Background In clinical trials, HCV salvage treatment with Sofosbuvir/Velpatasvir/Voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. Methods We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). Findings Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n=46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n=82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n=18/18, GT1b n=2/4), 89% in GT3 (n=59/66) and 100% in GT6 (n=3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were four serious AEs including one death and three hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. Conclusion This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most however serious AEs can occur in those with advanced liver disease.

Mast cell degranulation in the gut causes mucus secretion, mucosal edema, and increased gut permeability and may be responsible for some of the symptoms and signs of inflammatory bowel disease. We have used a novel monoclonal antibody (AAI) against tryptase expressed exclusively in the granules of mast cells to enumerate mast cells in rectal biopsies in order to study the effect of inflammatory bowel disease and drug treatment upon rectal mast cell numbers. Rectal mast cell numbers are significantly reduced in inflammatory bowel disease patients taking corticosteroids (mean 4.95 cells/mm2) when compared with control patients (10.1, P less than 0.001) and inflammatory bowel disease patients not taking corticosteroids (9.7, P less than 0.001 Wilcoxon rank sum test). The reduction in mast cell counts was independent of the degree of inflammation or architectural distortion. There was a negative correlation between the dose of corticosteroids and mast cell count (r = 0.53, P less than 0.05 Spearman rank correlation), and the mast cell count was reduced within a few days of treatment and remained low throughout steroid therapy. Mucosal mast cell depletion may be an important mechanism of action of corticosteroids in inflammatory bowel disease.

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AimThe outcome of patients with chronic heart failure (CHF) following an ischaemic event is poorly understood. We evaluated the management and outcomes of CHF patients presenting with an acute coronary syndrome (ACS) and explored changes in outcomes over time. Method and resultsA total of 5556 patients enrolled in the Australia -New Zealand population of the Global Registry of Acute Coronary Events (GRACE) between 1999 and 2007 were included. Patients with CHF (n ¼ 609) were compared with those without CHF (n ¼ 4947). Patients with CHF were on average 10 years older, were more likely to be female, had more co-morbidities and cardiac risk factors, and were more likely to have a prior history of angina, myocardial infarction, and revascularization by coronary artery bypass graft (CABG) when compared with those without CHF. CHF was associated with a substantial increase in in-hospital renal failure [odds ratio (OR) 1.76, 95% confidence interval (CI) 1.15-2.71], readmission post-discharge (OR 1.47, 95% CI 1.17-1.90), and 6-month mortality (OR 2.25, 95% CI 1. 55-3.27). Over the 9 year study period, in-hospital and 6 month mortality in those with CHF declined by absolute rates of 7.5% and 14%, respectively. This was temporally associated with an increase in prescription of thienopyridines, beta-blockers, statins, and angiotensin II receptor blockers, increased rates of coronary angiography, and 31.8% absolute increase in referral rates for cardiac rehabilitation. ConclusionsAcute coronary syndrome patients with pre-existing CHF are a very high risk group and carry a disproportionate mortality burden. Encouragingly, there was a marked temporal improvement in outcomes over a 9 year period with an increase in evidence-based treatments and secondary preventative measures.--