A greater frequency of circulating CCR7loPD-1hi follicular helper T cells indicates a durable clinical cure after Peg IFN-α therapy in chronic hepatitis B patients.

backgroundEmerging evidence indicates that the treatment duration of pegylated interferon-α and HBsAb may predict relapse in chronic hepatitis B (CHB) patients who achieved clinical cure. However, the host immunological mechanisms contributing to clinical relapse remain poorly characterized.

objectivesThis study aimed to identify the immunological factors associated with relapse in chronic hepatitis B (CHB) patients who achieved clinical cure based on pegylated interferon-alpha treatment.

methodsCHB patients who achieved HBsAg loss after discontinuing pegylated interferon-alpha therapy were enrolled and followed up for at least 96 weeks. HBcrAg and immunological markers, including the proportion of follicular helper T (Tfh) cells were assessed by flow cytometry. Peripheral blood cytokine levels were measured using a Luminex assay. The primary outcome was the correlation between immunological markers with relapse at the end of treatment (EOT) and end of follow-up (EOF).

resultsA total of 456 CHB patients were included. During the 96-week follow-up period, 37 patients (8.11%) experienced a relapse. Propensity score matching was performed at a 1:2 ratio, resulting in the inclusion of 37 relapsed (R) and 74 non-relapsed (NR) patients. The NR group exhibited higher proportions of Tfh cells than the R group in both EOT and EOF (EOT: 12.52% vs. 8.78%, p=0.008; EOF: 11.38% vs. 8.29%, p=0.008). A significantly greater proportion of CCR7loPD-1hi Tfh cells was observed in the NR group at the EOT (9.4% vs. 4.5%, p=0.009). The frequency of CCR7loPD-1hi Tfh cells was significantly and positively correlated with anti-HB levels in EOT (p=0.015, r=0.392). Serum levels (median, pg/mL) of CTLA-4 (EOT: 14.87 vs. 7.84; EOF: 14.87 vs. 7.97), PD-1 (EOT: 321.44 vs. 203.96; EOF: 288.45 vs. 166.04), and TIM-3 (EOT:4487 vs. 21254; EOF:2973 vs. 1768) were significantly higher in the R group than in the NR group at both EOT and EOF (p<0.05). At EOT, the HBcrAg level was significantly greater in the R than in the NR group (3.45±0.94 vs. 2.63±0.80 log10 U/mL, p=0.003).

conclusionsHigher frequencies of CCR7loPD-1hi Tfh cells, lower levels of sCTLA-4 as well as sPD-1 in EOT were protective factors for relapse among CHB patients who experienced HBsAg loss after pegylated interferon-alpha therapy. CCR7loPD-1hiTfh cells produced insufficient IL-21 in patients who experienced recurrent disease, which resulted in a decrease in the ability of B cells to produce anti-HBs.