Dear Editor,
We appreciate the editorial comments by Dr. Jang and Dr. Kim on our study regarding the long-term outcomes of chronic hepatitis B (CHB) patients who had metabolic diseases and initiated nucleos(t)ide analogue (NA) therapy [
1,
2]. The editorial highlighted the negative impact of diabetes on the long-term outcomes of CHB patients despite receipt of effective antiviral treatment, and suggested that treatment of diabetes should be optimized and incorporated as part of CHB management, in addition to antiviral therapy for CHB patients [
1].
As shown in our recent study, not all metabolic factors have equal risk of poor outcomes in CHB patients, and the presence of diabetes by itself was a more important factor impacting outcomes than the number of metabolic diseases [
2]. Thus, we agree with Dr. Jang and Dr. Kim that screening, diagnosis, and management of diabetes should be part of the treatment of CHB. Given the higher risk for adverse events among CHB patients with diabetes, diabetes should be added as a criterion for antiviral initiation, in addition to other host and viral factors such as liver enzymes, HBV DNA levels, etc., as recently proposed by the 2024 HBV treatment guideline by the World Health Organization (WHO) [
3]. The WHO recommends CHB patients without significant fibrosis (stage 2) who have diabetes be treated with antiviral therapy [
3]. Along similar lines, diabetes should also be one of the criteria for selecting high risk CHB patients for hepatocellular carcinoma (HCC) surveillance in addition to age, sex, and presence of cirrhosis in both untreated and treated CHB patients. Indeed, diabetes was one of the five components of the REAL-B score, an HCC risk score developed and validated in an international consortium of treated CHB patients [
4]. Additionally, the REAL-B score has been found to outperform other HCC risk scores for treated CHB patients that do not include diabetes as part of their algorithm [
5].
We also appreciate Dr. Jang and Dr. Kim’s comments on the complex interplay between diabetes, hepatic steatosis and CHB. In the current study, we found the presence of hepatic steatosis associated with a lower risk of cirrhosis, HCC, and liver-related death [
2], which is in line with results reported by a recent large meta-analysis that includes analysis of individual patient level data and matching methods to balance the background characteristics of CHB patients with and without hepatic steatosis [
6]. Though another recent systematic review and meta-analysis of this topic reported findings in the opposite direction [
7], the pooled results of this meta-analysis may be difficult to interpret as they were derived from different types of association measurements and included data that were not based on time-to-event data. As the editorial pointed out, the impact of diabetes on the adverse outcomes of CHB patients is independent of hepatic steatosis as the presence of hepatic steatosis was balanced between the diabetic and nondiabetic group via propensity score matching, with consistent results in sensitivity analyses that excluded patients with hepatic steatosis [
2]. However, our understanding of this interplay among this “trio” of diabetes, hepatic steatosis, and CHB is limited and further mechanistic studies are needed.
In summary, we agree that in addition to effective control of hepatitis B virus replication, prevention, screening, diagnosis and management of metabolic diseases especially diabetes is critical and requires collaboration with primary care and metabolic specialists. Diabetes should also be part of risk stratification for antiviral initiation and HCC surveillance.
FOOTNOTES
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Authors’ contribution
Manuscript drafting: RH. Review and revision: RH and MHN.
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Conflicts of Interest
Mindie H. Nguyen: Research grants via Stanford University: Pfizer, Enanta, Astra Zeneca, GSK, Delfi, Innogen, Exact Science, CurveBio, Gilead, Vir Biotech, Helio Health, National Institute of Health, Glycotest, Roche and personal fees from consulting/advisory board: Exelixis, Gilead, GSK. Rui Huang: none to disclose.
Abbreviations
REFERENCES
- 1. Jang H, Kim W. Type 2 diabetes as a key metabolic risk factor for adverse outcomes in nucleos(t)ide analogue-treated chronic hepatitis B: Editorial on “Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues”. Clin Mol Hepatol 2026;32:426-428.
- 2. Huang R, Jun DW, Toyoda H, Hsu YC, Trinh H, Nozaki A, et al. Impacts of metabolic syndrome diseases on long-term outcomes of chronic hepatitis B patients treated with nucleos(t)ide analogues. Clin Mol Hepatol 2025;31:1003-1017.
- 3. World Health Organization (WHO). 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 14 Apr 2024.
- 4. Yang HI, Yeh ML, Wong GL, Peng CY, Chen CH, Trinh HN, et al. Real-world effectiveness from the Asia Pacific Rim Liver Consortium for HBV risk score for the prediction of hepatocellular carcinoma in chronic hepatitis B patients treated with oral antiviral therapy. J Infect Dis 2020;221:389-399.
- 5. Yip TC, Wong VW, Lai MS, Lai JC, Tse YK, Liang LY, et al. Diabetes mellitus impacts on the performance of hepatocellular carcinoma risk scores in chronic hepatitis B patients. Clin Gastroenterol Hepatol 2023;21:2864-2875.e16.
- 6. Wong YJ, Nguyen VH, Yang HI, Li J, Le MH, Wu WJ, et al. Impact of fatty liver on long-term outcomes in chronic hepatitis B: a systematic review and matched analysis of individual patient data meta-analysis. Clin Mol Hepatol 2023;29:705-720.
- 7. Mao X, Cheung KS, Peng C, Mak LY, Cheng HM, Fung J, et al. Steatosis, HBV-related HCC, cirrhosis, and HBsAg seroclearance: A systematic review and meta-analysis. Hepatology 2023;77:1735-1745.
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