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( Mark S. Sulkowski ),( Henry Lik Yuen Chan ),( Jordan J. Feld ),( Kosh Agarwal ),( Christophe Hezode ),( Tarik Asselah ),( Peter J. Ruane ),( Norbert Gruener ),( Armand Abergel ),( Alessandra Mangia 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Background: Velpatasvir (VEL) is a pangenotypic HCV-NS5A inhibitor. This Phase 3 study evaluated treatment with a fixed dose combination of SOF/VEL for 12 weeks in patients with genotype 1, 2, 4, 5, or 6 HCV infection. Methods: Patients with genotype 1, 2, 4, or 6 chronic HCV infection were randomized 5:1 to received SOF/VEL (400 mg /100 mg daily) or placebo for 12 weeks. Patients with genotype 5 infection were enrolled to the SOF/VEL treatment group and patients with genotype 3 were evaluated in a separate study. Results: 740 patients were enrolled at 81 international sites: 60% male, 79% white, 32% treatment-experienced (TE), and 19% compensated- cirrhosis. Of the 624 patients treated with SOF/VEL, the genotype distribution was 53% GT1, 17% GT2, 19% GT4, 6% GT5 and 7 % GT6. Overall SVR12 for SOF/VEL-treated patients was 99.0% and the study met its primary efficacy endpoint. SVR12 rates by HCV genotype are presented in the table. Two of 328 patients (0.6%) with genotype-1 infection had virologic relapse. No patients with genotype 2, 4, 5, or 6, including 48 with cirrhosis, had virologic failure. Four patients did not achieve SVR12 for non-virologic reasons. AEs and laboratory abnormalities were similar in the SOF/VEL-treated patients compared with the 116 placebo-treated patients. One patient discontinued SOF/VEL treatment due to adverse-events. Conclusions: Treatment with the once daily, all-oral, single tablet regimen of SOF/VEL for 12 weeks is well tolerated and results in high SVR12 rates in treatment-naive and treatment-experienced genotype 1, 2, 4, 5, and 6 HCV-infected patients with and without cirrhosis.
Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity
Koo, Ja-Won,Quintanilla-Dieck, Lourdes,Jiang, Meiyan,Liu, Jianping,Urdang, Zachary D.,Allensworth, Jordan J.,Cross, Campbell P.,Li, Hongzhe,Steyger, Peter S. American Association for the Advancement of Scienc 2015 Science translational medicine Vol.7 No.298
<P>The ototoxic aminoglycoside antibiotics are essential to treat severe bacterial infections, particularly in neonatal intensive care units. Using a bacterial lipopolysaccharide (LPS) experimental model of sepsis, we tested whether LPS-mediated inflammation potentiates cochlear uptake of aminoglycosides and permanent hearing loss in mice. Using confocal microscopy and enzyme-linked immunosorbent assays, we found that low-dose LPS (endotoxemia) greatly increased cochlear concentrations of aminoglycosides and resulted in vasodilation of cochlear capillaries without inducing paracellular flux across the blood-labyrinth barrier (BLB) or elevating serum concentrations of the drug. Additionally, endotoxemia increased expression of both serum and cochlear inflammatory markers. These LPS-induced changes, classically mediated by Toll-like receptor 4 (TLR4), were attenuated in TLR4-hyporesponsive mice. Multiday dosing with aminoglycosides during chronic endotoxemia induced greater hearing threshold shifts and sensory cell loss compared to mice without endotoxemia. Thus, endotoxemia-mediated inflammation enhanced aminoglycoside trafficking across the BLB and potentiated aminoglycoside-induced ototoxicity. These data indicate that patients with severe infections are at greater risk of aminoglycoside-induced hearing loss than previously recognized.</P>