Characterisation of baseline complement values in patients with chronic hepatitis B virus infection in the phase IIb B-clear study

초록

Background and aims: The immune system plays an important role in disease pathogenesis and viral clearance of hepatitis B virus (HBV) infection, but the impact of HBV on the complement system, the inflammatory/immune state of patients ( pts) and implications for disease and treatment are poorly understood. Here we present associations between baseline complement factors, other laboratory and clinical characteristics, and nucleot (s)ide analogue (NA) treatment status in pts screened in the B-Clear trial. Method: B-Clear is an ongoing phase IIb trial (NCT04449029) to assess the efficacy and safety of bepirovirsen (BPV, GSK3228836), an antisense oligonucleotide, in pts with chronic HBV. Pts on either stable NA therapy (+NA), or not receiving NA therapy (-NA) were enrolled. All pts screened for B-Clear were included in this analysis; pts were grouped based on baseline values of complement C3 ([in g/L] low <0.9; normal 0.9–1.8; high >1.8) and C4 ([in g/L] low <0.1; normal 0.1–0.4; high >0.4) at screening. Descriptive statistics and 95% confidence intervals were used for comparison. Results: Of the 725 screened pts with data (N = 718 [+NA: n = 286; -NA: n = 432]): 83 had low C3 (+NA: n = 25; -NA: n = 58), 23 had low C4 (+NA: n = 4; -NA: n = 19), and 17 had both low C3 and C4 (+NA: n = 2; -NA: n = 15) (Table). A greater proportion of females had low C3 in the -NA group versus the +NA group (18%, versus 9%, respectively). Most pts with low C3 were Asian (+NA: 68%; -NA: 72%). In the +NA low C3 group, the mean hepatitis B virus surface antigen (HBsAg; 5911 IU/ml) and hepatitis B virus e-antigen (HBeAg; 41.5 U/ml) was higher vs the normal C3 mean HBsAg (4624 IU/ml) and HBeAg (11.9 U/ml). In the -NA low C3 group, the mean HBV DNA (12, 276, 923 IU/ml) and HBeAg (473 U/ml) was higher vs the normal C3 group (HBV DNA 7, 345, 220 IU/ml; HBeAg 249 U/ml), while HBsAg was lower (low C3 group 15735 IU/ml; high C3 group 18048 IU/ml). The complement split product C5a and factor Bb were similar, and mostly in the normal range, in pts with low, normal or high C3 in both the +NA and -NA groups. Conclusion: Preliminary findings indicate that gender, race, HBsAg, HBV DNA, and HBeAg level may all contribute to low C3 among pts with HBV. Observed differences may be due to different stages of disease or level of immune status for pts +NA, versus -NA. Due to low numbers of pts with low C4, no conclusions could be made regarding associations with baseline characteristics. [on behalf of the B-Clear study group].