Mericitabine and Either Boceprevir or Telaprevir in Combination with Peginterferon Alfa-2a plus Ribavirin for Patients with chronic Hepatitis C Genotype 1 Infection and Prior Null Response: The Randomized DYNAMO 1 and DYNAMO 2 Studies.

Most patients with chronic hepatitis C virus (HCV) genotype 1 infection who have had a pre- vious null response ( < 2-log 10 reduction in HCV RNA by treatment week 12) to peginter- feron/ribavirin (PegIFN/RBV) do not achieve a sustained virological response (SVR) when re-treated with a first-generation HCV protease inhibitor (PI) administered in combination with PegIFN/RBV. We studied the incremental benefits associated with adding mericitabine (nucleoside analog inhibitor of HCV polymerase) to PI plus PegIFN alfa-2a/RBV-based therapy in two double-blind randomized multicenter phase 2 trials (with boceprevir in DYNAMO 1, and with telaprevir in DYNAMO 2). The primary endpoint in both trials was SVR, defined as HCV RNA < 25 IU/mL 12 weeks after the end of treatment (SVR12). Over- all, the addition of mericitabine to PI plus PegIFN alfa-2a/RBV therapy resulted in SVR12 rates of 60 - 70% in DYNAMO 1 and of 71 - 96% in DYNAMO 2. SVR12 rates were similar in patients infected with HCV genotype 1a and 1b in both trials. The placebo control arms in both studies were stopped because of high rates of virological failure. Numerically lower relapse rates were associated with longer treatment with mericitabine (24 versus 12 weeks), telaprevir-containing regimens, and regimens that included 48 weeks of PegIFN alfa-2a/RBV therapy. No mericitabine resistance mutations were identified in any patient in either trial. The addition of mericitabine did not add to the safety burden associated with either telaprevir or boceprevir-based regimens. These studies demonstrate increased SVR rates and reduced relapse rates in difficult-to-treat patients when a nucleoside polymerase inhibitor with intermediate antiviral potency is added to regimens containing a first-genera- tion PI

Identification of HCV Resistant Variants against Direct Acting Antivirals in Plasma and Liver of Treatment Naïve Patients

Current standard-of-care treatment of chronically infected hepatitis C virus (HCV) patients involves direct-acting antivirals (DAA). However, concerns exist regarding the emergence of drug -resistant variants and subsequent treatment failure. In this study, we investigate potential natural drug-resistance mutations in the NS5B gene of HCV genotype 1b from treatment-naïve patients. Population-based sequencing and 454 deep sequencing of NS5B gene were performed on plasma and liver samples obtained from 18 treatment- naïve patients. The quasispecies distribution in plasma and liver samples showed a remarkable overlap in each patient. Although unique sequences in plasma or liver were observed, in the majority of cases the most dominant sequences were shown to be identical in both compartments. Neither in plasma nor in the liver codon changes were detected at position 282 that cause resistance to nucleos(t)ide analogues. However, in 10 patients the V321I change conferring resistance to nucleos(t)ide NS5B polymerase inhibitors and in 16 patients the C316N/Y/H non-nucleoside inhibitors were found mainly in liver samples. In conclusion, 454-deep sequencing of liver and plasma compartments in treatment naïve patients provides insight into viral quasispecies and the pre-existence of some drug-resistant variants in the liver, which are not necessarily present in plasma

Hospital quality measures: are process indicators associated with hospital standardized mortality ratios in French acute care hospitals?

International audienceAbstractBackgroundResults of associations between process and mortality indicators, both used for the external assessment of hospital care quality or public reporting, differ strongly across studies. However, most of those studies were conducted in North America or United Kingdom. Providing new evidence based on French data could fuel the international debate on quality of care indicators and help inform French policy-makers. The objective of our study was to explore whether optimal care delivery in French hospitals as assessed by their Hospital Process Indicators (HPIs) is associated with low Hospital Standardized Mortality Ratios (HSMRs).MethodsThe French National Authority for Health (HAS) routinely collects for each hospital located in France, a set of mandatory HPIs. Five HPIs were selected among the process indicators collected by the HAS in 2009. They were measured using random samples of 60 to 80 medical records from inpatients admitted between January 1st, 2009 and December 31, 2009 in respect with some selection criteria. HSMRs were estimated at 30, 60 and 90 days post-admission (dpa) using administrative health data extracted from the national health insurance information system (SNIIR-AM) which covers 77% of the French population. Associations between HPIs and HSMRs were assessed by Poisson regression models corrected for measurement errors with a simulation-extrapolation (SIMEX) method.ResultsMost associations studied were not statistically significant. Only two process indicators were found associated with HSMRs. Completeness and quality of anesthetic records was negatively associated with 30 dpa HSMR (0.72 [0.52–0.99]). Early detection of nutritional disorders was negatively associated with all HSMRs: 30 dpa HSMR (0.71 [0.54–0.95]), 60 dpa HSMR (0.51 [0.39–0.67]) and 90 dpa HSMR (0.52 [0.40–0.68]).ConclusionIn absence of gold standard of quality of care measurement, the limited number of associations suggested to drive in-depth improvements in order to better determine associations between process and mortality indicators. A smart utilization of both process and outcomes indicators is mandatory to capture aspects of the hospital quality of care complexity