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Many patients with chronic hepatitis B (CHB) may not conform to any of the defined phases and hence are classified as indeterminate. We aimed to characterize the baseline prevalence of indeterminate patients and their natural history, phase transition, and hepatocellular carcinoma (HCC) risk.This was a retrospective cohort study of 3366 adult untreated noncirrhotic CHB patients seen at 5 US clinics and 7 Taiwanese townships who had at least 1 year of serial laboratory data before enrollment with a mean follow-up period of 12.5 years. Patients' clinical phases were determined at baseline and through serial data during follow-up evaluation, based on the American Association for the Study of Liver Diseases 2018 guidance.At baseline, 1303 (38.7%) patients were in the indeterminate phase. By up to year 10 of follow-up evaluation, 686 patients (52.7%) remained indeterminate, while 283 patients (21.7%) became immune active. Compared with patients who remained inactive, patients who remained indeterminate had a higher 10-year cumulative HCC incidence (4.6% vs 0.5%; P.0001) and adjusted hazard ratio for HCC of 14.1 (P = .03). Among patients who remained indeterminate, age 45 years and older (adjusted hazard ratio, 18.4; P = .005) was associated independently with HCC development.Nearly 40% of patients had indeterminate CHB phase. Of these, half remained indeterminate and one-fifth transitioned to the immune active phase. HCC risk in persistently indeterminate CHB was 14 times higher than inactive CHB. Among persistently indeterminate CHB patients, age 45 years and older was associated with an 18 times higher risk for HCC development. Further studies are needed to evaluate the potential benefit of antiviral therapy for indeterminate patients, especially in the older subgroup.

Background: Infection with hepatitis B (HBV) or C (HCV) and non-alcoholic fatty liver disease (NAFLD) are major causes of liver disease in adults. However, data for children and adolescents are limited. To characterize the prevalence, trend, risk factors of HBV (HBsAg+ or anti-HBc Ab+), HCV (antibody+ or RNA+), and potential NAFLD (United States Fatty Liver Index>30) for this population. Methods: We analyzed 6,647 children and adolescents (aged 6-21 years) from the 1999-2016 National Health and Nutrition Examination Survey (NHANES). Findings: Among individuals aged 6-21 years, HBV prevalence decreased after 2011, from 0·72% in 1999-2004, ·85% in 2005-2010 to 0·27% in 2011-2016 (P 22/26 U/L female/male) (OR: 2·79, 95%CI: 1·63-4·75), dyslipidemia (OR: 3·29, 95%CI: 1·92-5·65), and ≥4 hours a day spent viewing television (OR: 2·16, 95%CI:1·29-3·59) significantly increased risk for potential NAFLD, but not Income: Poverty ratio, hours spent on computer use, or hypertension. Interpretation: While HBV prevalence has decreased in recent years among U.S. children and adolescents, HCV and potential NAFLD have increased. Public health efforts must seek further understanding of the driving factors of this increase so that age-appropriate interventions can be developed and implemented. Funding: None. Declaration of Interests: Ramsey Cheung has received research support from Gilead Sciences. Mindie H. Nguyen has received research support from Gilead, BMS, and Janssen, and has served as an advisory board member or consultant for Dynavax, Gilead, Alnylam, BMS, Novartis, Spring Bank, and Janssen. Other authors have no disclosures. Ethics Approval Statement: The NHANES protocol was approved by the National Center for Health Statistics Research Ethics Review Board, and written informed consent was obtained from all participants 18 years of age or older or from a parent/legal guardian of participants younger than 18 years. This study is considered exempt by the Institutional Review Board at Stanford University, Stanford, CA, USA.

Seroclearance of hepatitis B surface antigen (HBsAg) is a marker for clearance of chronic hepatitis B virus (HBV) infection, but reported annual incidence rates of HBsAg seroclearance vary. We performed a systematic review and meta-analysis to provide more precise estimates of HBsAg seroclearance rates among subgroups and populations.We searched PubMed, Embase, and the Cochrane library for cohort studies that reported HBsAg seroclearance in adults with chronic HBV infection with more than 1 year of follow-up and at least 1 repeat test for HBsAg. Annual and 5-, 10-, and 15-year cumulative incidence rates were pooled using a random effects model.We analyzed 34 published studies (with 42,588 patients, 303,754 person-years of follow-up, and 3194 HBsAg seroclearance events), including additional and updated aggregated data from 19 studies. The pooled annual rate of HBsAg seroclearance was 1.02% (95% CI, 0.79-1.27). Cumulative incidence rates were 4.03% at 5 years (95% CI, 2.49-5.93), 8.16% at 10 years (95% CI, 5.24-11.72), and 17.99% at 15 years (95% CI, 6.18-23.24). There were no significant differences between the sexes. A higher proportion of patients who tested negative for HBeAg at baseline had seroclearance (1.33%; 95% CI, 0.76-2.05) than those who tested positive for HBeAg (0.40%; 95% CI, 0.25-0.59) (P.01). Having HBsAg seroclearance was also associated with a lower baseline HBV DNA level (6.61 logIn a systematic review and meta-analysis, we found a low rate of HBsAg seroclearance in untreated and treated patients (pooled annual rate, approximately 1%). Seroclearance occurred mainly in patients with less active disease. Patients with chronic HBV infection should therefore be counseled on the need for lifelong treatment, and curative therapies are needed.