Systematic review with meta-analysis: development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis B surface antigen seroclearance

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The seroclearance of hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B (CHB) is considered to be associated with favourable clinical outcomes. However, previous studies with inconsistent findings reported that hepatocellular carcinoma (HCC) could still develop in those patients.


To establish the proportion of HCC occurrence in CHB patients after HBsAg seroclearance, a systematic review and meta-analysis was performed.


Databases of Medline, Web of Science and Embase were searched from inception to July 2015. The proportion of patients who developed HCC after HBsAg seroclearance was pooled by a random-effects model.


Twenty-eight studies were finally included, involving 34 952 patients with HBsAg seroclearance. The overall pooled proportion suggested that 2.29% (95% CI: 1.19–4.37%) CHB patients would develop HCC despite HBsAg seroclearance. In HBsAg seroclearance patients without cirrhosis and HCV co-infection, the pooled proportion of HCC development was 1.55% (95% CI: 0.92–2.61%). Moreover, patients with cirrhosis or age greater than 50 years at the time of HBsAg seroclearance were at significantly higher risk for HCC development. Nonetheless, the seroclearance of HBsAg was significantly associated with a reduced risk for HCC compared with persistently positive HBsAg (RR = 0.34, 95% CI: 0.20–0.56, P < 0.001).


Despite that HBsAg seroclearance can significantly reduce the risk for HCC, HCC can still develop in a proportion of CHB patient after HBsAg seroclearance. Closer attention should be paid to those patients with established cirrhosis or older age than 50 years at the time of HBsAg seroclearance.

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