Effect of Sofosbuvir-Based Hepatitis C Virus Therapy on Kidney Function in Patients with CKD.

BACKGROUND AND OBJECTIVES: Hepatitis C virus infection is common in patients with CKD and leads to accelerated progression to ESRD. Sofosbuvir is a potent direct-acting antiviral therapy against hepatitis C virus; however, there are concerns about its safety in patients with CKD. The objective of our study was to determine the safety and efficacy of sofosbuvir in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied a retrospective observational cohort of patients with CKD defined by eGFR<60 ml/min per 1.73 m2, ≥30 mg albuminuria per 1 g creatinine, or ≥200 mg proteinuria per 1 g creatinine who received sofosbuvir-based therapy in a large health care system. Regression models were constructed to predict likelihood of sustained virologic response, detect adverse events, and examine changes in eGFR from baseline to follow-up. RESULTS: Ninety-eight patients with CKD (42% stage 1 or 2 CKD and 58% stage 3 CKD) were included. Mean age was 62 years old, 78% were men, and 65% were white. Additionally, 49% of patients had diabetes, 38% of patients had cirrhosis, and 33% of patients had prior solid organ transplant. Overall sustained virologic response was 81% and varied by regimen used and viral genotype. Average baseline eGFR was equivalent to average on-treatment eGFR, but seven patients experienced a rise in creatinine ≥1.5 times baseline while taking sofosbuvir; all but one recovered. In patients with eGFR<60 ml/min per 1.73 m2 at baseline (stage 3 CKD), regression models showed that hepatitis C cure was associated with a 9.3 (95% confidence interval, 0.44 to 18) ml/min per 1.73 m2 improvement in eGFR during the 6-month post-treatment follow-up period. Adverse events were common (81%), but serious adverse events (17%) and treatment discontinuations (8%) were uncommon. CONCLUSIONS: Sofosbuvir-based direct-acting antiviral therapy is safe and effective in a cohort of patients with CKD infected with hepatitis C.

The rising incidence of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the United States and will soon be the leading indication for liver transplantation. NAFLD can lead to cirrhosis of the liver and is usually asymptomatic. Prompt referral to a hepatologist may halt the morbidity and mortality associated with NAFLD.

Pericardial, But Not Hepatic, Fat by CT Is Associated With CV Outcomes and Structure: The Multi-Ethnic Study of Atherosclerosis.

OBJECTIVES: The study sought to determine the associations between local (pericardial) fat and incident cardiovascular 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 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 MESA (Multi-Ethnic Study of Atherosclerosis) study with concomitant cardiac magnetic resonance imaging and computed tomography (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 coronary heart disease, and stroke as a function of pericardial and hepatic fat. Generalized additive models were used to assess the association between cardiac magnetic resonance indices of left ventricular (LV) structure and function and pericardial fat. Models were adjusted for relevant clinical, demographic, and cardiometabolic covariates. RESULTS: MESA study participants with higher pericardial and hepatic fat were more likely to be older, were more frequently men, and had a higher prevalence of cardiometabolic risk factors (including dysglycemia, dyslipidemia, hypertension), as well as adiposity-associated inflammation. Over a median 12.2-year follow-up (interquartile range: 11.6 to 12.8 years), pericardial fat was associated with a higher rate of incident hard ASCVD (standardized hazard ratio: 1.22; 95% confidence interval: 1.10 to 1.35; p = 0.0001). Hepatic fat by CT was not significantly associated with hard ASCVD (standardized hazard ratio: 0.96; 95% confidence interval: 0.86 to 1.08; p = 0.52). Higher pericardial fat was associated with greater indexed LV mass (37.8 g/m2.7 vs. 33.9 g/m2.7, highest quartile vs. lowest quartile; p < 0.01), LV mass-to-volume ratio (1.2 vs. 1.1, highest quartile 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). CONCLUSIONS: Pericardial fat is associated with poorer CVD prognosis and LV remodeling, independent of insulin resistance, inflammation, and CT measures of hepatic fat.

Lupus-like Immune Complex-mediated Glomerulonephritis in Patients with Hepatitis C Virus Infection Treated with Oral, Interferon-free, Direct-acting Antiviral Therapy.

Novel, all-oral interferon-free direct-acting antiviral agents have revolutionized the management of hepatitis C virus (HCV) infection by producing exceptional cure rates with minimal adverse events. While provocation or exacerbation of autoimmunity has been reported in HCV-infected patients receiving interferon, this phenomenon has not been reported in patients receiving interferon-free HCV therapy. We report the occurrence of three cases of lupus-like immune complex-mediated glomerulonephritis occurring shortly after exposure to sofosbuvir-based direct-acting antiviral therapies. In all three cases, renal function quickly improved with immunosuppression. However, two of the three patients developed infectious complications of immunosuppression and died. This is the first report of a lupus-like immune complex mediated glomerulonephritis occurring in the context of HCV eradication with all-oral direct-acting antiviral therapies.

Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents.

UNLABELLED: Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral direct-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. The authors studied 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 health care 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 two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7-2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine 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, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events. CONCLUSION: SVR12 rates for sofosbuvir-based DAA 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.

Use of sofosbuvir-based direct-acting antiviral therapy for hepatitis C viral infection in patients with severe renal insufficiency.

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 12 weeks was 67%. One patient had to discontinue antiviral therapy early due to side effects. No hepatobiliary or cardiovascular toxicity was reported.

Enhancing our understanding of current therapies for hepatitis C virus (HCV).

Great progress has been made in understanding the HCV genome and its molecular virology. This understanding has culminated in the development of direct-acting antiviral (DAA) agents targeting HCV viral proteins. Telaprevir (TVR) and boceprevir (BOC) were the first DAAs introduced for treatment of genotype 1 HCV in 2011; when used in combination with pegylated interferon (pegIFN) and ribavirin (RBV), these protease inhibitors improved efficacy in patients with chronic HCV infection compared to the traditional dual therapy. However, this combination was associated with adverse events that often led to early termination of therapy. In late 2013, the FDA approved a second wave of DAAs, sofosbuvir (SOF) and simeprevir (SMV). The use of SOF with SMV opened the door for IFN-free combination regimens. This combination was highly efficacious and well tolerated in patients with HCV genotype 1. Sofosbuvir and ledipasvir (LDV) fixed-dose oral combination (FDC) therapy, and paritaprevir/ritonavir, ombitasvir and dasabuvir ± RBV were recently approved, elevating sustained virologic response (SVR) rates to over 95 %. We are anticipating the approval of additional IFN-free regimens with comparable efficacy and tolerability but with the addition of pangenotypic coverage, fewer drug-drug interactions, and a high barrier to resistance. This review will summarize current management for chronic HCV infection.