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

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

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

Rui Huang et al. Gut. 2025.

. 2025 Jun 4:gutjnl-2025-335033.

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

Authors

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.

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Conflict of interest statement

Competing interests: DQH: advisory board: Gilead and Roche. C-HT: speaker: Roche. M-LY: research grant from AbbVie, BMS, Gilead, Merck and Roche Diagnostics; consultant: AbbVie, BMS, Gilead, Roche and Roche Diagnostics; speaker: AbbVie, BMS, Eisai, Gilead, Roche and Roche Diagnostics. HT: speaker’s bureau/fees: AbbVie, Gilead Sciences, Takeda Pharmaceutical, Eisai, Kowa, Terumo, Fujifilm WAKO, Chugai, AstraZeneca and Bayer. CW: research grants: Gilead Sciences and Roche. MHN: research grants via Stanford University from Pfizer, Enanta, AstraZeneca, GSK, Delfi, Innogen, Exact Science, CurveBio, Gilead, Vir Biotech, Helio Health, National Institute of Health and Glycotest; personal fees from consulting/advisory board: Exelixis, Gilead and GSK. Y-CH: research support: Gilead Sciences; consulting/advisory board: Gilead Sciences and Sysmex; speaker’s bureau: AbbVie, Bristol-Myers Squibb, Gilead Sciences, Grifols and Roche. TI: consulting/advisory board: Chugai Pharmaceutical and Ono Pharmaceutical; speaker’s bureau: Chugai Pharmaceutical and AstraZeneca. ME: speaker’s bureau: Gilead and Chugai. HNT: research support: Gilead, GSK, Novo Nordisk and Inventiva; consulting/advisory board: GSK; speaker’s bureau: Gilead; stock ownership: Gilead.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Full Text Sources