Chronic hepatitis B (CHB) infection remains a leading cause of hepatocellular carcinoma (HCC) and liver-related deaths globally. Nearly 300 million individuals are chronically infected with hepatitis B virus (HBV), among whom only a fraction have been diagnosed and linked to successful treatment [
1]. The beneficial effect of CHB antiviral therapies in sustained suppression of HBV viral replication, leading to reduced long-term risks of disease progression and HCC, is robust [
2-
4]. Despite these robust data, there remain contradictory guidelines and recommendations regarding “treatment-eligibility,” which in many cases are based on complex algorithms that incorporate various factors such as an individual’s age, country of origin, family history, comorbidities, liver disease severity, HBV e antigen status, alanine aminotransferase (ALT) levels, and HBV viral load [
5-
7]. While not the only factor, the complexities of these existing guidelines, in part, contribute to potential gaps in timely CHB treatment. However, there is building momentum to simplify and expand CHB treatment criteria [
8-
11], fueled by the growing body of evidence demonstrating clinical benefit of treating individuals with CHB who are outside of current “treatment-eligibility.”
In this issue of
Clinical and Molecular Hepatology, Hsu et al. performed an open-label extension phase study of the TORCH-B trial [
12], which enrolled adults with CHB who had serum HBV DNA >2,000 IU/mL and ALT levels between one to two folds of the upper limit of normal across six hospitals in Taiwan who were randomized to treatment with placebo or tenofovir disoproxil fumarate (TDF). The current study evaluated outcomes of patients that were rolled over to open-label treatment with TDF for 3 years. Among a total of 146 enrolled patients, 123 had paired biopsies before and after treatment to assess histological changes. The investigators observed that 60.2% (n=64) of patients experienced improvement in Ishak fibrosis score and 47.2% (n=58) experienced improvement in Knodell necroinflammation score. As expected, patients who switched from placebo to open-label TDF therapies also experienced significant improvements in virological and biochemical outcomes. While the length of follow up limited the ability to assess for clinical outcomes such as incidence of cirrhosis or HCC, the strength of this study is the demonstration of objective meaningful histological improvement resulting from antiviral therapy in CHB patients with only minimally elevated ALT and hence “ineligible” for treatment based on many existing guidelines.
These data add to the growing body of evidence supporting the benefits of antiviral therapy in CHB patients outside of current “treatment-eligibility” criteria. For example, Huang et al. [
13] performed a retrospective multi-center, multi-national cohort study of 3,366 adults with CHB, among whom 1,303 were in the indeterminate phase and hence not “eligible” for antiviral therapy. Over a 10-year follow up, 52.7% of patients remained in the indeterminate phase, whereas 21.7% of patients transitioned into the immune active phase. Compared to those remaining in the inactive phase, those who remained in the indeterminate phase had 14 times higher risk of HCC (4.6% vs. 0.5%, aHR 14.1,
P=0.03), which was even higher among patients who were age 45 years and older (aHR 18.4,
P=0.005). Similarly, Sinn et al. [
14] performed a retrospective multi-center study of 3,624 adults with untreated CHB. During a median follow up of 4.6 years, 161 patients developed HCC. Most striking, among the patients who developed HCC, 64.0%, 46.0%, and 33.5% did not meet CHB treatment eligibility criteria according to guidelines by the Asian Pacific Association for the Study of the Liver (APASL), the American Association for the Study of Liver Diseases (AASLD), and European Association for the Study of the Liver (EASL). Furthermore Y.S. Lim and others have also published extensively on the non-linear relationship of baseline HBV viral load on the long-term risks of HCC, arguing for the consideration of earlier initiation of antiviral therapy that is tailored to HBV DNA levels [
15-
17]. These studies and others continue to add to the growing body of evidence that implementing treatment even in so-called “ineligible” patients may still confer lasting benefit in reducing morbidity and mortality. While it is true that long-term risks of cirrhosis and HCC in the indeterminate phase are lower than those in the immune active phases, with the availability of safe and highly effective antiviral therapies, one has to question what degree of risk is acceptable. The emerging data from investigators such as Hsu et al. [
18] prompts us to reassess this question of acceptable risk and continues to make a convincing case towards expanding treatment for CHB.
FOOTNOTES
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Conflicts of Interest
The author has no conflicts to disclose.
Abbreviations
tenofovir disoproxil fumarate
REFERENCES
- 1. Polaris Observatory Collaborators. Global prevalence, cascade of care, and prophylaxis coverage of hepatitis B in 2022: a modelling study. Lancet Gastroenterol Hepatol 2023;8:879-907.
- 2. Tseng CH, Hsu YC, Chen TH, Ji F, Chen IS, Tsai YN, et al. Hepatocellular carcinoma incidence with tenofovir versus entecavir in chronic hepatitis B: a systematic review and metaanalysis. Lancet Gastroenterol Hepatol 2020;5:1039-1052.
- 3. Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-1531.
- 4. Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A. Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol 2010;53:348-356.
- 5. 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;67:1560-1599.
- 6. European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol 2017;67:370-398.
- 7. 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;10:1-98.
- 8. Dieterich D, Graham C, Wang S, Kwo P, Lim YS, Liu CJ, et al. It is time for a simplified approach to hepatitis B elimination. Gastro Hep Adv 2022;2:209-218.
- 9. Wong RJ, Kaufman HW, Niles JK, Kapoor H, Gish RG. Simplifying treatment criteria in chronic hepatitis B: reducing barriers to elimination. Clin Infect Dis 2023;76:e791-e800.
- 10. You H, Wang F, Li T, Xu X, Sun Y, Nan Y, et al. Guidelines for the prevention and treatment of chronic hepatitis B (version 2022). J Clin Transl Hepatol 2023;11:1425-1442.
- 11. World Health Organization. Guidelines for the prevention, diagnosis, care and treatment for people with chronic hepatitis B infection. WHO web site, <https://www.who.int/publications/i/item/9789240090903>. Accessed 29 Mar 2024.
- 12. 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, doubleblind, placebo-controlled, parallel-group, randomised trial. Lancet Infect Dis 2021;21:823-833.
- 13. 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;20:1803-1812.e5.
- 14. Sinn DH, Kim SE, Kim BK, Kim JH, Choi MS. The risk of hepatocellular carcinoma among chronic hepatitis B virus-infected patients outside current treatment criteria. J Viral Hepat 2019;26:1465-1472.
- 15. Choi WM, Kim GA, Choi J, Choi GH, Lee YB, Sinn DH, et al. Non-linear association of baseline viral load with on-treatment hepatocellular carcinoma risk in chronic hepatitis B. Gut 2024;73:649-658.
- 16. Choi WM, Kim GA, Choi J, Han S, Lim YS. Increasing ontreatment hepatocellular carcinoma risk with decreasing baseline viral load in HBeAg-positive chronic hepatitis B. J Clin Invest 2022;132:e154833.
- 17. Yang Z, Cheung RC, Jou JH, Lim JK, Lim YS, Wong RJ. Association of baseline hepatitis B virus DNA and on-treatment risk of cirrhosis and hepatocellular carcinoma. Gastroenterology Res 2024;17:109-115.
- 18. Hsu YC, Chen CY, Tseng CH, Chen CC, Lee TY, Bair MJ, et al. Antiviral therapy for chronic hepatitis B with mildly elevated aminotransferase: A rollover study from the TORCH-B trial. Clin Mol Hepatol 2025;31:213-226.
Citations
Citations to this article as recorded by
- Expanding treatment eligibility for chronic hepatitis B: Balancing benefits, limitations, and healthcare access: Correspondence to editorial on “Antiviral therapy for chronic hepatitis B with mildly elevated aminotransferase: A rollover study from the TOR
Yao-Chun Hsu, Chi-Yi Chen, Jaw-Town Lin
Clinical and Molecular Hepatology.2025; 31(2): e169. CrossRef
