This phase-2b study examined the safety and efficacy of an all-oral, interferon-free combination of the NS5A replication complex inhibitor daclatasvir (DCV), the NS3 protease inhibitor asunaprevir (ASV), and the nonnucleoside NS5B polymerase inhibitor beclabuvir (BCV) with or without ribavirin in patients with HCV genotype (GT) 1 infection.A total of 187 patients received 12 weeks of DCV 30 mg BID plus ASV 200 mg BID and BCV 150 mg BID (n = 86) or 75 mg BID with (n = 21) or without (n = 80) weight-based ribavirin BID. The primary endpoint was HCV RNA <25 IU/ml at post-treatment week 12 (SVR12).Overall, 90% of patients (169/187) in the combined treatment groups achieved SVR on or after post-treatment week 12. SVR rates were similar across subgroups (by mITT analysis), i.e. patients with cirrhosis (88%, 14/16), HCV GT-1a (90%, 137/155), and IL28B non-CC genotype (90%, 115/128). There were no drug-related serious AEs or grade 4 AEs. The most frequently reported AEs were headache, diarrhoea, fatigue and nausea. Addition of ribavirin to DCV+ASV+BCV was associated with decreased haemoglobin, compared with DCV+ASV+BCV alone. There were six grade 3/4 laboratory abnormalities noted, all unrelated to the study drugs. Viral breakthrough occurred in 2.5-4.8% of patients across groups and appeared unrelated to BCV dose or ribavirin inclusion.Results support phase 3 evaluation of a twice-daily, fixed-dose formulation of this DCV+ASV+BCV regimen with or without ribavirin in HCV GT-1-infected patients.
Background We conducted a Phase I dose-escalation trial of ADMVA, a Clade-B'/C-based HIV-1 candidate vaccine expressing env, gag, pol, nef, and tat in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers. Methodology/Principal Findings ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1×107 (low), 5×107 (mid), or 2.5×108 pfu (high)] volunteers were randomized in a 3∶1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNγ ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA. ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNγ ELISpot response rate to any HIV antigen was 0/12 (0%) in the placebo group, 3/12 (25%) in the low dosage group, 6/12 (50%) in the mid dosage group, and 8/13 (62%) in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%), 8/13 (62%), 6/12 (50%) and 10/13 (77%) in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement with the ability to neutralize HIV-1 SF162 in vitro. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses. Conclusions/Significance ADMVA was well-tolerated and elicited durable humoral and cellular immune responses. Trial Registration Clinicaltrials.gov NCT00252148
Background DNA-based vaccines have been safe but weakly immunogenic in humans to date. Methods and Findings We sought to determine the safety, tolerability, and immunogenicity of ADVAX, a multigenic HIV-1 DNA vaccine candidate, injected intramuscularly by in vivo electroporation (EP) in a Phase-1, double-blind, randomized placebo-controlled trial in healthy volunteers. Eight volunteers each received 0.2 mg, 1 mg, or 4 mg ADVAX or saline placebo via EP, or 4 mg ADVAX via standard intramuscular injection at weeks 0 and 8. A third vaccination was administered to eleven volunteers at week 36. EP was safe, well-tolerated and considered acceptable for a prophylactic vaccine. EP delivery of ADVAX increased the magnitude of HIV-1-specific cell mediated immunity by up to 70-fold over IM injection, as measured by gamma interferon ELISpot. The number of antigens to which the response was detected improved with EP and increasing dosage. Intracellular cytokine staining analysis of ELISpot responders revealed both CD4+ and CD8+ T cell responses, with co-secretion of multiple cytokines. Conclusions This is the first demonstration in healthy volunteers that EP is safe, tolerable, and effective in improving the magnitude, breadth and durability of cellular immune responses to a DNA vaccine candidate. Trial Registration ClinicalTrials.gov NCT00545987
Abstract Patients admitted to a medical intensive care unit during 21 days had rectal and urine samples cultured for vancomycin-resistant enterococci (VRE). The prevalence rate was 55.3%. Only enteral feedings were associated with acquisition of VRE. One-quarter of VRE transmission resulted from acquisition in the study unit, 35% arrived from other units, and 15% from other hospital.
Summary Most oils and gases in the southern Central Graben can be geochemically correlated to the Upper Jurassic Kimmeridge Clay and Heather Formations (and equivalents), however, many exceptions are evident and indicate alternative active source rocks. This region spanning the UK-Norway-Danish sectors contains multiple source rock intervals which can be positively correlated to fluids, including Middle Jurassic coals, Upper Permian sapropelic carbonates, Westphalian coals, Namurian shales and Devonian coals. This study focuses on two highly unusual oils from the Norwegian Bumblebee (2/2-5) and Møyfrid (2/2-1) discoveries, and gas from the Desmond (2/2-2) and Loven (2/3-1) discoveries in Norwegian Blocks 2/2 and 2/3. The unusual composition of oils results from highly restricted minibasins in rim synclines formed by halokinesis of Zechstein evaporites, which at first form a highly restricted lacustrine environment during the Middle-Upper Jurassic (the source of Møyfrid oils), before marine transgression(s) periodically flood the minibasin during the Upper Jurassic (source of Bumblebee oils). These localized basins may continue across much of the platform areas of the Central Graben, providing highly localized but potentially prolific inboard source kitchens. The dry, high maturity composition of Desmond gas samples indicates a late- to post-mature terrestrial source, most likely sourced from underlying Carboniferous coals.
