Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis

Abstract

Background & Aims: Long-term nucleos(t)ide analogue (Nuc) treatment can reduce hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV)-related cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in hepatitis B e antigen (HBeAg)-negative HBV-LC patients who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. Approach & Results: From two centers, 494 HBeAg-negative HBV-LC patients who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, hepatitis B surface antigen (HBsAg) loss, liver-related mortality/transplantation and overall survival rates were compared between two groups with 1:1 propensity score matching (PSM) of gender, prior treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end-of-therapy (EOT) in finite group or 3-year-on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/year and 10-year 15.7 vs. 26.8%, respectively; Log-rank test, p<0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log10 IU/mL, p=0.0026) and 7-8 times higher 10-year incidence of HBsAg loss (22.7 vs. 3%, p<0.0001). Multivariate Cox regression showed finite therapy an independent protective factor for HCC [adjusted hazard ratio(aHR): 0.593], liver-related mortality/transplantation (aHR: 0.312) and overall mortality (aHR: 0.382). Conclusions: Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.

Reply: Benefits of stopping therapy in patients with cirrhotic hepatitis B, true effect, or residual confounding?

“…We appreciate Dongelmans et al 1 for their comments and the opportunity for clarification and further discussion. The beneficial findings of our study 2 are indeed beyond expectation but not contradictory to the current paradigm. Before end-of-therapy, finite-group patients had also enjoyed the benefits of the current paradigm, including immune restoration and reversal of hepatic fibrosis/cirrhosis during 1–5 years of nucleos(t)ide analog (Nuc) therapy 3 .…”

“…Accordingly, the finite group had lower end-of-follow-up HBsAg level (119 vs. 209.7 IU/mL, p <0.0001), more often <100 IU/mL (45.6 vs. 29.9%, p <0.0001) and a much higher 10-year HBsAg loss rate. The beneficial virtuous cycle of the greater HBsAg decline and the immune response elicited by HBV relapse after Nuc withdrawal was speculated as the driver for decreasing transcription of integrated HBV DNA toward HBsAg loss and reduction of hepatic carcinogenesis 2 . Certainly, HBsAg loss may contribute to the lower incidence of HCC, but a 10-year rate difference (22.3% vs. 2.9%) was not great enough to become a significant independent factor for HCC.…”

Reply: Cautious interpretation of the association between finite treatment and better prognosis in initially HBeAg-negative hepatitis B patients with cirrhosis

“…We appreciate Deng et al 1 for their comments and the opportunity for clarification. To minimize bias, we set the end of nucleos(t)ide analog (Nuc) treatment (finite group) and 3-year-on-Nuc (continued group) as time 0 for propensity score matching 2 . This could be the best method second to randomized controlled trials.…”

Letter to the Editor: Benefits of stopping therapy in patients with cirrhotic hepatitis B, true effect or residual confounding?

“…We have read with great interest the article by Jeng et al 1 in which they reported a decreased HCC risk and mortality rate in patients with cirrhosis who stopped nucleo(s)tide analog therapy compared with patients who continued nucleo(s)tide analog therapy. These findings are highly interesting and may provide new insights into the anticarcinogenic mechanisms in patients with chronic hepatitis B.…”