Hepatitis B virus (HBV) remains one of the world’s most consequential pathogens. An estimated 254 million people were living with chronic HBV infection in 2022, and roughly 1.1 million deaths were attributed to the virus that year. China carries the heaviest national burden, with approximately 75 million infected individuals. Chronic infection drives cirrhosis and hepatocellular carcinoma (HCC), but accumulating evidence also links chronic HBV to elevated risks of digestive system malignancies, kidney disease, and mortality from cardiovascular and cerebrovascular conditions compared with the general population. Against this backdrop, the World Health Organization has endorsed a global strategy to eliminate viral hepatitis by 2030, emphasizing both the prevention of new infections and the expansion of diagnosis and treatment to reduce mortality among those already infected.

Loss of HBsAg is the central therapeutic goal in chronic hepatitis B and underpins the treatment endpoint known as functional cure. Spontaneous HBsAg seroclearance also occurs during the natural course of infection, though infrequently — roughly 1 percent of patients per year. Prior research has consistently shown that patients who clear HBsAg experience substantially lower rates of cirrhosis and HCC. What remained uncertain, however, was whether seroclearance is also associated with overall survival and, in particular, with extrahepatic mortality from cancers and cardiovascular disease — a question of growing importance as the population of people living with chronic hepatitis B ages and accumulates comorbidities.

To address this gap, investigators drew on the Chronic Hepatitis B Infection and Liver Disease (HEPCARE) study, a multicenter, prospective, community-based cohort in Jiangsu Province. Participants were recruited through serological surveys conducted between September 2009 and November 2010 and were required to be HBsAg-positive, hepatitis C antibody-negative, and free of cirrhosis and liver cancer at enrollment. Because HBV DNA measurements began at the 2012 follow-up, the analysis defined 2012 as baseline and followed participants through December 2023, with assessments in 2012, 2013, 2014, 2016, 2018, 2020, and 2023. After exclusions, 6551 participants entered the analytical pool, and after propensity score matching on age, sex, region, and baseline antiviral treatment status, the final matched cohort comprised 1029 individuals who achieved sustained HBsAg seroclearance with HBV DNA below 100 IU/mL and 2931 who remained persistently HBsAg-positive.

A key methodological strength of the study lies in its handling of time. HBsAg seroclearance is a time-dependent event that occurs during follow-up, and conventional analyses that treat it as a fixed baseline characteristic are vulnerable to immortal time bias, which can distort survival estimates. By conducting regular interval surveillance and using time-dependent Cox regression, the researchers could allocate person-time accurately according to each participant’s changing serovirological status. The exposure itself was stringently defined: seroclearance required HBsAg negativity together with HBV DNA below the quantification limit of 100 IU/mL, confirmed at two or more consecutive follow-up visits, with participants whose profiles suggested occult hepatitis B infection excluded to avoid misclassification.

The results were striking across multiple outcome domains. Over a median follow-up of roughly 11 years, participants who achieved sustained seroclearance had significantly lower incidence rates of cirrhosis (2.02 versus 3.97 per 1000 person-years) and HCC (2.97 versus 4.97 per 1000 person-years). In fully adjusted time-dependent Cox models, seroclearance was associated with a 55 percent lower hazard of cirrhosis (adjusted hazard ratio 0.45) and a 48 percent lower hazard of HCC (adjusted hazard ratio 0.52). Mortality told a similar story: 64 deaths occurred in the seroclearance group compared with 405 in the persistent infection group, corresponding to incidence rates of 7.55 and 12.17 per 1000 person-years, and seroclearance was associated with a 53 percent lower hazard of all-cause mortality (adjusted hazard ratio 0.47).

Perhaps the most novel findings concerned cause-specific mortality. Among the 469 deaths in the matched population, 146 were attributed to extrahepatic cancers, 117 to cardiovascular disease, and 112 to liver-related causes. Sustained seroclearance was associated with lower hazards of liver-related mortality (adjusted hazard ratio 0.46), extrahepatic cancer-related mortality (0.51), and cardiovascular mortality (0.56), with the strongest association observed for digestive system cancer-related mortality. When competing risks were formally accounted for using Fine–Gray subdistribution hazard models, these associations persisted for cirrhosis, HCC, liver-related mortality, and extrahepatic cancer-related mortality, and model-standardized cumulative incidences at 10 years were consistently lower in the seroclearance state for all major endpoints examined.

The investigators then asked whether HBsAg loss carries prognostic information beyond viral DNA suppression alone — a clinically important question, since suppressing HBV DNA below 100 IU/mL is a conventional treatment goal. In an analysis treating serovirological status as a three-state time-varying variable, the HBsAg-negative state with very low HBV DNA was associated with lower hazards of cirrhosis, HCC, all-cause mortality, extrahepatic cancer mortality, and cardiovascular mortality compared with the HBsAg-positive state at similarly low viral loads. Conversely, isolated HBV DNA suppression without seroclearance was not associated with lower extrahepatic mortality. Additional weighting analyses incorporating baseline HBV DNA attenuated the HCC estimate somewhat, suggesting that part of that association depends on differences in baseline viral burden, but the associations with all-cause and extrahepatic cancer mortality remained statistically significant.

To translate the associations into population-level terms, the team estimated population attributable fractions and restricted mean survival time. Persistent infection was associated with attributable fractions of approximately 48 percent for cirrhosis, 47 percent for liver-related mortality, 42 percent for all-cause mortality, 41 percent for HCC, 40 percent for extrahepatic cancer mortality, and 35 percent for cardiovascular mortality. Using age as the time scale, restricted mean survival time was estimated at 83.21 years in the seroclearance state versus 78.04 years in the persistent infection state — a 5.17-year difference within the observed age range, with the survival advantage widening notably after age 60. Sex-stratified analyses suggested that these inverse associations were generally stronger in men, with statistically significant interactions for all-cause and liver-related mortality, echoing prior evidence that men with chronic hepatitis B tend to experience less favorable long-term outcomes than women.

The authors caution that most seroclearance events in the cohort occurred spontaneously rather than through antiviral therapy, so the findings primarily reflect the prognosis associated with spontaneous HBsAg loss, which may partly reflect a favorable underlying viral-host profile and overall health status. Residual confounding from unmeasured factors such as socioeconomic status and healthcare utilization cannot be excluded, the assay’s quantification limit of 100 IU/mL may have classified some low-level viremia as undetectable, and the single-province, community-based design warrants validation in other populations, including cohorts enriched for treatment-induced functional cure. Biologically, the authors propose that persistent viral antigen exposure and chronic immune activation may impair tumor immune surveillance and promote systemic inflammation, whereas HBsAg clearance accompanies a marked reduction in antigen burden and partial restoration of HBV-specific immune responses — hypothesis-generating mechanisms that require further study. Nevertheless, the consistency of the associations across competing-risk models, three-state analyses, and extensive sensitivity analyses, combined with the substantial attributable burden and survival differences, positions sustained HBsAg seroclearance with very low HBV DNA as an informative long-term prognostic marker in chronic hepatitis B, and underscores the potential population health value of broader attainment of this serovirological state.

Subject of Research: HBsAg seroclearance and long-term hepatic and extrahepatic mortality risks in chronic hepatitis B

Article Title: HBsAg seroclearance with HBV DNA <100 IU/mL and long-term risks of adverse liver events, all-cause mortality, and cause-specific mortality in chronic hepatitis B: a prospective cohort study

Article References: Zhang, Y., Yao, W., Jiang, J., Qian, J., Chen, X., Jiang, Q., Yan, Y., Wang, S., Bai, H., He, C., Zhu, L., Jiang, T., Hu, Z., Shen, H., Zhai, X., & Song, C. (2026). HBsAg seroclearance with HBV DNA <100 IU/mL and long-term risks of adverse liver events, all-cause mortality, and cause-specific mortality in chronic hepatitis B: a prospective cohort study. The Lancet Regional Health – Western Pacific, 74, Article 101983. https://doi.org/10.1016/j.lanwpc.2026.101983

Image Credits: AI Generated

DOI: 10.1016/j.lanwpc.2026.101983

Keywords: hepatitis B, HBsAg seroclearance, functional cure, hepatocellular carcinoma, cirrhosis, all-cause mortality, extrahepatic cancer, cardiovascular mortality, HBV DNA, prospective cohort, population attributable fraction, chronic hepatitis B