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Rabaan AA, Bello KE, Radwan Z, Hassouneh AK, Alrasheed HA, Alotaibi J, Basrana B, Zaidan AA, Garout MA, Zaidan TI, Al Amri KA, Alshaikh SA, Al Alawi KH, A. Alalqam R, Tombuloglu H, Bouafia NA. The Dual Burden of Hepatitis B and C Among Drug Users in Asia: The First Systematic Review and Meta-Analysis. Pathogens 2025; 14:360. [PMID: 40333162 PMCID: PMC12030361 DOI: 10.3390/pathogens14040360] [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] [Subscribe] [Scholar Register] [Received: 03/13/2025] [Revised: 03/26/2025] [Accepted: 03/31/2025] [Indexed: 05/09/2025] Open
Abstract
Hepatitis B virus (HBV) and Hepatitis C virus (HCV) contribute significantly to morbidity and mortality among drug users in Asia. This study systematically reviews and analyzes the pooled prevalence of HBV and HCV, considering geographic and methodological variations. A meta-analysis following PRISMA guidelines included data from PubMed, Scopus, and Google Scholar on studies on HBV or HCV or a combination of both within Asia. A random-effects model estimated pooled prevalence, with subgroup analyses by region, study design, diagnostic method, and publication year. A total of 112 studies were analyzed. The pooled HBV prevalence among drug users was 14.3% (95% CI: 11.5-17.6), highest in Malaysia (28.7%) and Vietnam (26.6%). HCV prevalence was 58.6% (95% CI: 54.0-63.0), with the highest rates in Vietnam (63.5%) and China (62.9%). Retrospective studies reported a higher prevalence than cross-sectional ones. The use of ELISA for initial screening followed up by PCR reduced heterogeneity, improving diagnostic accuracy. HBV prevalence declined after 2010, while HCV rates remained persistently high. The high burden of HBV and HCV among drug users in Asia underscores an urgent public health concern. Targeted interventions, including vaccination, harm reduction strategies, and improved access to antiviral treatments, are essential to curbing transmission and enhancing health outcomes.
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Affiliation(s)
- Ali A. Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Public Health and Nutrition, The University of Haripur, Haripur 22610, Pakistan
| | - Kizito E. Bello
- Department of Microbiology, Kogi State (Prince Abubakar Audu) University, Anyigba 10008, Nigeria;
| | - Zaheda Radwan
- Medical Laboratory Department, Mohammed Al-Mana College for Medical Sciences, Dammam 34222, Saudi Arabia;
| | - Amal K. Hassouneh
- Clinical Pharmacy Department, King Saud Medical City, Riyadh 11362, Saudi Arabia;
| | - Hayam A. Alrasheed
- Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
| | - Jawaher Alotaibi
- Infectious Diseases Unit, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11564, Saudi Arabia;
| | - Bashayer Basrana
- Department of Infectious Disease, King Abdullah Medical Complex, Jeddah 6725, Saudi Arabia;
| | - Ali A. Zaidan
- Gastroenterology Department, King Fahad Armed Forces Hospital, Jeddah 23831, Saudi Arabia;
| | - Mohammed A. Garout
- Department of Community Medicine and Health Care for Pilgrims, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Tasneem I. Zaidan
- Pediatric Infectious Diseases Unit, Pediatric Department, King Abdulaziz Hospital, Jeddah 23831, Saudi Arabia;
| | | | - Sana A. Alshaikh
- Diagnostic Virology Laboratory, Maternity and Children Hospital, Eastern Health Cluster, Dammam 32253, Saudi Arabia;
| | - Kawthar Haider Al Alawi
- Nursing Department of Vaccine Clinic, Hospital: Al Jamaeen Primary Health Care, Dammam 32467, Saudi Arabia;
| | - Razi A. Alalqam
- Department of Medicine, Royal College of Surgeons, D02 YN77 Dublin, Ireland;
| | - Huseyin Tombuloglu
- Department of Genetics Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam 34221, Saudi Arabia;
| | - Nabiha A. Bouafia
- Infection Prevention and Control Centre of Excellence, Prince Sultan Medical Military City, Riyadh 12233, Saudi Arabia
- Preventive and Community Medicine Department, Faculty of Medicine, University of Sousse, Sousse 4002, Tunisia
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Zhong G, Jiang ZH, Wang XY, Chen QY, Zhang LJ, Hu LP, Huang ML, Huang YB, Hu X, Zhang WW, Harrison TJ, Fang ZL. Increasing Prevalence of Occult HBV Infection in Adults Vaccinated Against Hepatitis B at Birth. Vaccines (Basel) 2025; 13:174. [PMID: 40006721 PMCID: PMC11860204 DOI: 10.3390/vaccines13020174] [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: 12/11/2024] [Revised: 02/02/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES Immunization with the hepatitis B vaccine is the most effective means of preventing acute HBV infection. However, whether the primary vaccination of infants confers lifelong immunity remains controversial. Therefore, the ongoing surveillance of vaccine recipients is required. METHODS A longitudinal study was carried out based on LongAn county, one of the five clinical trial centers for hepatitis B immunization in China in the 1980s. Serum samples were collected and tested for HBV serological markers and DNA. RESULTS A total of 637 subjects born in 1987-1993 were recruited, including 503 males and 134 females. The total prevalence of HBsAg was 3.9%. The prevalence in females (8.2%) was significantly higher than that in males (2.8%) (p = 0.004). The prevalence of anti-HBc in females (52.2%) was also significantly higher than that in males (41.2%) (p = 0.021). The prevalence of anti-HBs was 42.7% and did not differ significantly between males (41.7%) and females (46.3%) (p = 0.347). Compared to data from surveillance over the last ten years, the positivity rate of HBsAg did not increase. The positivity rate of anti-HBs decreased significantly (p = 0.049) while that of anti-HBc increased significantly (p = 0.001). The prevalence of occult HBV infection (OBI) in 2024 (6.0%) was significantly higher than that in 2017 (1.6%) (p = 0.045). Subjects diagnosed with OBI in 2017 maintained occult infection in 2024. CONCLUSIONS Neonatal HBV vaccination maintained effective protection for at least 37 years. However, the prevalence of OBI increases with age in those vaccinated at birth, raising a new issue of how to prevent and control OBI in the post-universal infant vaccination era.
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Affiliation(s)
- Ge Zhong
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
| | - Zhi-Hua Jiang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
| | - Xue-Yan Wang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
| | - Qin-Yan Chen
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
| | - Lu-Juan Zhang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
| | - Li-Ping Hu
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
| | - Mei-Lin Huang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
- School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
| | - Yu-Bi Huang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
- School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
| | - Xue Hu
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
- School of Preclinical Medicine, Guangxi Medical University, Nanning 530021, China
| | - Wei-Wei Zhang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
| | - Tim J. Harrison
- Division of Medicine, University College London Medical School, London WC1E 6BT, UK;
| | - Zhong-Liao Fang
- Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning 530028, China; (G.Z.); (Z.-H.J.); (X.-Y.W.); (Q.-Y.C.); (L.-J.Z.); (L.-P.H.); (M.-L.H.); (Y.-B.H.); (X.H.); (W.-W.Z.)
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de Almeida Pondé RA. Detection of hepatitis B virus surface antigen, IgM and IgG antibodies to hepatitis B virus core antigen in the clinical classification and epidemiological surveillance of HBV infection. Mol Biol Rep 2025; 52:195. [PMID: 39903324 DOI: 10.1007/s11033-025-10278-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/20/2025] [Indexed: 02/06/2025]
Abstract
Hepatitis B virus surface antigen (HBsAg), IgM and IgG antibodies to hepatitis B virus core antigen (anti-HBcIgM and anti-HBcIgG) comprise serological markers of hepatitis B virus (HBV) infection of great importance in the epidemiological surveillance of hepatitis B, since they have been routinely considered for classifying the acute and chronic clinical forms of HBV infection. This classification is established according to the expression and dynamics of these markers in the infected person's bloodstream, which serves as the basis for the differential diagnosis between the two clinical entities. However, in certain circumstances, both acute and chronic infection, the detection of these markers may not occur in the bloodstream, favoring the occurrence of atypical serological profiles of infection, and compromising the correct infection clinical classification. In addition, the complex and varied nature of hepatitis B serological profiles may compromise the health professional's ability to analyze the case and, thus, correctly classify the infection's clinical form. Since the expression of these markers in the bloodstream occurs dynamically, with consequent changes in the patient's serological profile as he progresses towards recovery or chronicity, the diagnosis of acute or chronic infection may also be compromised, if it is established based on the collection of a single sample and without knowing the patient's clinical history and their epidemiological antecedents. This manuscript addresses the sensitivity and specificity of HBsAg, anti-HBcIgM, and anti-HBcIgG serological markers detection in the clinical classification of HBV infection and in the epidemiological surveillance of hepatitis B. This review is covering the clinical and epidemiological interpretations of the markers in and of themselves, not in reference to any specific assays.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde -SES/Superintendência de Vigilância em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil.
- , Rua 136 Qd F44 Lt 22/24 Ed. César Sebba- Setor Sul, Goiânia, Goiás, 74-093-250, Brazil.
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Pondé RADA, Amorim GDSP. Exchanges in the 'a' determinant of the hepatitis B virus surface antigen revisited. Virology 2024; 599:110184. [PMID: 39127000 DOI: 10.1016/j.virol.2024.110184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/02/2024] [Accepted: 07/17/2024] [Indexed: 08/12/2024]
Abstract
The hepatitis B virus surface antigen's (HBsAg) 'a' determinant comprises a sequence of amino acid residues located in the major hydrophilic region of the S protein, whose exchanges are closely associated with compromising the antigenicity and immunogenicity of that antigen. The HBsAg is generally present in the bloodstream of individuals with acute or chronic hepatitis B virus (HBV) infection. It is classically known as the HBV infection marker, and is therefore the first marker to be investigated in the laboratory in the clinical hypothesis of infection by this agent. One of the factors that compromises the HBsAg detection in the bloodstream by the assays adopted in serological screening in both clinical contexts is the loss of S protein antigenicity. This can occur due to mutations that emerge in the HBV genome regions that encode the S protein, especially for its immunodominant region - the 'a' determinant. These mutations can induce exchanges of amino acid residues in the S protein's primary structure, altering its tertiary structure and the antigenic conformation, which may not be recognized by anti-HBs antibodies, compromising the infection diagnosis. In addition, these exchanges can render ineffective the anti-HBs antibodies action acquired by vaccination, compromise the effectiveness of the chronically HBV infected patient's treatment, and also the HBsAg immunogenicity, by promoting its retention within the cell. In this review, the residues exchange that alter the S protein's structure is revisited, as well as the mechanisms that lead to the HBsAg antigenicity loss, and the clinical, laboratory and epidemiological consequences of this phenomenon.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde -SES/Superintendência de Vigilância Em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil; Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil.
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Delghandi S, Raoufinia R, Shahtahmasbi S, Meshkat Z, Gouklani H, Gholoobi A. An overview of occult hepatitis B infection (OBI) with emphasis on HBV vaccination. Heliyon 2024; 10:e37097. [PMID: 39281486 PMCID: PMC11402251 DOI: 10.1016/j.heliyon.2024.e37097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/25/2024] [Accepted: 08/27/2024] [Indexed: 09/18/2024] Open
Abstract
Background The prevalence of chronic hepatitis B virus (HBV) poses a significant threat to the lives of 257 million individuals globally, potentially resulting in severe outcomes such as liver cirrhosis or hepatocellular carcinoma. Among the existing preventive measures, yeast-derived vaccines have proven to be the most efficacious approach in combatting hepatitis B. Nonetheless, as scientific inquiries focus more on occult HBV infection (OBI) in vaccinated persons and the lingering risk of vertical transmission affecting 10-30 % of babies born to HBsAg-positive mothers, there is a growing apprehension regarding the inability of HBV vaccines to ensure complete immunity. This study aims to offer a more comprehensive understanding of the implications of widespread HBV vaccination initiatives on OBI while tackling the primary limitations associated with current vaccine formulations. Methods The exploration was conducted on PubMed, Scopus, and Web of Science databases to pinpoint research on OBI within vaccinated cohorts. A sum of 76 suitable studies was recognized. Discussion Multiple studies have documented the occurrence of OBI in fully vaccinated individuals, including both the general population and high-risk groups, such as newborns born to HBsAg-positive mothers. Factors contributing to vaccine failures include low-level anti-HBs antibodies, high maternal viral loads in mother-to-child transmission cases, as well as the presence of vaccine escape mutants and heterologous HBV genotypes. However, further research is needed to precisely understand the impact of active immunization on the emergence of OBI in vaccinated populations. Nonetheless, it is apparent that the advancement of more effective HBV vaccines could potentially lead to the extinction of HBV.
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Affiliation(s)
- Sara Delghandi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Division of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ramin Raoufinia
- Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sahar Shahtahmasbi
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Meshkat
- Antimicrobial Resistance Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Gouklani
- Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Aida Gholoobi
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Cakal B, Cavus B, Atasoy A, Altunok D, Poda M, Bulakci M, Gulluoglu M, Demirci M, Sener LT, Arslan AB, Arikan M, Akyuz F. Comparison of S gene mutations in patients with occult and chronic hepatitis B virus infection. Virus Res 2022; 318:198855. [PMID: 35798213 DOI: 10.1016/j.virusres.2022.198855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 06/28/2022] [Accepted: 06/30/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND AIM This study aimed to detect mutations in the HBV S gene and evaluate their relationship to occult hepatitis B virus (HBV) infection (OBI). METHODS The study included 32 patients with negative serum HBsAg and HBV DNA who underwent liver biopsy due to different clinical indications defined as the OBI group and 32 patients who underwent liver biopsy due to chronic hepatitis B (CHB) as the comparison group. The HBV S gene region was amplified by Nested PCR, and Sanger sequencing was performed. RESULTS At least one amino acid (aa) mutation was detected in the major hydrophilic region (MHR) of the HBV S gene in 14/32 (43.75%) of the patients with OBI and 8/32 (25.0%) with CHB. The genotype of all patients with OBI and CHB was HBV/D. Although 9 (28.1%) of the cases with OBI had sub-genotype HBV/D3, none of the patients with CHB had sub-genotype HBV/D3. Unlike patients with CHB, L15*, D33N, Q51P, V63F, L91I, P108S, T115I, P120L, T125M, Q129H, T189I, L216F, P217L mutations were detected in the HBV S gene in OBI cases. Also, P127T aa polymorphism was frequently detected. Mutation frequency in the HBV S gene in the major hydrophilic region (MHR) was higher in patients with OBI with sub-genotypes HBV/D3 and D2 than those with HBV/D1 and those with serotype HBV/ayw3 compared to those with HBV/ayw2 (p < 0.05). CONCLUSIONS Sub-genotypic-specific mutation patterns were seen in the "a" determinant region and T helper cell epitopes of HBsAg, especially in the C-terminus domain; this may be associated with OBI.
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Affiliation(s)
- Bulent Cakal
- Department of Medical Microbiology, Istanbul Faculty of Medicine, Istanbul University, Fatih, Istanbul 34093, Turkey.
| | - Bilger Cavus
- Department of Internal Medicine, Istanbul Faculty of Medicine, Division of Gastroenterohepatology, Istanbul University, Istanbul, Turkey
| | - Alp Atasoy
- Department of Internal Medicine, Istanbul Faculty of Medicine, Division of Gastroenterohepatology, Istanbul University, Istanbul, Turkey
| | - Damla Altunok
- Department of Internal Medicine, Istanbul Faculty of Medicine, Division of Gastroenterohepatology, Istanbul University, Istanbul, Turkey
| | - Mehves Poda
- Department of Genetics, Aziz Sancar Institute for Experimental Medical Research, Istanbul University, Istanbul, Turkey
| | - Mesut Bulakci
- Department of Radiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mine Gulluoglu
- Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Mehmet Demirci
- Department of Medical Microbiology, Faculty of Medicine, Kirklareli University, Kirklareli, Turkey
| | - Leyla Turker Sener
- Department of Biophysics Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | | | - Muzaffer Arikan
- Regenerative and Restorative Medicine Research Center (REMER), Research Institute for Health Sciences and Technologies (SABITA), Istanbul Medipol University, Istanbul, Turkey
| | - Filiz Akyuz
- Department of Internal Medicine, Istanbul Faculty of Medicine, Division of Gastroenterohepatology, Istanbul University, Istanbul, Turkey
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Molecular and Serological Characterization of Hepatitis B Virus (HBV)-Positive Samples with Very Low or Undetectable Levels of HBV Surface Antigen. Viruses 2021; 13:v13102053. [PMID: 34696483 PMCID: PMC8537069 DOI: 10.3390/v13102053] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Gaps remain in the detection of nucleic acid test (NAT) yield and occult hepatitis B virus (HBV) infection (OBI) by current HBV surface antigen (HBsAg) assays. The lack of detection may be due to HBsAg levels below current assay detection limits, mutations affecting HBsAg assays or HBsAg levels, or the masking of HBsAg by antibody to HBsAg (anti-HBs). In this study, we evaluate the incremental detection of NAT yield and OBI from five diverse geographic areas by an improved sensitivity HBsAg assay and characterize the samples relative to the viral load, anti-HBs status, and PreS1-S2-S mutations. Included is a comparison population with HBV DNA levels comparable to OBI, but with readily detectable HBsAg (High Surface-Low DNA, HSLD). METHODS A total of 347 samples collected from the USA, South Africa, Spain, Cameroon, Vietnam, and Cote D'Ivoire representing NAT yield (HBsAg(-), antibody to HBV core antigen (anti-HBc)(-), HBV DNA(+), N = 131), OBI (HBsAg(-), anti-HBc(+), HBV DNA(+), N = 188), and HSLD (HBsAg(+), anti-HBc(+), HBV DNA(+), N = 28) were tested with ARCHITECT HBsAg NEXT (HBsAgNx) (sensitivity 0.005 IU/mL). The sequencing of the PreS1-S2-S genes from a subset of 177 samples was performed to determine the genotype and assess amino acid variability, particularly in anti-HBs(+) samples. RESULTS HBsAgNx detected 44/131 (33.6%) NAT yield and 42/188 (22.3%) OBI samples. Mean HBV DNA levels for NAT yield and OBI samples were lower in HBsAgNx(-) (50.3 and 25.9 IU/mL) than in HBsAgNx(+) samples (384.1 and 139.5 IU/mL). Anti-HBs ≥ 10 mIU/mL was present in 28.6% HBsAgNx(+) and 45.2% HBsAgNx(-) OBI, and in 3.6% HSLD samples. The genotypes were A1, A2, B, C, D, E, F, and H. There was no significant difference between HBsAgNx(-) and HBsAgNx(+) in the proportion of samples harboring substitutions or in the mean number of substitutions per sample in PreS1, PreS2, or S for the NAT yield or OBI (p range: 0.1231 to >0.9999). A total of 21/27 (77.8%) of HBsAgNx(+) OBI carried S escape mutations, insertions, or stop codons. HSLD had more PreS1 and fewer S substitutions compared to both HBsAgNx(-) and HBsAgNx(+) OBI. Mutations/deletions associated with impaired HBsAg secretion were observed in the OBI group. CONCLUSIONS HBsAgNx provides the improved detection of NAT yield and OBI samples. Samples that remain undetected by HBsAgNx have exceptionally low HBsAg levels below the assay detection limit, likely due to low viremia or the suppression of HBsAg expression by host and viral factors.
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de Almeida Pondé RA. Detection of the serological markers hepatitis B virus surface antigen (HBsAg) and hepatitis B core IgM antibody (anti-HBcIgM) in the diagnosis of acute hepatitis B virus infection after recent exposure. Microbiol Immunol 2021; 66:1-9. [PMID: 34528725 DOI: 10.1111/1348-0421.12943] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/04/2021] [Accepted: 09/14/2021] [Indexed: 12/30/2022]
Abstract
The serological diagnosis of acute hepatitis B virus (HBV) infection after recent exposure has been established by the hepatitis B virus surface antigen (HBsAg) and anti-hepatitis B core IgM antibody (anti-HBcIgM) detection in serum, sometimes accompanied by the detection of hepatitis B "e" antigen (HBeAg). Despite this characteristic serological profile, misdiagnosis can occur in cases of unexpected or atypical behavior of the serological markers in the bloodstream, or if the true meaning of its expression is not properly investigated, or even if there is a possibility of interference from factors not necessarily linked to the infectious process, in the detection of these markers. This review discusses the influence of these variables on laboratory results for these two serological markers and, therefore, the potential risk of these variables compromising the correct diagnosis of acute infection after recent HBV exposure.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil.,Secretaria de Estado da Saúde-SES/Superintendência de Vigilância em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica-GVE/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil
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Enriquez-Navarro K, Maldonado-Rodriguez A, Rojas-Montes O, Torres-Ibarra R, Bucio-Ortiz L, De la Cruz MA, Torres-Flores J, Xoconostle-Cazares B, Lira R. Identification of mutations in the S gene of hepatitis B virus in HIV positive Mexican patients with occult hepatitis B virus infection. Ann Hepatol 2021; 19:507-515. [PMID: 32592870 DOI: 10.1016/j.aohep.2020.06.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 06/05/2020] [Accepted: 06/06/2020] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Occult hepatitis B virus infection (OBI) is characterized by the presence of replication-competent hepatitis B virus (HBV) DNA in the liver and/or serum of patients with undetectable levels of the HBV surface antigen (HBsAg). Due to the shared infection routes HIV positive patients are at higher risk of developing OBI, thus, the aim of this study was to determine the frequency of OBI in Mexican HIV-infected patients and to identify mutations in the HBV S gene that could be associated to the development of OBI. MATERIALS AND METHODS Plasma samples from 50 HIV-infected patients with undetectable levels of the HBsAg were obtained and analyzed. The Core, PreS and S genes were amplified by nested PCR and sequenced by the Sanger method. To analyze HBV diversity in the OBI-positive patients, ten sequences of 762bp from the HBV S gene were selected, cloned, and subsequently sequenced for mutational analyses. RESULTS OBI infection was found with a frequency of 36% (18/50). All the HBV sequences corresponded to the H genotype. The most common mutations were: C19Y, Q129H, E164D, and I195M, with a frequency of 44%, 36%, 39% and 48% respectively. CONCLUSIONS In this study, we report the presence of OBI in a cohort of Mexican HIV-infected patients with an overall prevalence of 36%. Mutational analyses revealed that four non-silent mutations were frequent in different regions of the HBsAg gene, suggesting that they might be associated to the development of OBI in this population, nevertheless, further studies are required to determine their role in the pathogenesis of OBI.
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Affiliation(s)
- Karina Enriquez-Navarro
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico; Posgrado en Biología Experimental, DCBS, Universidad Autónoma Metropolitana Iztapalapa, Mexico City, Mexico.
| | - Angelica Maldonado-Rodriguez
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.
| | - Othon Rojas-Montes
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.
| | - Rocio Torres-Ibarra
- Clinica de Hepatitis, Hospital de Infectologia Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico.
| | - Leticia Bucio-Ortiz
- Laboratorio de Fisiología Celular, Departamento de Ciencias de la Salud, Universidad Autónoma Metropolitana Iztapalapa, Mexico City, Mexico.
| | - Miguel A De la Cruz
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.
| | - Jesus Torres-Flores
- Laboratorio de Virología, Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico.
| | - Beatriz Xoconostle-Cazares
- Departamento de Biotecnología y Bioingeniería, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (IPN), Mexico City, Mexico.
| | - Rosalia Lira
- Unidad de Investigación Médica en Enfermedades Infecciosas y Parasitarias, UMAE Hospital de Pediatría, CMN Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City, Mexico.
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10
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Adesina OA, Akanbi OA, Opaleye OO, Japhet MO, Wang B, Oluyege AO, Klink P, Bock CT. Detection of Q129H Immune Escape Mutation in Apparently Healthy Hepatitis B Virus Carriers in Southwestern Nigeria. Viruses 2021; 13:1273. [PMID: 34210073 PMCID: PMC8310067 DOI: 10.3390/v13071273] [Citation(s) in RCA: 2] [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: 05/26/2021] [Revised: 06/27/2021] [Accepted: 06/27/2021] [Indexed: 12/12/2022] Open
Abstract
As the global effort to eradicate hepatitis B continues, immune escape mutations (IEMs) and drug resistance mutations (DRMs) affecting its diagnosis, treatment, and prevention are compromising this goal. However, knowledge about the prevalence and circulation of these mutations in Nigeria is scarce. Serum samples (n = 199) from apparently healthy prospective blood donors, pregnant women, and individuals presenting with fever in southwestern Nigeria were analyzed for the presence of IEMs and DRMs by means of nested PCR in the HBV S (HBs) and HBV polymerase (Pol) genes, followed by phylogenetic and mutational analyses. In total, 25.1% (n = 50/199) of samples were positive for HBV, as measured by PCR. In 41 samples (20.6%), both fragments could be amplified, whereas the HBs gene and the Pol gene fragment alone were detected in 0.5% (n = 1/199) and 4% (n = 8/199) of samples, respectively. Sequences were successfully obtained for all 42 HBs gene fragments but for only 31/49 Pol gene fragments (totaling 73 sequences from 44 individuals). All sequences were identified as HBV genotype E. IEMs were present in 18.2% (n = 8/44) of the sequences of HBV-positive individuals with available sequences. IEM Q129H was detected in eight out of the 44 (18.2%) HBV isolates sequenced in this study; however, no DRMs were observed. This study confirms the circulation of HBV IEMs and reports the presence of Q129H IEM for the first time in Nigeria. Intensified research on the dynamics of IEM is necessary in order to enhance the elimination of HBV.
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Affiliation(s)
- Olufisayo Adeyemi Adesina
- Department of Microbiology, Obafemi Awolowo University, Ile-Ife 220282, Nigeria; (O.A.A.); (M.O.J.)
- Department of Microbiology, Ekiti State University, Ado-Ekiti 360213, Nigeria;
| | - Olusola Anuoluwapo Akanbi
- Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, 13353 Berlin, Germany; (O.A.A.); (B.W.); (P.K.)
| | - Oluyinka Oladele Opaleye
- Department of Medical Microbiology and Parasitology, Ladoke Akintola University of Technology, Ogbomoso 230232, Nigeria;
| | | | - Bo Wang
- Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, 13353 Berlin, Germany; (O.A.A.); (B.W.); (P.K.)
| | | | - Patrycja Klink
- Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, 13353 Berlin, Germany; (O.A.A.); (B.W.); (P.K.)
| | - C.-Thomas Bock
- Division of Viral Gastroenteritis and Hepatitis Pathogens and Enteroviruses, Department of Infectious Diseases, Robert Koch Institute, 13353 Berlin, Germany; (O.A.A.); (B.W.); (P.K.)
- Institute of Tropical Medicine, University of Tuebingen, 72076 Tuebingen, Germany
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11
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The evolution and clinical impact of hepatitis B virus genome diversity. Nat Rev Gastroenterol Hepatol 2020; 17:618-634. [PMID: 32467580 DOI: 10.1038/s41575-020-0296-6] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/20/2020] [Indexed: 02/06/2023]
Abstract
The global burden of hepatitis B virus (HBV) is enormous, with 257 million persons chronically infected, resulting in more than 880,000 deaths per year worldwide. HBV exists as nine different genotypes, which differ in disease progression, natural history and response to therapy. HBV is an ancient virus, with the latest reports greatly expanding the host range of the Hepadnaviridae (to include fish and reptiles) and casting new light on the origins and evolution of this viral family. Although there is an effective preventive vaccine, there is no cure for chronic hepatitis B, largely owing to the persistence of a viral minichromosome that is not targeted by current therapies. HBV persistence is also facilitated through aberrant host immune responses, possibly due to the diverse intra-host viral populations that can respond to host-mounted and therapeutic selection pressures. This Review summarizes current knowledge on the influence of HBV diversity on disease progression and treatment response and the potential effect on new HBV therapies in the pipeline. The mechanisms by which HBV diversity can occur both within the individual host and at a population level are also discussed.
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12
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No evidence of occult HBV infection in population born after mass vaccination. Wien Med Wochenschr 2020; 170:218-223. [PMID: 32274600 DOI: 10.1007/s10354-020-00748-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 03/16/2020] [Indexed: 12/13/2022]
Abstract
Despite access to efficient hepatitis B virus (HBV) vaccine and universal immunization schedules, HBV infection remains a global health concern. HBV infection has decreased by this program. Nevertheless, breakthrough infections occur due to generation of occult HBV infection (OBI) and surface gene mutants in the immunized population. We aimed to determine the presence of OBI in a population born after initiation of nationwide HBV vaccination in Tehran, Iran. A HBV mass vaccination schedule was launched in Iran in 1993. For this study, we enrolled 1120 cases younger than 24 years. ELISA was applied to evaluate the presence of HBsAg, anti-HBs and anti-HBc. HBV-DNA presence was determined in all HBsAg-negative cases using nested polymerase chain reaction. The prevalence of HBsAg, anti-HBc and anti-HBs was 0.1, 0.54 and 39.9% respectively. Out of 6 anti-HBc-positive individuals, 4 cases also had anti-HBs. One case revealed HBsAg co-existence and the other one showed isolated anti-HBc. HBV-DNA was not detected in HBsAg-negative specimens. A very low prevalence of HBsAg and isolated anti-HBc was observed and no occult HBV infection was detected. It seems that evasion mutants are not a potential threat for HBV universal immunization efficacy in the vaccinated population.
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13
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Raimondo G, Locarnini S, Pollicino T, Levrero M, Zoulim F, Lok AS. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J Hepatol 2019; 71:397-408. [PMID: 31004683 DOI: 10.1016/j.jhep.2019.03.034] [Citation(s) in RCA: 336] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 03/20/2019] [Accepted: 03/28/2019] [Indexed: 02/06/2023]
Abstract
In October 2018 a large number of international experts with complementary expertise came together in Taormina to participate in a workshop on occult hepatitis B virus infection (OBI). The objectives of the workshop were to review the existing knowledge on OBI, to identify issues that require further investigation, to highlight both existing controversies and newly emerging perspectives, and ultimately to update the statements previously agreed in 2008. This paper represents the output from the workshop.
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Affiliation(s)
- Giovanni Raimondo
- Division of Clinical and Molecular Hepatology, University of Messina, Messina, Italy; Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratory at the Doherty Institute, Melbourne, Victoria, Australia
| | - Teresa Pollicino
- Division of Clinical and Molecular Hepatology, University of Messina, Messina, Italy; Department of Human Pathology, University of Messina, Messina, Italy
| | - Massimo Levrero
- Cancer Research Center of Lyon, INSERM U1052, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Fabien Zoulim
- Cancer Research Center of Lyon, INSERM U1052, Hospices Civils de Lyon, Lyon University, Lyon, France
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA
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14
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El-Maksoud MA, Habeeb MR, Ghazy HF, Nomir MM, Elalfy H, Abed S, Zaki MES. Clinicopathological study of occult hepatitis B virus infection in hepatitis C virus-associated hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2019; 31:716-722. [PMID: 30870221 DOI: 10.1097/meg.0000000000001388] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Occult hepatitis B virus infection (OBI) frequently occurs in patients with chronic hepatitis C (CHC) infection, but the influence of OBI on CHC outcome is still uncertain. The aim of the present study was to clarify the clinical and pathological characteristics of OBI in CHC-related hepatocellular carcinoma (HCC). PATIENTS AND METHODS DNA was obtained from serum and tumor tissue of patients with hepatitis C virus (HCV)-related HCC with negative HBsAg and from patients with HCV-related liver cirrhosis. HBV-DNA was detected using qPCR. Clinicopathological features were compared between patients with HCC with and without OBI. RESULTS On the basis of positive serum and tissue HBV-DNA typing, the overall frequency of OBI was 50% in patients with HCV-related HCC. HBV genotype D was the most dominant, constituting 35.3% of HCC cases. Almost 80% of patients with OBI had anti-HBc, whereas 20% of patients had no serological markers. Tissue HBV-DNA showed significant association with positive serum HBV-DNA, anti-HBc, and genotype D. There were no clinical differences between patients with HCC with and without OBI; however, patients with OBI tended to be younger. HCC cases with positive OBI were significantly associated with positive anti-HBc antibodies and late histological grades (3-4). Multivariate logistic regression analysis revealed that the presence of OBI was a predictor of more advanced HCC histological grades in patients with HCV infection. CONCLUSION OBI was detected in 50% of HCV-infected patients with HCC. OBI was strongly associated with the presence of anti-HBc antibodies. Patients with HCC with positive OBI were younger and had more advanced HCC histological grades.
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Affiliation(s)
| | | | | | - Manal M Nomir
- Clinical Pathology Student's Hospital, Mansoura University, Mansoura, Egypt
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15
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Candotti D, Assennato SM, Laperche S, Allain JP, Levicnik-Stezinar S. Multiple HBV transfusion transmissions from undetected occult infections: revising the minimal infectious dose. Gut 2019; 68:313-321. [PMID: 29959168 DOI: 10.1136/gutjnl-2018-316490] [Citation(s) in RCA: 80] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Revised: 05/25/2018] [Accepted: 05/28/2018] [Indexed: 12/18/2022]
Abstract
OBJECTIVE HBV infection by blood components is currently prevented in most developed countries by combining sensitive HBV surface antigen (HBsAg) assays, nucleic acid testing (NAT) and in a few of them antibodies against the HBV core antigen (anti-HBc) screening. HBV transmissions by blood components from three repeat donors tested negative for HBsAg and HBV DNA with a highly sensitive screening test (limit of detection (LOD): 3.4 IU/mL) were investigated. DESIGN 30 of the 47 recipients of components produced from these three donors were examined. Transfusion transmission was confirmed by phylogenetic analysis of viral sequences obtained from recipients and donors following viral particle concentration. RESULTS 9 of 31 (29%) recipients were infected: 7 infections were related to 200 mL of fresh frozen plasma and 2 infections to red blood cells containing 20 mL plasma. Transfusion transmission was confirmed by >99% identity of donor/recipient sequences in five cases, probable in three and possible in one. HBV active infection remained unsuspected for 24-57 months in three recipients. Five non-infected recipients carried anti-HBs when transfused. Six patients transfused with platelet concentrates treated with a pathogen reduction method were not infected. These data enabled to revise previous estimate of the minimal infectious dose from approximately 100 to 16 copies (or 3 IU) of HBV DNA. CONCLUSIONS HBV transfusion transmission from occult HBV infection carrying extremely low viral loads is related to plasma volume transfused and possibly prevented by anti-HBs. HBV blood safety could be further improved by either anti-HBc screening, HBV DNA NAT with a LOD of 0.8 copies/mL (0.15 IU/mL) or pathogen reduction of blood components.
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Affiliation(s)
- Daniel Candotti
- Department of Blood Transmitted Agents, National Institute of Blood Transfusion, Paris, France
| | | | - Syria Laperche
- Department of Blood Transmitted Agents, National Institute of Blood Transfusion, Paris, France
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16
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Viral Biomarkers in Chronic HBeAg Negative HBV Infection. Genes (Basel) 2018; 9:genes9100469. [PMID: 30262738 PMCID: PMC6210948 DOI: 10.3390/genes9100469] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/20/2018] [Accepted: 09/21/2018] [Indexed: 02/07/2023] Open
Abstract
Viral biomarkers are important tools for monitoring chronic hepatitis B virus (HBV) hepatitis B early antigen (HBeAg) negative infection, both in its natural course as well as during and after treatment. The biomarkers consist of antibodies against viral epitopes, viral proteins, and molecular surrogate markers of the quantity and transcriptional activity of the stable episomal HBV covalently closed circular DNA (cccDNA) which is located in the nuclei of the infected hepatocytes. HBV deoxyribonucleic acid (DNA) or else viral load measurement in plasma or serum is a marker of HBV replication of major clinical importance. HBV DNA is used for staging and treatment monitoring as described in international scientific guidelines. Quantification of HBV antigens, mainly hepatitis B surface antigen (HBsAg) as well as Hepatitis B core related antigen (HBcrAg), play an important yet secondary role, especially in cases of low or undetectable HBV DNA and has been evaluated for the classification of the inactive carrier state, as a predictor of subsequent HBsAg clearance, treatment outcome, and development of hepatocellular carcinoma (HCC). The measurement of the replicative intermediate HBV RNA in serum is currently evaluated and may also prove to be a significant biomarker particularly in patients treated with nucleot(s)ide analogs. This review focuses on the viral biomarkers mentioned above and their role in HBV, HBeAg negative, infection.
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17
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Colagrossi L, Hermans LE, Salpini R, Di Carlo D, Pas SD, Alvarez M, Ben-Ari Z, Boland G, Bruzzone B, Coppola N, Seguin-Devaux C, Dyda T, Garcia F, Kaiser R, Köse S, Krarup H, Lazarevic I, Lunar MM, Maylin S, Micheli V, Mor O, Paraschiv S, Paraskevis D, Poljak M, Puchhammer-Stöckl E, Simon F, Stanojevic M, Stene-Johansen K, Tihic N, Trimoulet P, Verheyen J, Vince A, Lepej SZ, Weis N, Yalcinkaya T, Boucher CAB, Wensing AMJ, Perno CF, Svicher V. Immune-escape mutations and stop-codons in HBsAg develop in a large proportion of patients with chronic HBV infection exposed to anti-HBV drugs in Europe. BMC Infect Dis 2018; 18:251. [PMID: 29859062 PMCID: PMC5984771 DOI: 10.1186/s12879-018-3161-2] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 05/23/2018] [Indexed: 12/27/2022] Open
Abstract
Background HBsAg immune-escape mutations can favor HBV-transmission also in vaccinated individuals, promote immunosuppression-driven HBV-reactivation, and increase fitness of drug-resistant strains. Stop-codons can enhance HBV oncogenic-properties. Furthermore, as a consequence of the overlapping structure of HBV genome, some immune-escape mutations or stop-codons in HBsAg can derive from drug-resistance mutations in RT. This study is aimed at gaining insight in prevalence and characteristics of immune-associated escape mutations, and stop-codons in HBsAg in chronically HBV-infected patients experiencing nucleos(t)ide analogues (NA) in Europe. Methods This study analyzed 828 chronically HBV-infected European patients exposed to ≥ 1 NA, with detectable HBV-DNA and with an available HBsAg-sequence. The immune-associated escape mutations and the NA-induced immune-escape mutations sI195M, sI196S, and sE164D (resulting from drug-resistance mutation rtM204 V, rtM204I, and rtV173L) were retrieved from literature and examined. Mutations were defined as an aminoacid substitution with respect to a genotype A or D reference sequence. Results At least one immune-associated escape mutation was detected in 22.1% of patients with rising temporal-trend. By multivariable-analysis, genotype-D correlated with higher selection of ≥ 1 immune-associated escape mutation (OR[95%CI]:2.20[1.32–3.67], P = 0.002). In genotype-D, the presence of ≥ 1 immune-associated escape mutations was significantly higher in drug-exposed patients with drug-resistant strains than with wild-type virus (29.5% vs 20.3% P = 0.012). Result confirmed by analysing drug-naïve patients (29.5% vs 21.2%, P = 0.032). Strong correlation was observed between sP120T and rtM204I/V (P < 0.001), and their co-presence determined an increased HBV-DNA. At least one NA-induced immune-escape mutation occurred in 28.6% of patients, and their selection correlated with genotype-A (OR[95%CI]:2.03[1.32–3.10],P = 0.001). Finally, stop-codons are present in 8.4% of patients also at HBsAg-positions 172 and 182, described to enhance viral oncogenic-properties. Conclusions Immune-escape mutations and stop-codons develop in a large fraction of NA-exposed patients from Europe. This may represent a potential threat for horizontal and vertical HBV transmission also to vaccinated persons, and fuel drug-resistance emergence. Electronic supplementary material The online version of this article (10.1186/s12879-018-3161-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Luna Colagrossi
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy
| | - Lucas E Hermans
- Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands.,Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Romina Salpini
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy
| | - Domenico Di Carlo
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy
| | - Suzan D Pas
- Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Marta Alvarez
- Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Granada, Spain
| | - Ziv Ben-Ari
- Liver Disease Centre, Sheba Medical Centre, Ramat Gan, Israel
| | - Greet Boland
- Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | | | - Nicola Coppola
- Malattie Infettive, Seconda Università degli studi di Napoli, Naples, Italy
| | | | - Tomasz Dyda
- Molecular Diagnostics Laboratory, Hospital of Infectious Diseases, Warsaw, Poland
| | - Federico Garcia
- Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Granada, Spain
| | - Rolf Kaiser
- Institute of Virology, University of Cologne, Cologne, Germany
| | - Sukran Köse
- Izmir Tepecik Education and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Izmir, Turkey
| | - Henrik Krarup
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Ivana Lazarevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Maja M Lunar
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Sarah Maylin
- Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France
| | | | - Orna Mor
- National HIV Reference Laboratory, Central Virology Laboratory, Ministry of Health, Tel Hashomer, Ramat Gan, Israel
| | - Simona Paraschiv
- Molecular Diagnostics Laboratory, National Institute for Infectious Diseases "Matei Bals", Bucharest, Romania
| | - Dimitros Paraskevis
- National Retrovirus Reference Centre, Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Mario Poljak
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | | | - François Simon
- Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France
| | - Maja Stanojevic
- Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | | | - Nijaz Tihic
- Institute of Microbiology, Polyclinic for Laboratory Diagnostics, University Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina
| | - Pascale Trimoulet
- Virology Laboratory, Centre Hospitalier Régional et Université "Victor Segalen", Bordeaux, France
| | - Jens Verheyen
- Institute of Virology, University-Hospital, University Duisburg-Essen, Essen, Germany
| | - Adriana Vince
- University of Zagreb School of Medicine and University Hospital for Infectious Diseases, Zagreb, Croatia
| | - Snjezana Zidovec Lepej
- University of Zagreb School of Medicine and University Hospital for Infectious Diseases, Zagreb, Croatia
| | - Nina Weis
- Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
| | | | - Charles A B Boucher
- Department of Viroscience, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - Annemarie M J Wensing
- Virology, Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands
| | - Carlo F Perno
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy.
| | - Valentina Svicher
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 1, 00133, Rome, Italy.
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Mardian Y, Yano Y, Wasityastuti W, Ratnasari N, Liang Y, Putri WA, Triyono T, Hayashi Y. Genetic polymorphisms of HLA-DP and isolated anti-HBc are important subsets of occult hepatitis B infection in Indonesian blood donors: a case-control study. Virol J 2017; 14:201. [PMID: 29061159 PMCID: PMC5654084 DOI: 10.1186/s12985-017-0865-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 10/11/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Occult hepatitis B infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in the serum and/or liver in HBsAg-negative individuals. OBI is associated with the risk of viral transmission, especially in developing countries, and with progressive liver disease and reactivation in immunosuppressive patients. The objective of this study was to evaluate the relation of OBI to HLA-DP single nucleotide polymorphisms (SNPs) encoding antigen-binding sites for the immune response to HBV infection. As HLA-DP variants affect the mRNA expression of HLA-DPA1 and HLA-DPB1 in the liver, we hypothesised that high levels of HLA-DPA1 and HLA-DPB1 expression favour OBI development. METHODS The study enrolled 456 Indonesian healthy blood donors (HBsAg negative). OBI was defined as the presence of HBV-DNA in at least two of four open reading frames (ORFs) of the HBV genome detected by nested PCR. SNPs in HLA-DPA1 (rs3077) and HLA-DPB1 (rs3135021, rs9277535, and rs2281388) were genotyped using real-time Taqman® genotyping assays. RESULTS Of 122 samples positive for anti-HBs and/or anti-HBc, 17 were determined as OBI. The minor allele in rs3077 was significantly correlated with OBI [odds ratio (OR) = 3.87, 95% confidence interval (CI) = 1.58-9.49, p = 0.0015]. The prevalence of the minor allele (T) was significantly higher in subjects with OBI than in those without (59% and 33%, respectively). The combination of haplotype markers (TGA for rs3077-rs3135021-rs9277535) was associated with increased risk of OBI (OR = 4.90, 95%CI = 1.12-21.52 p = 0.038). The prevalence of OBI was highest in the isolated anti-HBc group among the three seropositive categories: anti-HBs <500 mIU/ml, anti-HBs ≥500 mIU/ml, and isolated anti-HBc (29.41%, p = 0.014). CONCLUSION Genetic variants of HLA-DP and the presence of anti-HBc are important predictors of OBI in Indonesian blood donors. TRIAL REGISTRATION Ref: KE/FK/194/EC; registered 01 March 2013. Continuing approval Ref: KE/FK/536/EC; registered 12 May 2014.
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Affiliation(s)
- Yan Mardian
- Division of Infectious Disease Pathology, Department of Microbiology and Infectious Disease, Kobe University Graduate School of Medicine, 7-5-1 Chuo-ku, Kobe, 650-0017 Japan
- Division of Gastroenterohepatology, Department of Internal Medicine, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University/ Dr. Sardjito Hospital, Kesehatan Street No. 1, Sekip, Yogyakarta, 55281 Indonesia
| | - Yoshihiko Yano
- Division of Infectious Disease Pathology, Department of Microbiology and Infectious Disease, Kobe University Graduate School of Medicine, 7-5-1 Chuo-ku, Kobe, 650-0017 Japan
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Chuo-ku, Kobe, 650-0017 Japan
| | - Widya Wasityastuti
- Department of Physiology, Faculty of Medicine, Gadjah Mada University, Kesehatan Street No. 1, Sekip, Yogyakarta, 55281 Indonesia
| | - Neneng Ratnasari
- Division of Gastroenterohepatology, Department of Internal Medicine, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University/ Dr. Sardjito Hospital, Kesehatan Street No. 1, Sekip, Yogyakarta, 55281 Indonesia
| | - Yujiao Liang
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Chuo-ku, Kobe, 650-0017 Japan
| | - Wahyu Aristyaning Putri
- Division of Infectious Disease Pathology, Department of Microbiology and Infectious Disease, Kobe University Graduate School of Medicine, 7-5-1 Chuo-ku, Kobe, 650-0017 Japan
| | - Teguh Triyono
- Department of Clinical Pathology, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University/ Dr. Sardjito Hospital, Kesehatan Street No. 1, Sekip, Yogyakarta, 55281 Indonesia
| | - Yoshitake Hayashi
- Division of Infectious Disease Pathology, Department of Microbiology and Infectious Disease, Kobe University Graduate School of Medicine, 7-5-1 Chuo-ku, Kobe, 650-0017 Japan
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Chuo-ku, Kobe, 650-0017 Japan
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Mondal RK, Khatun M, Banerjee P, Ghosh A, Sarkar S, Santra A, Das K, Chowdhury A, Banerjee S, Datta S. Synergistic impact of mutations in Hepatitis B Virus genome contribute to its occult phenotype in chronic Hepatitis C Virus carriers. Sci Rep 2017; 7:9653. [PMID: 28852072 PMCID: PMC5574988 DOI: 10.1038/s41598-017-09965-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 08/02/2017] [Indexed: 12/16/2022] Open
Abstract
We characterized occult HBV (OHBV) from hepatitis B surface antigen (HBsAg)-negative chronic HCV carriers of Eastern India to explore the impact of genomic variability of HBV in causing undetectability of HBsAg and low viremia that define the occult phenomenon. Screening of sera samples revealed the presence of OHBV in 17.8% of HCV-infected patients. Determination of full-length OHBV sequences and comparison with that from HBsAg-positive carriers led to the detection of distinct substitutions/mutations in PreS2, S, P and X ORFs and in X-promoter and Enhancer-II of OHBV. These mutations were introduced in wild-type HBV and their effects were evaluated by transfection in Huh7 cells. In vitro assays demonstrated that S-substitutions resulted in antigenically modified HBsAg that escaped detection by immunoassays whereas those in ORF-P caused significant decline in viral replication. Impairment in Enhancer-II and X-promoter activities were noted due to occult-associated mutations that generated reduced pregenomic RNA and intracellular HBV-DNA. Additionally, Enhancer-II mutations altered the small to large surface protein ratio and diminished extracellular HBV-DNA and HBsAg secretion. Further, mutations in PreS2, X and enhancer-II increased Grp78-promoter activity, suggesting that OHBV could trigger endoplasmic reticulum stress. Thus viral mutations contribute synergistically towards the genesis of occult phenotype and disease progression.
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Affiliation(s)
- Rajiv Kumar Mondal
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Mousumi Khatun
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Priyanka Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Alip Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Sumanta Sarkar
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Amal Santra
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Kausik Das
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Simanti Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India.
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20
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Rendon JC, Cortes-Mancera F, Restrepo-Gutierrez JC, Hoyos S, Navas MC. Molecular characterization of occult hepatitis B virus infection in patients with end-stage liver disease in Colombia. PLoS One 2017; 12:e0180447. [PMID: 28686707 PMCID: PMC5501523 DOI: 10.1371/journal.pone.0180447] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 06/15/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) occult infection (OBI) is a risk factor to be taken into account in transfusion, hemodialysis and organ transplantation. The aim of this study was to identify and characterize at the molecular level OBI cases in patients with end-stage liver disease. METHODS Sixty-six liver samples were obtained from patients with diagnosis of end-stage liver disease submitted to liver transplantation in Medellin (North West, Colombia). Samples obtained from patients who were negative for the surface antigen of HBV (n = 50) were tested for viral DNA detection by nested PCR for ORFs S, C, and X and confirmed by Southern-Blot. OBI cases were analyzed by sequencing the viral genome to determine the genotype and mutations; additionally, viral genome integration events were examined by the Alu-PCR technique. RESULTS In five cases out of 50 patients (10%) the criteria for OBI was confirmed. HBV genotype F (subgenotypes F1 and F3), genotype A and genotype D were characterized in liver samples. Three integration events in chromosomes 5q14.1, 16p13 and 20q12 affecting Receptor-type tyrosine-protein phosphatase T, Ras Protein Specific Guanine Nucleotide Releasing Factor 2, and the zinc finger 263 genes were identified in two OBI cases. Sequence analysis of the viral genome of the 5 OBI cases showed several punctual missense and nonsense mutations affecting ORFs S, P, Core and X. CONCLUSIONS This is the first characterization of OBI in patients with end-stage liver disease in Colombia. The OBI cases were identified in patients with HCV infection or cryptogenic cirrhosis. The integration events (5q14.1, 16p13 and 20q12) described in this study have not been previously reported. Further studies are required to validate the role of mutations and integration events in OBI pathogenesis.
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Affiliation(s)
- Julio Cesar Rendon
- Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellin, Colombia
| | - Fabian Cortes-Mancera
- Grupo de Investigación e Innovacion Biomédica GIB, Facultad de Ciencias Exactas y Aplicadas, Instituto Tecnologico Metropolitano (ITM), Medellin, Colombia
| | - Juan Carlos Restrepo-Gutierrez
- Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellin, Colombia
- Unidad de Hepatologia y Trasplante Hepatico, Hospital Pablo Tobon Uribe, Medellin, Colombia
| | - Sergio Hoyos
- Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellin, Colombia
- Unidad de Hepatologia y Trasplante Hepatico, Hospital Pablo Tobon Uribe, Medellin, Colombia
| | - Maria-Cristina Navas
- Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia, UdeA, Medellin, Colombia
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21
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Hensel KO, Rendon JC, Navas MC, Rots MG, Postberg J. Virus-host interplay in hepatitis B virus infection and epigenetic treatment strategies. FEBS J 2017; 284:3550-3572. [PMID: 28457020 DOI: 10.1111/febs.14094] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Revised: 03/25/2017] [Accepted: 04/26/2017] [Indexed: 12/11/2022]
Abstract
Worldwide, chronic hepatitis B virus (HBV) infection is a major health problem and no cure exists. Importantly, hepatocyte intrusion by HBV particles results in a complex deregulation of both viral and host cellular genetic and epigenetic processes. Among the attempts to develop novel therapeutic approaches against HBV infection, several options targeting the epigenomic regulation of HBV replication are gaining attention. These include the experimental treatment with 'epidrugs'. Moreover, as a targeted approach, the principle of 'epigenetic editing' recently is being exploited to control viral replication. Silencing of HBV by specific rewriting of epigenetic marks might diminish viral replication, viremia, and infectivity, eventually controlling the disease and its complications. Additionally, epigenetic editing can be used as an experimental tool to increase our limited understanding regarding the role of epigenetic modifications in viral infections. Aiming for permanent epigenetic reprogramming of the viral genome without unspecific side effects, this breakthrough may pave the roads for an ambitious technological pursuit: to start designing a curative approach utilizing manipulative molecular therapies for viral infections in vivo.
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Affiliation(s)
- Kai O Hensel
- HELIOS Medical Centre Wuppertal, Paediatrics Centre, Centre for Clinical & Translational Research (CCTR), Faculty of Health, Centre for Biomedical Education & Research (ZBAF), Witten/Herdecke University, Germany
| | - Julio C Rendon
- Epigenetic Editing, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), The Netherlands.,Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia (UdeA), Medellin, Colombia
| | - Maria-Cristina Navas
- Grupo de Gastrohepatologia, Facultad de Medicina, Universidad de Antioquia (UdeA), Medellin, Colombia
| | - Marianne G Rots
- Epigenetic Editing, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), The Netherlands
| | - Jan Postberg
- HELIOS Medical Centre Wuppertal, Paediatrics Centre, Centre for Clinical & Translational Research (CCTR), Faculty of Health, Centre for Biomedical Education & Research (ZBAF), Witten/Herdecke University, Germany
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22
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Elkady A, Iijima S, Aboulfotuh S, Mostafa Ali E, Sayed D, Abdel-Aziz NM, Ali AM, Murakami S, Isogawa M, Tanaka Y. Characteristics of escape mutations from occult hepatitis B virus infected patients with hematological malignancies in South Egypt. World J Hepatol 2017; 9:477-486. [PMID: 28396718 PMCID: PMC5368625 DOI: 10.4254/wjh.v9.i9.477] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 09/19/2016] [Accepted: 12/13/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the prevalence and virological characteristics of occult hepatitis B virus (HBV) infections in patients with hematological malignancies in South Egypt. METHODS Serum samples were collected from 165 patients with hematological malignancies to monitor titers of HBV DNA, hepatitis B surface antigen (HBsAg), and antibodies to HBV core (anti-HBc) and surface antigens. Serum samples negative for HBsAg and positive for anti-HBc were subjected to nucleic acid extraction and HBV DNA detection by real-time polymerase chain reaction. DNA sequences spanning the S region were analyzed in cases with occult HBV infection. In vitro comparative study of constructed 1.24-fold wild type and S protein mutant HBV genotype D clones was further performed. RESULTS HBV DNA was detected in 23 (42.6%) of 54 patients with hematological malignancies who were HBsAg negative, but anti-HBc positive, suggesting the presence of occult HBV infection. The complete HBV genome was retrieved from 6 occult HBV patients, and P120T and S143L were detected in 3 and 2 cases, respectively. Site directed mutagenesis was done to produce 1.24-fold genotype D clones with amino acid mutations T120 and L143. The in vitro analyses revealed that a lower level of extracellular HBsAg was detected by chemiluminescence enzyme immunoassay (CLEIA) with the clone containing T120 mutation, compared with the wild type or the clone with S143L mutation despite the similar levels of extracellular and intracellular HBsAg detected by Western blot. Southern blot experiments showed that the levels of intracellular HBV DNA were not different between these clones. CONCLUSION Occult HBV infection is common in patients with hematological malignancies and associated with P120T and S143L mutations. 120T mutation impairs the detection of HBsAg by CLEIA.
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Affiliation(s)
- Abeer Elkady
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
| | - Sayuki Iijima
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
| | - Sahar Aboulfotuh
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
| | - Elsayed Mostafa Ali
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
| | - Douaa Sayed
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
| | - Nashwa M Abdel-Aziz
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
| | - Amany M Ali
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
| | - Shuko Murakami
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
| | - Masanori Isogawa
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
| | - Yasuhito Tanaka
- Abeer Elkady, Department of Clinical and Chemical Pathology, Medical School of South Valley University, Qena 83523, Egypt
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23
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Prevalence, Risk Behaviors, and Virological Characteristics of Hepatitis B Virus Infection in a Group of Men Who Have Sex with Men in Brazil: Results from a Respondent-Driven Sampling Survey. PLoS One 2016; 11:e0160916. [PMID: 27508385 PMCID: PMC4980030 DOI: 10.1371/journal.pone.0160916] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 07/27/2016] [Indexed: 12/20/2022] Open
Abstract
Background Men who have sex with men (MSM) are at increased risk of exposure to hepatitis B virus (HBV) compared with the general population. This study aims to assess the epidemiological and virological characteristics of HBV infection in a sample of MSM in Brazil, where data are scarce. Methods A cross-sectional study was conducted among MSM in the City of Goiânia, Central Brazil, from March to November 2014, using Respondent-Driven Sampling (RDS). After signing the consent form, participants were interviewed and a blood sample collected. All samples were tested for HBV serological markers and HBV DNA. HBV nucleotide sequence analysis was also performed. Results A total of 522 MSM were recruited in the study. The prevalence of HBV infection (current or past [presence of anti-HBc marker]) was 15.4% (95% CI: 8.7–25.8) and the rate of HBsAg carriers was 0.6% (95% CI: 0.2–1.6). About 40% (95% CI: 32.3–48.8) of the participants had serological evidence of previous HBV vaccination (reactive for isolated anti-HBs). In addition, 44.3% (95% CI: 36.1–52.9) were seronegative for all HBV markers. Age over 25 years old, receptive anal intercourse, previous sex with women, and history of sexually transmitted infections (STIs) were factors associated with HBV infection. HBV DNA was detected only in HBsAg-positive individuals. HBV isolates were classified into genotype A (subgenotypes A1 and A2), and some mutations were identified throughout the genome. Therefore, occult HBV infection was not observed in the study population. Conclusions Public health strategies should be improved for the MSM population in order to prevent HBV and other STIs, as well as to provide appropriate management of patients with active infections.
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Oliveira MP, Lemes PS, Matos MAD, Del-Rios NHA, Santos Carneiro MA, Costa Silva ÁM, Lopes CLR, Teles SA, Aires RS, Lago BV, Araujo NM, Martins RMB. Overt and occult hepatitis B virus infection among treatment-naïve HIV-infected patients in Brazil. J Med Virol 2016; 88:1222-9. [DOI: 10.1002/jmv.24462] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2015] [Indexed: 12/18/2022]
Affiliation(s)
- Marina Pedroso Oliveira
- Institute of Tropical Pathology and Public Health; Federal University of Goiás (UFG); Goiás Brazil
| | - Pollyanne Sousa Lemes
- Institute of Tropical Pathology and Public Health; Federal University of Goiás (UFG); Goiás Brazil
| | - Márcia Alves Dias Matos
- Institute of Tropical Pathology and Public Health; Federal University of Goiás (UFG); Goiás Brazil
| | | | | | - Ágabo Macedo Costa Silva
- Institute of Tropical Pathology and Public Health; Federal University of Goiás (UFG); Goiás Brazil
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