Adam J. Gehring

Background: There are no immunological biomarkers that predict control of chronic hepatitis B (CHB). The lack of immune biomarkers raises concerns for therapies targeting PD-1/PD-L1 because they have the potential for immune-related adverse events. Defining specific immune functions associated with control of HBV replication could identify patients likely to respond to anti-PD-1/PD-L1 therapies and achieve a durable functional cure. Methods: We enrolled immunotolerant, HBeAg+ immune-active (IA+), HBeAg− immune-active (IA−), inactive carriers, and functionally cured patients to test ex vivo PD-1 blockade on HBV-specific T cell functionality. Peripheral blood mononuclear cells were stimulated with overlapping peptides covering HBV proteins +/−α-PD-1 blockade. Functional T cells were measured using a 2-color FluoroSpot assay for interferon-γ and IL-2. Ex vivo functional restoration was compared to the interferon response capacity assay, which predicts overall survival in cancer patients receiving checkpoint inhibitors. Results: Ex vivo interferon-γ+ responses did not differ across clinical phases. IL-2+ responses were significantly higher in patients with better viral control and preferentially restored with PD-1 blockade. Inactive carrier patients displayed the greatest increase in IL-2 production, which was dominated by CD4 T cell and response to the HBcAg. The interferon response capacity assay significantly correlated with the degree of HBV-specific T cell restoration. Conclusions: IL-2 production was associated with better HBV control and superior to interferon-γ as a marker of T cell restoration following ex vivo PD-1 blockade. Our study suggests that responsiveness to ex vivo PD-1 blockade, or the interferon response capacity assay, may support stratification for α-PD-1 therapies.

Individuals who spontaneously clear hepatitis C virus (HCV) infection have demonstrated evidence of partial protective immunity, whereas treatment‐induced clearance provides little or no protection against reinfection. We aimed to investigate whether treatment of acute HCV infection with direct‐acting antivirals (DAA) prevents establishment of, or reverses, T‐cell exhaustion, leading to a virus‐specific T‐cell immune profile more similar to that seen in spontaneous clearance. The magnitude and breadth of HCV‐specific T‐cell responses before and after DAA or interferon‐based therapy in acute or chronic HCV were compared to those of participants with spontaneous clearance of infection, using Enzyme‐linked Immunospot (ELISPOT). PBMCs were available for 55 patients comprising 4 groups: spontaneous clearance ( n = 17), acute interferon ( n = 14), acute DAA ( n = 13) and chronic DAA ( n = 11). After controlling for sex, the magnitude of post‐treatment HCV‐specific responses after acute DAA treatment was greater than after chronic DAA or acute IFN treatment and similar to those found in spontaneous clearers. However, spontaneous clearers responded to more HCV peptide pools indicating greater breadth of response. In conclusion, early treatment with DAAs may prevent or reverse some degree of immune exhaustion and result in stronger HCV‐specific responses post‐treatment. However, individuals with spontaneous clearance had broader HCV‐specific responses.