e-Newsletter

Eosinophilic Oesophagitis: Updates and Management of a Global Disease​

Dr. Walter W. Chan Director, Centre for Gastrointestinal Motility Brigham and Women’s Hospital Associate Professor of Medicine Harvard Medical School Boston, USA

Clinical features and diagnosis of eosinophilic oesophagitis

Eosinophilic oesophagitis (EoE) is increasingly recognised as a global disease, with incidence rising in both Western and Asian populations.^1,2 It is a clinicopathologic condition defined by symptoms of oesophageal dysfunction and pathological confirmation of at least 15 eosinophils per high-power field on biopsy, after exclusion of other causes.³ Normally the oesophagus is devoid of eosinophils, but in EoE, an antigenic trigger initiates a Th2-driven inflammatory cascade, with cytokine release and eotaxin-3–mediated eosinophil recruitment.^4,5 Patients commonly present with dysphagia, chest pain or heartburn, often in association with allergic comorbidities.^6-8 Adaptive eating behaviours and symptom awareness are also frequent.

While endoscopic features such as rings, furrows or strictures may be observed, histologic sampling remains essential, as mucosa may appear normal. To maximise diagnostic yield, four to six biopsies should be obtained from both the proximal and distal oesophagus, which may also provide insights into treatment responsiveness, particularly to proton pump inhibitors (PPIs).⁹ Beyond histology, emerging tools such as the functional lumen imaging probe offer additional information on oesophageal distensibility and stricture formation, though these are not yet standard in routine practice.¹⁰

Management of EoE is guided by the ‘three Ds’: drugs, diet and dilation

Drugs remain the cornerstone of EoE treatment, with therapy aimed at both symptom relief and histologic remission. PPIs are considered as the first-line treatment options, achieving histologic remission in 40–50% of patients and symptom improvement in up to 60%.¹¹ Their benefits may extend beyond acid suppression, suggesting direct anti-inflammatory effects on the mucosa.¹² Standard induction of PPI involves twice-daily dosing for 10–12 weeks, followed by tapering to the lowest effective maintenance dose.^13,14 Topical corticosteroids, such as oral viscous budesonide and swallowed fluticasone, have been reported to achieve remission in 50–70% of cases and should also be maintained long term to prevent relapse.^15,16 For patients with more severe or refractory disease, dupilumab has proven effective by targeting the interleukin-4 and interleukin-13 pathways, leading to improvements in histology, endoscopy and symptoms, although cost remains a major limitation.

Dietary therapy represents another established strategy, with empiric elimination diets ranging from broad six-food exclusion to simplified one- or two-food models.¹⁷ Recent studies suggest that a one-food elimination diet, such as removing milk or wheat, may be effective and provide a practical alternative to broader approaches.¹⁸ Elemental diets remain highly effective but are often limited by cost and impact on quality of life.

Dilation serves as an important adjunct in fibrostenotic disease.  Achieving a luminal diameter of 16 mm is associated with meaningful relief of dysphagia, and while repeat sessions may be needed, the procedure is generally safe, with low complication rates.¹⁹

Individualised care with long term monitoring to prevent progression

Treatment should be individualised through shared decision-making, considering efficacy, safety, cost and patient preference. PPIs are often the most cost-effective first-line therapy, while corticosteroids, dietary approaches or biologics may be appropriate depending on disease severity and clinical context. Long-term monitoring with clinical, endoscopic and histologic assessments is essential to ensure durable control and to prevent progression to fibrostenosis.

References

1. Dellon ES, Hirano I. Gastroenterology 2018;154:1558-1574.
2. Hahn JW, et al. Clin Gastroenterol Hepatol 2023;21:1946-1956.
3. Liacouras C, et al. J Allergy Clin Immunol 2011;128:3-20.
4. Wechsler JB, et al. Gastroenterol Clin North Am 2014;43:219-227.
5. Straumann A, et al. J Allergy Clin Immunol 2001;108:954-961.
6. Kappelman MD, et al. Gastroenterology 2008;134:10-18.
7. Mackenzie SH, et al. Aliment Pharmacol Ther 2008;28:967-975.
8. Visaggi P, et al. Am J Gastroenterol 2025;120:469-472.
9. Nielsen JA, et al. Am J Gastroenterol 2014;109:363-372.
10. Carlson DA, et al. Gastroenterology 2024;166:a1-a32.
11. Lucendo AJ, et al. Clin Gastroenterol Hepatol 2025;23:a1-a26.
12. Winter RW, Chan WW, et al. Gastroenterology 2024;166:S1-1256.
13. Laserna-Mendieta EJ, et al. Aliment Pharmacol Ther 2020;52:798-807.
14. Muftah M, Chan WW, et al. J Clin Gastroenterol 2024;58:227-236.
15. Albert D, et al. Dig Dis Sci 2016;61:2048-2056.
16. Butz BK, et al. Gastroenterology 2014;147:390-399.
17. Dellon ES, et al. Gastroenterology 2014;147:358-366.
18. Kliewer KL, et al. Lancet Gastroenterol Hepatol 2023;8:826-838.
19. Beveridge CA, et al. Dig Dis Sci 2025;70:280-291.

Precision Medicine Approaches to Inflammatory Bowel Disease: Where Are We Now?

Professor David T. Rubin Chief, Section of Gastroenterology, Hepatology, and Nutrition Director, Inflammatory Bowel Disease Centre University of Chicago Chicago, USA

Persistent challenges in current inflammatory bowel disease management

Current treatment of inflammatory bowel disease (IBD) faces several persistent challenges. Management often follows a reactive approach, where patients must ‘earn’ therapies through disease progression or complications, while reliance on non-sustainable strategies such as corticosteroids remains widespread. The absence of robust head-to-head comparisons of advanced therapies contributes to uncertainty, and a clear therapeutic gap persists between clinical trial efficacy and real-world patient outcomes, particularly in ulcerative colitis (UC).¹

The limitations of precision medicine in IBD seeks to tailor prevention, diagnosis and treatment to an individual’s genetic, proteomic, environmental and lifestyle profile. Unlike traditional or stratified medicine, its goal is highly individualised care that can predict response and optimise outcomes. Potential benefits include predicting disease susceptibility, improving early detection, preventing progression, avoiding adverse drug effects and lowering trial costs and failure rates.² However, true precision medicine remains aspirational. Its progress is limited by the absence of clear molecular drivers, the multifactorial and dynamic nature of IBD, and historical under investment in industry and regulatory pathways. Current clinical decisions based on disease location, severity, comorbidities and patient preferences represent thoughtful personalised care but fall short of predictive, biomarker-driven precision.

Reclassifying IBD toward molecularly defined subtypes

Progress towards realising precision medicine in IBD will require reclassifying IBD beyond Crohn’s disease and UC toward molecularly defined subtypes that better reflect underlying biology and clinical features. The International Organization for the Study of IBD is developing a new classification system, expected to be released this year, supported by advances across multiple research areas. Current research focuses on:

• Genetic studies show that while most IBD cases are polygenic, monogenic forms offer important insights.³ Pharmacogenetics is already shaping clinical care, with variants in Nudix hydrolase 15 and thiopurine S-methyltransferase predicting thiopurine-induced leukopenia, particularly in Asian populations.⁴ In addition, the HLA-DQA105 genotype has been linked to heightened immune responses to anti–tumour necrosis factor agents, although its impact may depend more on drug concentrations than on antibody formation.^5,6

• Beyond genetics, serologic markers such as anti–Saccharomyces cerevisiae antibody titres can predict complicated disease courses in paediatric IBD and support early aggressive therapy. Moreover, novel autoantibodies are being studied in UC as potential predictors of onset and severity.^7,8

• The microbiome also holds promise, with faecal profiles distinguishing IBD from non-IBD and correlating with disease activity. However, current efforts are shifting toward understanding functional outputs rather than microbial composition alone.^9,10

Emerging biomarker-driven therapeutic targets

New therapeutics targets are also being explored. Early gene expression markers such as IL23A and TREM1 showed associations with treatment response but have yet to deliver consistent predictive value in clinical trials.^11,12 In contrast, tumour necrosis factor–like cytokine 1A (TL1A), a member of the TNF superfamily implicated in inflammation and fibrosis, is emerging as a promising biomarker and therapeutic target. Several anti-TL1A agents are in development, with phase 2 trials suggesting efficacy, particularly in biomarker-positive patients.¹³

Together, these advances suggest that while true precision medicine in IBD is not yet realised, ongoing work in genetics, serology, microbiome science and novel biologics is gradually closing the gap between aspiration and clinical application.

References:

1. Alsoud D, et al. Lancet Gastroenterol Hepatol 2021;6:589-595.
2. Verstockt B, et al. J Crohns Colitis 2021;15:1431-1442.
3. McGovern DP, et al. Gastroenterology 2015;149:1163-1176.
4. Schaeffeler E, et al. Genet Med 2019;21:2145-2150.
5. Maeda T, et al. Res 2022;20:90-100.
6. Heap GA, et al. Nat Genet 2014;46:1131-4.
7. Ricciuto A, et al. Gastroenterology 2021;160:403-436.
8. Livanos A, et al. Gastroenterology 2023;164:619-629.
9. Hansen SH, et al. Inflamm Bowel Dis 2025;31:2066-2080.
10. Zheng J, et al. Nat Med 2024;30:3555-3567.
11. Nishioka K, et al. J Gastroenterol 2021;56:976-987.
12. Gaujoux R, et al. Gut 2019;68:604-614.
13. Danese S, et al. Tamuzimod delivers promising long-term data in UC. Presented at: UEGW 2024; Vienna, Austria. Oct 12–15, 2024; Vienna, Austria.

Updates in the Management of Portal Hypertension in Cirrhosis

Dr. Jimmy Che-To Lai Assistant Professor Department of Medicine and Therapeutics The Chinese University of Hong Kong

Expanding the role of non-selective beta-blockers

A paradigm shift in the management of portal hypertension has emerged with the expanded role of non-selective beta-blockers (NSBBs), particularly carvedilol.¹ Traditionally prescribed to prevent variceal bleeding, NSBBs are now recommended to prevent overall clinical decompensation in patients with compensated cirrhosis. The current algorithm supports early initiation of carvedilol as soon as clinically significant portal hypertension (CSPH) is identified, using non-invasive markers such as a liver stiffness measurement (LSM) >20 to 25 kPa with a platelet count of <150 × 10⁹/L, or an LSM of >25 kPa alone.^2-4 However, findings from the pivotal PREDESCI trial were limited by the invasive requirement of hepatic venous pressure gradient (HVPG) confirmation and the predominance of untreated hepatitis C patients prior to the widespread availability of direct-acting antivirals.¹

Managing uncertainty in the Baveno VII ‘grey zone’

Given that the expanded role of NSBBs in cirrhosis management is anchored in the Baveno VII consensus criteria for diagnosing CSPH, a major challenge lies in managing patients in the Baveno VII ‘grey zone’, defined by LSM values of 15 to <25 kPa (with or without thrombocytopenia), which can include up to 50% of patients.⁵ Although not risk-free, with 5-year risks of 4.2% for hepatic decompensation and 10.4% for hepatocellular carcinoma having been reported, their management remains uncertain.⁶ Refining risk stratification with adjunct tools such as spleen stiffness measurement, oesophagogastroduodenoscopy or blood-based biomarkers like the VITRO score (von Willebrand factor/platelet ratio) can help reclassify patients in Baveno II ‘grey zone’, rule in or rule out CSPH and guide subsequent management decisions.^7-9 VITRO cut-offs (≤1.5 to rule out and ≥2.5 to rule in CSPH) have shown strong diagnostic accuracy, reclassifying patients more effectively and guiding selection for NSBB therapy.¹⁰

Adjust strategies beyond beta-blockers

Beyond beta-blockade, other therapeutic strategies are being explored:

• Anticoagulation, by correcting the prothrombotic imbalance of cirrhosis, has shown mortality benefits in portal vein thrombosis, but recent trials with rivaroxaban did not reduce decompensation or death.^11,12

• Statins can further lower portal pressure when combined with carvedilol, however, data in decompensated patients raise safety concerns such as the risk of rhabdomyolysis.^13,14

• Evidence for rifaximin remains inconsistent due to heterogeneous study designs and inconsistent outcomes.^15-17

• Endoscopic ultrasound is emerging as a valuable tool for direct portal pressure measurement, especially in metabolic dysfunction-associated steatotic liver disease where HVPG may be less reliable.¹⁸ It offers a one-stop potential by enabling both variceal assessment and therapeutic interventions such as coil deployment.

Integrating diagnostics and therapies for better outcomes

Together, these developments reflect a more nuanced and proactive approach to portal hypertension, emphasising early non-invasive diagnosis, improved risk stratification in the Baveno VII ‘grey zone’, and exploration of novel therapeutic strategies to complement NSBBs.

References:

1. Villanueva C, et al. Lancet 2019;393:1597-1608.
2. Abraldes JG, et al. Hepatology 2016;64:2173-2184.
3. Garcia-Tsao G, Abraldes JG. Gastroenterology 2021;161:770-773.
4. Kaplan DE, et al. Hepatology 2024;79:1180-1211.
5. Abraldes JG, et al. Hepatology 2016;64:2173-2184.
6. Lin H, Lai JC, et al. Aliment Pharmacol Ther 2023;58:920-928.
7. Dajti E, et al. Am J Gastroenterol 2022;117:1825-1833.
8. Lin H, Lai JC, et al. Aliment Pharmacol Ther 2023;58:920-928.
9. Dajti E, et al. J Hepatol 2025;82:490-498.
10. Jachs M, et al. Clin Gastroenterol Hepatol 2023;21:1854-1863.
11. Guerrero A, et al. J Hepatol 2023;79:69-78.
12. Puente A, et al. Rivaroxaban to prevent complications of portal hypertension in cirrhosis: The CIRROXABAN study. J Hepatol (in press).
13. Alvarado-Tapias E, et al. Hepatology 2025;82:140-154.
14. Pose E, et al. JAMA 2025;333:864-874.
15. Woodhouse C, Shawcross DL. Aliment Pharmacol Ther 2017;47:301-303.
16. Zeng X, et al. Hepatol Int 2021;15:155-165.
17. Thevenot T, et al. Effect of rifaximin in patients with severe cirrhosis and ascites: A randomized double blind placebo-controlled trial. J Hepatol (in press).

Endoscopic treatment of T1 colorectal cancer: What are we up to?

Dr. Vienna Man-Wah Ng Honorary Clinical Assistant Professor Division of Colorectal Surgery Department of Surgery The Chinese University of Hong Kong

Unmet need in T1 colorectal cancer management

With the start of colorectal cancer screening programmes, there has been an increase in patients diagnosed with malignant colorectal polyps.^1-4 A malignant polyp refers to a polyp with carcinoma cells invading through the muscularis mucosae into the submucosa, but not extending into the muscularis propria (i.e., pT1 according to TNM classification), regardless of lymph node involvement. The prevalence of malignant polyps diagnosed after endoscopic removal ranges from 0.2% to 5%, constituting 40% to 60% of stage I colorectal cancers.^1-4 Current international guidelines recommend salvage surgery for patients with any of the following high-risk histopathological features: deep submucosal invasion, poor differentiation, presence of lymphovascular invasion, high-grade tumour budding and positive resection margin.^5-8 However, over 80% of the final specimen shows no lymph node metastasis after radical colorectal resection.⁹  Surgery is associated with chance of stoma formation or urosexual dysfunction, as well as approximately 30% morbidity and 1% to 5% mortality.^10,11 Identifying an oncologically safe organ preservation strategy is essential to improve the outcomes and quality of life of patients with T1 colorectal cancer.

Growing evidence on endoscopic treatment

Recent evidence supported endoscopic resection as the first-line treatment for endoscopically resectable lesions, offering a viable option for organ preservation in T1 colorectal cancer.^12-17 Global studies found that curative endoscopic resection achieves outcomes comparable with surgery, demonstrating no-to-minimal increase in risk of recurrence.^12-17 The net benefit of salvage surgery appears to be significant only when the follow-up period exceeds 10 years.¹⁶ Local data reinforce these findings: An 8-year survival analysis led by The Chinese University of Hong Kong found no significant differences in long-term oncological outcomes (i.e., disease-free, cancer-specific and overall survival) between local excision alone and local excision followed by salvage surgery. In addition, piecemeal resection (hazard ratio [HR], 7.051 [1.856–26.794]; p=0.004) and the presence of two or more risk factors (HR, 8.552 [1.058–69.095]; p=0.044) were identified as key predictors of poorer disease-free survival, while the presence of a single risk factor alone, as suggested in current guidelines, was not associated with poor prognosis.

Optimising management of malignant colorectal polyps

Successful management of malignant colorectal polyps relies on three key considerations:

• Accurate prediction of T1 colorectal cancer cases with low risk of lymph node metastasis
• Appropriate selection of endoscopic treatment modality to achieve en-bloc resection
• Reliable histological evaluation and standardised pathological reporting to guide clinical decision and patient counselling

Patient selection for endoscopic resection

To identify colorectal lesions suitable for endoscopic resection, endoscopists are advised to perform the following assessments:

1. Conventional white light endoscopy is used to evaluate the size and morphology of neoplastic lesions. The Paris classification describes their endoscopic appearance. Paris type 0-IIc lesions with mucosal depression carry the highest risk of submucosal invasion and nodal metastasis.
2. Image-enhanced endoscopy further characterises neoplastic lesions. Narrow-band imaging is the most widely used method to assess colour, vascular and surface patterns.
   
   • A Japan Narrow Band Imaging Expert Team (JNET) type 3 lesion is characterised by a loose or interrupted vascular pattern and an amorphous surface pattern. It is highly suggestive of deep submucosal invasive cancer; thus, surgical treatment rather than endoscopic resection is advised.
   • A JNET type 2B lesion is characterised by an irregular vessel and surface pattern, which may indicate high-grade adenoma, superficial submucosal invasive cancer or deep submucosal invasive cancer; therefore, further assessment using magnifying chromoendoscopy is recommended to determine the appropriate treatment approach.
3. Magnifying chromoendoscopy evaluates the pit pattern of neoplastic lesions by using indigo carmine (0.1–0.5%) or crystal violet (0.05%) stains.
   
   • Kudo type V_N lesions (non-structural) → surgical treatment
   • Kudo type V_I lesions (irregular) → endoscopic resection if expertise is available

Choosing the appropriate endoscopic treatment modality

Based on tumour location, size and suspected depth of invasion, four endoscopic resection techniques can be considered: endoscopic mucosal resection, endoscopic submucosal dissection, endoscopic intermuscular dissection and endoscopic full-thickness resection (Table). The table below provides brief guidance on selecting the most appropriate treatment approach to achieve complete en-bloc resection in T1 colorectal cancer.

Table. Summary of endoscopic resection techniques.

EFTR, endoscopic full-thickness resection; EID, endoscopic intermuscular dissection; EMR, endoscopic mucosal resection; ESD, endoscopic submucosal dissection; R0, resection with horizontal and vertical clear margins; TAMIS, transanal minimally invasive surgery.

*Enbloc resection rate and R0 resection rate vary among EMR techniques (conventional EMR, underwater EMR and EMR with precutting). ^†Piecemeal EMR should be avoided in suspected T1 lesions due to unreliable evaluation of depth of submucosal invasion and vertical margin, as well as 7-fold increase in risk of local recurrence. ^‡Meta-analyses of retrospective and cohort studies have confirmed technically demanding average procedures times of 2–4 hours and a greater incidence of complications such as bleeding and perforation.^{18-21 §}This method can leave the mesorectal plane uninterrupted for future salvage surgery. ^¶Suitable for T1 rectal cancer with low risk of nodal metastasis or for patients unfit for rectal surgery under general anaesthesia.

Comprehensive post-treatment management

Reliable histological evaluation and standardised pathological reporting are essential in guiding clinical decisions and personalised management of T1 colorectal cancer. Curative resection is defined by en-bloc resection with clear margins and absence of high-risk pathological features, including poor differentiation, lymphovascular invasion, deep submucosal invasion (>1 mm) and high-grade tumour budding. However, the current controversy lies in whether deep submucosal invasion, in the absence of other risk factors, should be regarded as a sole indication for salvage surgery, given its low lymph node metastasis rate (~2.6%).²² Similarly, the definition of clear resection margin is also under debate. A recent study demonstrated similar risks of residual disease in resection margins measuring between 0.1 and 1mm compared with >1mm, supporting a more nuanced interpretation.²³   Therefore, standardised pathological reporting that includes all essential information enables better risk stratification and treatment planning. In cases of non-curative resection, options can be salvage surgery, adjuvant chemoradiotherapy or active surveillance. The risks and benefits of each option should be considered for each patient, especially in terms of its associated morbidity, functional and oncological outcomes. Future directions may involve the use of nomograms, AI-based prediction models and biomarkers to enhance risk stratification. Overall, multidisciplinary team management is key to delivering precise, individualised treatment for patients with T1 colorectal cancer.

References:

1. Shaukat A, et al. Gastroenterology 2020;159:1916-1934.
2. Hackelsberger A, et al. Endoscopy 1995;27:153-158.
3. Hermanek P, et al. Endoscopy 1983;15:16-20.
4. Netzer P, et al. Gut 1998;43:669-674.
5. NCCN Guidelines. Colon Cancer. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf.  Accessed 23 September 2025.
6. NCCN Guidelines. Rectal Cancer. https://www.nccn.org/professionals/physician_gls/pdf/rectal.pdf. Accessed 23 September 2025.
7. ESMO. ESMO Clinical Practice Guidelines: Gastrointestinal Cancers. https://www.esmo.org/guidelines/esmo-clinical-practice-guidelines-gastrointestinal-cancers. Accessed 23 September 2025.
8. JSCCR. JSSCR Guidelines for the Treatment of Colorectal Cancer. https://jsccr.jp/en/guideline/the-Treatment-of-Colorectal-Cancer.html. Accessed 23 September 2025.
9. Bosch, S.L., et al. Endoscopy 2013;45:827-834.
10. Sánchez-Guillén L, et al. Int J Colorectal Dis 2020;35:2227-2238.
11. Albaugh JA, et al. Clin Colon Rectal Surg 2017;30:201-206.
12. Lopez A, et al. Gut 2019;68:111-117.
13. Park E, et al. J Clin Med 2020;9:2451.
14. Yeh J, et al. Clin Gastroenterol Hepatol 2020;18:2813-2823.
15. Dang H, et al. Clin Gastroenterol Hepatol 2022;20:e298-e314.
16. Johnstone M, et al. Colorectal Dis 2023;25:1960-1972.
17. Chen Y, et al. Gastrointest Endosc 2023;97:1016-1030.
18. Kumarasinghe MP, et al. Mod Pathol 2020;33:986-1006.
19. Lian J, et al. Gastrointest Endosc 2012;76:763-770.
20. Park YM, et al. Surg Endosc 2011;25:2666-2677.
21. Facciorusso A, et al. World J Gastrointest Endosc 2014;6:555-563.
22. Zwager LW, et al. Gastroenterology 2022;163:174-189.
23. Gijsbers KM, et al. Endosc Int Open 2022;10:e282-e290.

Quantitative hepatitis B surface antigen profiles in an endemic population – How does it influence drug development strategies?
(Abstract of Thesis 2025)

Dr. Rex Wan-Hin Hui Department of Medicine Queen Mary Hospital The University of Hong Kong

In a recently published article in Gut,¹ our team established quantitative hepatitis B surface antigen (qHBsAg) profiles in a large cohort in Hong Kong.

qHBsAg is an increasingly important biomarker in the management of chronic hepatitis B (CHB). qHBsAg levels can predict liver-related events and can guide decisions for finite nucleos(t)ide analogue (NUC) therapy.² More importantly, qHBsAg is a key marker for predicting HBsAg seroclearance – a favorable endpoint in CHB. An inverse relationship between qHBsAg titre and HBsAg seroclearance probability has been observed, with qHBsAg <1000 IU/ml or 100 IU/ml frequently cited as predictors of spontaneous HBsAg seroclearance.^{3, 4}

HBsAg seroclearance is a rare event, and current CHB therapies cannot effectively attain this treatment endpoint (annual incidence ~1% with or without NUC therapy).⁵ Multiple novel drugs are hence under development with HBsAg seroclearance as a treatment target.⁶ In particular, RNA silencers (including antisense oligonucleotides and small-interfering RNAs) are the most advanced in development and have demonstrated promising results.^{7, 8} qHBsAg is one of the strongest predictors of HBsAg seroclearance after novel CHB therapies, and once again, qHBsAg <1000 IU/ml appears as the “magic number”.² In the landmark bepirovirsen (antisense oligonucleotide) trial, patients with qHBsAg <1000 IU/ml had a response rate over two times higher than patients with qHBsAg >1000 IU/ml.⁷ Similarly in the xalnesiran (small-interfering RNA) + pegylated interferon alpha combination trial, HBsAg seroclearance only occurred in patients with qHBsAg <1000 IU/ml.⁸ qHBsAg cutoffs have hence been included as inclusion criteria in most upcoming CHB clinical trials.

While qHBsAg is an important biomarker, qHBsAg profiles in CHB populations have not been well-defined, and prior reports were generally based on small treatment naïve patient cohorts only. In our study, we studied a large CHB cohort (n=4287) from Queen Mary Hospital, Hong Kong with both treatment naïve (n=2349) and NUC treated patients (n=1938).¹ The median qHBsAg level in the whole cohort was 630.8 (117.1 – 1875.5) IU/ml. 3437 patients (80.2%), 2516 patients (58.7%), and 997 patients (23.3%) had qHBsAg <3000 IU/ml, <1000 IU/ml, and <100 IU/ml respectively (69.2%, 46.9% and 22.9% in treatment naïve; 93.4%, 73.0% and 23.6% in NUC treated patients correspondingly) (Figure 1). Treatment naïve patients had significantly higher baseline qHBsAg than NUC treated patients (median qHBsAg 1257.0 vs 358.3 IU/ml respectively, p<0.001). Further analysis on predictors of baseline qHBsAg levels and age-stratified analysis was performed. These findings provided a clear snapshot on qHBsAg distributions in an endemic population, enabling informed decisions on treatment strategies.

Figure 1. qHBsAg profiles in the patient cohort

(Adopted with permission from Hui et al. Gut, 2025 (in press))¹

In the next part of our study, we established longitudinal qHBsAg profiles in our cohort.¹ With follow up for a median of 6.3 (5.7 – 14.3) years, we reported incidences of HBsAg seroclearance and longitudinal qHBsAg trajectories (Figure 2). Notably, while we demonstrated dynamic shifts in qHBsAg levels with a prevailing downward trend, long-term qHBsAg reduction did not occur in all patients. This has implications on patient prognostication, and may influence decisions for monitoring or for treatment initiation.

Figure 2. Longitudinal qHBsAg trajectories in the patient cohort

(Adopted with permission from Hui et al. Gut, 2025 (in press))¹

Finally, our study explored the role of the ALT/qHBsAg ratio in predicting qHBsAg trajectories. The ALT/qHBsAg ratio is a novel parameter reflecting host immune-mediated response intensity per IU/ml of qHBsAg.⁹ This parameter was first reported by our group in 2024, and has been shown to predict responses after NUC withdrawal and after pegylated interferon alpha therapy respectively.^{9, 10} In the current study, we determined an optimal ALT/qHBsAg ratio of 0.27 for predicting HBsAg seroclearance.¹ Baseline ALT/qHBsAg ratio ≥0.27 independently predicted HBsAg seroclearance (Hazard ratio 4.90, 95% CI 4.00-6.02, p<0.001), with robust predictive performance after stratification by NUC treatment and HBeAg status. We also demonstrated the predictive role of longitudinal ALT/qHBsAg changes, where longitudinal evolution of ALT/qHBsAg from <0.27 to ≥0.27 was independently associated with HBsAg seroclearance (Hazard ratio 1.92, 95% CI 1.31-2.79, p<0.001). This shows the strength of the ALT/qHBsAg ratio in predicting qHBsAg evolution, supporting its routine use in patient management.

With the emergence of novel therapies that can induce HBsAg seroclearance, a major paradigm shift is anticipated in the future of CHB care.⁶ Despite promising clinical trial data, the proportion of patients who are treatment-eligible or likely to be responsive to novel agents was unclear. Our study filled a critical literature gap and provided detailed qHBsAg profiling in a large cohort. In Hong Kong – an endemic population for CHB, >40% of patients had qHBsAg >1000 IU/ml, suggesting that they are unlikely to have spontaneous HBsAg seroclearance, but will also have suboptimal response to novel drugs. Personalized strategies with tailoring of drug choices and treatment durations will be necessary for targeting patients with qHBsAg >1000 IU/ml. The data on longitudinal qHBsAg trajectories and outcome prediction will also play a key role in designing treatment strategies and clinical trials. Our qHBsAg profiling data has garnered substantial interest from both academia and the pharmaceutical field. We anticipate that our data will be extensively utilized in the future development of CHB therapies.

References

1. Hui RW, Wu TK, Ho KC, et al. Large-scale profile study on hepatitis B surface antigen levels in chronic hepatitis B: Implications for drug development targeting functional cure. Gut 2025;In press.
2. Mak LY, Hui RW, Fung J, et al. The role of different viral biomarkers on the management of chronic hepatitis B. Clin Mol Hepatol 2023;29:263-276.
3. Seto WK, Wong DK, Fung J, et al. Serum hepatitis B surface antigen (HBsAg) kinetics in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. Hepatol Int 2012;7:119-26.
4. Seto WK, Wong DK, Fung J, et al. A large case-control study on the predictability of hepatitis B surface antigen levels three years before hepatitis B surface antigen seroclearance. Hepatology 2012;56:812-9.
5. Yeo YH, Ho HJ, Yang HI, et al. Factors Associated With Rates of HBsAg Seroclearance in Adults With Chronic HBV Infection: A Systematic Review and Meta-analysis. Gastroenterology 2019;156:635-46.
6. Hui RW, Mak LY, Fung J, et al. Prospect of emerging treatments for HBV functional cure. Clin Mol Hepatol 2024;31:S165-S181.
7. Yuen MF, Lim SG, Plesniak R, et al. Efficacy and Safety of Bepirovirsen in Chronic Hepatitis B Infection. N Engl J Med 2022;387:1957-1968.
8. Hou J-l, Zhang W, Xie Q, et al. Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B. N Engl J Med 2024;391:2098-2109.
9. Leung RH, Hui RW, Mak LY, et al. ALT to qHBsAg ratio predicts long-term HBsAg seroclearance after entecavir cessation in Chinese patients with chronic hepatitis B. J Hepatol 2024;81:218-226.
10. Wang J, Zhang Q, Zhang S, et al. ALT to qHBsAg ratio predicts HBsAg seroclearance in HBeAg-negative hepatitis B patients with Peg-IFN-α-based therapy. J Hepatol 2024.