HCC risk in CHB patients persists 12 years after HBsAg loss

Patients with chronic hepatitis B (CHB) still have a non-negligible risk of hepatocellular carcinoma (HCC) 12 years after achieving hepatitis B surface antigen (HBsAg) seroclearance, especially if cirrhosis is present, a large territory-wide real-world study in Hong Kong has shown.

HBsAg seroclearance is regarded as a realistic definition of CHB functional cure. [Hepatology 2019;71:1070-1092] Once achieved, it is usually durable and associated with reduced risks of HCC and liver-related complications. [J Hepatol 2017;68:63-72; J Viral Hepat 2021;28:601-612; Gut 2014;63:1648-1657; J Hepatol 2019;70:361-370]

In the current study, however, patients’ average cumulative incidence of HCC per year remained non-negligible and was similar between years 0–7 and years 8–12 after achieving HBsAg loss, although their risk of hepatic decompensation decreased after 7 years. [J Hepatol 2023;78:524-533]

The study included 9,769 CHB patients who achieved HBsAg seroclearance following a positive test result in 2000–2020. At the time of HBsAg loss (spontaneous, 80.9 percent; treatment-induced, 19.1 percent), the patients’ mean age was 57.4 years, 60.0 percent were male, 13.2 percent had cirrhosis, and most had compensated liver function.

At a median follow-up of 4.6 years, 106 patients (1.1 percent) developed HCC, while 124 (1.3 percent) developed hepatic decompensation. Older age, male sex, cirrhosis and lower platelet counts were associated with an increased risk of HCC development after HBsAg seroclearance, while cirrhosis and lower albumin were risk factors for hepatic decompensation after HBsAg loss.

The average cumulative incidence of HCC per year was 0.20 percent at 0–7 years and 0.19 percent at 8–12 years after HBsAg loss, respectively, with only a slight annual drop of 0.04 percent over time (p=0.265).

“In multivariable analysis, HBsAg loss for >7 years was not associated with a reduced risk of HCC [adjusted subdistribution hazard ratio (aSHR), 1.35; 95 percent confidence interval (CI), 0.83–2.19; p=0.230],” reported the researchers from the Chinese University of Hong Kong. “Among subgroups of patients with and without cirrhosis, a similar non-association was observed between years after HBsAg loss and risk of HCC development.”

The average cumulative incidence of hepatic decompensation per year was 0.26 percent at 0–7 years and 0.12 percent at 8–12 years after HBsAg loss, respectively, with an annual drop of 0.23 percent (p=0.012).

Multivariable analysis showed that HBsAg loss for >7 years was associated with a reduced risk of hepatic decompensation (aSHR, 0.55; 95 percent CI, 0.31–0.97; p=0.039), whereas the risk reduction associated with HBsAg loss for >5 years was not significant (aSHR, 0.88; 95 percent CI, 0.59–1.31; p=0.524). A similar trend in association was found in patients with or without cirrhosis.

During the study’s 12-year follow-up, HBsAg seroconversion occurred in 6.1 percent of patients, and was not a risk factor for HCC or hepatic decompensation after adjustment for other important risk factors.

“Based on the cost-effectiveness threshold of a 0.2 percent annual risk of HCC, long-term HCC surveillance is still warranted among patients with cirrhosis after HBsAg loss,” the researchers suggested. [Hepatology 2018;67:1560-1599] “For patients without cirrhosis who achieve HBsAg loss, major risk factors for HCC, including advanced age and male sex, should be considered to identify high-risk subgroups for whom HCC surveillance may be cost-effective.” [J Hepatol 2017;67:902-908; Aliment Pharmacol Ther 2021;53:321-331; J Hepatol 2015;62:1092-1099]

For patients who develop HBsAg seroconversion after seroclearance, monitoring was suggested for those with important risk factors for HCC and hepatic decompensation.