Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States (U.S.). The largest increases of incidence for HCV infection are reported in the Appalachian region. This study aimed to 1) examine the prevalence and trends of HCV infection in the U.S. from 1999 to 2012; 2) investigate barriers to HCV infection treatment in Northeast Tennessee and the U.S.; and 3) study characteristics and risk factors for HIV-infection and HCV-infection in Northeast Tennessee. In the U.S., data were obtained from the National Health and Nutrition Examination Survey (NHANES) 1999-2012 to study the prevalence of HCV infection and barriers to treatment. In Northeast Tennessee, hepatitis C and HIV/AIDS data were obtained from National Electronic Disease Surveillance System (NEDSS) and enhanced HIV/AIDS Reporting System (eHARS). Descriptive statistics and multiple logistic regression models were used for analysis. Odds ratios (OR) and 95% confidence intervals (CI) were reported. There was an estimated 3.8 million people having HCV antibody in the U.S. in 2012. No significant change was found in the prevalence of HCV infection during 1999 – 2012. The leading barrier to the treatment was cost issues in the U.S. (50.0%) and Northeast Tennessee (25.0%), respectively. HCV patients without symptoms in Northeast Tennessee were more likely to be untreated (OR: 3.08, 95% CI: 1.10-8.60) and patients without health insurance in the U.S. were more likely to be untreated than their counterparts (OR: 3.38, 95% CI: 1.14-10.05). The incidence of acute hepatitis C peaked in 2012-2013 in Northeast Tennessee, while the incidence of HIV/AIDS increased by 100% from 2013 to 2015. More injection drug users (IDUs) and less men who have sex with men (MSM) were observed in patients with HCV infection than in those with HIV infection (IDUs: 50.63% vs.16.38% p

Cellular immune responses to Hepatitis C (HCV) epitopes are crucial for successful host response to HCV infection. We investigated a platform to assess specific and global immune responses in HCV infection. We identified 57 HCV peptides from literature (24 of CD4+, 33 of CD8+ specificity) and tested them in two peptide pools to assess specific response in non-transplanted and post-liver transplant (LT) patients. Robust interferon-gamma (IFN) response to CD4+ peptide and mitogen stimulation was seen in sustained virological clearance. IFN response to the CD4+ peptide pool could differentiate between SVR and NR with 82% accuracy. In patients with recurrent HCV post-LT, HCV-specific responses were attenuated, but global immune responses were preserved. Significantly lower specific (CD4+) and global immune responses (mitogen response) were observed in patients with advanced allograft disease (fibrosis score>2). Quantiferon-HCV may identify patients likely to respond to anti-HCV treatment, as well as post-LT patients with aggressive HCV recurrence. / Experimental Surgery

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Hepatitis B virus (HBV) vaccination is recommended for individuals with hepatitis C virus (HCV) infection given their shared risk factors and increased liver-related morbidity and mortality upon super-infection. Vaccine responses in this setting are often blunted, with poor response rates to HBV vaccinations in chronically HCV-infected individuals compared to healthy subjects. In this study, we investigated the role of T cell immunoglobulin mucin domain-3 (Tim-3)-mediated immune regulation in HBV vaccine responses during HCV infection. We found that Tim-3, a marker for T cell exhaustion, was over-expressed on monocytes, leading to a differential regulation of IL-12/IL-23 production which in turn TH17 cell accumulation, in HCV-infected HBV vaccine non-responders compared to HCV-infected HBV vaccine responders or healthy subjects (HS). Importantly, ex vivo blockade of Tim-3 signaling corrected the imbalance of IL-12/IL-23 as well as the IL-17 bias observed in HBV vaccine non-responders during HCV infection. These results suggest that Tim-3-mediated dysregulation of innate to adaptive immune responses is involved in HBV vaccine failure in individuals with chronic HCV infection, raising the possibility that blocking this negative signaling pathway might improve the success rate of HBV immunization in the setting of chronic viral infection.

Hepatitis B virus (HBV) vaccination is recommended for individuals with hepatitis C virus (HCV) infection given their shared risk factors and increased liver-related morbidity and mortality upon super-infection. Vaccine responses in this setting are often blunted, with poor response rates to HBV vaccinations in chronically HCV-infected individuals compared to healthy subjects. In this study, we investigated the role of T cell immunoglobulin mucin domain-3 (Tim-3)-mediated immune regulation in HBV vaccine responses during HCV infection. We found that Tim-3, a marker for T cell exhaustion, was over-expressed on monocytes, leading to a differential regulation of IL-12/IL-23 production which in turn TH17 cell accumulation, in HCV-infected HBV vaccine non-responders compared to HCV-infected HBV vaccine responders or healthy subjects (HS). Importantly, ex vivo blockade of Tim-3 signaling corrected the imbalance of IL-12/IL-23 as well as the IL-17 bias observed in HBV vaccine non-responders during HCV infection. These results suggest that Tim-3-mediated dysregulation of innate to adaptive immune responses is involved in HBV vaccine failure in individuals with chronic HCV infection, raising the possibility that blocking this negative signaling pathway might improve the success rate of HBV immunization in the setting of chronic viral infection.