Characterization of changes in intrahepatic immune cell populations during HCV treatment with sofosbuvir and ribavirin

Abstract

Summary Treatment of chronic hepatitis C virus (HCV) infection with direct‐acting antivirals (DAAs) results in a sustained virologic response (SVR) in most patients. While highly efficacious, ~3%‐5% of patients do not achieve SVR despite having virus that appears susceptible. It is unclear whether host factors contribute to treatment failures, although innate and adaptive immunity may play a role. Previous studies showed that after DAA treatment, the composition of intrahepatic immune cells does not normalize relative to healthy volunteers, even in cases where SVR is achieved. We used paired pre‐ and post‐treatment liver biopsies from 13 patients treated with sofosbuvir and ribavirin, 4 of whom relapsed, to analyse intracellular immune changes during DAA treatment and explore correlations with inflammation and treatment outcome. We performed single marker immunohistochemistry followed by electronic image capture, manual annotation of parenchymal and non‐parenchymal regions, and quantitative image analysis. The predominant cellular change during treatment was a decrease in CD8+ cellular density in both parenchymal and non‐parenchymal regions. CD68+ Kupffer cell density correlated with hepatic inflammation (AST, ALT) pre‐treatment, but did not change during treatment. CD4+ cellular density decreased in non‐parenchymal regions and, intriguingly, was lower pre‐treatment in subjects who eventually relapsed. Other cellular markers (CD56, CD20), as well as markers of apoptosis (TIA‐1) and activated stellate cells, did not change significantly during treatment or differ by treatment outcome. The predominant intrahepatic cellular change during DAA treatment of chronic HCV infection is a reduction in CD8+ cellular density, but this did not correlate with treatment outcome.

The impact of DAA‐mediated HCV eradication on CD4+ and CD8+ T lymphocyte trajectories in HIV/HCV coinfected patients: Data from the ICONA Foundation Cohort

“…11,12,15 Moreover, the reduction of intrahepatic CD8 + T cell density is the predominant change that has been detected in liver biopsies of DAA treated patients. 16 Nonetheless, we found a reduction of CD8 + T cells only in patients who were treated with RBV-free DAA regimens, and, on the contrary, an increase in others. The reasons for these discrepant results remain unclear, and are probably multifactorial.…”

Direct-acting Antiviral in the Treatment of Chronic Hepatitis C: Bonuses and Challenges

“…Similarly, in clinical trials, Cody Orr et al speculated that the decrease of population of CD8+ T cells may be due to a decrease in HCV concentration, contributing to an intrahepatic cellular response to reduction in viral burden. In addition, the population of CD4+T cells also declined in the non-parenchymal region of liver, while the significant variation of frequencies of Kupffer cells associated with inflammation was not observed [70].…”

Outcome of cutaneous psoriasis in hepatitis C virus‐infected patients treated with Direct‐Acting Antiviral therapy

“…Chronic HCV infection is known to quite extensively affect the innate immune response, with an upregulation of interferon‐stimulated genes (ISG) both at intrahepatic and peripheral levels . Notably, a very recent study showed dynamic changes of the innate immune response in HCV patients under DAA treatment, with decreased levels of circulating ISG‐related chemokines at week 2 of therapy followed by a significant increase at weeks 4/8 . Thus, the very potent and rapid effect of the DAA cure may provoke changes in the innate immune response at systemic level and may indirectly influence clinical manifestations and outcomes of different diseases concomitant with CHC.…”

“…6,7 Notably, a very recent study showed dynamic changes of the innate immune response in HCV patients under DAA treatment, with decreased levels of circulating ISG-related chemokines at week 2 of therapy followed by a significant increase at weeks 4/8. 8,9 Thus, the very potent and rapid effect of the DAA cure may provoke changes in the innate im- during and after DAA treatment with the hope for obtaining important information about the pathogenesis of cutaneous psoriasis and possible new routes of therapeutic approaches for its cure.…”