Effect of Anti-HBs on Mortality Among Resolved HBV Infection: a Population-Based Prospective Cohort Study

Abstract Introduction Surveillance programs after hepatitis B surface antigen (HBsAg) loss are not yet well established, and the role of hepatitis B surface antibodies (anti-HBs) remains controversial. We aimed to evaluate the risk factors for increased mortality and the association between anti-HBs and all-cause and cause-specific mortality in a representative US (United States) population of patients with resolved HBV (Hepatitis B virus) infections. Methods Data were taken from the US National Health and Nutrition Examination Survey (NHANES) 1999–2018. A total of 3455 US adults with resolved HBV infection [defined as hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive] were enrolled in this study. The primary outcome measures were all-cause and cause-specific mortality from baseline until 31 December 2019. Results During a mean follow-up of 10.3 years, 741 deaths occurred. Age, race, marital status, smoking status, physical activity level, and presence of cirrhosis, diabetes, cardiovascular diseases, chronic obstructive pulmonary diseases, cancer, and anti-HBs were significant factors for increased mortality, and a nomogram tool was developed and validated for the risk stratification of mortality. Compared with participants who were anti-HBs positive, those who were anti-HBs negative had a 23% (hazard ratio 1.23, 95% CI 1.02–1.46) higher risk of all-cause mortality in NHANES 1999–2018. For cause-specific mortality, the fully adjusted hazard ratios of participants who were anti-HBs negative were 0.71 (95% CI 0.48–1.06) for heart disease, 1.44 (95% CI 1.01–2.05) for cancer, and 1.44 (95% CI 1.13–1.83) for other conditions, compared to those of participants who were anti-HBs positive. Conclusions Among US adults with resolved HBV infections, anti-HBs-negative status was associated with an increased risk of death from all causes and cancer, implying that the role of anti-HBs in resolved HBV infection should not be ignored. On the public health level, more rigorous surveillance was needed for populations of individuals who were isolated anti-HBc positive.