{
  "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 20 000–10 6 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.",
  "authors": [
    {
      "affiliations": [
        "Department of Infectious Disease, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China",
        "Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA",
        "Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China"
      ],
      "name": "Rui Huang"
    },
    {
      "affiliations": [
        "San Jose Gastroenterology, San Jose, California, USA"
      ],
      "name": "Huy N Trinh"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan"
      ],
      "name": "Satoshi Yasuda"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA",
        "Weill Cornell Medical College, New York, New York, USA"
      ],
      "name": "Angela Chau"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA"
      ],
      "name": "Mayumi Maeda"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA",
        "The University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USA",
        "Digestive Health Associates of Texas, Dallas, Texas, USA"
      ],
      "name": "Ai-Thien Do"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, National University Hospital, Singapore",
        "Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore"
      ],
      "name": "Daniel Q Huang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan"
      ],
      "name": "Takanori Ito"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan"
      ],
      "name": "Takashi Honda"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan"
      ],
      "name": "Masatoshi Ishigami"
    },
    {
      "affiliations": [
        "Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan"
      ],
      "name": "Ritsuzo Kozuka"
    },
    {
      "affiliations": [
        "University of Medicine and Pharmacy Carol Davila, Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, București, Romania"
      ],
      "name": "Carmen Monica Preda"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan"
      ],
      "name": "Cheng-Hao Tseng"
    },
    {
      "affiliations": [
        "Liver Unit Hospital Italiano de Buenos Aires, Buenos Aires, Argentina"
      ],
      "name": "Sebastián Marciano"
    },
    {
      "affiliations": [
        "Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan"
      ],
      "name": "Pei-Chien Tsai"
    },
    {
      "affiliations": [
        "Division of Gastroenterology, Department of Internal Medicine, Good Gang-An Hospital, Busan, South Korea"
      ],
      "name": "Dong Hyun Lee"
    },
    {
      "affiliations": [
        "Wong Clinics, San Francisco, California, USA"
      ],
      "name": "Christopher C Wong"
    },
    {
      "affiliations": [
        "Digestive Health Associates of Texas, Dallas, Texas, USA"
      ],
      "name": "Son Do"
    },
    {
      "affiliations": [
        "National Institute of Infectious Diseases, Tokyo, Japan"
      ],
      "name": "Keigo Kawashima"
    },
    {
      "affiliations": [
        "Chinese Hospital, San Francisco, California, USA"
      ],
      "name": "Jian Zhang"
    },
    {
      "affiliations": [
        "University of Medicine and Pharmacy Carol Davila, Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, București, Romania"
      ],
      "name": "Raluca Ioana Marin"
    },
    {
      "affiliations": [
        "University of Medicine and Pharmacy Carol Davila, Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, București, Romania"
      ],
      "name": "Irina Sandra"
    },
    {
      "affiliations": [
        "Palo Alto Medical Foundation, Mountain View Division, Mountain View, California, USA"
      ],
      "name": "Jiayi Li"
    },
    {
      "affiliations": [
        "Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan"
      ],
      "name": "Eiichi Ogawa"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA",
        "Gastroenterology and Hepatology, The Palo Alto Veterans Affairs Health Care System, Palo Alto, California, USA"
      ],
      "name": "Ramsey Cheung"
    },
    {
      "affiliations": [
        "Department of Infectious Disease, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China",
        "Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China"
      ],
      "name": "Jie Li"
    },
    {
      "affiliations": [
        "Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan",
        "Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan"
      ],
      "name": "Ming-Lung Yu"
    },
    {
      "affiliations": [
        "Liver Unit Hospital Italiano de Buenos Aires, Buenos Aires, Argentina"
      ],
      "name": "Adrián Gadano"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan"
      ],
      "name": "Yao-Chun Hsu"
    },
    {
      "affiliations": [
        "Liver Unit, Hospital Universitari Valle d’Hebron and Universitat Autònoma de Barcelona, Barcelona, and CIBEREHD del Instituto Carlos III, Barcelona, Spain"
      ],
      "name": "Maria Buti"
    },
    {
      "affiliations": [
        "Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan",
        "Department of Transfusion Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan"
      ],
      "name": "Masaru Enomoto"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, National University Health System, Singapore"
      ],
      "name": "Seng Gee Lim"
    },
    {
      "affiliations": [
        "Department of Infectious Disease, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China",
        "Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China"
      ],
      "name": "Chao Wu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan"
      ],
      "name": "Hidenori Toyoda"
    },
    {
      "affiliations": [
        "Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University Medical Center, Palo Alto, California, USA",
        "Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA"
      ],
      "name": "Mindie H Nguyen"
    }
  ],
  "title": "Differential HCC risk among HBV indeterminate types at baseline and by phase transition",
  "uid": "89884520-cd8c-50a4-89cc-6d945e99f0c4"
}