No abstract

Results of QFT-Plus are highly comparable to QFT-GIT. Although there is an indication that a true difference in interferon-γ release between the antigen tubes is associated with recent latent tuberculosis infection, the QFT-Plus could not be used to exclude recent exposure.

Background Multiple studies have described a higher incidence of venous thromboembolism (VTE) in people living with an HIV infection (PWH). However, data on the risk of recurrent VTE in this population are lacking, although this question is more important for clinical practice. This study aims to estimate the risk of recurrent VTE in PWH compared to controls and to identify risk factors for recurrence within this population. Methods and findings PWH with a first VTE were derived from the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort (2003-2015), a nationwide ongoing cohort following up PWH in care in the Netherlands. Uninfected controls were derived from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) follow-up study (1999-2003), a cohort of patients with a first VTE who initially participated in a case-control study in the Netherlands who were followed up for recurrent VTE. Selection was limited to persons with an index VTE suffering from deep vein thrombosis in the lower limbs and/or pulmonary embolism (PE). Participants were followed from withdrawal of anticoagulation to VTE recurrence, loss to follow-up, death, or end of study. We estimated incidence rates, cumulative incidence (accounting for competing risk of death) and hazard ratios (HRs) using Cox proportional hazards regression, adjusting for age, sex, and whether the index event was

Background The treatment success rate of drug-resistant tuberculosis (DR-TB) is alarmingly low. Therefore, more effective and less complex regimens are urgently required. Methods We compared the efficacy of an all oral DR-TB drug regimen consisting of bedaquiline (25 mg/kg), delamanid (2.5 mg/kg) and linezolid (100 mg/kg) (BDL) on the mycobacterial load in the lungs and spleen of TB infected mice during a treatment period of 24 weeks. This treatment was compared to the standard regimen of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE). Relapse was assessed 12 weeks post-treatment. Two logistic regression models were developed to compare the efficacy of both regimens. Results Culture negativity in the lungs was achieved at 8 and 20 weeks of treatment with BDL and HRZE, respectively. After 14 weeks of treatment only one mouse relapsed in the BDL group, while in the HRZE group relapse was still observed at 24 weeks of treatment. Predictions from the final mathematical models showed that a 95% cure rate was reached after 20.5 and 28.5 weeks of treatment with BDL and HRZE, respectively. Conclusion The BDL regimen was observed to be more effective than HRZE and could be a valuable option for the treatment of DR-TB.

By improving the translational value of preclinical models, more successful and focussed research to shorten the treatment duration of tuberculosis can be performed. Although the hollow fibre infection model (HFIM) is considered to be a valuable addition to the drug development pipeline, its exact role is not fully determined yet. As increasing the dose of rifamycins is being evaluated for its treatment shortening potential, additional in vitro modelling is of importance. Therefore we assessed increased dosing of rifampicin and rifapentine in our HFIM to gain more insight into the place of the HFIM in the drug development pipeline. Total and free-fraction concentrations corresponding to daily dosing of 2.7, 10 and 50 mg/kg rifampicin as well as 600 mg and 1,500 mg rifapentine were assessed in our HFIM using the Mycobacterium tuberculosis H37Rv strain. Drug activity and emergence of drug resistance were assessed by CFU counting and subsequent mathematical modelling over 14 days, and pharmacokinetic exposures were checked. Increasing rifampicin exposure above what is expected with the standard dose did not result in higher antimycobacterial activity. For rifapentine, only the highest concentration showed increased activity but clinical relevance of this observation is questionable. Moreover, the emergence of resistance to both drugs was unrelated to exposure. In conclusion, in the most simplistic experimental set-up, the results of the HFIM did not fully correspond to pre-existing clinical data. Including additional parameters and read-outs in this pre-clinical model could be of interest for proper assessment of the translational value of the HFIM.

The favorable treatment outcome rate for multidrug-resistant tuberculosis (MDR-TB) is only 54%, and therefore new drug regimens are urgently needed. In this study, we evaluated the activity of the combination of moxifloxacin and linezolid as a possible new MDR-TB regimen in a murine TB model and the value of the addition of the efflux pump inhibitor verapamil to this backbone. BALB/c mice were infected with drug-sensitive and were treated with human-equivalent doses of moxifloxacin (200 mg/kg of body weight) and linezolid (100 mg/kg) with or without verapamil (12.5 mg/kg) for 12 weeks. Pharmacokinetic parameters were collected during treatment at the steady state. After 12 weeks of treatment, a statistically significant decline in mycobacterial load in the lungs was observed with the moxifloxacin-linezolid regimen with and without verapamil (5.9 and 5.0 log CFU, respectively), but sterilization was not achieved yet. The spleens of all mice were culture negative after 12 weeks of treatment with both treatment modalities, and the addition of verapamil caused a significant reduction in relapse (14/14 positive spleens without versus 9/15 with verapamil, = 0.017). In conclusion, treatment with a combination regimen of moxifloxacin and linezolid showed a strong decline in mycobacterial load in the mice. The addition of verapamil to this backbone had a modest additional effect in terms of reducing mycobacterial load in the lung as well as reducing the spleen relapse rate. These results warrant further studies on the role of efflux pump inhibition in improving the efficacy of MDR-TB backbone regimens.

One of the reasons for the lengthy tuberculosis (TB) treatment is the difficulty to treat the nonmultiplying mycobacterial subpopulation. In order to assess the ability of (new) TB drugs to target this subpopulation, we need to incorporate dormancy models in our preclinical drug development pipeline. In most available dormancy models, it takes a long time to create a dormant state, and it is difficult to identify and quantify this nonmultiplying condition. The Mycobacterium tuberculosis 18b strain might overcome some of these problems, because it is dependent on streptomycin for growth and becomes nonmultiplying after 10 days of streptomycin starvation but still can be cultured on streptomycin-supplemented culture plates. We developed our 18b dormancy time-kill kinetics model to assess the difference in the activity of isoniazid, rifampin, moxifloxacin, and bedaquiline against log-phase growth compared to the nonmultiplying M. tuberculosis subpopulation by CFU counting, including a novel area under the curve (AUC)-based approach as well as time-to-positivity (TTP) measurements. We observed that isoniazid and moxifloxacin were relatively more potent against replicating bacteria, while rifampin and high-dose bedaquiline were equally effective against both subpopulations. Moreover, the TTP data suggest that including a liquid culture-based method could be of additional value, as it identifies a specific mycobacterial subpopulation that is nonculturable on solid media. In conclusion, the results of our study underline that the time-kill kinetics 18b dormancy model in its current form is a useful tool to assess TB drug potency and thus has its place in the TB drug development pipeline.

A systematic difference (overestimation) was noted for right ventricular size as assessed with knowledge-based reconstruction compared with conventional methods for analysis. Observer variability for the new method was comparable to what has been reported for the right ventricle in children and congenital heart disease with conventional analysis.