Progress towards “The Treat-All Approach” for hepatitis B

Chronic hepatitis B is a significant cause of morbidity and mortality worldwide with an estimated 254 million people chronically infected with the disease (1). It is the most common cause of hepatocellular carcinoma (HCC) internationally and a significant contributor to cirrhosis (2). Despite the global burden of this disease, the percentage of patients with hepatitis B virus (HBV) who are on treatment is low (1). Treatment is currently reserved for patients with clear evidence of liver damage, usually based on an elevated alanine aminotransferase (ALT) or confirmed advanced fibrosis/cirrhosis (3). This is a reactive approach and quite different from how other chronic viruses are managed. The World Health Organization (WHO) opt for a treat-all approach with other infections such as hepatitis C or human immunodeficiency virus. With these infections, the aim is to treat early as many people as possible (4). Hepatitis B is yet to adopt this approach, potentially due to uncertainty of the clinical trajectory in some patients, where it is felt the virus can be present and not lead to progressive liver disease. As more evidence emerges, this selective approach to treating hepatitis B may prove to be suboptimal.

Previous international guidelines have only recommended treatment of hepatitis B in non-cirrhotic patients if they have a raised viral load and an ALT level equal or greater than 2× the upper limit of normal (ULN). This is reflected in both the 2018 American Association for the Study of Liver Diseases (AASLD) and 2016 Asian Pacific Association for the Study of the Liver (APASL) guidelines (3,5). Emerging evidence suggests patients with significant fibrosis in the context of hepatitis B may still have a normal ALT (6), meaning these previous cut-offs may lead to undertreatment of patients who may benefit from treatment. Reassuringly, more recent publications, including the Gastroenterological Society of Australia (GESA) working group, do recommend treatment for patients with ALT greater than the ULN (30 IU/L in males, 19 IU/L in females), expanding the number of those who can be treated (7).

Of recent, there has been a movement towards earlier treatment of HBV (8,9). An idea of treating more people does carry with it various perceived benefits. This includes reducing rates of HCC and cirrhosis, reduced transmission of HBV to others, reduced health costs, and a simplified universal management strategy.

Lim et al. recently published the interim results of the “Early antiviral treatment with tenofovir alafenamide (TAF) to prevent serious clinical adverse events in adults with chronic hepatitis B and moderate or high viraemia” (ATTENTION) study (10). This open labelled randomised control trial focuses on earlier treatment of hepatitis B in patients with minimally raised ALT. They reviewed patients with a detectable viral load, but only minimal change in liver function tests—a group where treatment has currently not been recommended. They recruited non cirrhotic patients with an ALT between the ULN and 2× ULN with a HBV DNA level between 4log₁₀ IU/L and 8log₁₀ and randomised them to treatment with TAF or observation. After the interim analysis at 4 years, there was a trend to reduced decompensation and HCC in patients treated with TAF. Although not yet reaching statistical significance, the trend was promising. The trial’s final analysis is scheduled for 12 years, but an answer may be available sooner, depending on the next interim analysis. A positive result from this study will further highlight that more patients should be treated with antivirals with the aim of preventing adverse liver outcomes. To date, this is the first randomised controlled trial focusing on this patient cohort.

The ATTENTION study echoes rising concerns that treatment should be expanded to more patients with HBV. It aligns well with other emerging evidence. The “Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase” (TORCH-B) study concluded that treatment with tenofovir disoproxil fumarate reduces the changes of liver fibrosis in patients with minimally elevated ALT (11). Similarly, Sinn et al. showed in their cohort study that a significant proportion of patients with HBV who developed HCC did not meet criteria for treatment based on European Association for the Study of the Liver (EASL), APASL or AASLD guidelines (12). There is concern that the current approach is failing to capture patients who may potentially benefit from intervention and need re-evaluation.

Although clinical outcomes and preventing decompensation along with liver cancer is the most important goal, healthcare costs are also important. A treat-all approach to hepatitis B has been modelled in various settings (13-15). Nguyen et al. modelled different approaches to hepatitis B management in The Gambia population (14). They compared treatment guided by the WHO 2015 criteria, the EASL 2017 guidelines, the TREAT-B criteria or a treat-all approach. In this simulation, a treat-all approach was associated with an increase in years of life saved in comparison to a standard approach. This was predominantly driven by the reduced rates off HCC. The treat-all approach had a similar 5-year cost in comparison with the WHO criteria. It was however, less cost beneficial when compared to EASL and TREAT-B algorithms (14). Cost benefit has also been analysed in a western setting. Razavi-Shearer et al. analysed treatment models in the United States (13). Treating all patients led to estimated 59% decline in liver disease from 2020 to 2050. Additionally, chronic infections would reduce by 13% with an additional reduction in new cases. When modelling cost, this strategy was thought to be cost-effective, especially if the treatment price were to be negotiated down.

Not only does earlier treatment potentially reduce advanced liver disease, but it may also be linked with reduced disease transmission. It is well known that treatment prior to giving birth in HBV positive mothers is associated with lower risk of vertical transmission (1). It has also been postulated that treating younger adults would reduce sexual transmission hence reducing incidence of disease (16). Razavi-Shearer et al. suggested increased screening and treatment would prevent 11,100 new chronic infections and prevent 169,000 deaths in the United States (13).

Finally, a simplified, equitable approach to hepatitis B is paramount (17). The lack of consensus for treatment targets internationally makes it hard to provide universal care to patients. With no unanimous guidance, the standard of care differs. Some patients will inevitably remain under-monitored and under-treated with complex algorithms requiring knowledge of liver biochemistry, fibrosis scores and patients’ medical backgrounds. Providing a treat-all approach, or even just broadening indications, means more people have the choice to access medications which may alter their disease course. A simplified approach also makes treatment easier to understand for patients and medical professionals outside of the Hepatology field (17). EASL have published their new guidelines which increases the potential cohort in which treatment is recommended (18). A treat-all approach may be of more benefit in resource-scarce cohorts who do not have the infrastructure to monitor continually for signs of progression. Implementing safe and effective treatment in this group has the benefit of improving outcomes without the need for constant reassessment.

Treating all does pose some risks. It would potentially lead to some patients being exposed to medications when they may never actually develop liver damage. More exposure to antivirals may also increase drug resistance. These are challenging issues to address as the natural history of hepatitis B is unknown. Ideally, we should be able to identify and treat patients in which the virus is active and causing liver damage. This is where analysis of ALT has been used before—as a surrogate for liver damage. However, evidence suggests that a normal ALT does not rule out liver damage (19,20). Although a higher ALT is indicative of liver inflammation, over 50% of patients with a persistently normal ALT may have significant liver damage on biopsy (19). Given the simplicity and safety of current antivirals, overtreatment may be perceived as less harmful if some patients have advanced liver damage prevented. Higher drug exposure may raise concerns about resistance, but data shows this concern is minute due to the excellent resistance profiles of entecavir and especially tenofovir (21).

The ATTENTION study brings promising early results to an important question—should we be treating more people with chronic HBV infection? Expanding treatment may help prevent advanced liver disease and HCC, it may be cost effective, it simplifies management, and it makes treatment more universal. Potential overtreatment and drug resistance are identified issues to a treat-all approach, but their impact may be minor in comparison to the potential benefits. The outcomes of the ATTENTION trial will eagerly be awaited and may continue to shape how HBV is managed in the future.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Editorial Office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-78/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-25-78/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. World Health Organization. Guidelines for the Prevention, Diagnosis, Care and Treatment for People with Chronic Hepatitis B Infection. World Health Organization; 2024.
2. Farbod Y, Kankouni H, Moini M, et al. Hepatitis B-Induced Hepatocellular Carcinoma: Understanding Viral Carcinogenesis and Disease Management. J Clin Med 2025;14:2505. [Crossref] [PubMed]
3. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology 2018;67:1560-99. [Crossref] [PubMed]
4. World Health Organization. Consolidated Guidelines on HIV, Viral Hepatitis and Sti Prevention, Diagnosis, Treatment and Care for Key Populations. World Health Organization; 2022.
5. Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int 2016;10:1-98. [Crossref] [PubMed]
6. Li S, Shi L, Xu X, et al. Systematic review with meta-analysis: Significant histological changes among treatment-naïve chronic hepatitis B patients with normal alanine aminotransferase levels by different criteria. Aliment Pharmacol Ther 2023;58:648-58. [Crossref] [PubMed]
7. Hepatitis B Consensus Statement Working Group. Australian Consensus Recommendations for the Management of Hepatitis B Infection. Melbourne: Gastroenterological Society of Australia, 2022.
8. Lim YS, Kim WR, Dieterich D, et al. Evidence for Benefits of Early Treatment Initiation for Chronic Hepatitis B. Viruses 2023;15:997. [Crossref] [PubMed]
9. Zhang M, Kong Y, Xu X, et al. "Treat-all" Strategy for Patients with Chronic Hepatitis B Virus Infection in China: Are We There Yet? J Clin Transl Hepatol 2024;12:589-93. [Crossref] [PubMed]
10. Lim YS, Yu ML, Choi J, et al. Early antiviral treatment with tenofovir alafenamide to prevent serious clinical adverse events in adults with chronic hepatitis B and moderate or high viraemia (ATTENTION): interim results from a randomised controlled trial. Lancet Gastroenterol Hepatol 2025;10:295-305. [Crossref] [PubMed]
11. Hsu YC, Chen CY, Chang IW, 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;21:823-33. [Crossref] [PubMed]
12. Sinn DH, Kim SE, Kim BK, et al. The risk of hepatocellular carcinoma among chronic hepatitis B virus-infected patients outside current treatment criteria. J Viral Hepat 2019;26:1465-72. [Crossref] [PubMed]
13. Razavi-Shearer D, Estes C, Gamkrelidze I, et al. Cost-effectiveness of treating all hepatitis B-positive individuals in the United States. J Viral Hepat 2023;30:718-26. [Crossref] [PubMed]
14. Nguyen LBL, Lemoine M, Ndow G, et al. Treat All versus targeted strategies to select HBV-infected people for antiviral therapy in The Gambia, west Africa: a cost-effectiveness analysis. Lancet Glob Health 2024;12:e66-e78. [Crossref] [PubMed]
15. Zhang S, Wang C, Liu B, et al. Cost-effectiveness of expanded antiviral treatment for chronic hepatitis B virus infection in China: an economic evaluation. Lancet Reg Health West Pac 2023;35:100738. [Crossref] [PubMed]
16. Dusheiko G, Agarwal K, Maini MK. New Approaches to Chronic Hepatitis B. N Engl J Med 2023;388:55-69. [Crossref] [PubMed]
17. Dieterich D, Graham C, Wang S, et al. It Is Time for a Simplified Approach to Hepatitis B Elimination. Gastro Hep Adv 2023;2:209-18. [Crossref] [PubMed]
18. EASL Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol 2025;83:502-83. [Crossref] [PubMed]
19. Wei S, Xie Q, Liao G, et al. Patients with chronic hepatitis B who have persistently normal alanine aminotransferase or aged < 30 years may exhibit significant histologic damage. BMC Gastroenterol 2024;24:120. [Crossref] [PubMed]
20. Liu J, Wang J, Yan X, et al. Presence of Liver Inflammation in Asian Patients With Chronic Hepatitis B With Normal ALT and Detectable HBV DNA in Absence of Liver Fibrosis. Hepatol Commun 2022;6:855-66. [Crossref] [PubMed]
21. Lumley SF, Delphin M, Mokaya JF, et al. A systematic review and meta-analysis of the risk of hepatitis B virus (HBV) resistance in people treated with entecavir or tenofovir. J Clin Virol 2024;174:105711. [Crossref] [PubMed]