Occult Hepatitis B Virus Infection in Hepatic Diseases and Its Significance for the WHO’s Elimination Plan of Viral Hepatitis
Abstract
:1. The Liver and Pathologies
2. Hepatitis B Virus Characteristics
3. Global Strategy to Eradicate Viral Hepatitis, Focusing on the Context of OBI
3.1. Occult Hepatitis B Virus Infection
3.2. OBI and Hepatic Diseases
3.3. Mutations in HBV Genome Associated with Liver Diseases
4. The HBx Protein, ER Oxidative Stress, and HBV-DNA Integration
4.1. Endoplasmic Reticulum Stress and HBV Mutations
4.2. Viral DNA Integration and HCC
5. Immune Response and Biomarkers
6. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
- Aydin, M.M.; Akcali, K.C. Liver fibrosis. Turk. J. Gastroenterol. 2018, 29, 14–21. [Google Scholar] [CrossRef] [PubMed]
- Glaser, T.; Baiocchi, L.; Zhou, T.; Francis, H.; Lenci, I.; Grassi, G.; Kennedy, L.; Liangpunsakul, S.; Glaser, S.; Alpini, G.; et al. Pro-inflammatory signalling and gut-liver axis in non-alcoholic and alcoholic steatohepatitis: Differences and similarities along the path. J. Cell. Mol. Med. 2020, 24, 5955–5965. [Google Scholar] [CrossRef]
- Shao, M.; Ye, Z.; Qin, Y.; Wu, T. Abnormal metabolic processes involved in the pathogenesis of non-alcoholic fatty liver disease (Review). Exp. Ther. Med. 2020, 20, 26. [Google Scholar] [CrossRef]
- Svegliati-Baroni, G.; Patricio, B.; Lioci, G.; Macedo, M.P.; Gastaldelli, A. Gut-Pancreas-Liver Axis as a Target for Treatment of NAFLD/NASH. Int. J. Mol. Sci. 2020, 21, 5820. [Google Scholar] [CrossRef] [PubMed]
- Centers for Disease Control and Prevention. Viral Hepatitis; U.S. Centers for Disease Control and Prevention: Atlanta, GA, USA. Available online: https://www.cdc.gov/hepatitis/global/index.htm (accessed on 2 June 2023).
- Gines, P.; Krag, A.; Abraldes, J.G.; Sola, E.; Fabrellas, N.; Kamath, P.S. Liver cirrhosis. Lancet 2021, 398, 1359–1376. [Google Scholar] [CrossRef] [PubMed]
- Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018, 68, 394–424. [Google Scholar] [CrossRef]
- Villanueva, A. Hepatocellular Carcinoma. N. Engl. J. Med. 2019, 380, 1450–1462. [Google Scholar] [CrossRef]
- Rajoriya, N.; Combet, C.; Zoulim, F.; Janssen, H.L.A. How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualised approach? J. Hepatol. 2017, 67, 1281–1297. [Google Scholar] [CrossRef]
- Guo, H.; Jiang, D.; Zhou, T.; Cuconati, A.; Block, T.M.; Guo, J.T. Characterization of the intracellular deproteinized relaxed circular DNA of hepatitis B virus: An intermediate of covalently closed circular DNA formation. J. Virol. 2007, 81, 12472–12484. [Google Scholar] [CrossRef]
- Tsukuda, S.; Watashi, K. Hepatitis B virus biology and life cycle. Antivir. Res. 2020, 182, 104925. [Google Scholar] [CrossRef]
- Liu, C.-J.; Kao, J.-H. Global perspective on the natural history of chronic hepatitis B: Role of hepatitis B virus genotypes A to J. Semin. Liver Dis. 2013, 33, 97–102. [Google Scholar] [CrossRef] [PubMed]
- Chan, H.L.; Hui, A.Y.; Wong, M.L.; Tse, A.M.; Hung, L.C.; Wong, V.W.; Sung, J.J. Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut 2004, 53, 1494–1498. [Google Scholar] [CrossRef] [PubMed]
- Chan, H.L.; Tse, C.H.; Mo, F.; Koh, J.; Wong, V.W.; Wong, G.L.; Lam Chan, S.; Yeo, W.; Sung, J.J.; Mok, T.S. High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. J. Clin. Oncol. 2008, 26, 177–182. [Google Scholar] [CrossRef] [PubMed]
- Yang, H.I.; Yeh, S.H.; Chen, P.J.; Iloeje, U.H.; Jen, C.L.; Su, J.; Wang, L.Y.; Lu, S.N.; You, S.L.; Chen, D.S.; et al. Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J. Natl. Cancer Inst. 2008, 100, 1134–1143. [Google Scholar] [CrossRef]
- Ni, Y.H.; Chang, M.H.; Wang, K.J.; Hsu, H.Y.; Chen, H.L.; Kao, J.H.; Yeh, S.H.; Jeng, Y.M.; Tsai, K.S.; Chen, D.S. Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology 2004, 127, 1733–1738. [Google Scholar] [CrossRef] [PubMed]
- Ringelhan, M.; McKeating, J.A.; Protzer, U. Viral hepatitis and liver cancer. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2017, 372, 20160274. [Google Scholar]
- Alberts, C.J.; Clifford, G.M.; Georges, D.; Negro, F.; Lesi, O.A.; Hutin, Y.J.; de Martel, C. Worldwide prevalence of hepatitis B virus and hepatitis C virus among patients with cirrhosis at country, region, and global levels: A systematic review. Lancet Gastroenterol. Hepatol. 2022, 7, 724–735. [Google Scholar] [CrossRef] [PubMed]
- Pan American Health Organization. Hepatitis; World Health Organization Americas Region: Washington, DC, USA, 2024; Available online: https://www.paho.org/en/topics/hepatitis (accessed on 12 May 2023).
- World Health Organization. Hepatitis B.; World Health Organization: Geneva, Switzerland, 2022. Available online: https://www.who.int/news-room/fact-sheets/detail/hepatitis-b (accessed on 9 May 2023).
- Raimondo, G.; Allain, J.-P.; Brunetto, M.R.; Buendia, M.-A.; Chen, D.-S.; Colombo, M.; Craxì, A.; Donato, F.; Ferrari, C.; Gaeta, G.B.; et al. Statements from the Taormina expert meeting on occult hepatitis B virus infection. J. Hepatol. 2008, 49, 652–657. [Google Scholar] [CrossRef] [PubMed]
- Raimondo, G.; Locarnini, S.; Pollicino, T.; Levrero, M.; Zoulim, F.; Lok, A.S.; Taormina Workshop on Occult, H.B.V.I.F.M. Update of the statements on biology and clinical impact of occult hepatitis B virus infection. J. Hepatol. 2019, 71, 397–408. [Google Scholar] [CrossRef]
- Caviglia, G.P.; Abate, M.L.; Tandoi, F.; Ciancio, A.; Amoroso, A.; Salizzoni, M.; Saracco, G.M.; Rizzetto, M.; Romagnoli, R.; Smedile, A. Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR: A new tool to detect occult infection. J. Hepatol. 2018, 69, 301–307. [Google Scholar] [CrossRef]
- Im, Y.R.; Jagdish, R.; Leith, D.; Kim, J.U.; Yoshida, K.; Majid, A.; Ge, Y.; Ndow, G.; Shimakawa, Y.; Lemoine, M. Prevalence of occult hepatitis B virus infection in adults: A systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 2022, 7, 932–942. [Google Scholar] [CrossRef] [PubMed]
- Maldonado-Rodriguez, A.; Cevallos, A.M.; Rojas-Montes, O.; Enriquez-Navarro, K.; Alvarez-Munoz, M.T.; Lira, R. Occult hepatitis B virus co-infection in human immunodeficiency virus-positive patients: A review of prevalence, diagnosis and clinical significance. World J. Hepatol. 2015, 7, 253–260. [Google Scholar] [CrossRef] [PubMed]
- Torres-Baranda, R.; Bastidas-Ramirez, B.E.; Maldonado-Gonzalez, M.; Sanchez-Orozco, L.V.; Vazquez-Vals, E.; Rodriguez-Noriega, E.; Panduro, A. Occult hepatitis B in Mexican patients with HIV, an analysis using nested polymerase chain reaction. Ann. Hepatol. 2006, 5, 34–40. [Google Scholar] [CrossRef] [PubMed]
- Calux, S.J.; Silva, V.C.M.; Compri, A.P.; Lemos, M.F.; Santos, A.P.T.; Oba, I.T.; Mendes-Correa, M.C.J.; Moreira, R.C. Hepatitis B: Prevalence and occult infection in HIV-infected patients. Rev. Soc. Bras. Med. Trop. 2020, 53, e20180533. [Google Scholar] [CrossRef]
- Shi, Y.; Wu, Y.H.; Wu, W.; Zhang, W.J.; Yang, J.; Chen, Z. Association between occult hepatitis B infection and the risk of hepatocellular carcinoma: A meta-analysis. Liver Int. 2012, 32, 231–240. [Google Scholar] [CrossRef] [PubMed]
- Wu, J.; He, J.; Xu, H. Global prevalence of occult HBV infection in children and adolescents: A systematic review and meta-analysis. Ann. Hepatol. 2024, 29, 101158. [Google Scholar] [CrossRef] [PubMed]
- Samal, J.; Kandpal, M.; Vivekanandan, P. Molecular mechanisms underlying occult hepatitis B virus infection. Clin. Microbiol. Rev. 2012, 25, 142–163. [Google Scholar] [CrossRef] [PubMed]
- Wu, C.C.; Chen, Y.S.; Cao, L.; Chen, X.W.; Lu, M.J. Hepatitis B virus infection: Defective surface antigen expression and pathogenesis. World J. Gastroenterol. 2018, 24, 3488–3499. [Google Scholar] [CrossRef]
- Mak, L.Y.; Wong, D.K.; Pollicino, T.; Raimondo, G.; Hollinger, F.B.; Yuen, M.F. Occult hepatitis B infection and hepatocellular carcinoma: Epidemiology, virology, hepatocarcinogenesis and clinical significance. J. Hepatol. 2020, 73, 952–964. [Google Scholar] [CrossRef]
- Squadrito, G.; Cacciola, I.; Alibrandi, A.; Pollicino, T.; Raimondo, G. Impact of occult hepatitis B virus infection on the outcome of chronic hepatitis C. J. Hepatol. 2013, 59, 696–700. [Google Scholar] [CrossRef]
- Pollicino, T.; Saitta, C. Occult hepatitis B virus and hepatocellular carcinoma. World J. Gastroenterol. 2014, 20, 5951–5961. [Google Scholar] [CrossRef] [PubMed]
- Raimondo, G.; Saitta, C.; Lombardo, D.; Giraudi, P.J.; Rosso, N.; Ieni, A.; Lazzara, S.; Palmisano, S.; Bonazza, D.; Alibrandi, A.; et al. Occult hepatitis B virus infection predicts non-alcoholic steatohepatitis in severely obese individuals from Italy. Liver Int. 2020, 40, 1601–1609. [Google Scholar] [CrossRef] [PubMed]
- Saitta, C.; Caruso, A.; Maimone, S.; Filomia, R.; Cacciola, I.; Caccamo, G.; Franze, M.S.; Pitrone, C.; Alibrandi, A.; Gaeta, M.; et al. Antibody to hepatitis B virus core antigen positivity is a predictor of non-alcoholic fatty liver disease severity. Intern. Emerg. Med. 2022, 17, 1609–1616. [Google Scholar] [CrossRef] [PubMed]
- Pollicino, T.; Saitta, C.; Raimondo, G. Hepatocellular carcinoma: The point of view of the hepatitis B virus. Carcinogenesis 2011, 32, 1122–1132. [Google Scholar] [CrossRef] [PubMed]
- Roman, S. Occult Hepatitis B and Other Unexplored Risk Factors for Hepatocellular Carcinoma in Latin America. Ann. Hepatol. 2018, 17, 541–543. [Google Scholar] [CrossRef] [PubMed]
- Roman, S.; Fierro, N.A.; Moreno-Luna, L.E.; Panduro, A. Hepatitis B Virus Genotype H and Environmental Factors Associated to the Low Prevalence of Hepatocellular Carcinoma in Mexico. J. Cancer Ther. 2013, 4, 367–376. [Google Scholar] [CrossRef]
- Panduro, A.; Maldonado-Gonzalez, M.; Fierro, N.A.; Roman, S. Distribution of HBV genotypes F and H in Mexico and Central America. Antivir. Ther. 2013, 18, 475–484. [Google Scholar] [CrossRef] [PubMed]
- Kim, H.; Gong, J.R.; Lee, S.A.; Kim, B.J. Discovery of a Novel Mutation (X8Del) Resulting in an 8-bp Deletion in the Hepatitis B Virus X Gene Associated with Occult Infection in Korean Vaccinated Individuals. PLoS ONE 2015, 10, e0139551. [Google Scholar] [CrossRef] [PubMed]
- Song, B.C.; Kim, H.; Kim, S.H.; Cha, C.Y.; Kook, Y.H.; Kim, B.J. Comparison of full length sequences of hepatitis B virus isolates in hepatocellular carcinoma patients and asymptomatic carriers of Korea. J. Med. Virol. 2005, 75, 13–19. [Google Scholar] [CrossRef]
- Coppola, N.; Onorato, L.; Minichini, C.; Di Caprio, G.; Starace, M.; Sagnelli, C.; Sagnelli, E. Clinical significance of hepatitis B surface antigen mutants. World J. Hepatol. 2015, 7, 2729–2739. [Google Scholar] [CrossRef]
- Wang, C.; Teng, Z.; Zhu, Y.; Zhao, A.Z.; Sun, C. Associations between pre-S deletion mutation of hepatitis B virus and risk of hepatocellular carcinoma in the Asian population: A meta-analysis. Med. Sci. Monit. 2015, 21, 1072–1077. [Google Scholar] [PubMed]
- Chaturvedi, V.K.; Singh, A.; Dubey, S.K.; Hetta, H.F.; John, J.; Singh, M.P. Molecular mechanistic insight of hepatitis B virus mediated hepatocellular carcinoma. Microb. Pathog. 2019, 128, 184–194. [Google Scholar] [CrossRef] [PubMed]
- Fang, Z.L.; Sabin, C.A.; Dong, B.Q.; Wei, S.C.; Chen, Q.Y.; Fang, K.X.; Yang, J.Y.; Huang, J.; Wang, X.Y.; Harrison, T.J. Hepatitis B virus pre-S deletion mutations are a risk factor for hepatocellular carcinoma: A matched nested case-control study. J. Gen. Virol. 2008, 89, 2882–2890. [Google Scholar] [CrossRef] [PubMed]
- Wang, H.C.; Huang, W.; Lai, M.D.; Su, I.J. Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis. Cancer Sci. 2006, 97, 683–688. [Google Scholar] [CrossRef]
- Vivekanandan, P.; Kannangai, R.; Ray, S.C.; Thomas, D.L.; Torbenson, M. Comprehensive genetic and epigenetic analysis of occult hepatitis B from liver tissue samples. Clin. Infect. Dis. 2008, 46, 1227–1236. [Google Scholar] [CrossRef] [PubMed]
- Huang, H.P.; Hsu, H.Y.; Chen, C.L.; Ni, Y.H.; Wang, H.Y.; Tsuei, D.J.; Chiang, C.L.; Tsai, Y.C.; Chen, H.L.; Chang, M.H. Pre-S2 deletions of hepatitis B virus and hepatocellular carcinoma in children. Pediatr. Res. 2010, 67, 90–94. [Google Scholar] [CrossRef] [PubMed]
- Coppola, N.; Onorato, L.; Iodice, V.; Starace, M.; Minichini, C.; Farella, N.; Liorre, G.; Filippini, P.; Sagnelli, E.; de Stefano, G. Occult HBV infection in HCC and cirrhotic tissue of HBsAg-negative patients: A virological and clinical study. Oncotarget 2016, 7, 62706–62714. [Google Scholar] [CrossRef] [PubMed]
- Hatazawa, Y.; Yano, Y.; Okada, R.; Tanahashi, T.; Hayashi, H.; Hirano, H.; Minami, A.; Kawano, Y.; Tanaka, M.; Fukumoto, T.; et al. Quasispecies variant of pre-S/S gene in HBV-related hepatocellular carcinoma with HBs antigen positive and occult infection. Infect. Agents Cancer 2018, 13, 7. [Google Scholar] [CrossRef] [PubMed]
- Chen, C.H.; Changchien, C.S.; Lee, C.M.; Hung, C.H.; Hu, T.H.; Wang, J.H.; Wang, J.C.; Lu, S.N. Combined mutations in pre-s/surface and core promoter/precore regions of hepatitis B virus increase the risk of hepatocellular carcinoma: A case-control study. J. Infect. Dis. 2008, 198, 1634–1642. [Google Scholar] [CrossRef]
- Lee, H.; Kim, H.; Lee, S.A.; Won, Y.S.; Kim, H.I.; Inn, K.S.; Kim, B.J. Upregulation of endoplasmic reticulum stress and reactive oxygen species by naturally occurring mutations in hepatitis B virus core antigen. J. Gen. Virol. 2015, 96, 1850–1854. [Google Scholar] [CrossRef]
- Chua, P.K.; Wang, R.Y.; Lin, M.H.; Masuda, T.; Suk, F.M.; Shih, C. Reduced secretion of virions and hepatitis B virus (HBV) surface antigen of a naturally occurring HBV variant correlates with the accumulation of the small S envelope protein in the endoplasmic reticulum and Golgi apparatus. J. Virol. 2005, 79, 13483–13496. [Google Scholar] [CrossRef]
- Salpini, R.; Battisti, A.; Piermatteo, L.; Carioti, L.; Anastasiou, O.E.; Gill, U.S.; Di Carlo, D.; Colagrossi, L.; Duca, L.; Bertoli, A.; et al. Key mutations in the C-terminus of the HBV surface glycoprotein correlate with lower HBsAg levels in vivo, hinder HBsAg secretion in vitro and reduce HBsAg structural stability in the setting of HBeAg-negative chronic HBV genotype-D infection. Emerg. Microbes Infect. 2020, 9, 928–939. [Google Scholar] [CrossRef] [PubMed]
- Hou, J.; Wang, Z.; Cheng, J.; Lin, Y.; Lau, G.K.; Sun, J.; Zhou, F.; Waters, J.; Karayiannis, P.; Luo, K. Prevalence of naturally occurring surface gene variants of hepatitis B virus in nonimmunized surface antigen-negative Chinese carriers. Hepatology 2001, 34, 1027–1034. [Google Scholar] [CrossRef] [PubMed]
- Gherlan, G.S. Occult hepatitis B—The result of the host immune response interaction with different genomic expressions of the virus. World J. Clin. Cases 2022, 10, 5518–5530. [Google Scholar] [CrossRef] [PubMed]
- Lazarevic, I.; Banko, A.; Miljanovic, D.; Cupic, M. Immune-Escape Hepatitis B Virus Mutations Associated with Viral Reactivation upon Immunosuppression. Viruses 2019, 11, 778. [Google Scholar] [CrossRef] [PubMed]
- Makondo, E.; Bell, T.G.; Kramvis, A. Genotyping and molecular characterization of hepatitis B virus from human immunodeficiency virus-infected individuals in southern Africa. PLoS ONE 2012, 7, e46345. [Google Scholar] [CrossRef] [PubMed]
- Mayaphi, S.H.; Martin, D.J.; Mphahlele, M.J.; Blackard, J.T.; Bowyer, S.M. Variability of the preC/C region of hepatitis B virus genotype A from a South African cohort predominantly infected with HIV. J. Med. Virol. 2013, 85, 1883–1892. [Google Scholar] [CrossRef]
- Kim, D.W.; Lee, S.A.; Hwang, E.S.; Kook, Y.H.; Kim, B.J. Naturally occurring precore/core region mutations of hepatitis B virus genotype C related to hepatocellular carcinoma. PLoS ONE 2012, 7, e47372. [Google Scholar] [CrossRef] [PubMed]
- Wu, J.F.; Ni, Y.H.; Chen, H.L.; Hsu, H.Y.; Chang, M.H. The impact of hepatitis B virus precore/core gene carboxyl terminal mutations on viral biosynthesis and the host immune response. J. Infect. Dis. 2014, 209, 1374–1381. [Google Scholar] [CrossRef]
- Malik, A.; Singhal, D.K.; Albanyan, A.; Husain, S.A.; Kar, P. Hepatitis B virus gene mutations in liver diseases: A report from New Delhi. PLoS ONE 2012, 7, e39028. [Google Scholar] [CrossRef]
- Carman, W.F.; Jacyna, M.R.; Hadziyannis, S.; Karayiannis, P.; McGarvey, M.J.; Makris, A.; Thomas, H.C. Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 1989, 2, 588–591. [Google Scholar] [CrossRef] [PubMed]
- Chen, J.; Liu, B.; Tang, X.; Zheng, X.; Lu, J.; Zhang, L.; Wang, W.; Candotti, D.; Fu, Y.; Allain, J.P.; et al. Role of core protein mutations in the development of occult HBV infection. J. Hepatol. 2021, 74, 1303–1314. [Google Scholar] [CrossRef] [PubMed]
- Shinkai, N.; Tanaka, Y.; Ito, K.; Mukaide, M.; Hasegawa, I.; Asahina, Y.; Izumi, N.; Yatsuhashi, H.; Orito, E.; Joh, T.; et al. Influence of hepatitis B virus X and core promoter mutations on hepatocellular carcinoma among patients infected with subgenotype C2. J. Clin. Microbiol. 2007, 45, 3191–3197. [Google Scholar] [CrossRef] [PubMed]
- Arbuthnot, P.; Capovilla, A.; Kew, M. Putative role of hepatitis B virus X protein in hepatocarcinogenesis: Effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. J. Gastroenterol. Hepatol. 2000, 15, 357–368. [Google Scholar] [CrossRef] [PubMed]
- Kim, H.; Jee, Y.M.; Song, B.C.; Shin, J.W.; Yang, S.H.; Mun, H.S.; Kim, H.J.; Oh, E.J.; Yoon, J.H.; Kim, Y.J.; et al. Molecular epidemiology of hepatitis B virus (HBV) genotypes and serotypes in patients with chronic HBV infection in Korea. Intervirology 2007, 50, 52–57. [Google Scholar] [CrossRef] [PubMed]
- Khan, A.; Al Balwi, M.A.; Tanaka, Y.; Hajeer, A.; Sanai, F.M.; Al Abdulkarim, I.; Al Ayyar, L.; Badri, M.; Saudi, D.; Tamimi, W.; et al. Novel point mutations and mutational complexes in the enhancer II, core promoter and precore regions of hepatitis B virus genotype D1 associated with hepatocellular carcinoma in Saudi Arabia. Int. J. Cancer 2013, 133, 2864–2871. [Google Scholar] [CrossRef] [PubMed]
- Venard, V.; Corsaro, D.; Kajzer, C.; Bronowicki, J.P.; Le Faou, A. Hepatitis B virus X gene variability in French-born patients with chronic hepatitis and hepatocellular carcinoma. J. Med. Virol. 2000, 62, 177–184. [Google Scholar] [CrossRef] [PubMed]
- Gunther, S.; Piwon, N.; Will, H. Wild-type levels of pregenomic RNA and replication but reduced pre-C RNA and e-antigen synthesis of hepatitis B virus with C(1653) → T, A(1762) → T and G(1764) → A mutations in the core promoter. J. Gen. Virol. 1998, 79 Pt 2, 375–380. [Google Scholar] [CrossRef] [PubMed]
- Yeh, C.T.; So, M.; Ng, J.; Yang, H.W.; Chang, M.L.; Lai, M.W.; Chen, T.C.; Lin, C.Y.; Yeh, T.S.; Lee, W.C. Hepatitis B virus-DNA level and basal core promoter A1762T/G1764A mutation in liver tissue independently predict postoperative survival in hepatocellular carcinoma. Hepatology 2010, 52, 1922–1933. [Google Scholar] [CrossRef]
- Siddiqui, Z.I.; Farooqui, S.R.; Azam, S.A.; Afroz, M.; Wajid, S.; Parveen, S.; Kazim, S.N. A comparative study of hepatitis B virus X protein mutants K130M, V131I and KV130/131MI to investigate their roles in fibrosis, cirrhosis and hepatocellular carcinoma. J. Viral Hepat. 2017, 24, 1121–1131. [Google Scholar] [CrossRef]
- Kuang, S.Y.; Jackson, P.E.; Wang, J.B.; Lu, P.X.; Munoz, A.; Qian, G.S.; Kensler, T.W.; Groopman, J.D. Specific mutations of hepatitis B virus in plasma predict liver cancer development. Proc. Natl. Acad. Sci. USA 2004, 101, 3575–3580. [Google Scholar] [CrossRef] [PubMed]
- Lin, C.L.; Kao, J.H. Natural history of acute and chronic hepatitis B: The role of HBV genotypes and mutants. Best. Pract. Res. Clin. Gastroenterol. 2017, 31, 249–255. [Google Scholar] [CrossRef] [PubMed]
- Mun, H.S.; Lee, S.A.; Kim, H.; Hwang, E.S.; Kook, Y.H.; Kim, B.J. Novel F141L pre-S2 mutation in hepatitis B virus increases the risk of hepatocellular carcinoma in patients with chronic genotype C infections. J. Virol. 2011, 85, 123–132. [Google Scholar] [CrossRef]
- Chen, C.H.; Changchien, C.S.; Lee, C.M.; Tung, W.C.; Hung, C.H.; Hu, T.H.; Wang, J.H.; Wang, J.C.; Lu, S.N. A study on sequence variations in pre-S/surface, X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non-B, non-C hepatocellular carcinoma patients in Taiwan. Int. J. Cancer 2009, 125, 621–629. [Google Scholar] [CrossRef]
- Wei, F.; Zheng, Q.; Li, M.; Wu, M. The association between hepatitis B mutants and hepatocellular carcinoma: A meta-analysis. Medicine 2017, 96, e6835. [Google Scholar] [CrossRef] [PubMed]
- Doria, M.; Klein, N.; Lucito, R.; Schneider, R.J. The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. EMBO J. 1995, 14, 4747–4757. [Google Scholar] [CrossRef] [PubMed]
- Elmore, L.W.; Hancock, A.R.; Chang, S.F.; Wang, X.W.; Chang, S.; Callahan, C.P.; Geller, D.A.; Will, H.; Harris, C.C. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc. Natl. Acad. Sci. USA 1997, 94, 14707–14712. [Google Scholar] [CrossRef]
- Liu, S.; Koh, S.S.; Lee, C.G. Hepatitis B Virus X Protein and Hepatocarcinogenesis. Int. J. Mol. Sci. 2016, 17, 940. [Google Scholar] [CrossRef]
- Brechot, C. Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: Old and new paradigms. Gastroenterology 2004, 127, S56–S61. [Google Scholar] [CrossRef]
- Feitelson, M.A.; Lee, J. Hepatitis B virus integration, fragile sites, and hepatocarcinogenesis. Cancer Lett. 2007, 252, 157–170. [Google Scholar] [CrossRef]
- Wong, D.K.; Huang, F.Y.; Lai, C.L.; Poon, R.T.; Seto, W.K.; Fung, J.; Hung, I.F.; Yuen, M.F. Occult hepatitis B infection and HBV replicative activity in patients with cryptogenic cause of hepatocellular carcinoma. Hepatology 2011, 54, 829–836. [Google Scholar] [CrossRef]
- Yuki, N.; Nagaoka, T.; Yamashiro, M.; Mochizuki, K.; Kaneko, A.; Yamamoto, K.; Omura, M.; Hikiji, K.; Kato, M. Long-term histologic and virologic outcomes of acute self-limited hepatitis B. Hepatology 2003, 37, 1172–1179. [Google Scholar] [CrossRef] [PubMed]
- Chauhan, R.; Lahiri, N. Tissue- and Serum-Associated Biomarkers of Hepatocellular Carcinoma. Biomark. Cancer 2016, 8, 37–55. [Google Scholar] [CrossRef] [PubMed]
- Farazi, P.A.; Glickman, J.; Horner, J.; Depinho, R.A. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res. 2006, 66, 4766–4773. [Google Scholar] [CrossRef] [PubMed]
- Farazi, P.A.; Glickman, J.; Jiang, S.; Yu, A.; Rudolph, K.L.; DePinho, R.A. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 2003, 63, 5021–5027. [Google Scholar] [PubMed]
- Choi, Y.M.; Lee, S.Y.; Kim, B.J. Naturally Occurring Hepatitis B Virus Mutations Leading to Endoplasmic Reticulum Stress and Their Contribution to the Progression of Hepatocellular Carcinoma. Int. J. Mol. Sci. 2019, 20, 597. [Google Scholar] [CrossRef] [PubMed]
- Sun, H.; Chang, L.; Yan, Y.; Wang, L. Hepatitis B virus pre-S region: Clinical implications and applications. Rev. Med. Virol. 2021, 31, e2201. [Google Scholar] [CrossRef] [PubMed]
- Jain, D.; Murti, Y.; Khan, W.U.; Hossain, R.; Hossain, M.N.; Agrawal, K.K.; Ashraf, R.A.; Islam, M.T.; Janmeda, P.; Taheri, Y.; et al. Roles of Therapeutic Bioactive Compounds in Hepatocellular Carcinoma. Oxid. Med. Cell. Longev. 2021, 2021, 9068850. [Google Scholar] [CrossRef]
- Kim, S.Y.; Kyaw, Y.Y.; Cheong, J. Functional interaction of endoplasmic reticulum stress and hepatitis B virus in the pathogenesis of liver diseases. World J. Gastroenterol. 2017, 23, 7657–7665. [Google Scholar] [CrossRef] [PubMed]
- Raghunath, A.; Sundarraj, K.; Arfuso, F.; Sethi, G.; Perumal, E. Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance. Cancers 2018, 10, 481. [Google Scholar] [CrossRef]
- Mossenta, M.; Busato, D.; Dal Bo, M.; Toffoli, G. Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies. Cancers 2020, 12, 1668. [Google Scholar] [CrossRef]
- Juengpanich, S.; Shi, L.; Iranmanesh, Y.; Chen, J.; Cheng, Z.; Khoo, A.K.; Pan, L.; Wang, Y.; Cai, X. The role of natural killer cells in hepatocellular carcinoma development and treatment: A narrative review. Transl. Oncol. 2019, 12, 1092–1107. [Google Scholar] [CrossRef] [PubMed]
- Pollicino, T.; Squadrito, G.; Cerenzia, G.; Cacciola, I.; Raffa, G.; Craxi, A.; Farinati, F.; Missale, G.; Smedile, A.; Tiribelli, C.; et al. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. Gastroenterology 2004, 126, 102–110. [Google Scholar] [CrossRef] [PubMed]
- Sung, W.K.; Zheng, H.; Li, S.; Chen, R.; Liu, X.; Li, Y.; Lee, N.P.; Lee, W.H.; Ariyaratne, P.N.; Tennakoon, C.; et al. Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat. Genet. 2012, 44, 765–769. [Google Scholar] [CrossRef]
- Pollicino, T.; Caminiti, G. HBV-Integration Studies in the Clinic: Role in the Natural History of Infection. Viruses 2021, 13, 368. [Google Scholar] [CrossRef] [PubMed]
- Jang, J.W.; Kim, H.S.; Kim, J.S.; Lee, S.K.; Han, J.W.; Sung, P.S.; Bae, S.H.; Choi, J.Y.; Yoon, S.K.; Han, D.J.; et al. Distinct Patterns of HBV Integration and TERT Alterations between in Tumor and Non-Tumor Tissue in Patients with Hepatocellular Carcinoma. Int. J. Mol. Sci. 2021, 22, 7056. [Google Scholar] [CrossRef]
- Saitta, C.; Tripodi, G.; Barbera, A.; Bertuccio, A.; Smedile, A.; Ciancio, A.; Raffa, G.; Sangiovanni, A.; Navarra, G.; Raimondo, G.; et al. Hepatitis B virus (HBV) DNA integration in patients with occult HBV infection and hepatocellular carcinoma. Liver Int. 2015, 35, 2311–2317. [Google Scholar] [CrossRef] [PubMed]
- Rajaby, R.; Zhou, Y.; Meng, Y.; Zeng, X.; Li, G.; Wu, P.; Sung, W.K. SurVirus: A repeat-aware virus integration caller. Nucleic Acids Res. 2021, 49, e33. [Google Scholar] [CrossRef] [PubMed]
- Hoshida, Y.; Nijman, S.M.; Kobayashi, M.; Chan, J.A.; Brunet, J.P.; Chiang, D.Y.; Villanueva, A.; Newell, P.; Ikeda, K.; Hashimoto, M.; et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009, 69, 7385–7392. [Google Scholar] [CrossRef]
- Fanning, G.C.; Zoulim, F.; Hou, J.; Bertoletti, A. Therapeutic strategies for hepatitis B virus infection: Towards a cure. Nat. Rev. Drug Discov. 2019, 18, 827–844. [Google Scholar] [CrossRef]
- Shinkai, N.; Matsuura, K.; Sugauchi, F.; Watanabe, T.; Murakami, S.; Iio, E.; Ogawa, S.; Nojiri, S.; Joh, T.; Tanaka, Y. Application of a newly developed high-sensitivity HBsAg chemiluminescent enzyme immunoassay for hepatitis B patients with HBsAg seroclearance. J. Clin. Microbiol. 2013, 51, 3484–3491. [Google Scholar] [CrossRef] [PubMed]
- Zhang, K.; Liu, Y.; Chen, R.; Li, Q.; Xu, Z.; Si, L.; Cheng, Y.; Yang, Y.; Chen, J.; Xu, D.; et al. Antigenicity reduction contributes mostly to poor detectability of HBsAg by hepatitis B virus (HBV) S-gene mutants isolated from individuals with occult HBV infection. J. Med. Virol. 2018, 90, 263–270. [Google Scholar] [CrossRef]
- McMahon, B.J. Epidemiology and natural history of hepatitis B. Semin. Liver Dis. 2005, 25 (Suppl. 1), 3–8. [Google Scholar] [CrossRef]
- Wong, D.K.; Cheng, S.C.Y.; Mak, L.L.; To, E.W.; Lo, R.C.; Cheung, T.T.; Seto, W.K.; Fung, J.; Man, K.; Lai, C.L.; et al. Among Patients with Undetectable Hepatitis B Surface Antigen and Hepatocellular Carcinoma, a High Proportion Has Integration of HBV DNA into Hepatocyte DNA and No Cirrhosis. Clin. Gastroenterol. Hepatol. 2020, 18, 449–456. [Google Scholar] [CrossRef] [PubMed]
- Loomba, R.; Liang, T.J. Hepatitis B Reactivation Associated With Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions. Gastroenterology 2017, 152, 1297–1309. [Google Scholar] [CrossRef]
- Boni, C.; Laccabue, D.; Lampertico, P.; Giuberti, T.; Vigano, M.; Schivazappa, S.; Alfieri, A.; Pesci, M.; Gaeta, G.B.; Brancaccio, G.; et al. Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues. Gastroenterology 2012, 143, 963–973.e9. [Google Scholar] [CrossRef] [PubMed]
- Yuen, M.F.; Wong, D.K.; Lee, C.K.; Tanaka, Y.; Allain, J.P.; Fung, J.; Leung, J.; Lin, C.K.; Sugiyama, M.; Sugauchi, F.; et al. Transmissibility of hepatitis B virus (HBV) infection through blood transfusion from blood donors with occult HBV infection. Clin. Infect. Dis. 2011, 52, 624–632. [Google Scholar] [CrossRef]
- Chazouilleres, O.; Mamish, D.; Kim, M.; Carey, K.; Ferrell, L.; Roberts, J.P.; Ascher, N.L.; Wright, T.L. “Occult” hepatitis B virus as source of infection in liver transplant recipients. Lancet 1994, 343, 142–146. [Google Scholar] [CrossRef]
- Ogunwobi, O.O.; Harricharran, T.; Huaman, J.; Galuza, A.; Odumuwagun, O.; Tan, Y.; Ma, G.X.; Nguyen, M.T. Mechanisms of hepatocellular carcinoma progression. World J. Gastroenterol. 2019, 25, 2279–2293. [Google Scholar] [CrossRef]
Gen/Region | Genotype | Mutation | Function | OBI/HBsAg+ | Pathology | Reference |
---|---|---|---|---|---|---|
ORF-S | ||||||
PreS1 | A | Ins of CAACA at nt 503, T Del at nt 523 and 1368–1525 | Alteration of regulatory regions | OBI | HCC | [48] |
B, C | Dels in aa (31–80, 67–55, 92–119, 102–119, 1–83) | Immune escape | OBI | HCC in children | [49] | |
D, A | T40S, P124K, L54D, G76A, Dels in aa 4,8,17 and 86 | Descriptive study | OBI | HCC/Cirrhosis | [50] | |
C | W4R, L30S, I84T, Q118R/Stop | Evasion of the immune response | OBI | HCC | [51] | |
PreS2 | B, C | Dels in aa (1–5,7–20,5–21,12–29,1–12,8–23,1–21) | Evasion of the immune response (B-cell epitope) | OBI | HCC in children | [49] |
D, A | P41H, P66L | HCC | [50] | |||
C | N5D, S5F/D | HCC | [51] | |||
C | Deletions, M1I | Alteration of regulatory regions. Immune escape | HBsAg+ | HCC | [52] | |
S | C | W36L, T47K, N52D, V184A, F220L | Decrease HBsAg secretion, ER stress, and ROS | OBI | HCC | [53] |
C | W74L, L77R | Decrease HBsAg secretion | OBI | HCC | [54] | |
C | L42F/S, Y200F/S | Descriptive study. Evasion of the immune response | OBI | HCC | [51] | |
A, D | F19L, S59F, P24L and Q129H | Descriptive study | OBI | HCC | [50] | |
A, D | P203, S210R | Decrease HBsAg secretion, increase cell proliferation | HBsAg+ | HCC | [55] | |
CTL epitope | A, D | N40S, S45A, V47A | Immune escape, vaccine evasion, disease progression | OBI | HCC | [48] |
“a” det (124–147) | A, D | T125M | Immune escape | OBI | Cirrhosis | [48] |
MHR | B, C | Q101K, T115A, K122N, T123A, T126N, Q129N, G130R, T131I, M133T, F134L, C138Y, K141E, P142S, G145R, N146S, C147F/R | Naturally occurring immune escape variants | OBI | Cirrhosis, blood donors | [56] |
Outside MHR (N-t and C-t regions) | 41, 44, 48, 93, 96, 97, 171, 175, 176, 178, 185, 190, 207, and 213 positions | Immune escape variants | OBI | [57,58] | ||
ORF-C | ||||||
PreC | A, D | A1814T/C, T1815C, G1816T/A (M1L/T/I) | Reduce the expression of HBeAg | HBsAg+ | HCC | [59,60] |
A | G1862T (V17F) | Reduce HBeAg expression | HBsAg+ | HIV | [60] | |
A, C, D | G1896A (W28stop) | Inhibits the production of HBeAg | HBsAg+ | HCC | [61,62,63,64] | |
Core | B, C | C1913A, C1914A/T, G1915A/C (P5T/L/H) | Induces ERO | HBsAg+ | HCC | [53,61,63] |
C | E83D | Immune escape | HCC | [61] | ||
I97F | HBcAg assembly | HCC | ||||
Hot spot region | A, C, D | C2198A (L100I) | Immune evasion by CD4 T cells, disease progression | HBsAg+ | HCC | |
(aa 81–105) | W62R, P50H, S74G | Decreases secretion of HBcAg and HBeAg | Blood donor | [65] | ||
ORF-X | ||||||
EnhII/BCP | B, C | T1753A/C/G (I127T/N/S) | HCC predictor | HBsAg+ | HCC | [66,67,68] |
B, C, D | G1762T (K130M) | It partially contributes to cellular stress, tissue inflammation | HBsAg+ | HCC, fibrosis, cirrhosis | [68,69,70] | |
C | A1762T | Decreases life expectancy | HBsAg+ | HCC | [71,72] | |
B, C, D | G1764A (V131I) | Cellular stress, tissue inflammation | HBsAg+ | HCC, fibrosis, cirrhosis | [68,69,70,73] | |
C | Double mutation A1762T/G1764A | Cellular stress, tissue inflammation, decreases life expectancy | HBsAg+ | HCC | [72,74,75] | |
D | Triple mutationA1757/T1764/G1766 | Associated with the development of HCC | [69] | |||
D | Quadruple mutationT1673/G1679/T1773/G1775 | Synergistic effect on HCC development | ||||
C-t region | C | X8Del | Reduces HBsAg and virions secretion | OBI | None | [41] |
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Bucio-Ortiz, L.; Enriquez-Navarro, K.; Maldonado-Rodríguez, A.; Torres-Flores, J.M.; Cevallos, A.M.; Salcedo, M.; Lira, R. Occult Hepatitis B Virus Infection in Hepatic Diseases and Its Significance for the WHO’s Elimination Plan of Viral Hepatitis. Pathogens 2024, 13, 662. https://doi.org/10.3390/pathogens13080662
Bucio-Ortiz L, Enriquez-Navarro K, Maldonado-Rodríguez A, Torres-Flores JM, Cevallos AM, Salcedo M, Lira R. Occult Hepatitis B Virus Infection in Hepatic Diseases and Its Significance for the WHO’s Elimination Plan of Viral Hepatitis. Pathogens. 2024; 13(8):662. https://doi.org/10.3390/pathogens13080662
Chicago/Turabian StyleBucio-Ortiz, Leticia, Karina Enriquez-Navarro, Angélica Maldonado-Rodríguez, Jesús Miguel Torres-Flores, Ana María Cevallos, Mauricio Salcedo, and Rosalia Lira. 2024. "Occult Hepatitis B Virus Infection in Hepatic Diseases and Its Significance for the WHO’s Elimination Plan of Viral Hepatitis" Pathogens 13, no. 8: 662. https://doi.org/10.3390/pathogens13080662
APA StyleBucio-Ortiz, L., Enriquez-Navarro, K., Maldonado-Rodríguez, A., Torres-Flores, J. M., Cevallos, A. M., Salcedo, M., & Lira, R. (2024). Occult Hepatitis B Virus Infection in Hepatic Diseases and Its Significance for the WHO’s Elimination Plan of Viral Hepatitis. Pathogens, 13(8), 662. https://doi.org/10.3390/pathogens13080662