Limited Value of HBV‐RNA for Relapse Prediction After Nucleos(t)ide Analogue Withdrawal in HBeAg‐negative Hepatitis B Patients

ABSTRACT International guidelines suggest cessation of nucleos(t)ide analogues (NA) independent of HBsAg loss in HBeAg‐negative patients after 2–3 years of viral suppression. Detectable HBV‐RNA levels at the time of NA cessation were linked to a better prediction of relapse after NA withdrawal in small cohorts of HBeAg‐negative patients. This study proves the impact of HBV‐RNA levels in the prediction of relapse in a large cohort of HBeAg‐negative patients, mainly infected with genotype B or C. Serum levels of HBV‐RNA, HBsAg, anti‐HBc and HBcrAg were determined before NA withdrawal in 154 HBeAg‐negative patients, participating either in a therapeutic vaccination trial (NCT02249988) or in an observational register trial (NCT03643172). Importantly, vaccination showed no impact on relapse. Endpoints of the study were virological relapse (HBV‐DNA > 2000 IU/mL) or biochemical relapse (attendant ALT levels ≥ 2 × ULN) 24 weeks after NA cessation. Virological relapse occurred in 54.5% of patients ( N = 84/154), including eight patients (10%) developing an ALT flare. Baseline HBV‐RNA level did not differ significantly between relapsers and off‐treatment responders ( p = 0.92). No significant difference occurred in proportions of detectable HBV‐RNA levels between off‐treatment responders ( N = 27/70; 38.6%) and relapsers ( N = 31/84; 36.9%) ( p = 0.99). Combining predefined HBsAg cut‐offs (100 IU/mL, p = 0.0013), anti‐HBc cut‐offs (325 IU/mL, p = 0.0117) or HBcrAg cut‐offs (2 log U/mL, p = 0.66) with undetectable HBV‐RNA (HBsAg, p = 0.0057; anti‐HBc, p = 0.085; HBcrAg, p = 0.60) did not improve relapse prediction. The value of HBV‐RNA levels at timepoint of NA cessation for the prediction of relapse is limited in HBeAg‐negative patients. Trial Registration: ABX 203‐002: NCT02249988; Terminator 2: NCT03643172