Treatment Cessation in Chronic Hepatitis B: Predicting Off-Treatment Durability Via Combination of Viral Markers

Abstract

Background: Treatment cessation in nucleoside analoguetreated chronic hepatitis B (CHB) can be associated with high rates of disease relapse. Serum hepatitis B surface antigen (HBsAg) levels have been suggested as a marker reflecting immune control. We investigated the efficacy of treatment cessation and predictors of successful off-treatment durability in CHB patients with low serum HBsAg levels. Methods: We prospectively recruited consecutive non-cirrhotic HBsAgpositive patients treated with entecavir or tenofovir with serum HBsAg <200 IU/mL and fulfilling the European Association for the Study of the Liver (EASL) criteria for treatment cessation. Liver biochemistry, serum HBV DNA, HBsAg and hepatitis B core-related antigen (HBcrAg) were measured at baseline and every 6 weeks up to week 48 after treatment cessation. HBV reactivation was defined as HBV DNA >2,000 IU/mL. Treatment was re-initiated in patients with HBV reactivation and elevated alanine aminotransferase (ALT) (>40 U/L), or with two consecutive HBV DNA readings of >2,000 IU/mL (the second measurement taken within two weeks). Results: In this interim analysis, 103 patients (mean age 56.4 ±10.9 years, 67.0% male) with a mean nucleoside analogue treatment duration of 7.1 (±2.0) years were recruited. Median duration of follow-up after treatment cessation was 42 (IQR 29-48) weeks. Median baseline HBsAg and HBcrAg levels were 55.3 (16.9-89.5) IU/mL and 1.1 (0.3-4.7) kU/mL respectively. The cumulative rate of HBV reactivation at 48 weeks, calculated by the Kaplan-Meier method, was 59.2%. Among 78 patients with available viral measurements, baseline serum HBsAg ≤10 IUmL, compared to HBsAg >10 IU/mL, had a significantly lower cumulative rate of HBV reactivation (31.6% versus 66.1%, p=0.023). A lower baseline serum HBsAg level, via Cox regression, was associated with significantly lower rates of HBV reactivation (p=0.047, OR 1.005, 95%CI 1.001-1.010). A lower baseline serum HBcrAg level was associated with lower HBV reactivation rates in patients with baseline serum HBsAg >20 IU/mL (p=0.020, OR 1.034, 95%CI 1.005-1.063) but not among all patients (p=0.147). 16 (33.3%) patients with HBV reactivation developed ALT elevation (median ALT 104 U/L, IQR 62-151 U/L). All HBV reactivation cases were eventually controlled with either entecavir or tenofovir. Conclusion: HBV reactivation remained common after treatment cessation in HBsAg-positive patients with low HBsAg levels. Combining serum HBsAg and HBcrAg kinetics can identify patients with likely off-treatment durability after treatment discontinuation. (Clinicaltrials.gov identifier NCT02738554)