All TMC278 doses demonstrated potent and sustained efficacy comparable with efavirenz in treatment-naive patients over 96 weeks. TMC278 was well tolerated with lower incidences of neurological and psychiatric adverse events, rash and lower lipid elevations than those with efavirenz. TMC278 25 mg once daily was selected for further clinical development.

A recent study has shown the reproducibility of time to exhaustion (time limit: tlim) at the lowest velocity that elicits the maximal oxygen consumption (vVO2 max). The same study found an inverse relationship between this time to exhaustion at vVO2 max and vVO2 max among 38 élite long-distance runners (Billat et al. 1994b). The purpose of the present study was to compare the time to exhaustion at the power output (or velocity) at VO2 max for different values of VO2 max, depending on the type of exercise and not only on the aerobic capacity. The time of exhaustion at vVO2 max (tlim) has been measured among 41 élite (national level) sportsmen: 9 cyclists, 9 kayak paddlers, 9 swimmers and 14 runners using specific ergometers. Velocity or power at VO2 max (vVO2 max) was determined by continuous incremental testing. This protocol had steps of 2 min and increments of 50 W, 30 W, 0.05 m s-1 and 2 km-1 for cyclists, kayak paddlers, swimmers and runners, respectively. One week later, tlim was determined under the same conditions. After a warm-up of 10 min at 60% of their vVO2 max, subjects were concluded (in less than 45 s) to their vVO2 max and then had to sustain it as long as possible until exhaustion. Mean values of vVO2 max and tlim were respectively equal to 419 +/- 49 W (tlim = 222 +/- 91 s), 239 +/- 56 W (tlim = 376 +/- 134 s), 1.46 +/- 0.09 m s-1 (tlim = 287 +/- 160 s) and 22.4 +/- 0.8 km h-1 (tlim = 321 +/- 84 s), for cyclists, kayak paddlers, swimmers and runners. Time to exhaustion at vVO2 max was only significantly different between cycling and kayaking (ANOVA test, p < 0.05). Otherwise, VO2 max (expressed in ml min-1 kg-1) was significantly different between all sports except between cycling and running (p < 0.05). In this study, time to exhaustion at vVO2 max was also inversely related to VO2 max for the entire group of élite sportsmen (r = -0.320, p < 0.05, n = 41). The inverse relationship between VO2 max and tlim at vVO2 max has to be explained, it seems that tlim depends on VO2 max regardless of the type of exercise undertaken.

Summary The objectives of the present study were: (i) to assess the frequency of oral colonisation by Candida species in HIV‐positive patients and to compare it with a population of HIV‐negative individuals, (ii) to determine the prevalence of C. dubliniensis in both populations and (iii) to determine the susceptibility of C. dubliniensis and other Candida species isolated from HIV‐positive patients to the most commonly used antifungal agents. Oral samples were obtained from 101 HIV‐positive and 108 HIV‐negative subjects. For yeast identification, we used morphology in cornmeal agar, the API 20C Aux, growth at 45 °C, d‐xylose assimilation, morphology in sunflower seed agar and PCR. The frequency of isolation of Candida in HIV‐positive patients was: C. albicans, 60.7%; C. dubliniensis, 20.2%; C. glabrata, 5.6%; C. krusei, 5.6%; C. tropicalis, 4.5%; others, <5%. The frequency of isolation of Candida in HIV‐negative patients was: C. albicans, 73.9%; C. tropicalis, 15.5%; C. dubliniensis, 2.1%; C. glabrata, 2.1%; C. parapsilosis, 2.1%; others, <5%. The oral colonisation by yeast in the HIV‐positive patients was higher than that in the HIV‐negative subjects. The susceptibilities of 42 Candida isolates to three antifungal agents were determined. All isolates of C. dubliniensis were susceptible to fluconazole, although several individuals had been previously treated with this drug. Out of the 42 Candida isolates, 10 presented resistance to fluconazole and 10 to itraconazole. The presence of Candida species, resistant to commonly used antifungal agents, represents a potential risk in immunocompromised patients.

ATV+RAL, an experimental NRTI- and RTV-sparing regimen, achieved virologic suppression rates comparable to current standards of care for treatment-naïve patients. The overall profile did not appear optimal for further clinical development given its development of resistance to RAL and higher rates of hyperbilirubinemia with twice-daily ATV compared with ATV/RTV.

Summary Background Influenza continues to have a significant socioeconomic and health impact despite a long established vaccine program and approved antivirals. Preclinical data suggest combination antivirals might be more effective than oseltamivir alone in the treatment of influenza. Methods We conducted a randomized, double-blinded, multicenter phase 2 trial of combination antivirals versus monotherapy for the treatment of influenza. Participants ≥18 years with influenza at increased risk of complications from influenza were randomized by an online computer-generated randomization system to receive either oseltamivir, amantadine, and ribavirin or oseltamivir alone for 5 days, and followed for 28 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at Day 3. Among the secondary outcomes, there were safety and time to alleviation of influenza clinical symptoms. ClinicalTrials.gov Identifier: NCT01227967. Findings Between March 2011 and April 2016 we randomized 633 participants. Seven participants were excluded from analysis: 3 were given treatment without randomization, 3 withdrew before taking any medication, and 1 was lost to follow-up. The primary analysis included 394 participants, excluding 47 in the pilot phase, 172 without confirmed influenza, and 13 without an endpoint sample. 80 of 200 (40.0%) participants in the combination arm had virus detectable at Day 3 compared to 97 of 194 (50.0%) (95%C.I. 0.2–19.8%, p=0.046) in the control arm. There was no benefit, however, in multiple clinical secondary endpoints, such as median duration of symptoms (4.5 days in the combination arm vs 4.0 days in the oseltamivir arm; p = 0.21). Interpretation Although oseltamivir, amantadine, and ribavirin showed a statistically significant decrease in viral shedding at Day 3 relative to oseltamivir, this difference was not associated with improved clinical benefit. More work is needed to understand the lack of clinical benefit when a difference in virologic outcome was identified. Funding National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States.