TIGIT expression on natural killer cell subsets is an early indicator of alleviating liver inflammation following bulevirtide treatment in chronic hepatitis D.

[BACKGROUND AND AIMS] Bulevirtide (BLV) is a novel and the only approved treatment option for patients with chronic hepatitis D (CHD). BLV alleviates liver inflammation early during treatment when only minor HDV RNA changes are observed. We hypothesized that BLV treatment may influence immune cells in patients with CHD and performed a high-resolution analysis of natural killer (NK) cells before and during BLV therapy.

[APPROACH AND RESULTS] BLV-treated patients with CHD (n=20) from a single-center cohort were longitudinally analyzed for clinical, molecular, and virological parameters. Peripheral blood mononuclear cells were studied at baseline, and therapy weeks 3 and 48 by spectral flow cytometry. Healthy donors, patients with chronic hepatitis C after direct-acting antiviral treatment, and patients with chronic hepatitis B were used as controls. Overall, NK cell frequencies remained stable during BLV treatment. However, biochemical responders showed distinct NK cell immunophenotypic features before and during therapy. TIGIT expression increased on CD56 dim and CD56 bright NK cells during the course of BLV treatment and inversely correlated with ALT levels in CHD but not patients with CHC or CHB. High frequencies of TIGIT - CD57 + CD56 dim NK cells at baseline and low levels during therapy were indicative of a biochemical response.

[CONCLUSIONS] We here suggest that lacking the expression of the immune checkpoint inhibitor TIGIT on NK cell subtypes may be a hallmark of liver inflammation in HDV infection. BLV therapy is associated with a reappearance of TIGIT on these cells, which may be one mechanism of why liver enzymes rapidly improve during therapy.