Background-Spontaneous loss of hepatitis B surface antigen (HBsAg), or functional cure, in patients with chronic hepatitis B (CHB) significantly reduces liver-related complications. Differential rates have been suggested by individual studies performed in non-endemic and endemic regions, potentially related to likelihood of spontaneous clearance if CHB was acquired as an adult versus child. We systematically determined a pooled annual rate of HBsAg loss in untreated CHB-infected adults and examined impact of regional endemicity. Methods-Pubmed/EMBASE were searched for observational cohort studies and non-treatment arms of randomized controlled trials (RCTs) reporting proportion of patients with CHB achieving spontaneous HBsAg loss. RCTs were excluded from meta-analyses due to substantial cohort differences. Results were stratified on whether the underlying cohort primarily arose from an endemic, defined as CHB prevalence >2%, or non-endemic region. We explored sources of heterogeneity through univariate meta-regression. Results-Of 4771 screened, 66 studies (11 RCTs, 38 prospective and 17 retrospective cohort studies) met inclusion criteria and 55 were included in meta-analyses with exclusion of RCTs. Spontaneous HBsAg loss occurred in 3489 (7.6%) of 45,975 patients with 341,862 person-years of follow-up. The pooled annual incidence rate of HBsAg loss was 1.13% (0.92-1.36%, I 2 =96%). Rates did not differ by endemicity: 1.13% (0.85-1.45%) in endemic vs 1.29% (0.99-1.62%) in non-endemic cohorts. Meta-regression showed proportion of cohort HBeAg-negative and cohort age were primary contributors to substantial heterogeneity. Conclusion-Globally, spontaneous HBsAg loss occurs infrequently (~1% per year) in treatment-naïve adults with CHB infection. The low and homogeneous rate of HBsAg loss

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