Pegylated Interferon α-2a Triggers NK-Cell Functionality and Specific T-Cell Responses in Patients with Chronic HBV Infection without HBsAg Seroconversion

Abstract

Pegylated interferon α-2a (Peg-IFN-α) represents a therapeutic alternative to the prolonged use of nucleos(t)ide analog (NA) in chronic hepatitis B (CHB) infection. The mechanisms leading to a positive clinical outcome remain unclear. As immune responses are critical for virus control, we investigated the effects of Peg-IFN-α on both innate and adaptive immunity, and related it to the clinical evolution. The phenotypic and functional features of the dendritic cells (DCs), natural killer (NK) cells and HBV-specific CD4/CD8 T cells were analyzed in HBeAg-negative CHB patients treated for 48-weeks with NA alone or together with Peg-IFN-α, before, during and up to 2-years after therapy. Peg-IFN-α induced an early activation of DCs, a potent expansion of the CD56bright NK subset, and enhanced the activation and functionality of the CD56dim NK subset. Peg-IFN-α triggered an increase in the frequencies of Th1- and Th17-oriented HBV-specific CD4/CD8 T cells. Peg-IFN-α reversed the unresponsiveness of patients to a specific stimulation. Most of the parameters returned to baseline after the stop of Peg-IFN-α therapy. Peg-IFN-α impacts both innate and adaptive immunity, overcoming dysfunctional immune responses in CHB patients. These modulations were not associated with seroconversion, which questioned the benefit of the add-on Peg-IFN-α treatment.

NKp30+ NK cells are associated with HBV control during pegylated-interferon-alpha-2b therapy of chronic hepatitis B

“…In this study, we found an increase in CD56 bright NK cells during Peg-IFN-α-2b treatment (with or without ADV), which is in agreement with the Peg-IFN-α-2a-induced expansion of activated CD56 bright NK cells21. This is similar to the observed effect of IFNα therapy in HCV or HDV infection2223.…”

Unconventional T cells in chronic hepatitis B patients on long‐term suppressive therapy with tenofovir followed by a Peg‐IFN add‐on strategy: A randomized study

“…Noteworthy, in our study, Peg‐IFN was added to an effective antiviral therapy with TDF and to patients with a long‐term controlled HBV replication; nevertheless, the activation of peripheral iNKT cells might reflect their activity in liver tissue where these cells are more abundant and might represent a critical component of the complex immune response against HBV. Indeed, if long‐term therapy with NA partially restores the adaptive immunity, interferon‐α through a pleiotropic immunomodulating action may stimulate also the innate immune system, that is needed to achieve HBV replication control including nuclear cccDNA, and achieving HBsAg loss/anti‐HBs seroconversion …”

“…10,11 Our results also showed that CHB patients compared apy with NA partially restores the adaptive immunity, interferonα through a pleiotropic immunomodulating action may stimulate also the innate immune system, that is needed to achieve HBV replication control including nuclear cccDNA, and achieving HBsAg loss/anti-HBs seroconversion. 45 Several caveats in the experimental design of the present study must be acknowledged that include the small number of patients enrolled in the add-on arm that might have lowered the power of statistical analyses. Second, the add-on group had a statistically significant lower median age compared to NA group; this finding could have influenced the immunological results, although we did not confirm the association between age and iNKT/γδ T cells in our cohort.…”

The impact of currently licensed therapies on viral and immune responses in chronic hepatitis B: Considerations for future novel therapeutics

“…[85][86][87][88] Addition of Peg-IFNα, in a cohort of patients virally suppressed on NAs, induced the activation of DC's, expansion of CD56 bright NK cells and increased the frequency of Th1/Th17-orientated HBVspecific T cells. 93 Notably, these effects were not associated with improved clinical outcomes. Viral load reduction is able to maintain the immune stimulatory effects of Peg-IFNα, when administered in combination or sequence, compared to Peg-IFNα alone, which implies there may be beneficial outcomes with add-on or combination therapies.…”

“…Addition of Peg‐IFNα, in a cohort of patients virally suppressed on NAs, induced the activation of DC's, expansion of CD56 bright NK cells and increased the frequency of Th1/Th17‐orientated HBV‐specific T cells . Notably, these effects were not associated with improved clinical outcomes.…”