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Sukowati CHC, Jayanti S, Turyadi T, Muljono DH, Tiribelli C. Hepatitis B virus genotypes in precision medicine of hepatitis B-related hepatocellular carcinoma: Where we are now. World J Gastrointest Oncol 2024; 16:1097-1103. [PMID: 38660644 PMCID: PMC11037070 DOI: 10.4251/wjgo.v16.i4.1097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 01/30/2024] [Accepted: 03/06/2024] [Indexed: 04/10/2024] Open
Abstract
Hepatitis B virus (HBV) infection is a major player in chronic hepatitis B that may lead to the development of hepatocellular carcinoma (HCC). HBV genetics are diverse where it is classified into at least 9 genotypes (A to I) and 1 putative genotype (J), each with specific geographical distribution and possible different clinical outcomes in the patient. This diversity may be associated with the precision medicine for HBV-related HCC and the success of therapeutical approaches against HCC, related to different pathogenicity of the virus and host response. This Editorial discusses recent updates on whether the classification of HBV genetic diversity is still valid in terms of viral oncogenicity to the HCC and its precision medicine, in addition to the recent advances in cellular and molecular biology technologies.
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Affiliation(s)
- Caecilia H C Sukowati
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
| | - Sri Jayanti
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
| | - Turyadi Turyadi
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
| | - David H Muljono
- Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
- Faculty of Medicine and Health, University of Sydney, Sydney 2050, Australia
| | - Claudio Tiribelli
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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Shoraka S, Hosseinian SM, Hasibi A, Ghaemi A, Mohebbi SR. The role of hepatitis B virus genome variations in HBV-related HCC: effects on host signaling pathways. Front Microbiol 2023; 14:1213145. [PMID: 37588887 PMCID: PMC10426804 DOI: 10.3389/fmicb.2023.1213145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 07/12/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a significant global health issue, with a high prevalence in many regions. There are variations in the etiology of HCC in different regions, but most cases are due to long-term infection with viral hepatitis. Hepatitis B virus (HBV) is responsible for more than 50% of virus-related HCC, which highlights the importance of HBV in pathogenesis of the disease. The development and progression of HBV-related HCC is a complex multistep process that can involve host, viral, and environmental factors. Several studies have suggested that some HBV genome mutations as well as HBV proteins can dysregulate cell signaling pathways involved in the development of HCC. Furthermore, it seems that the pathogenicity, progression of liver diseases, response to treatment and also viral replication are different among HBV mutants. Understanding the relationship between HBV genome variations and host signaling pathway alteration will improve our understanding of the molecular pathogenesis of HBV-related HCC. Furthermore, investigating commonly dysregulated pathways in HBV-related HCC is necessary to discover more specific therapeutic targets and develop more effective strategies for HCC treatment. The objective of this review is to address the role of HBV in the HCC progression and primarily focus on the impacts of HBV genome variations on HCC-related signaling pathways.
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Affiliation(s)
- Shahrzad Shoraka
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
| | - Seyed Mahdi Hosseinian
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ayda Hasibi
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Ghaemi
- Department of Virology, Pasteur Institute of Iran, Tehran, Iran
| | - Seyed Reza Mohebbi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Yang C, Chen H, Zhou B, Yin J, Cao G, Hou J, Jiang D. The effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of hepatocellular carcinoma. Mol Carcinog 2022; 61:933-940. [PMID: 35880842 DOI: 10.1002/mc.23449] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 06/13/2022] [Accepted: 07/02/2022] [Indexed: 11/11/2022]
Abstract
Signal transducer and activator of transcription 4 (STAT4) is closely related to liver diseases and affects the processes of inflammation and carcinogenesis by regulating immune responses. A single-nucleotide polymorphism rs7574865 (T > G) in STAT4 has been reported to be associated with the risk of hepatocellular carcinoma (HCC). In addition, hepatitis B virus (HBV) mutations are crucial risk factors for HBV-induced HCC. However, the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC remain unknown. Rs7574865 was genotyped in 846 healthy controls (HCs), 968 chronic hepatitis B (CHB) subjects, 316 liver cirrhosis (LC) subjects and 1021 HCC subjects using Sequenom MassArray. HBV mutations were detected via direct sequencing. Multivariate logistic regression analysis was used to evaluate the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC. We found that the rs7574865 TT genotype was significantly associated with HBeAg seroconversion (TT vs. GG, p = 0.012; TT vs. GT, p = 0.033). The rs7574865 GG genotype was significantly associated with increased risks of CHB (p = 0.048), LC (p = 0.005) and HCC (p < 0.001). The interaction term between rs7574865 and HBV C1913A significantly increased the risk of progression from CHB to HCC (p = 0.038), while the interaction term between rs7574865 and HBV T1674C significantly increased the risk of progression from LC to HCC (p = 0.023). STAT4 rs7574865 is significantly associated with the risks of CHB, LC and HCC. The interactions of rs7574865 with HBV C1913A and T1674C mutations significantly increase the risk of HCC, which have the potential to identify HBV-infected individuals who tend to progress from CHB or LC to HCC.
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Affiliation(s)
- Chou Yang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianhua Yin
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Deke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
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In Vivo Modelling of Hepatitis B Virus Subgenotype A1 Replication Using Adeno-Associated Viral Vectors. Viruses 2021; 13:v13112247. [PMID: 34835053 PMCID: PMC8618177 DOI: 10.3390/v13112247] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/30/2021] [Accepted: 11/04/2021] [Indexed: 12/23/2022] Open
Abstract
The paucity of animal models that simulate the replication of the hepatitis B virus (HBV) is an impediment to advancing new anti-viral treatments. The work reported here employed recombinant adeno-associated viruses (AAVs) to model HBV subgenotype A1 and subgenotype D3 replication in vitro and in vivo. Infection with subgenotype A1 is endemic to parts of sub-Saharan Africa, and it is associated with a high risk of hepatocellular carcinoma. Recombinant AAV serotype 2 (AAV2) and 8 (AAV8) vectors bearing greater-than-genome-length sequences of HBV DNA from subgenotype A1 and D3, were produced. Transduced liver-derived cultured cells produced HBV surface antigen and core antigen. Administration of AAV8 carrying HBV subgenotype A1 genome (AAV8-A1) to mice resulted in the sustained production of HBV replication markers over a six-month period, without elevated inflammatory cytokines, expression of interferon response genes or alanine transaminase activity. Markers of replication were generally higher in animals treated with subgenotype D3 genome-bearing AAVs than in those receiving the subgenotype A1-genome-bearing vectors. To validate the use of the AAV8-A1 murine model for anti-HBV drug development, the efficacy of anti-HBV artificial primary-microRNAs was assessed. Significant silencing of HBV markers was observed over a 6-month period after administering AAVs. These data indicate that AAVs conveniently and safely recapitulate the replication of different HBV subgenotypes, and the vectors may be used to assess antivirals’ potency.
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Panicker S, Kumar CPG, Selvaraj V, Prabu R, Chandrasekar C, Valan AS, Kumar JS, Raja K. Molecular epidemiology of HBV among HIV infected individuals in Chennai, south India. Virus Res 2021; 300:198439. [PMID: 33930486 DOI: 10.1016/j.virusres.2021.198439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 04/13/2021] [Accepted: 04/23/2021] [Indexed: 12/25/2022]
Abstract
Hepatitis B is a major co-infection among people with HIV (PWHIV) worldwide. There is a paucity of data on HBV genetic diversity in India, which would be useful for targeted preventive and management interventions. To characterize the distribution of HBV genotypes and sub-genotypes, samples of 180 HIV-HBV co-infected individuals from a study previously conducted to estimate the prevalence of HBV co-infection were analyzed. Nested PCR using type-specific primers was used to identify the various HBV genotypes. Partial HBV S sequences were generated for a subset of samples using Sanger sequencing. Mutation analysis was done using the online HBVseq program. PCR based genotyping documented D (69.4 %) and A (5.6 %) to be the major genotypes in the study population. Infection with multiple genotypes was observed in 25 % co-infected individuals. D2, D5, A2, and A1 were the sub-genotypes detected. Mutations 184K and 173L were identified. HBV genotypes/ sub-genotypes play a pivotal role in the clinical outcome of chronic hepatitis B (CHB). Therefore, monitoring of CHB cases is needed to track disease progression, including early detection of hepatocellular carcinoma.
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Affiliation(s)
- S Panicker
- ICMR-National Institute of Epidemiology, Chennai, 600077, India
| | - C P Girish Kumar
- ICMR-National Institute of Epidemiology, Chennai, 600077, India.
| | - V Selvaraj
- ICMR-National Institute of Epidemiology, Chennai, 600077, India
| | - R Prabu
- ICMR-National Institute of Epidemiology, Chennai, 600077, India
| | - C Chandrasekar
- Government Hospital of Thoracic Medicine, Chennai, 600047, India
| | - A S Valan
- Government Hospital of Thoracic Medicine, Chennai, 600047, India
| | - J Suria Kumar
- Government Hospital of Thoracic Medicine, Chennai, 600047, India
| | - K Raja
- Government Hospital of Thoracic Medicine, Chennai, 600047, India
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Colli A, Nadarevic T, Miletic D, Giljaca V, Fraquelli M, Štimac D, Casazza G. Abdominal ultrasound and alpha-foetoprotein for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease. Cochrane Database Syst Rev 2021; 4:CD013346. [PMID: 33855699 PMCID: PMC8078581 DOI: 10.1002/14651858.cd013346.pub2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs mostly in people with chronic liver disease and ranks sixth in terms of global instances of cancer, and fourth in terms of cancer deaths for men. Despite that abdominal ultrasound (US) is used as an initial test to exclude the presence of focal liver lesions and serum alpha-foetoprotein (AFP) measurement may raise suspicion of HCC occurrence, further testing to confirm diagnosis as well as staging of HCC is required. Current guidelines recommend surveillance programme using US, with or without AFP, to detect HCC in high-risk populations despite the lack of clear benefits on overall survival. Assessing the diagnostic accuracy of US and AFP may clarify whether the absence of benefit in surveillance programmes could be related to under-diagnosis. Therefore, assessment of the accuracy of these two tests for diagnosing HCC in people with chronic liver disease, not included in surveillance programmes, is needed. OBJECTIVES Primary: the diagnostic accuracy of US and AFP, alone or in combination, for the diagnosis of HCC of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting. Secondary: to assess the diagnostic accuracy of abdominal US and AFP, alone or in combination, for the diagnosis of resectable HCC; to compare the diagnostic accuracy of the individual tests versus the combination of both tests; to investigate sources of heterogeneity in the results. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic-Test-Accuracy Studies Register, Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, until 5 June 2020. We applied no language or document-type restrictions. SELECTION CRITERIA Studies assessing the diagnostic accuracy of US and AFP, independently or in combination, for the diagnosis of HCC in adults with chronic liver disease, with cross-sectional and case-control designs, using one of the acceptable reference standards, such as pathology of the explanted liver, histology of resected or biopsied focal liver lesion, or typical characteristics on computed tomography, or magnetic resonance imaging, all with a six-months follow-up. DATA COLLECTION AND ANALYSIS We independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest-plots, and tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS We included 373 studies. The index-test was AFP (326 studies, 144,570 participants); US (39 studies, 18,792 participants); and a combination of AFP and US (eight studies, 5454 participants). We judged at high-risk of bias all but one study. Most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time-interval between the index test and the reference standard was rarely defined. Most studies with AFP had a case-control design. We also had major concerns for the applicability due to the characteristics of the participants. As the primary studies with AFP used different cut-offs, we performed a meta-analysis using the hierarchical-summary-receiver-operating-characteristic model, then we carried out two meta-analyses including only studies reporting the most used cut-offs: around 20 ng/mL or 200 ng/mL. AFP cut-off 20 ng/mL: for HCC (147 studies) sensitivity 60% (95% CI 58% to 62%), specificity 84% (95% CI 82% to 86%); for resectable HCC (six studies) sensitivity 65% (95% CI 62% to 68%), specificity 80% (95% CI 59% to 91%). AFP cut-off 200 ng/mL: for HCC (56 studies) sensitivity 36% (95% CI 31% to 41%), specificity 99% (95% CI 98% to 99%); for resectable HCC (two studies) one with sensitivity 4% (95% CI 0% to 19%), specificity 100% (95% CI 96% to 100%), and one with sensitivity 8% (95% CI 3% to 18%), specificity 100% (95% CI 97% to 100%). US: for HCC (39 studies) sensitivity 72% (95% CI 63% to 79%), specificity 94% (95% CI 91% to 96%); for resectable HCC (seven studies) sensitivity 53% (95% CI 38% to 67%), specificity 96% (95% CI 94% to 97%). Combination of AFP (cut-off of 20 ng/mL) and US: for HCC (six studies) sensitivity 96% (95% CI 88% to 98%), specificity 85% (95% CI 73% to 93%); for resectable HCC (two studies) one with sensitivity 89% (95% CI 73% to 97%), specificity of 83% (95% CI 76% to 88%), and one with sensitivity 79% (95% CI 54% to 94%), specificity 87% (95% CI 79% to 94%). The observed heterogeneity in the results remains mostly unexplained, and only in part referable to different cut-offs or settings (surveillance programme compared to clinical series). The sensitivity analyses, excluding studies published as abstracts, or with case-control design, showed no variation in the results. We compared the accuracy obtained from studies with AFP (cut-off around 20 ng/mL) and US: a direct comparison in 11 studies (6674 participants) showed a higher sensitivity of US (81%, 95% CI 66% to 90%) versus AFP (64%, 95% CI 56% to 71%) with similar specificity: US 92% (95% CI 83% to 97%) versus AFP 89% (95% CI 79% to 94%). A direct comparison of six studies (5044 participants) showed a higher sensitivity (96%, 95% CI 88% to 98%) of the combination of AFP and US versus US (76%, 95% CI 56% to 89%) with similar specificity: AFP and US 85% (95% CI 73% to 92%) versus US 93% (95% CI 80% to 98%). AUTHORS' CONCLUSIONS In the clinical pathway for the diagnosis of HCC in adults, AFP and US, singularly or in combination, have the role of triage-tests. We found that using AFP, with 20 ng/mL as a cut-off, about 40% of HCC occurrences would be missed, and with US alone, more than a quarter. The combination of the two tests showed the highest sensitivity and less than 5% of HCC occurrences would be missed with about 15% of false-positive results. The uncertainty resulting from the poor study quality and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Tin Nadarevic
- Department of Radiology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Damir Miletic
- Department of Radiology , Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Vanja Giljaca
- Department of Gastroenterology, Heart of England NHS Foundation Trust, Birmingham, UK
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca´ Granda - Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Davor Štimac
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Giovanni Casazza
- Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Milan, Italy
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rt269I Type of Hepatitis B Virus (HBV) Polymerase versus rt269L Is More Prone to Mutations within HBV Genome in Chronic Patients Infected with Genotype C2: Evidence from Analysis of Full HBV Genotype C2 Genome. Microorganisms 2021; 9:microorganisms9030601. [PMID: 33803998 PMCID: PMC7999911 DOI: 10.3390/microorganisms9030601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 12/03/2022] Open
Abstract
Recently, it has been reported that the rt269I type of hepatitis B virus (HBV) polymerase (Pol) versus the rt269L type is more significantly related to lower viral replication and HBeAg negative infections in chronic hepatitis B (CHB) patients of genotype C2. In this study, we compared mutation rates within HBV genomes between rt269L and rt269I using a total of 234 HBV genotype C2 full genome sequences randomly selected from the HBV database (115 of rt269L and 119 of rt269I type). When we applied the Benjamini and Hochberg procedure for multiple comparisons, two parameters, dN and d, at the amino acids level in the Pol region were significantly higher in the rt269I type than in the rt269L type. Although it could not reach statistical significance from the Benjamini and Hochberg procedure, nonsynonymous (NS) mutations in the major hydrophilic region (MHR) or “a” determinant in the surface antigens (HBsAg ORF) related to host immune escape or vaccine escape are more frequently generated in rt269I strains than in rt269L. We also found that there are a total of 19 signature single nucleotide polymorphisms (SNPs), of which 2 and 17 nonsynonymous mutation types were specific to rt269L and rt269I, respectively: Of these, most are HBeAg negative infections (preC-W28*, X-V5M and V131I), lowered HBV DNA or virion production (C-I97F/L, rtM204I/V) or preexisting nucleot(s)ide analog resistance (NAr) (rtN139K/H, rtM204I/V and rtI224V) or disease severity (preC-W28*, C-I97F/L, C-Q182K/*, preS2-F141L, S-L213I/S, V/L5M, T36P/S/A, V131I, rtN139K/H, rtM204I/V and rtI224V). In conclusion, our data showed that rt269I types versus rt269L types are more prone to overall genome mutations, particularly in the Pol region and in the MHR or “a” determinant in genotype C2 infections and are more prevalent in signature NS mutations related to lowered HBV DNA replication, HBsAg and HBeAg secretion and potential NAr variants and hepatocellular carcinoma (HCC), possibly via type I interferon (IFN-I)-mediated enhanced inflammation. Our data suggest that rt269L types could contribute to liver disease progression via the generation of immune escape or enhanced persistent infection in chronic patients of genotype C2.
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LCR based quick detection of hotspot G1896A mutation in patients with different spectrum of hepatitis B. J Infect Public Health 2021; 14:651-654. [PMID: 33857724 DOI: 10.1016/j.jiph.2021.01.013] [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: 11/26/2020] [Revised: 01/12/2021] [Accepted: 01/16/2021] [Indexed: 11/24/2022] Open
Abstract
G1896A switch is one of the hotspots in subjects affected with hepatitis B. This hotspot mutation is observed in all the different spectrum of hepatitis B, and it has a very dangerous and a long lasting effect. The major purpose of the study was to screen G1986A mutations at a large scale and also to establish ligase chain reaction as a mutation testing tool. Polymerase chain reaction (PCR) and Nucleotide Sequencing was done to identify the G1896A mutation in the precore region of the genome. All the 331 HBV positive patients were screened. Almost 29% (24/82) of the cases remarkably had the presence of G1896A mutation confirmed by LCR and direct sequencing. The precore G1896A mutation is responsible for one third of the patients suffering from precore stop codon mutation. It clearly exhibits that LCR is 100% in sync with direct sequencing and is extremely reliable and the results are highly reproducible.
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Kumar A, Acharya SK, Singh SP, Arora A, Dhiman RK, Aggarwal R, Anand AC, Bhangui P, Chawla YK, Datta Gupta S, Dixit VK, Duseja A, Kalra N, Kar P, Kulkarni SS, Kumar R, Kumar M, Madhavan R, Mohan Prasad V, Mukund A, Nagral A, Panda D, Paul SB, Rao PN, Rela M, Sahu MK, Saraswat VA, Shah SR, Shalimar, Sharma P, Taneja S, Wadhawan M. 2019 Update of Indian National Association for Study of the Liver Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri II Recommendations. J Clin Exp Hepatol 2020; 10:43-80. [PMID: 32025166 PMCID: PMC6995891 DOI: 10.1016/j.jceh.2019.09.007] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Accepted: 09/15/2019] [Indexed: 01/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality, and healthcare expenditure in patients with chronic liver disease in India. The Indian National Association for Study of the Liver (INASL) had published its first guidelines on diagnosis and management of HCC (The Puri Recommendations) in 2014, and these guidelines were very well received by the healthcare community involved in diagnosis and management of HCC in India and neighboring countries. However, since 2014, many new developments have taken place in the field of HCC diagnosis and management, hence INASL endeavored to update its 2014 consensus guidelines. A new Task Force on HCC was constituted that reviewed the previous guidelines as well as the recent developments in various aspects of HCC that needed to be incorporated in the new guidelines. A 2-day round table discussion was held on 5th and 6th May 2018 at Puri, Odisha, to discuss, debate, and finalize the revised consensus statements. Each statement of the guideline was graded according to the Grading of Recommendations Assessment Development and Evaluation system with minor modifications. We present here the 2019 Update of INASL Consensus on Prevention, Diagnosis, and Management of Hepatocellular Carcinoma in India: The Puri-2 Recommendations.
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Key Words
- AFP, alpha-fetoprotein
- AIH, autoimmune hepatitis
- ALT, alanine aminotransferase
- DAA, direct-acting antiviral
- DALY, disability-adjusted life-year
- DNA, deoxyribonucleic acid
- GRADE, Grading of Recommendations Assessment Development and Evaluation
- Gd-BOPTA, gadolinium benzyloxypropionictetraacetate
- Gd-EOB-DTPA, gadolinium ethoxybenzyl diethylenetriamine penta-acetic acid
- HBV, hepatitis B virus
- HBeAg, hepatitis B envelope antigen
- HCC, hepatocellular carcinoma
- HIV, human immunodeficiency virus
- IARC, International Agency for Research on Cancer
- IFN, interferon
- INASL, Indian National Association for Study of the Liver
- MiRNA, micro-RNA
- NAFLD, non-alcoholic fatty liver disease
- NASH, non-alcoholic steatohepatitis
- PIVKA, protein induced by vitamin K absence
- RFA
- RNA, ribonucleic acid
- SVR, sustained virological response
- TACE
- TACE, trans-arterial chemoembolization
- TARE, transarterial radioembolization
- TNF, tumor necrosis factor
- WHO, World Health Organization
- liver cancer
- targeted therapy
- transplant
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Affiliation(s)
- Ashish Kumar
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Subrat K. Acharya
- Department of Gastroenterology and Hepatology, KIIT University, Patia, Bhubaneswar, Odisha, 751 024, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Cuttack, Dock Road, Manglabag, Cuttack, Odisha, 753 007, India
| | - Anil Arora
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, 226 014, India
| | - Anil C. Anand
- Department of Gastroenterology, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, 110 076, India
| | - Prashant Bhangui
- Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, CH Baktawar Singh Road, Sector 38, Gurugram, Haryana, 122 001, India
| | - Yogesh K. Chawla
- Department of Gastroenterology, Kalinga Institute of Medical Sciences (KIMS), Kushabhadra Campus (KIIT Campus-5), Patia, Bhubaneswar, Odisha, 751 024, India
| | - Siddhartha Datta Gupta
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Vinod K. Dixit
- Department of Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, 221 005, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Naveen Kalra
- Department of Radio Diagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Premashish Kar
- Department of Gastroenterology and Hepatology, Max Super Speciality Hospital, Vaishali, Ghaziabad, Uttar Pradesh, 201 012, India
| | - Suyash S. Kulkarni
- Division of Interventional Radiology, Tata Memorial Hospital, Dr. E Borges Road, Parel, Mumbai, Maharashtra, 400 012, India
| | - Rakesh Kumar
- Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110 070, India
| | - Ram Madhavan
- Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita University, Peeliyadu Road, Ponekkara, Edappally, Kochi, Kerala, 682 041, India
| | - V.G. Mohan Prasad
- Department of Gastroenterology, VGM Gastro Centre, 2100, Trichy Road, Rajalakshmi Mills Stop, Singanallur, Coimbatore, Tamil Nadu, 641 005, India
| | - Amar Mukund
- Department of Radiology, Institute of Liver & Biliary Sciences, Sector D-1, Vasant Kunj, New Delhi, 110 070, India
| | - Aabha Nagral
- Department of Gastroenterology, Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
| | - Dipanjan Panda
- Department of Oncology, Institutes of Cancer, Indraprastha Apollo Hospital, Sarita Vihar, New Delhi, 110 076, India
| | - Shashi B. Paul
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Padaki N. Rao
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, No. 6-3-661, Punjagutta Road, Somajiguda, Hyderabad, Telangana, 500 082, India
| | - Mohamed Rela
- The Institute of Liver Disease & Transplantation, Gleneagles Global Health City, 439, Cheran Nagar, Perumbakkam, Chennai, Tamil Nadu, 600 100, India
| | - Manoj K. Sahu
- Department of Medical Gastroenterology, IMS & SUM Hospital, K8 Kalinga Nagar, Shampur, Bhubaneswar, Odisha 751 003, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, 226 014, India
| | - Samir R. Shah
- Department of Gastroenterology, Jaslok Hospital & Research Centre, 15, Dr Deshmukh Marg, Pedder Road, Mumbai, Maharashtra, 400 026, India
| | - Shalimar
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Praveen Sharma
- Institute of Liver Gastroenterology & Pancreatico Biliary Sciences, Sir Ganga Ram Hospital, Rajinder Nagar, New Delhi, 110 060, India
| | - Sunil Taneja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, 160 012, India
| | - Manav Wadhawan
- Liver & Digestive Diseases Institute, Institute of Liver & Digestive Diseases, BLK Super Specialty Hospital, Delhi, 110 005, India
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10
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Sinha M, Sundar K, Premalata CS, Asati V, Murali A, Bajpai AK, Davuluri S, Acharya KK, Lakshmaiah KC, Babu K G, Jacob LA, Nandan D, Velayutham D, Datta S, Jayshree RS. Pro-oncogenic, intra host viral quasispecies in Diffuse large B cell lymphoma patients with occult Hepatitis B Virus infection. Sci Rep 2019; 9:14516. [PMID: 31601912 PMCID: PMC6787061 DOI: 10.1038/s41598-019-51157-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 09/26/2019] [Indexed: 02/08/2023] Open
Abstract
Non Hodgkin lymphoma, predominantly Diffuse Large B-cell Lymphoma (DLBCL) has been reported to have a significant association with Hepatitis B virus (HBV). We investigated the presence of different gene segments of HBV in plasma, B-cells and tumor tissues from DLBCL patients and explored the genetic variability of HBV within and across different compartments in a host using Next Generation Sequencing. Despite all 40 patients being HBV seronegative, 68% showed evidence of occult HBV. Sequencing of these gene segments revealed inter-compartment viral variants in 26% of them, each with at least one non-synonymous mutation. Between compartments, core gene variants revealed Arg94Leu, Glu86Arg and Ser41Thr while X gene variants revealed Phe73Val, Ala44Val, Ser146Ala and Ser147Pro. In tumor compartments per se, several mis-sense mutations were detected, notably the classic T1762A/A1764G mutation in the basal core promoter. In addition, a virus surface antigen mis-sense mutation resulting in M125T was detected in all the samples and could account for surface antigen negativity and occult HBV status. It would be interesting to further explore if a temporal accumulation of viral variants within a favored niche, like patients’ lymphocytes, could bestow survival advantage to the virus, and if certain pro-oncogenic HBV variants could drive lymphomagenesis in DLBCL.
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Affiliation(s)
- Mahua Sinha
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India.
| | - Keerthana Sundar
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India
| | - C S Premalata
- Department of Pathology, Kidwai Cancer Institute, Bengaluru, India
| | - Vikas Asati
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | - Alka Murali
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India.,Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, India
| | | | | | - Kshitish K Acharya
- Institute of Bioinformatics and Applied Biotechnology (IBAB), Bengaluru, India.,Shodhaka Life Sciences Pvt. Ltd., Bengaluru, India
| | - K C Lakshmaiah
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | - Govind Babu K
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | - Linu A Jacob
- Department of Medical Oncology, Kidwai Cancer Institute, Bengaluru, India
| | | | | | - Sibnarayan Datta
- Molecular Virology Laboratory, Defence Research Laboratory, Tezpur, Assam, India
| | - R S Jayshree
- Department of Microbiology, Kidwai Cancer Institute, Bengaluru, India
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11
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Chen H, Luo S, Lu W, Chen Z, Chen J, Zheng S, Yu J. Serum protein expression patterns in detecting a new viral protein in HBeAg-negative chronic hepatitis B. J Viral Hepat 2019; 26 Suppl 1:90-97. [PMID: 31380583 DOI: 10.1111/jvh.13166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Accepted: 05/15/2019] [Indexed: 12/09/2022]
Abstract
We analysed the changes in viral protein expression in HBeAg-negative chronic hepatitis B (CHB). In total, 160 samples were obtained from individuals infected by hepatitis B virus (HBV) and divided into four groups. Group A included 71 cases of hepatitis B e antigen (HBeAg)-negative CHB, Group B included 58 cases of inactive seroconverters and Group C included 31 cases of HBeAg-positive CHB. Group D included 22 normal healthy individuals as a control. All serum samples were examined using surface enhance laser desorption/ionization time of flight-mass spectrometry (SELDI-TOF-MS). The results indicated that a peak with 4140 m/z increased markedly in Group A at 1295.55 ± 745.87, which was significantly different from that in Group B at 896.99 ± 534.86 (P = 0.013). This peak indicated a close relationship with HBV DNA replication and may contribute to pathogenesis of HBeAg-negative chronic hepatitis.
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Affiliation(s)
- Huguang Chen
- Infectious Diseases Department,, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shuya Luo
- Binjiang Hospital, Hangzhou, Zhejiang, China
| | - Weili Lu
- Infectious Diseases Department, The People's Hospital of Quzhou, Quzhou, Zhejiang, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jiamin Chen
- Department of Gastroenterology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Shu Zheng
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jiekai Yu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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12
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Chen X, Wu F, Liu Y, Lou J, Zhu B, Zou L, Chen W, Gong J, Wang Y, Zhong R. The contribution of serum hepatitis B virus load in the carcinogenesis and prognosis of hepatocellular carcinoma: evidence from two meta-analyses. Oncotarget 2018; 7:49299-49309. [PMID: 27384478 PMCID: PMC5226509 DOI: 10.18632/oncotarget.10335] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Accepted: 06/13/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND AIM The meta-analysis aimed to quantify and summarize the contribution of serum hepatitis B virus (HBV) DNA load in the carcinogenesis and prognosis of hepatocellular carcinoma (HCC). RESULTS Nine independent studies with a total of 1162 cases and 9365 participants on risk of HCC and seventeen studies with 1342 cases and 2891 participants on recurrence of HCC were finally included. The non-liner dose-response association between HBV DNA level and HCC risk was observed, with P value equal to 0.02 for linear test. Compared with 2 log10copies/ml HBV DNA level carriers, the summary relative risk of HCC were 1.65(95% CI: 0.94-2.92) for 4.5 log10copies/ml, 2.20(95% CI: 1.00-4.85) for 5.5 log10copies/ml, 3.06(95% CI: 1.11-8.44) for 6.5 log10copies/ml. Moreover, individuals with high viral load (HBV DNA levels > 105copies/ml) presented significant association with increased risk of HCC recurrence, with the pooled RR of 1.69 (95% CI: 1.49-1.92). MATERIALS AND METHODS Pertinent studies were identified by searching PubMed, Embase and ISI Web of science databases up to January 2016 and by reviewing the references of retrieved articles. The dose-response meta-analysis was precisely performed to calculate the summary relative risks (RRs) by quantizing the association between HBV load and risk of HCC. Besides, the contribution of HBV load on recurrence of HCC was further clarified by general meta-analysis. CONCLUSIONS These findings indicated a non-linear dose-response relationship between serum HBV DNA level and risk of HCC, and confirmed the significant contribution of serum HBV DNA level in the prognosis of HCC.
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Affiliation(s)
- Xueqin Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.,Department of Medical Quality Management, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China
| | - Fan Wu
- Abdominal Surgery Department, Cancer Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Yanmei Liu
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jiao Lou
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Beibei Zhu
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Li Zou
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jing Gong
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ying Wang
- Department of Virology, Wuhan Centers for Disease Prevention and Control, Wuhan, Hubei, China
| | - Rong Zhong
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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13
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Su C, Lin Y, Mao Q, Wu D, Zhu L, Najera I, Garcia-Alcalde F, Niu J. Association study between mannose-binding lectin haplotypes and X gene mutation of hepatitis B virus from treatment naïve patients. Aging (Albany NY) 2017; 8:2862-2870. [PMID: 27824315 PMCID: PMC5191875 DOI: 10.18632/aging.101097] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 10/24/2016] [Indexed: 01/26/2023]
Abstract
Mannose binding lectin (MBL) plays important role in the innate immunity of human. Mutations in the MBL2 gene can significantly change the serum level of MBL, and consequently alter the susceptibility and progression of infectious disease. However, the association between the MBL2 profile and the HBV mutation and quasispecies complexity has not yet been reported. Our approach includes the study of the MBL2 gene genotype as well as ultra-deep sequencing of the HBV viruses obtained from the plasma of 50 treatment naïve patients with chronic HBV infection. We found that the liver function was better among patients within the high MBL2 group with respect to those within the medium/low MBL2 group. Likewise, the number of mutations in the HBV X gene as well as the viral quasispecies complexity were significantly higher in medium/low MBL2 production group. Nucleotide substitution rates were also higher within the medium/low MBL2 production group in all positions described to have an influence in liver cancer development, except for A1499G. In this work we show that the MBL2 profile may have an impact on the HBV X gene mutations as well as on viral quasispecies complexity.
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Affiliation(s)
- Chenghao Su
- Xiamen Center for Disease Control and Prevention, Xiamen, Fujian 361021, China
| | - Yong Lin
- Xiamen Center for Disease Control and Prevention, Xiamen, Fujian 361021, China.,School of Public Health, Fujian Medical University, Fuzhou, Fujian 351022, China
| | - Qianguo Mao
- Xiamen Hospital of Traditional Chinses Medicine, Xiamen, Fujian 361001, China
| | - Daitze Wu
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases, Roche Innovation Center Shanghai 201203, China
| | - Lina Zhu
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases, Roche Innovation Center Shanghai 201203, China
| | - Isabel Najera
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases, Roche Innovation Center Basel 4070, Switzerland
| | - Fernando Garcia-Alcalde
- Roche Pharma Research and Early Development, Immunology, Inflammation and Infectious Diseases, Roche Innovation Center Basel 4070, Switzerland
| | - Jianjun Niu
- Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, China
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14
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Hepatitis B virus (HBV) X gene mutations and their association with liver disease progression in HBV-infected patients. Oncotarget 2017; 8:105115-105125. [PMID: 29285238 PMCID: PMC5739625 DOI: 10.18632/oncotarget.22428] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/17/2017] [Indexed: 12/13/2022] Open
Abstract
Hepatitis B virus (HBV) is one of the most widespread human pathogens causing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). This study investigated the clinical impact of single and combinational mutations in HBx gene on the pathogenesis of HCC during progressive stages of liver disease. The patients were categorized into inactive HBV carriers, active carriers, cirrhosis and HCC groups based on disease severity. Male sex, age > 50 years, and high serum alanine aminotransferase level were associated with risk of progressive liver disease. I127T, V131I, and F132Y/I/R mutations showed a significant increasing trend associated with the disease progression to HCC. H94Y and K130M mutations were also significantly associated with severe liver disease. One double mutation (K130M+V131I) and two triple mutations (I127T+K130M+V131L and K130M+V131I+F132Y) were observed, with significant rising prevalence through progressive clinical phases of liver disease to HCC. Several single and combinational mutations in HBx correlating with severity and progressive clinical phases of HBV infection were identified. The mutational combinations may have a synergistic effect in accelerating the progression to HCC. These specific patterns of HBx mutations can be useful in predicting the clinical outcome of HBV-infected patients and may serve as early markers of high risk of developing HCC.
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15
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Chachá SGF, Gomes-Gouvêa MS, Malta FDM, Ferreira SDC, Villanova MG, Souza FF, Teixeira AC, Passos ADDC, Pinho JRR, Martinelli ADLC. Basal core promoter and precore mutations among hepatitis B virus circulating in Brazil and its association with severe forms of hepatic diseases. Mem Inst Oswaldo Cruz 2017; 112:626-631. [PMID: 28902288 PMCID: PMC5572448 DOI: 10.1590/0074-02760160540] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 04/11/2017] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND In Brazil, few studies have investigated the prevalence of infection with the precore (PC) and basal core promoter (BCP) mutants of the hepatitis B virus (HBV). OBJECTIVES This study aimed to analyse the frequency of PC and BCP mutations among patients infected with HBV and to evaluate the association between the variants and advanced hepatic disease. METHODS A total of 161 patients infected with HBV were studied. To identify PC and BCP mutations, a 501-bp fragment of HBV DNA was amplified and sequenced. FINDINGS PC and BCP regions from HBV strains were successfully amplified and sequenced in 129 and 118 cases, respectively. PC and BCP mutations were detected in 61.0% and 80.6% of the cases, respectively. The A1762T/G1764A variant was identified in 36.7% of the patients with grade 1 and 2 liver fibrosis (29/79) and in 81.8% of the patients with grade 3 and 4 liver fibrosis (9/11) (p < 0.01); in 76.9% of the patients with cirrhosis (10/13) and in 38.1% of the patients without cirrhosis (40/105) (p = 0.01); and in 77.8% of the patients with hepatocellular carcinoma (HCC) (7/9) and in 39.4% of the patients without HCC (43/109) (p = 0.03). MAIN CONCLUSIONS A high prevalence of HBV PC and BCP mutants was found. The A1762T/G1764A variant was independently associated with advanced forms of liver fibrosis, hepatic cirrhosis, and HCC.
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Affiliation(s)
- Silvana Gama Florencio Chachá
- Universidade Federal de São Carlos, Departamento de Medicina, São Carlos, SP, Brasil
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Divisão de Gastroenterologia, Ribeirão Preto, SP, Brasil
| | - Michele Soares Gomes-Gouvêa
- Faculdade de Medicina da Universidade de São Paulo, Instituto de Medicina Tropical, Departamento de Gastroenterologia, Laboratório de Gastroenterologia e Hepatologia Tropical, São Paulo, SP, Brasil
| | - Fernanda de Mello Malta
- Faculdade de Medicina da Universidade de São Paulo, Instituto de Medicina Tropical, Departamento de Gastroenterologia, Laboratório de Gastroenterologia e Hepatologia Tropical, São Paulo, SP, Brasil
| | - Sandro da Costa Ferreira
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Divisão de Gastroenterologia, Ribeirão Preto, SP, Brasil
| | - Márcia Guimarães Villanova
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Divisão de Gastroenterologia, Ribeirão Preto, SP, Brasil
| | - Fernanda Fernandes Souza
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Divisão de Gastroenterologia, Ribeirão Preto, SP, Brasil
| | - Andreza Correa Teixeira
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Divisão de Gastroenterologia, Ribeirão Preto, SP, Brasil
| | - Afonso Dinis da Costa Passos
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Medicina Social, Ribeirão Preto, SP, Brasil
| | - João Renato Rebello Pinho
- Faculdade de Medicina da Universidade de São Paulo, Instituto de Medicina Tropical, Departamento de Gastroenterologia, Laboratório de Gastroenterologia e Hepatologia Tropical, São Paulo, SP, Brasil
- Hospital Israelita Albert Einstein, São Paulo, SP, Brasil
| | - Ana de Lourdes Candolo Martinelli
- Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Clínica Médica, Divisão de Gastroenterologia, Ribeirão Preto, SP, Brasil
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16
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Liu WC, Wu IC, Lee YC, Lin CP, Cheng JH, Lin YJ, Yen CJ, Cheng PN, Li PF, Cheng YT, Cheng PW, Sun KT, Yan SL, Lin JJ, Yang JC, Chang KC, Ho CH, Tseng VS, Chang BCH, Wu JC, Chang TT. Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus. J Pathol 2017; 243:176-192. [PMID: 28696069 DOI: 10.1002/path.4938] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 05/31/2017] [Accepted: 07/04/2017] [Indexed: 12/26/2022]
Abstract
This study investigated hepatitis B virus (HBV) single-nucleotide variants (SNVs) and deletion mutations linked with hepatocellular carcinoma (HCC). Ninety-three HCC patients and 108 non-HCC patients were enrolled for HBV genome-wide next-generation sequencing (NGS) analysis. A systematic literature review and a meta-analysis were performed to validate NGS-defined HCC-associated SNVs and deletions. The experimental results identified 60 NGS-defined HCC-associated SNVs, including 41 novel SNVs, and their pathogenic frequencies. Each SNV was specific for either genotype B (n = 24) or genotype C (n = 34), except for nt53C, which was present in both genotypes. The pathogenic frequencies of these HCC-associated SNVs showed a distinct U-shaped distribution pattern. According to the meta-analysis and literature review, 167 HBV variants from 109 publications were categorized into four levels (A-D) of supporting evidence that they are associated with HCC. The proportion of NGS-defined HCC-associated SNVs among these HBV variants declined significantly from 75% of 12 HCC-associated variants by meta-analysis (Level A) to 0% of 10 HCC-unassociated variants by meta-analysis (Level D) (P < 0.0001). PreS deletions were significantly associated with HCC, in terms of deletion index, for both genotypes B (P = 0.030) and C (P = 0.049). For genotype C, preS deletions involving a specific fragment (nt2977-3013) were significantly associated with HCC (HCC versus non-HCC, 6/34 versus 0/32, P = 0.025). Meta-analysis of preS deletions showed significant association with HCC (summary odds ratio 3.0; 95% confidence interval 2.3-3.9). Transfection of Huh7 cells showed that all of the five novel NGS-defined HCC-associated SNVs in the small surface region influenced hepatocarcinogenesis pathways, including endoplasmic reticulum-stress and DNA repair systems, as shown by microarray, real-time polymerase chain reaction and western blot analysis. Their carcinogenic mechanisms are worthy of further research. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Wen-Chun Liu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - I-Chin Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Yen-Chien Lee
- Department of Oncology, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan, ROC.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | | | - Ji-Hong Cheng
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan, ROC
| | - Chia-Jui Yen
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Pei-Fu Li
- Institute of Medical Informatics, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Yi-Ting Cheng
- Institute of Medical Informatics, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Pei-Wen Cheng
- Department of Information and Learning Technology, Science and Engineering College, National University of Tainan, Tainan, Taiwan, ROC
| | - Koun-Tem Sun
- Department of Information and Learning Technology, Science and Engineering College, National University of Tainan, Tainan, Taiwan, ROC
| | - Shu-Ling Yan
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Jia-Jhen Lin
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Jui-Chu Yang
- Human Biobank, Research Centre of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
| | - Kung-Chao Chang
- Human Biobank, Research Centre of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
| | - Cheng-Hsun Ho
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Vincent S Tseng
- Department of Computer Science, National Chiao Tung University, Hsinchu, Taiwan, ROC
| | | | - Jaw-Ching Wu
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.,Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
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17
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Abstract
BACKGROUND More and more studies focus on the relationship between hepatitis B virus (HBV) basal core promoter/precore (BCP/PC) mutations, but it remains controvercial, we conducted a meta-analysis to investigate the features of hepatitis B virus basal core promoter/precore mutations on the progression of hepatocellular carcinoma (HCC). METHODS A comprehensive search was conducted for articles published between January 1, 2005 and December 31, 2015 using the following databases: PubMed, Embase, Cochrane Library, Wanfang, and China National Knowledge Infrastructure. Medical subject heading terms were prioritized in setting the search strategy. Search terms included ("hepatitis B virus"), ("mutation or mutations or mutant"), and ("hepatocellular carcinoma" or "liver cancer" or hepatoma). A meta-analysis of pooled results from case-control studies examined the association between mutations G1896A, A1762T, G1764A, and A1762T/G1764A and the risk of HCC. RESULTS We included 29 articles for analysis and found that G1896A (summary odds ratios [OR] = 2.04, 95% confidence interval [CI] = 1.41-2.95), A1762T (summary OR = 3.96, 95% CI = 1.98-7.92), G1764A (summary OR = 3.48, 95% CI = 1.99-6.09), and A1762T/G1764A (summary OR = 3.96, 95% CI = 2.77-5.65) are each associated with a statistically significant increase in the risk of HCC. CONCLUSION In summary, we found that G1896A, A1762T, G1764A, and A1762T/G1764A are associated with an increased risk of HCC.
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Affiliation(s)
- Fangfang Wei
- Department of Infectious Disease, Guangdong Second Provincial General Hospital
| | | | - Maoyin Li
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Maosheng Wu
- Department of Infectious Disease, Guangdong Second Provincial General Hospital
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Kim H, Lee SA, Kim BJ. X region mutations of hepatitis B virus related to clinical severity. World J Gastroenterol 2016; 22:5467-5478. [PMID: 27350725 PMCID: PMC4917607 DOI: 10.3748/wjg.v22.i24.5467] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/17/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major health problem, with more than 240 million people chronically infected worldwide and potentially 650000 deaths per year due to advanced liver diseases including liver cirrhosis and hepatocellular carcinoma (HCC). HBV-X protein (HBx) contributes to the biology and pathogenesis of HBV via stimulating virus replication or altering host gene expression related to HCC. The HBV X region contains only 465 bp encoding the 16.5 kDa HBx protein, which also contains several critical cis-elements such as enhancer II, the core promoter and the microRNA-binding region. Thus, mutations in this region may affect not only the HBx open reading frame but also the overlapped cis-elements. Recently, several types of HBx mutations significantly associated with clinical severity have been described, although the functional mechanism in most of these cases remains unsolved. This review article will mainly focus on the HBx mutations proven to be significantly related to clinical severity via epidemiological studies.
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Lee D, Lyu H, Chung YH, Kim JA, Mathews P, Jaffee E, Zheng L, Yu E, Lee YJ, Ryu SH. Genomic change in hepatitis B virus associated with development of hepatocellular carcinoma. World J Gastroenterol 2016; 22:5393-5399. [PMID: 27340355 PMCID: PMC4910660 DOI: 10.3748/wjg.v22.i23.5393] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 03/21/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the genomic changes in hepatitis B virus (HBV) and evaluate their role in the development of hepatocellular carcinoma (HCC) in patients chronically infected with genotype C HBV.
METHODS: Two hundred and forty chronic hepatitis B (CHB) patients were subjected and followed for a median of 105 mo. HCC was diagnosed in accordance with AASLD guidelines. The whole X, S, basal core promoter (BCP), and precore regions of HBV were sequenced using the direct sequencing method.
RESULTS: All of the subjects were infected with genotype C HBV. Out of 240 CHB patients, 25 (10%) had C1653T and 33 (14%) had T1753V mutation in X region; 157 (65%) had A1762T/G1764A mutations in BCP region, 50 (21%) had G1896A mutation in precore region and 67 (28%) had pre-S deletions. HCC occurred in 6 patients (3%). The prevalence of T1753V mutation was significantly higher in patients who developed HCC than in those without HCC. The cumulative occurrence rates of HCC were 5% and 19% at 10 and 15 years, respectively, in patients with T1753V mutant, which were significantly higher than 1% and 1% in those with wild type HBV (P < 0.001).
CONCLUSION: The presence of T1753V mutation in HBV X-gene significantly increases the risk of HCC development in patients chronically infected with genotype C HBV.
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20
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Kim H, Lee SA, Do SY, Kim BJ. Precore/core region mutations of hepatitis B virus related to clinical severity. World J Gastroenterol 2016; 22:4287-4296. [PMID: 27158197 PMCID: PMC4853686 DOI: 10.3748/wjg.v22.i17.4287] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/10/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Despite the availability of an effective vaccine, hepatitis B virus (HBV) infection remains a major health problem, with more than 350 million chronically infected people worldwide and over 1 million annual deaths due to cirrhosis and liver cancer. HBV mutations are primarily generated due both to a lack of proofreading capacity by HBV polymerase and to host immune pressure, which is a very important factor for predicting disease progression and therapeutic outcomes. Several types of HBV precore/core (preC/C) mutations have been described to date. The host immune response against T cells drives mutation in the preC/C region. Specifically, preC/C mutations in the MHC class II restricted region are more common than in other regions and are significantly related to hepatocellular carcinoma. Certain mutations, including preC G1896A, are also significantly related to HBeAg-negative chronic infection. This review article mainly focuses on the HBV preC/C mutations that are related to disease severity and on the HBeAg serostatus of chronically infected patients.
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21
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Yang Z, Zhuang L, Lu Y, Xu Q, Tang B, Chen X. Naturally occurring basal core promoter A1762T/G1764A dual mutations increase the risk of HBV-related hepatocellular carcinoma: a meta-analysis. Oncotarget 2016; 7:12525-36. [PMID: 26848866 PMCID: PMC4914302 DOI: 10.18632/oncotarget.7123] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 01/23/2016] [Indexed: 02/05/2023] Open
Abstract
Basal core promoter (BCP) A1762T/G1764A dual mutations in hepatocarcinogenesis remain controversial. Published studies up to June 1, 2015 investigating the frequency of A1762T/G1764A dual mutations from chronic hepatitis B virus (HBV) infection, including hepatocellular carcinoma (HCC), were systematically identified. A total of 10,240 patients with chronic HBV infection, including 3729 HCC cases, were included in 52 identified studies. HCC patients had a higher frequency of BCP A1762T/G1764A dual mutations compared with asymptomatic HBsAg carriers (ASC) and patients with chronic hepatitis B (CHB) and liver cirrhosis (LC) (OR = 5.59, P < 0.00001; OR = 2.87, P < 0.00001; OR = 1.55, P = 0.02, respectively). No statistically significant difference was observed in the frequency of A1762T/G1764A dual mutations in cirrhotic HCC versus non-cirrhotic HCC patients (OR = 2.06, P = 0.05). Chronic HBV-infected patients and HCC patients with genotype B had a significantly lower risk of A1762T/G1764A dual mutations compared with patients with genotype C (OR = 0.30, P < 0.0001 and OR = 0.34, P = 0.04, respectively). In HBV genotype C subjects, A1762T/G1764A dual mutations contributed to significantly higher risk for HCC developing compared with non-mutation ones (OR = 3.47, P < 0.00001). In conclusion, A1762T/G1764A dual mutations increase the risk of HBV-related hepatocellular carcinoma, particularly in an HBV genotype C population, even without progression to cirrhosis.
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Affiliation(s)
- Zongguo Yang
- 1 Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Liping Zhuang
- 2 Fudan University Shanghai Cancer Center, Shanghai, China
- 3 Shanghai Medical College, Fudan University, Shanghai, China
| | - Yunfei Lu
- 1 Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Qingnian Xu
- 1 Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Bozong Tang
- 1 Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xiaorong Chen
- 1 Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
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22
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Yang Y, Sun JW, Zhao LG, Bray F, Xiang YB. Quantitative evaluation of hepatitis B virus mutations and hepatocellular carcinoma risk: a meta-analysis of prospective studies. Chin J Cancer Res 2015; 27:497-508. [PMID: 26543337 PMCID: PMC4626822 DOI: 10.3978/j.issn.1000-9604.2015.10.05] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 09/02/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The temporal relationship between hepatitis B virus (HBV) mutations and hepatocellular carcinoma (HCC) remains unclear. METHODS We conducted a meta-analysis including cohort and nested case-control studies to prospectively examine the HCC risk associated with common variants of HBV in the PreS, Enhancer II, basal core promoter (BCP) and precore regions. Pertinent studies were identified by searching PubMed, Web of Science and the Chinese Biological Medicine databases through to November 2014. Study-specific risk estimates were combined using fixed or random effects models depending on whether significant heterogeneity was detected. RESULTS Twenty prospective studies were identified, which included 8 cohort and 12 nested case-control studies. There was an increased risk of HCC associated with any PreS mutations with a pooled relative risk (RR) of 3.82 [95% confidence interval (CI): 2.59-5.61]. The pooled-RR for PreS deletion was 3.98 (95% CI: 2.28-6.95), which was higher than that of PreS2 start codon mutation (pooled-RR=2.63, 95% CI: 1.30-5.34). C1653T in Enhancer II was significantly associated with HCC risk (pooled-RR=1.83; 95% CI: 1.21-2.76). For mutations in BCP, statistically significant pooled-RRs of HCC were obtained for T1753V (pooled-RR=2.09; 95% CI: 1.49-2.94) and A1762T/G1764A double mutations (pooled-RR=3.11; 95% CI: 2.08-4.64). No statistically significant association with HCC risk was observed for G1896A in the precore region (pooled-RR=0.77; 95% CI: 0.47-1.26). CONCLUSIONS This study demonstrated that PreS mutations, C1653T, T1753V, and A1762T/G1764A, were associated with an increased risk of HCC. Clinical practices concerning the HCC risk prediction and diagnosis may wish to focus on patients with these mutations.
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Korba B, Shetty K, Medvedev A, Viswanathan P, Varghese R, Zhou B, Roy R, Makambi K, Ressom H, Loffredo CA. Hepatitis C virus Genotype 1a core gene nucleotide patterns associated with hepatocellular carcinoma risk. J Gen Virol 2015; 96:2928-2937. [PMID: 26296571 DOI: 10.1099/jgv.0.000219] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Specific sequence changes in codons 70 and 91 of the hepatitis C virus genotype 1b (HCV GT1b) core gene have been associated with increased risk of hepatocellular carcinoma (HCC). Essentially all previous studies were conducted in Asian populations with a wide range of liver disease, and none were conducted specifically in GT1a-infected individuals. We conducted a pilot study in a multiethnic population in the USA with HCV-related cirrhosis to determine if this association extended to GT1a-infected individuals and to determine if other sequence changes in the HCV core gene were associated with HCC risk. HCV core gene sequences from sera of 90 GT1 HCV carriers with cirrhosis (42 with HCC) were analysed using standard RT-PCR-based procedures. Nucleotide sequence data were compared with reference sequences available from GenBank. The frequency of sequence changes in codon 91 was not statistically different between HCC (7/19) and non-HCC (11/22) GT1b carriers. In GT1a carriers, sequence changes in codon 91 were observed less often than in GT1b carriers but were not observed in non-HCC subjects (4/23 vs 0/26, P = 0.03, Fisher's exact test). Sequence changes in codon 70 were not distributed differently between HCC and non-HCC GT1a and 1b carriers. Most importantly, for GT1a carriers, a panel of specific nucleotide changes in other codons was collectively present in all subjects with HCC, but not in any of the non-HCC patients. The utility of this test panel for early detection of HCC in GT1a-infected individuals needs to be assessed in larger populations, including longitudinal studies.
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Affiliation(s)
- Brent Korba
- Department of Microbiology and Immunology, Georgetown University, Washington, DC 20057, USA
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA
| | - Kirti Shetty
- Division of Gastroenterology & Hepatology, Johns Hopkins University, Sibley Memorial Hospital, Washington, DC 20016, USA
| | - Alexei Medvedev
- Department of Microbiology and Immunology, Georgetown University, Washington, DC 20057, USA
| | - Prasanth Viswanathan
- Department of Microbiology and Immunology, Georgetown University, Washington, DC 20057, USA
| | - Rency Varghese
- Department of Oncology, Georgetown University, Washington, DC 20057, USA
| | - Bin Zhou
- Department of Oncology, Georgetown University, Washington, DC 20057, USA
| | - Rabindra Roy
- Department of Oncology, Georgetown University, Washington, DC 20057, USA
| | - Kepher Makambi
- Department of Biostatistics, Georgetown University, Washington, DC 20057, USA
| | - Habtom Ressom
- Department of Oncology, Georgetown University, Washington, DC 20057, USA
| | - Christopher A Loffredo
- Department of Biostatistics, Georgetown University, Washington, DC 20057, USA
- Department of Oncology, Georgetown University, Washington, DC 20057, USA
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Ghaziani T, Sendi H, Shahraz S, Zamor P, Bonkovsky HL. Hepatitis B and liver transplantation: molecular and clinical features that influence recurrence and outcome. World J Gastroenterol 2014; 20:14142-55. [PMID: 25339803 PMCID: PMC4202345 DOI: 10.3748/wjg.v20.i39.14142] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2014] [Revised: 04/29/2014] [Accepted: 05/25/2014] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) continues to be a major cause of morbidity and mortality worldwide. It is estimated that about 350 million people throughout the world are chronically infected with HBV. Some of these people will develop hepatic cirrhosis with decompensation and/or hepatocellular carcinoma. For such patients, liver transplantation may be the only hope for cure or real improvement in quality and quantity of life. Formerly, due to rapidity of recurrence of HBV infection after liver transplantation, usually rapidly progressive, liver transplantation was considered to be contraindicated. This changed dramatically following the demonstration that hepatitis B immune globulin (HBIG), could prevent recurrent HBV infection. HBIG has been the standard of care for the past two decades or so. Recently, with the advent of highly active inhibitors of the ribose nucleic acid polymerase of HBV (entecavir, tenofovir), there has been growing evidence that HBIG needs to be given for shorter lengths of time; indeed, it may no longer be necessary at all. In this review, we describe genetic variants of HBV and past, present, and future prophylaxis of HBV infection during and after liver transplantation. We have reviewed the extant medical literature on the subject of infection with the HBV, placing particular emphasis upon the prevention and treatment of recurrent HBV during and after liver transplantation. For the review, we searched PubMed for all papers on the subject of "hepatitis B virus AND liver transplantation". We describe some of the more clinically relevant and important genetic variations in the HBV. We also describe current practices at our medical centers, provide a summary and analysis of comparative costs for alternative strategies for prevention of recurrent HBV, and pose important still unanswered questions that are in need of answers during the next decade or two. We conclude that it is now rational and cost-effective to decrease and, perhaps, cease altogether, the routine use of HBIG during and following liver transplantation for HBV infection. Here we propose an individualized prophylaxis regimen, based on an integrated approach and risk-assessment.
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25
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Datta S, Ghosh A, Dasgupta D, Ghosh A, Roychoudhury S, Roy G, Das S, Das K, Gupta S, Basu K, Basu A, Datta S, Chowdhury A, Banerjee S. Novel point and combo-mutations in the genome of hepatitis B virus-genotype D: characterization and impact on liver disease progression to hepatocellular carcinoma. PLoS One 2014; 9:e110012. [PMID: 25333524 PMCID: PMC4198185 DOI: 10.1371/journal.pone.0110012] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 09/04/2014] [Indexed: 12/14/2022] Open
Abstract
Background The contribution of chronic hepatitis B virus (HBV) infection in the pathogenesis of hepatocellular carcinoma (HCC) through progressive stages of liver fibrosis is exacerbated by the acquisition of naturally occurring mutations in its genome. This study has investigated the prevalence of single and combo mutations in the genome of HBV-genotype D from treatment naïve Indian patients of progressive liver disease stages and assessed their impact on the disease progression to HCC. Methods The mutation profile was determined from the sequence analysis of the full-length HBV genome and compared with the reference HBV sequences. SPSS 16.0 and R software were used to delineate their statistical significance in predicting HCC occurrence. Results Age was identified as associated risk factor for HCC development in chronic hepatitis B (CHB) patients (p≤0.01). Beyond the classical mutations in basal core promoter (BCP) (A1762T/G1764A) and precore (G1862T), persistence of progressively accumulated mutations in enhancer-I, surface, HBx and core were showed significant association to liver disease progression. BCP_T1753C, core_T147C, surface_L213I had contributed significantly in the disease progression to HCC (p<0.05) in HBeAg positive patients whereas precore_T1858C, core_I116L, core_P130Q and preS1_S98T in HBeAg negative patients. Furthermore, the effect of individual mutation was magnified by the combination with A1762T/G1764A in HCC pathogenesis. Multivariate risk analysis had confirmed that core_P130Q [OR 20.71, 95% CI (1.64–261.77), p = 0.019] in B cell epitope and core_T147C [OR 14.58, 95% CI (1.17–181.76), p = 0.037] in CTL epitope were two independent predictors of HCC in HBeAg positive and negative patients respectively. Conclusions Thus distinct pattern of mutations distributed across the entire HBV genome may be useful in predicting HCC in high-risk CHB patients and pattern of mutational combinations may exert greater impact on HCC risk prediction more accurately than point mutations and hence these predictors may support the existing surveillance strategies in proper management of the patients.
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Affiliation(s)
- Somenath Datta
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Alip Ghosh
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Debanjali Dasgupta
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Amit Ghosh
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Shrabasti Roychoudhury
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Gaurav Roy
- Molecular Virology Laboratory, Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Soumyojit Das
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Kausik Das
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Subash Gupta
- Centre for Liver & Biliary Surgery, Indraprastha Apollo Hospital, New Delhi, India
| | - Keya Basu
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Analabha Basu
- National Institute of Biomedical Genomics, Kalyani, India
| | - Simanti Datta
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Abhijit Chowdhury
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
| | - Soma Banerjee
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India
- * E-mail:
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Kumar A, Acharya SK, Singh SP, Saraswat VA, Arora A, Duseja A, Goenka MK, Jain D, Kar P, Kumar M, Kumaran V, Mohandas KM, Panda D, Paul SB, Ramachandran J, Ramesh H, Rao PN, Shah SR, Sharma H, Thandassery RB. The Indian National Association for Study of the Liver (INASL) Consensus on Prevention, Diagnosis and Management of Hepatocellular Carcinoma in India: The Puri Recommendations. J Clin Exp Hepatol 2014; 4:S3-S26. [PMID: 25755608 PMCID: PMC4284289 DOI: 10.1016/j.jceh.2014.04.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 04/08/2014] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the major causes of morbidity, mortality and healthcare expenditure in patients with chronic liver disease. There are no consensus guidelines on diagnosis and management of HCC in India. The Indian National Association for Study of the Liver (INASL) set up a Task-Force on HCC in 2011, with a mandate to develop consensus guidelines for diagnosis and management of HCC, relevant to disease patterns and clinical practices in India. The Task-Force first identified various contentious issues on various aspects of HCC and these issues were allotted to individual members of the Task-Force who reviewed them in detail. The Task-Force used the Oxford Center for Evidence Based Medicine-Levels of Evidence of 2009 for developing an evidence-based approach. A 2-day round table discussion was held on 9th and 10th February, 2013 at Puri, Odisha, to discuss, debate, and finalize the consensus statements. The members of the Task-Force reviewed and discussed the existing literature at this meeting and formulated the INASL consensus statements for each of the issues. We present here the INASL consensus guidelines (The Puri Recommendations) on prevention, diagnosis and management of HCC in India.
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Key Words
- AFP, alpha-fetoprotein
- AIIMS, All India Institute of Medical Sciences
- ASMR, age standardized mortality rate
- BCLC, Barcelona-Clinic Liver Cancer
- CEUS, contrast enhanced ultrasound
- CT, computed tomography
- DCP, des-gamma-carboxy prothrombin
- DDLT, deceased donor liver transplantation
- DE, drug eluting
- FNAC, fine needle aspiration cytology
- GPC-3, glypican-3
- GS, glutamine synthase
- Gd-EOB-DTPA, gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid
- HBV, Hepatitis B virus
- HCC, hepatocellular carcinoma
- HCV, Hepatitis C virus
- HSP-70, heat shock protein-70
- HVPG, hepatic venous pressure gradient
- ICG, indocyanine green
- ICMR, Indian Council of Medical Research
- INASL, Indian National Association for Study of the Liver
- LDLT, living donor liver transplantation
- MRI, magnetic resonance imaging
- Mabs, monoclonal antibodies
- NAFLD, non-alcoholic fatty liver disease
- OLT, orthotopic liver transplantation
- PAI, percutaneous acetic acid injection
- PEI, percutaneous ethanol injection
- PET, positron emission tomography
- PVT, portal vein thrombosis
- RECIST, Response Evaluation Criteria in Solid Tumors
- RFA
- RFA, radio frequency ablation
- SVR, sustained viral response
- TACE
- TACE, transarterial chemoembolization
- TART, trans-arterial radioisotope therapy
- UCSF, University of California San Francisco
- liver cancer
- targeted therapy
- transplant
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Affiliation(s)
- Ashish Kumar
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Subrat K. Acharya
- Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Road, New Delhi 110 029, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Cuttack, Odisha, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
| | - Anil Arora
- Department of Gastroenterology & Hepatology, Sir Ganga Ram Hospital, New Delhi, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Mahesh K. Goenka
- Department of Gastroenterology, Apollo Gleneagles Hospital, 58, Canal Circular Road, Kolkata, West Bengal 700 054, India
| | - Deepali Jain
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Premashish Kar
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Vinay Kumaran
- Department of Surgical Gastroenterology and Liver Transplantation, Sir Ganga Ram Hospital, New Delhi, India
| | - Kunisshery M. Mohandas
- Department of Digestive Diseases, Tata Medical Center, Kolkata, West Bengal 700156, India
| | - Dipanjan Panda
- Department of Oncology, Institute of Liver & Biliary Sciences, New Delhi, India
| | - Shashi B. Paul
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Jeyamani Ramachandran
- Department of Hepatology, Christian Medical College, Vellore, Tamil Nadu 632 004, India
| | - Hariharan Ramesh
- Department of Surgical Gastroenterology, Lakeshore Hospital and Research Center, Cochin, Kerala, India
| | - Padaki N. Rao
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Somajiguda, Hyderabad, India
| | - Samir R. Shah
- Department of Gastroenterology, Jaslok Hospital and Research Centre, Peddar Road, Mumbai, Maharashtra 400 026, India
| | - Hanish Sharma
- Department of Gastroenterology, All India Institute of Medical Sciences, Ansari Road, New Delhi 110 029, India
| | - Ragesh B. Thandassery
- Department of Gastroenterology, Apollo Gleneagles Hospital, 58, Canal Circular Road, Kolkata, West Bengal 700 054, India
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27
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Kar P. Risk factors for hepatocellular carcinoma in India. J Clin Exp Hepatol 2014; 4:S34-42. [PMID: 25755609 PMCID: PMC4284237 DOI: 10.1016/j.jceh.2014.02.155] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Accepted: 02/19/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an important cause of death all over the world, more so in Asia and Africa. The representative data on epidemiology of HCC in India is very scanty and cancer is not a reportable disease in India and the cancer registries in India are mostly urban. 45 million people who are suffering from chronic Hepatitis B virus (HBV) infection and approximately 15 million people who are afflicted with chronic Hepatitis C virus (HCV) infection in India. HBV and HCV infection is considered an important etiologic factor in HCC. Positive association between HCC and consumption of alcohol where alcohol contribute as a cofactor for hepatotoxins and hepatitis viruses. Aflatoxin contamination in the diets, Hepatitis B virus infection and liver cirrhosis in Andhra Pradesh, India and direct chronic exposure to aflatoxins was shown to cause liver cirrhosis. Cirrhosis of liver of any cause lead to develop about 70%-90% of HCC. Aflatoxin interact synergistically with Hepatitis B virus (HBV)/Hepatitis C virus (HCV) infection which increase the risk of HCC. HBV infection, HBV infection with Aflatoxin exposure, viral infection and alcohol consumption leading to overt cirrhosis of the liver, alcohol consumption leading to cirrhosis of the liver with viral infection are the predominant risk factor for the development of HCC. HCV and alcohol are also associated with HCC in India. Indians develop diabetes at younger age, Asians have strong genetic susceptibility for type II diabetes. Diabetes mellitus is identified as a risk factor for HCC. Prevention of viral infection by universal vaccination against hepatitis virus, HCC surveillance program, preventing alcoholic liver diseases, fungal contamination of grains and ground crops to prevent basically Aflatoxin exposure are important measures to prevent liver diseases and HCC among those at risk.
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Key Words
- AFB1, aflatoxin B1
- DM, diabetes mellitus
- GT, glucose tolerance
- HBV, Hepatitis B virus
- HBsAg, hepatitis-B surface antigen
- HCC
- HCC, hepatocellular carcinoma
- HCV, Hepatitis C virus
- IARC, International Agency for Research on Cancer
- NAFLD, non-alcoholic fatty liver disease
- RR, relative risk
- aflatoxin
- risk factor
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Affiliation(s)
- Premashis Kar
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi 110002, India
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28
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Liu LP, Hu BG, Ye C, Ho RLK, Chen GG, Lai PBS. HBx mutants differentially affect the activation of hypoxia-inducible factor-1α in hepatocellular carcinoma. Br J Cancer 2013; 110:1066-73. [PMID: 24346287 PMCID: PMC3929872 DOI: 10.1038/bjc.2013.787] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Revised: 11/19/2013] [Accepted: 11/27/2013] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mutations in HBx gene are frequently found in HBV-associated hepatocellular carcinoma (HCC). Activation of hypoxia-inducible factor-1α (HIF-1α) contributes to HCC development and progression. Wild-type HBx has been demonstrated to activate HIF-1α, but the effect of HBx mutations on HIF-1α has not been elucidated. METHODS HBx mutations were identified by gene sequencing in 101 HCC tissues. Representative HBx mutants were cloned and transfected into HCC cells. Expression and activation of HIF-1α were analysed by western blot and luciferase assays, respectively. The relationship between HBx mutants and HIF-1α expression in HCC tissues was also evaluated. RESULTS The dual mutations K130M/V131I enhanced the functionality of HBx as they upregulated the expression and transcriptional activity of HIF-1α. The C-terminal truncations and deletion mutations, however, weakened the ability of HBx to upregulate HIF-1α. Meanwhile, the C-terminus was further found to be essential for the stability and transactivation of HBx. In the HCC tissues, there was a positive association between the HBx mutants and HIF-1α expression. CONCLUSION Different mutations of HBx exert differentiated effects on the functionality of HIF-1α, however, the overall activity of HBx mutants appears to increase the expression and transcriptional activity of HIF-1α.
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Affiliation(s)
- L-P Liu
- 1] Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China [2] Department of Hepatobiliary and Pancreas Surgery, the Second Clinical Medical College of Jinan University (Shenzhen People's Hospital), Shenzhen, Guangdong Province, China
| | - B-G Hu
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - C Ye
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - R L K Ho
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - G G Chen
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | - P B S Lai
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
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29
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Rodriguez-Frias F, Buti M, Tabernero D, Homs M. Quasispecies structure, cornerstone of hepatitis B virus infection: Mass sequencing approach. World J Gastroenterol 2013; 19:6995-7023. [PMID: 24222943 PMCID: PMC3819535 DOI: 10.3748/wjg.v19.i41.6995] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 07/23/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is a DNA virus with complex replication, and high replication and mutation rates, leading to a heterogeneous viral population. The population is comprised of genomes that are closely related, but not identical; hence, HBV is considered a viral quasispecies. Quasispecies variability may be somewhat limited by the high degree of overlapping between the HBV coding regions, which is especially important in the P and S gene overlapping regions, but is less significant in the X and preCore/Core genes. Despite this restriction, several clinically and pathologically relevant variants have been characterized along the viral genome. Next-generation sequencing (NGS) approaches enable high-throughput analysis of thousands of clonally amplified regions and are powerful tools for characterizing genetic diversity in viral strains. In the present review, we update the information regarding HBV variability and present a summary of the various NGS approaches available for research in this virus. In addition, we provide an analysis of the clinical implications of HBV variants and their study by NGS.
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30
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Araujo OC, Barros JJF, do Ó KM, Nabuco LC, Luz CA, Perez RM, Niel C, Villela-Nogueira CA, Araujo NM. Genetic variability of hepatitis B and C viruses in Brazilian patients with and without hepatocellular carcinoma. J Med Virol 2013; 86:217-23. [PMID: 24338810 DOI: 10.1002/jmv.23837] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2013] [Indexed: 12/18/2022]
Abstract
Most cases of hepatocellular carcinoma (HCC) are due to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection worldwide. The aim of this study was to determine the viral genotypes and frequency of 17 mutations (15 for HBV and 2 for HCV), described previously as able to influence the course of chronic liver disease, in patients with and without HCC. This transversal study included 157 Brazilian patients with chronic hepatitis B (n = 51) and C (n = 106). Of these, 12 and 40 patients had HBV- and HCV-related HCC, respectively. Nucleotide sequencing of core promoter, pre-core, and pre-S/S regions of HBV and core region of HCV strains was performed to determine their genotypes and the frequency of the respective mutations. Among the HBV isolates, subgenotype A1 was the most prevalent in both patients with (90%) and without (61%) HCC. Fourteen out of the 15 mutations under study, as well as five different pre-S deletions, were identified. Core promoter T1753V, A1762T, and G1764A mutations were more frequent in patients with HCC than in those without, although with no statistical difference. However, a significant correlation was observed between T1753V mutation and elevation of transaminases levels (P < 0.05). As for HCV, mutation at residue 70 in the core protein of genotype 1b strains was significantly more frequent in patients with cirrhosis (56.3%) than in those without (9.1%) (P = 0.018). The detection of some key mutations in the genomes of HBV and HCV might be helpful to predict the clinical outcome of patients with chronic liver disease.
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Affiliation(s)
- Oscar C Araujo
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, Fiocruz, Rio de Janeiro, Brazil
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31
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Medhi S, Sarma MP, Asim M, Kar P. Genetic variants of heat shock protein A1L2437 and A1B1267 as possible risk factors for hepatocellular carcinoma in India. J Viral Hepat 2013; 20:e141-7. [PMID: 23490384 DOI: 10.1111/jvh.12021] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Accepted: 09/01/2012] [Indexed: 02/03/2023]
Abstract
To study the role of heat shock protein A1L (HSPA1L) and A1B (HSPA1B) polymorphisms and subsequent risk of hepatocellular carcinoma (HCC) in India. Subjects enrolled included 185 cases of HCC, 182 cases of chronic hepatitis (CH) and 200 healthy controls. Genomic DNA was typed for HSPA1L2437 and HSPA1B1267 SNP using polymerase chain reaction with restriction fragment length polymorphism. Other risk factors were also analysed. Hepatitis B virus (HBV) infection, older age >35 years and high aflatoxin level in urine increased the risk of HCC. The frequencies of HSPA1L BB genotype and B allele in HCC were more than in CH [odds ratio (OR): 9.83; P = 0.000], but also in HBV-related HCC than Chronic Hepatitis B (CHB) [OR: 3.44; P = 0.004] and HCV-related HCC compared to CHC [OR: 6.32; P = 0.010]. The frequency of HSPA1B genotype in the homozygous state was more in CH [OR: 6.01; P = 0.001] and is a good marker to predict the risk of HCV-related CH (CHC) compared to controls. HCV-related HCC has a higher frequency of the B allele of HSPA1B than healthy controls [OR: 3.95; P = 0.000] and CHC [OR: 2.35; P = 0.000], respectively. The frequencies increased further significantly in CHC compared to healthy controls [OR: 9.26; P = 0.000]. The risk for the development of CH and HCC compared to healthy controls irrespective of the aetiology was significant in terms of the HSPA1B marker than HSPA1L in the Indian population.
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Affiliation(s)
- S Medhi
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
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32
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Tong S, Li J, Wands JR, Wen YM. Hepatitis B virus genetic variants: biological properties and clinical implications. Emerg Microbes Infect 2013; 2:e10. [PMID: 26038454 PMCID: PMC3636426 DOI: 10.1038/emi.2013.10] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/30/2013] [Accepted: 02/04/2013] [Indexed: 12/15/2022]
Abstract
Hepatitis B virus (HBV) causes a chronic infection in 350 million people worldwide and greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. The majority of chronic HBV carriers live in Asia. HBV can be divided into eight genotypes with unique geographic distributions. Mutations accumulate during chronic infection or in response to external pressure. Because HBV is an RNA-DNA virus the emergence of drug resistance and vaccine escape mutants has become an important clinical and public health concern. Here, we provide an overview of the molecular biology of the HBV life cycle and an evaluation of the changing role of hepatitis B e antigen (HBeAg) at different stages of infection. The impact of viral genotypes and mutations/deletions in the precore, core promoter, preS, and S gene on the establishment of chronic infection, development of fulminant hepatitis and liver cancer is discussed. Because HBV is prone to mutations, the biological properties of drug-resistant and vaccine escape mutants are also explored.
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Affiliation(s)
- Shuping Tong
- Liver Research Center, Rhode Island Hospital, The Alpert Warren School of Medicine, Brown University , Providence, RI 02906, USA ; Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University , Shanghai 200032, China
| | - Jisu Li
- Liver Research Center, Rhode Island Hospital, The Alpert Warren School of Medicine, Brown University , Providence, RI 02906, USA
| | - Jack R Wands
- Liver Research Center, Rhode Island Hospital, The Alpert Warren School of Medicine, Brown University , Providence, RI 02906, USA
| | - Yu-Mei Wen
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University , Shanghai 200032, China
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33
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Wong GLH, Chan HLY, Yiu KKL, Lai JWY, Chan VKK, Cheung KKC, Wong EWN, Wong VWS. Meta-analysis: The association of hepatitis B virus genotypes and hepatocellular carcinoma. Aliment Pharmacol Ther 2013; 37:517-26. [PMID: 23305043 DOI: 10.1111/apt.12207] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2012] [Revised: 11/29/2012] [Accepted: 12/19/2012] [Indexed: 01/30/2023]
Abstract
BACKGROUND A meta-analysis on the risk of hepatocellular carcinoma (HCC) among hepatitis B virus (HBV) genotypes is warranted as the current data are conflicting. AIM To investigate the relative risk of HCC among the four major HBV genotypes (A-D). METHODS A meta-analysis was performed based on literature search from electronic databases and bibliography between 1950 and 2012. All abstracts with keywords 'hepatitis B', 'hepatocellular carcinoma' and 'genotype' were screened. Studies were included if they reported HBV genotype as an exposure and HCC as an outcome. RESULTS Nine hundred and eighty-eight abstracts were found through literature search, among them 43 studies were eligible for this meta-analysis. A total of 14,545 patients with an average age of 43 years were included; 71% were male patients and 17% had cirrhosis. In 33 studies, HCC was found in 1541/6060 (25%) genotype C vs. 550/4417 (12%) genotype B HBV-infected patients [odds ratio (OR) = 2.05, 95% confidence interval (CI) = 1.52-2.76, P < 0.001]. No difference in the risk of HCC was found among genotype A (71/517, 14%) vs. genotype D (170/1506, 11%) HBV-infected patients in 14 studies (OR = 0.94, 95% CI = 0.67-1.32). In 10 studies, the risk of HCC was also found higher among genotype C (498/1659, 30%) than genotype A&D (103/1403, 7%) HBV-infected patients (OR = 2.34, 95% CI = 1.63-3.34, P < 0.001). Subgenotype Ce and Cs HBV-infected patients had similar risk on HCC (OR = 1.13, 95% CI = 0.76-1.67, P = 0.54). On funnel plot analysis, there was no significant publication bias in all comparisons. CONCLUSION Genotype C hepatitis B virus is associated with a higher risk of hepatocellular carcinoma than other major hepatitis B virus genotypes.
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Affiliation(s)
- G L-H Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, China
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34
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Lyu H, Lee D, Chung YH, Kim JA, Lee JH, Jin YJ, Park W, Mathews P, Jaffee E, Zheng L, Yu E, Lee YJ. Synergistic effects of A1896, T1653 and T1762/A1764 mutations in genotype c2 hepatitis B virus on development of hepatocellular carcinoma. J Viral Hepat 2013; 20:219-24. [PMID: 23383661 PMCID: PMC3609415 DOI: 10.1111/j.1365-2893.2012.01654.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Accepted: 06/01/2012] [Indexed: 12/14/2022]
Abstract
The effects of genomic changes in hepatitis B virus (HBV) on the occurrence of hepatocellular carcinoma (HCC) are still unclear, especially in relation to the genotype of HBV. In this study, we examined the effects of genomic changes in HBV of genotype C2 on the development of HCC. A total of 318 patients with HBV-associated HCC and 234 patients with chronic hepatitis B (CHB) were studied. All of HCC cases were diagnosed histologically and treated with surgical resection. The whole of the X, S, basal core promoter (BCP) and precore regions of the viral genome from sera or liver tissues were sequenced. All subjects had HBV of genotype C2. The prevalence of the T1653 mutation in the X region and the A1896 mutation in the precore region of HBV was significantly higher in the HCC group than in the control CHB group (22% vs 11%, P = 0.003; 50% vs 23%, P < 0.001, respectively). Moreover, the T1762/A1764 mutations in the BCP region in combination with either T1653 or A1896 were more common in the HCC compared with the CHB group (BCP+X1653: 18% vs 11%, P = 0.05; BCP+PC, 40% vs 15%, P < 0.001, respectively). In multivariate analysis, T1653 and A1896 were revealed to be independent risk factors for HCC development. G1896A in the precore region and C1653T mutation in the X region of genotype C2 HBV are important risk factors for HCC development. Also, the A1762T/G1764A double mutation may act in synergy with C1653T to increase the risk of HCC in patients chronically infected with HBV genotype C2.
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Affiliation(s)
- H. Lyu
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - D. Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center
| | - Y.-H. Chung
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center
| | - J. A. Kim
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center
| | - J.-H. Lee
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center
| | - Y.-J. Jin
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center
| | - W. Park
- Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center
| | - P. Mathews
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - E. Jaffee
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - L. Zheng
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - E. Yu
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center
| | - Y. J. Lee
- Department of Hepatobiliary Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
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35
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Mathews P, Lee D, Chung YH, Kim JA, Lee JH, Jin YJ, Park W, Lyu H, Jaffee E, Zheng L, Yu E, Lee YJ. Effects of genomic changes in hepatitis B virus on postoperative recurrence and survival in patients with hepatocellular carcinoma. Ann Surg Oncol 2012; 20:1216-22. [PMID: 23104706 DOI: 10.1245/s10434-012-2706-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Indexed: 12/13/2022]
Abstract
PURPOSE To determine whether the genomic changes in hepatitis B virus (HBV) affect the clinical outcomes of hepatocellular carcinoma (HCC) in patients with HBV-associated HCC treated with curative surgical resection. METHODS A total of 247 patients with HBV-associated HCC were treated with curative surgical resection. They were followed regularly for a median of 30 months. The whole X, S, basal core promoter (BCP), and precore regions of HBV were sequenced. RESULTS The genomic changes such as the G1896A at precore, the A1762T/G1764A at BCP, the C1653T and the T1753V at X gene, and pre-S2 deletion were not significantly associated with postoperative recurrence of HCC or survival of patients after curative resection. However, in univariate analysis, younger age, elevated serum α-fetoprotein level, elevated serum alanine aminotransferase level, larger tumor size, microvascular invasion, and advanced Cancer of the Liver Italian Program stage were closely associated with shorter survival after surgical resection. In multivariate analysis, only microvascular invasion revealed to be an independent risk factor of postoperative recurrence (relative risk [RR] 5.406; P < 0.001); the independent risk factors of shorter survival appeared to be infiltrative type (RR 5.110; P = 0.032), larger tumor size (RR 1.976; P = 0.047), and microvascular invasion (RR 6.118; P < 0.001). CONCLUSIONS The postoperative recurrence or survival period may not be affected by the genomic changes at the precore, BCP, X, and pre-S2 regions in HBV of genotype C2 in patients with HBV-associated HCC treated with curative surgical resection. Rather, it may be closely associated with tumor characteristics, such as the size and type of HCC or presence of microvascular invasion.
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Affiliation(s)
- Priya Mathews
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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36
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Heriyanto DS, Yano Y, Utsumi T, Anggorowati N, Rinonce HT, Lusida MI, Soetjipto, Triwikatmani C, Ratnasari N, Maduseno S, Purnama PB, Nurdjanah S, Hayashi Y. Mutations within enhancer II and BCP regions of hepatitis B virus in relation to advanced liver diseases in patients infected with subgenotype B3 in Indonesia. J Med Virol 2012; 84:44-51. [PMID: 22095534 DOI: 10.1002/jmv.22266] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Studies on the characteristics of mutations within the hepatitis B virus (HBV) genome, their roles in the pathogenesis of advanced liver diseases, and the involvement of host properties of HBV-infected individuals have not been conducted in subgenotype B3-infected populations. For addressing this issue, 40 cases with HBV surface antigen (HBsAg)-positive advanced liver diseases, including advanced liver cancer and cirrhosis (male 31, female 9, age 54.4 ± 11.6-year-old), were collected and compared with 109 cases with chronic hepatitis B (male 71, female 38, age 38.0 ± 13.4-year-old). Mutations in enhancer II (Enh II) and basal core promoter (BCP)/precore regions were analyzed by PCR-direct sequencing method. HBV viral load was examined by real-time PCR. For all examined regions, the prevalence of mutation was significantly higher in cases with advanced liver diseases. Multivariate analysis showed that, in patients older than 45 years, C1638T and T1753V mutations constituted independent risk factors for the advancement of liver diseases. The presence of C1638T and T1753V mutations may serve as predictive markers for the progression of liver diseases in Indonesia and other countries, where subgenotype B3 infection is prevalent.
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Affiliation(s)
- Didik Setyo Heriyanto
- Center for Infectious Diseases, Graduate School of Medicine, Kobe University, Kobe, Japan
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Cheng CP, Lee PF, Liu WC, Wu IC, Chin CY, Chang TT, Tseng VS. Analysis of precore/core covariances associated with viral kinetics and genotypes in hepatitis B e antigen-positive chronic hepatitis B patients. PLoS One 2012; 7:e32553. [PMID: 22384271 PMCID: PMC3288105 DOI: 10.1371/journal.pone.0032553] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 02/01/2012] [Indexed: 12/17/2022] Open
Abstract
Hepatitis B virus (HBV) is one of the most common DNA viruses that can cause aggressive hepatitis, cirrhosis and hepatocellular carcinoma. Although many people are persistently infected with HBV, the kinetics in serum levels of viral loads and the host immune responses vary from person to person. HBV precore/core open reading frame (ORF) encoding proteins, hepatitis B e antigen (HBeAg) and core antigen (HBcAg), are two indicators of active viral replication. The aim of this study was to discover a variety of amino acid covariances in responses to viral kinetics, seroconversion and genotypes during the course of HBV infection. A one year follow-up study was conducted with a total number of 1,694 clones from 23 HBeAg-positive chronic hepatitis B patients. Serum alanine aminotransferase, HBV DNA and HBeAg levels were measured monthly as criteria for clustering patients into several different subgroups. Monthly derived multiple precore/core ORFs were directly sequenced and translated into amino acid sequences. For each subgroup, time-dependent covariances were identified from their time-varying sequences over the entire follow-up period. The fluctuating, wavering, HBeAg-nonseroconversion and genotype C subgroups showed greater degrees of covariances than the stationary, declining, HBeAg-seroconversion and genotype B. Referring to literature, mutation hotspots within our identified covariances were associated with the infection process. Remarkably, hotspots were predominant in genotype C. Moreover, covariances were also identified at early stage (spanning from baseline to a peak of serum HBV DNA) in order to determine the intersections with aforementioned time-dependent covariances. Preserved covariances, namely representative covariances, of each subgroup are visually presented using a tree-based structure. Our results suggested that identified covariances were strongly associated with viral kinetics, seroconversion and genotypes. Moreover, representative covariances may benefit clinicians to prescribe a suitable treatment for patients even if they have no obvious symptoms at the early stage of HBV infection.
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Affiliation(s)
- Chun-Pei Cheng
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Fen Lee
- Institute of Medical Informatics, National Cheng Kung University, Tainan, Taiwan
| | - Wen-Chun Liu
- Department of Biotechnology, Ming Dao University, Changhua, Taiwan
| | - I-Chin Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
- Graduate Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan
- Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Chu-Yu Chin
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan
- Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan
- Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan
| | - Vincent S. Tseng
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan
- Institute of Medical Informatics, National Cheng Kung University, Tainan, Taiwan
- * E-mail:
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Zhou JY, Zhang L, Li L, Gu GY, Zhou YH, Chen JH. High hepatitis B virus load is associated with hepatocellular carcinomas development in Chinese chronic hepatitis B patients: a case control study. Virol J 2012; 9:16. [PMID: 22244446 PMCID: PMC3349554 DOI: 10.1186/1743-422x-9-16] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Accepted: 01/13/2012] [Indexed: 02/06/2023] Open
Abstract
Background Persistent hepatitis B virus (HBV) infection is a risk factor for hepatocellular carcinoma (HCC) development. This study aimed to clarify whether the high HBV DNA level is associated with HCC development by comparing HBV DNA levels between HBV infected patients with and without HCC. Results There were 78 male and 12 female patients in each group and there was no statistical difference between these two group patients' average ages. The HBV DNA level in the HCC patients was 4.73 ± 1.71 Log10 IU/ml while 3.90 ± 2.01 Log10 IU/ml in non-HCC patients (P < 0.01). The HBeAg positive rate was 42.2% (38/90) in the HCC group while 13.3% (12/90) in the non-HCC group (P < 0.001). Compared with patients with HBV DNA level of < 3 Log10 IU/ml, the patients with level of 3 to < 4, 4 to < 5, 5 to < 6, or ≥ 6 Log10 IU/ml had the odds ratio for HCC of 1.380 (95% CI, 0.544-3.499), 3.671 (95% CI, 1.363-9.886), 5.303 (95% CI, 1.847-15.277) or 3.030 (95% CI, 1.143-8.036), respectively. Conclusions HBV-related HCC patients had higher HBV DNA level than non-HCC counterparts. Our findings imply that active HBV replication is associated with the HCC development.
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Affiliation(s)
- Jin-Yong Zhou
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
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Kumar R, Pahal V, Singh J. Prevalence of Genotype D and Precore/Core Promoter Mutations in Hepatitis B Virus-infected Population of North India. J Clin Exp Hepatol 2011; 1:73-6. [PMID: 25755318 PMCID: PMC3940627 DOI: 10.1016/s0973-6883(11)60125-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Accepted: 08/24/2011] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) isolates (21) from Punjab (North India) were studied for genotype distribution and precore/core promoter mutations. Assays of alanine aminotransaminase (ALT) and HBeAg were performed in all isolates. Genotypes were determined in all the samples by restriction fragment length polymorphism and the precore/core promoter mutations were studied by amplification and by direct sequencing of precore/core promoter region. Sixty-two percent of the isolates had higher ALT levels and 57% of the isolates were HBeAg negative. It was observed that 90% of the isolates were HBV D genotype (subgenotype D1 and D2) and 10% of the isolates were HBV A genotype (subgenotype A1). Amplification and sequencing of the precore/core promoter region showed 1762(A-T) and 1764(G-A) mutations in 29% and 19% of the isolates, respectively. 1809(C/T) mutation was observed in 71% of the isolates under study. Novel precore and core promoter mutations like 1690(A), 1695(A/T/G), 1700(A/C), 1703(c), 1850(A) and 1915(A/G) were observed in HBV-infected population of the state of Punjab (North India). Deletion and insertional mutations were also observed in some patients. (J CLIN EXP HEPATOL 2011;1:73-76).
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Affiliation(s)
- Rajesh Kumar
- Department of Biochemistry, Kurukshetra University, Kurukshetra - 136119, Haryana, India
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Lack of association between FOS polymorphisms and clearance of HBV infection as well as HCC occurrence. Genes Genomics 2011. [DOI: 10.1007/s13258-010-0179-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Aakanksha, Asim M, Sharma PK, Das BC, Kar P. Analysis of carriers of hepatitis B virus from a tertiary referral hospital: does the viral load change during the natural course of infection? J Med Virol 2011; 83:1151-8. [PMID: 21520137 DOI: 10.1002/jmv.22074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/27/2011] [Indexed: 01/27/2023]
Abstract
This study was designed to determine the prevalence, forms of transmission, mutational profile and viral load at baseline of hepatitis B virus (HBV) carriers in Delhi. HBV surface antigen (HBsAg)-positive patients were enrolled and evaluated clinically for liver function, serological markers for hepatitis B and HBV DNA quantitation. Tests were carried out again 1 year later and the results were compared. Liver biopsy was carried out on all carriers with active viral replication. HBV DNA-positive samples were subjected to polymerase chain reaction single-stranded conformation polymorphism (PCR-SSCP) to screen mutations in the Precore, core, and the X-gene prior to sequencing analysis. Among the 100 patients examined, HBeAg was detected in 23% and 40% were HBV DNA-positive. Of the 40 HBV DNA-positive cases, 8 had precore/core mutations, [G1896A (10%), T2066A (12.5%), T2050C (10%), and G1888A (7.5%)]. No X gene mutants were detected. Reduction in viral load was higher in HBeAg-positive patients, as compared to HBeAg-negative patients, over 1 year. At follow-up, 2/8 HBV mutants corresponded with altered liver function and morphological changes suggestive of chronic hepatitis. One patient was re-designated as DNA-negative on follow-up and had wild-type virus infection with a relatively low viral load. The predominant route for HBV transmission was determined to be parenteral. Twenty percent of the HBV carriers were infected with precore and core mutant HBV. Although the clinical and biochemical profiles of these HBV carriers remained largely stable on follow-up, there was evidence of spontaneous reduction in the mean viral load over the 1-year study period.
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Affiliation(s)
- Aakanksha
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
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