HBsAg seroclearance further reduces hepatocellular carcinoma risk after complete viral suppression with nucleos(t)ide analogues

•Patients without complete viral suppression have the highest risk of HCC.•NA-induced HBsAg seroclearance leads to lower HCC risk than complete viral suppression alone.•Patients with HBsAg seroclearance and complete viral suppression have a similar risk of hepatic events. Background & AimsIn treated patients with chronic hepatitis B (CHB) who have achieved complete viral suppression, it is unclear if functional cure as indicated by hepatitis B surface antigen (HBsAg) seroclearance confers additional clinical benefit. We compared the risk of hepatocellular carcinoma (HCC) and hepatic events in nucleos(t)ide analogue (NA)-treated patients with and without HBsAg seroclearance.MethodsWe performed a territory-wide retrospective cohort study on all patients with CHB who had received entecavir and/or tenofovir disoproxil fumarate (TDF) for at least 6 months between 2005 and 2016 from Hospital Authority, Hong Kong. Patients’ demographics, comorbidities, and laboratory parameters were analyzed. The primary outcome was HCC. The secondary outcomes were hepatic events including cirrhotic complications, liver transplantation, and liver-related mortality.ResultsA total of 20,263 entecavir/TDF-treated patients with CHB were identified; 17,499 (86.4%) patients had complete viral suppression; 376 (2.1%) achieved HBsAg seroclearance. At a median (interquartile range) follow-up of 4.8 (2.8–7.0) years, 603 (3.5%) and 121 (4.4%) patients with and without complete viral suppression developed HCC; 2 (0.5%) patients with HBsAg seroclearance developed HCC. Compared to complete viral suppression, lack of complete viral suppression was associated with a higher risk of HCC (7.8% vs. 5.6% at 8 years, Gray’s test, p <0.001) (adjusted hazard ratio [aHR] 1.69; 95% CI 1.36–2.09; p <0.001); patients who achieved functional cure had a lower risk of HCC (0.6% vs. 5.6% at 8 years, Gray’s test, p <0.001) (aHR 0.24; 95% CI 0.06–0.97; p = 0.045) but not hepatic events (aHR 0.99; 95% CI 0.30–3.26; p = 0.991).ConclusionsPatients who achieved HBsAg seroclearance on top of complete viral suppression with entecavir/TDF treatment may have a lower risk of HCC but not hepatic events.Lay summaryWe investigated 20,263 nucleos(t)ide analogue (NA)-treated patients with chronic hepatitis B. Patients with NA-induced hepatitis B surface antigen seroclearance on top of complete viral suppression have a lower risk of hepatocellular carcinoma but not hepatic events than those only achieving complete viral suppression under prolonged NA treatment. In treated patients with chronic hepatitis B (CHB) who have achieved complete viral suppression, it is unclear if functional cure as indicated by hepatitis B surface antigen (HBsAg) seroclearance confers additional clinical benefit. We compared the risk of hepatocellular carcinoma (HCC) and hepatic events in nucleos(t)ide analogue (NA)-treated patients with and without HBsAg seroclearance. We performed a territory-wide retrospective cohort study on all patients with CHB who had received entecavir and/or tenofovir disoproxil fumarate (TDF) for at least 6 months between 2005 and 2016 from Hospital Authority, Hong Kong. Patients’ demographics, comorbidities, and laboratory parameters were analyzed. The primary outcome was HCC. The secondary outcomes were hepatic events including cirrhotic complications, liver transplantation, and liver-related mortality. A total of 20,263 entecavir/TDF-treated patients with CHB were identified; 17,499 (86.4%) patients had complete viral suppression; 376 (2.1%) achieved HBsAg seroclearance. At a median (interquartile range) follow-up of 4.8 (2.8–7.0) years, 603 (3.5%) and 121 (4.4%) patients with and without complete viral suppression developed HCC; 2 (0.5%) patients with HBsAg seroclearance developed HCC. Compared to complete viral suppression, lack of complete viral suppression was associated with a higher risk of HCC (7.8% vs. 5.6% at 8 years, Gray’s test, p <0.001) (adjusted hazard ratio [aHR] 1.69; 95% CI 1.36–2.09; p <0.001); patients who achieved functional cure had a lower risk of HCC (0.6% vs. 5.6% at 8 years, Gray’s test, p <0.001) (aHR 0.24; 95% CI 0.06–0.97; p = 0.045) but not hepatic events (aHR 0.99; 95% CI 0.30–3.26; p = 0.991). Patients who achieved HBsAg seroclearance on top of complete viral suppression with entecavir/TDF treatment may have a lower risk of HCC but not hepatic events.