Pegylated interferon α-2b add-on to nucleos(t)ide analogues reduces hepatocellular carcinoma and decompensation in advanced fibrotic chronic hepatitis B

doi:10.3748/wjg.121641

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Retrospective Cohort Study

Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastroenterol. Dec 7, 2026; 32(45): 121641
Published online Dec 7, 2026. doi: 10.3748/wjg.121641

Pegylated interferon α-2b add-on to nucleos(t)ide analogues reduces hepatocellular carcinoma and decompensation in advanced fibrotic chronic hepatitis B

Xiang-Yong Li, Jing-Tao Huang, Ting Liu, Ying-Yi Li, Long Zhe, Hong Cao, Bing-Liang Lin

Xiang-Yong Li, Jing-Tao Huang, Ting Liu, Ying-Yi Li, Long Zhe, Hong Cao, Bing-Liang Lin, Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China

Co-first authors: Xiang-Yong Li and Jing-Tao Huang.

Co-corresponding authors: Hong Cao and Bing-Liang Lin.

Author contributions: Li XY and Huang JT contributed to analysis, writing-original draft, and methodology as co-first authors; Li XY, Huang JT, and Lin BL contributed to writing-review and editing; Li XY, Liu T, Li YY, Zhe L, and Cao H contributed to data curation; Li XY, Cao H, and Lin BL contributed to conceptualisation; Huang JT and Liu T contributed to investigation; Cao H and Lin BL contributed to supervision as co-corresponding authors; all authors have read and approved the final manuscript.

AI contribution statement: We used DeepSeek in helping translating reviewing letter from Chinese into English during the drafting of the point-by-point response to reviewers. The scientific content, arguments, and detailed responses were all written by the authors. The AI tool did not participate in any part of the study design or data interpretation. None of the images in the manuscript were generated by AI.

Supported by National Science and Technology Major Project for the Prevention and Control of Emerging and Major Infectious Diseases, No. 2025ZD01906901; Natural Science Foundation of Guangdong, No. 2022A1515012597; and Special Funding for Clinical Research of Wu Jieping Medical Foundation, No. 320.6750.2022-06-31.

Institutional review board statement: Ethical approval for this study was provided by Third Affiliated Hospital of Sun Yat-sen University Medical Ethics Committee (approval No. II-2026-098-01).

Informed consent statement: Third Affiliated Hospital of Sun Yat-sen University Medical Ethics Committee waived the informed consent form.

Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.

STROBE statement: The authors have read the STROBE Statement – checklist of items, and the manuscript was prepared and revised according to the STROBE Statement – checklist of items.

Data sharing statement: Raw data were generated at Third Affiliated Hospital of Sun Yat-sen University. Derived data supporting the findings of this study are available from the corresponding author on request.

Corresponding author: Hong Cao, MD, PhD, Professor, Chief Physician, Department of Infectious Disease, Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Tianhe District, Guangzhou 510630, Guangdong Province, China. caohong@mail.sysu.edu.cn

Received: March 30, 2026
Revised: April 28, 2026
Accepted: June 9, 2026
Published online: December 7, 2026
Processing time: 200 Days and 14.5 Hours

Abstract

BACKGROUND

The current therapeutic strategy of adding pegylated interferon (Peg-IFN) α-2b to nucleos(t)ide analogues (NAs) is primarily aimed at achieving functional cure. However, its value in improving prognosis and the suitable candidates for this combination strategy in patients with hepatitis B virus (HBV)-related advanced fibrosis or compensated cirrhosis remain to be further explored.

AIM

To evaluate the long-term prognosis benefit of add-on Peg-IFNα-2b therapy in patients with HBV-related advanced fibrosis or compensated cirrhosis.

METHODS

This retrospective cohort study enrolled patients diagnosed with HBV-related advanced fibrosis or compensated cirrhosis. Participants were divided into two groups: (1) Those receiving combination therapy (Peg-IFNα-2b add-on to ongoing NA treatment); and (2) Those receiving NA monotherapy. A 1:1 propensity score matching approach was applied to balance baseline characteristics between groups. In survival analysis, the outcomes of hepatocellular carcinoma (HCC) and decompensated cirrhosis were stratified by baseline clinical features and established HCC risk scores.

RESULTS

The analysis included 302 matched pairs, with a median follow-up duration of 220 weeks. Combination therapy was associated with a significantly lower risk of developing HCC (hazard ratio = 0.22; 95%CI: 0.11-0.48) and decompensated cirrhosis (hazard ratio = 0.39; 95%CI: 0.20-0.77) than NA monotherapy. These benefits were particularly pronounced among patients classified as intermediate-to-high risk by validated HCC prediction models and in those with persistent biochemical abnormalities lasting > 12 months.

CONCLUSION

Add-on therapy with Peg-IFNα-2b to NAs is significantly associated with reduced HCC and decompensation in high-risk patients with HBV-related advanced fibrosis or cirrhosis, supporting its use in this population.

Keywords: Chronic hepatitis B; Hepatitis B-related cirrhosis; Pegylated interferon α-2b add-on therapy; Risk stratification; Hepatocellular carcinoma; Decompensated cirrhosis; Therapeutic strategy

Core Tip: This large-scale, propensity score-matched cohort study provides evidence that a pegylated interferon α-2b add-on strategy reduces the risk of hepatocellular carcinoma and decompensated cirrhosis among patients with hepatitis B virus-related advanced fibrosis or compensated cirrhosis. The benefits of combination therapy were particularly pronounced in patients classified as having an intermediate-to-high risk of hepatocellular carcinoma. A persistently elevated transaminase level for > 12 months also identified a patient population that derived significant benefit from this approach These results indicate that a prognosis-oriented approach with pegylated interferon α-2b add-on therapy should be considered.