveries are the firm background for current and future developments in treatment. There are three consecutive and partly overlapping chronological periods to treatment milestones beginning with recombinant standard interferon-alpha (IFN-α) in the 1980s, then oral antivirals from 1998 to the present and in 2005 pegylated IFN-α (PEG-IFN). The renewed interest in PEG-IFN-α treatment is now focused on both HBeAg-positive and HBeAg-negative chronic hepatitis B and it now also aims at HBsAg loss when associated with on-treatment monitoring of serum HBV DNA and HBsAg levels, resulting in the closest thing to a cure of hepatitis B. The impressive progress made in all aspects of hepatitis B research suggests that curative therapy may be developed for all patients and for all phases of HBV infection in the foreseeable future. However for the moment, realistic efforts should be made to make treatment as widely available and affordable as possible and to apply current therapies to significantly reduce HBV morbidity and mortality.
Collapse
Affiliation(s)
- Stephanos J Hadziyannis
- Department of Medicine and Hepatology, Henry Dunant Hospital and Liver Research Unit, Athens University, Evgenidion Hospital, Athens, Greece.
| |
Collapse
|
|
19
|
Brunetto MR, Oliveri F, Colombatto P, Moriconi F, Ciccorossi P, Coco B, Romagnoli V, Cherubini B, Moscato G, Maina AM, Cavallone D, Bonino F. Hepatitis B surface antigen serum levels help to distinguish active from inactive hepatitis B virus genotype D carriers. Gastroenterology 2010; 139:483-90. [PMID: 20451520 DOI: 10.1053/j.gastro.2010.04.052] [Citation(s) in RCA: 300] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2009] [Revised: 03/31/2010] [Accepted: 04/29/2010] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS The accurate identification of inactive (serum HBV-DNA persistently <or=2000 IU/mL) hepatitis B virus (HBV) carriers (IC) is difficult because of wide and frequent HBV-DNA fluctuations. We studied whether hepatitis B surface antigen (HBsAg) serum levels (HBsAgsl) quantification may contribute to diagnosis of HBV phases in untreated hepatitis B e antigen-negative genotype D asymptomatic carriers. METHODS HBsAgsl were measured at baseline and end of follow-up and correlated with virologic and biochemical profiles of 209 consecutive carriers followed-up prospectively (median, 29; range, 12-110 months). HBV phases were defined after 1-year monthly monitoring of HBV-DNA and transaminases. RESULTS HBsAgsl were significantly lower in 56 inactive carriers (IC) than 153 active carriers (AC): median, 62.12 (range, 0.1-4068) vs median, 3029 (range, 0.5-82,480) IU/mL; P<.001. Among AC, HBsAgsl were lower in 31 AC whose viremia remained persistently <20,000 IU/mL (AC1) than in 122 AC with fluctuations>or=20,000 IU/mL (AC2): 883 (0.5-7838) vs 4233 (164-82,480) IU/mL, P=.002. HBV infection was less productive in IC and AC1 than AC2 (log10 HBV-DNA/HBsAgsl ratios 0.25 and 0.49 vs 2.06, respectively, P<.001) and in chronic hepatitis than cirrhosis (1.97 vs 2.34, respectively; P=.023). The combined single point quantification of HBsAg (<1000 IU/mL) and HBV-DNA (<or=2000 IU/mL) identified IC with 94.3% diagnostic accuracy, 91.1% sensitivity, 95.4% specificity, 87.9% positive predictive value, 96.7% negative predictive value. During follow-up, HBsAgsl were stable in AC but declined in IC (yearly median decline, -0.0120 vs -0.0768 log10 IU/mL, respectively, P<.001), 10 of whom cleared HBsAg. CONCLUSIONS HBsAgsl vary during chronic hepatitis B e antigen-negative genotype D infection and are significantly lower in IC. Single-point combined HBsAg and HBV-DNA quantification provides the most accurate identification of IC, comparable with that of long-term tight monitoring.
Collapse
|
|
20
|
Efficacy of pre-S-containing HBV vaccine combined with lamivudine in the treatment of chronic HBV infection. Dig Dis Sci 2009; 54:2026-30. [PMID: 19016327 DOI: 10.1007/s10620-008-0586-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2008] [Accepted: 10/17/2008] [Indexed: 12/25/2022]
Abstract
Treatment of chronic hepatitis B (CHB) is difficult. The response rate to interferon (IFN) as well as nucleoside analogs is not more than 30% in general. While interferon has many side effects, development of resistance in most of the nucleoside analogs precludes long-term use. Both groups of drugs are most efficacious in patients who already had or develop strong cellular immunity with treatment. A pre-S2-containing vaccine was shown to enhance cellular immunity and suppress hepatitis B virus (HBV)-DNA in subjects with chronic hepatitis B. We aimed to test the efficacy of short-term use of a nucleoside analog in combination with a pre-S2-containing vaccine in patients with CHB. In this open study, 48 consecutive patients (32 males and 16 females, mean age +/- SD: 33 +/- 12 years) with CHB without cirrhosis were treated with 100 mg/day lamivudine and four weekly intramuscular injections of Genhevac B 20 mcg (six doses) for 24 weeks. While 19 patients were hepatitis B e antigen (HBeAg) positive (+ve), 29 patients were Anti-HBe/HBV-DNA +ve at the outset. Response was defined as seroconversion to anti-HBe in HBeAg +ve subjects and normalization of alanine aminotransferase (ALT) with loss of HBV-DNA in anti-HBe/HBV-DNA +ve subjects. HBeAg seroconversion occurred in 5/19 subjects (26%). Eighteen of 29 anti-HBe/HBV-DNA +ves responded. In the follow-up, while relapse was not observed in any of the patients who seroconverted, 11/18 from the anti-HBe/HBV-DNA +ve group relapsed, resulting in a sustained response (SR) rate of 24% in this group. All the relapses happened in the first 48 weeks of follow-up, with no relapse thereafter. Pretreatment high serum HBV-DNA was a strong negative predictor of sustained response (SR) in HBeAg +ve group. Pretreatment serum ALT over 2 x upper limit of normal and HBV-DNA less than 200 pg/ml appeared positive predictors. None of HBeAg +ve previous interferon failures responded. Twenty-four weeks of lamivudine and hepatitis B vaccine treatment induces SR in around 1/4 of the patients with CHB. Most of the responders had high ALT and relatively low DNA.
Collapse
|
|
21
|
Ma H, Wei L, Guo F, Zhu S, Sun Y, Wang H. Clinical features and survival in Chinese patients with hepatitis B e antigen-negative hepatitis B virus-related cirrhosis. J Gastroenterol Hepatol 2008; 23:1250-8. [PMID: 18624896 DOI: 10.1111/j.1440-1746.2008.05499.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIM To compare the clinical features of hepatitis B e antigen (HBeAg)-negative and HBeAg-positive cirrhosis, and to define the survival and prognostic indicators of Chinese HBeAg-negative hepatitis B virus (HBV)-related cirrhosis. METHODS Two hundred and seventeen patients with chronic hepatitis B cirrhosis were studied. Survival was calculated using the Kaplan-Meier method. Proportional hazards Cox regression procedure was used to identify independent predictors of survival. The relationship between HBV-DNA viral load and prognosis was also investigated. RESULTS The mean follow-up time was 35 months (3-47 months). HBeAg-negative liver cirrhosis patients comprised the greatest number of cirrhosis patients. Median alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, median total leukocytes (WBC), hemoglobin (Hb), platelet (Plt) and HBV-DNA levels and the proportion of HBV-DNA > 10(5) copies/mL were lower in HBeAg-negative patients. There were fewer complications in patients treated with lamivudine than in other patients. Survival rates were significantly reduced in patients with HBeAg-negative cirrhosis (P = 0.0024). The baseline Child-Pugh scores and more than one decompensation during follow up were independent variables correlated with survival of HBeAg-negative liver cirrhosis patients (P = 0.006 and P = 0.001, respectively). The HBV-DNA viral load did not correlate with any complications or mortality rates of HBeAg-negative patients. CONCLUSIONS The clinical features of HBeAg-negative and -positive liver cirrhosis differ. Survival was significantly reduced for Chinese patients with HBeAg-negative than -positive cirrhosis. Factors contributing to the prognosis were baseline Child-Pugh scores and the presence of more than one decompensation during follow up.
Collapse
Affiliation(s)
- Hui Ma
- Peking University Hepatology Institute, Peking University People's Hospital, Beijing, China
| | | | | | | | | | | |
Collapse
|
|
22
|
Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J Hepatol 2008; 48:335-52. [PMID: 18096267 DOI: 10.1016/j.jhep.2007.11.011] [Citation(s) in RCA: 955] [Impact Index Per Article: 56.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The natural history of chronic hepatitis B virus (HBV) infection and disease is complex and highly variable. We review the natural history of chronic hepatitis B with emphasis on the rates of disease progression and factors influencing the course of the liver disease. Chronic hepatitis B is characterized by an early replicative phase (HBeAg positive chronic hepatitis) and a late low or non-replication phase with HBeAg seroconversion and liver disease remission (inactive carrier state). Most patients become inactive carriers after spontaneous HBeAg seroconversion with good prognosis, but progression to HBeAg negative chronic hepatitis due to HBV variants not expressing HBeAg occurs at a rate of 1-3 per 100 person years following HBeAg seroconversion. The incidence of cirrhosis appears to be about 2-fold higher in HBeAg negative compared to HBeAg positive chronic hepatitis. In the cirrhotic patient the 5-year cumulative risk of developing hepatocellular carcinoma is 17% in East Asia and 10% in the Western Europe and the United States and the 5-year liver related death rate is 15% in Europe and 14% in East Asia. There is a growing understanding of viral, host and environmental factors influencing disease progression, which ultimately could improve the management of chronic hepatitis B.
Collapse
Affiliation(s)
- Giovanna Fattovich
- Department of Surgical and Gastroenterological Sciences, University of Verona, Piazzale L.A. Scuro, 10, Verona 37134, Italy.
| | | | | |
Collapse
|
|
23
|
Gish RG, Lau DTY, Schmid P, Perrillo R. A pilot study of extended duration peginterferon alfa-2a for patients with hepatitis B e antigen-negative chronic hepatitis B. Am J Gastroenterol 2007; 102:2718-23. [PMID: 17662102 DOI: 10.1111/j.1572-0241.2007.01449.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Forty-eight weeks of peginterferon alfa-2a is the approved regimen for chronic hepatitis B (CHB). Standard interferon is more effective for hepatitis B e antigen (HBeAg)-negative CHB when given for longer than 1 yr. This study evaluated peginterferon alfa-2a for 60 wk, alone or in combination with lamivudine. METHODS Thirteen patients with HBeAg-negative CHB received peginterferon alfa-2a (180 microg/week) for 60 wk or peginterferon alfa-2a (180 microg/week) for 12 wk followed by 48 wk of peginterferon alfa-2a plus lamivudine. The primary end point, sustained virologic response (SVR), was defined as a reduction in hepatitis B virus deoxyribonucleic acid (HBV DNA) of >or=2 log10 copies/mL and HBV DNA<20,000 copies/mL at 24 wk of follow-up (week 84). Hepatitis B surface antigen (HBsAg) concentrations were analyzed and compared to changes in HBV DNA. RESULTS SVR was achieved by 9/13 patients (69%). At week 84, HBV DNA was undetectable by polymerase chain reaction in 5/13 (38%) patients, and 3 additional patients had a sustained 2-3 log reduction in HBV DNA. Five patients demonstrated a >90% decrease in HBsAg concentration at week 60, including 3 with undetectable HBV DNA at week 84 and a fourth who met criteria for SVR. CONCLUSIONS Sixty weeks of peginterferon alfa-2a with or without lamivudine resulted in a higher rate of SVR compared to historical controls with HBeAg-negative CHB treated with 48 wk of pegylated interferon. Larger studies are necessary to assess if longer duration therapy is more effective than the standard regimen and results in a greater decline in HBsAg concentration.
Collapse
Affiliation(s)
- Robert G Gish
- Division of Hepatology and Complex Gastroenterology, California Pacific Medical Center, San Francisco, California, USA
| | | | | | | |
Collapse
|
|
24
|
|
|
25
|
Yurdaydin C, Bozkaya H, Karaaslan H, Onder FO, Erkan OE, Yalçin K, Değertekin H, Bozdayi AM, Uzunalimoğlu O. A pilot study of 2 years of interferon treatment in patients with chronic delta hepatitis. J Viral Hepat 2007; 14:812-6. [PMID: 17927618 DOI: 10.1111/j.1365-2893.2007.00875.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
High dose interferon treatment for 1 year is the only established treatment for chronic hepatitis D, but it is associated with a high relapse rate after treatment discontinuation. In this study, patients were treated with 10 MU interferon alpha 2b, thrice weekly for 2 years. Twenty-three patients were recruited and 15 completed the 2-year treatment and 6 months follow-up periods. Treatment response was assessed biochemically [normal alanine aminotransferase (ALT)], virologically (undetectable hepatitis D virus RNA) and histologically (at least 2 point decrease in the Knodell score) at the end of treatment (EOT) and at the end of follow-up. Out of 15 patients who finished the 2-year treatment period, seven patients (47%) had a biochemical response but only two (13%) had a normal ALT after follow-up. ALT decreased from the baseline value of 143.1 +/- 121.7 (mean +/- SD) to 39.7 +/- 20.6 (P < 0.01) at EOT. Virological response was observed in six patients at EOT and in two patients at follow-up. Two patients lost hepatitis B surface antigen. Of the 12 patients with paired liver biopsies, a histological improvement was observed in eight patients. Interferon treatment leads to a complete or partial response in a substantial number of patients but 2 years of treatment does not appear to increase sustained response rates over 1 year treatment.
Collapse
Affiliation(s)
- C Yurdaydin
- Gastroenterology Section, University of Ankara Medical School, Turkey.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Pungpapong S, Kim WR, Poterucha JJ. Natural history of hepatitis B virus infection: an update for clinicians. Mayo Clin Proc 2007; 82:967-75. [PMID: 17673066 DOI: 10.4065/82.8.967] [Citation(s) in RCA: 137] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Significant progress has been made in the past few decades in understanding the natural history of HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. In immunocompetent adults, most HBV infections spontaneously resolve, whereas in most neonates and infants they become chronic. Those with chronic HBV may present in 1 of 4 phases of infection: (1) in a state of immune tolerance, (2) with hepatitis B e antigen (HBeAg)positive chronic hepatitis, (3) as an inactive hepatitis B surface antigen carrier, or (4) with HBeAg-negative chronic hepatitis. Of these, HBeAg-positive and HBeAg-negative chronic hepatitis may progress to cirrhosis and its long-term sequelae including hepatic decompensation and hepatocellular carcinoma. Several prognostic factors, such as serum HBV DNA concentrations, HBeAg status, serum aminotransferases, and certain HBV genotypes, have been identified to predict long-term outcome. These data emphasize the importance of monitoring all patients with chronic HBV infection to identify candidates for and select optimal timing of antiviral treatment, to recognize those at risk of complications, and to implement surveillance for early detection of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Surakit Pungpapong
- Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | | | | |
Collapse
|
|
27
|
Hadziyannis SJ. Treatment paradigms on hepatitis B e antigen-negative chronic hepatitis B patients. Expert Opin Investig Drugs 2007; 16:777-86. [PMID: 17501691 DOI: 10.1517/13543784.16.6.777] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The primary goal of treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B (CHB) is potent and durable suppression of hepatitis B virus (HBV) replication. It results in biochemical and histological remission of CHB and is the prerequisite for the prevention of cirrhosis, its life-threatening complications and hepatocellular carcinoma. Responses that are durable after the cessation of treatment are referred to as sustained virological responses, whereas those persisting under therapy are referred to as treatment-maintained virological responses. Treatment paradigms of sustained virological response in HBeAg-negative CHB are practically restricted to conventional IFN-alpha and pegylated interferons (peg-IFNs), and are limited only to patients with compensated liver disease. Long-lasting maintained virological responses without HBV resistance in HBeAg-negative CHB are achievable by all approved nucleos(t)ide analogues (lamivudine, adefovir and entecavir) in highly variable rates, depending on their potency, rapidity of virological response and genetic barrier to resistance. The maintenance of response under 5 years of adefovir treatment represents the most effective treatment paradigm for HBeAg-negative CHB, whereas such long-term data with entecavir and tenofovir monotherapy may become available in the near future. In patients with lamivudine-resistant HBV mutants, the recommended treatment strategy is to add adefovir at the same time as continuing treatment with lamivudine. There are no treatment paradigms as yet of combination therapy from the very outset with two nucleoside analogues for use in treatment-naive patients.
Collapse
|
|
28
|
Verma S, Thuluvath PJ. Correlation between hepatitis B virus DNA levels and liver histology: is the controversy because of paucity of data? J Clin Gastroenterol 2007; 41:339-42. [PMID: 17413597 DOI: 10.1097/mcg.0b013e31803238c6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
|
|
29
|
Kaymakoglu S, Danalioglu A, Demir K, Karaca C, Akyuz F, Onel D, Badur S, Cevikbas U, Besisik F, Cakaloglu Y, Okten A. Long-term results of interferon alpha monotherapy in patients with HBeAg-negative chronic hepatitis B. Dig Dis Sci 2007; 52:727-31. [PMID: 17237999 DOI: 10.1007/s10620-006-9445-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2006] [Accepted: 05/12/2006] [Indexed: 01/18/2023]
Abstract
We sought to evaluate the long-term results of interferon-alpha (IFN-alpha) therapy in patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. Eighty HBeAg-negative naive patients (62 men; mean age, 39.9 years) who received IFN-alpha for 6 months were studied. Alanine aminotransferase normalization with undetectable HBV-DNA by molecular hybridization was accepted as response. All patients but 1 were precirrhotic stage. At the end of treatment, 44 (55%) patients responded, and they were followed for a mean of 59.5 months (range, 18-132). Twenty-seven patients (61.4%) showed recurrence (63% in first year). Responses at 6 months and at the end of the follow-up period 42.5% and 30% (including 7 patients without end treatment response), respectively. Recurrence of HBV replication was not detected after the 2-years follow-up period. Histologic improvement was observed in 83.3% patients with end-of-follow-up response. HBsAg became negative in 4 patients (5%). On multivariate analysis, younger age (P = .04) and lower GGT level (P = .037) were independent factors for prediction of end-of-follow-up response. Nearly half of the patients with HBeAg-negative chronic hepatitis B responds to IFN-alpha at the end of therapy. Despite the high recurrence rates, response continues in about one third of patients after a mean of 59.5 months.
Collapse
Affiliation(s)
- Sabahattin Kaymakoglu
- Department of Gastroenterohepatology, Istanbul Medical Faculty, Istanbul University, Capa 34390, Istanbul, Turkey.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Hoda K, Nguyen MH. Chronic hepatitis B virus infection in patients with “Normal” ALT levels. ACTA ACUST UNITED AC 2007. [DOI: 10.1007/bf02942175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
|
|
31
|
Abstract
Chronic hepatitis B virus infection afflicts 400 million people worldwide and untreated will progress to cirrhosis in 15-40% of individuals, with an associated increased risk for the development of hepatocellular carcinoma. The 'inactive carrier state' carries a benign prognosis with a very low risk of cirrhosis or hepatocellular carcinoma. However, the hepatitis B e antigen (HBeAg)-positive chronic hepatitis state is an active disease state with increased risk for progressing to cirrhosis and hepatocellular carcinoma. The HBeAg-negative mutant variety of chronic hepatitis B has been associated with a higher incidence of cirrhosis at initial presentation and more frequent progression to hepatocellular carcinoma compared with the wild-type hepatitis B. Five medications are currently approved by the US FDA for the treatment of chronic hepatitis B: interferon-alpha, lamivudine, adefovir dipivoxil, entecavir and peginterferon-alpha-2a. Interferon-alpha therapy has been shown to increase the rate of HBeAg and hepatitis B DNA loss with a small chance of hepatitis B surface antigen loss, but has significant adverse effects and is ineffective against the HBeAg-negative mutant. Lamivudine is a safely used, orally administered drug with good efficacy, but is associated with the development of a lamivudine-resistant (Lam-R) mutant in a large proportion of patients after long-term therapy. High relapse rates after lamivudine therapy make this medication less effective in the HBeAg-negative mutant also. Adefovir dipivoxil is a safely used, orally administered drug, which is effective against the Lam-R mutant. Adefovir dipivoxil is effective against the wild-type and HBeAg-negative hepatitis B and has a very low incidence of resistance development. Entecavir is a highly potent and selective new oral drug against hepatitis B. It has demonstrated no resistance development in treatment-naive patients, but a low incidence of resistance in patients infected with prior Lam-R mutants. Peginterferon-alpha-2a is administered once weekly and has improved efficacy compared with standard interferon-alpha and lamivudine. However, it has a similar adverse-effect profile to standard interferon-alpha. Pharmacoeconomic studies have demonstrated a cost benefit in treating chronic hepatitis B patients compared with no therapy. However, results have been conflicting, with earlier studies showing a cost advantage of lamivudine over interferon-alpha and a more recent, comprehensive study favouring interferon-alpha monotherapy in HBeAg-negative patients and adefovir dipivoxil 'salvage' after lamivudine resistance development in HBeAg-positive patients.
Collapse
Affiliation(s)
- Steven-Huy B Han
- David Geffen School of Medicine at UCLA, Los Angeles, California 90095-7302, USA.
| |
Collapse
|
|
32
|
Zhang K, Imazeki F, Fukai K, Arai M, Kanda T, Mikata R, Yokosuka O. Analysis of the complete hepatitis B virus genome in patients with genotype C chronic hepatitis in relation to HBeAg and anti-HBe. J Med Virol 2007; 79:683-93. [PMID: 17457922 DOI: 10.1002/jmv.20849] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
To investigate the relationship between viral factors and the development of chronic hepatitis B, the entire hepatitis B virus (HBV) genome of chronic carriers at different disease stages were analyzed. Eighty genotype C HBV carriers including 12 hepatitis B e antigen (HBeAg) positive asymptomatic carriers (Group A), 49 HBeAg positive patients with chronic liver diseases (Group B) and 19 anti-HBe positive patients with chronic liver diseases (Group C) were studied. HBV nucleic acid from serum samples was sequenced directly and compared with GenBank reference sequences HBV X01587 and M12906. On phylogenetic analysis, 76 cases were genotype C2. Of the 76 genotype C2 cases, the nucleotide and amino acid substitution rates in the precore/core region were significantly higher in Groups B and C than in Group A, also in Group C than in Group B. The nucleotide substitution rates in the full genome and the core promoter region were significantly higher in Group C than in Group A, also in group C than in Group B. The nucleotide and amino acid substitution rates in the X region were significantly higher in Group C than in Group A. The amino acid substitution rate in the pre-S2 region was significantly higher in Group C than in Group B. Deletion mutations were found mainly in Groups B and C. This whole genome analysis of HBV chronic carriers suggested that the nucleotide substitutions and deletions in HBV were closely associated with the pathogenesis of chronic HBV infection.
Collapse
Affiliation(s)
- KaiYu Zhang
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | | | | | | | | | | | | |
Collapse
|
|
33
|
Scotto G, Palumbo E, Fazio V, Cibelli DC, Saracino A, Tartaglia A, Angarano G. Prolonged lamivudine treatment in patients with chronic active anti-HBe-positive hepatitis. Am J Ther 2006; 13:218-22. [PMID: 16772763 DOI: 10.1097/01.mjt.0000158341.93235.5e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The efficacy of lamivudine (LAM) at 100 mg/d for 1 year in normalizing serum ALT levels and suppressing HBV DNA has been demonstrated in many studies. However, frequent relapses make long-term results modest. In the present study, we evaluated the efficacy of LAM administered for 3 years in patients with chronic active anti-HBe-positive hepatitis. Thirty-four patients with chronic active anti-HBe-positive hepatitis were treated with LAM (100 mg) once daily for 3 years. Before treatment, all patients demonstrated serum ALT levels >2 times normal levels for >6 months and HBV DNA positivity >5 pg/mL as determined by the sandwich hybridization test for nucleic acid. Both ALT and HBV DNA were monitored during therapy. After 12 months of therapy, 24 of 34 patients (70.6%) showed evidence of HBV DNA clearance and normal ALT levels; 22 of 34 (64.7%) and 19 of 34 (55.8%) patients maintained a complete response after 2 and 3 years of therapy, respectively. The long-term LAM therapy (>1 year) was not associated with an increase in the response of intially nonresponder patients. The YMDD variant emerged in 17.6% of patients in the first year, in 35.2% during the second year, and 52.9% during the third year of treatment. LAM was well tolerated during the 3-year therapy in all patients. Patients with chronic active anti-HBe-positive hepatitis demonstrated that the LAM response rate tends to decrease over time due to the emergence of YMDD variants.
Collapse
Affiliation(s)
- Gaetano Scotto
- Infectious Diseases Unit, University of Foggia, Foggia, Italy.
| | | | | | | | | | | | | |
Collapse
|
|
34
|
Buti M. Tratamiento de la hepatitis crónica B HBeAg negativo. GASTROENTEROLOGÍA Y HEPATOLOGÍA 2006; 29:50-53. [DOI: 10.1157/13097578] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
35
|
Abstract
Significant progress has been made during the last 2 years in the treatment of chronic hepatitis B (CHB). Treatment decisions differ significantly depending on whether patients are HBeAg+ or HBeAg-, treatment-naive or nucleoside/nucleotide-resistant, and in early or advanced stages of liver disease. Courses of finite duration, aiming to achieve sustained off-therapy responses, are practically restricted to HBeAg+ patients with compensated chronic liver disease, whereas long-term therapy aiming to achieve maintained on-therapy remission is mostly applicable to HBeAg- individuals either with early or advanced liver disease. A course of finite duration with pegylated (PEG)-IFN-alpha-2a offers the highest probability of sustained off-therapy response in HBeAg+ individuals, as well as in some HBeAg- individuals. Long-term therapy with nucleoside/nucleotide analogues, both in HBeAg+ and HBeAg- CHB, has most favourable effects on patient outcome, provided that virological and biochemical remission is maintained without development of viral resistance. The best results are achievable with potent analogues suppressing serum hepatitis B virus (HBV) DNA to non-detectability by most sensitive techniques. The best 2-year resistance profile has hitherto been reported with entecavir monotherapy, and the best long-term resistance profile was seen with adefovir of 5-year duration. Adefovir is effective in most lamivudine (LAM)-resistant patients, but should be administered as an add-on rather than as a substitute for LAM. Combination therapies have entered the treatment arena of CHB by the side doors of LAM-resistance and of end-stage liver disease, and the most recent results suggest that treatment with combinations of two strong nucleosides/nucleotides with different resistance profiles may turn out to be the optimal first-line/first choice option in CHB.
Collapse
Affiliation(s)
- Stephanos J Hadziyannis
- Athens University, Department of Medicine and Hepatology, Henry Dunant Hospital, 107 Messogion Ave, 11526 Athens, Greece.
| |
Collapse
|
|
36
|
Fung SK, Wong FSH, Wong DKH, Hussain MT, Lok ASF. Hepatitis B virus genotypes, precore and core promoter variants among predominantly Asian patients with chronic HBV infection in a Canadian center. Liver Int 2006; 26:796-804. [PMID: 16911461 DOI: 10.1111/j.1478-3231.2006.01297.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIMS The epidemiology of hepatitis B virus (HBV) infection in North America may be changing as a result of immigration from endemic countries. The purpose of this study was to determine the prevalence of HBV genotypes, precore (PC) and core promoter (CP) variants, and the proportion of patients meeting treatment criteria for HBV. METHODS A cross-sectional study of consecutive HBV patients attending a Canadian tertiary liver center was conducted. HBV DNA was quantified by polymerase chain reaction assay. HBV genotypes and variants were determined using a line probe assay. RESULTS Two hundred and seventy-two patients were enrolled; 200 were not receiving treatment at enrollment, of whom 116 were men and 84 women with a mean age 42+/-14 years. Among this group, 177 (88%) patients were Asian and 19 (10%) were Caucasian and 69 (35%) patients were hepatitis B e antigen (HBeAg) positive. Genotypes B and C were found in 42% and 50% untreated patients, respectively; while CP and PC were detected in 52% and 43% patients, respectively. Approximately 20% patients not receiving treatment (29% HBeAg positive, 14% HBeAg negative) met AASLD guidelines for antiviral therapy. If lower cutoff values for alanine aminotransferase and HBV DNA levels were used, 49% patients would qualify for treatment. CONCLUSIONS The vast majority of patients at a Canadian tertiary referral center were Asian. Virological and clinical characteristics of these patients reflect their country of origin. Our findings highlight the need to monitor the changing patterns of HBV infection in countries with large immigrant populations.
Collapse
Affiliation(s)
- Scott K Fung
- Department of Medicine, University of Toronto, Toronto, ON, Canada
| | | | | | | | | |
Collapse
|
|
37
|
Baltayiannis G, Katsanos K, Karayiannis P, Tsianos EV. Interferon-alpha therapy in HBeAg-negative chronic hepatitis B: a long-term prospective study from north-western Greece. Aliment Pharmacol Ther 2006; 24:525-33. [PMID: 16886919 DOI: 10.1111/j.1365-2036.2006.03008.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
AIMS To determine the long-term response to interferon-alpha therapy in patients with hepatitis B e antigen-negative chronic hepatitis B, and the factors independently associated with response and survival. METHODS Sixty-three patients with documented hepatitis B e antigen-negative chronic hepatitis B treated with interferon-alpha for a year were followed-up for a period of 6 years. RESULTS Sustained biochemical and virological response was seen in 34.91% and 33.33% of patients at 6 and 12 months of follow-up, respectively, and histological improvement in 54.5% of sustained responders compared with non-responders (7.1%, P = 0.004, chi-squared test), at 6 months of follow-up. Multivariate analysis showed that patients with hepatitis B virus-DNA levels at 6 months of treatment <10,000 copies/mL had a low probability of relapse, compared with those with levels >10 000 copies/mL (P = 0.032). Age (>65 years) and hepatitis B virus-DNA level at 6 months of treatment (>10,000 copies/mL) were the independent factors for disease progression and survival (P = 0.041 and P = 0.044 respectively). At 6 years, a sustained response was still present in 19.04% of patients and 4.8% of them had developed anti-HBs. CONCLUSION Hepatitis B virus-DNA monitoring by quantitative polymerase chain reaction at 6 months of treatment may allow for early prediction of response to interferon-alpha, and may serve as an indicator of disease progression in the future.
Collapse
Affiliation(s)
- G Baltayiannis
- First Division of Internal Medicine, and Hepatogastroenterology Unit, Medical School, University of Ioannina, Ioannina, Greece
| | | | | | | |
Collapse
|
|
38
|
Abstract
The worldwide burden of hepatitis B mandates accurate and timely diagnosis of patients infected with the hepatitis B virus (HBV) and the use of treatment strategies derived from evidence-based guidelines. HBV is a DNA virus that produces a series of viral protein products circulating HBV DNA. Serologic and nucleic acid testing are critical to disease prevention and treatment objectives. Information from such testing helps determine patients' infectivity and immune status, appropriate monitoring strategies, and the efficacy of treatment, as well as providing data that contributes to a better understanding of the natural history and epidemiology of the disease. This article reviews the clinical use of state-of-the-art serologic and nucleic acid tests, including the relevance of hepatitis B e antigen and antibody and HBV DNA measurements as markers of disease activity. Viral load can be used to distinguish between active and inactive disease, define response to therapy, and detect the development of antiviral resistance. Some recent reports have suggested that high viral load is associated with poorer patient outcomes (eg, more rapid progression to cirrhosis and a higher incidence of hepatocellular carcinoma). Durable suppression of HBV DNA is evolving to become the primary goal of therapy, although all currently licensed medications have used histology as the primary end point of therapy. Suggested frequencies for HBV DNA monitoring are presented.
Collapse
Affiliation(s)
- Robert G Gish
- Division of Hepatology and Complex GI, Physician Foundation, California Pacific Medical Center, San Francisco, California, USA.
| | | |
Collapse
|
|
39
|
Mendy ME, Kaye S, van der Sande M, Rayco-Solon P, Waight PA, Shipton D, Awi D, Snell P, Whittle H, McConkey SJ. Application of real-time PCR to quantify hepatitis B virus DNA in chronic carriers in The Gambia. Virol J 2006; 3:23. [PMID: 16594999 PMCID: PMC1482686 DOI: 10.1186/1743-422x-3-23] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2005] [Accepted: 04/04/2006] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND/AIM The study aimed at developing a real-time quantitative PCR assay to monitor HBV serum virus load of chronic carriers enrolled in therapeutic trials. METHOD Quantitative real-time PCR assay was carried out using SYBR-Green signal detection and primers specific to the S gene. Thermal cycling was performed in an ABi 5700 sequence detection system. The assay was calibrated against an international HBV DNA standard and inter- and intra-assay reproducibility determined. Levels of viral load were monitored for 1-year in lamivudine treated carriers. Correlation between HBV DNA levels and HBeAg sero-status was determined in untreated carriers. RESULTS The qPCR assay showed good intra- and inter-assay reproducibility over a wide dynamic range (1.5 x 103 to 1.5 x 108 copies/mL) and correlated well with those from a commercial assay (r = 0.91, (p < 0.001). Viral load levels dropped dramatically but temporarily during and after a short course of lamivudine therapy. HBV DNA was a more reliable indicator of the presence of virus than HBe antigen and was detected in 77.0% (161/209) of HBeAg negative and in all HBeAg positive carriers. CONCLUSION This method is reliable, accurate, and reproducible. HBV DNA Quantification by qPCR can be used to monitor the efficacy of HBV therapy and useful in understanding the natural history of HBV in an endemic area.
Collapse
Affiliation(s)
- Maimuna E Mendy
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
- Viral Disease programme, Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
| | - Steve Kaye
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
- Imperial college, London, UK
| | - Marianne van der Sande
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
- RIVM, Bithoven, The Netherlands
| | - Pura Rayco-Solon
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
- Nutrition centre of the Philippines, Philippines
| | - Pauline A Waight
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
- National Protection Agency, Collindale, London, UK
| | - Deborah Shipton
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
| | - Dorka Awi
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
| | - Paul Snell
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
| | - Hilton Whittle
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
| | - Samuel J McConkey
- Medical Research Council, Atlantic Boulevard, Fajara, P O Box 273, Banjul, The Gambia
- Royal College of Surgeons in Ireland, Dublin, Ireland
| |
Collapse
|
|
40
|
Buti M, Casado MA, Calleja JL, Salmerón J, Aguilar J, Rueda M, Esteban R. Cost-effectiveness analysis of lamivudine and adefovir dipivoxil in the treatment of patients with HBeAg-negative chronic hepatitis B. Aliment Pharmacol Ther 2006; 23:409-19. [PMID: 16423000 DOI: 10.1111/j.1365-2036.2006.02767.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
AIM To estimate the cost-effectiveness over a 4-year duration of lamivudine and adefovir dipivoxil for patients with hepatitis B 'e' antigen-negative chronic hepatitis B. METHODS A decision analysis model has been used to perform a cost-effectiveness analysis of lamivudine and adefovir dipivoxil from the perspective of the Spanish Public Health System. Data were obtained from clinical trials. RESULTS For the base-case, the total estimated cost per patient treated with lamivudine or adefovir dipivoxil for 4 years was 11,457 and 21,939 respectively. Virological response at year 4 for the lamivudine arm was 40.4% and 78.0% for the adefovir dipivoxil arm. The average cost-effectiveness ratio (cost per responding patient at year 4) was 28,375 for the lamivudine arm and 28,132 for the adefovir dipivoxil arm. The incremental cost-effectiveness ratio of adefovir dipivoxil vs. lamivudine (cost per additional responding patient with adefovir dipivoxil) was 27,872, demonstrating that this cost was slightly lower than the average cost-effectiveness ratios of adefovir dipivoxil or lamivudine. The sensitivity analysis demonstrated that the factors that most influence the cost-effectiveness were the response to adefovir dipivoxil and lamivudine at year 4. CONCLUSION Long-term treatment with adefovir dipivoxil is a cost-effective strategy in patients with chronic hepatitis B 'e' antigen-negative hepatitis.
Collapse
Affiliation(s)
- M Buti
- Department of Hepatology, Hospital Vall d'Hebrón, Barcelona, Spain.
| | | | | | | | | | | | | |
Collapse
|
|
41
|
Yim HJ, Lok ASF. Natural history of chronic hepatitis B virus infection: what we knew in 1981 and what we know in 2005. Hepatology 2006; 43:S173-81. [PMID: 16447285 DOI: 10.1002/hep.20956] [Citation(s) in RCA: 367] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Remarkable progress has been made in our understanding of the natural history of chronic hepatitis B virus (HBV) infection in the past 25 years. Availability of sensitive HBV DNA assays and application of sophisticated immunological techniques led to the recognition that HBV replication persists throughout the course of chronic HBV infection, and host immune response plays a pivotal role in HBV-related liver disease. Knowledge of the HBV genome organization and replication cycle led to the unraveling of HBV genotypes and molecular variants, which contribute to the heterogeneity in outcome of chronic HBV infection. The natural course of chronic HBV infection is now perceived as consisting of 4 phases: immune tolerance, immune clearance [hepatitis B e antigen (HBeAg)-positive chronic hepatitis], inactive carrier state, and reactivation (HBeAg-negative chronic hepatitis B). Understanding the dynamic nature of chronic HBV infection is crucial in the management of HBV carriers and underscores the need for long-term monitoring. Accumulating evidence indicates that antiviral therapy can prevent progression of HBV-related liver disease, particularly among patients with sustained response. Newer antiviral therapies with improved efficacy and decreased risk of resistance may lead to a complete revision of the chapter on the natural history of chronic HBV infection on the occasion of the golden jubilee of Hepatology.
Collapse
Affiliation(s)
- Hyung Joon Yim
- Division of Gastroenterology, University of Michigan, Ann Arbor, MI 48109-0362, USA
| | | |
Collapse
|
|
42
|
Colombo M, Lampertico P. Natural History of Chronic Hepatitis B and Hepatocellular Carcinoma. VIRAL HEPATITIS 2005:263-268. [DOI: 10.1002/9780470987131.ch16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
43
|
Karayiannis P, Carman WF, Thomas HC. Molecular Variations in the Core Promoter, Precore and Core Regions of Hepatitis B Virus, and their Clinical Significance. VIRAL HEPATITIS 2005:242-262. [DOI: 10.1002/9780470987131.ch15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
44
|
Buti M, Jardi R, Rodriguez-Frias F, Valdes A, Schaper M, Esteban R, Guardia J. Changes in different regions of hepatitis B virus gene in hepatitis B 'e' antigen-negative patients with chronic hepatitis B: the effect of long-term lamivudine therapy. Aliment Pharmacol Ther 2005; 21:1349-56. [PMID: 15932365 DOI: 10.1111/j.1365-2036.2005.02503.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Lamivudine therapy for chronic hepatitis B has been associated with changes in different regions of the hepatitis B virus nucleotide sequence. AIM To study changes in the sequences of polymerase and precore/core promoter regions of hepatitis B virus, before and during 5 years of therapy with lamivudine. METHODS Eighty consecutive samples were taken from 10 chronic hepatitis B 'e' antigen-negative patients. RESULTS Nine patients carried hepatitis B virus precore mutations during the study. Before therapy, wild type was replaced by A1896 in two (20%) cases. During treatment, A1896 reverted transitory to wild type in five cases (50%) and in one case wild type was replaced by A1896. The continuous detection of precore mutations during therapy was associated with a lower response rate. YMDD mutations were observed in nine cases and both, L180M and M204V/I mutations were simultaneously detected in six cases. About 75% of the patients with M204V mutations were responders and none with M204I or mixed pattern sustained response. CONCLUSION Hepatitis B 'e' antigen-negative patients exhibit changes in the precore regions both spontaneously and under lamivudine therapy, the transitory reversion to wild type being most frequently witnessed. Patients carrying M204V mutations are more likely to respond to therapy. If, in further studies, these results are confirmed some patients with YMDD mutations could benefit from prolonging the duration of lamivudine therapy.
Collapse
Affiliation(s)
- M Buti
- Liver Unit, Servicio de Hepatologia, Hospital General Universitario Valle de Hebron, Barcelona, Spain.
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Papatheodoridis GV, Petraki K, Cholongitas E, Kanta E, Ketikoglou I, Manesis EK. Impact of interferon-alpha therapy on liver fibrosis progression in patients with HBeAg-negative chronic hepatitis B. J Viral Hepat 2005; 12:199-206. [PMID: 15720536 DOI: 10.1111/j.1365-2893.2005.00582.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The possible effect of interferon-alpha (IFNa) on liver fibrosis progression has not been adequately studied in chronic hepatitis B. We evaluated 147 patients with HBeAg-negative chronic hepatitis B who had > or =2 liver biopsies and had been treated with IFNa (n = 120) or had remained untreated (n = 27). The median interval between the two biopsies was 24 (12-160) months. All biopsies were scored blindly by a single liver histopathologist according to the classification of Ishak et al. (J Hepatol 1995; 22: 696-699). IFNa induced sustained biochemical response in 30, initial response and subsequent relapse in 57 and no response in 33 patients. Fibrosis improved in 17.5% of treated (sustained responders: 40%, relapsers: 9%, nonresponders: 12%) and 4% of untreated patients and worsened in 34% (sustained responders: 7%, relapsers: 40%, nonresponders: 48%) and 70% of cases, respectively (P = 0.002). The annual rate of fibrosis progression was worse in the untreated (0.427 +/- 0.119) than in treated patients (0.067 +/- 0.052, P = 0.001). However, the fibrosis progression rate in the untreated patients was not significantly different than the net fibrosis progression rate (after subtraction of IFNa duration) in nonresponders or relapsers. In multivariate analysis, worse fibrosis progression rate was associated with older age (P = 0.010), worse baseline grading score (P < 0.001), lower baseline fibrosis (P = 0.035) and the type of response to IFNa (P = 0.032). In conclusion, in HBeAg-negative chronic hepatitis B, IFNa significantly reduces the rate of fibrosis progression, but such an effect is mainly observed in patients with sustained biochemical responses. In relapsers and nonresponders, fibrosis benefit equals the treatment period. The strongest factor associated with fibrosis progression is the change in necroinflammatory activity.
Collapse
|
|
46
|
Wang Y, Wei L, Jiang D, Cong X, Fei R, Xiao J, Wang Y. In vitro resistance to interferon of hepatitis B virus with precore mutation. World J Gastroenterol 2005; 11:649-55. [PMID: 15655815 PMCID: PMC4250732 DOI: 10.3748/wjg.v11.i5.649] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Chronic hepatitis B virus (HBV) infection is predominantly treated with interferon alpha (IFN-α), which results in an efficient reduction of the viral load only in 20-40% of treated patients. Mutations at HBV precore prevail in different clinical status of HBV infection. The roles of precore mutation in the progression of chronic hepatitis and interferon sensitivity are still unknown. The aim of this study was to explore if there was any relationship between HBV precore mutation and sensitivity to interferon in vitro.
METHODS: HBV replication-competent recombinant constructs with different patterns of precore mutations were developed. Then the recombinants were transiently transfected into hepatoma cell line (Huh7) by calcium phosphate transfection method. With or without IFN, viral products in culture medium were collected and quantified 3 d after transfection.
RESULTS: We obtained 4 recombinant constructs by orientation-cloning 1.2-fold-overlength HBV genome into pUC18 vector via the EcoRI and Hind III and PCR mediated site-directed mutagenesis method. All the recombinants contained mutations within precore region. Huh7 cells transfected with recombinants secreted HBsAg and HBV particles into the cell culture medium, indicating that all the recombinants were replication-competent. By comparing the amount of HBV DNA in the medium, we found that HBV DNA in medium reflecting HBV replication efficiency was different in different recombinants. Recombinants containing precore mutation had fewer HBV DNAs in culture medium than wild type. This result showed that recombinants containing precore mutation had lower replication efficiency than wild type. HBV DNA was decreased in pUC18-HBV1.2-WT recombinants after IFN was added while others with precore mutations were not, indicating that HBV harboring precore mutation was less sensitive to IFN in cell culture system.
CONCLUSION: These data indicate that HBV harboring precore mutation may be resistant to IFN in vitro.
Collapse
Affiliation(s)
- Yan Wang
- Hepatology Institute, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing 100044, China
| | | | | | | | | | | | | |
Collapse
|
|
47
|
You J, Zhuang L, Cheng HY, Yan SM, Qiao YW, Huang JH, Tang BZ, Ma YL, Wu GB, Qu JY, Wu RX. A randomized, controlled, clinical study of thymosin alpha-1 versus interferon-alpha in [corrected] patients with chronic hepatitis B lacking HBeAg in China [corrected]. J Chin Med Assoc 2005; 68:65-72. [PMID: 15759817 DOI: 10.1016/s1726-4901(09)70137-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND This study was designed to compare the efficacy and safety of thymosin-alphal (T-alpha1) with that of interferon-alpha (IFN-alpha) in patients with chronic hepatitis B who were positive for hepatitis B virus (HBV) DNA and hepatitis B envelope antibody (anti-HBe). METHODS Fifty-six patients were randomly divided into groups A and B. Both groups were comparable (p > 0.05) at baseline regarding age, sex, and alanine aminotransferase (ALT) levels. Group A patients received T-alpha1 1.6 mg subcutaneously twice weekly, while group B patients received IFN-alpha 5 million IU daily for 15 days, then thrice weekly for 6 months. Results from the 2 groups were compared with data from a group of 30 patients never treated with IFN-alpha and who were followed-up for 12 months (historical control [HC] group); the 3 groups were comparable (p > 0.05). RESULTS After treatment, a complete response (ALT normalization and HBV DNA loss) occurred in 8 of 26 patients in group A (30.8%) and 14 of 30 in group B (46.7%; chi2 = 1.476, p = 0.224). After a follow-up period of 6 months, a complete response was observed in 11 of 26 patients in group A (42.3%) and 7 of 30 in group B (23.3%; chi2 = 2.299, p = 0.129). The rate of complete response was significantly greater in the IFN-alpha than HC group at the end of therapy (46.7% vs 3.3%; chi2 = 15.022, p = 0.0001), and in the T-alphal than HC group at the end of follow-up (42.3% vs 3.3%; chi2 = 12.566, p = 0.0001). Ten of the 12 T-alphal responders (i.e. partial responders; 83.3%) experienced sustained, non-detectable HBV DNA after 6 months' treatment; 6 of the 14 T-alphal non-responders (42.9%) showed a delayed response of non-detectable HBV DNA during the follow-up period. Corresponding values for group B patients were 50% (9/18) and 0% (0/12). The rate of delayed response was significantly higher in group A than the other 2 groups (chi2 = 6.686, p = 0.010; chi2 = 4.964, p = 0.038), whereas the rate of flare was higher in group B than in the other 2 groups (chi2 = 3.445, p = 0.063; chi2 = 7.668, p = 0.006), during the follow-up period. Unlike IFN-alpha, T-alphal was well tolerated, i.e. no adverse effects were noted in group A. CONCLUSION These results suggest that a 6-month course of T-alpha1 therapy is effective and safe in patients with anti-HBe-positive chronic hepatitis B; T-alpha1 can reduce HBV replication in such patients. Compared with IFN-alpha, T-alpha1 is better tolerated and seems to induce a gradual and more sustained normalization of ALT and loss of HBV DNA. Combination therapy with T-alpha1 and IFN-alpha or nucleoside analogs for hepatitis B warrants further study.
Collapse
Affiliation(s)
- Jing You
- Department of Infectious Diseases, The First Affiliated Hospital of Kunming Medical College, Yunnan Province, China.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Fung SK, Wong F, Hussain M, Lok ASF. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat 2004; 11:432-8. [PMID: 15357648 DOI: 10.1111/j.1365-2893.2004.00556.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Lamivudine has demonstrated efficacy for the treatment of hepatitis B e antigen-negative chronic hepatitis B (e-CHB). However, treatment withdrawal after 1 year has been associated with a high rate of relapse while long-term treatment is associated with increasing risks of drug resistance. We report our treatment experience of 50 Chinese-Canadian patients with e-CHB. All patients received lamivudine for 2 years. Treatment was withdrawn at month 24 in patients who had undetectable hepatitis B virus (HBV) DNA by PCR and normal aminotransferases during the second year of therapy. All patients had HBV genotype B or C. Biochemical response at months 6, 12 and 24 was 74%, 71% and 66%, respectively. HBV DNA was undetectable at months 6, 12 and 24 by hybrid capture and PCR assays in 100%, 92% and 86%; and 94%, 88% and 74% patients, respectively. The cumulative rates of genotypic resistance (GR) after 1 and 2 years were 15% and 25%, respectively. Four (44%) patients with GR experienced a hepatitis flare. The probability of clinical and virological relapse 6, 12, and 18 months after treatment withdrawal were 12% and 30%, 18% and 50%, and 30% and 50%, respectively. Reinstitution of lamivudine resulted in prompt virological and biochemical responses. Our study demonstrates that a sustained response can be achieved after a 2-year course of lamivudine in a subset of patients with e-CHB.
Collapse
Affiliation(s)
- S K Fung
- Department of Medicine, University of Toronto, Toronto, Ont., Canada.
| | | | | | | |
Collapse
|
|
49
|
Chu CM, Hung SJ, Lin J, Tai DI, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med 2004; 116:829-34. [PMID: 15178498 DOI: 10.1016/j.amjmed.2003.12.040] [Citation(s) in RCA: 210] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2003] [Revised: 11/21/2003] [Accepted: 12/08/2003] [Indexed: 02/06/2023]
Abstract
BACKGROUND Natural history studies of hepatitis B virus infection have shown relapse of hepatitis in 5% to 15% of patients and progression to cirrhosis in 2% to 6% annually. Follow-up of patients beginning at the early phase of infection might provide data with less referral bias than in previous studies. METHODS Test of liver biochemistry, assessment of virological markers, and ultrasound examinations were performed at regular intervals during the course of hepatitis B e antigen (HBeAg) to antibody (anti-HBe) seroconversion in 240 HBeAg carriers with normal alanine aminotransferase levels at baseline. Factors predictive of cirrhosis were identified by multivariate analysis. RESULTS We enrolled 130 men and 110 women. The mean (+/- SD) age at entry was 27.6 +/- 6.2 years. During the HBeAg-positive phase, 29% of patients had alanine aminotransferase levels > or =200 U/L, 3% had bilirubin levels > or =2.0 mg/dL, and 5% had two or more episodes of alanine aminotransferase levels > or =200 U/L. The mean age at anti-HBe seroconversion was 31.3 +/- 7.0 years, with remission of hepatitis in all patients. However, hepatitis recurred in 36 patients (15%), with an annual rate of 2.2%. Thirteen patients (5%) progressed to cirrhosis. The annual incidence of cirrhosis was 0.5%, and the cumulative probability of cirrhosis after 17 years was 12.6%. Age at anti-HBe seroconversion and relapse of hepatitis were independent risk factors for cirrhosis. CONCLUSION The clinical severity of chronic hepatitis B was milder in this cohort than in previous studies. Delayed HBeAg seroconversion and relapse of hepatitis were associated with increased risk of cirrhosis.
Collapse
Affiliation(s)
- Chia-Ming Chu
- Liver Research Unit, Chang Gung Memorial Hospital, and Chang Gung University, Taipei, Taiwan.
| | | | | | | | | |
Collapse
|
|
50
|
Wai CT, Fontana RJ. Clinical significance of hepatitis B virus genotypes, variants, and mutants. Clin Liver Dis 2004; 8:321-52, vi. [PMID: 15481343 DOI: 10.1016/j.cld.2004.02.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Emerging evidence suggests that hepatitis B virus (HBV) genotypes may influence the rate of spontaneous and interferon-induced hepatitis B e antigen (HBeAg) seroconversion as well as the natural history of liver disease. In contrast, the dinical significance of precore and core promoter variants associated with HBeAg negative liver disease is less certain in light of the many competing host and virologic factors noted in reported studies. HBV surface mutants are primarily associated with prior vaccine or hepatitis B immune globulin exposure and do not appear to have untoward virulence or association with occult HBV infection. Polymerase mutants with reduced drug sensitivity and phenotypic resistance are commonly detected in patients receiving prolonged antiviral therapy and have a variable impact on disease outcomes. The introduction of additional nucleoside/nucleotide analog agents will likely lead to the development of further unique polymerase mutants with varying pathogenicity and cross-resistance to existing drugs.
Collapse
Affiliation(s)
- Chun-Tao Wai
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA
| | | |
Collapse
|