Medicine (St Vincent's) - Theses
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ItemStudies investigating the clinical impact and immunological host response to viral eradication in hepatitis C infection( 2019)Australia now has improved access to HCV treatment for individuals with all stages of liver disease. There is limited data however, documenting any long-term clinical benefit of viral eradication in those with early stage liver disease. We report on the long-term outcomes of a well-characterised cohort of CHC subjects with predominantly early stage liver disease, whom paired liver fibrosis assessments were performed more than 10 years apart. We show in a real-world setting, that both early and curative HCV treatment halts fibrosis progression. Our data supports the early treatment of all people with CHC regardless of liver fibrosis stage, to prevent long-term liver sequelae. In subjects with acute / subacute HCV infection, we identify predictors of innate immunological response in peripheral blood mononuclear cells, to differentiate spontaneous clearers to those who progress to chronic infection. Our data strongly implicates TLR4 signaling in the persistence of HCV infection. Those who developed chronic infection had higher TLR4 expression on peripheral monocytes and NK cells and increased IFN-gamma response to TLR4 stimulation. We also observed increased TLR7 responsiveness in this group. We confirm the previously noted associations of IFNL4 genotype and plasma IP-10. Our data presents TLR4 as a potential biomarker for predicting clearance. This would clinically translate to individuals presenting with acute / subacute HCV infection, being able to defer drug therapy and its associated morbidity and cost. In subjects with chronic HCV infection, we demonstrate a clear effect of direct antiviral agent (DAA) mediated viral suppression therapy on patterns of TLR signaling in subjects with chronic HCV-1. We show that peripheral monocytic TLR2, TLR4 and TLR7 signaling is down-regulated early on in treatment, with a strong trend to higher baseline TLR signaling being associated with viral clearance with the DAAs. We are the first study to demonstrate a relationship between TLR signaling activity and IFN-free therapy for HCV. We hypothesise that the HCV virus directly stimulates the TLR pathways to induce an antiviral effect, with higher TLR signaling evident among those who respond to DAA therapy. This was accompanied by a reduction in PBMC ISG expression, NK activation markers and plasma levels of inflammatory cytokines / chemokines, with restoration of the innate immune response. Despite excellent treatment options, the mechanisms responsible for viral eradication in HCV have remained poorly defined. Previous data suggest a link between innate immunity and HCV pathogenesis, as well as spontaneous viral clearance. The data suggested that antiviral therapy alone was not sufficient to clear virus and supported a key role for innate immunity contributing to viral clearance. Our results strongly implicate TLR signaling / expression in HCV viral clearance. We believe TLR agonists must be considered as a potential HCV vaccine candidate and further research in this area is required.