Differential HCC risk among HBV indeterminate types at baseline and by phase transition

Rui Huang; Huy N Trinh; Satoshi Yasuda; Angela Chau; Mayumi Maeda; Ai-Thien Do; Daniel Q Huang; Takanori Ito; Takashi Honda; Masatoshi Ishigami; Ritsuzo Kozuka; Carmen Monica Preda; Cheng-Hao Tseng; Sebastián Marciano; Pei-Chien Tsai; Dong Hyun Lee; Christopher C Wong; Son Do; Keigo Kawashima; Jian Zhang; Raluca Ioana Marin; Irina Sandra; Jiayi Li; Eiichi Ogawa; Ramsey Cheung; Jie Li; Ming-Lung Yu; Adrián Gadano; Yao-Chun Hsu; Maria Buti; Masaru Enomoto; Seng Gee Lim; Chao Wu; Hidenori Toyoda; Mindie H Nguyen

doi:10.1136/gutjnl-2025-335033

Differential HCC risk among HBV indeterminate types at baseline and by phase transition

Gut. 2025 Jun 4:gutjnl-2025-335033. doi: 10.1136/gutjnl-2025-335033. Online ahead of print.

Authors

Rui Huang^{1

2

3}, Huy N Trinh⁴, Satoshi Yasuda⁵, Angela Chau^{2

6}, Mayumi Maeda², Ai-Thien Do^{2

7

8}, Daniel Q Huang^{9

10}, Takanori Ito¹¹, Takashi Honda¹¹, Masatoshi Ishigami¹¹, Ritsuzo Kozuka¹², Carmen Monica Preda¹³, Cheng-Hao Tseng¹⁴, Sebastián Marciano¹⁵, Pei-Chien Tsai¹⁶, Dong Hyun Lee¹⁷, Christopher C Wong¹⁸, Son Do⁸, Keigo Kawashima¹⁹, Jian Zhang²⁰, Raluca Ioana Marin¹³, Irina Sandra¹³, Jiayi Li²¹, Eiichi Ogawa²², Ramsey Cheung^{2

23}, Jie Li^{1

3}, Ming-Lung Yu^{16

24}, Adrián Gadano¹⁵, Yao-Chun Hsu²⁵, Maria Buti²⁶, Masaru Enomoto^{12

27}, Seng Gee Lim²⁸, Chao Wu^{1

3}, Hidenori Toyoda²⁹, Mindie H Nguyen^{30

31}

Affiliations

¹ Department of Infectious Disease, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China.
² Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA.
³ Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China.
⁴ San Jose Gastroenterology, San Jose, California, USA.
⁵ Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan.
⁶ Weill Cornell Medical College, New York, New York, USA.
⁷ The University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USA.
⁸ Digestive Health Associates of Texas, Dallas, Texas, USA.
⁹ Division of Gastroenterology and Hepatology, National University Hospital, Singapore.
¹⁰ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
¹¹ Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
¹² Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
¹³ University of Medicine and Pharmacy Carol Davila, Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, București, Romania.
¹⁴ Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan.
¹⁵ Liver Unit Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
¹⁶ Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
¹⁷ Division of Gastroenterology, Department of Internal Medicine, Good Gang-An Hospital, Busan, South Korea.
¹⁸ Wong Clinics, San Francisco, California, USA.
¹⁹ National Institute of Infectious Diseases, Tokyo, Japan.
²⁰ Chinese Hospital, San Francisco, California, USA.
²¹ Palo Alto Medical Foundation, Mountain View Division, Mountain View, California, USA.
²² Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan.
²³ Gastroenterology and Hepatology, The Palo Alto Veterans Affairs Health Care System, Palo Alto, California, USA.
²⁴ Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
²⁵ Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan.
²⁶ Liver Unit, Hospital Universitari Valle d'Hebron and Universitat Autònoma de Barcelona, Barcelona, and CIBEREHD del Instituto Carlos III, Barcelona, Spain.
²⁷ Department of Transfusion Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
²⁸ Division of Gastroenterology and Hepatology, National University Health System, Singapore.
²⁹ Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan mindiehn@stanford.edu hmtoyoda@spice.ocn.ne.jp.
³⁰ Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA mindiehn@stanford.edu hmtoyoda@spice.ocn.ne.jp.
³¹ Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA.

PMID: 40467102
DOI: 10.1136/gutjnl-2025-335033

Abstract

Background: Patients with chronic hepatitis B (CHB) with indeterminate phase make up a diverse cohort with likely different outcomes.

Objective: We compared the hepatocellular carcinoma (HCC) risk in indeterminate CHB with different baseline types and by phase transition.

Design: This was a retrospective cohort study of 1986 (94.2% Asian) patients with indeterminate CHB from nine countries/regions. Patients were classified according to baseline hepatitis B e-antigen (HBeAg), alanine aminotransferase (ALT) and HBV DNA. The cumulative HCC incidence was compared.

Results: Based on the 2018 American Association for the Study of Liver Disease guidance, most indeterminate patients were HBeAg negative (84.9%). The 20-year HCC incidence was highest in type 1 (HBeAg positive, ALT<1×upper limit of normal (ULN), HBV DNA 20 000-10⁶ IU/mL, 36.2%) and lowest in type 8 (HBeAg negative, ALT 1-2×ULN, HBV DNA<2000 IU/mL, 1.9%). The 20-year HCC incidence of those who remained indeterminate was 4.7%. Cumulative HCC incidence rates were high in patients with indeterminate CHB who transitioned to immune tolerant (15 years: 16.5%) or immune active (20 years: 13.7%) phase but low for those who transitioned to immune inactive phase (20 years: 2.5%). In multivariable analysis, compared with type 8, higher HCC risk was seen with HBeAg-positive type 1 (adjusted HR (aHR)=40.1, p<0.001), type 2 (ALT 1-2×ULN, HBV DNA≥20 000 IU/mL, aHR=25.1, p<0.001), HBeAg-negative type 9 (ALT>2×ULN, HBV DNA<2000 IU/mL, aHR=4.6, p=0.032) and type 10 (ALT<1×ULN, HBV DNA<2000 IU/mL but with moderate to severe inflammation/fibrosis, aHR=7.3, p=0.033). Similar directions in HCC risks were found in analyses based on the 2017 European Association for the Study of the Liver guideline.

Conclusion: Several types of indeterminate CHB had high HCC risk. These data support the potential expansion of treatment criteria for higher risk types of indeterminate CHB.

Keywords: HEPATITIS B.