Efficacy of NAs in combination with Peg-IFN for functional cure in patients with CHB: a meta-analysis of RCTs

The goal of treating chronic hepatitis B (CHB) is to achieve functional cure. We aimed to evaluate the efficacy of the combination of nucleoside (acid) analogues (NAs) and pegylated interferon (Peg-IFN) on the functional cure of CHB patients at the EOT and at the EOF. PubMed, Embase, and Web of Science were searched systematically up to March 15, 2025. Sixteen RCTs on CHB patients receiving combination or monotherapy were included. Compared with NAs treatment, the NAs combined with Peg-IFN treatment group significantly improved HBsAg clearance rate (RR: 14.05, 95% CI 6.13–32.20) and HBsAg seroconversion rate (RR: 12.82, 95% CI 5.08–32.33) at the EOT. Moreover, compared with NAs treatment, the NAs combined with Peg-IFN treatment group significantly improved HBsAg clearance rate (RR: 7.70, 95% CI 4.24–13.98), HBsAg seroconversion rate (RR: 11.93, 95% CI 5.14–27.67) at the EOF. However, compared with Peg-IFN monotherapy, the combination therapy group did not show any improvement in HBsAg clearance rate, HBsAg seroconversion rate, and the rate of qHBsAg decrease > 1 log10 IU/mL at the EOT and the EOF. Moreover, in terms of safety, the Peg-IFN monotherapy group showed more ALT flares (ALT > 5 × ULN) during the treatment process. Compared with NAs therapy, Peg-IFN combined with NAs therapy significantly improves functional cure rate. However, combination therapy shows no additional advantage over Peg-IFN monotherapy in achieving functional cure. The Peg-IFN monotherapy group has a higher incidence of ALT flares than the combination therapy group.