Background Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral directly-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. Methods Case series of patients with HCV-MCS who were treated with sofosbuvir-based regimens and historical controls treated with pegylated interferon and ribavirin in a single healthcare network. HCV-MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (N=7) was established by kidney biopsy (N=5) or by ≥ 2 of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (N=2). Results Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% male, 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7 – 2.47 mg/dL.) Four patients received Rituximab concurrent with DAA therapy. Sustained virological response rate at twelve weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5%, and completely disappearing in 4 of 9 cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12 rate with 100% experiencing at least one adverse event, and 50% experiencing premature discontinuation due to adverse events. Conclusion SVR12 rates for sofosbuvir-based direct acting antiviral regimens in HCV-MCS were 83%, significantly higher than historical controls treated with pegylated interferon and ribavirin. Patients with glomerulonephritis experienced improvement in renal function, including those not concomitantly treated with immunosuppression.

Objectives To determine the associations between local (pericardial) fat and incident CV disease (CVD) events and cardiac remodeling independent of markers of overall adiposity. Background The impact of pericardial fat—a local fat depot encasing the heart—on myocardial function and long-term cardiovascular (CV) prognosis independent of systemic consequences of adiposity or hepatic fat is an area of active debate. Methods We studied 4,234 participants enrolled in the Multi-Ethnic Study of Atherosclerosis with concomitant cardiac magnetic resonance (CMR) imaging and computed tomographic (CT) measurements for pericardial fat volume and hepatic attenuation (a measure of liver fat). Poisson and Cox regression were used to estimate the annualized risk of incident hard atherosclerotic CVD (ASCVD), all-cause death, heart failure, all-cause CVD, hard CHD and stroke as a function of pericardial and hepatic fat. Generalized additive models were used to assess the association between CMR indices of left ventricular (LV) structure and function and pericardial fat. Models were adjusted for relevant clinical, demographic, and cardiometabolic covariates. Results MESA participants with higher pericardial and hepatic fat were more likely to be older, more frequently male, and had a higher prevalence of cardiometabolic risk factors (including dysglycemia, dyslipdemia, hypertension), as well as adiposity-associated inflammation. Over a median 12.2-year follow-up (IQR 11.6–12.8 years), pericardial fat was associated with a higher rate of incident hard ASCVD (standardized hazard ratio [SHR] 1.22, 95% confidence interval [CI] 1.10–1.35, P=0.0001; hepatic fat by CT was not significantly associated with hard ASCVD (SHR 0.96, 95% CI 0.86–1.08, P=0.52). Higher pericardial fat was associated with greater indexed LV mass (37.8 vs. 33.9 g/m2.7, highest vs. lowest quartile, P<0.01), LV mass-to-volume ratio (1.2 vs. 1.1, highest vs. lowest quartile, P<0.01). In adjusted models, a higher pericardial fat volume was associated with greater LV mass (P<0.0001) and concentricity (P<0.0001). Conclusion Pericardial fat is associated with poorer CVD prognosis and LV remodeling, independent of insulin resistance, inflammation and CT measures of hepatic fat.

Sofosbuvir-based direct-acting antiviral therapy revolutionized the treatment of hepatitis C virus (HCV) infection; however, sofosbuvir use is not approved for patients with severe renal insufficiency [estimated glomerular filtration (eGFR) rate below 30 mL/min] or end stage renal disease (ESRD) based on concerns raised during premarket animal testing over hepatobiliary and cardiovascular toxicity in this population. We report the first published data on use of sofosbuvir-based regimens in patients with severe renal insufficiency and ESRD focusing on clinical efficacy and safety. Six patients were treated with full dose sofosbuvir; three received sofosbuvir and simeprevir, two received sofosbuvir and ribavirin and one received sofosbuvir, ribavirin, and interferon. Three of the patients had cirrhosis. On-treatment viral suppression was 100% and sustained virological response (SVR) rate at twelve weeks was 67%. One patient had to discontinue antiviral therapy early due to side effects. No hepatobiliary or cardiovascular toxicity was reported.

Sofosbuvir-based direct-acting antiviral therapy is safe and effective in a cohort of patients with CKD infected with hepatitis C.