Model to predict on-treatment restoration of functional HBV-specific CD8⁺ cell response foresees off-treatment HBV control in eAg-negative chronic hepatitis B

Background Hepatitis B virus (HBV)-specific CD8(+) cell response restoration during nucleos(t)ide analogue (NUC) treatment could lead to off-treatment HBV control in e-antigen-negative chronic hepatitis B (CHBe(-)). Aim To predict this response with variables involved in T-cell exhaustion for use as a treatment stopping tool. Methods In NUC-treated CHBe(-) patients, we considered a functional response in cases with HBV-specific CD8(+) cells against core and polymerase HBV epitopes able to proliferate and secrete type I cytokines after antigen encounter. We performed a logistic regression model (LRM) to predict the likelihood of developing this response, based on patient age (subrogate of infection length), HBsAg level, NUC therapy starting point and duration (antigenic pressure). We discontinued treatment and assessed HBV DNA dynamics, HBsAg decline and loss during off-treatment follow-up according to LRM likelihood. Results We developed an LRM that predicted the presence of a proliferative type I cytokine-secreting CD8(+) cell response, which correlated positively with treatment duration and negatively with treatment initiation after the age of 40 years and with age adjusted by HBsAg level. We observed a positive correlation between LRM probability and intensity of proliferation, number of epitopes with the functional proliferating response and type I cytokine secretion level. Off-treatment, HBsAg loss, HBsAg decline >50% and HBV control were more frequent in the group with >90% LRM probability. Conclusions Short-term low-level antigen exposure and early long-term NUC treatment influence the restoration of a functional HBV-specific CD8(+) cell response. Based on these predictors, a high likelihood of detecting this response at treatment withdrawal is associated with off-treatment HBV control and HBsAg decline and loss.