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1
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Sallam E, Aboulnaga S, Samy A, Beltagy D, Desouky JME, Abdel-Hamid H, Fetouh H. Synthesis, characterization of new heterocyclic compound: pyrazolyl hydrazino quinoxaline derivative: 3-[5-(hydroxy1methyl)-1-phenylpyrazol-3-yl]-2-[2, 4, 5-trimethoxybenzylidine] hydrazonyl-quinoxaline of potent antimicrobial, antioxidant, antiviral, and antitumor activity. J Mol Struct 2023. [DOI: 10.1016/j.molstruc.2022.133983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Chen QY, Jia HH, Wang XY, Shi YL, Zhang LJ, Hu LP, Wang C, He X, Harrison TJ, Jackson JB, Wu L, Fang ZL. Analysis of entire hepatitis B virus genomes reveals reversion of mutations to wild type in natural infection, a 15 year follow-up study. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2022; 97:105184. [PMID: 34902556 DOI: 10.1016/j.meegid.2021.105184] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 12/03/2021] [Accepted: 12/08/2021] [Indexed: 06/14/2023]
Abstract
It has been reported that some mutations in the genome of hepatitis B virus (HBV) may predict the outcome of the virus infection. However, evolutionary data derived from long-term longitudinal analysis of entire HBV genomes using next generation sequencing (NGS) remain rare. In this study, serum samples were collected from asymptomatic hepatitis B surface antigen (HBsAg) carriers from a long-term prospective cohort. The entire HBV genome was amplified by polymerase chain reaction (PCR) and sequenced using NGS. Twenty-eight time series serum samples from nine subjects were successfully analysed. The Shannon entropy (Sn) ranged from 0 to 0.89, with a median value of 0.76, and the genetic diversity (D) ranged from 0 to 0.013, with a median value of 0.004. Intrahost HBV viral evolutionary rates ranged from 2.39E-04 to 3.11E-03. Double mutations at nt1762(A → T) and 1764(G → A) and a stop mutation at nt1896(G → A) were seen in all sequences from subject BO129 in 2007. However, in 2019, most sequences were wild type at these positions. Deletions between nt 2920-3040 were seen in all sequences from subject TS115 in 2007 and 2013 but these were not present in 2004 or 2019. Some sequences from subject CC246 had predicted escape substitutions (T123N, G145R) in the surface protein in 2004, 2013 and 2019 but none of the sequences from 2007 had these changes. In conclusion, HBV mutations may revert to wild type in natural infection. Clinicians should be wary of predicting long-term prognoses on the basis of the presence of mutations.
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Affiliation(s)
- Qin-Yan Chen
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Hui-Hua Jia
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China; School of Preclinical Medicine, Guangxi Medical University, 22 ShuangYong Road, Nanning, Guangxi 530021, China
| | - Xue-Yan Wang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Yun-Liang Shi
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Lu-Juan Zhang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Li-Ping Hu
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Chao Wang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China
| | - Xiang He
- Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou 511430, China
| | - Tim J Harrison
- Division of Medicine, University College London Medical School, London, UK
| | - J Brooks Jackson
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, USA
| | - Li Wu
- Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa, Iowa City, USA
| | - Zhong-Liao Fang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, China.
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Kilonzo SB, Gunda D, Ning Q, Han M. Where Hepatitis B and Hepatitis E Meet: Epidemiological and Clinical Aspects. HEPATITIS MONTHLY 2019; 19. [DOI: 10.5812/hepatmon.93840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/09/2019] [Indexed: 08/30/2023]
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Mehmankhah M, Bhat R, Anvar MS, Ali S, Alam A, Farooqui A, Amir F, Anwer A, Khan S, Azmi I, Ali R, Ishrat R, Hassan MI, Minuchehr Z, Kazim SN. Structure-Guided Approach to Identify Potential Inhibitors of Large Envelope Protein to Prevent Hepatitis B Virus Infection. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1297484. [PMID: 31772697 PMCID: PMC6854180 DOI: 10.1155/2019/1297484] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 06/10/2019] [Accepted: 07/02/2019] [Indexed: 01/05/2023]
Abstract
Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, which can lead to hepatocellular carcinoma. The role of HBV envelope proteins is crucial in viral morphogenesis, infection, and propagation. Thus, blocking the pleiotropic functions of these proteins especially the PreS1 and PreS2 domains of the large surface protein (LHBs) is a promising strategy for designing efficient antivirals against HBV infection. Unfortunately, the structure of the LHBs protein has not been elucidated yet, and it seems that any structure-based drug discovery is critically dependent on this. To find effective inhibitors of LHBs, we have modeled and validated its three-dimensional structure and subsequently performed a virtual high-throughput screening against the ZINC database using RASPD and ParDOCK tools. We have identified four compounds, ZINC11882026, ZINC19741044, ZINC00653293, and ZINC15000762, showing appreciable binding affinity with the LHBs protein. The drug likeness was further validated using ADME screening and toxicity analysis. Interestingly, three of the four compounds showed the formation of hydrogen bonds with amino acid residues lying in the capsid binding region of the PreS1 domain of LHBs, suggesting the possibility of inhibiting the viral assembly and maturation process. The identification of potential lead molecules will help to discover more potent inhibitors with significant antiviral activities.
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Affiliation(s)
- Mahboubeh Mehmankhah
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Ruchika Bhat
- Department of Chemistry & School of Biological Sciences, Indian Institute of Technology Delhi, New Delhi 110016, India
| | - Mohammad Sabery Anvar
- Systems Biotechnology Department, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Shahnawaz Ali
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Aftab Alam
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Anam Farooqui
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Fatima Amir
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Ayesha Anwer
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Saniya Khan
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Iqbal Azmi
- Multidisciplinary Center for Advanced Research and Studies, Jamia Millia Islamia, New Delhi 110025, India
| | - Rafat Ali
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Romana Ishrat
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Md. Imtaiyaz Hassan
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Zarrin Minuchehr
- Systems Biotechnology Department, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Syed Naqui Kazim
- Center for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
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KASL clinical practice guidelines for management of chronic hepatitis B. Clin Mol Hepatol 2019; 25:93-159. [PMID: 31185710 PMCID: PMC6589848 DOI: 10.3350/cmh.2019.1002] [Citation(s) in RCA: 165] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Accepted: 03/25/2019] [Indexed: 02/06/2023] Open
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Clinical Manifestations and Laboratory Tests of AECHB and Severe Hepatitis (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7418529 DOI: 10.1007/978-94-024-1603-9_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This chapter describes the clinical symptoms and signs of AECHB and HBV ACLF, classification, grading of HBV ACLF and their features, diagnostic principles and standards in liver pathology, biochemistry, and virology of HBV ACLF.
Liver failure is defined as serious damage to the liver cause by a variety of etiologies, leading to liver function disorder or even decompensation, and clinical syndromes with coagulopathy, jaundice, hepatic encephalopathy, and ascites. Severe hepatitis B can be indicated pathologically by apparent hepatocellular necrosis, including extensive multifocal, confluent, bridging, sub-massive or massive necrosis. Laboratory tests during the course of severe exacerbation of chronic hepatitis B can reflect pathological changes and liver function in a timely manner, providing objective and informative reference data for evaluation of disease severity and treatment efficacy. Among the most important laboratory tests are those for prothrombin activity, international normalized ratio, and increases in total bilirubin concentration. Severe hepatitis B is associated with interactions between the virus and host factors. Detection of HBV DNA, HBV genotype, quasispecies and HBV mutation can provide important theoretical bases for the prevention, control or mitigation of the progress of severe hepatitis B. Noninvasive imaging modalities can be used to visualize the entire liver and parts of it. Measuring liver volume to evaluate liver size and liver reserve capacity is regarded as important in diagnosis, surgical approach and prognostic evaluation of patients with severe exacerbation of chronic hepatitis B and liver failure. Model for End-Stage Liver Disease (MELD) is the first quantitative method developed to assess whether a patient with liver failure requires a liver transplant. The predictive value of the MELD model has been improved by the MELD-Na, iMELD, and MESO models. Several other valuable prognostic models have been developed. For example, for patients with HBV-ACLF, the established TPPM scoring system was found to be more predictive than MELD score.
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Coffin CS, Terrault NA. Treatment of HCV, HDV, or HIV Coinfection. HEPATITIS B VIRUS AND LIVER DISEASE 2018:239-262. [DOI: 10.1007/978-981-10-4843-2_13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Valaydon ZS, Locarnini SA. The virological aspects of hepatitis B. Best Pract Res Clin Gastroenterol 2017; 31:257-264. [PMID: 28774407 DOI: 10.1016/j.bpg.2017.04.013] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 04/28/2017] [Indexed: 01/31/2023]
Abstract
Human hepatitis B virus (HBV) is a hepatotropic virus that is responsible for a significant burden of disease, causing liver disease and hepatocellular carcinoma. It is a small DNA virus with a replication strategy that is similar to that of a retrovirus. HBV is prone to mutagenesis and under the influence of diverse selection pressures, has evolved into a pool of quasispecies, genotypes and mutants, which confers a significant survival advantage. The genome is small, circular, and compact but has a complex replication strategy. The viral life cycle involves the formation of a covalently closed circular DNA (cccDNA), which is organized into a minichromosome that is the template for the synthesis of viral mRNA. HBV DNA (double-stranded linear form) can also integrate into the host genome, ensuring lifelong persistence of the virus. To date, despite great advances in therapeutics, once HBV is chronically established, it is incurable. This is by virtue of many aspects of its virological structure and viral life cycle. In this review, we aim to discuss important aspects of the virology of HBV with a focus on clinical implications.
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Affiliation(s)
- Zina S Valaydon
- Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia; Department of Gastroenterology, St. Vincent's Hospital, Fitzroy, Victoria, Australia; Department of Medicine, Eastern Hill Academic Centre, The University of Melbourne, Parkville, Victoria, Australia.
| | - Stephen A Locarnini
- Division of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute, Parkville, Victoria, Australia
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Lee HW, Park JY, Kim BK, Kim MY, Lee JI, Kim YS, Yoon KT, Han KH, Ahn SH. Efficacy of switching from adefovir to tenofovir in chronic hepatitis B patients who exhibit suboptimal responses to adefovir-based combination rescue therapy due to resistance to nucleoside analogues (SATIS study). Clin Mol Hepatol 2016; 22:443-449. [PMID: 27880997 PMCID: PMC5266340 DOI: 10.3350/cmh.2016.0037] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/22/2016] [Accepted: 08/30/2016] [Indexed: 12/17/2022] Open
Abstract
Background/Aims It remains to be determined whether switching from adefovir (ADV) to tenofovir (TDF) provides better virological outcomes in patients exhibiting suboptimal responses to ADV plus nucleoside analogue (ADV+NA) therapy for NA-resistant chronic hepatitis B (CHB). Methods In this prospective trial, patients who showed partial responses (defined as serum hepatitis B virus [HBV] DNA >60 IU/mL) to ADV+NA therapy for NA resistance were randomly allocated to receive TDF plus NA (TDF+NA group, n=16) or to continue their current therapy (ADV+NA group, n=16). The primary end point was the proportion of patients with complete virological response (CVR, defined as serum HBV DNA <60 IU/mL) at 48 weeks. Results The median age was 52 years (16 men), and 28 were positive for hepatitis B e antigen (HBeAg). The baseline characteristics did not differ significantly between the two groups. The proportion with CVR was significantly higher in the TDF+NA group than in the ADV+NA group at 24 weeks (81.3% vs. 25.0%, P=0.001) and 48 weeks (87.5% vs. 37.5%, P=0.002). Furthermore, a decrease in the serum HBV DNA level of >2log10 IU/mL was more likely in the TDF+NA group at both 24 and 48 weeks (68.8% vs. 56.3%, P=0.014 vs. 81.3% vs. 56.3%, P=0.001, respectively). During the follow-up, the rate of HBeAg seroconversion was higher in the TDF+NA group than the ADV+NA group (12.5% vs. 6.25%, P=0.640), as was that for the hepatitis B surface antigen (6.25% vs. 0%, P=0.080). No serious adverse events due to antiviral agents occurred. Conclusion In patients exhibiting suboptimal responses to ADV+NA therapy for NA-resistant CHB, switching from ADV to TDF might provide better virological outcomes.
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Affiliation(s)
- Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Moon Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jung Il Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Young Suk Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea
| | - Kwang-Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.,Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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Liu C, Cai D, Zhang L, Tang W, Yan R, Guo H, Chen X. Identification of hydrolyzable tannins (punicalagin, punicalin and geraniin) as novel inhibitors of hepatitis B virus covalently closed circular DNA. Antiviral Res 2016; 134:97-107. [PMID: 27591143 DOI: 10.1016/j.antiviral.2016.08.026] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 08/24/2016] [Accepted: 08/29/2016] [Indexed: 02/07/2023]
Abstract
The development of new agents to target HBV cccDNA is urgently needed because of the limitations of current available drugs for treatment of hepatitis B. By using a cell-based assay in which the production of HBeAg is in a cccDNA-dependent manner, we screened a compound library derived from Chinese herbal remedies for inhibitors against HBV cccDNA. Three hydrolyzable tannins, specifically punicalagin, punicalin and geraniin, emerged as novel anti-HBV agents. These compounds significantly reduced the production of secreted HBeAg and cccDNA in a dose-dependent manner in our assay, without dramatic alteration of viral DNA replication. Furthermore, punicalagin did not affect precore/core promoter activity, pgRNA transcription, core protein expression, or HBsAg secretion. By employing the cell-based cccDNA accumulation and stability assay, we found that these tannins significantly inhibited the establishment of cccDNA and modestly facilitated the degradation of preexisting cccDNA. Collectively, our results suggest that hydrolyzable tannins inhibit HBV cccDNA production via a dual mechanism through preventing the formation of cccDNA and promoting cccDNA decay, although the latter effect is rather minor. These hydrolyzable tannins may serve as lead compounds for the development of new agents to cure HBV infection.
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Affiliation(s)
- Chunlan Liu
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 43001, Hubei, China
| | - Dawei Cai
- Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA
| | - Lin Zhang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 43001, Hubei, China
| | - Wei Tang
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 43001, Hubei, China
| | - Ran Yan
- Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA
| | - Haitao Guo
- Department of Microbiology and Immunology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
| | - Xulin Chen
- State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 43001, Hubei, China.
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12
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Tong Y, Liu B, Liu H, Zheng H, Gu J, Liu H, Lin M, Ding Y, Song C, Li Y. New universal primers for genotyping and resistance detection of low HBV DNA levels. Medicine (Baltimore) 2016; 95:e4618. [PMID: 27537600 PMCID: PMC5370826 DOI: 10.1097/md.0000000000004618] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
HBV (hepatitis B virus) genotyping is important in determining the clinical manifestation of disease and treatment response, particularly, in patients with low viral loads. Also, sensitive detection of HBV antiviral drug resistance mutations is essential for monitoring therapy response.Asensitive direct sequencing method for genotyping and the drug resistance mutation detection of low levels of HBV DNA in patients' plasma is developed by PCR amplification of the DNA with novel universal primers.The novel, common, and universal primers were identified by alignment of RT region of all the HBV DNA sequences in databases. These primers could efficiently amplify the RT region of HBV virus at low DNA levels by directly sequencing the resulting PCR products, and mapping with the reference sequence made it possible to clearly obtain the HBV subtypes and identify the resistance mutations in the samples with HBV DNA level as low as 20 IU/mL. We examined the reliability of the method in clinical samples, and found it could detect the HBV subtypes and drug resistance mutations in 80 clinical HBV samples with low HBV DNA levels ranging from 20 to 200 IU/mL.This method is a sensitive and reliable direct sequencing method for HBV genotyping and antiviral drug resistance mutation detection, and is helpful for efficiently monitoring the response to therapy in HBV patients.
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Affiliation(s)
- Yongqing Tong
- Department of Clinical Laboratory
- Clinical Molecular Diagnostic Center, Renmin Hospital of Wuhan University
| | - Bei Liu
- Department of Pathology Affiliated Tianyou Hospital of Wuhan University of Science and Technology, Wuhan
| | - Hui Liu
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hongyun Zheng
- Clinical Molecular Diagnostic Center, Renmin Hospital of Wuhan University
| | - Jian Gu
- Department of Clinical Laboratory
| | - Hang Liu
- Clinical Molecular Diagnostic Center, Renmin Hospital of Wuhan University
| | - Min Lin
- Pennsylvania State University College of Medicine and Hershey Medical center, Hershey, PA
- New York University College of Arts and Science, New York, NY
| | - Yali Ding
- Pennsylvania State University College of Medicine and Hershey Medical center, Hershey, PA
| | - Chunhua Song
- Pennsylvania State University College of Medicine and Hershey Medical center, Hershey, PA
- Correspondence: Yan Li, Department of Clinical Laboratory, Renmin Hospital of Wuhan University, 99 Ziyang Road of Wuchang District, Wuhan 430060, China (e-mail: ); Chunhua Song, Pennsylvania State University College of Medicine, Penn State Hershey Children's Hospital, PO Box 850, 500 University Drive, Hershey, PA 17033 (e-mail: )
| | - Yan Li
- Department of Clinical Laboratory
- Clinical Molecular Diagnostic Center, Renmin Hospital of Wuhan University
- Correspondence: Yan Li, Department of Clinical Laboratory, Renmin Hospital of Wuhan University, 99 Ziyang Road of Wuchang District, Wuhan 430060, China (e-mail: ); Chunhua Song, Pennsylvania State University College of Medicine, Penn State Hershey Children's Hospital, PO Box 850, 500 University Drive, Hershey, PA 17033 (e-mail: )
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14
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The Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of chronic hepatitis B. Clin Mol Hepatol 2016; 22:18-75. [PMID: 27044762 PMCID: PMC4825166 DOI: 10.3350/cmh.2016.22.1.18] [Citation(s) in RCA: 150] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 02/22/2016] [Indexed: 01/10/2023] Open
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Croagh CM, Desmond PV, Bell SJ. Genotypes and viral variants in chronic hepatitis B: A review of epidemiology and clinical relevance. World J Hepatol 2015; 7:289-303. [PMID: 25848459 PMCID: PMC4381158 DOI: 10.4254/wjh.v7.i3.289] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Revised: 12/04/2014] [Accepted: 12/29/2014] [Indexed: 02/06/2023] Open
Abstract
The Hepatitis B Virus (HBV) has a worldwide distribution and is endemic in many populations. It is constantly evolving and 10 genotypic strains have been identified with varying prevalences in different geographic regions. Numerous stable mutations in the core gene and in the surface gene of the HBV have also been identified in untreated HBV populations. The genotypes and viral variants have been associated with certain clinical features of HBV related liver disease and Hepatocellular carcinoma. For example Genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion, and more advanced liver disease. Genotype A is associated with a greater risk of progression to chronicity in adult acquired HBV infections. Genotype D is particularly associated with the precore mutation and HBeAg negative chronic hepatitis B (CHB). The genotypes prevalent in parts of West Africa, Central and South America, E, F and H respectively, are less well studied. Viral variants especially the Basal Core Promotor mutation is associated with increased risk of fibrosis and cancer of the liver. Although not currently part of routine clinical care, evaluation of genotype and viral variants may provide useful adjunctive information in predicting risk about liver related morbidity in patients with CHB.
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Affiliation(s)
- Catherine Mn Croagh
- Catherine MN Croagh, Paul V Desmond, Sally J Bell, Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Victoria 3065, Australia
| | - Paul V Desmond
- Catherine MN Croagh, Paul V Desmond, Sally J Bell, Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Victoria 3065, Australia
| | - Sally J Bell
- Catherine MN Croagh, Paul V Desmond, Sally J Bell, Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Victoria 3065, Australia
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Cho YK, Cui XJ, Jeong SU, Song BC. Different mechanism of selection of adefovir-resistant mutant viruses during adefovir monotherapy in patients with lamivudine-resistant chronic hepatitis B. Antiviral Res 2014; 112:8-17. [PMID: 25303802 DOI: 10.1016/j.antiviral.2014.09.013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Revised: 08/29/2014] [Accepted: 09/29/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Adefovir (ADV) resistance is more frequent in lamivudine (LMV)-resistant chronic hepatitis B (CHB) patients than in nucleos(t)ide analogue-naïve patients. The majority of LMV-resistant mutants harbor the rtM204V/I mutation, while a minor fraction harbor the rtA181V/T mutation. We aimed to elucidate the mechanism of the high rate of ADV resistance in LMV-resistant patients during ADV therapy. METHODS We performed a clonal analysis of HBV reverse transcriptase in treatment-naïve (n = 3) and LMV-resistant patients before ADV therapy (n = 14). Dynamic changes in the viral population (n = 9) during ADV therapy were also analyzed. RESULTS Before ADV therapy, rtA181V/T was observed in 30 of 680 clones (4.4%) from 7 patients with LMV resistance under dominant rt204V/I mutation and in one of 150 clones in treatment-naïve patients. The rtA181V/T mutation was more frequently found in clones from LMV-resistant patients than in treatment-naïve patients (p = 0.029). The rtN236T mutation was not observed in any clone. During ADV therapy, most rtM204V/I mutants were replaced by wild type in all 3 patients without the rtA181V/T mutation and in one patient with the rtA181V/T mutation. Subsequently, wild type was replaced by the rtN236T and/or rtA181V/T mutant. In patients with the rtA181V/T mutation (n = 6), the rtA181V/T mutant overtook the rtM204V/I mutant in 3 of 4 patients with ADV resistance. In 2 patients without ADV resistance, most of the viral population was replaced by wild type by the last follow-up. CONCLUSION The high rate of ADV resistance in patients with LMV-resistance might be attributable to preexisting rtA181V/T mutant virus.
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Affiliation(s)
- Yoo-Kyung Cho
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Xiu-Ji Cui
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Seung Uk Jeong
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea
| | - Byung-Cheol Song
- Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Republic of Korea.
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Bang KB, Kim HJ. Management of antiviral drug resistance in chronic hepatitis B. World J Gastroenterol 2014; 20:11641-11649. [PMID: 25206270 PMCID: PMC4155356 DOI: 10.3748/wjg.v20.i33.11641] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 01/10/2014] [Accepted: 05/28/2014] [Indexed: 02/07/2023] Open
Abstract
Rescue antiviral treatment for patients with resistance to preexisting nucleos(t)ide analogues remains a clinical challenge. The correct choice of a first-line treatment of high potency and with a high genetic barrier to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and the emergence of drug resistance. The management of treatment failure and drug resistance requires a precise and accurate clinical and virologic monitoring. Combination treatment with antiviral drugs that belong to different groups is associated with a lower chance of developing resistance to rescue drugs. To guarantee better control of viral replication in patients with drug resistance, the addition of another drug without a cross resistance profile should be given as early as possible, preferably at the time when genotypic resistance emerges. Long-term surveillance for treatment efficacy and possible emergence of drug resistance should be continued to prevent the emergence of multidrug-resistant strains.
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Woo HY, Choi JY, Yoon SK, Suh DJ, Paik SW, Han KH, Um SH, Kim BI, Lee HJ, Cho M, Lee CK, Kim DJ, Hwang JS. Rescue therapy with adefovir in decompensated liver cirrhosis patients with lamivudine-resistant hepatitis B virus. Clin Mol Hepatol 2014; 20:168-76. [PMID: 25032183 PMCID: PMC4099332 DOI: 10.3350/cmh.2014.20.2.168] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 05/30/2014] [Accepted: 06/05/2014] [Indexed: 12/14/2022] Open
Abstract
Background/Aims Adefovir dipivoxil (ADV) is a nucleotide analogue that is effective against lamivudine-resistant hepatitis B virus (HBV). The aim of this study was to determine the long-term clinical outcomes after ADV rescue therapy in decompensated patients infected with lamivudine-resistant HBV. Methods In total, 128 patients with a decompensated state and lamivudine-resistant HBV were treated with ADV at a dosage of 10 mg/day for a median of 33 months in this multicenter cohort study. Results Following ADV treatment, 86 (72.3%) of 119 patients experienced a decrease in Child-Pugh score of at least 2 points, and the overall end-stage liver disease score decreased from 16±5 to 14±10 (mean ± SD, P<0.001) during the follow-up period. With ADV treatment, 67 patients (56.3%) had undetectable serum HBV DNA (detection limit, 0.5 pg/mL). Virologic breakthrough occurred in 38 patients (36.1%) and 9 patients had a suboptimal ADV response. The overall survival rate was 89.9% (107/119), and a suboptimal response to ADV treatment was associated with both no improvement in Child-Pugh score (≥2 points; P=0.001) and high mortality following ADV rescue therapy (P=0.012). Conclusions Three years of ADV treatment was effective and safe in decompensated patients with lamivudine-resistant HBV.
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Affiliation(s)
- Hyun Young Woo
- Department of Internal Medicine, Pusan National University College of Medicine, Pusan, Korea
| | - Jong Young Choi
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Kew Yoon
- Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
| | - Dong Jin Suh
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung Woon Paik
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kwang Hyub Han
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Soon Ho Um
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Byung Ik Kim
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Heon Ju Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Mong Cho
- Department of Internal Medicine, Pusan National University College of Medicine, Pusan, Korea
| | - Chun Kyon Lee
- Department of Internal Medicine, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Chuncheon, Korea
| | - Jae Seok Hwang
- Department of Internal Medicine, Keimyung University College of Medicine, Daegu, Korea
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Hardikar W, Schwarz KB. Treatment options for chronic hepatitis B and C infection in children. Expert Rev Anti Infect Ther 2014; 4:583-91. [PMID: 17009938 DOI: 10.1586/14787210.4.4.583] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
There has been a dramatic increase in treatment options for both chronic hepatitis B (CHB) and chronic hepatitis C (CHC) infection in adults over the past 5-10 years, resulting in standardized regimes for initial treatment, relapsers and even infection in the setting of recurrence post-liver transplantation. These regimes have resulted in the halting of the disease progression, reduction in the risk of hepatocellular carcinoma and removal of these infections as a contraindication for liver transplantation. However, treatment in children must be considered carefully in the context of the natural history of these infections and host factors, particularly the immunological mileu, which may affect response to therapy. The as yet unknown long-term effects of medications must also be balanced with the probability of significant life-long morbidity or mortality from chronic hepatitis and its complications. Furthermore, the development of drug resistance, particularly in the case of CHB, has significant implications for the pediatric patient who may exhaust effective therapeutic options at a relatively young age. For these reasons, initiation of therapy must be based on sound criteria. Based on the current data, we recommend that therapy should be offered to children with CHB who have an elevation in alanine aminotransferase (>2-3 x upper limit of normal) for more than 6 months. Therapy with interferon-alpha should be offered in the majority of cases with the aim of immune clearance as measured by early antigen seroconversion. By contrast, treatment indication for CHC in children remains controversial. If used, combination therapy with pegylated interferon and ribavirin is likely to produce the highest rates of sustained viral response.
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Affiliation(s)
- Winita Hardikar
- Royal Children's Hospital, Department of Gastroenterology and Nutrition, Melbourne, Australia.
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Prior exposure to lamivudine increases entecavir resistance risk in chronic hepatitis B Patients without detectable lamivudine resistance. Antimicrob Agents Chemother 2014; 58:1730-7. [PMID: 24395227 DOI: 10.1128/aac.02483-13] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The efficacy of entecavir (ETV) treatment in chronic hepatitis B (CHB) patients who were exposed to lamivudine (LAM) but had no detectable LAM resistance (LAM-R) is not well evaluated. In this study, we aimed to evaluate whether the probability of developing genotypic resistance to ETV in LAM-exposed patients with or without LAM-R is comparable to that in antiviral-naive patients. This retrospective cohort study included 500 consecutive patients with CHB who started ETV monotherapy at a single tertiary hospital in Korea. The patients were divided into three groups: nucleos(t)ide analogue (NA)-naive patients (group 1, n=142), patients who were previously exposed to LAM and had no currently or previously detected LAM-R (group 2, n=233), and patients with LAM-R when starting ETV (group 3, n=125). The overall median ETV treatment duration was 48.7 months. The probabilities of virologic breakthrough were significantly increased not only in group 3 (hazard ratio [HR]=14.4, P<0.001) but also in group 2 (HR=5.0, P<0.001) compared to group 1. Genotypic ETV resistance (ETV-R) developed more frequently in group 2 (HR=13.0, P=0.013) as well as group 3 (HR=43.9, P<0.001) than in group 1: the probabilities of developing ETV-R in groups 1, 2, and 3 were <1.0%, 8.0%, and 28.2%, respectively, at month 48. The results of this study indicate that ETV-R occurred more frequently in LAM-exposed patients, even though they had no detectable LAM-R, than in NA-naive patients. Therefore, LAM-exposed CHB patients, regardless of the presence or absence of LAM-R, should be monitored more cautiously for the development of ETV-R during ETV monotherapy.
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Huang ZB, Zhao SS, Huang Y, Dai XH, Zhou RR, Yi PP, Chen RC, Li WT, Zhang BX, Li N, Fan XG. Comparison of the efficacy of Lamivudine plus adefovir versus entecavir in the treatment of Lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis. Clin Ther 2013; 35:1997-2006. [PMID: 24238791 DOI: 10.1016/j.clinthera.2013.10.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Revised: 10/07/2013] [Accepted: 10/08/2013] [Indexed: 12/22/2022]
Abstract
BACKGROUND Hepatitis B virus infection remains 1 of the major health threats worldwide. Currently, lamivudine plus adefovir combination therapy or entecavir monotherapy is usually used for the treatment of patients with lamivudine-resistant chronic hepatitis B (CHB). However, there are few systematic comparisons between the efficacy of lamivudine plus adefovir and the efficacy of entecavir in the treatment of these patients. OBJECTIVE The goal of this systematic study and meta-analysis was to assess the efficacy of lamivudine plus adefovir compared with entecavir for the treatment of patients with lamivudine-resistant CHB. METHODS A comprehensive literature search of PUBMED, Web of Science, WANFANG database, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Review, were screened to obtain citations from January 1990 to January 2012 in this study. Data analysis was done by using the Review Manager Software 5.1. RESULTS Eight studies were suitable for analysis. A total of 696 patients with lamivudine-resistant CHB were studied and grouped according to treatment: 341 patients in the entecavir group and 355 patients in the lamivudine plus adefovir group. The results found that the rates of undetectable hepatitis B virus DNA levels, alanine aminotransferase normalization, hepatitis B e antigen loss, and hepatitis B e antigen seroconversion were not significantly different between the lamivudine plus adefovir group and the entecavir group. Moreover, the rate of adverse reactions was also not significantly different between the 2 groups. However, virologic breakthrough for the patients with lamivudine resistance was higher in the entecavir group than in the lamivudine plus adefovir group. CONCLUSIONS For these CHB patients with lamivudine resistance, lamivudine plus adefovir was a better treatment option than entecavir alone.
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Affiliation(s)
- Ze-Bing Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Viral Hepatitis, Hunan Province, China
| | - Shu-Shan Zhao
- Eight-year Program Student, Xiangya Hospital, Central South University, Changsha, China
| | - Yan Huang
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Viral Hepatitis, Hunan Province, China
| | - Xia-Hong Dai
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Zhejiang University, Hangzhou, China
| | - Rong-Rong Zhou
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Viral Hepatitis, Hunan Province, China
| | - Pan-Pan Yi
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Viral Hepatitis, Hunan Province, China
| | - Ruo-Chan Chen
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Viral Hepatitis, Hunan Province, China
| | - Wen-Ting Li
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Viral Hepatitis, Hunan Province, China
| | - Bao-Xin Zhang
- Department of Infectious Diseases, Hunan Provincial Corps Hospital of Chinese, People's Armed Police Forces, Changsha, China
| | - Ning Li
- Department of Blood Transfusion, Xiangya Hospital, Central South University, Changsha, China
| | - Xue-Gong Fan
- Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China; Key Laboratory of Viral Hepatitis, Hunan Province, China.
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Han Y, Zhang Y, Mei Y, Wang Y, Liu T, Guan Y, Tan D, Liang Y, Yang L, Yi X. Analysis of hepatitis B virus genotyping and drug resistance gene mutations based on massively parallel sequencing. J Virol Methods 2013; 193:341-7. [PMID: 23773806 DOI: 10.1016/j.jviromet.2013.06.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 05/17/2013] [Accepted: 06/06/2013] [Indexed: 01/05/2023]
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Srivastava M, Rungta S, Dixit VK, Shukla SK, Singh TB, Jain AK. Predictors of survival in hepatitis B virus related decompensated cirrhosis on tenofovir therapy: an Indian perspective. Antiviral Res 2013; 100:300-5. [PMID: 24012998 DOI: 10.1016/j.antiviral.2013.08.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 08/21/2013] [Accepted: 08/27/2013] [Indexed: 12/12/2022]
Abstract
Decompensated cirrhosis has low survival rate compared to compensated state. Effective viral suppression due to antiviral therapy (tenofovir) has been shown to slow disease progression and may delay the burden of liver transplantation. We aimed to evaluate the usefulness of various prognostic indicators in predicting the 24-months survival in HBV related decompensated cirrhosis after tenofovir therapy and to evaluate the post-treatment outcome. Ninety-six HBV related decompensated patients on antiviral (tenofovir) therapy were prospectively studied for 24months survival and mortality. Cutoff levels for several prognostic indicators were generated by ROC. Prediction of overall probability of mortality was also calculated. The overall probability of survival observed at 12months was 0.947 whereas at 24months it was found to be 0.833. According to Cox proportional hazards model, the univariate analysis revealed cutoff of >7.4logcopies/ml for HBV DNA, >1.2mg/dl for serum creatinine, >3.7mg/dl for total bilirubin, ⩽0.75 for platelets count, >10 for CTP and >20 for MELD as predictors of poor survival. Multivariate analysis showed MELD score of >20 was the most robust predictor of mortality, with 58 times higher risk (HR: 58.73, p<0.001). Post-treatment response with tenofovir for 24months significantly improved the hepatic functions and reverses decompensation and showed incredible efficacy in improvement of hepatic functional status with reduced viremia in a great majority of decompensated cirrhosis subjects having high MELD and HBV DNA level.
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Affiliation(s)
- Manjita Srivastava
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, U.P., India
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Maier M, Liebert UG, Wittekind C, Kaiser T, Berg T, Wiegand J. Clinical Relevance of Minimal Residual Viremia during Long-Term Therapy with Nucleos(t)ide Analogues in Patients with Chronic Hepatitis B. PLoS One 2013; 8:e67481. [PMID: 23826307 PMCID: PMC3694892 DOI: 10.1371/journal.pone.0067481] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 05/19/2013] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Successful therapy of chronic hepatitis B with nucleos(t)ide analogues (NUCs) has been defined by undetectable HBV-DNA determined with conventional PCR (lower limit of detection (LLD) 60-80 IU/mL) in clinical registration trials. However, current EASL guidelines recommend highly sensitive real-time PCR (LLD<10-20 IU/mL) and define treatment response by HBV-DNA<10 IU/mL. AIM We evaluated frequency and relevance of minimal residual viremia (MRV) during long-term NUC-treatment in a real-life setting. METHODS Frozen serum samples (HBV-DNA negative by in-house PCR, LLD <73 IU/mL) were re-analyzed by real-time PCR (LLD<10 IU/mL, Abbott, Germany). MRV was defined by real time PCR positivity and conventional PCR negativity. RESULTS 237 samples of six HBsAg carriers and 27 NUC-treated CHB patients were analyzed (treatment period 28 (11-111) months, different treatment regimens with mono- or combination therapy). MRV was detected in 31/33 individuals (n = 160/237 serum samples) and more frequent in HBsAg carriers (95%) and HBeAg positive (87%) compared to HBeAg negative patients (53%) (p<0.0001, respectively). Five HBsAg carriers, five HBeAg positive, and four HBeAg negative individuals were continuously HBV-DNA positive. MRV was not significantly more often observed during NUC-monotherapies compared to combination therapies. Concomitant immunosuppressive therapy was present in nine cases and did not influence the results. Viral resistance occurred in three immunocompetent patients with adefovir or lamivudine monotherapy. CONCLUSIONS MRV is frequently observed during long-term NUC-therapy. Adjustment of treatment with highly potent NUCs does not seem to be necessary in case of minimal residual viremia in a real-life setting.
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Affiliation(s)
- Melanie Maier
- Universitätsklinikum Leipzig, Institut für Virologie, Leipzig, Germany
| | - Uwe G. Liebert
- Universitätsklinikum Leipzig, Institut für Virologie, Leipzig, Germany
| | | | - Thorsten Kaiser
- Universitätsklinikum Leipzig, Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Leipzig, Germany
| | - Thomas Berg
- Universitätsklinikum Leipzig, Department für Innere Medizin, Dermatologie und Neurologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Leipzig, Germany
| | - Johannes Wiegand
- Universitätsklinikum Leipzig, Department für Innere Medizin, Dermatologie und Neurologie, Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Leipzig, Germany
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Coffin CS, Osiowy C, Myers RP, Gill MJ. Virology and clinical sequelae of long-term antiviral therapy in a North American cohort of hepatitis B virus (HBV)/human immunodeficiency virus type 1 (HIV-1) co-infected patients. J Clin Virol 2013; 57:103-8. [PMID: 23465393 DOI: 10.1016/j.jcv.2013.02.004] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Revised: 02/01/2013] [Accepted: 02/05/2013] [Indexed: 02/07/2023]
Abstract
UNLABELLED There are limited recent data worldwide on clinical and virological outcomes in hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfected patients on dual active antiretroviral therapy (ART). METHODS We completed a retrospective review of 53 coinfected patients. HBV DNA in plasma was tested by PCR (sensitivity <20-<55 IU/ml or ∼100-300 copies/ml, Roche Diagnostics). Quantitative hepatitis B surface antigen (qHBsAg) was measured by an in-house assay (calibration range 0.24-62.5 IU/ml). HBV genotyping was done by line probe assay, and HBV variants determined by sequencing the HBV polymerase (P)/overlapping surface (S) gene. RESULTS There were 7% (4/53) non-liver related deaths, ∼11% (6/53) had >F2 fibrosis, including 3 with cirrhosis. The median CD4+ T cell count was 415 cells/mm(3) (range 60-1310). 54% (28/51) were HBeAg-positive, and 81% (43/53) on ART had undetectable HBV DNA but only 5% (3/51) lost HBeAg. In 11/53 with HBV sequencing, 90% (10/11) were found to have HBV genotype A (HBV-A) and/or 27% (3/11) had a mixed A/G infection. Anti-HBV drug resistant mutations were detected in 54% (6/11) (i.e., any combination of rtV173L, rtL180M, M204V) and 45% (5/11) had an immune escape mutation (sP120S). In 12 with qHBsAg testing, the majority (9/12) had low-level qHBsAg ∼1-3 log(10) IU/ml. SUMMARY Liver disease occurs in ∼10% of coinfected patients on ART and many have low-level HBV DNA and qHBsAg. In those sequenced most were HBV-A or mixed A/G genotype, and several carry P and S mutants highlighting the complex molecular virology of HBV during HIV coinfection.
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Affiliation(s)
- C S Coffin
- Liver Unit, Division of Gastroenterology and Hepatology, Department of Medicine, 3280 Hospital Drive NW, University of Calgary, Calgary, AB T2N 4Z6, Canada.
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Park H, Park JY, Kim SU, Kim DY, Han KH, Chon CY, Ahn SH. Efficacy of switching to telbivudine plus adefovir in suboptimal responders to lamivudine plus adefovir. World J Gastroenterol 2013; 19:7671-7679. [PMID: 24431895 PMCID: PMC3837266 DOI: 10.3748/wjg.v19.i43.7671] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2013] [Revised: 09/14/2013] [Accepted: 09/16/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the efficacy of telbivudine (LdT) + adefovir (ADV) vs continuation of lamivudine (LAM) + ADV in patients with LAM-resistant chronic hepatitis B (CHB) who show a suboptimal response to LAM + ADV. METHODS This was a randomized, active-control, open-label, single-center, parallel trial. All eligible patients were enrolled in this study in Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea, between March 2010 and March 2011. Hepatitis Be antigen (HBeAg)-positive CHB patients whose serum hepatitis B virus (HBV) DNA remained detectable despite at least 6 mo of LAM + ADV therapy were included. Enrolled patients were randomized to either switching to LdT (600 mg/d orally) plus ADV (10 mg/d orally) (LdT + ADV group) or to continuation with LAM (100 mg/d orally) plus ADV (10 mg/d orally) (LAM + ADV group), and were followed for 48 wk. One hundred and six patients completed the 48-wk treatment period. Serum HBV DNA, HBeAg status, liver biochemistry and safety were monitored at baseline and week 12, 24, 36 and 48. RESULTS The duration of prior LAM + ADV treatment was 18.3 (LdT + ADV) and 14.9 mo (LAM + ADV), respectively (P = 0.131). No difference was seen in baseline serum HBV DNA between the two groups [3.66 (LdT + ADV) vs 3.76 (LAM + ADV) log10 IU/mL, P = 0.729]. At week 48, although there was no significant difference in the mean reduction of serum HBV DNA from baseline between LdT + ADV group and LAM + ADV group (-0.81 vs -0.47 log10 IU/mL, P = 0.167), more patients in the LdT + ADV group had undetectable HBV DNA levels compared to those in the LAM + ADV group (30.2% vs 11.5%, P = 0.019). Three patients with LdT + ADV treatment and 2 patients with LAM + ADV treatment achieved HBeAg loss. The patients in both groups tolerated the treatment well without serious adverse events. The proportion of patients with estimated glomerular filtration rate ≥ 90 mL/min per 1.73 m(2) in the LdT + ADV group increased from 49.1% (26/53) at baseline to 58.5% (31/53) at week 48, while that in the LAM + ADV group decreased from 37.7% (20/53) at baseline to 30.2% (16/53) at week 48. CONCLUSION The switch to LdT + ADV in suboptimal responders to LAM + ADV showed a significantly higher rate of virologic response at week 48. These results suggest that LdT + ADV could be a therapeutic option for patients who are unable to use enofovir disoproxil fumarate for any reason.
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Hepatitis B vaccines. Vaccines (Basel) 2013. [DOI: 10.1016/b978-1-4557-0090-5.00025-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025] Open
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Ooi M, Teoh NC. Can long term therapy with oral nucleos(t)ide analogs influence the prognosis of chronic hepatitis B-related complications? J Gastroenterol Hepatol 2012; 27:1541-3. [PMID: 22994430 DOI: 10.1111/j.1440-1746.2012.07221.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Chen EQ, Zhou TY, Bai L, Wang JR, Yan LB, Liang LB, Tang H. Lamivudine plus adefovir or telbivudine plus adefovir for chronic hepatitis B patients with suboptimal response to adefovir. Antivir Ther 2012; 17:973-979. [PMID: 22728692 DOI: 10.3851/imp2190] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2012] [Indexed: 02/05/2023]
Abstract
BACKGROUND There is no standard management of chronic hepatitis B (CHB) patients with suboptimal response to nucleoside/nucleotide analogues (NAs). This study aimed to evaluate two different NA combination therapies in patients with suboptimal response to adefovir (ADV). METHODS In this study, 72 CHB patients with suboptimal response to ADV were assessed, with 37 patients receiving lamivudine plus ADV (group A) and 35 patients receiving telbivudine plus ADV (group B). RESULTS Baseline characteristics between two groups were similar. At month 12, rates of biochemical response (BR) and virological response (VR) were similar between groups A and B (17/19 versus 18/20 for BR, [P=0.269] and 30/37 versus 31/35 for VR [P=0.377]), and cumulative rates of serological response were greater in group B than in group A (10/26 versus 2/28 in hepatitis B e antigen [HBeAg] loss [P=0.006] and 7/26 versus 1/28 in HBeAg/hepatitis B e antibody seroconversion [P=0.022]). After 12-month treatment, 8.1% (3/37) of patients in group A and 5.7% (2/35) of patients in group B had VR; among patients in group A, two had rtM204V/I and rtL180M and one had rtN236T, whereas the two patients in group B had rtM204I+rtL180M. CONCLUSIONS Both combination therapies led to a significant decrease in HBV DNA. HBeAg serological outcomes were higher with telbivudine plus ADV combination therapy.
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Affiliation(s)
- En-Qiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, People's Republic of China
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Abstract
Antiviral therapy of chronic hepatitis B remains a clinical challenge. The primary goal of therapy is to prevent liver disease progression. Because of the mechanism of viral persistence in infected hepatocytes, long-term antiviral therapy is needed in the majority of patients. Incomplete viral suppression and emergence of drug resistance is a major concern. The correct choice of a first-line potent therapy to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and drug resistance. Clinical studies have demonstrated that drugs with a high barrier to resistance, such as entecavir and tenofovir, have significantly lower rates of resistance when compared with those with a low barrier to resistance such as lamivudine, adefovir, or telbivudine. Management of treatment failure requires a precise clinical and accurate virologic monitoring as well as an early treatment intervention with appropriate complementary drugs with respect to their cross-resistance profile. Long-term surveillance for treatment efficacy and possible emergence of drug resistance is necessary for those patients who have been sequentially treated with multiple antivirals. Finally, the identification of novel treatment targets remains a major research challenge to improve the efficacy of current antiviral therapy.
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Affiliation(s)
- Fabien Zoulim
- INSERM, U1052, Cancer Research Center of Lyon, 69003 Lyon, France.
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Abstract
UNLABELLED The guideline on the management of chronic hepatitis B (CHB) was first developed in 2004 and revised in 2007 by the Korean Association for the Study of the Liver (KASL). Since then there have been many developments, including the introduction of new antiviral agents and the publications of many novel research results from both Korea and other countries. In particular, a large amount of knowledge on antiviral resistance--which is a serious issue in Korea--has accumulated, which has led to new strategies being suggested. This prompted the new guideline discussed herein to be developed based on recent evidence and expert opinion. TARGET POPULATION The main targets of this guideline comprise patients who are newly diagnosed with CHB and those who are followed or treated for known CHB. This guideline is also intended to provide guidance for the management of patients under the following special circumstances: malignancy, transplantation, dialysis, coinfection with other viruses, pregnancy, and children.
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MESH Headings
- Acute Disease
- Adolescent
- Adult
- Aged
- Alanine Transaminase/blood
- Antiviral Agents/therapeutic use
- Asian People
- Aspartate Aminotransferases/blood
- Carcinoma, Hepatocellular/diagnosis
- Carcinoma, Hepatocellular/etiology
- Child
- Child, Preschool
- Coinfection/drug therapy
- DNA, Viral/blood
- Drug Resistance, Viral
- Drug Therapy, Combination
- Female
- Hepatitis B Surface Antigens/blood
- Hepatitis B e Antigens/blood
- Hepatitis B virus/genetics
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/diagnosis
- Hepatitis B, Chronic/drug therapy
- Humans
- Immunosuppression Therapy
- Infectious Disease Transmission, Vertical/prevention & control
- Liver/pathology
- Liver/physiology
- Liver Cirrhosis/physiopathology
- Liver Neoplasms/diagnosis
- Liver Neoplasms/etiology
- Liver Transplantation
- Male
- Middle Aged
- Pregnancy
- Renal Dialysis
- Republic of Korea
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Devi U, Locarnini S. Role of Resistance Testing During Oral Antiviral Therapy of Chronic Hepatitis B. ACTA ACUST UNITED AC 2012. [DOI: 10.1007/s11901-012-0132-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Simple scoring system predicting genotypic resistance during rescue therapy for Lamivudine-resistant chronic hepatitis B. J Clin Gastroenterol 2012; 46:243-50. [PMID: 21716122 DOI: 10.1097/mcg.0b013e318225f559] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
GOAL In this study, we aimed to devise a simple scoring system predicting the risk of genotypic resistance (GR) to current rescue therapies for patients with lamivudine (LAM)-resistant chronic hepatitis B. BACKGROUND LAM and adefovir (ADV) combination therapy should be recommended for an initial rescue therapy against LAM-resistant hepatitis B virus (HBV). However, there still are many LAM-resistant patients being treated with entecavir (ETV) or ADV monotherapy. STUDY This retrospective cohort study included consecutive patients treated for LAM-resistant chronic hepatitis B with ETV or ADV monotherapy, or LAM/ADV combination therapy. The cumulative probabilities of GR and virological responses and breakthrough according to clinical variables were analyzed by survival analyses and derived an index for future GR. RESULTS A total of 224 patients were included (median treatment duration=117.9 wk). Using risk factors indentified on multivariable analyses, a simple index for future GR (Antiviral Resistance Prediction Index, ARPI) was developed with 3 clinical variables: the rescue therapy regimens (+0, ADV; +1, ETV; +2, LAM/ADV), HBV DNA reduction at 12 weeks (+0, <3 log10 copies/mL; +1, >3 log10 copies/mL), and the initial HBV DNA level (+0, >10 copies/mL; +1, <10 copies/mL). No patient with ARPI ≥2 exhibited GR, whereas 47% of the patients with an ARPI <2 developed GR by week 144 (P=0.005). CONCLUSIONS The results of this study suggest that the ARPI is a simple and early index that can be used to determine the risk for subsequent GR during rescue therapy for LAM-resistant chronic hepatitis B.
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Kwak MS, Choi JW, Lee JS, Kim KA, Suh JH, Cho YS, Won SY, Park BK, Lee CK. Long-term efficacy of entecavir therapy in chronic hepatitis B patients with antiviral resistance to lamivudine and adefovir. J Viral Hepat 2011; 18:e432-8. [PMID: 21914060 DOI: 10.1111/j.1365-2893.2011.01461.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
No studies have reported the long-term effects of entecavir switching in patients with multidrug resistance who developed resistance after lamivudine/adefovir sequential therapy. We evaluated the efficacy of 96 weeks of entecavir therapy in patients with resistance to lamivudine/adefovir sequential therapy. In total, 33 patients with chronic hepatitis B virus (HBV) infection with evidence of active viral replication (HBV DNA levels ≥ 10(5) copies/mL) or a history of treatment failure to lamivudine/adefovir sequential therapy between April 2007 and July 2009 were treated with entecavir (1.0 mg daily) for at least 48 weeks. The rates of alanine transaminase (ALT) normalization and HBV DNA negativity were 66.7% (14/21) and 24.2% (8/33) at 48 weeks, respectively. The initial HBV DNA level was the only factor that was inversely associated with serum HBV DNA negativity after 48 weeks of entecavir therapy (P < 0.023). At 96 weeks, the rates of ALT normalization and HBV DNA negativity were 77.8% (7/9) and 16.7% (3/18), respectively. Viral breakthrough occurred in 21.2% (7/33) and 78.9% (15/19) of patients at 48 and 96 weeks, respectively. Patients who achieved a HBV DNA level of <4 log(10) copies/mL at 48 weeks maintained a similar HBV DNA level and a normal ALT level until 96 weeks. Entecavir monotherapy for 96 weeks was not efficacious for patients with lamivudine/adefovir-resistant HBV. The initial HBV DNA level was the only predictive factor for antiviral efficacy. However, patients who achieved a HBV DNA level of <4 log(10) copies/mL with a normal ALT level at 48 weeks should maintain, rather than stop, entecavir therapy.
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Affiliation(s)
- M S Kwak
- Department of Internal Medicine, National Health Insurance Corporation Ilsan Hospital, Goyang, Korea
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Han KH, Hong SP, Choi SH, Shin SK, Cho SW, Ahn SH, Hahn JS, Kim SO. Comparison of multiplex restriction fragment mass polymorphism and sequencing analyses for detecting entecavir resistance in chronic hepatitis B. Antivir Ther 2011; 16:77-87. [PMID: 21311111 DOI: 10.3851/imp1702] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Drug resistance is a major limitation to the long-term efficacy of controlling chronic hepatitis B (CHB). There is a growing need to analyse multiple mutations associated with drug resistance because sequential or combinational use of antivirals is increasingly being used in treatment. In this study, we introduced a multiplex restriction fragment mass polymorphism (RFMP) assay for detecting mutations conferring entecavir and lamivudine resistance, and compared its performance with direct or clonal sequencing assays. METHODS Multiplex PCR was performed with mixed primers designed to interrogate rt184, rt202, rt204 and rt250. The PCR products were digested with restriction enzymes and the resulting fragments were analysed by mass spectrometry. A total of 251 serum samples, taken serially from 45 patients who received entecavir treatment after confirmed diagnosis of lamivudine resistance and inadequate adefovir dipivoxil response, were analysed by the multiplex RFMP assay. RESULTS The multiplex RFMP assay correctly identified known viral sequences with sufficient analytical sensitivity to detect as few as 100 IU/ml of HBV and with superior ability to determine haplotypes composed of neighbouring variations. Complex mutational patterns and relative abundances determined by multiplex RFMP assay were in good concordance with results obtained by direct or clonal sequencing analyses. Defined mixtures were successfully and consistently identified at 2% relative concentration of mutant versus wild-type virus by the assay. CONCLUSIONS The multiplex RFMP assay is an accurate and sensitive means to detect entecavir and lamivudine resistance mutations, simultaneously. The method is expected to enable early and efficient diagnosis of multiple drug resistance mutations for optimal management of CHB.
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Affiliation(s)
- Kyung Ho Han
- National Institute of Food and Drug Safety Evaluation, Korea Food and Drug Administration, Seoul, South Korea
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Abstract
Chronic hepatitis B (CHB) is a major public health problem affecting up to 400 million people globally. Complications of CHB including liver failure and hepatocellular carcinoma result in 1.2 million deaths per year, making CHB the 10th leading cause of mortality worldwide. The natural history of CHB is variable and complex. The past decade witnessed important developments for the therapy of hepatitis B and marked the new era of oral therapy. The ultimate goal of CHB therapy is to arrest the progression of liver injury and to prevent the development of liver failure and hepatocellular carcinoma. Currently, six agents are approved for the treatment of CHB. Each of these agents, given as monotherapy, has been shown to produce virological, biochemical, and histological benefits for both HBeAg positive and negative CHB. There are, however, limitations in spite of their efficacy. The significant side-effect profile of interferon, for example, limits its long-term use. The approved oral agents are tolerable with prolonged use but drug resistance could limit long-term monotherapy. To date, combination therapy with nucleoside analogue and pegylated interferon or two nucleos(t)ide analogues given for one year does not show superiority in durability of response compared to monotherapy. Ongoing research effort is critical to identify the ideal hepatitis B therapy that is safe, effective, and produces durable response with a finite course of therapy. It is equally important to conduct a well designed, prospective natural history study to identify predictors of disease progression. This will accurately guide treatment strategy for this important disease.
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Affiliation(s)
- Daryl T-Y Lau
- Associate Professor of Medicine, Harvard Medical School (HMS), Director of Translational Liver Research, Beth Israel Deaconess Medical Center, HMS Liver Center, Division of Gastroenterology, Department of Medicine, 110 Francis Street, Suite 4A, Boston, MA 02215.
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Pais R, Benhamou Y. [Long-term therapy for chronic hepatitis B in HIV co-infected patients]. ACTA ACUST UNITED AC 2011; 34 Suppl 2:S136-41. [PMID: 21095517 DOI: 10.1016/s0399-8320(10)70033-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
As human immunodeficiency virus (HIV) and hepatitis B virus (HBV) are acquired through the same routes of contamination, the prevalence of HBV serological markers found in the HIV-infected population is approximately 7%. Liver-related mortality and morbidity is higher in HIV/HBV co-infected patients than in HBV mono-infected patients. Both viruses must be considered before a treatment decision is made. According to the European consensus conference on the treatment of chronic hepatitis B and C in HIV coinfected patients, treatment is based on whether there is an existing indication of anti- HIV therapy or not. In patients with no indication of anti-HIV therapy, drugs with dual anti-viral activity (lamivudine, entecavir, tenofovir disoproxil fumarate) should not be used due to the risk of developing HIV-resistance. Interferon or adefovir in combination with telbivudine are recommended. In patients with an indication of anti-HIV therapy, a backbone of highly active anti-retroviral therapy should include tenofovir in combination with lamivudine or emtricitabine. The same regimen is recommended in patients who develop lamivudine resistance.
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Affiliation(s)
- R Pais
- Service d'Hépato-Gastroentérologie, Hôpital Pitié-Salpêtrière, Paris, France
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38
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Wu S, Imazeki F, Kurbanov F, Fukai K, Arai M, Kanda T, Yonemitsu Y, Tanaka Y, Mizokami M, Yokosuka O. Evolution of hepatitis B genotype C viral quasi-species during hepatitis B e antigen seroconversion. J Hepatol 2011; 54:19-25. [PMID: 20932594 DOI: 10.1016/j.jhep.2010.06.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2009] [Revised: 06/04/2010] [Accepted: 06/07/2010] [Indexed: 01/21/2023]
Abstract
BACKGROUND & AIMS Although the evolution of viral quasi-species may be related to the pathological status of disease, little is known about this phenomenon in hepatitis B, particularly with respect to hepatitis B e antigen (HBeAg) seroconversion. METHODS Nucleotide sequences of the hepatitis B virus (HBV) X/precore/core region was analyzed at five time-points in four groups of chronic hepatitis B patients, interferon-induced seroconverters (IS, N = 9), interferon non-responders (IN, N = 9), spontaneous seroconverters (SS, N = 9), and non-seroconverters (SN, N = 9) followed during 60 months on an average. Only patients with genotype C were studied. RESULTS Analysis of 1800 nucleotide sequences showed that there was no statistical difference between the nucleotide genetic distances of seroconverters (IS and SS; 6.9 × 10⁻³ substitutions (st)/site and 6.7 × 10⁻³ st/site, respectively) and those of non-seroconverters (IN and SN; 5.3 × 10⁻³ st/site and 3.8 × 10⁻³ st/site, respectively) before seroconversion. Compared to non-seroconverters (IN and SN; 5.1 × 10⁻³ st/site and 5.9 × 10⁻³ st/site, respectively), the sequence diversity of seroconverters (IS and SS; 10.9 × 10⁻³ st/site and 9.9 × 10⁻³ st/site, respectively) was significantly higher after seroconversion (p < 0.05), and was higher in seroconverters after seroconversion than before seroconversion (p < 0.05), while this changed very little in non-seroconverters during the observation period. Phylogenetic trees showed greater complexity in secoconverters than non-seroconverters. Parsimony-based estimation of the direction of sequence change between descendants and ancestors before HBeAg seroconversion, revealed higher frequencies of transversional A to T substitution in seroconverters (0.06 vs. 0.02, p = 0.0036) that coincided with the dynamics of quasi-species possessing A1762T mutation. CONCLUSIONS The distinctly greater viral diversity in HBeAg seroconverters after seroconversion could be related to escape mutants resulting from stronger selection pressure.
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Affiliation(s)
- Shuang Wu
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.
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Yang HW, Lee BS, Lee TH, Lee HY, Nam KW, Kang YW, Chae HB, Kim SH, Kim SB, Lee HI, Kim AN, Song IH, Lee SH, Kim HS. Efficacy of initial treatment with clevudine in naive patients with chronic hepatitis B. Korean J Intern Med 2010; 25:372-6. [PMID: 21179274 PMCID: PMC2997965 DOI: 10.3904/kjim.2010.25.4.372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2009] [Revised: 01/22/2010] [Accepted: 09/14/2010] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND/AIMS Clevudine, a pyrimidine nucleoside analogue, has potent antiviral effects in patients with chronic viral hepatitis B (CHB). We report the efficacy of initial treatment with clevudine in naïve patients with CHB living in Daejeon and Chungcheong Province, South Korea. METHODS One hundred five adults with CHB were administered 30 mg of clevudine per day for an average of 51 weeks. We evaluated viral markers and liver biochemistry retrospectively every 3 months. RESULTS Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatitis B virus (HBV) DNA before the treatment were 184 ± 188 IU/L, 150 ± 138 IU/L, and 7.1 ± 1.2 log copies/mL, respectively. Undetectable rates (< 60 IU/mL) of DNA were 36.2%, 68.9%, 83.6%, 76.2%, and 75.8% at 12, 24, 36, 48, and 60 weeks, respectively. Seroconversion rates were 9.1%, 13.6%, 24.6%, 26.5%, and 26.1% and ALT normalization rates were 64.5%, 78.1%, 87.9%, 90.0% at 12, 24, 36, and 48 weeks, respectively. Six patients (5.7%) had a viral breakthrough. CONCLUSIONS Clevudine is a useful drug in the initial treatment of patients with CHB, with a potent antiviral effect and low incidence of viral breakthrough.
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Affiliation(s)
- Hyeon Woong Yang
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea
| | - Byung Seok Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Tae Hee Lee
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Heon Young Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Kwan Woo Nam
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Young Woo Kang
- Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea
| | - Hee Bok Chae
- Department of Internal Medicine, Chungbuk National University College of Medicine, Cheongju, Korea
| | - Seok Hyun Kim
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
| | - Seok Bae Kim
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Hyang Ie Lee
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea
| | - An Na Kim
- Department of Internal Medicine, Eulji University School of Medicine, Daejeon, Korea
| | - Il Han Song
- Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Hong Su Kim
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
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Serin MS, Bekiroglu E, Polat S, Dogen A, Tezcan S, Aslan G, Sezgin O, Altintas E, Emekdas G, Ucbilek E. Detection of hepatitis B virus polymerase gene variants associated with Lamivudine, Adefovir and Entecavir resistance and some undefined mutations isolated from chronic hepatitis B patients in the south of Turkey. MOLECULAR GENETICS, MICROBIOLOGY AND VIROLOGY 2010. [DOI: 10.3103/s0891416810040075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Abstract
The introduction of nucleos(t)ide analog therapy has seen the emergence of antiviral drug resistance, which has become the main factor limiting the long-term application of these antiviral agents for patients with chronic hepatitis B. The prevention of resistance requires the adoption of strategies that effectively control virus replication and exploit an understanding of the mechanisms and processes that drive the emergence of drug resistance, namely high replication rates, low fidelity of the hepatitis B virus rt/polymerase, selective pressure of the nucleos(t)ide analog, role of replication space (liver turnover), fitness of the mutant, and genetic barrier to the drug.
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Molecular characteristics and functional analysis of full-length hepatitis B virus quasispecies from a patient with chronic hepatitis B virus infection. Virus Res 2010; 150:43-8. [DOI: 10.1016/j.virusres.2010.02.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2009] [Revised: 02/16/2010] [Accepted: 02/16/2010] [Indexed: 12/15/2022]
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Gonzalez SA, Keeffe EB. Entecavir for the long-term treatment of chronic hepatitis B. Expert Rev Anti Infect Ther 2010; 7:1053-62. [PMID: 19883325 DOI: 10.1586/eri.09.75] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Hepatitis B virus is a major cause of chronic liver disease worldwide and is associated with an increased risk of hepatocellular carcinoma, progressive hepatic fibrosis and end-stage liver disease. Suppression of HBV replication is recognized as the primary on-treatment goal of antiviral therapy, as reduction of serum HBV DNA to low or undetectable levels is highly likely to have a positive impact on long-term clinical outcomes in HBV-associated chronic liver disease. Entecavir is an oral nucleoside analogue that effectively inhibits HBV polymerase, resulting in rapid viral suppression. Long-term data on patients receiving entecavir for chronic hepatitis B have demonstrated high potency, a low incidence of antiviral drug resistance and good tolerability, making entecavir an ideal first-line agent for the treatment of chronic hepatitis B.
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Affiliation(s)
- Stevan A Gonzalez
- Division of Hepatology, Baylor Regional Transplant Institute, Baylor All Saints Medical Center, 1400 8th Avenue, Building C, 1st Floor, Fort Worth, TX 76104, USA.
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Choe WH, Hong SP, Kim BK, Ko SY, Jung YK, Kim JH, Yeon JE, Byun KS, Kim KH, Ji SI, Kim SO, Lee CH, Kwon SY. Evolution of hepatitis B virus mutation during entecavir rescue therapy in patients with antiviral resistance to lamivudine and adefovir. Antivir Ther 2010; 14:985-93. [PMID: 19918102 DOI: 10.3851/imp1417] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The efficacy of entecavir (ETV) monotherapy in treatment-experienced patients with chronic hepatitis B (CHB) is debatable. METHODS A total of 22 hepatitis B e antigen (HBeAg)-positive CHB patients who had shown viral breakthrough or suboptimal response with lamivudine (3TC) and adefovir disoproxil (ADV) therapy were treated with 1.0 mg of ETV. Clinical and virological parameters were monitored every 3 months. Restriction fragment mass polymorphism assays were used to detect antiviral resistance. RESULTS During 3TC and ADV therapy, 11 patients had rtM204V/I mutations, 2 had rtA181V/T or rtN236T, 7 had both and 2 had no 3TC- or ADV-related mutations. After switching to ETV monotherapy, the median change in serum hepatitis B virus (HBV) DNA level was -2.1 log(10) copies/ml. Virological response (HBV DNA<300 copies/ml) was achieved in 1 of 18 patients with pre-existing rt204 mutations, whereas it was achieved in all 4 patients without pre-existing rt204 mutations regardless of the presence of rt181 or rt236 mutations. Changes in mutational patterns during ETV therapy showed that rt204 mutations persisted or re-emerged. Relative abundances of rtM204V/I mutations in total viral populations gradually increased under ETV rescue, whereas those with rtA181V/T and rtN236T mutations decreased. ETV resistance mutations (rtL180M+rtT184I/L[rtS202G]+rtM204V) were detected in five patients with pre-existing rt204 mutations. CONCLUSIONS ETV monotherapy resulted in a limited virological response in patients who had previously failed 3TC and ADV rescue therapy. The limited efficacy might be associated with residual or reselected rtM204V/I mutations leading to ETV resistance. Combination treatment including potent antiviral agents should be recommended for patients with pre-existing rtM204V/I mutations.
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Affiliation(s)
- Won Hyeok Choe
- Department of Internal Medicine, Konkuk University School of Medicine, Konkuk University Hospital, Seoul, South Korea
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Li Y, Zhu M, Guo Y, Chen W, Li G. Full-length hepatitis B virus sequences from naïve patients with fluctuation of viral load during ADV monotherapy. Virus Genes 2009; 40:155-62. [PMID: 20012680 DOI: 10.1007/s11262-009-0429-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Accepted: 11/26/2009] [Indexed: 12/25/2022]
Abstract
The reasons for adefovir dipivoxil (ADV) treatment failures appear diverse. Few studies have reported full-length hepatitis B virus (HBV) genome in patients with ADV treatment failures. The patients were from a phase III clinical trial that investigated the antiviral response to ADV in China. Seven patients had increase in HBV-DNA (>1 log(10) copies/ml above on-treatment nadir) at week 52. The serum HBV-DNA levels were above 10(4)copies/ml at week 92 in four of them. Sixteen full-length HBV genomes from the four patients at four time points were sequenced using cloning sequencing method. The frequency of substitutions at week 52 was higher than at weeks 28(16 wt) and 92(80). HBV-DNA reduction was correlated negatively with the frequency of substitutions at the three time points. No published ADV-resistant mutations were detected. The mutations, including substitutions in immunogenic epitopes and conserved sites of the polymerase gene, were frequent during ADV treatment. Amino acid deletions in X gene and basal core promoter/pre-core mutations appeared before or during ADV treatment. The substitutions in immunogenic epitopes (mainly of the surface gene) and conserved sites of the polymerase gene other than ADV-resistant mutations may have influenced antiviral efficacy in the study. More potent antiviral drugs may be important to rescue individual patients and for public health safety. It is needed to study how these substitutions influence HBV replication, disease progression, and antiviral treatment efficacy.
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Affiliation(s)
- Yongwei Li
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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Shim JH, Suh DJ, Kim KM, Lim YS, Lee HC, Chung YH, Lee YS. Efficacy of entecavir in patients with chronic hepatitis B resistant to both lamivudine and adefovir or to lamivudine alone. Hepatology 2009; 50:1064-71. [PMID: 19637288 DOI: 10.1002/hep.23145] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
UNLABELLED Entecavir (ETV) is currently recommended as a rescue therapy purely for adefovir (ADV)-resistant chronic hepatitis B virus (HBV) infections. We evaluated the efficacy of ETV in patients who were resistant to lamivudine (LAM)/ADV sequential therapy and in those resistant to LAM monotherapy. Fifty LAM/ADV-resistant and 38 LAM-resistant patients who received ETV 1 mg/day for at least 48 weeks were enrolled. Mean baseline serum HBV DNA and alanine aminotransferase (ALT) levels were significantly lower in the LAM/ADV-resistant group, compared with the LAM-resistant group (6.90 versus 7.62 log(10) copies/mL and 102.6 versus 160.2 IU/L; both P < 0.05); hepatitis B e antigen (HBeAg) status and LAM-resistant mutation patterns were similar in the two groups. At week 48, mean reductions in HBV DNA and ALT levels were significantly less in the LAM/ADV-resistant group (-2.96 versus -4.86 log(10) copies/mL and -68.3 versus -128.9 IU/L; both P < 0.05). Achievement of undetectable HBV DNA was also less common in the LAM/ADV-resistant group (10.0% versus 34.2%; P = 0.006), although the rates of HBeAg loss and ALT normalization did not differ between the two groups. Resistance to both LAM and ADV was an independent risk factor for failure of HBV DNA negativity at week 48 (odds ratio, 0.138; P = 0.019). In both LAM/ADV-resistant and LAM-resistant groups, primary responders (> or =1 log decline in HBV DNA at week 12) achieved a significantly greater decrease in HBV DNA levels over the 48-week period, compared with primary nonresponders (-4.18 versus -0.97 and -5.37 versus -2.15 log(10) copies/mL, respectively; both P < 0.05). CONCLUSION The 48-week ETV treatment was less effective in LAM/ADV-resistant than in LAM-resistant patients. Continuing ETV monotherapy could be determined based on the virological response at 12 weeks in LAM/ADV-resistant patients.
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Affiliation(s)
- Ju Hyun Shim
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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47
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Abstract
Australia has had a proud and enviable record of seminal contributions to hepatology, with many contributors. Thus, any attempt to summarize these contributions ab initio in a brief review article is a significant challenge, primarily because it is so easy to overlook or underestimate particular aspects. In this article, I have confined my comments primarily to the areas where the contributions have had a significant global impact and have clearly been recognized internationally. This means that many worthwhile Australian additions will be omitted if there was less apparent international impact. The first significant interest in liver disease in Australia was from the Melbourne group at the Walter and Eliza Hall Institute (WEHI) and Royal Melbourne Hospital, leading to seminal contributions to the description, diagnosis, aetiopathogenesis and therapy of autoimmune hepatitis and primary biliary cirrhosis. Others from Royal Prince Alfred Hospital in Sydney contributed substantially to the effects of immunosuppression of autoimmune hepatitis and to early descriptions of primary sclerosing cholangitis. Other areas where Australians have contributed significantly include steatohepatitis, iron metabolism (and in particular hemochromatosis), viral hepatitis (both at the molecular and clinical level), portal hypertension, and transplant immunology. The remarkable contribution of Professor Dame Sheila Sherlock to Australian hepatology is also summarized.
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Affiliation(s)
- Lawrie W Powell
- University of Queensland, Centre for the Advancement of Clinical Research, Royal Brisbane, Queensland, Australia.
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48
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Randomized controlled study investigating viral suppression and serological response following pre-S1/pre-S2/S vaccine therapy combined with lamivudine treatment in HBeAg-positive patients with chronic hepatitis B. Antimicrob Agents Chemother 2009; 53:5134-40. [PMID: 19770281 DOI: 10.1128/aac.00276-09] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The aim of the current study was to evaluate viral suppression following combined treatment with an S/pre-S1/pre-S2 vaccine and lamivudine in patients with chronic hepatitis B. We established a randomized, controlled clinical trial to compare the responses of three different treatment groups: those receiving vaccine monotherapy, lamivudine monotherapy, or combination treatment. Viral response was evaluated via hepatitis B virus (HBV) DNA suppression using different levels of classification. Seroconversion was evaluated via HBeAg loss, HBeAg seroconversion, HBsAg loss, and anti-HBs response. We found that the group receiving combination treatment demonstrated a significant increase in viral suppression over that for the lamivudine or vaccine monotherapy group, although the HBeAg seroconversion rate was not different. This enhanced suppression effect in the combination group was reversed after the discontinuation of vaccine treatment, suggesting that booster doses are required for a sustained viral response. Anti-HBs was detected in 55/120 vaccine recipients, but only 3 patients demonstrated HBsAg loss, indicating that the vaccine-induced anti-HBs was unable to completely neutralize HBsAg in the serum. At the study end point, anti-HBs responders showed significantly higher HBeAg seroconversion rates, greater suppression of HBV DNA levels, and a lower median reduction in HBV DNA levels than those of anti-HBs nonresponders. Our results suggest that combined treatment with the vaccine and lamivudine was significantly more effective than lamivudine monotherapy in the short term and was especially successful in producing viral suppression and an enhanced anti-HBs antibody response.
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49
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Abstract
Chronic infections with HBV and HCV are a major cause of liver-associated morbidity and mortality worldwide. An increased knowledge of HBV and HCV virology, natural history and predictors of virological response has led to the development of new strategies to improve treatment outcomes. The use of new antiviral agents with greater potency and a high genetic barrier to resistance, as well as on-treatment monitoring of virological response, may result in improved outcomes in HBV therapy. A greater understanding of predictors of virological response has led to the ability to individualize therapy in chronic HCV infection. Several new antiviral agents specifically targeting HCV are in development and should have a major impact on treatment response rates over the next few years.
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Affiliation(s)
- Stevan A Gonzalez
- Division of Gastroenterology & Hepatology, Stanford University Medical Center, 750 Welch Road, Suite 210, Palo Alto, CA 94304-1509, USA
| | - Emmet B Keeffe
- Division of Hepatology, Baylor All Saints Medical Center, 1400 8th Avenue, Building C, 1st Floor, Fort Worth, TX 76104, USA
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50
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Abstract
HBV replicates through reverse transcription of an RNA intermediate; the inherent lack of proofreading causes a high mutation frequency. Mutations in the precore and core promoter regions that abolish or reduce the production of hepatitis B e antigen occur most commonly. Patients with these HBV variants remain viremic and can develop progressive liver disease. Mutations in the core promoter region are associated with an increased risk of hepatocellular carcinoma. Exogenous selection pressure might favor certain mutations. Mutations in the HBV polymerase that confer resistance to nucleoside and nucleotide analog treatments are a major barrier to the success of therapy for hepatitis B. The development of antiviral drug resistance negates the initial treatment response and can lead to hepatitis flares and hepatic decompensation. Prompt addition of another drug to which the virus is not cross-resistant is required. Mutations in the HBV surface protein that facilitate escape from host immunity are responsible for the failure of immune prophylaxis in infants who received HBV vaccine and in liver transplant recipients who received hepatitis B immune globulin.
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