This preliminary study involving patients with HCV genotype 1 infection who had not had a response to prior therapy showed that a sustained virologic response can be achieved with two direct-acting antiviral agents only. In addition, a high rate of sustained virologic response was achieved when the two direct-acting antiviral agents were combined with peginterferon alfa-2a and ribavirin. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT01012895.).

Recurrent HCV infection following liver transplantation can lead to accelerated allograft injury that is difficult to treat with interferon. The aim of this study is to describe the first ever use of an interferon‐free, all oral regimen in a liver transplant recipient with severe recurrent HCV. A 54‐year‐old male with HCV genotype 1b developed severe cholestatic HCV at 6 months posttransplant with ascites, AST 503 IU/mL, alkaline phosphatase of 298 IU/mL, HCV RNA of 12 000 000 IU/mL, and histological cholestasis with pericellular fibrosis. Sofosbuvir, an HCV polymerase inhibitor (400 mg/day), and daclatasvir, an HCV NS5A replication complex inhibitor (60 mg/day), were co‐administered for 24 weeks. Within 4 weeks of initiating treatment, serum HCV RNA levels became undetectable and liver biochemistries normalized with concomitant resolution of ascites. The patient achieved a sustained virological response with undetectable HCV RNA at 9 months posttreatment. During and following treatment, the daily dose and blood level of tacrolimus remained stable and unchanged. The rapid and sustained suppression of HCV replication in this liver transplant recipient provides great promise for the use of combination oral antiviral regimens in other immunosuppressed and interferon refractory HCV patients.

Treatment for chronic hepatitis C virus (HCV) infection is evolving from interferon (IFN)-based therapy to direct-acting antiviral (DAA) agents, yet some safety concerns have arisen involving cardiac toxicity. In this study, we sought to better understand the potential off-target toxicities of new DAAs. We retrospectively evaluated the clinical and pathological findings of the sentinel case in a phase II study that led to clinical development discontinuation for BMS-986094, an HCV nucleotide polymerase (nonstructural 5B) inhibitor. We also report on outcomes from other patients in the same study, including electrocardiogram changes, cardiovascular biomarkers, and transthoracic echocardiograms. Thirty-four patients received IFN-free BMS-986094 regimens. Six patients had left ventricular ejection fractions (LVEFs) <30%, 8 had LVEFs 30%-50%, and 11 required hospitalization for suspected cardiotoxicity. Of the patients with LVEF <50%, 6 had normalization of systolic function after a median of 20 days. T-wave inversions were the most sensitive predictor of LVEF dysfunction. B-type natriuretic peptide levels increased over time and correlated with the degree of LVEF dysfunction. Pathological analysis of cardiac tissue revealed severe myocyte damage with elongated myofibrils without gross necrosis. These findings were consistent with some results of recent primate studies that were conducted to further investigate the potential mechanisms of BMS-986094 toxicity. Conclusion: A novel nucleotide analog polymerase inhibitor developed for HCV treatment may cause a toxic cardiomyopathy. Ongoing surveillance of DAAs for cardiotoxicities may be beneficial, especially among patients at higher risk for cardiovascular disease. (HEPATOLOGY 2015;62:409-416) C hronic hepatitis C virus (HCV) infection affects more than 3% (170 million) of the world's population and is a major cause of liver cirrhosis and hepatocellular carcinoma.1 Historically, HCV treatments have included pegylated (Peg) interferon (IFN)-a and ribavirin (RBV), but these agents are limited by restricted efficacy and frequent side effects.2 New regimens comprised of direct-acting antivirals (DAAs) that target different steps in the HCV life cycle are in development and some have received breakthrough therapy status by the U.S. Food and Drug Administration (FDA). [3][4][5] One DAA in development was BMS-986094 (formerly INX-08189), a nucleotide analog HCV nonstructural 5B polymerase inhibitor.6 BMS-986094, either alone or combined with RBV, was well tolerated and exhibited dose-dependent antiviral activity in treatment-na€ ıve HCV genotype 1-infected patients over 7 days of treatment. 7 In part A of a phase II study, the combination of BMS-986094 with Peg-IFN-a and RBV appeared to be well tolerated in patients with HCV genotype 2 or 3 infection.8 After review of safety data, BMS-986094 was evaluated in IFN-free combinations with daclatasvir (DCV) and

Adenosine, released by cells in an injurious or hypoxic environment, possesses potent anti-inflammatory effects by inhibiting the production of proinflammatory cytokines and superoxide anions (O 2 ؊ ). We hypothesized that adenosine compounds also induced heterologous desensitization of chemokine receptors, which played a critical role in leukocyte trafficking. Our studies using adenosine receptor subtype-specific agonists revealed that pretreatment with adenosine compounds suppressed RANTES-induced chemotaxis and Ca 2؉