Incidence, Factors, and Patient-Level Data for Spontaneous HBsAg Seroclearance: A Cohort Study of 11,264 Patients

Abstract

Introduction: Spontaneous hepatitis B surface antigen (HBsAg) seroclearance, the functional cure of hepatitis B infection, occurs rarely. Prior original studies are limited by insufficient sample size and/or follow-up, and recent meta-analyses are limited by inclusion of only study-level data and lack of adjustment for confounders to investigate HBsAg seroclearance rates in most relevant subgroups. Using a cohort with detailed individual patient data, we estimated spontaneous HBsAg seroclearance rates through patient and virologic characteristics.

Methods: We analyzed 11,264 untreated patients with chronic hepatitis B with serial HBsAg data from 4 North American and 8 Asian Pacific centers, with 1,393 patients with HBsAg seroclearance (≥2 undetectable HBsAg ≥6 months apart) during 106,192 person-years. The annual seroclearance rate with detailed categorization by infection phase, further stratified by hepatitis B e antigen (HBeAg) status, sex, age, and quantitative HBsAg (qHBsAg), was performed.

Results: The annual seroclearance rate was 1.31% (95% confidence interval: 1.25-1.38) and over 7% in immune inactive patients aged ≥55 years and with qHBsAg <100 IU/mL. The 5-, 10-, 15-, and 20-year cumulative rates were 4.74%, 10.72%, 18.80%, and 24.79%, respectively. On multivariable analysis, male (adjusted hazard ratio [aHR] = 1.66), older age (41-55 years: aHR = 1.16; >55 years: aHR = 1.21), negative HBeAg (aHR = 6.34), and genotype C (aHR = 1.82) predicted higher seroclearance rates, as did lower hepatitis B virus DNA and lower qHBsAg (P < 0.05 for all), and inactive carrier state.

Discussion: The spontaneous annual HBsAg seroclearance rate was 1.31%, but varied from close to zero to about 5% among most chronic hepatitis B subgroups, with older, male, HBeAg-negative, and genotype C patients with lower alanine aminotransferase and hepatitis B virus DNA, and qHBsAg independently associated with higher rates (see Visual Abstract, Supplementary Digital Content 2, http://links.lww.com/CTG/A367).

Figure 1.

Cumulative incidence rate of spontaneous hepatitis B surface antigen (HBsAg) seroclearance. Gray shade denotes 95% confidence interval (CI) of the cumulative incidence rate.

Figure 2.

Cumulative incidence rate of spontaneous hepatitis B surface antigen seroclearance. (a) Age (years). Levels of significance: P < 0.001 (log-rank test). (b) Sex. Levels of significance: P < 0.001 (log-rank test). (c) Study setting. Levels of significance: P < 0.001 (log-rank test). (d) Ethnicity. Levels of significance: P = 0.400 (log-rank test). Color shades denote 95% confidence interval of the cumulative incidence rate. Corresponding risk tables can be found in Table 4A–D (see Supplementary Digital Content 1, http://links.lww.com/CTG/A366).

Figure 3.

Cumulative incidence rate of spontaneous hepatitis B surface antigen (HBsAg) seroclearance. (a) Hepatitis B e antigen status. Levels of significance: P < 0.001 (log-rank test). (b) Hepatitis B virus DNA (IU/mL). Levels of significance: P < 0.001 (log-rank test). (c) Quantitative HBsAg (IU/mL). Levels of significance: P < 0.001 (log-rank test). (d) Genotype. Levels of significance: P < 0.001 (log-rank test). Color shades denote 95% confidence interval of the cumulative incidence rate. Corresponding risk tables can be found in Table 5A–D (see Supplementary Digital Content 1, http://links.lww.com/CTG/A366).

Figure 4.

Cumulative incidence rate of spontaneous hepatitis B surface antigen seroclearance according to phases of chronic hepatitis B infection. Levels of significance: P < 0.001 (log-rank test). Color shades denote 95% CI of the cumulative incidence rate. The phase of infection was defined according to the American Association for the Study of Liver Diseases 2018 guideline. 95% CI, 95% confidence interval.