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Tawada A, Kanda T, Imazeki F, Yokosuka O. Prevention of hepatitis B virus-associated liver diseases by antiviral therapy. Hepatol Int 2016; 10:574-593. [PMID: 27026375 DOI: 10.1007/s12072-016-9720-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Accepted: 02/28/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) is a major cause of acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, particularly in Asia-Pacific countries. The major complications in HBV carriers are hepatocellular carcinoma (HCC), liver failure and esophageal varices following the progression to cirrhosis, while some develop HCC without cirrhosis. The progression to liver fibrosis and these other complications could be prevented by treatment with nucleos(t)ide analogues (NUCs); however, NUCs must be continuously administered for a long time. Peginterferon could lead to HBV surface antigen loss. It is difficult to use peginterferon in HBV-infected patients with decompensated cirrhosis. Acute liver failure due to HBV infection and acute exacerbation of chronic hepatitis B could be treated by NUCs. Universal vaccination programs against HBV could prevent new HBV infections globally. Here, we review the currently available treatments for HBV infection.
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Affiliation(s)
- Akinobu Tawada
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
- Safety and Health Organization, Chiba University, Chiba, 263-8522, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
| | - Fumio Imazeki
- Safety and Health Organization, Chiba University, Chiba, 263-8522, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
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Belyhun Y, Maier M, Liebert UG. HIV therapy with unknown HBV status is responsible for higher rate of HBV genome variability in Ethiopia. Antivir Ther 2016; 22:97-111. [PMID: 27354181 DOI: 10.3851/imp3060] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/23/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND In Ethiopia, HBV and HIV are co-circulating. Since patients are not routinely tested for HBV, the use of antiretroviral drugs could contribute to unintended HBV drug resistance and surface gene variability during HIV coinfection. METHODS A total of 161 hepatitis B surface antigen (HBsAg)-positive sera from 58 HIV-coinfected and 103 drug-naive HBV-monoinfected individuals were characterized for HBV drug resistance and immune escape HBsAg variants. HBV polymerase/surface gene fragment of 716 bp was analysed by direct sequencing. RESULTS In 34 out of 161 study subjects (21.1%) HBV drug resistance mutations (DRMs) were detected with a frequency of 3.1% rtL80F/I, 0.6% rtA181V, 1.2% rtT184S, 6.2% rtV173L, 10.6% rtL180M, 10.6% rtM204V/I and 8.1% rtI233V. The prevalence of the major DRMs in HBV-HIV-coinfected individuals was significantly higher than monoinfected individuals (41.4% versus 10.7%). Lamivudine selected DRMs, that is, rtL180M (29.3%) and rtM204V/I (29.3%) and rtV173L (15.5%) were more prevalent in HBV-HIV-coinfected individuals but absent in HBV-monoinfected individuals. Despite the finding that rtL180M and rtM204V/I were higher among ART-experienced individuals, the overall prevalence of DRMs (48.0% versus 36.4%) showed no significance difference among antiretroviral therapy (ART) status. The study also revealed higher frequency and heterogeneity of putative and known immune escape HBsAg mutations both in the major hydrophilic region (MHR; 68.3%) and outside the MHR (82.5%) of the surface gene. In particular, the 'a' determinant surface gene mutations (sT125S, sA128V, sQ129H/R, sT131I, sC137S, sT143M, sD144D/E, sG145R, sT148P) and the majority of clustered/multiple as well as drug selected immune escape HBsAg mutations were more prevalent in HBV-HIV-coinfected individuals. CONCLUSIONS HIV therapy without HBV co-management in Ethiopia fosters emergence and circulation of HBV variants of public health importance. It is highly recommended to include HBV testing and co-management as part of routine HIV care programmes for a better ART selection.
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Affiliation(s)
- Yeshambel Belyhun
- Institute of Virology, Faculty of Medicine, Leipzig University, Leipzig, Germany.,School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Melanie Maier
- Institute of Virology, Faculty of Medicine, Leipzig University, Leipzig, Germany
| | - Uwe Gerd Liebert
- Institute of Virology, Faculty of Medicine, Leipzig University, Leipzig, Germany
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Hua W, Zhang G, Guo S, Li W, Sun L, Xiang G. Microarray-based genotyping and detection of drug-resistant HBV mutations from 620 Chinese patients with chronic HBV infection. Braz J Infect Dis 2015; 19:291-5. [PMID: 25982306 PMCID: PMC9425391 DOI: 10.1016/j.bjid.2015.03.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 03/12/2015] [Accepted: 03/12/2015] [Indexed: 02/07/2023] Open
Abstract
Background Research has shown that hepatitis B virus (HBV) genotypes are closely linked to the clinical manifestations, treatment, and prognosis of the disease. Objective To study the association between genotype and drug-resistant HBV mutations in 620 Chinese patients with chronic HBV infection. Methods HBV DNA levels were determined using real-time quantitative PCR in plasma samples. Microarrays were performed for the simultaneous detection of HBV genotypes (HBV/B, C, and D) and drug-resistance-related hotspot mutations. A portion of the samples analyzed using microarrays was selected randomly and the data were confirmed using direct DNA sequencing. Results Most samples were genotype C (471/620; 76.0%), followed by genotype B (149/620; 24.0%). Among the 620 patient samples, 17 (2.7%) had nucleotide analogs (NA) resistance-related mutations. Of these, nine and eight patients carried lamivudine (LAM)-/telbivudine (LdT)-resistance mutations (rtL180M, rtM204I/V) and adefovir (ADV)-resistance mutations (rtA181T/V, rtN236T), respectively. No patients had both lamivudine (LAM)- and either adefovir (ADV) or entecavir (ETV) resistance mutations. Additionally, out of the 620 patient samples, 64.0% (397/620) were also detected with the precore stop-codon mutation (G1896A) by microarray assay. Conclusion The results of the current study revealed that the prevalence of nucleotide analogs (NA)-resistance in Chinese hospitalized HBV-positive patients was so low that intensive nucleotide analogs (NA)-resistance testing before nucleotide analog (NA) treatment might not be required. In addition, the present study suggests that chronic HBV patients with genotype C were infected with fitter viruses and had an increased prevalence of nucleotide analogs (NA)-resistance mutations compared to genotype B virus.
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Affiliation(s)
- Wenhao Hua
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
| | - Guanbin Zhang
- National Engineering Research Center for Beijing Biochip Technology, Beijing, China
| | - Shujun Guo
- Department of Infectious Disease, Pingdingshan General Hospital Medical Group, Pingdingshan City, Henan Province, China
| | - Weijie Li
- Department of Clinical Laboratory, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lanhua Sun
- National Engineering Research Center for Beijing Biochip Technology, Beijing, China
| | - Guangxin Xiang
- National Engineering Research Center for Beijing Biochip Technology, Beijing, China
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Xu J, Wu B, Wang JH, Huang L, Wang DY, Zhao L, Zhao GP, Wang Y. Pre-existing mutations in reverse transcriptase of hepatitis B virus in treatment-naive Chinese patients with chronic hepatitis B. PLoS One 2015; 10:e0117429. [PMID: 25821965 PMCID: PMC4379075 DOI: 10.1371/journal.pone.0117429] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 12/23/2014] [Indexed: 02/06/2023] Open
Abstract
High rate of viral replication and lacking of proofreading activity in hepatitis B virus (HBV) polymerase lead to the generation of mutations in HBV virus. Mutations in the reverse transcriptase (RT) region of HBV polymerase are demonstrated to be strongly associated with drug resistance during antiviral treatment. However, the presence of mutations as well as its clinical significance in treatment-naïve hepatitis patients (defined as pre-existing mutations) need to be further investigated. In the present study, a total of 168 serum samples from treatment-naive chronic hepatitis B (CHB) patients were collected, and the RT region of HBV polymerase was sequenced. The results showed that pre-existing mutations in the RT region of HBV polymerase were detected in 43 of 168 (25.6%) treatment-naive CHB patients within which there were no well-characterized primary nucleotide analogs (NAs) resistance sites. Three dominant sites at rt191, rt207 and rt226 were found mutant in 7(16.28%), 8(18.60%), and 14(32.56%) samples respectively among these 43 patients. No significant correlation was found between pre-existing mutations and gender, age, HBV genotype, ALT, HBeAg or HBV DNA loads. However, patients with pre-existing RT mutations under HBeAg sero-negative status exhibited decreased HBV DNA loads, which contributed to the decreased HBV DNA loads in the total HBeAg sero-negative patients. The above investigation indicated that there was a prevalence of pre-existing mutations in RT region of HBV polymerase which might affect the serum HBV DNA level in treatment-naive CHB patients. Its effects on the occurrence of NAs resistance and the prognosis after treatment need to be further investigated.
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Affiliation(s)
- Jie Xu
- Department of Infectious Diseases, No.3 People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Biao Wu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai/Shanghai Academy of Science and Technology, Shanghai, China
| | - Jing-Hui Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Huang
- Department of Infectious Diseases, No.3 People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Deng-yu Wang
- Shanghai Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai/Shanghai Academy of Science and Technology, Shanghai, China
| | - Ling Zhao
- Department of Infectious Diseases, No.3 People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guo-ping Zhao
- Shanghai Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai/Shanghai Academy of Science and Technology, Shanghai, China
| | - Ying Wang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai/Shanghai Academy of Science and Technology, Shanghai, China
- * E-mail:
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Lee AJ, Lee CH, Jeon CH. Analysis of reverse transcriptase gene mutations in the hepatitis B virus at a university hospital in Korea. Ann Lab Med 2014; 34:230-4. [PMID: 24790911 PMCID: PMC3999322 DOI: 10.3343/alm.2014.34.3.230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 10/07/2013] [Accepted: 02/13/2014] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Most mutations in the reverse transcriptase (RT) gene of the hepatitis B virus (HBV) are related to resistance to antiviral agents. Cross-sectional studies on the mutations of this gene are rare. Thus, we analyzed the mutation patterns of RT genes and their biochemical parameters. METHODS From 2009 to 2012, 301 blood specimens from patients with chronic hepatitis B at Daegu Catholic University Medical Center were retrospectively analyzed for the RT gene sequence of HBV, ALT, hepatitis B e antigen (HBeAg), and HBV DNA. The mutation patterns of the RT gene were compared with the biochemical parameters. RESULTS Of the 301 patients, 100 (33.2%) had no RT gene mutations. The remaining showed the following mutation patterns: rtM204I/V (50.2%), rtL180M (39.2%), and rtA181T/V (19.6%). Combined mutations were found in 146 cases (48.5%). Of these, the combination of amino acid changes at rt180+rt204 (49.3%) was most frequently detected, followed by rt181+rt236 (11.0%) and rt173+rt180+rt204 (9.6%). In the mutated group, HBV DNA and HBeAg positive rates were significantly higher (P<0.05 for both). Phenotypic analysis showed that lamivudine resistance was most frequently detected (34.6%), followed by adefovir resistance (15.6%). Multidrug resistance was detected in 48 cases (15.9%). The adefovir-resistant group had a higher proportion of cases with HBV loads greater than 2,000 IU/mL. CONCLUSIONS We found correlations between the mutation status of the RT domain and biochemical parameters such as HBV DNA and HBeAg positive rate. The presence of RT gene mutations could therefore be utilized to predict clinical status.
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Affiliation(s)
- A-Jin Lee
- Department of Laboratory Medicine, College of Medicine, Catholic University of Daegu, Daegu, Korea
| | - Chang Hyeong Lee
- Department of Internal Medicine, College of Medicine, Catholic University of Daegu, Daegu, Korea
| | - Chang-Ho Jeon
- Department of Laboratory Medicine, College of Medicine, Catholic University of Daegu, Daegu, Korea
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Xu Z, Wu G, Li F, Bai J, Xing W, Zhang D, Zeng C. Positive selection signals of hepatitis B virus and their association with disease stages and viral genotypes. INFECTION GENETICS AND EVOLUTION 2013; 19:176-87. [PMID: 23871771 DOI: 10.1016/j.meegid.2013.07.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 06/27/2013] [Accepted: 07/06/2013] [Indexed: 12/18/2022]
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Song ZL, Cui YJ, Zheng WP, Teng DH, Zheng H. Diagnostic and therapeutic progress of multi-drug resistance with anti-HBV nucleos(t)ide analogues. World J Gastroenterol 2012; 18:7149-7157. [PMID: 23326119 PMCID: PMC3544016 DOI: 10.3748/wjg.v18.i48.7149] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2012] [Revised: 11/02/2012] [Accepted: 11/06/2012] [Indexed: 02/06/2023] Open
Abstract
Nucleos(t)ide analogues (NA) are a breakthrough in the treatment and management of chronic hepatitis B. NA could suppress the replication of hepatitis B virus (HBV) and control the progression of the disease. However, drug resistance caused by their long-term use becomes a practical problem, which influences the long-term outcomes in patients. Liver transplantation is the only choice for patients with HBV-related end-stage liver disease. But, the recurrence of HBV after transplantation often caused by the development of drug resistance leads to unfavorable outcomes for the recipients. Recently, the multi-drug resistance (MDR) has become a common issue raised due to the development and clinical application of a variety of NA. This may complicate the antiviral therapy and bring poorly prognostic outcomes. Although clinical evidence has suggested that combination therapy with different NA could effectively reduce the viral load in patients with MDR, the advent of new antiviral agents with high potency and high genetic barrier to resistance brings hope to antiviral therapy. The future of HBV researches relies on how to prevent the MDR occurrence and develop reasonable and effective treatment strategies. This review focuses on the diagnostic and therapeutic progress in MDR caused by the anti-HBV NA and describes some new research progress in this field.
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Convergence and coevolution of hepatitis B virus drug resistance. Nat Commun 2012; 3:789. [PMID: 22510694 PMCID: PMC3337990 DOI: 10.1038/ncomms1794] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2011] [Accepted: 03/19/2012] [Indexed: 12/28/2022] Open
Abstract
Treatment with lamivudine of patients infected with hepatitis B virus (HBV) results in a high rate of drug resistance, which is primarily associated with the rtM204I/V substitution in the HBV reverse transcriptase domain. Here we show that the rtM204I/V substitution, although essential, is insufficient for establishing resistance against lamivudine. The analysis of 639 HBV whole-genome sequences obtained from 11 patients shows that rtM204I/V is independently acquired by more than one intra-host HBV variant, indicating the convergent nature of lamivudine resistance. The differential capacity of HBV variants to develop drug resistance suggests that fitness effects of drug-resistance mutations depend on the genetic structure of the HBV genome. An analysis of Bayesian networks that connect rtM204I/V to many sites of HBV proteins confirms that lamivudine resistance is a complex trait encoded by the entire HBV genome rather than by a single mutation. These findings have implications for public health and offer a more general framework for understanding drug resistance.
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Ramachandran S, Zhai X, Thai H, Campo DS, Xia G, Ganova-Raeva LM, Drobeniuc J, Khudyakov YE. Evaluation of intra-host variants of the entire hepatitis B virus genome. PLoS One 2011; 6:e25232. [PMID: 21949887 PMCID: PMC3176825 DOI: 10.1371/journal.pone.0025232] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2011] [Accepted: 08/30/2011] [Indexed: 02/07/2023] Open
Abstract
Genetic analysis of hepatitis B virus (HBV) frequently involves study of intra-host variants, identification of which is commonly achieved using short regions of the HBV genome. However, the use of short sequences significantly limits evaluation of genetic relatedness among HBV strains. Although analysis of HBV complete genomes using genetic cloning has been developed, its application is highly labor intensive and practiced only infrequently. We describe here a novel approach to whole genome (WG) HBV quasispecies analysis based on end-point, limiting-dilution real-time PCR (EPLD-PCR) for amplification of single HBV genome variants, and their subsequent sequencing. EPLD-PCR was used to analyze WG quasispecies from serum samples of patients (n = 38) infected with HBV genotypes A, B, C, D, E and G. Phylogenetic analysis of the EPLD-isolated HBV-WG quasispecies showed the presence of mixed genotypes, recombinant variants and sub-populations of the virus. A critical observation was that HBV-WG consensus sequences obtained by direct sequencing of PCR fragments without EPLD are genetically close, but not always identical to the major HBV variants in the intra-host population, thus indicating that consensus sequences should be judiciously used in genetic analysis. Sequence-based studies of HBV WG quasispecies should afford a more accurate assessment of HBV evolution in various clinical and epidemiological settings.
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Affiliation(s)
- Sumathi Ramachandran
- Molecular Epidemiology and Bioinformatics Laboratory, Division of Viral Hepatitis, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
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Yu N, Cui J, Zhou GB, Zhang YJ, Chen JL. Variations in the large surface protein gene of hepatitis B virus in vivo: a longitudinal study and application. Shijie Huaren Xiaohua Zazhi 2009; 17:2840-2845. [DOI: 10.11569/wcjd.v17.i27.2840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To develop a method for longitudinal study of variations in the large surface protein gene of hepatitis B virus (HBV) in vivo and apply it to the investigation of the dynamics of HBV quasispecies.
METHODS: Two HBV carriers were included in the study. Patient 1 was a 38-year-old male who received no anti-virus therapy before and during the longitudinal study, while patient 2 was a 22-year-old female who received continuous adefovir dipivoxil (ADV) therapy during the one-year longitudinal study. Serum samples were collected from the two patients over the longitudinal period. Nucleic acids were extracted from the serum samples and used as templates to amplify the HBV large surface protein gene. The resulting PCR products were cloned into the pMD18-T vector and sequenced. Variation analysis was performed using sequence alignment tools to characterize and evaluate the dynamic changes of HBV quasispecies.
RESULTS: Of 24 large surface protein gene sequences (10 from patient 1 and 14 from patient 2) analyzed, two from patient 2 contained a 30-nt deletion in PreS2 coding region. Online HBV genotype analysis showed that all the 24 sequences belonged to genotype C. The divergence values (DA, DB and DC) of HBV large surface protein gene from patient 1 were 0.29, 0.16 and 0.23, respectively, while those from patient 2 were 0.80, 2.30 and 1.82, respectively. The 'a' determinant region was perfectly identical among the 10 sequences from patient 1. In patient 2, G145R mutation was found in two sequences (29%) at the beginning and in six sequences (86%) at the end of the study. Four point mutations also were noted in the 'a' determinant region of one sequence from patient 2 at the end of the study.
CONCLUSION: Our results support the quasispecies distribution of HBV inside human hosts. It is feasible to use divergence values DA, DB and DC to characterize and evaluate the dynamic changes of HBV quasispecies. ADV therapy may increase the diversity of HBV quasispecies and thereby raise the risk of developing drug resistance.
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