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Should Indications for Antiviral Therapy for Hepatitis B Be Broadened to Include Immune-Tolerant Patients, Inactive Carriers, or Patients in the “Gray Zone”?

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Abstract

Purpose of Review

Current antiviral therapy effectively suppresses hepatitis B virus (HBV) replication and improves the prognosis. It cannot cure HBV infection. Current clinical guidelines do not advocate universal treatment for all with chronic hepatitis B. However, recent studies are deliberating the expansion of treatment eligibility criteria to encompass those in immune-tolerant, inactive carrier, and gray zone statuses. This review examines the updated information regarding this issue.

Recent Findings

For immune-tolerant patients and patients in the gray zone, treatment eligibility might be considered for those with active or significant fibrosis/inflammation, especially those that remain in the immune-tolerant phase older than 30–40. Current evidence does not suggest that antiviral treatment would be beneficial for true inactive carriers.

Summary

Evidence-based management is crucial in current antiviral therapy. Appropriate monitoring and evaluation help identify individuals who would benefit from antiviral treatment. Expanding indications may hinge on new evidence or curative therapies with finite durations if available.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. World Health Organization. Global hepatitis report. Geneva, Switzerland: World Health Organization; 2019.

    Google Scholar 

  2. Global health sector strategy on viral hepatitis 2016–2021. Towards ending viral hepatitis. 2016. [press release]. 2016.

  3. Ko C, Chakraborty A, Chou WM, Hasreiter J, Wettengel JM, Stadler D, et al. Hepatitis B virus genome recycling and de novo secondary infection events maintain stable cccDNA levels. J Hepatol. 2018;69(6):1231–41. https://doi.org/10.1016/j.jhep.2018.08.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ghany MG, Lok AS. Functional cure of hepatitis B requires silencing covalently closed circular and integrated hepatitis B virus DNA. J Clin Invest. 2022;132(18). https://doi.org/10.1172/JCI163175.

  5. Bertoletti A, Ferrari C. Adaptive immunity in HBV infection. J Hepatol. 2016;64(1 Suppl):S71–83. https://doi.org/10.1016/j.jhep.2016.01.026.

    Article  CAS  PubMed  Google Scholar 

  6. Yip TC, Wong GL, Chan HL, Tse YK, Lam KL, Lui GC, et al. HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues. J Hepatol. 2019;70(3):361–70. https://doi.org/10.1016/j.jhep.2018.10.014.

    Article  CAS  PubMed  Google Scholar 

  7. Cornberg M, Lok AS, Terrault NA, Zoulim F. Guidance for design and endpoints of clinical trials in chronic hepatitis B - report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference. J Hepatol. 2020;72(3):539–57. https://doi.org/10.1016/j.jhep.2019.11.003.

    Article  CAS  PubMed  Google Scholar 

  8. Chu CM, Hung SJ, Lin J, Tai DI, Liaw YF. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels. Am J Med. 2004;116(12):829–34. https://doi.org/10.1016/j.amjmed.2003.12.040.

    Article  CAS  PubMed  Google Scholar 

  9. Lee HA, Lee HW, Kim IH, Park SY, Sinn DH, Yu JH, et al. Extremely low risk of hepatocellular carcinoma development in patients with chronic hepatitis B in immune-tolerant phase. Aliment Pharmacol Ther. 2020;52(1):196–204. https://doi.org/10.1111/apt.15741.

    Article  CAS  PubMed  Google Scholar 

  10. Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, et al. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007;46(2):395–401. https://doi.org/10.1002/hep.21724.

    Article  PubMed  Google Scholar 

  11. Lee HW, Kim EH, Lee J, Kim SU, Park JY, Kim DY, et al. Natural history of untreated HBeAg-positive chronic HBV infection with persistently elevated HBV DNA but normal alanine aminotransferase. Clin Transl Gastroenterol. 2020;11(3):e00140. https://doi.org/10.14309/ctg.0000000000000140.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Andreani T, Serfaty L, Mohand D, Dernaika S, Wendum D, Chazouilleres O, et al. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol. 2007;5(5):636–41. https://doi.org/10.1016/j.cgh.2007.01.005.

    Article  PubMed  Google Scholar 

  13. Liaw YF, Chu CM. Hepatitis B virus infection. Lancet. 2009;373(9663):582–92. https://doi.org/10.1016/S0140-6736(09)60207-5.

    Article  CAS  PubMed  Google Scholar 

  14. Chu CM, Liaw YF. Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion. J Viral Hepat. 2007;14(3):147–52. https://doi.org/10.1111/j.1365-2893.2006.00810.x.

    Article  PubMed  Google Scholar 

  15. • Chen YC, Chu CM, Liaw YF. Age-specific prognosis following spontaneous hepatitis B e antigen seroconversion in chronic hepatitis B. Hepatology. 2010;51(2):435–44. https://doi.org/10.1002/hep.23348. (This long-term cohort study provides important information of natural history of HBeAg-positive patients.)

    Article  PubMed  Google Scholar 

  16. • Hsu YS, Chien RN, Yeh CT, Sheen IS, Chiou HY, Chu CM, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002;35(6):1522–7. https://doi.org/10.1053/jhep.2002.33638. (This long-term cohort study provides important information of natural history after HBeAgseroconversion.)

    Article  PubMed  Google Scholar 

  17. • Lee WM, King WC, Janssen HLA, Ghany MG, Fontana RJ, Fried M, et al. Hepatitis B e antigen loss in adults and children with chronic hepatitis B living in North America: a prospective cohort study. J Viral Hepat. 2021;28(11):1526–38. https://doi.org/10.1111/jvh.13591. (The prospective study determines the rate and predictors of HBeAg loss in chronic hepatitis B patients in the Western cohort.)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tai DI, Lin SM, Sheen IS, Chu CM, Lin DY, Liaw YF. Long-term outcome of hepatitis B e antigen-negative hepatitis B surface antigen carriers in relation to changes of alanine aminotransferase levels over time. Hepatology. 2009;49(6):1859–67. https://doi.org/10.1002/hep.22878.

    Article  CAS  PubMed  Google Scholar 

  19. Kumada T, Toyoda H, Yasuda S, Ito T, Tanaka J. Mortality of inactive hepatitis B virus carriers in Japan is similar to that of the general population. Hepatol Res. 2022;52(1):81–92. https://doi.org/10.1111/hepr.13723.

    Article  CAS  PubMed  Google Scholar 

  20. Chu CM, Liaw YF. Incidence and risk factors of progression to cirrhosis in inactive carriers of hepatitis B virus. Am J Gastroenterol. 2009;104(7):1693–9. https://doi.org/10.1038/ajg.2009.187.

    Article  PubMed  Google Scholar 

  21. Yeo YH, Tseng TC, Hosaka T, Cunningham C, Fung JYY, Ho HJ, et al. Incidence, factors, and patient-level data for spontaneous HBsAg seroclearance: a cohort study of 11,264 patients. Clin Transl Gastroenterol. 2020;11(9):e00196. https://doi.org/10.14309/ctg.0000000000000196.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Yeo YH, Ho HJ, Yang HI, Tseng TC, Hosaka T, Trinh HN, et al. Factors associated with rates of HBsAg seroclearance in adults with chronic HBV infection: a systematic review and meta-analysis. Gastroenterology. 2019;156(3):635-46 e9. https://doi.org/10.1053/j.gastro.2018.10.027.

    Article  CAS  PubMed  Google Scholar 

  23. Zhou K, Contag C, Whitaker E, Terrault N. Spontaneous loss of surface antigen among adults living with chronic hepatitis B virus infection: a systematic review and pooled meta-analyses. Lancet Gastroenterol Hepatol. 2019;4(3):227–38. https://doi.org/10.1016/S2468-1253(18)30308-X.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kuang XJ, Jia RR, Huo RR, Yu JJ, Wang JJ, Xiang BD, Li LQ, Peng Z, Zhong JH. Systematic review of risk factors of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. J Viral Hepat. 2018;25(9):1026–37. https://doi.org/10.1111/jvh.12905.

    Article  CAS  PubMed  Google Scholar 

  25. Yip TC, Wong VW, Lai MS, Lai JC, Hui VW, Liang LY, Tse YK, Chan HL, Wong GL. Risk of hepatic decompensation but not hepatocellular carcinoma decreases over time in patients with hepatitis B surface antigen loss. J Hepatol. 2023;78(3):524-533. 1016/j.jhep.2022.11.020

  26. •• Jeng WJ, Papatheodoridis GV, Lok ASF. Hepatitis B. Lancet. 2023;401(10381):1039–52. https://doi.org/10.1016/S0140-6736(22)01468-4. (The updated review provides the comprehensive evidences of HBV.)

    Article  CAS  PubMed  Google Scholar 

  27. Lee SK, Kwon JH, Lee SW, Jang JW, Nam H, Baik KW, et al. Sustained off therapy response after peglyated interferon favours functional cure and no disease progression in chronic hepatitis B. Liver Int. 2021;41(2):288–94. https://doi.org/10.1111/liv.14701.

    Article  CAS  PubMed  Google Scholar 

  28. Sun J, Ding H, Chen G, Wang G, Wei L, Zhang J, et al. Sustained serological and complete responses in HBeAg-positive patients treated with peginterferon alfa-2b: a 6-year long-term follow-up of a multicenter, randomized, controlled trial in China. BMC Gastroenterol. 2019;19(1):65. https://doi.org/10.1186/s12876-019-0981-5.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Marcellin P, Bonino F, Yurdaydin C, Hadziyannis S, Moucari R, Kapprell HP, et al. Hepatitis B surface antigen levels: association with 5-year response to peginterferon alfa-2a in hepatitis B e-antigen-negative patients. Hepatol Int. 2013;7(1):88–97. https://doi.org/10.1007/s12072-012-9343-x.

    Article  PubMed  Google Scholar 

  30. Hoofnagle JH, Di Bisceglie AM, Waggoner JG, Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B. Gastroenterology. 1993;104(4):1116–21. https://doi.org/10.1016/0016-5085(93)90281-g.

    Article  CAS  PubMed  Google Scholar 

  31. Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98. https://doi.org/10.1007/s12072-015-9675-4.

    Article  CAS  PubMed  Google Scholar 

  32. Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261–83. https://doi.org/10.1002/hep.28156.

    Article  PubMed  Google Scholar 

  33. Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67(4):1560–99. https://doi.org/10.1002/hep.29800.

    Article  PubMed  Google Scholar 

  34. European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67(2):370–98. https://doi.org/10.1016/j.jhep.2017.03.021.

    Article  Google Scholar 

  35. Loomba R, Liu J, Yang HI, Lee MH, Lu SN, Wang LY, et al. Synergistic effects of family history of hepatocellular carcinoma and hepatitis B virus infection on risk for incident hepatocellular carcinoma. Clin Gastroenterol Hepatol. 2013;11(12):1636-45 e1-3. https://doi.org/10.1016/j.cgh.2013.04.043.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Mason WS, Gill US, Litwin S, Zhou Y, Peri S, Pop O, et al. HBV DNA integration and clonal hepatocyte expansion in chronic hepatitis B patients considered immune tolerant. Gastroenterology. 2016;151(5):986-98 e4. https://doi.org/10.1053/j.gastro.2016.07.012.

    Article  CAS  PubMed  Google Scholar 

  37. Bertoletti A, Kennedy PT. The immune tolerant phase of chronic HBV infection: new perspectives on an old concept. Cell Mol Immunol. 2015;12(3):258–63. https://doi.org/10.1038/cmi.2014.79.

    Article  CAS  PubMed  Google Scholar 

  38. Kennedy PTF, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, Tan AT, et al. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology. 2012;143(3):637–45. https://doi.org/10.1053/j.gastro.2012.06.009.

    Article  CAS  PubMed  Google Scholar 

  39. Park JJ, Wong DK, Wahed AS, Lee WM, Feld JJ, Terrault N, et al. Hepatitis B virus–specific and global T-cell dysfunction in chronic hepatitis B. Gastroenterology. 2016;150(3):684-95 e5. https://doi.org/10.1053/j.gastro.2015.11.050.

    Article  CAS  PubMed  Google Scholar 

  40. Nguyen MH, Garcia RT, Trinh HN, Lam KD, Weiss G, Nguyen HA, et al. Histological disease in Asian-Americans with chronic hepatitis B, high hepatitis B virus DNA, and normal alanine aminotransferase levels. Am J Gastroenterol. 2009;104(9):2206–13. https://doi.org/10.1038/ajg.2009.248.

    Article  CAS  PubMed  Google Scholar 

  41. Xie Q, Hu X, Zhang Y, Jiang X, Li X, Li J. Decreasing hepatitis B viral load is associated with a risk of significant liver fibrosis in hepatitis B e antigen positive chronic hepatitis B. J Med Virol. 2014;86(11):1828–37. https://doi.org/10.1002/jmv.24000.

    Article  CAS  PubMed  Google Scholar 

  42. Chen J, Xu CR, Xi M, Hu WW, Tang ZH, Zang GQ. Predictors of liver histological changes and a sustained virological response to peginterferon among chronic hepatitis B e antigen-positive patients with normal or minimally elevated alanine aminotransferase levels. J Viral Hepat. 2017;24(7):573–9. https://doi.org/10.1111/jvh.12679.

    Article  CAS  PubMed  Google Scholar 

  43. Kim GA, Lim YS, Han S, Choi J, Shim JH, Kim KM, et al. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B. Gut. 2018;67(5):945–52. https://doi.org/10.1136/gutjnl-2017-314904.

    Article  CAS  PubMed  Google Scholar 

  44. Yoo JJ, Park SY, Moon JE, Lee YR, Lee HA, Lee J, et al. Long-term prognosis and the need for histologic assessment of chronic hepatitis B in the serological immune-tolerant phase. Clin Mol Hepatol. 2023;29(2):482–95. https://doi.org/10.3350/cmh.2022.0322.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Chan HL, Chan CK, Hui AJ, Chan S, Poordad F, Chang TT, et al. Effects of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase and high levels of hepatitis B virus DNA. Gastroenterology. 2014;146(5):1240–8. https://doi.org/10.1053/j.gastro.2014.01.044.

    Article  CAS  PubMed  Google Scholar 

  46. Wu IC, Lai CL, Han SH, Han KH, Gordon SC, Chao YC, et al. Efficacy of entecavir in chronic hepatitis B patients with mildly elevated alanine aminotransferase and biopsy-proven histological damage. Hepatology. 2010;51(4):1185–9. https://doi.org/10.1002/hep.23424.

    Article  CAS  PubMed  Google Scholar 

  47. Jonas MM, Chang MH, Sokal E, Schwarz KB, Kelly D, Kim KM, et al. Randomized, controlled trial of entecavir versus placebo in children with hepatitis B envelope antigen-positive chronic hepatitis B. Hepatology. 2016;63(2):377–87. https://doi.org/10.1002/hep.28015.

    Article  CAS  PubMed  Google Scholar 

  48. • Rosenthal P, Ling SC, Belle SH, Murray KF, Rodriguez-Baez N, Schwarzenberg SJ, et al. Combination of entecavir/peginterferon alfa-2a in children with hepatitis B e antigen-positive immune tolerant chronic hepatitis B virus infection. Hepatology. 2019;69(6):2326–37. https://doi.org/10.1002/hep.30312. (Randomized controlled trial for immune-tolerant pediatric patients.)

    Article  CAS  PubMed  Google Scholar 

  49. • Feld JJ, Terrault NA, Lin HS, Belle SH, Chung RT, Tsai N, et al. Entecavir and peginterferon alfa-2a in adults with hepatitis B e antigen-positive immune-tolerant chronic hepatitis B virus infection. Hepatology. 2019;69(6):2338–48. https://doi.org/10.1002/hep.30417. (Randomized controlled trial for immune-tolerant adult patients.)

    Article  CAS  PubMed  Google Scholar 

  50. •Fattovich G, Olivari N, Pasino M, D’Onofrio M, Martone E, Donato F. Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years. Gut. 2008;57(1):84-90. https://doi.org/10.1136/gut.2007.128496. (Natural history of CHB patients in a Caucasian cohort.)

  51. Lee HW, Kim SU, Baatarkhuu O, Park JY, Kim DY, Ahn SH, et al. Comparison between chronic hepatitis B patients with untreated immune-tolerant phase vs. those with virological response by antivirals. Sci Rep. 2019;9(1):2508. https://doi.org/10.1038/s41598-019-39043-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lin HC, Jeng RWJ, Liu J, Lee MH, Batrla-Utermann R, Lu SN, et al. Persistent high HBsAg levels predict lower risk of hepatocellular carcinoma in HBeAg-seropositive chronic hepatitis B patients. J Hepatol. 2021;75:S715.

    Google Scholar 

  53. • Zhou K, Wahed AS, Cooper S, Di Bisceglie AM, Fontana RJ, Ghany MG, et al. Phase transition is infrequent among North American adults with e-antigen-negative chronic hepatitis B and low-level viremia. Am J Gastroenterol. 2019;114(11):1753-63. https://doi.org/10.14309/ajg.0000000000000400. (The multicenter study reveals the prevalence of indeterminate patients, and their phase transition and hepatocellular carcinoma risk.)

  54. Huang DQ, Li X, Le MH, Le AK, Yeo YH, Trinh HN, et al. Natural history and hepatocellular carcinoma risk in untreated chronic hepatitis B patients with indeterminate phase. Clin Gastroenterol Hepatol. 2022;20(8):1803-12 e5. https://doi.org/10.1016/j.cgh.2021.01.019.

    Article  CAS  PubMed  Google Scholar 

  55. Bonacci M, Lens S, Marino Z, Londono MC, Rodriguez-Tajes S, Mas A, et al. Anti-viral therapy can be delayed or avoided in a significant proportion of HBeAg-negative Caucasian patients in the gray zone. Aliment Pharmacol Ther. 2018;47(10):1397–408. https://doi.org/10.1111/apt.14613.

    Article  CAS  PubMed  Google Scholar 

  56. Oliveri F, Surace L, Cavallone D, Colombatto P, Ricco G, Salvati N, et al. Long-term outcome of inactive and active, low viraemic HBeAg-negative-hepatitis B virus infection: benign course towards HBsAg clearance. Liver Int. 2017;37(11):1622–31. https://doi.org/10.1111/liv.13416.

    Article  CAS  PubMed  Google Scholar 

  57. • Yapali S, Talaat N, Fontana RJ, Oberhelman K, Lok AS. Outcomes of patients with chronic hepatitis B who do not meet criteria for antiviral treatment at presentation. Clin Gastroenterol Hepatol. 2015;13(1):193-201 e1. https://doi.org/10.1016/j.cgh.2014.07.019. (This study provides important information of phase transition and adverse outcome in treatment-ineligible patients under stringent monitoring.)

  58. •• Lok AS, Perrillo R, Lalama CM, Fried MW, Belle SH, Ghany MG, et al. Low incidence of adverse outcomes in adults with chronic hepatitis B virus infection in the era of antiviral therapy. Hepatology. 2021;73(6):2124–40. https://doi.org/10.1002/hep.31554. (The multiethnic study reveals the low incidence of adverse outcomes in the large cohort of North American adults with predominantly inactive, chronic HBV without cirrhosis.)

    Article  CAS  PubMed  Google Scholar 

  59. Huang DQ, Lee DH, Le MH, Le A, Yeo YH, Trinh HN, et al. Liver complications in untreated treatment-ineligible versus treated treatment-eligible patients with hepatitis B. Dig Dis. 2023;41(1):115–23. https://doi.org/10.1159/000526933.

    Article  PubMed  Google Scholar 

  60. Huang DQ, Tran A, Yeh ML, Yasuda S, Tsai PC, Huang CF, et al. Antiviral therapy substantially reduces hepatocellular carcinoma risk in chronic hepatitis B patients in the indeterminate phase. Hepatology. 2023.

  61. Tseng TC, Hosaka T, Liu CJ, Suzuki F, Hong CM, Kumada H, et al. Hepatitis B core-related antigen stratifies the risk of liver cancer in HBeAg-negative patients with indeterminate phase. Am J Gastroenterol. 2022;117(5):748–57. https://doi.org/10.14309/ajg.0000000000001691.

    Article  CAS  PubMed  Google Scholar 

  62. Choi GH, Kim GA, Choi J, Han S, Lim YS. High risk of clinical events in untreated HBeAg-negative chronic hepatitis B patients with high viral load and no significant ALT elevation. Aliment Pharmacol Ther. 2019;50(2):215–26. https://doi.org/10.1111/apt.15311.

    Article  CAS  PubMed  Google Scholar 

  63. Gan QY, Wang JX, Qian F, Wang YL, Huang Y, Zhang ZL, et al. Clinical and histological features of patients with chronic hepatitis B virus infection in the gray zone. J Viral Hepat. 2023;30(10):803–9. https://doi.org/10.1111/jvh.13873.

    Article  CAS  PubMed  Google Scholar 

  64. Yu HS, Jiang H, Li MK, Yang BL, Smayi A, Chen JN, et al. Lowering the threshold of alanine aminotransferase for enhanced identification of significant hepatic injury in chronic hepatitis B patients. World J Gastroenterol. 2023;29(35):5166–77. https://doi.org/10.3748/wjg.v29.i35.5166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Jiang SW, Lian X, Hu AR, Lu JL, He ZY, Shi XJ, et al. Liver histopathological lesions is severe in patients with normal alanine transaminase and low to moderate hepatitis B virus DNA replication. World J Gastroenterol. 2023;29(16):2479–94. https://doi.org/10.3748/wjg.v29.i16.2479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wang J, Yan X, Zhu L, Liu J, Qiu Y, Li Y, et al. Significant histological disease of patients with chronic hepatitis B virus infection in the gray zone. Aliment Pharmacol Ther. 2022. https://doi.org/10.1111/apt.17272.

    Article  PubMed  PubMed Central  Google Scholar 

  67. •• Hsu YC, Chen CY, Chang IW, Chang CY, Wu CY, Lee TY, et al. Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): a multicentre, double-blind, placebo-controlled, parallel-group, randomised trial. Lancet Infect Dis. 2021;21(6):823–33. https://doi.org/10.1016/S1473-3099(20)30692-7. (The RCT provides important information about treatment’s impact on gray zone patients.)

    Article  CAS  PubMed  Google Scholar 

  68. • Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468–75. https://doi.org/10.1016/S0140-6736(12)61425-1. (The RCT provides important information about treatment’s impact on fibrosis regression.)

    Article  CAS  PubMed  Google Scholar 

  69. • Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52(3):886–93. https://doi.org/10.1002/hep.23785. (The RCT provides important information about treatment’s impact on fibrosis regression.)

    Article  CAS  PubMed  Google Scholar 

  70. •• Jeng WJ, Lok AS. Should treatment indications for chronic hepatitis B be expanded? Clin Gastroenterol Hepatol. 2021;19(10):2006–14. https://doi.org/10.1016/j.cgh.2020.04.091. (The review examines the evidences for and against expansion of treatment to patients in whom treatment is not recommended based on current guidelines.)

    Article  CAS  PubMed  Google Scholar 

  71. Chen JD, Yang HI, Iloeje UH, You SL, Lu SN, Wang LY, et al. Carriers of inactive hepatitis B virus are still at risk for hepatocellular carcinoma and liver-related death. Gastroenterology. 2010;138(5):1747–54. https://doi.org/10.1053/j.gastro.2010.01.042.

    Article  PubMed  Google Scholar 

  72. Abdo AA, Bzeizi KI, Babatin MA, AlSohaibani F, AlMana H, Alsaad KO, et al. Predictors of significant fibrosis in chronic hepatitis B patients with low viremia. J Clin Gastroenterol. 2014;48(6):e50-6. https://doi.org/10.1097/MCG.0b013e3182a9a2e1.

    Article  CAS  PubMed  Google Scholar 

  73. Zhang C, Li JW, Wu Z, Zhao H, Wang GQ. Significant histologic changes are not rare in treatment-naive hepatitis B patients with normal alanine aminotransferase level: a meta-analysis. J Clin Transl Hepatol. 2021;9(5):615–25. https://doi.org/10.14218/JCTH.2020.00136.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Paik N, Sinn DH, Lee JH, Oh IS, Kim JH, Kang W, et al. Non-invasive tests for liver disease severity and the hepatocellular carcinoma risk in chronic hepatitis B patients with low-level viremia. Liver Int. 2018;38(1):68–75. https://doi.org/10.1111/liv.13489.

    Article  PubMed  Google Scholar 

  75. Cao Z, Liu Y, Ma L, Lu J, Jin Y, Ren S, et al. A potent hepatitis B surface antigen response in subjects with inactive hepatitis B surface antigen carrier treated with pegylated-interferon alpha. Hepatology. 2017;66(4):1058–66. https://doi.org/10.1002/hep.29213.

    Article  CAS  PubMed  Google Scholar 

  76. de Niet A, Jansen L, Stelma F, Willemse SB, Kuiken SD, Weijer S, et al. Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial. Lancet Gastroenterol Hepatol. 2017;2(8):576–84. https://doi.org/10.1016/S2468-1253(17)30083-3.

    Article  PubMed  Google Scholar 

  77. Cho JY, Paik YH, Sohn W, Cho HC, Gwak GY, Choi MS, et al. Patients with chronic hepatitis B treated with oral antiviral therapy retain a higher risk for HCC compared with patients with inactive stage disease. Gut. 2014;63(12):1943–50. https://doi.org/10.1136/gutjnl-2013-306409.

    Article  CAS  PubMed  Google Scholar 

  78. Kim HS, Baatarkhuu O, Lee HW, Park JY, Kim DY, Ahn SH, et al. Fibrosis-matched outcomes between chronic hepatitis B patients with drug-induced virological response and inactive carriers. Liver Int. 2019;39(1):81–9. https://doi.org/10.1111/liv.13948.

    Article  PubMed  Google Scholar 

  79. Chinese Society of Hepatology, Chinese Medical Association, Chinese Society of Infectious Diseases. Guidelines for the prevention and treatment of chronic hepatitis B (version 2022). Zhonghua Gan Zang Bing Za Zhi. 2022;30(12):1309-1331. https://doi.org/10.3760/cma.j.cn501113-20221204-00607.

  80. Shin JW, Jung SW, Lee SB, Lee BU, Park BR, Park EJ, Park NH. Medication nonadherence increases hepatocellular carcinoma, cirrhotic complications, and mortality in chronic hepatitis B patients treated with entecavir. Am J Gastroenterol. 2018;113(7):998–1008. https://doi.org/10.1038/s41395-018-0093-9.

    Article  CAS  PubMed  Google Scholar 

  81. Lim SG, Wai CT, Rajnakova A, Kajiji T, Guan R. Fatal hepatitis B reactivation following discontinuation of nucleoside analogues for chronic hepatitis B. Gut. 2002;51(4):597–9. https://doi.org/10.1136/gut.51.4.597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wang HH, Sun SL, Jau RC, Tantoh DM, Hsu SY, Nfor ON, Chen PH, Liu WH, Ko JL, Liaw YP. Risk of HBV infection among male and female first-time blood donors born before and after the July 1986 HBV vaccination program in Taiwan. BMC Public Health. 2021;21(1):1831. https://doi.org/10.1186/s12889-021-11846-x.

    Article  PubMed  PubMed Central  Google Scholar 

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YCL: acquisition of data, wrote the main manuscript text; WJJ: conception or design of the work, paper revision. All the authors reviewed the manuscript.

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Correspondence to Wen-Juei Jeng.

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Liu, YC., Jeng, WJ. Should Indications for Antiviral Therapy for Hepatitis B Be Broadened to Include Immune-Tolerant Patients, Inactive Carriers, or Patients in the “Gray Zone”?. Curr Hepatology Rep 23, 11–21 (2024). https://doi.org/10.1007/s11901-024-00635-w

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