Prevalence of occult hepatitis B virus infection in adults: a systematic review and meta-analysis

Background: Despite growing concerns about transmissibility and clinical impact, occult hepatitis B virus (HBV) infection has received little attention in the hepatitis elimination agenda. We aimed to estimate the prevalence of occult HBV infection at a global and regional scale and in specific populations. Methods: For this systematic review and meta-analysis, we searched the MEDLINE, Embase, Global Health, and Web of Science databases for articles published in any language between Jan 1, 2010, and Aug 14, 2019. We included original articles and conference abstracts of any study design that reported the proportion of HBsAg-negative adults (aged ≥18 years) who are positive for HBV DNA (ie, people with occult HBV infection). The prevalence of occult HBV infection was pooled, using the DerSimonian-Laird random-effects model, in the general population and specific groups defined by the type of study participants (blood donors; other low-risk populations; high-risk populations; and people with advanced chronic liver disease), and stratified by HBV endemicity in each country. We also assessed the performance of anti-HBc as an alternative biomarker to detect occult HBV infection. The study was registered with PROSPERO, CRD42019115490. Findings: 305 of 3962 articles were eligible, allowing a meta-analysis of 140 521 993 individuals tested for HBV DNA. Overall, only two studies evaluated occult HBV infection in the general population, precluding unbiased global and regional estimates of occult HBV infection prevalence. In blood donors, occult HBV infection prevalence mirrored HBV endemicity: 0·06% (95% CI 0·00–0·26) in low-endemicity countries, 0·12% (0·04–0·23) in intermediate-endemicity countries, and 0·98% (0·44–1·72), in high-endemicity countries (p=0·0012). In high-risk groups, occult HBV infection prevalence was substantial, irrespective of endemicity: 5·5% (95% CI 2·9–8·7) in low-endemicity countries, 5·2% (2·5–8·6) in intermediate-endemicity countries, and 12·0% (3·4–24·7) in high-endemicity countries. The pooled sensitivity of anti-HBc to identify occult HBV infection was 77% (95% CI 62–88) and its specificity was 76% (68–83). Interpretation: A substantial proportion of people carry occult HBV infection, especially among high-risk groups across the globe and people living in highly endemic countries. Occult HBV infection should be part of the global viral hepatitis elimination strategy. Funding: None.