52-week efficacy and safety of telbivudine with conditional tenofovir intensification at week 24 in HBeAg-positive chronic Hepatitis B

Background and Aims: The Roadmap concept is a therapeutic framework in chronic hepatitis B for the intensification of nucleoside analogue monotherapy based on early virologic response. The efficacy and safety of this approach applied to telbivudine treatment has not been investigated. Methods: A multinational, phase IV, single-arm open-label study (ClinicalTrials.gov ID NCT00651209) was undertaken in HBeAg-positive, nucleoside-naive adult patients with chronic hepatitis B. Patients received telbivudine (600 mg once-daily) for 24 weeks, after which those with undetectable serum HBV DNA (<300 copies/mL) continued to receive telbivudine alone while those with detectable DNA received telbivudine plus tenofovir (300 mg once-daily). Outcomes were assessed at Week 52. Results: 105 patients commenced telbivudine monotherapy, of whom 100 were included in the efficacy analysis. Fifty-five (55%) had undetectable HBV DNA at Week 24 and continued telbivudine monotherapy; 45 (45%) received tenofovir intensification. At Week 52, the overall proportion of undetectable HBV DNA was 93% (93/100) by last-observation-carried-forward analysis (100% monotherapy group, 84% intensification group) and no virologic breakthroughs had occurred. ALT normalization occurred in 77% (87% monotherapy, 64% intensification), HBeAg clearance in 43% (65% monotherapy, 16% intensification), and HBeAg seroconversion in 39% (62% monotherapy, 11% intensification). Six patients had HBsAg clearance. Myalgia was more common in the monotherapy group (19% versus 7%). No decrease in the mean glomerular filtration rate occurred in either treatment group at Week 52. Conclusions: Telbivudine therapy with tenofovir intensification at Week 24, where indicated by the Roadmap strategy, appears effective and well tolerated for the treatment of chronic hepatitis B. Trial Registration: ClinicalTrials.gov NCT0065120

Evaluation of Effectiveness and Safety of High-Dose Daptomycin: Results from Patients Included in the European Cubicin® Outcomes Registry and Experience

Introduction: Daptomycin, a rapid concentration-dependent bactericidal antibiotic, is approved at a dose of 4Â&nbsp;mg/kg/day for the treatment of complicated skin and soft tissue infections (cSSTI) and at a dose of 6Â&nbsp;mg/kg/day for the treatment of Staphylococcus aureus right-sided infective endocarditis (RIE) and bacteremia associated with cSSTI and RIE. Studies have reported the successful use of high-dose daptomycin (&gt;6Â&nbsp;mg/kg/day) in patients with difficult-to-treat infections. The present analysis evaluated the effectiveness and safety of high doses (&gt;6Â&nbsp;mg/kg/day) of daptomycin for the treatment of different Gram-positive infections. Methods: European Cubicin® Outcomes Registry and Experience (EU-CORE) is a non-interventional, multicenter, retrospective, patient registry designed to collect real-world data from patients treated with daptomycin between 2006 and 2012. Clinical outcomes were assessed at the end of daptomycin treatment for three dose groups: â\u89¤6, &gt;6 to &lt;8, and â\u89¥8Â&nbsp;mg/kg/day. Safety was assessed for up to 30Â&nbsp;days post-daptomycin treatment. Results: Of the 6075 patients enrolled in EU-CORE, 4892 patients received daptomycin doses â\u89¤6Â&nbsp;mg/kg/day, while 1097 patients received high doses (&gt;6Â&nbsp;mg/kg/day). The primary infections with the largest proportion of patients treated with a high dose (&gt;6Â&nbsp;mg/kg/day) were osteomyelitis (37.1%), foreign body/prosthetic infection (31.6%), and endocarditis (27.6%). S.Â&nbsp;aureus was identified in 42.9% of patients with positive cultures treated with either â\u89¤6 or &gt;6Â&nbsp;mg/kg/day. The overall clinical success rate was 82.0% (899/1097) with high doses (&gt;6Â&nbsp;mg/kg/day) and 80.3% (3928/4890) with doses â\u89¤6Â&nbsp;mg/kg/day. Numerically higher clinical success rate was observed for endocarditis and foreign body/prosthetic infection, as well as for coagulase-negative staphylococcal and enterococcal infections, with high-dose daptomycin treatment. There were no new or unexpected safety findings at doses &gt;6Â&nbsp;mg/kg/day. Conclusion: These results suggested that daptomycin at doses &gt;6Â&nbsp;mg/kg/day was effective and well tolerated. High-dose daptomycin is a potential therapeutic option in patients with difficult-to-treat Gram-positive infections. Funding: This study was funded by Novartis Pharma AG

Efficacy and safety of TOBI Podhaler® in Pseudomonas <i>aeruginosa</i>-infected bronchiectasis patients:iBEST study

Introduction: The study aimed to determine the efficacy of a safe and well-tolerated dose and regimen of tobramycin inhalation powder (TIP) on Pseudomonas aeruginosa (Pa) sputum density in patients with bronchiectasis (BE). Methods: This is a phase II, double-blind, randomised study in BE patients aged 6518 years with chronic Pa infection. Patients were randomised 1:1:1 to either Cohort A: 3 capsules of TIP O.D. (84 mg); Cohort B: 5 capsules O.D. (140 mg) or Cohort C: 4 capsules B.I.D. (224 mg). Within each cohort, patients were further randomised 2:2:1 either to TIP continuously, TIP cyclically (alternating 28 days of TIP and placebo) or placebo for 16 weeks, respectively, and were followed up for 8 weeks. Results: Overall, 107 patients were randomised to Cohorts A (n=34), B (n=36) and C (n=37). All three TIP doses significantly reduced the Pa sputum density from baseline to Day 29 versus placebo in a dose-dependent manner (p 640.0001, each). A smaller proportion of patients in the continuous-TIP (34.1%) and cyclical-TIP (35.7%) groups experienced pulmonary exacerbations versus placebo (47.6%) and also required fewer anti-pseudomonal antibiotics (38.6% on continuous-TIP and 42.9% on cyclical-TIP) versus placebo (57.1%) although not statistically significant. Pulmonary exacerbation of BE was the most frequent (37.4%) adverse event (AE). Overall, TIP was well tolerated, however, 23.4% of the patients discontinued the study drug due to AEs. Conclusion: Continuous- and cyclical-TIP regimens with all three doses were safe and effective in reducing the Pa sputum density in patients with BE and chronic Pa infection

Changes from baseline in HBV DNA by post-Week 24 treatment (efficacy population).

<p>Changes from baseline in HBV DNA by post-Week 24 treatment (efficacy population).</p

Patient disposition.

<p>Patient disposition.</p

Week 52 glomerular filtration rate (MDRD) changes, by baseline rate and treatment (efficacy population).

<p>Week 52 glomerular filtration rate (MDRD) changes, by baseline rate and treatment (efficacy population).</p

Most common (≥5%) all-cause adverse events through Week 52 (safety population).

*<p>Intensification patients may have had an event during both the telbivudine only and intensification periods. Overall numbers with an indicated event may therefore be less than the row total.</p><p>doi:10.1371/journal.pone.0054279.t003</p

Demographics and baseline characteristics (efficacy population) according to post-Week 24 treatment.

<p>doi:10.1371/journal.pone.0054279.t001</p

Study design.

<p>Study design.</p