Next Article in Journal
Competitive Cooperation of Hemagglutinin and Neuraminidase during Influenza A Virus Entry
Next Article in Special Issue
Caucasian Ethnicity, but Not Treatment Cessation Is Associated with HBsAg Loss Following Nucleos(t)ide Analogue-Induced HBeAg Seroconversion
Previous Article in Journal
Genetic Variability and Evolution of Hepatitis E Virus

Viruses 2019, 11(5), 457; https://doi.org/10.3390/v11050457

Review
Roles of Hepatitis B Virus Mutations in the Viral Reactivation after Immunosuppression Therapies
Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan
*
Author to whom correspondence should be addressed.
Received: 19 April 2019 / Accepted: 16 May 2019 / Published: 19 May 2019

Abstract

:
Reactivation of hepatitis B virus (HBV) is a major problem in patients receiving chemotherapy for malignant diseases or immunosuppression therapies. It has been thought that a reduction in the immune responses might result in the reactivation of HBV replication from covalently closed circular DNA (cccDNA) residing in hepatocytes. However, not only the host’s immune status, but also viral mutations have been reported to be associated with reactivation. Especially, several case reports about amino acid mutations in hepatitis B surface antigen (HBsAg) that escape from immune reactions have been reported, and recent reports showed that the frequencies of such mutations are higher than previously expected. In this review, we summarize the characteristics of viral mutations, including immune escape mutations in HBV-reactivated patients, and discuss their significance.
Keywords:
HBV; reactivation; immune escape mutation; HBsAg

1. Introduction

Hepatitis B virus (HBV) infection is a worldwide health problem. HBsAg-positive patients with high levels of serum HBV DNA and alanine aminotransferase (ALT) are targets of anti-viral therapies because they are at high risk of liver cirrhosis and hepatocellular carcinoma (HCC) [1]. It is estimated that almost one third of people in the world experience infection [2] and, among them, almost 248 million persons are estimated to have hepatitis B surface antigen (HBsAg) [3]. Generally, HBsAg-positive persons are considered to have HBV persistent infection, and those in whom HBsAg has cleared are thought to be in a cured status. It is known that anti-cancer chemotherapies or immunosuppressive therapies can induce HBV reactivation not only in HBsAg-positive patients, but also in HBsAg-cleared patients [4]. What is the cause of HBV reactivation even in such patients?
In HBV infection, T-cell and B-cell responses affect the outcome of the liver disease [5]. These responses are essential to control HBV infection in the natural course. HBV-specific T-cell responses suppress viral replication by both cytopathic effects [6] and non-cytopathic cytokine pathways [7]. B-cells produce neutralizing antibodies against HBV and inhibit the spread of HBV infection to other hepatocytes. It has been revealed that covalently closed circular DNA (cccDNA) persists in the hepatocytes of patients who cleared HBsAg with such immune responses [8]. The presence of cccDNA and the weakened immune responses are thought to enable HBV reactivation in patients with resolved infection [9]. Because HBsAg-cleared patients have antibodies against HBs (HBsAb) and/or those against hepatitis B core (HBcAb), patients with these antibodies should be monitored carefully during chemo/immunosuppression therapies [9].
The definition of HBV reactivation was proposed by the American Association of the Study for the Liver Diseases in 2013 as either an exacerbation of chronic HBV infection or reactivation of past HBV infection after the start of immunosuppressive therapy [10]. An exacerbation of chronic HBV infection was defined as HBsAg positivity with ≥2 log10 increase in the HBV DNA levels from the baseline levels, an HBV DNA level of >100 IU/mL in a person with undetectable HBV DNA at baseline, or an HBV DNA level of ≥100,000 IU/mL in a person whose HBV DNA was not tested at baseline. Reactivation of past HBV was defined as reverse HBsAg seroconversion (HBsAg-negative becomes HBsAg-positive), or the appearance of HBV DNA in the absence of HBsAg.
In regard to the factors associated with HBV reactivation, not only the types of drugs used for chemo/immunosuppression therapies, but also the viral mutations have been reported. Recently, the high frequency of HBsAg mutations in HBV-reactivated patients has been reported [11,12]. HBV with these HBsAg mutations is considered to escape from recognition by the immune system, and this may be important in considering the mechanisms of the HBV reactivation. Here we summarize the recent findings on the viral mutations, including immune escape mutations found in HBV-reactivated patients with chemo/immunosuppression therapies, and we discuss the mechanisms of HBV reactivation.

2. HBsAg Mutations Found in HBV-Reactivated Patients After Chemotherapies/Immunosuppression Therapies

The envelope proteins of HBV are encoded by the preS/S gene. Three hepatitis B surface proteins (large (LHBs), middle (MHBs), and small (SHBs or HBsAg)) are translated from three different initiation codons to the common termination codon. The amino acid sequence of HBsAg consists of three major parts: N-terminal region (amino acids 1–99), major hydrophilic region (MHR, amino acids 100–169), and C-terminal region (amino acids 170–226). MHR contains major epitopes exposed on the surface of HBV particles, and especially, the “a” determinant (amino acids 124–147) is a major target of neutralizing antibodies [13,14].
The escape mutations in the “a” determinant were reported to be present in HBV-infected patients who had been vaccinated [13]. It is known that the binding affinity of HBsAb to HBsAg with these mutations is weak. An HBV-reactivated case after chemotherapy who had an escape mutation was reported first by Carman et al. in 1995 [15]. The case developed fulminant hepatitis and had the G145R mutation in the “a” determinant. Subsequently, some case reports showing HBV-reactivated patients with escape mutations in HBsAg appeared [16,17]. Recently, Salpini et al. reported that 79% of 29 HBV-reactivated patients with immunosuppression therapy had HBV with amino acid mutations in the immune-active HBs regions based on results from direct and ultradeep sequencing using plasma samples [12]. All patients were infected with genotype D HBV, and the percentage was significantly higher than in patients with chronic infection of genotype D HBV. Most (8/13) of the mutations are located within MHR, including the “a” determinant, and, of note, some (5/13) mutations were found in class I/II-restricted T-cell epitopes, suggesting that escape from T-cell responses might play a role in HBV reactivation. The mutations in MHR contain those making additional N-linked glycosylation (NLG) sites, which reduce HBsAb recognition. Colson et al. performed direct sequencing of S gene using serum samples from 16 HBV-reactivated patients who were negative for HBsAg before chemotherapy, and showed that all patients had at least one amino acid mutation in MHR [11]. Most patients were genotype D (13/16), and it is considered that escape mutations in MHR of HBsAg might be associated with most HBV reactivations after immunosuppressive therapies, at least in patients with genotype D HBV. In Table 1, the mutations in HBsAg that were found in HBV-reactivated patients are summarized. Most mutations were identified with direct sequencing of S gene using serum samples. As shown in the table, some mutations were reported to reduce the recognition by antibodies using in vitro assays such as the western blotting analysis and enzyme-linked immunosorbent assay (ELISA). It should be taken into account that the wild type amino acids at some positions differ among genotypes. Additionally, several mutations could induce the overlapping transcriptase domain of polymerase, including rtA181T/S, which is known to cause drug resistance. Although these polymerase mutations might affect the viral replication, their significance in the reactivation is unknown. To elucidate the general roles of HBsAg mutations in HBV reactivation, more HBV-reactivated patients, including those with HBV of genotypes other than genotype D, have to be analyzed in future studies.

3. Mechanisms by Which Immune Escape Mutations Arise in HBV-Reactivated Patients

As described above, immune escape mutations in HBsAg were found in patients with HBV reactivation, although the frequencies could vary among the genotypes of HBV. Why are such mutations present? A possible reason is the selection of immune escape mutants during the treatment with immunosuppressive therapies. In HBsAg-disappeared patients, the immune system, including HBsAb in the serum, suppresses HBV replication. HBsAb in excess binds to HBsAg and inhibits the detection of low-level HBsAg in most assays. Also, it binds to the infectious HBV particles (Dane particles) and inhibits the entry to hepatocytes. Even if a small amount of immune escape mutant emerges as a random event, excessive HBsAb might inhibit the spread of mutant HBV. In an immunosuppression state, the production of HBsAb decreases, and Dane particles with immune escape mutations, which are less recognized by HBsAb, might become easier to enter into uninfected hepatocytes, which might spread the infection. Therefore, less or an undetectable level of HBsAb at the start of immunosuppressive therapy could be a risk factor for HBV reactivation [42,43,44,45]. In this context, the escape mutations might be results from reduced selection pressure, and their high frequencies in reactivated patients might indicate that these have critical roles during the reactivation. Additionally, the administration of glucocorticoids, which stimulate glucocorticoid-responsive element (GRE), increases the transcription from cccDNA [46] and might boost the chance of mutation.
Another possible reason is underestimation of the HBsAg level because of immune escape mutations. As shown in Table 1, many mutations in MHR were reported to reduce recognition by antibodies and might reduce the signal of HBsAg detection with various methods such as ELISA and chemiluminescent immunoassay (CLIA). To detect immune escape mutants, some methods use a polyclonal antibody or a mixture of some monoclonal antibodies, but there is still a possibility that HBsAg signals are reduced by the presence of such mutations [47]. Therefore, an HBV carrier with escape mutants can be misdiagnosed as in a state of resolved infection because of the presence of HBsAb and/or HBcAb. Being unaware of HBV infection might lead to HBV reactivation from the lack of prophylaxis with the nucleos(t)ide analogue. We should pay an attention to such patients, including occult infection of HBV.

4. Precore Mutation in Patients With HBV Reactivation

Several papers showed that the precore G1896A mutation, which makes a stop codon in the precore/core protein and abrogates the HBeAg expression, was associated with HBV reactivation [48,49,50,51,52]. Fatal cases of HBV reactivation harboring this mutation have been reported [53,54]. Also, some papers reported that the core promoter mutations of A1762T/G1764A were found in the reactivated patients. The association between these mutations and fulminant hepatitis in acute infection has been reported [55]. The precore mutation is considered to make the replication capacity higher if there are no or only weak adaptive immune responses [56]. On the other hand, these mutations were found frequently in the inactive HBV carriers, indicating that the HBV clones with these mutations are selected after pressure from the immune responses. These mutations reduce the expression of HBeAg, which is considered to have an immunoregulatory role and to be required for the development of persistent infection [57]. Therefore, HBV with the core promoter/precore mutations has high replication capacity and can cause stronger immune responses. If these mutations are present with immune escape mutations, it might enhance the HBV reactivation further. Although the frequency of the co-presence of these mutations has not been reported, we previously reported a genotype C HBV-reactivated case with immune escape mutations of P120A + G145R and mixed type precore mutation (G1896R) [23].

5. Conclusions

Immune escape mutations in HBsAg were frequently found in HBV-reactivated patients. The frequency was reported mainly in patients with genotype D HBV, but further studies in patients with HBV of genotypes other than D will be required to reveal the difference among HBV genotypes. The emergence of mutants might suggest the mechanisms of HBV reactivation, which could be important for the prevention of reactivation.

Author Contributions

J.I. and T.N. compiled the complete draft and modification of the manuscript. A.M. provided critiques on the work and finalized the article prior to submission.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Dienstag, J.L. Hepatitis B virus infection. N. Engl. J. Med. 2008, 359, 1486–1500. [Google Scholar] [CrossRef] [PubMed]
  2. Lee, W.M. Hepatitis B virus infection. N. Engl. J. Med. 1997, 337, 1733–1745. [Google Scholar] [CrossRef]
  3. Schweitzer, A.; Horn, J.; Mikolajczyk, R.T.; Krause, G.; Ott, J.J. Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965 and 2013. Lancet 2015, 386, 1546–1555. [Google Scholar] [CrossRef]
  4. Hoofnagle, J.H. Reactivation of hepatitis B. Hepatology 2009, 49, S156–S165. [Google Scholar] [CrossRef][Green Version]
  5. Das, A.; Maini, M.K. Innate and adaptive immune responses in hepatitis B virus infection. Dig. Dis. 2010, 28, 126–132. [Google Scholar] [CrossRef]
  6. Moriyama, T.; Guilhot, S.; Klopchin, K.; Moss, B.; Pinkert, C.A.; Palmiter, R.D.; Brinster, R.L.; Kanagawa, O.; Chisari, F.V. Immunobiology and pathogenesis of hepatocellular injury in hepatitis B virus transgenic mice. Science 1990, 248, 361–364. [Google Scholar] [CrossRef] [PubMed]
  7. Kakimi, K.; Lane, T.E.; Wieland, S.; Asensio, V.C.; Campbell, I.L.; Chisari, F.V.; Guidotti, L.G. Blocking chemokine responsive to gamma-2/interferon (IFN)-gamma inducible protein and monokine induced by IFN-gamma activity in vivo reduces the pathogenetic but not the antiviral potential of hepatitis B virus-specific cytotoxic T lymphocytes. J. Exp. Med. 2001, 194, 1755–1766. [Google Scholar] [CrossRef] [PubMed]
  8. Werle-Lapostolle, B.; Bowden, S.; Locarnini, S.; Wursthorn, K.; Petersen, J.; Lau, G.; Trepo, C.; Marcellin, P.; Goodman, Z.; Delaney, W.E.t.; et al. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 2004, 126, 1750–1758. [Google Scholar] [CrossRef] [PubMed]
  9. 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] [PubMed]
  10. Hwang, J.P.; Lok, A.S. Management of patients with hepatitis B who require immunosuppressive therapy. Nat. Rev. Gastroenterol. Hepatol. 2014, 11, 209–219. [Google Scholar] [CrossRef]
  11. Colson, P.; Borentain, P.; Coso, D.; Motte, A.; Aurran-Schleinitz, T.; Charbonnier, A.; Stoppa, A.M.; Chabannon, C.; Serrero, M.; Bertrand, J.; et al. Hepatitis B virus reactivation in HBsAg-negative patients is associated with emergence of viral strains with mutated HBsAg and reverse transcriptase. Virology 2015, 484, 354–363. [Google Scholar] [CrossRef][Green Version]
  12. Salpini, R.; Colagrossi, L.; Bellocchi, M.C.; Surdo, M.; Becker, C.; Alteri, C.; Aragri, M.; Ricciardi, A.; Armenia, D.; Pollicita, M.; et al. Hepatitis B surface antigen genetic elements critical for immune escape correlate with hepatitis B virus reactivation upon immunosuppression. Hepatology 2015, 61, 823–833. [Google Scholar] [CrossRef] [PubMed][Green Version]
  13. Carman, W.F.; Zanetti, A.R.; Karayiannis, P.; Waters, J.; Manzillo, G.; Tanzi, E.; Zuckerman, A.J.; Thomas, H.C. Vaccine-induced escape mutant of hepatitis B virus. Lancet 1990, 336, 325–329. [Google Scholar] [CrossRef]
  14. Brown, S.E.; Howard, C.R.; Zuckerman, A.J.; Steward, M.W. Affinity of antibody responses in man to hepatitis B vaccine determined with synthetic peptides. Lancet 1984, 2, 184–187. [Google Scholar] [CrossRef]
  15. Carman, W.F.; Korula, J.; Wallace, L.; MacPhee, R.; Mimms, L.; Decker, R. Fulminant reactivation of hepatitis B due to envelope protein mutant that escaped detection by monoclonal HBsAg ELISA. Lancet 1995, 345, 1406–1407. [Google Scholar] [CrossRef]
  16. Westhoff, T.H.; Jochimsen, F.; Schmittel, A.; Stoffler-Meilicke, M.; Schafer, J.H.; Zidek, W.; Gerlich, W.H.; Thiel, E. Fatal hepatitis B virus reactivation by an escape mutant following rituximab therapy. Blood 2003, 102, 1930. [Google Scholar] [CrossRef]
  17. Alexopoulou, A.; Dourakis, S.P.; Pandelidaki, H.; Archimandritis, A.J.; Karayiannis, P. Detection of a hepatitis B surface antigen variant emerging in a patient with chronic lymphocytic leukaemia treated with fludarabine. J. Med. Virol. 2006, 78, 1043–1046. [Google Scholar] [CrossRef]
  18. Svicher, V.; Cento, V.; Bernassola, M.; Neumann-Fraune, M.; Van Hemert, F.; Chen, M.; Salpini, R.; Liu, C.; Longo, R.; Visca, M.; et al. Novel HBsAg markers tightly correlate with occult HBV infection and strongly affect HBsAg detection. Antiviral Res. 2012, 93, 86–93. [Google Scholar] [CrossRef][Green Version]
  19. Wu, C.; Shi, H.; Wang, Y.; Lu, M.; Xu, Y.; Chen, X. A case of hepatitis B reactivation due to the hepatitis B virus escape mutant in a patient undergoing chemotherapy. Virol. Sin. 2012, 27, 369–372. [Google Scholar] [CrossRef]
  20. Hyakumura, M.; Walsh, R.; Thaysen-Andersen, M.; Kingston, N.J.; La, M.; Lu, L.; Lovrecz, G.; Packer, N.H.; Locarnini, S.; Netter, H.J. Modification of Asparagine-Linked Glycan Density for the Design of Hepatitis B Virus Virus-Like Particles with Enhanced Immunogenicity. J. Virol. 2015, 89, 11312–11322. [Google Scholar] [CrossRef][Green Version]
  21. Ceccarelli, L.; Salpini, R.; Sarmati, L.; Svicher, V.; Bertoli, A.; Sordillo, P.; Ricciardi, A.; Perno, C.F.; Andreoni, M.; Sarrecchia, C. Late hepatitis B virus reactivation after lamivudine prophylaxis interruption in an anti-HBs-positive and anti-HBc-negative patient treated with rituximab-containing therapy. J. Infect. 2012, 65, 180–183. [Google Scholar] [CrossRef]
  22. Kfoury Baz, E.M.; Zheng, J.; Mazuruk, K.; Van Le, A.; Peterson, D.L. Characterization of a novel hepatitis B virus mutant: demonstration of mutation-induced hepatitis B virus surface antigen group specific "a" determinant conformation change and its application in diagnostic assays. Transfus. Med. 2001, 11, 355–362. [Google Scholar] [CrossRef] [PubMed]
  23. Inoue, J.; Kondo, Y.; Wakui, Y.; Kogure, T.; Morosawa, T.; Fujisaka, Y.; Umetsu, T.; Takai, S.; Nakamura, T.; Shimosegawa, T. Reactivation of resolved hepatitis B virus infection with immune escape mutations after long-term corticosteroid therapy. Clin. J. Gastroenterol. 2016, 9, 93–98. [Google Scholar] [CrossRef] [PubMed]
  24. Cheung, W.I.; Chan, H.L.; Leung, V.K.; Tse, C.H.; Fung, K.; Lin, S.Y.; Wong, A.; Wong, V.W.; Chau, T.N. Reactivation of hepatitis B virus infection with persistently negative HBsAg on three HBsAg assays in a lymphoma patient undergoing chemotherapy. J. Clin. Virol. 2010, 47, 193–195. [Google Scholar] [CrossRef]
  25. Hsu, C.W.; Yeh, C.T.; Chang, M.L.; Liaw, Y.F. Identification of a hepatitis B virus S gene mutant in lamivudine-treated patients experiencing HBsAg seroclearance. Gastroenterology 2007, 132, 543–550. [Google Scholar] [CrossRef] [PubMed]
  26. Kucinskaite-Kodze, I.; Pleckaityte, M.; Bremer, C.M.; Seiz, P.L.; Zilnyte, M.; Bulavaite, A.; Mickiene, G.; Zvirblis, G.; Sasnauskas, K.; Glebe, D.; et al. New broadly reactive neutralizing antibodies against hepatitis B virus surface antigen. Virus Res. 2016, 211, 209–221. [Google Scholar] [CrossRef] [PubMed]
  27. Martel, N.; Cotte, L.; Trabaud, M.A.; Trepo, C.; Zoulim, F.; Gomes, S.A.; Kay, A. Probable corticosteroid-induced reactivation of latent hepatitis B virus infection in an HIV-positive patient involving immune escape. J. Infect. Dis. 2012, 205, 1757–1761. [Google Scholar] [CrossRef]
  28. Blaich, A.; Manz, M.; Dumoulin, A.; Schuttler, C.G.; Hirsch, H.H.; Gerlich, W.H.; Frei, R. Reactivation of hepatitis B virus with mutated hepatitis B surface antigen in a liver transplant recipient receiving a graft from an antibody to hepatitis B surface antigen- and antibody to hepatitis B core antigen-positive donor. Transfusion 2012, 52, 1999–2006. [Google Scholar] [CrossRef] [PubMed]
  29. 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]
  30. Ito, K.; Qin, Y.; Guarnieri, M.; Garcia, T.; Kwei, K.; Mizokami, M.; Zhang, J.; Li, J.; Wands, J.R.; Tong, S. Impairment of hepatitis B virus virion secretion by single-amino-acid substitutions in the small envelope protein and rescue by a novel glycosylation site. J. Virol. 2010, 84, 12850–12861. [Google Scholar] [CrossRef]
  31. Zheng, X.; Weinberger, K.M.; Gehrke, R.; Isogawa, M.; Hilken, G.; Kemper, T.; Xu, Y.; Yang, D.; Jilg, W.; Roggendorf, M.; et al. Mutant hepatitis B virus surface antigens (HBsAg) are immunogenic but may have a changed specificity. Virology 2004, 329, 454–464. [Google Scholar] [CrossRef][Green Version]
  32. Sadeghi, A.; Shirvani-Dastgerdi, E.; Tacke, F.; Yagmur, E.; Poortahmasebi, V.; Poorebrahim, M.; Mohraz, M.; Hajabdolbaghi, M.; Rasoolinejad, M.; Abbasian, L.; et al. HBsAg mutations related to occult hepatitis B virus infection in HIV-positive patients result in a reduced secretion and conformational changes of HBsAg. J. Med. Virol. 2017, 89, 246–256. [Google Scholar] [CrossRef]
  33. Verheyen, J.; Neumann-Fraune, M.; Berg, T.; Kaiser, R.; Obermeier, M. The detection of HBsAg mutants expressed in vitro using two different quantitative HBsAg assays. J. Clin. Virol. 2012, 54, 279–281. [Google Scholar] [CrossRef]
  34. Fylaktou, A.; Daoudaki, M.; Dimou, V.; Sianou, E.; Papaventsis, D.; Mavrovouniotis, I.; Fouzas, I.; Papanikolaou, V. Hepatitis B reactivation in a renal transplant patient due to a surface antigen mutant strain: a case report. Transplant Proc. 2012, 44, 2773–2775. [Google Scholar] [CrossRef]
  35. Schubert, A.; Michel, D.; Mertens, T. Late HBsAg seroreversion of mutated hepatitis B virus after bone marrow transplantation. BMC Infect. Dis. 2013, 13, 223. [Google Scholar] [CrossRef] [PubMed]
  36. Huang, C.H.; Yuan, Q.; Chen, P.J.; Zhang, Y.L.; Chen, C.R.; Zheng, Q.B.; Yeh, S.H.; Yu, H.; Xue, Y.; Chen, Y.X.; et al. Influence of mutations in hepatitis B virus surface protein on viral antigenicity and phenotype in occult HBV strains from blood donors. J. Hepatol. 2012, 57, 720–729. [Google Scholar] [CrossRef] [PubMed]
  37. Kim, K.H.; Lee, K.H.; Chang, H.Y.; Ahn, S.H.; Tong, S.; Yoon, Y.J.; Seong, B.L.; Kim, S.I.; Han, K.H. Evolution of hepatitis B virus sequence from a liver transplant recipient with rapid breakthrough despite hepatitis B immune globulin prophylaxis and lamivudine therapy. J. Med. Virol. 2003, 71, 367–375. [Google Scholar] [CrossRef]
  38. Ando, T.; Kojima, K.; Isoda, H.; Eguchi, Y.; Honda, T.; Ishigami, M.; Kimura, S. Reactivation of resolved infection with the hepatitis B virus immune escape mutant G145R during dasatinib treatment for chronic myeloid leukemia. Int. J. Hematol. 2015, 102, 379–382. [Google Scholar] [CrossRef] [PubMed]
  39. Protzer-Knolle, U.; Naumann, U.; Bartenschlager, R.; Berg, T.; Hopf, U.; Meyer zum Buschenfelde, K.H.; Neuhaus, P.; Gerken, G. Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation. Hepatology 1998, 27, 254–263. [Google Scholar] [CrossRef][Green Version]
  40. Yatsuji, H.; Noguchi, C.; Hiraga, N.; Mori, N.; Tsuge, M.; Imamura, M.; Takahashi, S.; Iwao, E.; Fujimoto, Y.; Ochi, H.; et al. Emergence of a novel lamivudine-resistant hepatitis B virus variant with a substitution outside the YMDD motif. Antimicrob. Agents Chemother. 2006, 50, 3867–3874. [Google Scholar] [CrossRef] [PubMed]
  41. Karatayli, E.; Karayalcin, S.; Karaaslan, H.; Kayhan, H.; Turkyilmaz, A.R.; Sahin, F.; Yurdaydin, C.; Bozdayi, A.M. A novel mutation pattern emerging during lamivudine treatment shows cross-resistance to adefovir dipivoxil treatment. Antivir. Ther. 2007, 12, 761–768. [Google Scholar] [PubMed]
  42. Huang, Y.H.; Hsiao, L.T.; Hong, Y.C.; Chiou, T.J.; Yu, Y.B.; Gau, J.P.; Liu, C.Y.; Yang, M.H.; Tzeng, C.H.; Lee, P.C.; et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J. Clin. Oncol. 2013, 31, 2765–2772. [Google Scholar] [CrossRef]
  43. Hsu, C.; Tsou, H.H.; Lin, S.J.; Wang, M.C.; Yao, M.; Hwang, W.L.; Kao, W.Y.; Chiu, C.F.; Lin, S.F.; Lin, J.; et al. Chemotherapy-induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study. Hepatology 2014, 59, 2092–2100. [Google Scholar] [CrossRef]
  44. Seto, W.K.; Chan, T.S.; Hwang, Y.Y.; Wong, D.K.; Fung, J.; Liu, K.S.; Gill, H.; Lam, Y.F.; Lie, A.K.; Lai, C.L.; et al. Hepatitis B reactivation in patients with previous hepatitis B virus exposure undergoing rituximab-containing chemotherapy for lymphoma: a prospective study. J. Clin. Oncol. 2014, 32, 3736–3743. [Google Scholar] [CrossRef] [PubMed]
  45. Kusumoto, S.; Tanaka, Y.; Suzuki, R.; Watanabe, T.; Nakata, M.; Takasaki, H.; Fukushima, N.; Fukushima, T.; Moriuchi, Y.; Itoh, K.; et al. Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study. Clin. Infect. Dis. 2015, 61, 719–729. [Google Scholar] [CrossRef][Green Version]
  46. Tur-Kaspa, R.; Burk, R.D.; Shaul, Y.; Shafritz, D.A. Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proc. Natl. Acad. Sci. USA 1986, 83, 1627–1631. [Google Scholar] [CrossRef] [PubMed]
  47. Thibault, V.; Servant-Delmas, A.; Ly, T.D.; Roque-Afonso, A.M.; Laperche, S. Performance of HBsAg quantification assays for detection of Hepatitis B virus genotypes and diagnostic escape-variants in clinical samples. J. Clin. Virol. 2017, 89, 14–21. [Google Scholar] [CrossRef]
  48. Steinberg, J.L.; Yeo, W.; Zhong, S.; Chan, J.Y.; Tam, J.S.; Chan, P.K.; Leung, N.W.; Johnson, P.J. Hepatitis B virus reactivation in patients undergoing cytotoxic chemotherapy for solid tumours: precore/core mutations may play an important role. J. Med. Virol. 2000, 60, 249–255. [Google Scholar] [CrossRef]
  49. Yeo, W.; Zhong, S.; Chan, P.K.; Ho, W.M.; Wong, H.T.; Chan, A.S.; Johnson, P.J. Sequence variations of precore/core and precore promoter regions of hepatitis B virus in patients with or without viral reactivation during cytotoxic chemotherapy. J. Viral Hepat. 2000, 7, 448–458. [Google Scholar] [CrossRef]
  50. Dai, M.S.; Lu, J.J.; Chen, Y.C.; Perng, C.L.; Chao, T.Y. Reactivation of precore mutant hepatitis B virus in chemotherapy-treated patients. Cancer 2001, 92, 2927–2932. [Google Scholar] [CrossRef][Green Version]
  51. Chen, P.M.; Yao, N.S.; Wu, C.M.; Yang, M.H.; Lin, Y.C.; Hsiao, L.T.; Yen, C.C.; Wang, W.S.; Fan, F.S.; Chiou, T.J.; et al. Detection of reactivation and genetic mutations of the hepatitis B virus in patients with chronic hepatitis B infections receiving hematopoietic stem cell transplantation. Transplantation 2002, 74, 182–188. [Google Scholar] [CrossRef] [PubMed]
  52. Alexopoulou, A.; Theodorou, M.; Dourakis, S.P.; Karayiannis, P.; Sagkana, E.; Papanikolopoulos, K.; Archimandritis, A.J. Hepatitis B virus reactivation in patients receiving chemotherapy for malignancies: role of precore stop-codon and basic core promoter mutations. J. Viral Hepat. 2006, 13, 591–596. [Google Scholar] [CrossRef] [PubMed]
  53. Sugauchi, F.; Tanaka, Y.; Kusumoto, S.; Matsuura, K.; Sugiyama, M.; Kurbanov, F.; Ueda, R.; Mizokami, M. Virological and clinical characteristics on reactivation of occult hepatitis B in patients with hematological malignancy. J. Med. Virol. 2011, 83, 412–418. [Google Scholar] [CrossRef]
  54. Marusawa, H.; Imoto, S.; Ueda, Y.; Chiba, T. Reactivation of latently infected hepatitis B virus in a leukemia patient with antibodies to hepatitis B core antigen. J. Gastroenterol. 2001, 36, 633–636. [Google Scholar] [CrossRef]
  55. Inoue, J. Factors involved in the development of fulminant hepatitis B: Are the mutations of hepatitis B virus implicated? Hepatol. Res. 2009, 39, 1053–1055. [Google Scholar] [PubMed]
  56. Inoue, J.; Ueno, Y.; Wakui, Y.; Fukushima, K.; Kondo, Y.; Kakazu, E.; Ninomiya, M.; Niitsuma, H.; Shimosegawa, T. Enhanced replication of hepatitis B virus with frameshift in the precore region found in fulminant hepatitis patients. J. Infect. Dis. 2011, 204, 1017–1025. [Google Scholar] [CrossRef]
  57. Milich, D.; Liang, T.J. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology 2003, 38, 1075–1086. [Google Scholar] [CrossRef][Green Version]
Table 1. Reported mutations of HBsAg that were found in HBV-reactivated patients with chemotherapies/immunosuppression therapies.
Table 1. Reported mutations of HBsAg that were found in HBV-reactivated patients with chemotherapies/immunosuppression therapies.
HBsAg RegionAmino Acid PositionSpecific HBV Genotype aMutant Amino AcidReferencesNote b
N-terminalF8A, C, DL, P[11]rtI16T, rtP17T/A
C48 G[12]rtV56G
V96 A[12]
MHRY100 [12]Reduces recognition by antibodies in vitro (Y100S) [18]
M103 I[11,12]rtV112F/L/I
L109 Del, I, Q[11,12]rtS117Y
L110CR, I[16,19]Shown only in case reports, rtT118N
S114B, C, D [12]
T115 [12]
T116 N[11]Reduces recognition by antibodies in vitro [18], make an additional N-glycosylation site [20], rtH124Q
T118 K[12,21]Reduces recognition by antibodies with P120Q in vitro [22], rtH126Q
P120 A, T[12,23,24]Reduces recognition by antibodies in vitro (P120A) [25], rtT128S/N
R122DK[16]Reduces recognition by antibodies in vitro [26], rtP130Q
K122 A, B, CR[24,27]Reduces recognition by antibodies in vitro [27]
cC124 N[17]Shown only in a case report, rtL132K
cT126A, B, DN, I[11]rtD134E
cI126 CT[11]
cP127 S[28]Shown only in a case report, rtS135F
cQ129 R[28]Shown only in a case report
cG130 R[17]Reduces recognition by antibodies with M133T and F134L in vitro [29], rtR138K/T
cM133 T[24]Makes an additional N-glycosylation site [30]
cF134A, B, CI, Y, S, L[11,16,24]Reduces recognition by antibodies in vitro (F134S) [31], rtV142D, S143T/A
cY134 DF, N, H[11,12]rtV142E/A
cS136 Y, F[11]Reduces recognition by antibodies in vitro (S136Y) [32]
cP142 L[16]Reduces recognition by antibodies in vitro [33]
cS143C, DL[12]Reduces recognition by antibodies with Y100S or T116N in vitro [18]
cD144 A, E[11,12,16,24,27,34,35]Reduces recognition by antibodies in vitro (D144A [36], D144E [27,37]), rtR153G
cG145 R, A, E[11,15,23,24,35,38]Reduces recognition by antibodies in vitro (G145R [31], G145A [39]), rtR153Q/P
cN146 S[17]Shown only in a case report
E164 G, V[11]
C-terminalS171 F[12,17]
W172 L, C[11]rtA181T/S [40,41]
S174 N[11]
L175 S[11,12,17]
V177 A, L[11]rtS185T
G185 E[12,17]
V190 A[12]
S193 L[11]
MHR, major hydrophilic region. a If the wild type amino acid at each position is different among genotypes A–D, the specific genotypes with the indicated wild type amino acid are shown. b The amino acid mutations that could be caused in the overlapping reverse transcriptase domain of polymerase by the same nucleotide mutations are shown in italic type. c Amino acid positions within the “a” determinant.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Back to TopTop