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Background: During chronic hepatitis C virus (HCV) infection, Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels mark active liver inflammation and tissue damage, while albumin reflects synthetic liver function and nutritional status. Transient Elastography (TE) is a clinical measure of liver stiffness that facilitates evaluation of liver damage stage. While a portion of the TE score is attributable to liver fibrosis and relatively irreversible damage, another component of the TE score is attributable to liver inflammation or edema. Markers of inflammation during chronic HCV infection include soluble markers of immune activation, which are also associated with morbid outcome (including cardiovascular disease and liver-disease progression). Whether soluble markers of immune activation or changes in their level during HCV therapy relate to normalization of AST, ALT, Albumin, or TE score, is not clear. Methods: We evaluated soluble markers of immune activation (plasma sCD14, IL-6, sCD163, autotaxin [ATX], and Mac2BP) and TE score, and their relationship in 20 HCV-infected patients before, during, and after HCV-directed IFN-free direct-acting antiviral (DAA) therapy. We evaluated normalization of parameters and the relationship between each over a 6-month window. Results: Before therapy, serum AST levels positively correlated with plasma levels of sCD14, sCD163, and Mac2BP, while ALT levels positively correlated with Mac2BP. Serum albumin level negatively correlated with plasma IL-6 and ATX levels. IFN-free therapy uniformly resulted in sustained virological response at 12 and 24 weeks after therapy completion. After initiation of therapy AST and ALT normalized, while levels of ATX, Mac2BP, sCD163, and TE score partially normalized over 6 months. Additionally, change in AST level and APRI score correlated with change in sCD163, IL-6, and Mac2BP levels, and change in ALT correlated with change in IL-6 and Mac2BP levels. Improvement in TE score correlated with a decrease in the level of sCD14 at week 4, and almost statistically significant with decrease in sCD14 at weeks 20-24 after initiation of IFN-free HCV therapy. Conclusions: Soluble markers of immune activation normalize or partially normalize at different rates after initiation of curative HCV DAA therapy, and TE scores improve, with wide variability in the degree of absolute improvement in liver stiffness from patient to patient. Decline magnitude of sCD14 was associated with improvement in TE score, while magnitude of improvement in AST correlated with reduction in sCD163 levels. These data provide support for a model where monocyte/Kupffer cell activation may account for a portion of the liver inflammation and edema, which is at least partially reversible following initiation of HCV DAA therapy.

Abstract Background: There is a continued need for strategies to prevent influenza. While cetylpyridinium chloride (CPC), a broad-spectrum antimicrobial agent, has an extensive antimicrobial spectrum, its ability to affect respiratory viruses has not been studied in detail. Objectives: Here, we evaluate the ability of CPC to disrupt influenza viruses in vitro and in vivo. Methods: The virucidal activity of CPC was evaluated against susceptible and oseltamivir- resistant strains of influenza viruses. The effective virucidal concentration (EC) of CPC was determined using a hemagglutination assay and tissue culture infective dose assay. The effect of CPC on viral envelope morphology and ultrastructure was evaluated using transmission electron microscopy (TEM). The ability of influenza virus to develop resistance was evaluated after multiple passaging in sub-inhibitory concentrations of CPC. Finally, the efficacy of CPC in formulation to prevent and treat influenza infection was evaluated using the PR8 murine influenza model. Results: The virucidal effect of CPC occurred within 10 minutes, with mean EC50 and EC2log ranging between 5 to 20 µg/mL, for most strains of influenza tested regardless of type and resistance to oseltamivir. Examinations using TEM showed that CPC disrupted the integrity of the viral envelope and its morphology. Influenza viruses demonstrated no resistance to CPC despite prolonged exposure. Treated mice exhibited significantly increased survival and maintained body weight compared to untreated mice. Conclusions: The antimicrobial agent CPC possesses virucidal activity against susceptible and resistant strains of influenza virus by targeting and disrupting the viral envelope. Substantial virucidal activity is seen even at very low concentrations of CPC without development of resistance. Moreover, CPC in formulation reduces influenza-associated mortality and morbidity in vivo. Keywords: Cetylpyridinium Chloride, CPC, Influenza, Respiratory tract illness, respiratory virus, quaternary ammonium compound