No abstract

clinicaltrials.gov Identifier:NCT01878799.

Background Direct acting anti-HCV drugs have demonstrated a high cure rate and favorable tolerability. The development of shorter courses of therapy may improve affordability and adherence. Sofosbuvir and ledipasvir together with ribavirin have yielded high efficacy when administered for 8, but not for 6 weeks. We hypothesized that addition of a third potent directly acting antiviral to sofosbuvir and ledipasvir would allow for shortened durations of therapy. Methods In this single center, open-label cohort, phase 2 atrial, sixty HCV GT-1 treatment naïve patients were sequentially enrolled onto three arms and treated with 12 weeks of sofosbuvir and ledipasvir (an NS5B nucleotide polymerase inhibitor and an NS5A inhibitor, respectively) (n=20); or 6 weeks with sofosbuvir, ledipasvir, and GS-9669 (a non-nucleoside NS5B inhibitor) (n=20) or 6 weeks with sofosbuvir, ledipasvir and GS-9451 (an NS3/4A protease inhibitor) (n=20). Patients and investigators were unmasked to treatment assignment. The primary efficacy analysis was SVR12 (HCV RNA less than the level of quantitation 12 weeks after treatment completion). Findings All subjects treated with sofosbuvir and ledipasvir for 12 weeks achieved SVR12 (95%CI: 83–100%). Nineteen of 20 patients (95% CI: 75–100%) treated with sofosbuvir, ledipasvir and GS-9669 achieved SVR12, with 1 patient relapsing 2 weeks after completion of therapy. Nineteen of 20 patients (95% CI: 75–100%) treated with sofosbuvir, ledipasvir, and GS-9451 for 6 weeks achieved SVR12, one patient was lost to follow up after achieving SVR4. There were no discontinuations of treatment due to adverse events. Interpretation In this small proof of concept study, two different three drug regimens administered for 6 weeks resulted in high cure rates for HCV infection with excellent tolerability. Funding NIAID, National Cancer Institute and Clinical Center Intramural Program. Clinical Trials.gov number NCT01805882. The study was also supported in part by the German Research Foundation (DFG) by the clinical research unit KFO 129 and a Collaborative Research and Development Agreement between NIH and Gilead Sciences.

A case of tuberculous peritonitis complicating continuous ambulatory peritoneal dialysis (CAPD) in a 37-year-old man who presented with fever, abdominal pain, and a malfunctioning Tenckhoff catheter is reported. The patient was initially treated for presumed bacterial peritonitis but remained febrile and had persistent abdominal pain and peritoneal fluid pleocytosis, despite broad-spectrum antibiotic therapy. Mycobacterium tuberculosis was isolated in a culture of peritoneal fluid, and the patient responded promptly to antituberculous therapy. More than 50 cases of tuberculous peritonitis complicating CAPD that have been reported in the English-language literature since the initial case was reported in 1980 are reviewed. The most common symptoms are fever (78%), abdominal pain (92%), and cloudy dialysate (90%); 76% of cases had a predominance of polymorphonuclear cells in peritoneal fluid. A smear for acid-fast bacilli or a culture was positive in 73% of cases. The peritoneal dialysis catheter was removed in 53% of cases, although this was rarely considered necessary for cure of tuberculosis. The attributable mortality rate is 15%, with the most significant factor being treatment delay (mean time from presentation to initiation of treatment, 6.74 weeks). We conclude that tuberculosis is an important diagnostic consideration for CAPD patients with peritonitis that is refractory to broad-spectrum antibiotics.

Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 g/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.Staphylococcus aureus is a leading cause of healthcare-associated and community-onset bacteremia in the United States and abroad (15,23,24). A recent study showed that S. aureus infection was reported as a discharge diagnosis for 0.8% of all hospital inpatients, or an average of 292,045 inpatients per year (19). Infections caused by methicillin-resistant S. aureus (MRSA) in hospitalized patients as well as in otherwise healthy patients with no obvious risk factors are an emerging problem (3,8,18). Current therapy for S. aureus bacteremia (SAB), particularly for MRSA bacteremia, is less than adequate. This fact is supported by the high rates of complications, including mortality, relapsing infection, and metastatic infections (infective endocarditis, bone and joint infections, and suppurative abscesses), associated with SAB (1,2,6,7,11,14,22). Taken together, these observations indicate that novel therapies for SAB are urgently needed.One potential strategy to improve clinical outcomes of SAB is adjunctive therapy using passive immunization with monoclonal antibodies that target S. aureus. Tefibazumab (Aurexis) is a humanized immunoglobulin G1 monoclonal antibody that specifically recognizes clumping factor A (ClfA) with a high affinity. ClfA, a surface adhesin protein found on virtually all strains of S. aureus, is an MSCRAMM (microbial surface components recognizing adhesive matrix molecules) protein that mediates the adhesion of S. aureus to fibrinogen (10,16,17). In preclinic...