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Adewuyi O‘S, Balogun MS, Otomaru H, Abimiku A, Ahumibe AA, Ilori E, Luong QA, Mba N, Avong JC, Olaide J, Okunromade O, Ahmad A, Akinpelu A, Ochu CL, Olajumoke B, Abe H, Ihekweazu C, Ifedayo A, Toizumi M, Moriuchi H, Yanagihara K, Idris J, Yoshida LM. Molecular Epidemiology, Drug-Resistant Variants, and Therapeutic Implications of Hepatitis B Virus and Hepatitis D Virus Prevalence in Nigeria: A National Study. Pathogens 2025; 14:101. [PMID: 39861062 PMCID: PMC11768191 DOI: 10.3390/pathogens14010101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/12/2025] [Accepted: 01/13/2025] [Indexed: 01/27/2025] Open
Abstract
Information on circulating HBV (sub-)genotype, variants, and hepatitis D virus (HDV) coinfection, which vary by geographical area, is crucial for the efficient control and management of HBV. We investigated the genomic characteristics of HBV (with a prevalence of 8.1%) and the prevalence of HDV in Nigeria. We utilised 777 HBV-positive samples and epidemiological data from the two-stage sampled population-based, nationally representative Nigeria HIV/AIDS Indicator and Impact Survey conducted in 2018. We assessed 732 HBV DNA-extracted samples with detectable viral loads (VLs) for (sub-)genotypes and variants by whole-genome pre-amplification, nested PCR of the s-and pol-gene, and BigDye Terminator sequencing. We conducted HDV serology. In total, 19 out of the 36 + 1 states in Nigeria had a high prevalence of HBV (≥8%), with the highest prevalence (10.4%) in the north-central geopolitical zone. Up to 33.2% (95% CI 30.0-36.6) of the participants had detectable VLs of ≥300 copies/mL. The predominant circulating HBV genotype was E with 98.4% (95% CI 97.1-99.1), followed by A with 1.6% (95% CI 0.9-2.9). Drug-resistant associated variants and immune escape variants were detected in 9.3% and 0.4%, respectively. The seroprevalence of HDV was 7.34% (95% CI 5.5-9.2). Nigeria has subtype E as the major genotype with many variants.
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Affiliation(s)
- Oludare ‘Sunbo Adewuyi
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan (H.M.)
- Department of Paediatric Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan (M.T.)
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | - Muhammad Shakir Balogun
- Nigeria Field Epidemiology and Laboratory Training Programme, Abuja 900231, Nigeria;
- African Field Epidemiology Network, Asokoro, Abuja 900231, Nigeria
| | - Hirono Otomaru
- Department of Paediatric Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan (M.T.)
| | - Alash’le Abimiku
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Anthony Agbakizu Ahumibe
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan (H.M.)
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | - Elsie Ilori
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | - Que Anh Luong
- Department of Paediatric Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan (M.T.)
| | - Nwando Mba
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | | | - John Olaide
- Department of Paediatric Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan (M.T.)
| | - Oyeladun Okunromade
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | - Adama Ahmad
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | - Afolabi Akinpelu
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | - Chinwe Lucia Ochu
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | - Babatunde Olajumoke
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | - Haruka Abe
- Vietnam Research Station, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan
| | - Chikwe Ihekweazu
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
- WHO Hub for Pandemic and Epidemic Intelligence, Prinzessinnenstrasse 17-18, 10969 Berlin, Germany
| | - Adetifa Ifedayo
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
- Foundation for Innovative New Diagnostics, 1202 Geneva, Switzerland
| | - Michiko Toizumi
- Department of Paediatric Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan (M.T.)
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan
| | - Hiroyuki Moriuchi
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan (H.M.)
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan
- Department of Paediatrics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan
| | - Katsunori Yanagihara
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan (H.M.)
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan
- Department of Laboratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan
| | - Jide Idris
- Nigeria Centre for Disease Control and Prevention, Abuja 240102, Nigeria (O.O.); (C.L.O.)
| | - Lay-Myint Yoshida
- Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523, Japan (H.M.)
- Department of Paediatric Infectious Diseases, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan (M.T.)
- School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki 852-8523, Japan
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He C, Wu X, You Z, Zhou T, Diao L, Yang Y, Wu L, Yang X, Xu Z, Zhao X, Chen Z, Lin Q, Huang H, Xu X, Zhang M, Wang Y. Evaluation of genotype characteristics and drug resistance mutations in patients with chronic hepatitis B. Sci Rep 2024; 14:27575. [PMID: 39528567 PMCID: PMC11555265 DOI: 10.1038/s41598-024-77362-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatitis B is one of the public health priorities worldwide, especially in the Southwest China. Our study aimed to investigate the relationship between genotypes and drug resistance mutations among HBV patients in Southwest China, with the objective of providing guidance for clinical antiviral treatment. A total of 4266 chronic hepatitis B (CHB) patients treated in the Qianjiang Hospital of Chongqing University were included in our study from 2014 to 2020. Both genotypes and drug-resistant mutations of CHB patients were determined by polymerase chain reaction (PCR). Genotype B and genotype C were the main HBV genotypes in our study. We found 54 mutation patterns, including 9 single-site mutations and 45 multiple-site mutations, accounting for 57.64% and 42.36%, respectively. rtM204I/V/S (485/1936) was the most common single-site mutation type, and rtL180M + rtM204I/V (482/1936) was the most common multiple-site mutation type. 1372 CHB patients were resistant to LAM + LDT, and 342 CHB patients were resistant to ADV. There was only 1 CHB patient who exhibited resistance to LAM + LDT + ADV + ETV, with a specific mutation pattern of rtA181T + rtT184L + rtM204V. Our study demonstrated trends in genetic mutations and drug resistance in CHB patients to enable timely adjustment of antiviral treatment strategies.
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Affiliation(s)
- Changlong He
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Chongqing Medical University, Yixue Yuan Road No. 1, Chongqing, 400016, China
| | - Xiaoli Wu
- Department of Clinical Laboratory, Chengdu Sixth People's Hospital, 16 Jianshe South Street, Chenghua District, Chengdu, 610051, China
| | - Zhonglan You
- Department of Infectious Diseases, The First Hospital Affiliated to the Army Medical University (AMU), Chongqing, 400038, China
| | - Tao Zhou
- Department of hepatobiliary Surgery, Chongqing Qianjiang Center Hospital, Chongqing University Qianjiang Hospital, No. 360 South Section, Zhengzhou Road, Qianjiang District, Chongqing, 409000, China
| | - Liping Diao
- Physical Examination Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China
| | - Ying Yang
- Department of Pain Management, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Liqun Wu
- Advanced Nursing, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Xiaoying Yang
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Zhousong Xu
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Xiaohong Zhao
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Zhongping Chen
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Qing Lin
- Department of Infectious Disease, People's Hospital of Jiulongpo District, Chongqing, 400050, China
| | - Huacui Huang
- Department of Clinical Laboratory, People's Hospital of Xindu District, Chengdu, 610599, China
| | - Xin Xu
- Department of Neurology, Chongqing Key Laboratory of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| | - Mingjun Zhang
- Department of Clinical Laboratory, People's Hospital of Jiulongpo District, Chongqing, 400050, China.
| | - Yonghong Wang
- Department of Clinical Laboratory, Chongqing Qianjiang Central Hospital, Qianjiang Key Laboratory of Chongqing Qianjiang Central Hospital Laboratory Medicine, Chongqing University Qianjiang Hospital, No. 360 South Section, Zhengzhou Road, Qianjiang District, Chongqing, 409000, China.
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Ohsaki E, Suwanmanee Y, Ueda K. Chronic Hepatitis B Treatment Strategies Using Polymerase Inhibitor-Based Combination Therapy. Viruses 2021; 13:v13091691. [PMID: 34578273 PMCID: PMC8473100 DOI: 10.3390/v13091691] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/19/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022] Open
Abstract
Viral polymerase is an essential enzyme for the amplification of the viral genome and is one of the major targets of antiviral therapies. However, a serious concern to be solved in hepatitis B virus (HBV) infection is the difficulty of eliminating covalently closed circular (ccc) DNA. More recently, therapeutic strategies targeting various stages of the HBV lifecycle have been attempted. Although cccDNA-targeted therapies are attractive, there are still many problems to be overcome, and the development of novel polymerase inhibitors remains an important issue. Interferons and nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are the only therapeutic options currently available for HBV infection. Many studies have reported that the combination of interferons and NRTI causes the loss of hepatitis B surface antigen (HBsAg), which is suggestive of seroconversion. Although NRTIs do not directly target cccDNA, they can strongly reduce the serum viral DNA load and could suppress the recycling step of cccDNA formation, improve liver fibrosis/cirrhosis, and reduce the risk of hepatocellular carcinoma. Here, we review recent studies on combination therapies using polymerase inhibitors and discuss the future directions of therapeutic strategies for HBV infection.
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Jiang H, Cheng ST, Ren JH, Ren F, Yu HB, Wang Q, Huang AL, Chen J. SIRT6 Inhibitor, OSS_128167 Restricts Hepatitis B Virus Transcription and Replication Through Targeting Transcription Factor Peroxisome Proliferator-Activated Receptors α. Front Pharmacol 2019; 10:1270. [PMID: 31708789 PMCID: PMC6823301 DOI: 10.3389/fphar.2019.01270] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 10/04/2019] [Indexed: 01/11/2023] Open
Abstract
Hepatitis B virus (HBV) is a major public health threat and anti-HBV drugs are limited to nucleos(t)ide analogs (NAs) and pegylated interferon alpha (Peg-IFNα). Toward identifying an effective compound for HBV treatment is important to suppress and eradicate HBV. In this study, we explored the anti-viral effect of Sirtuin 6 (SIRT6) inhibitor, OSS_128167, in HBV transcription and replication. Firstly, we found that OSS_128167 could decrease the level of HBV core deoxyribonucleic acid (DNA) and 3.5-Kb ribonucleic acid (RNA) in vitro. Furthermore, the level of HBV DNA and 3.5-Kb RNA were also markedly suppressed by OSS_128167 administration in HBV transgenic mice. In addition, we found that depletion of SIRT6 inhibited HBV transcription and replication in HepG2.2.15 and HBV-infected HepG2-sodium taurocholate cotransporting polypeptide cells, whereas overexpression of SIRT6 enhanced HBV transcription and replication. Importantly, the positive effect of SIRT6 overexpression on HBV transcription could be blocked by OSS_128167 treatment. Further mechanism studies showed that HBV core promoter was significantly activated by SIRT6 through upregulating peroxisome proliferator-activated receptors α (PPARα) expression. And ectopical expression of SIRT6 or PPARα relieved the restriction of HBV transcription mediated by OSS_128167. In summary, our results showed that OSS_128167 might serve as a potential antiviral agent for HBV therapy and SIRT6 played a pivotal role in HBV transcription and replication.
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Affiliation(s)
- Hui Jiang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Sheng-Tao Cheng
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Ji-Hua Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Fang Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Hai-Bo Yu
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Qing Wang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Ai-Long Huang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
| | - Juan Chen
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Department of Infectious Diseases, Institute for Viral Hepatitis, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China
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Liu C, Lin J, Xun Z, Huang J, Huang E, Chen T, He Y, Lin N, Yang B, Ou Q. Establishment of Coamplification at Lower Denaturation Temperature PCR/Fluorescence Melting Curve Analysis for Quantitative Detection of Hepatitis B Virus DNA, Genotype, and Reverse Transcriptase Mutation and Its Application in Diagnosis of Chronic Hepatitis B. J Mol Diagn 2019; 21:1106-1116. [PMID: 31607557 DOI: 10.1016/j.jmoldx.2019.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 08/05/2019] [Accepted: 08/06/2019] [Indexed: 12/23/2022] Open
Abstract
Dynamic and real-time hepatitis B virus (HBV) DNA, genotype, and reverse transcriptase mutation analysis plays an important role in diagnosing and monitoring chronic hepatitis B (CHB) and in assessing the therapeutic response. We established a highly sensitive coamplification at lower denaturation temperature PCR (COLD-PCR) coupled with probe-based fluorescence melting curve analysis (FMCA) for precision diagnosis of CHB patients. The imprecision with %CV and detection limit of HBV DNA detected by COLD-PCR/FMCA were 2.58% to 4.42% and 500 IU/mL, respectively. For mutation, the imprecision and detection limit were 3.35% to 6.49% and 1%, respectively. Compared with Sanger sequencing, the coincidence rates of genotype and mutation were 96.0% and 82.5%, respectively, whereas the inconsistent data resulted from a low proportion (<20%) of mixed genotypes or mixed mutations. The mutation ratio in HBV infection patients was as follows: hepatitis B e antigen (HBeAg)-positive infection (0/0.0%) < HBeAg-negative infection (16/4.5%) < HBeAg-positive hepatitis (30/5.5%) < HBeAg-negative hepatitis (36/6.5%). In patients with entecavir therapy, the proportion of mutation at baseline or week 4 in virologic response (VR) group was <4%, whereas in the partial VR group, it was mostly ≥4%. COLD-PCR/FMCA provides a novel tool with high sensitivity, convenience, and practicability for the simultaneous quantification of HBV DNA, genotype, and mutation. It might be used for distinguishing the different phases of HBV infection and predicting VR of CHB patients.
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Affiliation(s)
- Can Liu
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Gene Diagnostic Laboratory, Fujian Medical University, Fuzhou, People's Republic of China; Fujian Key Laboratory of Laboratory Medicine, Fuzhou, People's Republic of China
| | - Jinpiao Lin
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Gene Diagnostic Laboratory, Fujian Medical University, Fuzhou, People's Republic of China; Fujian Key Laboratory of Laboratory Medicine, Fuzhou, People's Republic of China
| | - Zhen Xun
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Gene Diagnostic Laboratory, Fujian Medical University, Fuzhou, People's Republic of China; Fujian Key Laboratory of Laboratory Medicine, Fuzhou, People's Republic of China
| | - Jinlan Huang
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Gene Diagnostic Laboratory, Fujian Medical University, Fuzhou, People's Republic of China; Fujian Key Laboratory of Laboratory Medicine, Fuzhou, People's Republic of China
| | - Er Huang
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Gene Diagnostic Laboratory, Fujian Medical University, Fuzhou, People's Republic of China; Fujian Key Laboratory of Laboratory Medicine, Fuzhou, People's Republic of China
| | - Tianbin Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Gene Diagnostic Laboratory, Fujian Medical University, Fuzhou, People's Republic of China; Fujian Key Laboratory of Laboratory Medicine, Fuzhou, People's Republic of China
| | - Yujue He
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Gene Diagnostic Laboratory, Fujian Medical University, Fuzhou, People's Republic of China; Fujian Key Laboratory of Laboratory Medicine, Fuzhou, People's Republic of China
| | - Ni Lin
- School of Medical Technology and Engineering, Fujian Medical University, Fuzhou, People's Republic of China
| | - Bin Yang
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Gene Diagnostic Laboratory, Fujian Medical University, Fuzhou, People's Republic of China; Fujian Key Laboratory of Laboratory Medicine, Fuzhou, People's Republic of China
| | - Qishui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People's Republic of China; Gene Diagnostic Laboratory, Fujian Medical University, Fuzhou, People's Republic of China; Fujian Key Laboratory of Laboratory Medicine, Fuzhou, People's Republic of China.
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Zheng S, Liu L, Lu J, Zhang X, Shen H, Zhang H, Xue Y, Lin L. Efficacy and safety of tenofovir disoproxil fumarate in Chinese patients with chronic hepatitis B virus infection: A 2-year prospective study. Medicine (Baltimore) 2019; 98:e17590. [PMID: 31626130 PMCID: PMC6824756 DOI: 10.1097/md.0000000000017590] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
To date, a small number of studies concerning the effects and safety of tenofovir disoproxil fumarate (TDF) in Chinese individuals were conducted. In this study, we aimed to assess the antiviral effects and nephrotoxicity of TDF in Chinese patients with chronic hepatitis B virus (HBV) infection.Patients with chronic HBV infection were prospectively recruited and TDF treatment was given for 96 weeks. HBV serologic markers, HBV DNA, creatinine and phosphorus were collected.Fifty-seven treatment-naïve and 48 treatment-experienced patients were recruited. Irrespective of the prior treatment history, more than 95% of patients achieved virological response during 96 weeks treatment with TDF. Estimated glomerular filtration rate (eGFR) significantly declined in the first year of treatment in patients with chronic hepatitis B or younger age (<65 years old) (both P < .05), while that was not achieved in patients with liver cirrhosis or older age (≥65 years old) (both P > .05). For patients who were treatment-naïve or treated previously with adefovir dipivoxil, eGFR declined at the 48th week; however, eGFR was partially recovered at the 96th week. Furthermore, multivariable analysis showed that basal eGFR <90 mL/min/1.73 m (P = .001; odds ratio: 4.821; 95% confidence interval: 1.904-12.206) is the only independent risk factor for eGFR <90 mL/min/1.73 m at the 96th week.TDF has potent antiviral effect in both treatment-naïve and treatment-experienced patients.
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Affiliation(s)
- Shuqin Zheng
- Department of Liver Diseases
- Institute for the Study of Liver Diseases
| | - Longgen Liu
- Department of Liver Diseases
- Institute for the Study of Liver Diseases
| | - Jianchun Lu
- Department of Liver Diseases
- Institute for the Study of Liver Diseases
| | - Xiujun Zhang
- Department of Liver Diseases
- Institute for the Study of Liver Diseases
| | | | | | - Yuan Xue
- Department of Liver Diseases
- Institute for the Study of Liver Diseases
| | - Lin Lin
- Institute for the Study of Liver Diseases
- Department of Pharmacy, The Third People's Hospital of Changzhou, Changzhou, Jiangsu, China
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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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Zhang X, Chen X, Wei M, Zhang C, Xu T, Liu L, Xu Z. Potential resistant mutations within HBV reverse transcriptase sequences in nucleos(t)ide analogues-experienced patients with hepatitis B virus infection. Sci Rep 2019; 9:8078. [PMID: 31147594 PMCID: PMC6542804 DOI: 10.1038/s41598-019-44604-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 05/16/2019] [Indexed: 12/17/2022] Open
Abstract
This study was performed to analyze the potential resistant mutations within HBV reverse transcriptase (RT) sequences against nucleos(t)ide analogues (NA). HBV DNA RT region spanning from amino acid 169 to 250 was amplified and sequenced from 435 HBV patients who experienced NA treatment. Among study’s cohort, genotypes B and C infected patients were 55.9% and 44.1%, respectively. Mutations were recorded in 54.7% (238/435) patients at 22 positions. Genotype C displayed significant higher frequency of potential NA resistant mutations than genotype B (63.0% vs. 48.1%, P = 0.003). Moreover, eight mutation sites, including 180, 181, 191, 200, 202, 221, 229 and 224, in genotype C showed significant higher frequencies than in genotype B. In contrast, mutation at site 236 was more common in genotype B. Notably, 11 mutations at position 169, 202, 250, 173, 180, 200, 207, 214, 237, 242 and 245 coexisted with M204I or V. Substitutions at nine non-classical mutation sites (191, 207, 213, 218, 221, 224, 229, 238 and 242) were detected in patients with virological breakthrough. Particularly, tenofovir (TDF) resistance was observed in one patient undergoing TDF monotherapy and experienced several NA treatment before. These results might provide clinical useful information under antiviral therapy.
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Affiliation(s)
- Xiaoman Zhang
- Clinical Liver Center, the 910th hospital of People's Liberation Army, Quanzhou, 362000, China
| | - Xianli Chen
- Department of Infectious and Liver Disease, Xiang'an hospital of Xiamen University, Xiamen, 361000, China
| | - Meijuan Wei
- Clinical Liver Center, the 910th hospital of People's Liberation Army, Quanzhou, 362000, China.,Clinical Liver Center, Decheng hospital of Quanzhou Affiliated of Huaqiao University, Quanzhou, 362000, China
| | - Chunyu Zhang
- Clinical Liver Center, the 910th hospital of People's Liberation Army, Quanzhou, 362000, China
| | - Tao Xu
- Clinical Liver Center, the 910th hospital of People's Liberation Army, Quanzhou, 362000, China
| | - Liguan Liu
- Clinical Liver Center, the 910th hospital of People's Liberation Army, Quanzhou, 362000, China
| | - Zhengju Xu
- Clinical Liver Center, the 910th hospital of People's Liberation Army, Quanzhou, 362000, China.
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Zhang P, Zhai S, Chang J, Guo JT. In Vitro Anti-hepatitis B Virus Activity of 2',3'-Dideoxyguanosine. Virol Sin 2018; 33:538-544. [PMID: 30421112 PMCID: PMC6335223 DOI: 10.1007/s12250-018-0065-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2018] [Accepted: 10/11/2018] [Indexed: 11/30/2022] Open
Abstract
2',3'-dideoxyguanosine (DoG) has been demonstrated to inhibit duck hepatitis B virus (DHBV) replication in vivo in a duck model of HBV infection. In the current study, the in vitro antiviral effects of DoG on human and animal hepadnaviruses were investigated. Our results showed that DoG effectively inhibited HBV, DHBV, and woodchuck hepatitis virus (WHV) replication in hepatocyte-derived cells in a dose-dependent manner, with 50% effective concentrations (EC50) of 0.3 ± 0.05, 6.82 ± 0.25, and 23.0 ± 1.5 μmol/L, respectively. Similar to other hepadnaviral DNA polymerase inhibitors, DoG did not alter the levels of intracellular viral RNA but induced the accumulation of a less-than-full-length viral RNA species, which was recently demonstrated to be generated by RNase H cleavage of pgRNA. Furthermore, using a transient transfection assay, DoG showed similar antiviral activity against HBV wild-type, 3TC-resistant rtA181V, and adefovir-resistant rtN236T mutants. Our results suggest that DoG has potential as a nucleoside analogue drug with anti-HBV activity.
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Affiliation(s)
- Pinghu Zhang
- Institute of Translational Medicine and Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001 China
- Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, PA 18902 USA
- Qinghai Himalayan Experimental Animal Center, Xining, 810006 China
| | - Shuo Zhai
- Institute of Translational Medicine and Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001 China
| | - Jinhong Chang
- Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, PA 18902 USA
| | - Ju-Tao Guo
- Baruch S. Blumberg Institute, Hepatitis B Foundation, Doylestown, PA 18902 USA
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Lu JC, Liu LG, Lin L, Zheng SQ, Xue Y. Incident hepatocellular carcinoma developing during tenofovir alafenamide treatment as a rescue therapy for multi-drug resistant hepatitis B virus infection: A case report and review of the literature. World J Clin Cases 2018; 6:671-674. [PMID: 30430123 PMCID: PMC6232567 DOI: 10.12998/wjcc.v6.i13.671] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 09/05/2018] [Accepted: 10/11/2018] [Indexed: 02/05/2023] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is a potent nucleotide analogue with high barrier to resistance, which is recommended for multi-drug resistant hepatitis B virus (HBV) infection. However, nephrotoxicity has been reported during TDF treatment, and tenofovir alafenamide (TAF), which has comparable efficacy to TDF and improves bone and renal safety, can be used as a replacement strategy. Herein, we describe a clinical case concerning a 60-year-old individual suffering liver cirrhosis and renal dysfunction, and being infected with multidrug-resistant HBV. When failing treatment with TDF, he received TAF as a rescue therapy. TAF effectively inhibited HBV replication without worsening renal function or serum phosphorus abnormality. Furthermore, hepatocellular carcinoma (HCC) occurred during TAF treatment despite controlling the viral load. The risk of HCC could not be eliminated and should be monitored during TAF treatment.
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Affiliation(s)
- Jian-Chun Lu
- Department of Liver Diseases, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
- Institute of Hepatology, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
| | - Long-Gen Liu
- Department of Liver Diseases, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
- Institute of Hepatology, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
| | - Lin Lin
- Institute of Hepatology, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
- Department of Pharmacy, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
| | - Shu-Qin Zheng
- Department of Liver Diseases, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
- Institute of Hepatology, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
| | - Yuan Xue
- Department of Liver Diseases, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
- Institute of Hepatology, the Third People’s Hospital of Changzhou, Changzhou 213000, Jiangsu Province, China
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11
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Guo X, Wu J, Wei F, Ouyang Y, Li Q, Liu K, Wang Y, Zhang Y, Chen D. Trends in hepatitis B virus resistance to nucleoside/nucleotide analogues in North China from 2009-2016: A retrospective study. Int J Antimicrob Agents 2018; 52:201-209. [PMID: 29654894 DOI: 10.1016/j.ijantimicag.2018.04.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 03/29/2018] [Accepted: 04/04/2018] [Indexed: 12/13/2022]
Abstract
Nucleos(t)ide analogues (NAs) are widely used in anti-hepatitis B virus (anti-HBV) therapy for effective inhibition of HBV replication. However, HBV resistance to NAs has emerged, resulting in virus reactivation and disease recurrence. Data on the current dynamics of HBV resistance are still rare in China. This study analysed 4491 plasma samples with HBV primary genotypic resistance mutations representative of the general HBV resistance situation in northern China from 2009-2016. We found that entecavir (ETV), representing 57.6% (12 713/22 060) of NA users in North China in 2016, has become the major NA for treating Chinese patients infected with HBV. Despite >50% of M204I/V±L180M among all HBV resistance cases annually and extensive exposure of patients to lamivudine (LAM), telbivudine (LdT) and adefovir dipivoxil (ADV), ETV resistance also showed a dramatically increased incidence, which rose to 17.1% in 2016. Moreover, A181T/V, ETV resistance mutations and multidrug resistance mutations were found more frequently in HBV genotype C compared with genotype B (21.2% vs. 8.5%, 12.4% vs. 7.9% and 5.9% vs. 3.0%, respectively), whereas M204I and N236T were more predominant in genotype B than genotype C (40.3% vs. 20.8% and 11.3% vs. 1.8%, respectively). In conclusion, we report the dynamic changes of HBV NA resistance mutation patterns and the current NA usage profile for anti-HBV treatment in North China over the past 8 years. These data provide valuable information on HBV NA resistance that is an important reference for clinicians to devise more effective treatment regimens for individual patients.
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Affiliation(s)
- Xianghua Guo
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Jushan Wu
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Feili Wei
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yabo Ouyang
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Qing Li
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Kai Liu
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yanjun Wang
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China
| | - Yulin Zhang
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China.
| | - Dexi Chen
- Beijing You An Hospital, Capital Medical University, Beijing 100069, China; Beijing Institute of Hepatology, Beijing 100069, China; Beijing Precision Medicine and Transformation Engineering Technology Research Center of Hepatitis and Liver Cancer, Beijing 100069, China; Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao City, Shandong Province 266003, China.
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