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Berhanu L, Desye B, Daba C, Berihun G, Geto AK. Seroprevalence and risk factors of hepatitis B virus infection among healthcare workers in Africa: A systematic review and meta-analysis. PLoS One 2025; 20:e0319986. [PMID: 40131963 PMCID: PMC11936272 DOI: 10.1371/journal.pone.0319986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 02/11/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND Healthcare workers are at an increased risk of hepatitis B virus infection due to potential exposure to blood and other infectious materials. The infection can lead to acute liver disease and chronic liver complications such as cirrhosis and liver cancer. It can impact workforce health, leading to absenteeism, and increased healthcare costs. Hence, this study aimed to determine the seroprevalence and risk factors of the hepatitis B virus among healthcare workers in Africa. MATERIALS AND METHODS The protocol for this systematic review and meta-analysis was registered on PROSPERO with the registration number CRD42024556654. Literatures were searched from PubMed, Science Direct, HINARI, African Online Journal, Google Scholar, Google, Semantic Scholar, and Directory of Open Access Journals using relevant search terms. The process of searching relevant articles was completed on 1 August 2024. Studies with a quality evaluation indicator score of 50% or above were included in this study. The random effect model was used to measure the pooled seroprevalence and associated factors of hepatitis B virus infection among healthcare workers in Africa. The finding of the meta-analysis was presented using forest plots with a 95% confidence interval. RESULT Among 26 studies selected for meta-analysis, 6983 participants were included. The inclusion of 26 studies showed that the pooled prevalence of hepatitis B virus infection among healthcare workers was 17.2% (95% CI: 8.36, 26.04). Healthcare workers diagnosed with liver disease were 5.01 times more likely to having hepatitis B virus infection compared to those who were not diagnosed (POR = 5.01: 95% CI; 2.25,7.77). In addition, healthcare workers who did not receive technical training were 2.70 times more likely to having HBV infection than those who received training (POR = 2.70:95% CI; 1.10, 4.30). Furthermore, healthcare workers aged 40 years and above were 2.53 times more likely to having hepatitis B virus infection than young healthcare workers (POR = 2.53: 95% CI; 1.29,3.77). CONCLUSION The pooled prevalence of hepatitis B virus infection was high. Previously diagnosed liver diseases, the absence of technical training, and the age of healthcare workers were the factors influencing the pooled prevalence of HBV infection among healthcare workers. Hence, providing appropriate medical follow-up for healthcare workers diagnosed with liver disease, comprehensive training and education, and early detection and diagnosis of healthcare workers aged 40 years and above are the most important interventions to prevent the risk of hepatitis B virus infection.
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Affiliation(s)
- Leykun Berhanu
- Department of Environmental Health, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
| | - Belay Desye
- Department of Environmental Health, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
| | - Chala Daba
- Department of Environmental Health, College of Medicine and Health Sciences, Wollo University, Dessie, Ethiopia
- National Centre for Epidemiology and Population Health, The Australian National University, Canberra, ACT, Australia
| | - Gete Berihun
- Department of Environmental Health, College of Medicine and Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Abebe Kassa Geto
- Department of Public Health, College of Health Sciences, Woldia University, Woldia, Ethiopia
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Sedohara A, Takahashi K, Arai K, Arizono K, Tuvshinjargal K, Saito M, Nakahara F, Tsutsumi T, Ikeuchi K, Adachi E, Yotsuyanagi H. Characterization of mutations in hepatitis B virus DNA isolated from Japanese HBsAg-positive blood donors in 2021 and 2022. Arch Virol 2024; 169:103. [PMID: 38632180 PMCID: PMC11023964 DOI: 10.1007/s00705-024-06016-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 02/04/2024] [Indexed: 04/19/2024]
Abstract
Missense mutations in certain small envelope proteins diminish the efficacy of antibodies. Consequently, tracking the incidence and types of vaccine-escape mutations (VEMs) was crucial both before and after the introduction of universal hepatitis B vaccination in Japan in 2016. In this study, we isolated hepatitis B virus (HBV) DNA from 58 of 169 hepatitis B surface antigen (HBsAg)-positive blood samples from Japanese blood donors and determined the nucleotide sequence encoding the small envelope protein. DNA from six (10%) of the samples had VEMs, but no missense mutations, such as G145R, were detected. Complete HBV genome sequences were obtained from 29 of the 58 samples; the viral genotype was A1 in one (3%), A2 in three (10%), B1 in nine (31%), B2 in five (17%), B4 in one (3%), and C2 in 10 (34%) samples. Tenofovir-resistance mutations were detected in two (7%) samples. In addition, several core promoter mutations, such as 1762A>T and 1764G>A, and a precore nonsense mutation, 1986G>A, which are risk factors for HBV-related chronic liver disease, were detected. These findings provide a baseline for future research and highlight the importance of ongoing monitoring of VEMs and drug resistance mutations in HBV DNA from HBsAg-positive blood donors without HBV antibodies.
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Affiliation(s)
- Ayako Sedohara
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Kazuaki Takahashi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Keiko Arai
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kotaro Arizono
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Khulan Tuvshinjargal
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Makoto Saito
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Fumio Nakahara
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan
| | - Takeya Tsutsumi
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Ikeuchi
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Eisuke Adachi
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- Department of Infectious Disease and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
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Tanaka A, Yamagishi N, Hasegawa T, Miyakawa K, Goto N, Matsubayashi K, Satake M. Marked reduction in the incidence of transfusion-transmitted hepatitis B virus infection after the introduction of antibody to hepatitis B core antigen and individual donation nucleic acid amplification screening in Japan. Transfusion 2023; 63:2083-2097. [PMID: 37767806 DOI: 10.1111/trf.17546] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 08/20/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023]
Abstract
BACKGROUND In Japan, 41 million blood donations have been screened for hepatitis B virus (HBV) during the past 8.4 years using individual donation nucleic acid amplification testing (ID-NAT) and antibody to hepatitis B core antigen (anti-HBc) screening. STUDY DESIGN AND METHODS Transfusion-transmitted HBV infection (TT-HBV) incidence was examined. Donated blood implicated in TT-HBV was analyzed for infection stage and DNA levels. Causative HBV strains were phylogenetically analyzed. RESULTS Among 5162 (0.013%) ID-NAT positives, window period (WP) and occult HBV infection (OBI) accounted for 3.4% (176) and 11.5% (594), respectively. No OBI-related TT-HBV occurred. Seven blood donations caused eight TT-HBV cases, six of which were in the pre-ID-NAT WP, leaving one with an unresolved infection stage. Seven cases were caused by platelet concentrate (180 mL plasma) and one case by fresh-frozen plasma (200 mL plasma), which contained estimated infectious doses varying between 2 and 2300 HBV virions. HBV subgenotypes in five cases were HBV/A2. Complete genome sequences of the transmitting A2 strains were nearly identical (99.6%-100%) and clustered in a group that included HBV/HIV-1 coinfections and a higher proportion of donors in the acute infection phase (69%) than the other group of HBV/A2 sequences (5%). DISCUSSION The incidence of observed TT-HBV cases has significantly reduced to 0.19 per million in the ID-NAT screening period. OBI-related TT-HBV was eliminated by anti-HBc screening. Established TT-HBV cases were caused by blood products with large plasma volumes containing extremely low HBV concentrations derived from blood donors at a very early infection stage.
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Affiliation(s)
- Ami Tanaka
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
| | - Naoji Yamagishi
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
| | - Takashi Hasegawa
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
| | - Keiko Miyakawa
- Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
| | - Naoko Goto
- Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
| | - Keiji Matsubayashi
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
| | - Masahiro Satake
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
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Momose H, Murayama A, Yamada N, Matsubayashi K, Matsuoka S, Ikebe E, Kuramitsu M, Muramatsu M, Kato T, Hamaguchi I. Performance evaluation of in vitro diagnostic kits for hepatitis B virus infection using the regional reference panel of Japan. Virol J 2023; 20:93. [PMID: 37165426 PMCID: PMC10170722 DOI: 10.1186/s12985-023-02054-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 04/26/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a global public health concern. Precise and sensitive detection of viral markers, including HBV DNA and HBs antigen (Ag), is essential to determine HBV infection. METHODS The sensitivities and specificities of 5 HBV DNA and 14 HBsAg kits were evaluated using World Health Organization International Standards (WHO IS) and the Regional Reference Panel (RRP) consisting of 64 HBsAg-negative and 80 HBsAg-positive specimens. RESULTS All 5 HBV DNA kits detected HBV DNA in the WHO IS at a concentration of 10 IU/mL. The sensitivity and specificity to the RRP were 98.8-100% and 96.9-100%, respectively. HBV DNA titers were well correlated among the 5 kits regardless of HBV genotype. However, discordance of the HBV DNA titer was found in 5 specimens measured by CAP/CTM HBV v2.0. Among 12 automated HBsAg kits, the minimum detectable concentrations in the WHO IS varied from 0.01 to 0.1 IU/mL. Two lateral flow assays were positive for WHO IS concentrations greater than or equal to 1.0 and 0.1 IU/mL, respectively. When analyzed by the RRP, 12 automated kits exhibited a sensitivity of 98.8-100%, and 2 lateral flow assays showed sensitivities of 93.8% and 100%. The specificities of HBsAg kits were 100%. In the quantification of HBsAg, some kits showed a poor correlation of measurements with each other and showed up to a 1.7-fold difference in the regression coefficient of HBsAg titers. There were variations in the correlations of measurements among HBsAg kits when analyzed by genotype. CONCLUSIONS Five HBV DNA kits showed sufficient sensitivity and specificity to determine HBV infection. HBV DNA titers were compatible with each other irrespective of HBV genotypes. HBsAg kits had enough sensitivity and specificity to screen for HBV infection. One of the lateral flow assays had a nearly equivalent sensitivity to that of the automated HBsAg kit. HBsAg titers quantified by the evaluated kits were not compatible across the kits. Genotype-dependent amino acid variations might affect the quantification of HBsAg titers.
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Affiliation(s)
- Haruka Momose
- Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Asako Murayama
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Norie Yamada
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Keiji Matsubayashi
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, 2-1-67 Tatsumi, Koto-ku, Tokyo, 135-8521, Japan
| | - Sahoko Matsuoka
- Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Emi Ikebe
- Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Madoka Kuramitsu
- Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan
| | - Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo, 162-8640, Japan.
| | - Isao Hamaguchi
- Research Center for Biological Products in the Next Generation, National Institute of Infectious Diseases, 4-7-1 Gakuen, Musashimurayama, Tokyo, 208-0011, Japan.
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Kafeero HM, Ndagire D, Ocama P, Kato CD, Wampande E, Walusansa A, Kajumbula H, Kateete D, Ssenku JE, Sendagire H. Mapping hepatitis B virus genotypes on the African continent from 1997 to 2021: a systematic review with meta-analysis. Sci Rep 2023; 13:5723. [PMID: 37029173 PMCID: PMC10082212 DOI: 10.1038/s41598-023-32865-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 04/04/2023] [Indexed: 04/09/2023] Open
Abstract
Hepatitis B virus (HBV) has ten genotypes (A-J) and over 40 sub-genotypes based on the divergence of ≥ 8% and 4 to < 8% in the complete genome respectively. These genotypes and sub-genotypes influence the disease prognosis, response to therapy and route of viral transmission. Besides, infection with mixed genotypes and recombinant genotypes has also been reported. This study aimed at mapping the de novo genotypes and correlate them with the immigration trends in order to inform future research on the underlying reasons for the relative distribution of HBV genotypes from a large sample size pooled from many primary studies. Data was extracted from 59 full research articles obtained from Scopus, PubMed, EMBASE, Willy library, African Journal Online (AJOL) and Google Scholar. Studies that investigated the genotypes, sub-genotypes, mixed genotypes and recombinant were included. The Z-test and regression were used for the analysis. The study protocol is registered with PROSPERO under the registration number CRD42022300220. Overall, genotype E had the highest pooled prevalence significantly higher than all the other genotypes (P < 0.001). By region, genotype A posted the highest pooled prevalence in eastern and southern Africa, E in west Africa and D in north Africa (P < 0.0001). Regarding the emerging genotypes B and C on the African continent, genotype B was significantly higher in south Africa than C (P < 0.001). In contrast, genotype C was significantly higher in east Africa than west Africa (P < 0.0001). The A1 and D/E were the most diverse sub-genotypes and genotype mixtures respectively. Finally, we observed a general progressive decrease in the prevalence of predominant genotypes but a progressive increase in the less dominant by region. Historical and recent continental and intercontinental migrations can provide a plausible explanation for the HBV genotype distribution pattern on the African continent.
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Affiliation(s)
- Hussein Mukasa Kafeero
- Department of Medical Microbiology, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda.
- Department of Medical Microbiology, Habib Medical School, Faculty of Health Sciences, Islamic University in Uganda, P. O Box 7689, Kampala, Uganda.
| | - Dorothy Ndagire
- Department of Plant Sciences, Microbiology and Biotechnology, College of Natural Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Ponsiano Ocama
- Department of Medicine, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Charles Drago Kato
- Department of Biomolecular Resources and Biolab Sciences, College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Eddie Wampande
- Department of Biomolecular Resources and Biolab Sciences, College of Veterinary Medicine, Animal Resources and Biosecurity, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Abdul Walusansa
- Department of Medical Microbiology, Habib Medical School, Faculty of Health Sciences, Islamic University in Uganda, P. O Box 7689, Kampala, Uganda
| | - Henry Kajumbula
- Department of Medical Microbiology, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - David Kateete
- Department of Molecular Biology and Immunology, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Jamilu E Ssenku
- Department of Plant Sciences, Microbiology and Biotechnology, College of Natural Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
| | - Hakim Sendagire
- Department of Medical Microbiology, College of Health Sciences, Makerere University, P. O Box 7062, Kampala, Uganda
- Department of Medical Microbiology, Habib Medical School, Faculty of Health Sciences, Islamic University in Uganda, P. O Box 7689, Kampala, Uganda
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Bello KE, Mat Jusoh TNA, Irekeola AA, Abu N, Mohd Amin NAZ, Mustaffa N, Shueb RH. A Recent Prevalence of Hepatitis B Virus (HBV) Genotypes and Subtypes in Asia: A Systematic Review and Meta-Analysis. Healthcare (Basel) 2023; 11:healthcare11071011. [PMID: 37046937 PMCID: PMC10094200 DOI: 10.3390/healthcare11071011] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/05/2023] Open
Abstract
Background and Aim: Despite introducing the hepatitis B virus (HBV) vaccine, the incidence of the Hepatitis B virus globally is still a major health concern. This systematic review and meta-analysis were conducted to provide detailed information on the prevalence of HBV genotypes and subtypes in circulation in Asia. Methods: A systematic search for articles describing the prevalence of HBV genotypes and subtypes in Asia was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Results: Our search returned 207 eligible articles involving 49,279 genotypes and 7457 subtypes representing 28 Asian countries. A meta-analysis was performed on our eligible studies using the Random effect Model. The pooled prevalence of HBV genotypes showed that genotype C (30.9%) (95% CI, 27.5–34.5%; I2 = 97.57%; p < 0.001) was the most common HBV genotype in Asia, followed by genotype B (17.8%) (95% CI, 15.5–20.4%; I2 = 97.26%; p < 0.001) and genotype D (15.4%) (95% CI, 11.8–19.8%). Vietnam had the highest prevalence of genotype B, Lebanon had the highest prevalence of genotypes C, and Jordan had the highest prevalence of genotype D. There was variation in genotypic prevalence with respect to the target genes for HBV genotyping. Reverse dot blot hybridization had the highest estimate of genotypes B and C. HBV subtype C2 (40.0%) (95% CI, 33.3–47.0) is the most prevalent HBV subtype. Conclusion: Evidence from this study reveals that HBV genotypes C and B are the most dominant HBV genotypes in Asia, and HBV subtype C2 is more endemic in Asia.
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Affiliation(s)
- Kizito Eneye Bello
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Department of Microbiology, Faculty of Natural Science, Kogi State University (Prince Abubakar Audu University), Anyigba 1008, Kogi State, Nigeria
| | - Tuan Nur Akmalina Mat Jusoh
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
| | - Ahmad Adebayo Irekeola
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Microbiology Unit, Department of Biological Sciences, College of Natural and Applied Sciences, Summit University Offa, Offa 4412, Kwara State, Nigeria
| | - Norhidayah Abu
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Advanced Materials Research Centre (A.M.R.E.C.), Lot 34 Jalan Hi-Tech 2/3, Kulim Hi-Tech Park, Kulim 09000, Kedah, Malaysia
| | - Nur Amalin Zahirah Mohd Amin
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
| | - Nazri Mustaffa
- Department of Medicine, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
| | - Rafidah Hanim Shueb
- Department of Medical Microbiology and Parasitology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia
- Institute for Research in Molecular Medicine (I.N.F.O.R.M.M.), Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia
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Kato T, Akari H. [Neutralization of hepatitis B virus with vaccine-escape mutations by novel hepatitis B vaccine with large-HBs antigen]. Uirusu 2023; 72:149-158. [PMID: 38220203 DOI: 10.2222/jsv.72.149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2024]
Abstract
Although the current hepatitis B (HB) vaccine comprising yeast-derived small hepatitis B surface antigen (HBsAg) is potent and safe and used worldwide, specific concerns should not be ignored, such as the attenuated prophylaxis against hepatitis B virus (HBV) infection with specific amino acid polymorphisms, called vaccine-escape mutations (VEMs). We investigated a novel HB vaccine consisting of large-HBsAg that covers the shortcomings of the current HB vaccine in a nonhuman primate model. The yeast-derived large-HBsAg was mixed with the adjuvant and used to immunize rhesus macaques, and the induction of antibodies to HBsAg was compared with that of the current HB vaccine. The current HB vaccine predominantly induced antibodies to small-HBsAg, whereas immunization with the large-HBsAg vaccine mainly induced antibodies to the preS1 region. Although the antibodies induced by the current HB vaccine could not prevent infection of HBV with VEMs, the large-HBsAg vaccine-induced antibodies neutralized infection of HBV with VEMs at levels similar to those of the wild type. The HBV genotypes that exhibited attenuated neutralization by induced antibodies differed between these vaccines. In conclusion, the novel HB vaccine consisting of large-HBsAg was revealed to be useful to compensate for shortcomings of the current HB vaccine. The combined use of these HB vaccines may be able to induce antibodies that can neutralize HBV strains with VEMs or multiple HBV genotypes.
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Affiliation(s)
- Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hirofumi Akari
- Center for the Evolutionary Origins of Human Behavior, Kyoto University, Aichi, Japan
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Sakamoto K, Ito K, Yotsuyanagi H, Yatsuhashi H, Tanaka Y, Hige S, Takikawa Y, Ueno Y, Yamamoto K, Imazeki F, Inoue J, Kurosaki M, Umemura T, Toyoda H, Mita E, Michitaka K, Maeshiro T, Yamada N, Suetsugu A, Kawanaka M, Seko Y, Matsuura K, Okumura A, Fukuzawa Y, Sugiyama M, Mizokami M, Yoneda M. Trends of hepatitis B virus genotype distribution in chronic hepatitis B patients in Japan. J Gastroenterol 2022; 57:971-980. [PMID: 36173513 DOI: 10.1007/s00535-022-01921-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 09/07/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) is one of the most prevalent chronic viral infections that causes chronic hepatitis B (CHB). In Japan, genotypes B and C account for most of acute and chronic cases of hepatitis. However, previous studies showed that the prevalence of genotype A in CHB gradually increased every 5 years. Therefore, we have conducted a nationwide survey to comprehensively investigate the trends of HBV genotype distribution in CHB patients in Japan. METHODS 4421 CHB patients were recruited between 2015 and 2016. Clinical characteristics and distribution of CHB patients among different age groups and genotypes in 2015-2016 was compared with those in 2000-2001, 2005-2006, and 2010-2011. RESULTS The percentages of genotype A, B, C, and D were 4.0, 16.2, 79.1, and 0.7%, respectively. While the overall percentage of CHB patients with genotype A did not change in the past 5 years, CHB with genotype A increased in young adults. On the other hand, the peak distribution of CHB with genotypes B and C, two genotypes with the largest patient population, has shifted to an older age group. CONCLUSIONS In Japan, the peak distribution for CHB with genotypes B and C advanced to an older age group while CHB with genotype A expanded in a younger age group. Given the universal HBV vaccination launch in Japan in 2016, these pre-vaccination survey data provide important baseline information for comparative studies of the impact of universal vaccination on HBV genotypes.
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Affiliation(s)
- Kazumasa Sakamoto
- Department of Gastroenterology, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Kiyoaki Ito
- Department of Gastroenterology, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroshi Yatsuhashi
- Clinical Research Center, Department of Hepatology, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Shuhei Hige
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yasuhiro Takikawa
- Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Kazuhide Yamamoto
- Department of Internal Medicine, Okayama Saiseikai General Hospital, Okayama, Japan
| | - Fumio Imazeki
- Safety and Health Organization, Chiba University, Chiba, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Musashino, Japan
| | - Takeji Umemura
- Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki, Japan
| | - Eiji Mita
- Department of Gastroenterology and Hepatology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Kojiro Michitaka
- Gastroenterology Center, Ehime Prefectural Central Hospital, Matsuyama, Japan
| | - Tatsuji Maeshiro
- Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Norie Yamada
- Department of Internal Medicine, Center for Liver Diseases, Seizankai Kiyokawa Hospital, Tokyo, Japan
| | - Atsushi Suetsugu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine2, Kawasaki Medical School, Okayama, Japan
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Akinori Okumura
- Department of Gastroenterology, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Yoshitaka Fukuzawa
- Department of Gastroenterology, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
| | - Masaya Sugiyama
- Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Yoneda
- Department of Gastroenterology, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
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9
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Delobel D, Furutani Y, Nagoshi S, Tsubota A, Miyasaka A, Watashi K, Wakita T, Matsuura T, Usui K. SEB genotyping: SmartAmp-Eprimer binary code genotyping for complex, highly variable targets applied to HBV. BMC Infect Dis 2022; 22:516. [PMID: 35659601 PMCID: PMC9164387 DOI: 10.1186/s12879-022-07458-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 05/09/2022] [Indexed: 11/10/2022] Open
Abstract
Background SmartAmp-Eprimer Binary code (SEB) Genotyping is a novel isothermal amplification method for rapid genotyping of any variable target of interest. Methods After in silico alignment of a large number of sequences and computational analysis to determine the smallest number of regions to be targeted by SEB Genotyping, SmartAmp primer sets were designed to obtain a binary code of On/Off fluorescence signals, each code corresponding to a unique genotype. Results Applied to HBV, we selected 4 targets for which fluorescence amplification signals produce a specific binary code unique to each of the 8 main genotypes (A–H) found in patients worldwide. Conclusions We present here the proof of concept of a new genotyping method specifically designed for complex and highly variable targets. Applied here to HBV, SEB Genotyping can be adapted to any other pathogen or disease carrying multiple known mutations. Using simple preparation steps, SEB Genotyping provides accurate results quickly and will enable physicians to choose the best adapted treatment for each of their patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-022-07458-4.
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10
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Hepatitis B virus (HBV) serological patterns among the HBsAg negative hospital attendees screened for immunization. Sci Rep 2022; 12:7425. [PMID: 35523938 PMCID: PMC9076922 DOI: 10.1038/s41598-022-11535-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Accepted: 04/20/2022] [Indexed: 12/29/2022] Open
Abstract
The Hepatitis B virus (HBV) is a highly infectious virus and is endemic in Uganda. It is one of the major etiological agents for liver diseases including liver cancer. In this work, we evaluated the prevalence of the HBV serological markers and the associated socio-demographic factors among hepatitis B surface antigen (HBsAg) seronegative persons screened during routine immunization against the virus in eastern Uganda. Data on the socio-demographic characteristics were collected using a structured questionnaire, while that on the serological markers were obtained from serum samples and evaluated by using the 5-panel HBV One Step Hepatitis B Virus Combo Test Device (FastepR, HBV-P43M). The following markers were evaluated by the panel: HBsAg, HBsAb, HBcAb, and HBeAb. Data were analyzed using SPSS (version 26), and multinomial logistic regression was used to elicit the adjusted odds ratio. All the analysis were performed at a 95% confidence limit, and a P value ≤ 0.05 was considered significant. The 424 participants included in this study were mainly female (62.3%), married (55.4%) and aged 30 years and above (54.2%). The seropositivity of the HBsAb, HBeAb, HBcAb marker prevalence rates was 48(11.3%), 73(17.2%) and 45(10.6%) respectively. The majority of the participants (327, 77.1%) did not present with any marker. Married paricipants were significantly associated with reduced HBsAb seropositvity rate, whereas young people aged 18–29 years were associated the with increased odds of HBsAb seropositivity (p < 0.05). Male participants were significantly associated with the HBeAb and HBcAb seropositivity (p < 0.05). Similarly, contact with an HBV infected person was significantly associated with HBeAb and HBcAb seropositivity (p < 0.05). Further still, blood transfusion was significantly associated with the increased risk of HBcAb seropositivity (P < 0.05). This study has revealed a prevalence of HBV serological markers among the HBsAg seronegative persons in this community and an increased risk of transmission of the virus in the community. Our findings have key consequences pertaining the interventions that are pertinent in the control and prevention of the spread of the virus among apparently health persons.
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11
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Disproportionate Distribution of HBV Genotypes A and D and the Recombinant Genotype D/E in the High and Low HBV Endemic Regions of Uganda: A Wake-Up Call for Regional Specific HBV Management. Int J Hepatol 2022; 2022:3688547. [PMID: 35070455 PMCID: PMC8767397 DOI: 10.1155/2022/3688547] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 11/08/2021] [Accepted: 12/17/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) is the leading cause of liver-related diseases. In Uganda, there is a regional disparity in the HBV burden. Our study was aimed at establishing the circulating genotypes in a low and a high endemic region to give plausible explanations for the differences in regional burden and guide the future management of the disease. METHODS A total of 200 HBsAg-seropositive subjects were recruited into the study by convenience sampling. The HBsAg Rapid Test Strip (Healgen Scientific Limited Liability Company, Houston, TX77047- USA) was used to screen for HBsAg while the Roche machine (Roche, Basel Switzerland/Abbot Technologies (USA)) was used to determine the viral load. The Chemistry Analyzer B120 (Mindray, China) was used for chemistry analysis. For HBV genotyping, total DNA was extracted from whole blood using the QIAamp® DNA extraction kit. Nested PCR amplification was performed using Platinum Taq DNA Polymerase (Invitrogen Corporation, USA) to amplify the 400 bp HBV polymerase gene. Purification of nested PCR products was performed using Purelink PCR product purification kit (Life Technologies, USA). Automated DNA sequencing was performed using BigDye Terminator v3.1 Cycle Sequencing Kit on 3130 Genetic Analyzer (Applied Biosystems, USA). The NCBI HBV genotyping tool (https://www.ncbi.nlm.nih.gov/projects/genotyping/formpage.cgi) was used for determination of genotype for each HBV sequence. Pearson's chi-square, multinomial logistic regression, and Mann-Whitney U tests were used for the analysis. All the analyses were done using SPSS version 26.0 and MedCalc software version 19.1.3 at 95% CI. A p < 0.05 was considered statistically significant. RESULTS Majority of our study subjects were female (64.5%), youth (51.0%), and married (62.0%). Overall, genotype A was the most prevalent (46%). Genotype D and the recombinant genotype D/E were proportionately more distributed in the high endemic (38.2%) and low endemic (36.5%) regions, respectively. Genotype D was significantly more prevalent in the high endemic region and among the elderly (p < 0.05). Genotype D was significantly associated with elevated viral load and direct bilirubin (p < 0.05). The recombinant genotype D/E was significantly associated with elevated viral load (p < 0.05). Similarly, genotype A was significantly associated with elevated AST and GGT, lowered viral load, and normal direct bilirubin levels (p < 0.05). CONCLUSION There is disproportionate distribution of genotypes A and D and the recombinant genotype D/E in the low and high endemic regions of Uganda. This probably could explain the differences in endemicity of HBV in our country signifying the need for regional specific HBV management and control strategies.
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12
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Hayashi S, Nagaoka K, Tanaka Y. Blood-Based Biomarkers in Hepatitis B Virus-Related Hepatocellular Carcinoma, Including the Viral Genome and Glycosylated Proteins. Int J Mol Sci 2021; 22:11051. [PMID: 34681709 PMCID: PMC8540379 DOI: 10.3390/ijms222011051] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) development and is a global public health issue. High performance biomarkers can aid the early detection of HCC development in HBV-infected individuals. In addition, advances in the understanding of the pathogenesis of HBV infection and in clinical laboratory techniques have enabled the establishment of disease-specific tests, prediction of the progression of liver diseases, including HCC, and auxiliary diagnosis of HCC, using blood-based methods instead of biopsies of liver or HCC tissues. Viral factors such as the HBV genotype, HBV genetic mutations, HBV DNA, and HBV-related antigens, as well as host factors, such as tumor-associated proteins and post-translational modifications, especially glycosylated proteins, can be blood-based, disease-specific biomarkers for HCC development in HBV-infected patients. In this review, we describe the clinical applications of viral biomarkers, including the HBV genome and glycosylated proteins, for patients at a risk of HBV-related HCC, based on their molecular mechanisms. In addition, we introduce promising biomarker candidates for practical use, including colony stimulating factor 1 receptor (CSF1R), extracellular vesicles, and cell-free, circulating tumor DNA. The clinical use of such surrogate markers may lead to a better understanding of the risk of disease progression and early detection of HCC in HBV-infected patients, thereby improving their prognosis.
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Affiliation(s)
| | | | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan; (S.H.); (K.N.)
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13
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Kafeero HM, Ndagire D, Ocama P, Kudamba A, Walusansa A, Sendagire H. Prevalence and predictors of hepatitis B virus (HBV) infection in east Africa: evidence from a systematic review and meta-analysis of epidemiological studies published from 2005 to 2020. Arch Public Health 2021; 79:167. [PMID: 34537079 PMCID: PMC8449462 DOI: 10.1186/s13690-021-00686-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 09/02/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The epidemiology of hepatitis B virus (HBV) in the general population in east Africa is not well documented. In this meta-analysis, we examined 37 full published research articles to synthesise up-to-date data on the prevalence and predictors of the HBV burden for the effective prevention and management of the virus in our region. METHODS We examined 37 full published research articles found using PubMed, Scopus, African Journal Online (AJOL), and Google Scholar between May and October 2020. Dichotomous data on HBV prevalence and predictors of infection were extracted from the individual studies. The HBV prevalence, test of proportion, relative risk, and I2 statistics for heterogeneity were calculated using MedCalc software version 19.1.3. Begg's tests was used to test for publication bias. Sources of heterogeneity were analysed through sensitivity analysis, meta-regression, and sub-group analysis at 95% CI. P < 0.05 was considered significant for all analyses. RESULTS The prevalence of HBV was generally high (6.025%), with publications from Kenya (8.54%), Uganda (8.454%) and those from between 2011 and 2015 (8.759%) reporting the highest prevalence (P < 0.05). Blood transfusion, scarification, promiscuity, HIV seropositivity, and being male were independent predictors significantly associated with HBV infection (P < 0.05), with the male sex being the most strongly associated predictor of HBV infection. Meta-regressions for the pooled HBV prevalence and sample size, as well as the year of publication, lacked statistical significance (P > 0.05). Omitting the study with the largest sample size slightly increased pooled HBV prevalence to 6.149%, suggesting that the studies are robust. Begg's test showed no evidence of publication bias for overall meta-analysis (p > 0.05). CONCLUSION The burden of HBV is still high, with the male sex, blood transfusion, body scarification, and HIV seropositivity being potential predictors of infection. Thus, it is important to scale up control and prevention measures targeting persons at high risk.
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Affiliation(s)
- Hussein Mukasa Kafeero
- Department of Medical Microbiology, Faculty of Health Sciences, Habib Medical School, Islamic University in Uganda, P.O. Box 7689, Kampala, Uganda.
- Department of Medical Microbiology, College of Health Sciences, Makerere University, P.O. Box 7062, Kampala, Uganda.
| | - Dorothy Ndagire
- Department of Plant Sciences, Microbiology and Biotechnology, College of Natural Sciences, Makerere University, P.O. Box 7062, Kampala, Uganda
| | - Ponsiano Ocama
- Department of Medicine, College of Health Sciences, Makerere University, P.O. Box 7062, Kampala, Uganda
| | - Ali Kudamba
- Department of Human Physiology, Faculty of Health Sciences, Habib Medical School, Islamic University in Uganda, P.O. Box 7689, Kampala, Uganda
| | - Abdul Walusansa
- Department of Medical Microbiology, Faculty of Health Sciences, Habib Medical School, Islamic University in Uganda, P.O. Box 7689, Kampala, Uganda
| | - Hakim Sendagire
- Department of Medical Microbiology, Faculty of Health Sciences, Habib Medical School, Islamic University in Uganda, P.O. Box 7689, Kampala, Uganda
- Department of Medical Microbiology, College of Health Sciences, Makerere University, P.O. Box 7062, Kampala, Uganda
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14
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Matsuno T, Matsuura H, Fujii S, Tanaka A, Satake M, Kinoshita T, Tomita A, Matsui Y, Sugiura Y, Miura Y. Prolonged incubation period of hepatitis B in a recipient of a nucleic acid amplification test-negative hepatitis B virus window donation. Transfusion 2021; 61:2782-2787. [PMID: 34258757 DOI: 10.1111/trf.16557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 05/24/2021] [Accepted: 05/27/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND The occurrence of transfusion-transmitted hepatitis B virus (HBV) infection has fallen dramatically due to continuous improvements in pre-transfusion laboratory testing. However, the characteristics of transfusion-transmitted HBV infection caused by individual donor nucleic acid amplification test (ID-NAT)-negative blood products are unclear. CASE PRESENTATION A 76-year-old woman with acute myeloid leukemia was diagnosed with transfusion-transmitted HBV infection after receiving apheresis platelets derived from an ID-NAT-negative blood donation. This case was diagnosed definitively as transfusion-mediated because complete nucleotide homology of a 1556 bp region of the HBV Pol/preS1-preS2-S genes and a 23 bp region of the HBV core promoter/precore between the donor and recipient strains was confirmed by PCR-directed sequencing. The case is uncommon with respect to the unexpectedly prolonged HBV-DNA incubation period of nearly 5 months after transfusion (previously, the longest period observed since the recent implementation of ID-NAT pre-transfusion laboratory testing in Japan was 84 days). Slow-replicating HBV genotype A2 may contribute to the prolonged incubation period; also, the quantity of apheresis platelets delivered in a large volume of plasma, and/or the immune response of the recipient suffering from a hematological neoplasm, may have contributed to establishment of HBV infection in the recipient. This was supported by analysis of three previously documented cases of transfusion-transmitted HBV infection by blood products derived from ID-NAT-negative donations in Japan. CONCLUSION Continuous monitoring of HBV infection for longer periods (>3 months) may be required after transfusion of blood components from an ID-NAT-negative HBV window donation.
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Affiliation(s)
- Takahiro Matsuno
- Department of Blood Transfusion, Fujita Health University Hospital, Toyoake, Aichi, Japan
| | - Hideaki Matsuura
- Department of Blood Transfusion, Fujita Health University Hospital, Toyoake, Aichi, Japan.,Department of Molecular Laboratory Medicine, Fujita Health University School of Medical Sciences, Toyoake, Aichi, Japan
| | - Sumie Fujii
- Department of Transfusion Medicine and Cell Therapy, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Ami Tanaka
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
| | - Masahiro Satake
- Central Blood Institute, Blood Service Headquarters, Japanese Red Cross Society, Tokyo, Japan
| | | | - Akihiro Tomita
- Department of Hematology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Yusuke Matsui
- School of Public Health, Division of Infectious Diseases and Vaccinology, University of California, Berkeley, California, USA
| | - Yukari Sugiura
- Department of Blood Transfusion, Fujita Health University Hospital, Toyoake, Aichi, Japan
| | - Yasuo Miura
- Department of Blood Transfusion, Fujita Health University Hospital, Toyoake, Aichi, Japan.,Department of Transfusion Medicine and Cell Therapy, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
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15
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Ko K, Nagashima S, Yamamoto C, Takahashi K, Matsuo J, Ohisa M, Akita T, Matyakubov J, Mirzaev U, Katayama K, Masaki T, Tanaka J. Eighteen-year follow-up cohort study on hepatitis B and C virus infections related long-term prognosis among hemodialysis patients in Hiroshima. J Med Virol 2020; 92:3436-3447. [PMID: 32579260 DOI: 10.1002/jmv.26215] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/14/2020] [Accepted: 06/22/2020] [Indexed: 12/15/2022]
Abstract
This study aimed to investigate the prevalence trend of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and their genotype distribution among hemodialysis patients, determining their long-term prognosis and the risk factors to the mortality. This cohort study used both the medical data and the blood samples of hemodialysis patients at nine dialysis centers in Hiroshima from 1999 to 2017. Hepatitis B surface antigen (HBsAg) and anti-HCV were screened and then amplification was done to positive sera by polymerase chain reaction for genotyping. Data were employed for multiple regressions to determine the associated risk factors. A total of 3968 patients were subdivided into three groups: who started hemodialysis before 1990, during 1991 to 2001, and after 2002. The periodic prevalence of HBsAg decreased from 2.8% to 1.3% and that of anti-HCV from 33.3% to 9.5% in the three groups. By multiple regressions, the adjusted hazard ratio of diabetes mellitus (DM) ranges from 1.59 to 2.12 and that of HCV RNA positivity ranges from 1.18 to 1.48 (P < .05). Heart failure is the primary cause of death in all groups. Genotype C2 is predominant for HBV and genotype 1b is predominant for HCV. The decreasing trend of both HBV and HCV was found in the cohort. DM and HCV RNA were the significant risk factors leading to poor prognosis among hemodialysis patients. The similar genotype distribution of both HBV and HCV was found as general population. This alarmed to provide early diagnosis, prompt, and adequate treatment to HCV infection among hemodialysis patients.
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Affiliation(s)
- Ko Ko
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shintaro Nagashima
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Chikako Yamamoto
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Takahashi
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Junko Matsuo
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Masayuki Ohisa
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomoyuki Akita
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Jamshid Matyakubov
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Epidemiological Monitoring Unit, Khorezm Regional Center to fight againt HIV/AIDS, Khorezm Region, Urgench, Uzbekistan
| | - Ulugbek Mirzaev
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Department of Hepatology, Scientific Research Institute of Virology, Ministry of Health of Uzbekistan, Tashkent, Uzbekistan
| | - Keiko Katayama
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takao Masaki
- Department of Nephrology, Hiroshima University Hospital, Hiroshima, Japan
| | - Junko Tanaka
- Department of Epidemiology, Infectious Diseases Control and Prevention, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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16
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Inoue T, Tanaka Y. Cross-Protection of Hepatitis B Vaccination among Different Genotypes. Vaccines (Basel) 2020; 8:456. [PMID: 32824318 PMCID: PMC7563454 DOI: 10.3390/vaccines8030456] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 08/09/2020] [Accepted: 08/12/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B (HB) vaccination is the most effective method for preventing HB virus (HBV) infection. Universal HB vaccination containing recombinant HB surface antigens (HBsAg) is recommended. Our data revealed that human monoclonal HB surface antibody (anti-HBs) from individuals inoculated with genotype C-based HB vaccine induced cross-protection against HBV genotype A infection. An in vitro infection model demonstrated anti-HBs-positive sera from individuals inoculated with genotype A- or C-based HB vaccine harbored polyclonal anti-HBs that could bind to non-vaccinated genotype HBV. However, because there were low titers of anti-HBs specific for HBsAg of non-vaccinated genotype, high anti-HBs titers would be required to prevent non-vaccinated genotype HBV infection. Clinically, the 2015 Centers for Disease Control and Prevention guidelines state that periodic monitoring of anti-HBs levels after routine HB vaccination is not needed and that booster doses of HB vaccine are not recommended. However, the American Red Cross suggests that HB-vaccine-induced immune memory might be limited; although HB vaccination can prevent clinical liver injury (hepatitis), subclinical HBV infections of non-vaccinated genotypes resulting in detectable HB core antibody could not be completely prevented. Therefore, monitoring anti-HBs levels after routine vaccination might be necessary for certain subjects in high-risk groups.
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Affiliation(s)
- Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Yasuhito Tanaka
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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17
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Tsutsumi T, Sato H, Kikuchi T, Ikeuchi K, Lim LA, Adachi E, Koga M, Okushin K, Kawahara T, Koibuchi T, Yotsuyanagi H. Factors associated with clearance of hepatitis B virus surface antigen in patients infected with human immunodeficiency virus. Medicine (Baltimore) 2020; 99:e21271. [PMID: 32702915 PMCID: PMC7373618 DOI: 10.1097/md.0000000000021271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Owing to similar routes of transmission, hepatitis B virus (HBV) and human immunodeficiency virus (HIV) coinfection commonly occurs. Compared with patients infected with only HBV, coinfected patients develop persistent HBV infection followed by advanced liver diseases. However, the characteristics of HIV-infected patients who can achieve the clearance of HBV surface antigen (HBsAg) have not been clarified. In this study, we retrospectively examined patients coinfected with HBV and HIV and determined the host factors associated with HBsAg clearance.Among HIV-infected patients who visited our hospital between 1994 and 2017, we examined medical records of those who were seropositive for HBsAg at least once. Among them, patients who cleared HBsAg afterward were regarded as "cured," while those who remained HBsAg-seropositive until 2017 were "chronic."HBsAg seropositivity was found in 57 patients, and among them, 27 male patients were cured whereas 18 were chronic. The cured patients were significantly younger and had higher CD4 cell and platelet counts than the chronic patients. In addition, the cured patients had higher levels of transaminases after the detection of HBsAg. Multivariate analysis revealed age as an independent factor. Analyses of the patients infected with genotype A also showed that the cured patients had significantly higher CD4 cell counts.Considering that the CD4 cell and platelet counts were higher in the cured patients, immunological and liver functions were closely associated with HBsAg clearance. Higher levels of transaminases in the cured patients may also reflect the immunological function leading to HBsAg clearance.
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Affiliation(s)
- Takeya Tsutsumi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
| | - Hidenori Sato
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Tadashi Kikuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Kazuhiko Ikeuchi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
| | - Lay Ahyoung Lim
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Eisuke Adachi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Michiko Koga
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
| | - Kazuya Okushin
- Department of Infection Control and Prevention, Graduate School of Medicine, The University of Tokyo
| | - Takuya Kawahara
- Central Coordinating Unit, Clinical Research Support Center, The University of Tokyo Hospital, Tokyo, Japan
| | - Tomohiko Koibuchi
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo
- Department of Infectious Diseases and Applied Immunology, IMSUT Hospital of The Institute of Medical Science, The University of Tokyo
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18
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Morishita A, Fujita K, Iwama H, Chiyo T, Fujihara S, Oura K, Tadokoro T, Mimura S, Nomura T, Tani J, Yoneyama H, Kobayashi K, Kamada H, Guan Y, Nishiyama A, Okano K, Suzuki Y, Himoto T, Shimotohno K, Masaki T. Role of microRNA-210-3p in hepatitis B virus-related hepatocellular carcinoma. Am J Physiol Gastrointest Liver Physiol 2020; 318:G401-G409. [PMID: 31905024 DOI: 10.1152/ajpgi.00269.2019] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatitis B virus (HBV)-related hepatocarcinogenesis is not necessarily associated with the liver fibrotic stage and is occasionally seen at early fibrotic stages. MicroRNAs (miRNAs) are essentially 18- to 22-nucleotide-long endogenous noncoding RNAs. Aberrant miRNA expression is a common feature of various human cancers. The aberrant expression of specific miRNAs has been shown in hepatocellular carcinoma (HCC) tissue compared with nontumor tissue. Thus, we examined targetable miRNAs as a potential new biomarker related to the high risk of HBV-related hepatocarcinogenesis, toward the prevention of cancer-related deaths. HCC tissue samples from 29 patients who underwent hepatectomy at our hospital in 2002-2013 were obtained. We extracted the total RNA and analyzed it by microRNA array, real-time RT-PCR, and three comparisons: 1) HBV-related HCC and adjacent nontumor tissue, 2) HCV-related HCC and adjacent nontumor tissue, and 3) non-HBV-, non-HCV-related HCC and adjacent nontumor tissue. We also performed a functional analysis of miRNAs specific for HBV-related HCC by using HBV-positive HCC cell lines. MiR-210-3p expression was significantly increased only in the HBV-related HCC tissue samples. MiR-210-3p expression was upregulated, and the levels of its target genes were reduced in the HBV-positive HCC cells. The inhibition of miR-210-3p enhanced its target gene expression in the HBV-positive HCC cells. In addition, miR-210-3p regulated the HBx expression in HBV-infected Huh7/NTCP cells. The enhanced expression of miR-210-3p was detected specifically in HBV-related HCC and regulated various target genes, including HBx in the HBV-positive HCC cells. MiR-210-3p might, thus, be a new biomarker for the risk of HBV-related HCC.NEW & NOTEWORTHY Our present study demonstrated that miR-210-3p is the only microRNA with enhanced expression in HBV-related HCC, and the enhanced expression of miR-210-3p upregulates HBx expression. Therefore, miR-210-3p might be a pivotal biomarker of HBV-related hepatocarcinogenesis, and the inhibition of miR-210-3p could prevent inducing hepatocarcinogenesis related to HBV infection.
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Affiliation(s)
- Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University, Kagawa, Japan
| | - Taiga Chiyo
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Shima Mimura
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Kiyoyuki Kobayashi
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Hideki Kamada
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Yu Guan
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University, Kagawa, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan
| | - Takashi Himoto
- Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa, Japan
| | - Kunitada Shimotohno
- Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
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19
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Inoue J, Akahane T, Nakayama H, Kimura O, Kobayashi T, Kisara N, Sato T, Morosawa T, Izuma M, Kakazu E, Ninomiya M, Iwata T, Takai S, Nakamura T, Sano A, Niitsuma H, Masamune A. Comparison of hepatitis B virus genotypes B and C among chronically hepatitis B virus-infected patients who received nucleos(t)ide analogs: A multicenter retrospective study. Hepatol Res 2019; 49:1263-1274. [PMID: 31254482 DOI: 10.1111/hepr.13398] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 05/18/2019] [Accepted: 06/21/2019] [Indexed: 12/11/2022]
Abstract
AIM Hepatitis B virus genotype B (HBV/B) has been reported to have less risk of liver cirrhosis and hepatocellular carcinoma (HCC), but long-term observation has rarely been reported. We aimed to clarify the characteristics of HBV/B in nucleos(t)ide analog-treated patients in an area where HBV/B is more prevalent than in other areas of Japan. METHODS A total of 498 chronically HBV-infected patients treated with nucleos(t)ide analog (lamivudine, entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide fumarate) for >6 months (mean 70.6 months) were included from nine hospitals in northeast Japan. The frequencies of hepatitis B surface antigen loss and HCC occurrence were analyzed. RESULTS Among 427 patients whose genotype could be determined, 34.0% and 64.4% were infected with HBV/B and genotype C (HBV/C), respectively. The age of patients with HBV/B was significantly older than those with HBV/C (57.7 vs. 48.1). The cumulative rate of hepatitis B surface antigen loss was significantly higher in HBV/B than in HBV/C (3.6% vs. 0.7% at 10 years). Among 480 patients without HCC history, HCC occurrence was found in 40 patients (13.4% at 10 years). There was no cumulative rate difference of HCC occurrence among the genotypes, but after propensity score matching for age/sex, it was significantly lower in HBV/B than in HBV/C (5.3% vs. 18.5% at 10 years). CONCLUSIONS Although a lower rate of HCC occurrence in HBV/B was shown by an age/sex-matched analysis than that in HBV/C, patients with HBV/B were significantly older and had a comparative risk of HCC occurrence in nucleos(t)ide analog-treated patients.
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Affiliation(s)
- Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai
| | - Takehiro Akahane
- Department of Gastroenterology, Japanese Red Cross Ishinomaki Hospital, Ishinomaki
| | - Haruo Nakayama
- Department of Gastroenterology, Iwaki City Medical Center, Iwaki
| | - Osamu Kimura
- Department of Gastroenterology, South Miyagi Medical Center, Ogawara
| | | | - Norihiro Kisara
- Department of Gastroenterology, Japan Community Health Care Organization Sendai South Hospital, Sendai
| | | | | | - Masaaki Izuma
- Department of Internal Medicine, Tome Citizen Hospital, Tome, Japan
| | - Eiji Kakazu
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai
| | - Masashi Ninomiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai
| | - Tomoaki Iwata
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai
| | - Satoshi Takai
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai
| | - Takuya Nakamura
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai
| | - Akitoshi Sano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai
| | - Hirofumi Niitsuma
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai
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20
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Khan S, Madan M, Virmani SK. Prevalence of Hepatitis B Virus, Genotypes, and Mutants in HBsAg-Positive Patients in Meerut, India. IRANIAN BIOMEDICAL JOURNAL 2019; 23. [PMID: 31103024 PMCID: PMC6661126 DOI: 10.29252/.23.5.354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Background Genetic changeability of hepatitis B virus (HBV) signifies a challenge for the sensitivity of immunologic and molecular diagnostics. Therefore, knowing the spread of HBV genotypes (GENs) and mutation has considerable impacts on treatment strategies, vaccination program, diagnosis, and prevention. The present study aimed to detect HBV GENs and mutants in HBsAg-positive patients. Methods The study conducted on 4927 patients in Meerut, India, between March 2013 and April 2017. The blood specimens were analyzed for HBsAg using an ELISA kit, then the blood samples from HBsAg-positive patients were subjected to HBeAg assay and DNA isolation. Amplification of the HBV DNA of pre-S gene and pre-core or basal core promoter region were performed by RT-PCR and sequenced to analyze both GEN and mutation. Results According to the results, 245 cases were positive for HBsAg, and 55 were HBeAg-positive. With regard to HBV DNA levels, 16 samples were found positive in PCR assay with 7 (43.8%) less than 2000 IU/mL, 4 (25%) between >2000 and 20,000 IU/mL, and 5 (3.25%) >20,000 IU/mL. No mutations were detected in GENs B and A. The prevalence of HBV GENs B and A were 68.8% (n = 11) and 31.25% (n = 6), respectively. Conclusion GEN-B was more prevalent in comparison to GEN-A. The genetic diversity of HBV and distribution of its GENs and mutation improve the current knowledge of epidemiological, clinical and virological patterns of hepatitis B in this region, which help physicians to prescribe proper antiviral/interferon therapy according to current genotyping pattern.
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Affiliation(s)
- Salman Khan
- Department of Microbiology, Netaji Subhash Chandra Bose Subharti Medical College, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India; ,Corresponding Author: Salman Khan ,Department of Microbiology, Neta ji Subhash Chandra Bose Subharti Medical College, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India; Mobile: (+91)8 791288978; E-mail:
| | - Molly Madan
- Department of Microbiology, Netaji Subhash Chandra Bose Subharti Medical College, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India
| | - Sunil Kumar Virmani
- Department of Medicine, Netaji Subhash Chandra Bose Subharti Medical College, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India
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21
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Atsama Amougou M, Marchio A, Bivigou-Mboumba B, Noah Noah D, Banai R, Atangana PJA, Fewou Moundipa P, Pineau P, Njouom R. Enrichment in selected genotypes, basal core and precore mutations of hepatitis B virus in patients with hepatocellular carcinoma in Cameroon. J Viral Hepat 2019; 26:1086-1093. [PMID: 31106515 DOI: 10.1111/jvh.13131] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 04/18/2019] [Accepted: 05/03/2019] [Indexed: 12/21/2022]
Abstract
Worldwide, the development of hepatocellular carcinoma (HCC) is known to be influenced by several hepatitis B viral factors. However, the effect of hepatitis B virus (HBV) genotypes and a landscape of nucleotide changes affecting the precore (PC) and basal core promoter (BCP) during infection leading to HCC remain largely unknown in the Central Africa region. Thus, we performed a case-control study on patients with HBV-related HCC and matched controls without HCC but with chronic HBV infection. Genotypes and mutation spectrums were evaluated using a hemi-nested amplification and sequencing analysis focused on the BCP and PC regions. We identified the co-circulation of HBV quasi-subgenotype A3 (QS-A3) and genotype E in both groups. Interestingly, HBV-QS-A3 was significantly more prevalent in patients with HCC (80.0%) than in controls (31.9%, P = 4.5 E-7, OR = 11.5, 95% CI: 3.8-38.5). HBV mutation spectra and nucleotide changes were significantly more polymorphic in patients with HCC. Remarkably, HCC patients infected with HBV-QS-A3 were significantly more mutated compared to patients infected with genotype E (P < 0.0001). In addition, G:C>T:A transversions, generally associated with aflatoxin B1 exposure in tropical regions, were significantly more prevalent in HCC patients infected either with HBV-QS-A3 or HBV genotype E (P = 2.2 E-05) when compared to controls. In conclusion, our results indicate that patients infected with HBV-QS-A3 are at increased risk to develop HCC. In addition, viral genomes isolated for patients with tumour are more heavily altered than those found in controls. Preferential targeting of these patients for antiviral treatment is of paramount importance to reduce future HCC incidence in Cameroon.
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Affiliation(s)
- Marie Atsama Amougou
- Centre Pasteur of Cameroon, Yaounde, Cameroon.,Laboratory of Pharmacology and Toxicology of University of Yaounde I, Yaounde, Cameroon
| | - Agnes Marchio
- Unité Organisation nucléaire et Oncogenèse, Institut Pasteur, INSERM U993, Paris, France
| | - Berthold Bivigou-Mboumba
- Unité Mixte de Recherches VIH et Maladies Infectieuses Associées (UMR VIH-MIA), Centre International de Recherches Médicales de Franceville (CIRMF), Libreville, Gabon
| | | | | | | | - Paul Fewou Moundipa
- Laboratory of Pharmacology and Toxicology of University of Yaounde I, Yaounde, Cameroon
| | - Pascal Pineau
- Unité Organisation nucléaire et Oncogenèse, Institut Pasteur, INSERM U993, Paris, France
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22
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Haga H, Saito T, Okumoto K, Tomita K, Katsumi T, Mizuno K, Nishina T, Watanabe H, Ueno Y. Incidence of development of hepatocellular carcinoma in Japanese patients infected with hepatitis B virus is equivalent between genotype B and C in long term. J Viral Hepat 2019; 26:866-872. [PMID: 30924226 DOI: 10.1111/jvh.13099] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Revised: 02/01/2019] [Accepted: 02/21/2019] [Indexed: 12/19/2022]
Abstract
Hepatitis B virus (HBV) genotypes B (HBV/B) and C (HBV/C) are the most prevalent genotypes among Japanese patients with hepatitis. Reportedly, HBV/C infection has been associated with more severe disease progression, manifesting as developing cirrhosis and hepatocellular carcinoma (HCC), than HBV/B infection. However, no long-term studies have examined the development of HCC in HBV/B-infected patients in Japan. The aims of our study were to compare the incidence of HCC in HBV/B- or HBV/C-infected patients. A total of 241 patients were followed up among 295 hepatitis B surface antigen (HBsAg)-positive carriers. Genotypes of HBV were A in 1% (4/295), B in 61% (179/295), C in 37% (110/295) and D in 1% (2/295) patients, and 96% of HBV/B were infected with subgenotype Bj. The mean age at HCC diagnosis was significantly higher in HBV/B than in HBV/C (67.0 ± 10.0 vs 57.7 ± 8.0 years, P < 0.001). The value of FIB-4 index was significantly higher in HBV/B than in HBV/C (P < 0.01). The rate of HCC was higher in HBV/C than in HBV/B, and a significant difference was observed until the 20-year observation period (P = 0.048). However, thereafter, HCC associated with HBV/B increased, and no significant difference was observed between HBV/B and HBV/C. HCC development was consistently observed even in HBV/B infection, especially among elderly patients with advanced fibrosis compared with HBV/C. HBV/B-infected patients developed HCC later in life, and in the long term, we found no differences in incidence of HCC development rates between these two genotypes.
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Affiliation(s)
- Hiroaki Haga
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Takafumi Saito
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan.,School of Nursing, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kazuo Okumoto
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kyoko Tomita
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Tomohiro Katsumi
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Kei Mizuno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Taketo Nishina
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hisayoshi Watanabe
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Yoshiyuki Ueno
- Department of Gastroenterology, Yamagata University Faculty of Medicine, Yamagata, Japan
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23
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Hoshi Y, Hasegawa T, Yamagishi N, Mizokami M, Sugiyama M, Matsubayashi K, Uchida S, Nagai T, Satake M. Optimal titer of anti-HBs in blood components derived from donors with anti-HBc. Transfusion 2019; 59:2602-2611. [PMID: 31168835 DOI: 10.1111/trf.15393] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 04/17/2019] [Accepted: 04/28/2019] [Indexed: 12/21/2022]
Abstract
BACKGROUND The ultimate strategy to cope with transfusion-transmitted hepatitis B virus (HBV) infection caused by transfusion of blood from donors with historical HBV infection is to reject all donors having anti-HBV core antigen (anti-HBc). However, this strategy would result in a huge loss of blood donors and subsequent blood inventory collapse. On the other hand, anti-HBc-positive blood is reportedly not infectious when containing more than 100 mIU/mL of anti-HBV surface antigen (anti-HBs). STUDY DESIGN AND METHODS In Japan, anti-HBc-positive blood has been used for transfusion if it contained 200 mIU/mL or more of anti-HBs. First, to verify the screening policy, clinical outcomes for transfusion of such blood were analyzed for the 2008-2012 period. Second, human hepatocyte-repopulated severe combined immunodeficiency mice were inoculated with HBV preincubated with varying doses of anti-HBs, then viremic status was followed. The effects of anti-HBs across different HBV genotypes were also investigated. RESULTS Twenty-three transfusion-transmitted HBV infections related to anti-HBc-positive blood components were identified. None of the blood responsible for these cases contained 200 mIU/mL or more of anti-HBs. When 100 μL of plasma containing 104 copies of HBV and 20 mIU of anti-HBs was injected into severe combined immunodeficiency mice, no viremia was detected within 13 weeks. Genotype C anti-HBs was capable of total inhibition of genotype A HBV replication, whereas genotype A anti-HBs inhibited genotype C HBV to a lesser extent. CONCLUSION Anti-HBc-positive blood containing 200 mIU/mL or more of anti-HBs appears safe as a transfusion component. HBV vaccination seems effective between HBV genotypes A and C.
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Affiliation(s)
- Yuji Hoshi
- Central Blood Institute, Japanese Red Cross Blood Service Headquarters, Tokyo, Japan
| | - Takashi Hasegawa
- Central Blood Institute, Japanese Red Cross Blood Service Headquarters, Tokyo, Japan
| | - Naoji Yamagishi
- Central Blood Institute, Japanese Red Cross Blood Service Headquarters, Tokyo, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Chiba, Japan
| | - Masaya Sugiyama
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Chiba, Japan
| | - Keiji Matsubayashi
- Central Blood Institute, Japanese Red Cross Blood Service Headquarters, Tokyo, Japan
| | - Shigeharu Uchida
- Central Blood Institute, Japanese Red Cross Blood Service Headquarters, Tokyo, Japan
| | - Tadashi Nagai
- Central Blood Institute, Japanese Red Cross Blood Service Headquarters, Tokyo, Japan
| | - Masahiro Satake
- Central Blood Institute, Japanese Red Cross Blood Service Headquarters, Tokyo, Japan
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24
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Ogura S, Tameda M, Sugimoto K, Ikejiri M, Usui M, Ito M, Takei Y. A substitution in the pre-S1 promoter region is associated with the viral regulation of hepatitis B virus. Virol J 2019; 16:59. [PMID: 31046787 PMCID: PMC6498540 DOI: 10.1186/s12985-019-1169-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 04/23/2019] [Indexed: 12/19/2022] Open
Abstract
Background Much evidence has demonstrated the influence of Hepatitis B virus (HBV) mutations on the clinical course of HBV infection. As large (L) protein plays a crucial role for viral entry, we hypothesized that mutations in the pre-S1 promoter region might affect the expression of L protein and subsequently change the biological characters of virus. Methods Patients infected with genotype C HBV were enrolled for analysis. HBV DNA sequences were inserted into a TA cloning vector and analyzed. To evaluate the effects of mutations in the pre-S1 promoter region, promoter activity and the expression of mRNA and L protein were analyzed using HepG2 cells. Results In total, 35 patients were enrolled and 13 patients (37.1%) had a single base substitution in the pre-S1 promoter region; the most frequent substitution was a G-to-A substitution at the 2765th base (G2765A) in the Sp1 region. The HBV viral load showed a negative correlation with the substitution ratio of the Sp1 region or G2765A (r = − 0.493 and − 0.473, respectively). Among those with a viral load ≤5.0 log IU/ml, patients with the G2765A substitution showed a significantly lower HBV viral load than those with the wild-type sequence. HepG2 cells transfected with the G2765A substitution vector showed reduced luciferase activity of the pre-S1 promoter, as well as reduced expression of pre-S1 mRNA and L protein. Furthermore, the G2765A substitution greatly reduced the L protein expression level of vector-produced virus particles. Conclusion G2765A substitution in the pre-S1 promoter reduced the expression of L protein and resulted in a low viral load and less severe disease in chronic HBV infections.
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Affiliation(s)
- Suguru Ogura
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Masahiko Tameda
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
| | - Kazushi Sugimoto
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. .,Department of Central Laboratory, Mie University Hospital, Tsu, Japan.
| | - Makoto Ikejiri
- Department of Central Laboratory, Mie University Hospital, Tsu, Japan
| | - Masanobu Usui
- Department of Hepatobiliary Pancreatic and Transplant Surgery, Mie University Graduate School of Medicine, Tsu, Japan
| | - Masaaki Ito
- Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yoshiyuki Takei
- Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan
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25
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Hashimoto K, Miura K, Takaoka Y, Nomoto H, Watanabe S, Tsukui M, Morimoto N, Isoda N, Nagashima S, Takahashi M, Okamoto H, Yamamoto H. A 79-year-old Woman with Acute Hepatitis B Caused by the Infection of Subgenotype D1 Hepatitis B Virus in Japan: A Case Study. Intern Med 2018; 57:3099-3104. [PMID: 29877273 PMCID: PMC6262716 DOI: 10.2169/internalmedicine.0977-18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
A 79-year-old Japanese woman was diagnosed with acute hepatitis B based on laboratory tests showing positivity for IgM-class antibody against hepatitis B virus (HBV) core and hepatitis B surface antigen (HBsAg) as well as elevated transaminases. A phylogenetic analysis revealed that the HBV strain obtained from the patient belonged to genotype D/subgenotype D1, similar to strains circulating in foreign countries but different from those in Japan. The clinical course was favorable. HBsAg became negative within 10 weeks after the onset. To our knowledge, this is the first report of acute hepatitis B caused by subgenotype D1 HBV in Japan.
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Affiliation(s)
- Kosei Hashimoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan
| | - Kouichi Miura
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan
| | - Yoshinari Takaoka
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan
| | - Hiroaki Nomoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan
| | - Shunji Watanabe
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan
| | - Mamiko Tsukui
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan
| | - Naoki Morimoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan
| | - Norio Isoda
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Japan
| | - Hironori Yamamoto
- Division of Gastroenterology, Department of Medicine, Jichi Medical University School of Medicine, Japan
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Genetic variability in coding regions of the surface antigen and reverse transcriptase domain of hepatitis B virus polymerase, Colombia, 2002-2014. BIOMEDICA 2018; 38:37-50. [PMID: 30184362 DOI: 10.7705/biomedica.v38i3.3871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 11/10/2017] [Indexed: 11/21/2022]
Abstract
Introduction: Despite the availability of an effective vaccine and treatment to reduce the viral load and progressive hepatocellular injury, approximately 240 million people worldwide are chronically infected with the hepatitis B virus (HBV). In Colombia, the circulation of different viral genotypes has been confirmed. Mutations in the genome have been associated to antiviral therapy resistance, viral escape to neutralizing antibodies, occult infection and progression to hepatocellular carcinoma.
Objective: To identify the genotypes and the presence of mutations in the coding region of the surface (S) antigen and the reverse transcriptase (RT) domain of the polymerase of HBV obtained from serum samples for hepatitis B diagnosis received by the Instituto Nacional de Salud during the period 2002-2014.
Materials and methods: A total of 495 serum samples with previous HBsAg reactive result were used for molecular detection. A fragment of 1,591 nucleotides was sequenced, and the corresponding phylogenetic analysis was performed.
Results: We detected the viral genome of HBV in 66 samples and 28 were successfully sequenced. The phylogenetic analysis allowed the identification of subgenotypes F3 and A2. The L180M and M204V resistance mutations were simultaneously identified in one sample, while the I169L resistance mutation was identified in another one. A single escape mutation, P120Q, was identified in one more. Two samples showed a deletion of 105 nucleotides in the preS1-preS2 region.
Conclusions: The circulation of genotypes/subgenotypes F3 and A2 of HBV in Colombia was corroborated, as well as the presence of some resistance and escape mutations. The present study constitutes a contribution to the molecular epidemiology of HBV in Colombia.
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Serum miRNAs Predicting Sustained HBs Antigen Reduction 48 Weeks after Pegylated Interferon Therapy in HBe Antigen-Negative Patients. Int J Mol Sci 2018; 19:ijms19071940. [PMID: 30004437 PMCID: PMC6073286 DOI: 10.3390/ijms19071940] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 06/23/2018] [Accepted: 06/29/2018] [Indexed: 12/12/2022] Open
Abstract
The therapeutic goal for hepatitis B virus (HBV) infection is HBs antigen (HBsAg) seroclearance, which is achieved through 48-week pegylated interferon (Peg-IFN) therapy. This study aimed to identify predictive biomarkers for sustained HBsAg reduction by analyzing serum microRNAs. Twenty-two consecutive chronic HBV infection patients negative for HBe antigen (HBeAg) with HBV-DNA levels <5 log copies/mL, alanine aminotransferase (ALT) <100 U/L, and compensated liver functions, were enrolled. The patients were subcutaneously injected with Peg-IFNα-2a weekly for 48 weeks (treatment period), followed by the 48-week observation period. HBsAg 1-log drop relative to baseline levels recorded at the end of the observation period was considered effective. Sera were obtained at weeks 0 and 24 during the treatment period analyzed for microRNAs. The microRNA (miRNA) antiviral activity was evaluated in vitro using Huh7/sodium taurocholate cotransporting polypeptide (NTCP) cells. As a result, six patients achieved the HBsAg 1-log drop after the observation periods. Comparison of serum microRNA levels demonstrated that high miR-6126 levels at week 24 predicted HBsAg 1-log drop. Furthermore, miR-6126 reduced HBsAg in culture medium supernatants and intracellular HBV-DNA quantities in Huh7/NTCP cells. In conclusion, high serum miR-6126 levels during Peg-IFN therapy predicted the HBsAg 1-log drop 48 weeks after the completion of therapy. In vitro assays revealed that miR-6126 was able to suppress HBsAg production and HBV replication.
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Long-Term Follow-Up of Acute Hepatitis B: New Insights in Its Natural History and Implications for Antiviral Treatment. Genes (Basel) 2018; 9:genes9060293. [PMID: 29895748 PMCID: PMC6027296 DOI: 10.3390/genes9060293] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 06/04/2018] [Accepted: 06/07/2018] [Indexed: 12/15/2022] Open
Abstract
Acute hepatitis B infection (AHB) is still a common viral acute hepatitis worldwide. As vaccination, antiviral treatment, and immigration are bound to affect the epidemiological landscape of HBV infections, and some of its aspects need to be investigated: (1) the circulation of vaccine escape mutants and of primary drug resistant strains; (2) the change in HBV genotype prevalence; and (3) the clinical implications of AHB and the probability of chronification. The serological, virological, and clinical parameters of 75 patients, acutely infected by HBV, were gathered for a retrospective study. Long-term follow up, either to complete seroconversion or for up to five years, was possible for 44 patients. Sequence analysis of the reverse transcriptase/HBsAg and precore regions was performed to investigate the molecular epidemiology and pathogenesis of recent infections by HBV. Genotype distribution in AHB in Italian patients was radically different from that of chronic infections, with a dramatic increase of extra-European genotypes (A1, F), suggesting that a proportion of AHBs are currently related to imported strains. None of the documented infections occurred in vaccinated individuals, while HBsAg variants (potentially vaccine escape variants) were rare and less prevalent than in chronic infections. No drug resistant strains were observed. Spontaneous viral clearance occurred in all but three cases. Time to viral clearance was inversely proportional to liver damage, but HBsAg titer on day 28 and, better still, HBsAg decay from day 0 to day 28 after admission, were the best predictors of chronification. They are, thus, potentially useful to guide antiviral treatment to prevent chronic evolution.
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Virological and Clinical Characteristics of Hepatitis B Virus Genotype A. J Gastroenterol 2018; 53:18-26. [PMID: 28687901 DOI: 10.1007/s00535-017-1367-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 06/30/2017] [Indexed: 02/04/2023]
Abstract
Hepatitis B virus (HBV) infection is one of the most prevalent chronic viral infections in humans. The overall prevalence of hepatitis B surface antigen (HBsAg) is reported to be 3.6%; however, it varies depending upon the geographic area. HBV is classified into ten genotypes (A through J) on the basis of an intergroup genomic divergence of > 8%. Specifically, HBV genotype A exhibits several unique virological and clinical characteristics and can be further classified into seven subtypes. Among them, subtype A2 or Ae (A2/[e]) is occasionally responsible for nosocomial infection and among homosexual males. Regarding virological factors, the G1896A precore mutation is rarely observed in genotype A as it would disrupt an essential stem-loop structure in the ε signal essential for pregenomic RNA packaging. HBV genotype A also harbors a 6-nucleotide C-terminal insertion in the hepatitis B-e antigen (HBeAg) precursor, resulting in a variable-length HBeAg protein product observed in serum of positive patients. These molecular traits likely contribute to the specific clinical presentation of genotype A-infected patients, such as mild acute hepatitis B (AHB), longer persistence of HBsAg positivity in AHB, and increased chronicity after AHB in adults. However, genotype A shows a better response to interferon than other genotypes in chronic hepatitis B patients. Here, we review the virological and clinical characteristics of HBV genotype A that will be useful in elucidating the association among persistent viral infection, host genetic factors, and treatment in future studies.
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Kato M, Hamada-Tsutsumi S, Okuse C, Sakai A, Matsumoto N, Sato M, Sato T, Arito M, Omoteyama K, Suematsu N, Okamoto K, Kato T, Itoh F, Sumazaki R, Tanaka Y, Yotsuyanagi H, Kato T, Kurokawa MS. Effects of vaccine-acquired polyclonal anti-HBs antibodies on the prevention of HBV infection of non-vaccine genotypes. J Gastroenterol 2017; 52:1051-1063. [PMID: 28197802 DOI: 10.1007/s00535-017-1316-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 01/31/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND In universal hepatitis B (HB) vaccination, single vaccine-derived polyclonal anti-HBs antibodies (anti-HBs) need to inhibit infection of HB viruses (HBV) of non-vaccine genotypes. We experimentally addressed this issue. METHODS Anti-HBs-positive sera were obtained by vaccination with genotype A- or C-derived HBs antigen (HBsAg, gtA-sera or gtC-sera). Their reactivity to genotype A- and C-derived HBsAg (gtA-Ag and gtC-Ag) was measured by ELISA. The capacity of sera to neutralize HBV was evaluated using an in vitro infection model. RESULTS Of 135 anti-gtA-Ag-reactive gtA-sera, 134 (99.3%) were anti-gtC-Ag-reactive. All (100%) 120 anti-gtC-Ag-reactive gtC-sera were anti-gtA-Ag-reactive. The reactivity to gtA-Ag was strongly correlated with that to gtC-Ag (gtA-sera, ρ = 0.989; gtC-sera, ρ = 0.953; p < 0.01). In gtA-sera (n = 10), anti-HBs to gtA-Ag were less completely absorbed with gtC-Ag (96.4%) than with gtA-Ag (100%, p < 0.05). Similarly, in gtC-sera (n = 10), anti-HBs to gtC-Ag were less completely absorbed with gtA-Ag (96.0%) than with gtC-Ag (100%, p < 0.01). Thus, 3.6 and 4.0% of anti-HBs in gtA-sera and gtC-sera were vaccine genotype HBsAg-specific, respectively. In the neutralization test, gtA-sera (n = 4) and gtC-sera (n = 3) with anti-HBs titers adjusted to 100 mIU/mL equally inhibited genotype C HBV infection (92.8 vs. 95.4%, p = 0.44). However, at 30 mIU/mL, the gtA-sera less effectively inhibited infection than the gtC-sera (60.2 vs. 90.2%, p < 0.05). CONCLUSIONS Vaccination with genotype A- or C-derived HBsAg provided polyclonal anti-HBs that sufficiently bound to non-vaccine genotype HBsAg. However, a small portion of anti-HBs were specific to the vaccine genotype HBsAg. High anti-HBs titers would be required to prevent HBV infection of non-vaccine genotypes. UMIN/CTR UMIN000014363.
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Affiliation(s)
- Masaki Kato
- Disease Biomarker Analysis and Molecular Regulation, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-Ku, Kawasaki, 216-8511, Japan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Susumu Hamada-Tsutsumi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Chiaki Okuse
- Division of Gastroenterology and Hepatology, Kawasaki Municipal Tama Hospital, Kawasaki, Japan
| | - Aiko Sakai
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Nobuyuki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Masaaki Sato
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
| | - Toshiyuki Sato
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
| | - Mitsumi Arito
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
| | - Kazuki Omoteyama
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
| | - Naoya Suematsu
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
| | - Kazuki Okamoto
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
| | - Takanobu Kato
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Fumio Itoh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Ryo Sumazaki
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroshi Yotsuyanagi
- Department of Infectious Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tomohiro Kato
- Clinical Proteomics and Molecular Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan
| | - Manae Suzuki Kurokawa
- Disease Biomarker Analysis and Molecular Regulation, St. Marianna University Graduate School of Medicine, 2-16-1, Sugao, Miyamae-Ku, Kawasaki, 216-8511, Japan.
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Natural history of acute and chronic hepatitis B: The role of HBV genotypes and mutants. Best Pract Res Clin Gastroenterol 2017; 31:249-255. [PMID: 28774406 DOI: 10.1016/j.bpg.2017.04.010] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 04/28/2017] [Indexed: 01/31/2023]
Abstract
Molecular epidemiologic studies reveal remarkable differences in the geographical distribution of hepatitis B virus (HBV) genotypes. The frequency of mutants among HBV genotypes also varies. The role of HBV genotypes/mutants in the pathogenesis of HBV infection and natural history of HBV infection has been extensively investigated. The distribution of HBV genotypes in acute hepatitis B patients reflects the predominant genotypes in a given geographic area. In chronic hepatitis B patients, genotype C and D have a higher frequency of basal core promoter A1762T/G1764A mutations than genotype A and B. HBV genotypes C, D and F carry a higher lifetime risk of cirrhosis and HCC development than genotype A and B. HBV pre-S/S gene mutations were associated with immune escape of hepatitis B immunoglobulin or vaccine-induced immunity. Mutations in the pre-S, core promoter and X regions correlate with an increased risk of cirrhosis and HCC. In summary, HBV genotypes and mutants are associated with the disease progression and long-term outcome of HBV infection. They may serve as viral genetic markers for risk stratification of chronic hepatitis B patients in clinical practice.
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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 SY, Lee SH, Kim JE, Kim H, Kim K, Kook YH, Kim BJ. Identification of Novel A2/C2 Inter-Genotype Recombinants of Hepatitis B Virus from a Korean Chronic Patient Co-Infected with Both Genotype A2 and C2. Int J Mol Sci 2017; 18:737. [PMID: 28358313 PMCID: PMC5412322 DOI: 10.3390/ijms18040737] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Revised: 03/21/2017] [Accepted: 03/27/2017] [Indexed: 12/16/2022] Open
Abstract
Nearly all cases of Hepatitis B virus (HBV) infections in South Korea have the C2 genotype. Here, we have identified a chronically infected patient who was co-infected with HBV of both the A2 and C2 genotypes by screening 135 Korean chronically infected patients using direct sequencing protocols targeting the 1032-bp polymerase reverse transcriptase (RT) region. Further polymerase chain reaction (PCR)-cloning analysis (22 clones) of the RT showed that this patient had genotype C2 (12 clones), genotype A2 (six clones) and A2/C2 inter-genotype HBV recombinants (four clones). BootScan analysis showed that three of the four recombinants have different types of recombination breakpoints in both the RT and overlapping hepatitis B surface antigen (HBsAg) region. Given the significance of HBsAg as a diagnostic or vaccination target against HBV infection, clinical implications of these identified recombinants should be studied in the future. To our knowledge, this is the first report on A2/C2 inter-genotype HBV recombinants.
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Affiliation(s)
- So-Young Lee
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
| | - Seung-Hee Lee
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
| | - Ji-Eun Kim
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
| | - Hong Kim
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
| | - Kijeong Kim
- Department of Microbiology, School of Medicine, Chung-Ang University, Seoul 156-756, Korea.
| | - Yoon-Hoh Kook
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.
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Ishii A, Nishikawa H, Enomoto H, Iwata Y, Kishino K, Shimono Y, Hasegawa K, Nakano C, Takata R, Nishimura T, Yoh K, Aizawa N, Sakai Y, Ikeda N, Takashima T, Iijima H, Nishiguchi S. Clinical implications of serum Wisteria floribunda agglutinin-positive Mac-2-binding protein in treatment-naïve chronic hepatitis B. Hepatol Res 2017; 47:204-215. [PMID: 26990490 DOI: 10.1111/hepr.12703] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Revised: 02/01/2016] [Accepted: 03/14/2016] [Indexed: 12/12/2022]
Abstract
AIM To examine the relationship between serum Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ -M2BP) levels and liver histological findings for patients with treatment naïve chronic hepatitis B (CHB). METHODS A total of 189 treatment naïve-CHB patients were analyzed. We examined the effect of pretreatment serum WFA+ -M2BP levels on histological findings compared with other laboratory markers, including aspartate aminotransferase (AST) to platelet ratio index, Fibrosis-4 index, platelet count, AST to alanine aminotransferase (ALT) ratio, and hyaluronic acid as liver fibrosis markers, and AST value, ALT value, and serum interferon-γ-inducible protein-10 level as liver inflammation markers. RESULTS The WFA+ -M2BP value ranged from 0.3 cut-off index (COI) to 12.9 COI (median value, 1.2 COI). The degree of liver fibrosis was significantly stratified according to WFA+ -M2BP level in each group except for groups F2 and F3 and the degree of liver inflammation activity was significantly stratified according to WFA+ -M2BP level in each group. For predicting F4, WFA+ -M2BP level yielded the highest area under the receiver operating characteristic curve (AUROC) with a level of 0.87 and for predicting advanced liver fibrosis (≥F3) and significant liver fibrosis (≥F2), WFA+ -M2BP level yielded the second highest AUROCs (both, 0.77) among six fibrotic markers. For predicting severe (A3) or significant liver inflammation activity (≥A2), AUROCs of WFA+ -M2BP level were 0.78 and 0.76. CONCLUSION The WFA+ -M2BP level can be a useful marker for assessing liver histological findings in patients with treatment-naïve CHB, although it has several limitations.
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Affiliation(s)
- Akio Ishii
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Hiroki Nishikawa
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Yoshinori Iwata
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Kyohei Kishino
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Yoshihiro Shimono
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Kunihiro Hasegawa
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Chikage Nakano
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Ryo Takata
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Takashi Nishimura
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Kazunori Yoh
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Nobuhiro Aizawa
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Yoshiyuki Sakai
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Naoto Ikeda
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Tomoyuki Takashima
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
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Nishikawa H, Enomoto H, Iwata Y, Kishino K, Shimono Y, Hasegawa K, Nakano C, Takata R, Nishimura T, Yoh K, Ishii A, Aizawa N, Sakai Y, Ikeda N, Takashima T, Iijima H, Nishiguchi S. Clinical implication of serum Wisteria floribunda agglutinin positive Mac-2-binding protein level on hepatitis B e-antigen loss or seroconversion in hepatitis B e-antigen positive patients. Hepatol Res 2016; 46:1065-1073. [PMID: 26787135 DOI: 10.1111/hepr.12655] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 01/08/2016] [Accepted: 01/12/2016] [Indexed: 02/06/2023]
Abstract
AIM To examine the impact of pretreatment Wisteria floribunda agglutinin positive Mac-2-binding protein (WFA+ -M2BP) level on hepatitis B e-antigen (HBeAg) loss or HBeAg seroconversion (SC) for patients with nucleoside/nucleotide analog (NUC) therapy naive HBeAg positive chronic hepatitis B (CHB). METHODS A total of 57 patients were analyzed. All subjects were initially treated with NUC. We examined the impact of pretreatment WFA+ -M2BP level on HBeAg loss and HBeAg SC using univariate and multivariate analyses. RESULTS There were 36 men and 21 women (median age, 39 years). The WFA+ -M2BP cut-off index (COI) level ranged 0.43-12.9 (median, 1.55). WFA+ -M2BP level in patients with F3 or F4 was significantly higher than that with F0-F2. WFA+ -M2BP level in patients with A2 or 3 was significantly higher than that with A0 or 1. For all cases, the 1- and 3-year cumulative HBeAg loss rates were 10.5% and 34.4% and the corresponding cumulative HBeAg SC rates were 8.8% and 29.0%, respectively. In the multivariate analysis, in terms of HBeAg loss, pretreatment HBV DNA of 5 log copies/mL or more and pretreatment WFA+ -M2BP level of more than 1.55 COI tended to be significant factors linked to loss of HBeAg, while in terms of HBeAg SC, pretreatment HBV DNA of 5 log copies/mL or more was an independent predictor and pretreatment WFA+ -M2BP level of more than 1.55 COI tended to be a significant factor. CONCLUSION Pretreatment WFA+ -M2BP level may be a useful predictor for HBeAg loss or SC after NUC therapy for patients with HBeAg positive CHB.
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Affiliation(s)
- Hiroki Nishikawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan.
| | - Yoshinori Iwata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Kyohei Kishino
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Yoshihiro Shimono
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Kunihiro Hasegawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Chikage Nakano
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Ryo Takata
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Takashi Nishimura
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Kazunori Yoh
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Akiio Ishii
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Nobuhiro Aizawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Yoshiyuki Sakai
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Naoto Ikeda
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Tomoyuki Takashima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
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Morikawa K, Shimazaki T, Takeda R, Izumi T, Umumura M, Sakamoto N. Hepatitis B: progress in understanding chronicity, the innate immune response, and cccDNA protection. ANNALS OF TRANSLATIONAL MEDICINE 2016; 4:337. [PMID: 27761441 DOI: 10.21037/atm.2016.08.54] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus (HBV) infection is a serious health threat around the world. Despite the availability of an effective hepatitis B vaccine, the number of HBV carriers is estimated to be as high as 240 million worldwide. Global mortality due to HBV-related liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) may be as high as 1 million deaths per year. HBV is transmitted via blood and body fluids, and is much more infectious than both human immunodeficiency virus (HIV) and hepatitis C virus. While HBV infection exhibits a variety of clinical presentations, even asymptomatic carriers can develop HCC without liver fibrosis. Current therapeutic options against HBV include pegylated interferon (Peg-IFN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs), with clinical studies showing a significant association between loss of HBV DNA and a decrease in cancer risk. However, the ultimate goal of HBV therapy is a complete cure of HBV-including the elimination of covalently closed circular DNA (cccDNA)-in order to further decrease the risk of developing HCC. The development of hepatitis B is associated with the host immune response to virus-infected hepatocytes, as HBV is understood to lack direct cytotoxicity. While HBV-specific CD8+ T cells are thus involved in hepatitis development, they also play an important role in eliminating HBV infection. Indeed, the innate immune response during the initial phase of HBV infection is essential to the induction of acquired immunity. However, the innate immune response to HBV infection, including the roles of specific immunocompetent cells and associated molecules, is not well understood. In this review, we focus on the current understanding of the mechanisms underlying hepatitis development by HBV infection. We also address the mechanisms by which HBV protects cccDNA.
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Affiliation(s)
- Kenichi Morikawa
- Division of Gastroenterology and Hepatology, Hokkaido University Hospital, Hokkaido, Japan;; Division of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Tomoe Shimazaki
- Division of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Rei Takeda
- Division of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Takaaki Izumi
- Division of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Machiko Umumura
- Division of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Naoya Sakamoto
- Division of Gastroenterology and Hepatology, Hokkaido University Hospital, Hokkaido, Japan;; Division of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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Hepatitis B virus genotypes: epidemiological and clinical relevance in Asia. Hepatol Int 2016; 10:854-860. [PMID: 27300749 DOI: 10.1007/s12072-016-9745-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 05/27/2016] [Indexed: 02/08/2023]
Abstract
Hepatitis B virus (HBV) is characterized by a high genetic heterogeneity since it replicates via a reverse transcriptase that lacks proofreading ability. Up to now, ten genotypes (A-J) have been described, with genotype A and D being ubiquitous but most prevalent in Europe and Africa, genotype B and C being confined to Asia and Oceania. Infections with other genotypes such as E, F, G and H are also occasionally observed in Asia. Genotype I is rare and can be found in Laos, Vietnam, India and China, whereas genotype J has been described in Japan and Ryukyu. Novel variants generated by recombination and co-infection with other genotypes have gradually gotten worldwide attention and may be correlated with certain clinical features. There are substantial differences in HBV infection regarding prevalence, clinical manifestation, disease progression and response to antiviral therapy. Due to the complex interplay among viral, host and environmental factors, the relationship between HBV genotypes and clinical profiles remains incompletely revealed. In general, genotype A is associated with better response to interferon therapy; genotype C, and to lesser extent B, usually represent a risk factor for perinatal infection and are associated with advanced liver diseases such as cirrhosis and hepatocellular carcinoma; genotype D may be linked with poor response to interferon therapy. Future studies with better design and larger sample size are warranted to further clarify the controversial issues and guide the day-to-day clinical practice.
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Molecular Evolution and Phylodynamics of Acute Hepatitis B Virus in Japan. PLoS One 2016; 11:e0157103. [PMID: 27280441 PMCID: PMC4900519 DOI: 10.1371/journal.pone.0157103] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 05/24/2016] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV) is prevalent worldwide and causes liver diseases, including acute and chronic hepatitis. Ten HBV genotypes (A–J) with distinct geographic distributions have been reported. Cases of acute HBV infection with genotype A have increased in Japan nationwide since the 1990s, mainly through sexual transmission. To investigate the molecular evolution and phylodynamics of HBV genotypes, we collected acute HBV isolates acquired in Japan from 1992–2002. Full genomes were obtained for comprehensive phylogenetic and phylodynamic analysis, with other Japanese HBV sequences from GenBank that were isolated during 1991–2010. HBV genotypes were classified using the maximum-likelihood and Bayesian methods. The GMRF Bayesian Skyride was used to estimate the evolution and population dynamics of HBV. Four HBV genotypes (A, B, C, and H) were identified, of which C was the major genotype. The phylodynamic results indicated an exponential growth between the 1960s and early 1990s; this was followed by a population bottleneck after 1995, possibly linked with successful implementation of a nationwide vaccination program. However, HBV/A increased from 1990 to 2003–2004, and then started to decrease. The prevalence of genotype A has increased over the past 10 years. Phylodynamic inference clearly demonstrates a steady population growth compatible with an ongoing subepidemic; this might be due to the loss of immunity to HBV in adolescents and people being born before the vaccination program. This is the first phylodynamic study of HBV infection in Japan and will facilitate understanding the molecular epidemiology and long-term evolutionary dynamics of this virus in Japan.
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Tong S, Revill P. Overview of hepatitis B viral replication and genetic variability. J Hepatol 2016; 64:S4-S16. [PMID: 27084035 PMCID: PMC4834849 DOI: 10.1016/j.jhep.2016.01.027] [Citation(s) in RCA: 309] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 01/18/2016] [Accepted: 01/25/2016] [Indexed: 02/06/2023]
Abstract
Chronic infection with hepatitis B virus (HBV) greatly increases the risk for liver cirrhosis and hepatocellular carcinoma (HCC). HBV isolates worldwide can be divided into ten genotypes. Moreover, the immune clearance phase selects for mutations in different parts of the viral genome. The outcome of HBV infection is shaped by the complex interplay of the mode of transmission, host genetic factors, viral genotype and adaptive mutations, as well as environmental factors. Core promoter mutations and mutations abolishing hepatitis B e antigen (HBeAg) expression have been implicated in acute liver failure, while genotypes B, C, subgenotype A1, core promoter mutations, preS deletions, C-terminal truncation of envelope proteins, and spliced pregenomic RNA are associated with HCC development. Our efforts to treat and prevent HBV infection are hampered by the emergence of drug resistant mutants and vaccine escape mutants. This paper provides an overview of the HBV life cycle, followed by review of HBV genotypes and mutants in terms of their biological properties and clinical significance.
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Affiliation(s)
- Shuping Tong
- Liver Research Center, Rhode Island Hospital, The Alpert Warren School of Medicine, Brown University, Providence, RI, USA; Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Peter Revill
- Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne, VIC, Australia ()
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Chauhan R, Singh AK, Rooge S, Varshney A, Kumar M, Sarin SK. Analysis of hepatitis B virus genotype changes in patients with chronic hepatitis B infection on tenofovir therapy. J Med Virol 2016; 88:1364-75. [PMID: 26858138 DOI: 10.1002/jmv.24489] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2016] [Indexed: 12/14/2022]
Abstract
Antiviral therapy for chronic hepatitis B (CHB) is often required for prolonged periods. We investigated the instance of one HBV genotype switching to another during tenofovir therapy. Of the 67 patients, genotype A was present in 6 (8.9%), D in 43 (65.6%), C in 1 (1.5%), and mixed in 17 (23.8%) patients. Genotype changes were detected in 51 (76.1%) patients on therapy during a follow-up of 192 (range 52-312) weeks. Inter-genotype changes were seen in 17 (33.3%) and intra-genotype in 28 (55%) and both inter- and intra-genotype in 6 of 51 (11.7%) patients. The distribution of genotypes in patients achieving complete virological response was genotype D, 32/43 (74.4%); genotype A, 6/6 (100%); and mixed genotypes, 13/17 (76.47%). The cumulative time of genotype switch among genotype A was 12 months (range 6-18), in genotype D, 12 months (range 6-48), and mixed genotype, 18 months (range 6-24). The type of inter-genotype switch most frequently detected among genotype A1 was from A1 to D1 5/6 (83.3%), followed by mixed to genotype D3 7/13 (54%) and among intra-genotype changes, from D1 to D3 in 14/20 (70%). Pretreatment HBV genotype was the only factor predicting inter-genotype switches with genotype A or mixed genotypes more likely to undergo inter-genotype switches as compared to genotype D patients (OR 66.6 [13.6-327.0, P < 0.001]). Compared to genotype D, genotype A, and mixed genotypes are more inclined to switch while on tenofovir therapy. Genotypes tend to switch and select to a particular type possibly due to constant antiviral drug pressure. J. Med. Virol. 88:1364-1375, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ranjit Chauhan
- Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India.,Molecular Virology and Hepatology Research Group, Faculty of Medicine, Division of BioMedical Sciences, Health Science Centre, Memorial University, St John's, Newfoundland and Labrador, Canada
| | - Avishek K Singh
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sheetalnath Rooge
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Aditi Varshney
- Department of Research, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K Sarin
- Department of Gastroenterology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, New Delhi, India.,Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
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Ito K, Yotsuyanagi H, Sugiyama M, Yatsuhashi H, Karino Y, Takikawa Y, Saito T, Arase Y, Imazeki F, Kurosaki M, Umemura T, Ichida T, Toyoda H, Yoneda M, Tanaka Y, Mita E, Yamamoto K, Michitaka K, Maeshiro T, Tanuma J, Korenaga M, Murata K, Masaki N, Koike K, Mizokami M. Geographic distribution and characteristics of genotype A hepatitis B virus infection in acute and chronic hepatitis B patients in Japan. J Gastroenterol Hepatol 2016; 31:180-189. [PMID: 26110395 DOI: 10.1111/jgh.13030] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2015] [Revised: 06/01/2015] [Accepted: 06/02/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS The prevalence of sexually transmitted acute infections of the genotype A hepatitis B virus (HBV) has been increasing in Japan. Genotype A HBV is associated with an increased risk of HBV progression to chronic infection after acute hepatitis B (AHB) in adults. A nationwide survey was conducted to evaluate the geographic distribution, clinical, and virologic characteristics of genotype A AHB and chronic hepatitis B (CHB) in Japan. METHODS Five hundred seventy AHB patients were recruited between 2005 and 2010, and 3682 CHB patients were recruited between 2010 and 2011. HBV genotypes were determined for 552 and 3619 AHB and CHB patients, respectively. Clinical characteristics were compared among different genotypes in AHB and CHB patients. Genomic characteristics of HBV genotype A were examined by molecular evolutionary analysis. RESULTS Hepatitis B virus genotype A was the predominant genotype for AHB between 2005 and 2010. Phylogenetic analysis showed that all strains in the AHB patients with genotype A were classified into subtype Ae. Among CHB patients, the occurrence of genotype A was 4.1%, and genotype A was spreading in young adults. In genotype A CHB patients, early stage liver diseases were predominant, although liver diseases progressed to cirrhosis or hepatocellular carcinoma in some patients. CONCLUSIONS The distribution of HBV genotypes is quite different between AHB and CHB in Japanese patients. Genotype A infection is spreading in young adults of Japanese CHB patients. Sequences derived from Japanese AHB patients were identical to or closely resembled the sequences derived from other Japanese AHB patients.
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Affiliation(s)
- Kiyoaki Ito
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute
| | - Hiroshi Yotsuyanagi
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo
| | - Masaya Sugiyama
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa
| | | | - Yoshiyasu Karino
- Department of Gastroenterology, Sapporo Kosei General Hospital, Sapporo
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka
| | - Takafumi Saito
- Department of Gastroenterology, Yamagata University School, Yamagata
| | | | - Fumio Imazeki
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba
| | - Masayuki Kurosaki
- Division of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo
| | - Takeji Umemura
- Department of Medicine, Shinshu University School of Medicine, Matsumoto
| | - Takafumi Ichida
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka
| | - Hidenori Toyoda
- Department of Gastroenterology, Ogaki Municipal Hospital, Ogaki
| | - Masashi Yoneda
- Department of Gastroenterology, Aichi Medical University School of Medicine, Nagakute
| | - Yasuhito Tanaka
- Nagoya City University Graduate School of Medical Sciences, Nagoya
| | - Eiji Mita
- National Hospital Organization Osaka National Hospital, Osaka
| | - Kazuhide Yamamoto
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Okayama
| | - Kojiro Michitaka
- Department of Gastroenterology, Ehime University Graduate School of Medicine, Toon
| | - Tatsuji Maeshiro
- First Department of Internal Medicine, University Hospital, Faculty of Medicine, University of the Ryukyu, Okinawa, Japan
| | - Junko Tanuma
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa
| | - Kazumoto Murata
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa
| | - Kazuhiko Koike
- Department of Internal Medicine, Graduate School of Medicine, The University of Tokyo
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa
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Inoue J, Kondo Y, Umetsu T, Yamamoto T, Miura M, Mano Y, Kobayashi T, Obara N, Niitsuma H, Kogure T, Nakagome Y, Kimura O, Iwata T, Morosawa T, Fujisaka Y, Shimosegawa T. Shifting hepatitis B virus genotypes of acute hepatitis B patients in northeast Japan. J Med Virol 2016; 88:69-78. [PMID: 26113372 DOI: 10.1002/jmv.24309] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2015] [Indexed: 12/17/2022]
Abstract
It has been reported that acute hepatitis B (AHB) patients with genotype A HBV (HBV/A) have been increasing since the 1990s in metropolitan areas in Japan. However, little is known about the trends of HBV genotypes in AHB patients in northeast Japan where genotype B HBV (HBV/B) prevails more than in other areas. In this study, we aimed to clarify the changes in the HBV genotypes and clinical characteristics of AHB patients in this area. HBV genotypes were determined by direct sequencing (n = 125) or enzyme immunoassay (n = 9) using serum samples from AHB patients including fulminant hepatitis in 1987-2014. Among 134 patients, 26 (19%), 33 (25%), and 75 (56%) patients were infected with HBV of genotypes A, B, and C, respectively. HBV/A emerged from 2001 and the percentage was increased gradually up to 48% in 2010-2014, whereas HBV/B was reduced from 40% in 1987-1994 to 10% in 2010-2014. Phylogenetic analysis showed that three major subgenotype A2 strains had come into this area serially. The levels of HBV DNA and prothrombin time were higher in HBV/A patients than other genotypes. This study could not show significant difference in the HBsAg-positive period among genotypes nor the effect of nucleoside analogues to shorten the HBsAg-positive period. A higher level of initial HBV DNA was associated with late disappearance of HBsAg. In conclusion, the percentage of HBV/A in AHB patients has been increasing in northeast Japan since 2001, which is later than metropolitan areas, whereas that of HBV/B is decreasing.
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Affiliation(s)
- Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuteru Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Teruyuki Umetsu
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeshi Yamamoto
- Department of Gastroenterology, Tohoku Pharmaceutical University Hospital, Sendai, Japan
| | - Masahito Miura
- Department of Gastroenterology, South Miyagi Medical Center, Miyagi, Japan
| | - Yutaka Mano
- Department of Gastroenterology, Sendai Medical Center, Sendai, Japan
| | - Tomoo Kobayashi
- Department of Hepatology, Tohoku Rosai Hospital, Sendai, Japan
| | - Noriyuki Obara
- Department of Gastroenterology, Iwate Prefectural Central Hospital, Morioka, Japan
| | - Hirofumi Niitsuma
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takayuki Kogure
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yu Nakagome
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Osamu Kimura
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoaki Iwata
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tatsuki Morosawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuyuki Fujisaka
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Yokoyama Y, Miyagi T, Hikita H, Yoshioka T, Mukai K, Nawa T, Sakamori R, Ohkawa K, Hiramatsu N, Takahashi T, Suemizu H, Ryo A, Tatsumi T, Takehara T. The Hepatitis B Virus Genotype Affects the Persistence of Viral Replication in Immunodeficient NOG Mice. PLoS One 2015; 10:e0144775. [PMID: 26658490 PMCID: PMC4682774 DOI: 10.1371/journal.pone.0144775] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 11/23/2015] [Indexed: 02/07/2023] Open
Abstract
Background & Aims At least eight genotypes of Hepatitis B virus (HBV) have been identified. HBV genotype C is the most common genotype in Japan, although the incidence of HBV genotype A is increasing. The reason underlying the differences in viral multiplication of the HBV genotypes is unclear, especially in vivo. The purpose of this study was to elucidate the differences in HBV load and the persistence of viremia in vivo between genotypes A and C. Methods Immunodeficient NOG mice were transfected by hydrodynamic injection with the HBV expression plasmids pHBA1.2 or pHBC1.2, which contain overlength (1.2-mer) copies of the genomes of HBV genotype A or C, respectively. Results One day after transfection, the number of HBcAg-positive hepatocytes and serum HBV DNA levels were similar between mice transfected with pHBA1.2 and pHBC1.2. Serum levels of HBV DNA, HBsAg and HBeAg in mice transfected with pHBA1.2 were maintained over 5 months. In contrast, those in mice with pHBC1.2 gradually decreased over time and reached undetectable levels within 3 months after transfection. HBcAg-stained hepatocytes were detected in mice transfected with pHBA1.2, but not pHBC1.2, 5 months post-transfection. Double-staining immunohistochemistry revealed that the number of cleaved caspase3-stained, HBcAg-positive hepatocytes in the pHBC1.2-transfected mice was higher than in the pHBA1.2-transfected mice 3 days post-transfection. Moreover, the plasmid DNA and covalently closed circular DNA levels were decreased in the livers of pHBC1.2-transfected mice. These results suggested that hepatocytes expressing HBV genotype C were eliminated by apoptosis in the absence of immune cells more often than in hepatocytes expressing HBV genotype A. Conclusions Immunodeficient mice transfected with HBV genotype A develop persistent viremia, whereas those transfected with HBV genotype C exhibit transient viremia accompanied by apoptosis of HBV-expressing hepatocytes. This differences may affect the clinical courses of patients infected with HBV genotypes A and C.
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Affiliation(s)
- Yoshinobu Yokoyama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takuya Miyagi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Teppei Yoshioka
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kaori Mukai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takatoshi Nawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kazuyoshi Ohkawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Naoki Hiramatsu
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takeshi Takahashi
- Laboratory Animal Research Department, Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan
| | - Hiroshi Suemizu
- Laboratory Animal Research Department, Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan
| | - Akihide Ryo
- Department of Microbiology, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- * E-mail:
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Sarkar N, Pal A, Das D, Saha D, Biswas A, Bandopadhayay B, Chakraborti M, Ghosh M, Chakravarty R. Virological Characteristics of Acute Hepatitis B in Eastern India: Critical Differences with Chronic Infection. PLoS One 2015; 10:e0141741. [PMID: 26571502 PMCID: PMC4646492 DOI: 10.1371/journal.pone.0141741] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 10/12/2015] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B Virus (HBV) manifests high genetic variability and is classifiable into ten genotypes (A-J). HBV infection can lead to variable clinical outcomes, ranging from self-limiting acute hepatitis to active chronic hepatitis, cirrhosis and hepatocellular carcinoma. The present study characterizes HBV strains circulating among patients with acute (AHB) and chronic HBV infection (CHB). Among a total of 653 HBsAg positive cases, 40 manifested acute infection. After sequencing the surface(S), basal core promoter/pre-core(BCP/PC) and the X gene regions, phylogenetic tree was constructed using MEGA4 by neighbor-joining method. Statistical robustness was established with bootstrap analysis. Nucleotide diversity was determined by Shannon entropy per site using the Entropy program of the Los Alamos National Laboratories. Analyses of acute patients revealed that HBV/D2 is the major circulating sub-genotype and commonly associated with sexual promiscuity and the age group between15-30 years. Comparison of AHB and CHB patients revealed that HBeAg positivity, ALT levels and genotype D were significantly high in AHB, whereas CHB patients were predominantly male, had a high viral load, and were commonly associated with genotype C. The frequencies of mutations in the S, BCP/PC, and X gene were low in AHB as compared to CHB. Drug resistant mutations were not detectable in the polymerase gene of AHB. Average nucleotide diversity in AHB was considerably low as compared to CHB. Further, the highest average ΔH (average difference in entropy between chronic and acute infection) was observed in the BCP/PC region implying that this region was most vulnerable to mutations upon HBV persistence, especially in case of genotype C. Additionally, among all substitutions, the A1762T and G1764A BCP mutations were the strongest indicators of chronicity. In conclusion, the study exhibits a general portrait of HBV strains circulating among acute hepatitis B patients in Eastern India and their intricate differences with chronic patients which should be useful from the clinical point of view.
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Affiliation(s)
- Neelakshi Sarkar
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Ananya Pal
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Dipanwita Das
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Debraj Saha
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Avik Biswas
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Bhaswati Bandopadhayay
- Department of Virology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India
| | - Mandira Chakraborti
- Department of Virology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India
| | - Mrinmoy Ghosh
- Department of Medicine, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Runu Chakravarty
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
- * E-mail:
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Characterization of Acute and Chronic Hepatitis B Virus Genotypes in Canada. PLoS One 2015; 10:e0136074. [PMID: 26406309 PMCID: PMC4583310 DOI: 10.1371/journal.pone.0136074] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 07/26/2015] [Indexed: 12/11/2022] Open
Abstract
Objective The prevalence and distribution of hepatitis B virus (HBV) genotypes in Canada is not known. Genotypic analysis may contribute to a better understanding of HBV strain distribution and transmission risk. Methods HBV surface antigen (HBsAg) positive samples of acute (n = 152) and chronic (n = 1533) HBV submitted for strain analysis or reference genotype testing between 2006 and 2012 were analyzed. The HBsAg coding region was amplified to determine the HBV genotype by INNO-LiPA assay or sequence analysis. Single and multivariate analyses were used to describe genotypes’ associations with known demographic and behavioral risk factors for 126 linked cases of acute HBV. Results Nine genotypes were detected (A to I), including mixed infections. Genotype C (HBV/C) dominated within chronic infections while HBV/D and A prevailed among acute HBV cases. History of incarceration and residing with a chronic HBV carrier or injection drug user were the most frequently reported risks for acute HBV infection. Over time, HBV/A increased among both acute and chronic infections, and HBV/C and HBV/D decreased among chronic infections. Conclusion Chronic and acute HBV genotypes in Canada differ in the relative distribution and their associations with known risk factors, suggesting different routes of transmission and clinical progression of infection.
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Kiyohara T, Ishii K, Mizokami M, Sugiyama M, Wakita T. Seroepidemiological study of hepatitis B virus markers in Japan. Vaccine 2015; 33:6037-42. [PMID: 26341564 DOI: 10.1016/j.vaccine.2015.08.034] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 07/03/2015] [Accepted: 08/11/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND In Japan, since 1986, selective vaccination has been implemented as a hepatitis B prevention strategy. The target of vaccination is the infant born to a hepatitis B surface antigen (HBsAg)-positive mother. The current Japanese hepatitis B prevention strategy focuses on reducing the number of HBV carriers but overlooks the risk to susceptible populations. We conducted a nationwide HBV seroepidemiological study to explore the next hepatitis B control strategy. METHODS We used sera derived from healthy individuals collected nationwide from 2005 through 2011 to investigate the HBsAg seroprevalence among children aged 4-9 years and 10-15 years (3000 samples) and hepatitis B core antibody (HBcAb) seroprevalence among people 10-39 years of age (600 samples). FINDINGS Among sera from 3000 children, 5 (0.17%) specimens were HBsAg-positive. There was no significant difference in HBsAg prevalence between age groups. Among 600 samples, 15 (2.5%) were HBcAb-positive. Out of 15 samples, 4 were from teenagers. Both HBsAg- and HBcAb-positive sera were found mainly in the Southern area of Japan. CONCLUSION The prevalence of HBsAg among children was 0.17% in the present study. This is higher than the prevalence reported in previous studies performed in the local area or in blood donors. The prevalence of HBcAb is also higher than we estimated. One of the reasons for this discrepancy from previous studies may be due to the small sample size and the impact of HBV high-endemic areas included in the present nationwide study. Nevertheless, our findings revealed that the opportunities for acquiring HBV infection in the susceptible population were more frequent than we thought, especially in some localities. Hepatitis B vaccination should be introduced into the routine child immunization program for susceptible populations, and the selective vaccination program should be continued for high-risk children.
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Affiliation(s)
- Tomoko Kiyohara
- Department of Virology II, National Institute of Infectious Diseases, 4-7-1, Gakuen, Musashi-murayama, Tokyo 208-0011, Japan.
| | - Koji Ishii
- Department of Virology II, National Institute of Infectious Diseases, 4-7-1, Gakuen, Musashi-murayama, Tokyo 208-0011, Japan.
| | - Masashi Mizokami
- Department of Hepatic Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Konodai, Ichikawa, Chiba 272-8516, Japan.
| | - Masaya Sugiyama
- Department of Hepatic Diseases, The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, 1-7-1 Konodai, Ichikawa, Chiba 272-8516, Japan.
| | - Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, 4-7-1, Gakuen, Musashi-murayama, Tokyo 208-0011, Japan.
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Tajiri K, Shimizu Y. Unsolved problems and future perspectives of hepatitis B virus vaccination. World J Gastroenterol 2015; 21:7074-7083. [PMID: 26109794 PMCID: PMC4476869 DOI: 10.3748/wjg.v21.i23.7074] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Revised: 03/23/2015] [Accepted: 05/04/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is still a serious worldwide problem, and vaccination is the most effective strategy for primary prevention of the infection. Although universal vaccination may be required for total eradication, several countries, including Japan, have not yet adopted universal vaccination programs. Some individuals are non-responders to HBV vaccine and several mechanisms responsible for their poor response have been proposed. To overcome non-response, third generation vaccines with pre-S proteins have been developed. These vaccines have shown better anti-HBs responses and may also be effective in preventing infection by HBV with S mutant. Improvement of vaccine efficacy by intradermal administration, or co-administration with cytokines or adjuvants, may also be effective in non-responders. The necessity, timing and method of booster vaccination in responders with decreased anti-HBs responses, and effective vaccination against S-mutant HBV, are issues requiring resolution in the global prevention of HBV infection.
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Impact of HBV genotypes A and D genetic variability on infection evolution. INFECTION GENETICS AND EVOLUTION 2015; 33:281-7. [PMID: 25989376 DOI: 10.1016/j.meegid.2015.05.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Revised: 05/04/2015] [Accepted: 05/16/2015] [Indexed: 02/07/2023]
Abstract
HBV is characterized by a high genetic variability, which is the basis of its classification into eight genotypes (A-H). HBV infection is associated with different outcomes, from self-limiting acute hepatitis to active chronic hepatitis, asymptomatic carriage, and occult infection. The aim of this study was to analyze the genetic variability of HBV genotypes A and D isolates from 79 cases of self-limiting acute hepatitis and chronic hepatitis, in order to identify HBV variants associated with resolution or chronicity of acute HBV infection. The entire preS-S sequence and a fragment of 346 bp of the preC-C region, containing Enhancer II and Basal Core Promoter sequences, were analyzed. A phylogenetic analysis of preS/S region showed that the 45.45% (15/33) of isolates from acute hepatitis cases were genotype A compared to 8.69% (4/46) of chronic hepatitis cases. (p = 0.0002). Mutations associated with immune-escape (T131N, D144A/E, G145K), amino acid polymorphisms in "a determinant" domain of S protein and mutations/deletions in preC/C region were found in isolates from acute and chronic hepatitis B cases. In this study mutations/deletions in preS-S and preC-C regions, usually associated with fulminant acute hepatitis, advanced forms of liver disease and increased risk for HCC, were identified in HBV strains of genotype A and D obtained both from patients with self-limiting acute HBV infection and from persistent infected patients. This founding probably is due to the natural viral evolution under host immune response and to the circulation of a wide variety of HBV strains in our geographic area because of the ancient introduction of genotype D and the migrant fluxes from North Africa. Moreover, the analysis of circulation of new HBV antigenic variants is fundamental for the epidemiological surveys and for the evaluation of the impact of viral evolution on vaccine prophylaxis strategies.
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Abstract
At least 10 hepatitis B virus (HBV) genotypes (A to J) with distinct geographic distributions and several HBV mutants, including precore/core promoter mutations and pre-S/S deletion mutations, have been recognized to be not only predictive of liver disease progression but also associated with response to antiviral therapy. HBV genotype-specific pathogenesis may contribute to heterogeneous clinical outcomes in chronic hepatitis B patients across the world. For example, patients with HBV genotypes C and D infection have a lower rate of spontaneous HBeAg seroconversion. In addition, HBV genotypes C and D have a higher frequency of core promoter and pre-S mutations than genotypes A and B. Genotypes C and D also carry a higher lifetime risk of cirrhosis and HCC development than genotypes A and B. Core promoter and pre-S mutations also correlate with an increased risk of hepatocellular carcinoma (HCC). Therapeutically, genotypes A and B patients have a better response to interferon-based therapy than genotypes C and D patients, but the response to nucleos(t)ide analogs is comparable across different HBV genotypes. In conclusion, HBV genotypes and variants may serve as viral genetic markers to predict disease progression as well as help practicing physicians optimize individualized antiviral therapy in clinical practice.
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Affiliation(s)
- Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei 106, Taiwan Department of Psychology, National Chengchi University, Taipei 106, Taiwan
| | - Jia-Horng Kao
- Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 100, Taiwan Hepatitis Research Center, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 100, Taiwan Department of Medical Research, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 100, Taiwan
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Iqbal K, Klevens RM, Kainer MA, Baumgartner J, Gerard K, Poissant T, Sweet K, Vonderwahl C, Knickerbocker T, Khudyakov Y, Xia GL, Roberts H, Teshale E. Epidemiology of Acute Hepatitis B in the United States From Population-Based Surveillance, 2006-2011. Clin Infect Dis 2015; 61:584-92. [PMID: 25904365 DOI: 10.1093/cid/civ332] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 04/15/2015] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND An estimated 20 000 new hepatitis B virus (HBV) infections occur each year in the United States. We describe the results of enhanced surveillance for acute hepatitis B at 7 federally funded sites over a 6-year period. METHODS Health departments in Colorado, Connecticut, Minnesota, Oregon, Tennessee, 34 counties in New York state, and New York City were supported to conduct enhanced, population-based surveillance for acute HBV from 2006 through 2011. Demographic and risk factor data were collected on symptomatic cases using a standardized form. Serum samples from a subset of cases were also obtained for molecular analysis. RESULTS In the 6-year period, 2220 acute hepatitis B cases were reported from the 7 sites. For all sites combined, the incidence rate of HBV infection declined by 19%, but in Tennessee incidence increased by 90%, mainly among persons of white race/ethnicity and those aged 40-49 years. Of all reported cases, 66.1% were male, 57.1% were white, 58.4% were aged 30-49 years, and 60.1% were born in the United States. The most common risk factor identified was any drug use, notably in Tennessee; healthcare exposure was also frequently reported. The most common genotype for all reported cases was HBV genotype A (82%). CONCLUSIONS Despite an overall decline in HBV infection, attributable to successful vaccination programs, a rise in incident HBV infection related to drug use is an increasing concern in some localities.
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Affiliation(s)
- Kashif Iqbal
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - R Monina Klevens
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | | | | | | | | | | | | | | | - Yury Khudyakov
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Guo-Liang Xia
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Henry Roberts
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Eyasu Teshale
- Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia
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