Prediction of sustained response after nucleo(s)tide analogue cessation using HBsAg and HBcrAg levels – a multicenter study (CREATE)

Abstract

Background: Predictors of successful nucleo(s)tide analogue (NA) therapy withdrawal remain elusive. We studied the relationship between end-of-treatment levels of hepatitis B core related antigen (HBcrAg) and surface antigen (HBsAg) and outcome after therapy cessation. Methods: HBeAg-negative patients with undetectable HBV DNA who discontinued NA therapy in centers in Asia and Europe were enrolled. HBcrAg and HBsAg were measured at treatment cessation, and associations with off-treatment outcomes were explored. SCALE-B score (comprising HBcrAg, HBsAg, ALT, age and tenofovir use) was calculated as previously reported. Endpoints included sustained virological response (VR, HBV DNA<2,000 IU/mL), HBsAg loss and ALT flares (>3x ULN). Re-treated patients were considered non-responders. Results: We analysed 572 patients, 457 (80%) were Asian and 95 (17%) were HBeAg positive at start of NA therapy. The median treatment duration was 295 weeks. VR was observed in 267 (47%), HBsAg loss in 24 (4.2%) and ALT flare in 92 (16%) patients. VR (67% versus 42%) and HBsAg loss (15% versus 1.5%) was more frequently observed in non-Asian patients (p<0.001). Lower HBcrAg levels were associated with higher rates of VR (OR 0.701, p<0.001) and HBsAg loss (OR 0.476, p<0.001) and lower rates of ALT flares (OR 1.288, p=0.005). Similar results were observed with HBsAg (VR: OR 0.812, p=0.011; HBsAg loss: OR 0.380, p<0.001; ALT flare: OR 1.833, p<0.001). Lower SCALE-B scores were associated with higher rates of VR, HBsAg loss and lower rates of ALT flares in both Asian and non-Asian patients(p<0.001, figure). Conclusion: In this multicenter study, off-treatment outcomes after NA cessation varied with ethnicity. Lower levels of HBcrAg and HBsAg were associated with favourable outcomes. A risk score comprising both factors (SCALE-B) can be used for risk stratification.