Efficacy and safety of entecavir, peginterferon alfa-2b and GM-CSF combination therapy: the anchor randomized controlled trial.

BACKGROUND AND AIM: Functional cure is considered the advanced treatment goal for patients with chronic hepatitis B (CHB). We aimed to evaluate hepatitis B surface antigen (HBsAg) loss rates after combination treatment of entecavir (ETV) and peginterferon alfa-2b (Peg-IFN) with or without granulocyte-macrophage colony-stimulating factor (GM-CSF).

METHODS

In this randomized controlled trial, virally suppressed patients undergoing nucleos(t)ide analogs with HBsAg < 3000 IU/mL were randomized 1:1:1 to receive either ETV for 96 weeks (E group), or 48 weeks of Peg-IFN + ETV, followed by 48-week Peg-IFN alone (EP group), or 48 weeks of Peg-IFN + ETV + GM-CSF, followed by 48-week Peg-IFN alone (EPG group). The primary outcome is HBsAg loss at week 96.

RESULTS

Among 249 patients (81 in E group, 83 in EP group and 85 in EPG group), EP group (30.12%, 25.30%) and EPG group (22.35%, 20.00%) achieved significantly higher HBsAg loss and HBsAg seroconversion rates than E group (0.00%, 0.00%; p < .0001, p < .0001) at week 96. At week 120, HBsAg loss was maintained in 22 of 25 patients (88.00%) in EP group and 15 of 19 (78.95%) in EPG group. During the 24-week off-treatment follow-up, late HBsAg loss occurred in one EP and three EPG patients. Multivariate analysis showed that age, baseline HBsAg level, and 24-week HBsAg decline correlated with HBsAg loss and HBsAg seroconversion at week 96. 24-week HBV RNA decline correlated with HBsAg loss. The HBsAg dynamics during therapy could predict HBsAg loss with an area under the curve of 0.944. More patients in EP group and EPG group experienced adverse events than E group.

CONCLUSION

In virally suppressed patients with HBsAg level < 3000 IU/mL, ETV plus Peg-IFN significantly increased HBsAg loss and HBsAg seroconversion, whereas adding GM-CSF conferred no additional efficacy benefit. Age, early on-treatment HBsAg level and 24-week HBV RNA decline correlated with HBsAg loss. This trial is registered at ClinicalTrials.gov, NCT02327416.