Drug-susceptible Tuberculosis Research Articles

Ultra-Short Antimicrobial Peptoids Show Propensity for Membrane Activity Against Multi-Drug Resistant Mycobacterium tuberculosis.

Tuberculosis (TB) results in both morbidity and mortality on a global scale. With drug resistance on the increase, there is an urgent need to develop novel anti-mycobacterials. Thus, we assessed the anti-mycobacterial potency of three novel synthetic peptoids against drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis in vitro using Minimum Inhibitory Concentration, killing efficacy and intracellular growth inhibition assays, and in vivo against mycobacteria infected BALB/c mice. In addition, we verified cell selectivity using mammalian cells to assess peptoid toxicity. The mechanism of action was determined using flow cytometric analysis, and microfluidic live-cell imaging with time-lapse microscopy and uptake of propidium iodide. Peptoid BM 2 demonstrated anti-mycobacterial activity against both drug sensitive and MDR M. tuberculosis together with an acceptable toxicity profile that showed selectivity between bacterial and mammalian membranes. The peptoid was able to efficiently kill mycobacteria both in vitro and intracellularly in murine RAW 264.7 macrophages, and significantly reduced bacterial load in the lungs of infected mice. Flow cytometric and time lapse fluorescence microscopy indicate mycobacterial membrane damage as the likely mechanism of action. These data demonstrate that peptoids are a novel class of antimicrobial which warrant further investigation and development as therapeutics against TB.

Delays in HIV and TB diagnosis and treatment initiation in co-infected patients in Colombia.

We investigated the delays in the diagnosis of tuberculosis and/or HIV, their treatment initiation, and factors associated with each delay. All drug-susceptible tuberculosis cases diagnosed in 2014 and 2015 in Colombia, with a confirmed diagnosis of HIV were included. A total of 1909 patients were registered with tuberculosis/HIV co-infection. Seventy-nine percent of patients were men, 50% had sputum smear-negative tuberculosis, culture was done in 50% of cases, 68.5% had <200 CD4 cell count at diagnosis, and 35% had concurrent tuberculosis/HIV diagnosis. Delays in the tuberculosis diagnosis were identified in 54.8% of the patients, and delays in tuberculosis and HIV treatment initiation in 41.8% and 27.4%, respectively. The risk factors associated with delay in tuberculosis diagnosis were age between 15–34 and ≥45 years, and those patients who received tuberculin skin test. The risk factor associated with antiretroviral therapy initiation delay was previously-treated tuberculosis patients after failure. It is necessary to implement strategies for early detection and treatment initiation of HIV and to use rapid test for tuberculosis diagnosis in this population.

The Bewildering Antitubercular Action of Pyrazinamide.

Pyrazinamide (PZA) is a cornerstone antimicrobial drug used exclusively for the treatment of tuberculosis (TB). Due to its ability to shorten drug therapy by 3 months and reduce disease relapse rates, PZA is considered an irreplaceable component of standard first-line short-course therapy for drug-susceptible TB and second-line treatment regimens for multidrug-resistant TB. Despite over 60 years of research on PZA and its crucial role in current and future TB treatment regimens, the mode of action of this unique drug remains unclear. Defining the mode of action for PZA will open new avenues for rational design of novel therapeutic approaches for the treatment of TB. In this review, we discuss the four prevailing models for PZA action, recent developments in modulation of PZA susceptibility and resistance, and outlooks for future research and drug development.

Outcomes of extended duration therapy for drug-susceptible cavitary pulmonary tuberculosis.

BackgroundExtending the continuation phase treatment duration is recommended to improve outcomes of drug-susceptible cavitary pulmonary tuberculosis (TB), but limited data are available on extended treatment outcomes.MethodsWe evaluated outcomes of 67 patients with drug-susceptible cavitary pulmonary TB who had received extended therapy. The primary endpoint of our study was the rate of a favorable outcome (cured or treatment completion without recurrence).ResultsOf the 67 patients, 40 (59.7%) were culture negative and 27 (40.3%) were culture positive two months after treatment initiation. The median treatment duration was 275 days. Extended duration therapy resulted in a 100% treatment success rate and 2.5% recurrence rate in patients with a negative culture at month 2. However, patients with a positive culture at month 2, showed a 74.1% treatment success rate and 8.0% recurrence rate (P<0.001 and P=0.554, respectively). In multivariable analyses, positive culture at month 2 was associated with greater odds of unfavorable outcomes (adjusted OR, 17.04, 95% CI, 1.68–177.92).ConclusionsWhile extending the continuation phase was associated with favorable outcomes in pulmonary TB patients with negative culture at month 2, the same could not be achieved in those with positive culture at month 2, suggesting that this condition might not be overcome by merely extending the continuation phase.

Whole genome sequencing of Mycobacterium tuberculosis isolates and clinical outcomes of patients treated for multidrug-resistant tuberculosis in Tanzania

BackgroundTuberculosis (TB), particularly multi- and or extensive drug resistant TB, is still a global medical emergency. Whole genome sequencing (WGS) is a current alternative to the WHO-approved probe-based methods for TB diagnosis and detection of drug resistance, genetic diversity and transmission dynamics of Mycobacterium tuberculosis complex (MTBC). This study compared WGS and clinical data in participants with TB.ResultsThis cohort study performed WGS on 87 from MTBC DNA isolates, 57 (66%) and 30 (34%) patients with drug resistant and susceptible TB, respectively. Drug resistance was determined by Xpert® MTB/RIF assay and phenotypic culture-based drug-susceptibility-testing (DST). WGS and bioinformatics data that predict phenotypic resistance to anti-TB drugs were compared with participant’s clinical outcomes. They were 47 female participants (54%) and the median age was 35 years (IQR): 29–44). Twenty (23%) and 26 (30%) of participants had TB/HIV co-infection BMI < 18 kg/m2 respectively. MDR-TB participants had MTBC with multiple mutant genes, compared to those with mono or polyresistant TB, and the majority belonged to lineage 3 Central Asian Strain (CAS). Also, MDR-TB was associated with delayed culture-conversion (median: IQR (83: 60–180 vs. 51:30–66) days). WGS had high concordance with both culture-based DST and Xpert® MTB/RIF assay in detecting drug resistance (kappa = 1.00).ConclusionThis study offers comparison of mutations detected by Xpert and WGS with phenotypic DST of M. tuberculosis isolates in Tanzania. The high concordance between the different methods and further insights provided by WGS such as PZA-DST, which is not routinely performed in most resource-limited-settings, provides an avenue for inclusion of WGS into diagnostic matrix of TB including drug-resistant TB.

Population Pharmacokinetics and Dosing of Ethionamide in Children with Tuberculosis.

Ethionamide has proven efficacy against both drug-susceptible and some drug-resistant strains of Mycobacterium tuberculosis Limited information on its pharmacokinetics in children is available, and current doses are extrapolated from weight-based adult doses. Pediatric doses based on more robust evidence are expected to improve antituberculosis treatment, especially in small children. In this analysis, ethionamide concentrations in children from 2 observational clinical studies conducted in Cape Town, South Africa, were pooled. All children received ethionamide once daily at a weight-based dose of approximately 20 mg/kg of body weight (range, 10.4 to 25.3 mg/kg) in combination with other first- or second-line antituberculosis medications and with antiretroviral therapy in cases of HIV coinfection. Pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling. The MDR-PK1 study contributed data for 110 children on treatment for multidrug-resistant tuberculosis, while the DATiC study contributed data for 9 children treated for drug-susceptible tuberculosis. The median age of the children in the studies combined was 2.6 years (range, 0.23 to 15 years), and the median weight was 12.5 kg (range, 2.5 to 66 kg). A one-compartment, transit absorption model with first-order elimination best described ethionamide pharmacokinetics in children. Allometric scaling of clearance (typical value, 8.88 liters/h), the volume of distribution (typical value, 21.4 liters), and maturation of clearance and absorption improved the model fit. HIV coinfection decreased the ethionamide bioavailability by 22%, rifampin coadministration increased clearance by 16%, and ethionamide administration by use of a nasogastric tube increased the rate, but the not extent, of absorption. The developed model was used to predict pediatric doses achieving the same drug exposure achieved in 50- to 70-kg adults receiving 750-mg once-daily dosing. Based on model predictions, we recommend a weight-banded pediatric dosing scheme using scored 125-mg tablets.

New Insights in Design and Development of Antitubercular Drugs

Background: Tuberculosis, an infectious disease caused mainly by the Mycobacterium tuberculosis accounts for the highest number of deaths worldwide. Despite curing millions, the currently used drug regimens are bounded by various limitations such as long course of therapy, emergence of resistance and permanent tissue damage. The treatment of multidrug-resistant and extremely drugresistant tuberculosis is a challenging task due to its reliance on second-line drugs which are less potent and more toxic than those used in the clinical management of drug-susceptible tuberculosis. Therefore, the major challenges in the upcoming years are to overcome the emergence of increased number of multidrug-resistant as well as extensively drug-resistant strains and the ineptness of the current treatment regimens against latent tuberculosis. Bedaquiline and Delamanid are the only new anti-TB drugs that have been currently approved since more than 40 years after discovery of isoniazid. Bedaquiline is the first diarylquinoline derivative that has showed resilient culture conversion at 24 weeks in phase IIb trials. Methods: Extensive literature search on the topic was undergone using a focused question. Results: Fifty-eight research articles from journals of repute are included in the review. The vaccine and peptide-based conjugates are recent developments against Mycobacterium for selective and specific targeting to the desired tissues. Conclusion: In this review, we have focused on the different classes of chemical as well as plant based compounds as potent antitubercular agents against multidrug-resistant tuberculosis strains. This review falls light on the importance of research been undergoing in different parts of the world to combat the ever increasing problem of mycobacterial resistance and the various treatment options available for the treatment of tuberculosis.

The novel potential biomarkers for multidrug-resistance tuberculosis using UPLC-Q-TOF-MS.

The lack of rapid and efficient diagnostics impedes largely the epidemic control of multidrug-resistant tuberculosis, and might misguide the therapeutic strategies as well. This study aimed to identify novel multidrug-resistant tuberculosis biomarkers to improve the early intervention, symptomatic treatment and control of the prevalence of multidrug-resistant tuberculosis. The serum small molecule metabolites in healthy controls, patients with drug-susceptible tuberculosis, and patients with multidrug-resistant tuberculosis were screened using ultra-high-performance liquid chromatography combined with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS). The differentially abundant metabolites were filtered out through multidimensional statistical analysis and bioinformatics analysis. Compared with drug-susceptible tuberculosis patients and healthy controls, the levels of 13 metabolites in multidrug-resistant tuberculosis patients altered. Among them, the most significant changes were found in N1-Methyl-2-pyridone-5-carboxamide (N1M2P5C), 1-Myristoyl-sn-glycerol-3-phosphocholine (MG3P), Caprylic acid (CA), and D-Xylulose (DX). And a multidrug-resistant tuberculosis/drug-susceptible tuberculosis differential diagnostic model was built based on these four metabolites, achieved the accuracy, sensitivity, and specificity of 0.928, 86.7%, and 86.7%, respectively. The enrichment analysis of metabolic pathways showed that the phospholipid remodeling of cell membranes was active in multidrug-resistant tuberculosis patients. In addition, in patients with tuberculosis, the metabolites of dipalmitoyl phosphatidylcholine (DPPC), a major component of pulmonary surfactant, were down-regulated. N1M2P5C, MG3P, CA, and DX may have the potential to serve as novel multidrug-resistant tuberculosis biomarkers. This research provides a preliminary experimental basis to further investigate potential multidrug-resistant tuberculosis biomarkers. Impact statement The MDR-TB incidence remains high, making the effective control of TB epidemic yet challenging. Rapid and accurate diagnosis is vitally important for improving the therapeutic efficacy and controlling the prevalence of drug resistance TB. Metabolomics has dramatic potential to distinguish MDR-TB and DS-TB. N1M2P5C, MG3P, CA, and DX that we identified in this study might have potential as novel MDR-TB biomarkers. The phospholipid remodeling of cell membranes was highly active in MDR-TB. The DPPC metabolites in TB were significantly down-regulated. This work aimed to investigate potential MDR-TB biomarkers to enhance the clinical diagnostic efficacy. The metabolic pathway distinctly altered in MDR-TB might provide novel targets to develop new anti-TB drugs.

Challenge of the Rising Multidrug-Resistant Tuberculosis in China: A Predictive Study Using Markov Modeling

Background: Multidrug-resistant tuberculosis (MDR-TB) is emerging in China. We used a dynamic Markov model to predict the longitudinal trends of MDR-TB in China by 2050, and assess the effects of alternative control measures. Methods Eight states of TB transmission were set up in the Markov model using a hypothetical cohort of 100,000 people. Prevalence of MDR-TB and bacteriological confirmed drug-susceptible TB (DS-TB+) were simulated. MDR-TB was stratified into being treated with the recommended regimen or not. Findings: Under the current China’s TB control conditions, by 2050, prevalence of DS-TB+ could be estimated to decrease to 39 per 100,000 people, a 37·1% reduction from 2019 , whereas MDR-TB would increase by three times to 58/100,000. Furthermore, by the year of 2050, 86·2% of the MDR-TB cases would be left untreated. If the detection rate of MDR-TB could reach 50% or 70% at 5% per year, the decline of MDR-TB prevalence would be 25·9% and 36·2% respectively. If treatment coverage was improved to 70% or 100% by 5% yearly , MDR-TB prevalence in 2050 would gain a reduction of 13·8% and 24·1%, respectively. If both detection rate and treatment coverage could reach 70%, the prevalence of MDR-TB would be reduced to 28/100, 000, a 51·7% reduction by 2050. Interpretation: MDR-TB, especially untreated MDR-TB, would rise rapidly under current MDR-TB control strategies in China. Interventions on promoting effective detection and treatment of MDR-TB are imperative in the fights against MDR-TB epidemics. Funding Statement: The Sweden-China (VR-NSFC) joint project (PI, Biao Xu, 81361138019 and Sven Hoffner, 540-2013-8797). Declaration of Interests: The authors stated: None declared. Ethics Approval Statement: Not required.

4-month moxifloxacin containing regimens in the treatment of patients with sputum-positive pulmonary tuberculosis in South India - a randomised clinical trial.

Shortening tuberculosis (TB) treatment duration is a research priority. We tested the efficacy and safety of 3- and 4-month regimens containing moxifloxacin in a randomised clinical trial in pulmonary TB (PTB) patients in South India. New, sputum-positive, adult, HIV-negative, non-diabetic PTB patients were randomised to 3- or 4-month moxifloxacin regimens [moxifloxacin (M), isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E)] or to a control regimen (2H3 R3 Z3 E3 /4R3 H3 ) [C]. The 4 test regimens were 3R7 H7 Z7 E7 M7 [M3], 2R7 H7 Z7 E7 M7 /2R7 H7 M7 [M4], 2R7 H7 Z7 E7 M7 /2R3 H3 M3 [M4-I] or 2R7 H7 Z7 E7 M7 /2R3 H3 E3 M3 [M4-IE]. Treatment was directly observed. Clinical and bacteriological assessments were done monthly during treatment and for 24months post-treatment. The primary end point was TB recurrence post-treatment. Of 1371 patients, randomised, modified intention-to-treat (ITT) analysis was done in 1329 and per-protocol (PP) analysis in 1223 patients. Regimen M3 was terminated due to high TB recurrence rates. 'Favourable' response at end of treatment was 96-100% in the moxifloxacin regimensand 93% in the control regimen. Among these, the TB recurrence occurred in 4.1% in the M4 regimen and in 4.5% in the control regimen and demonstrated equivalence within a 5% margin (95% CI -3.68, 4.55). Similar findings were observed in modified ITT analysis. The TB recurrence rates in the M4-I and M4-IE regimens did not show equivalence with the control regimen. Sixteen (1.4%) of 1087 patients in the moxifloxacin regimens required treatment modification. The 4-month daily moxifloxacin regimen [M4] was found to be equivalent and as safe as the 6-month thrice-weekly control regimen.

Shortened Tuberculosis Treatment for People with HIV in South Africa. A Model-based Evaluation and Cost-effectiveness Analysis.

Rationale: Recent tuberculosis treatment trials failed to show that some 4-month (4m) regimens were noninferior to conventional 6-month (6m) regimens for a composite clinical outcome. Novel shortened regimens may still have important clinical and economic benefits in populations with high loss to follow-up (LTFU) and in subgroups such as people with human immunodeficiency virus.Objectives: To identify scenarios in which a novel 4m regimen would be preferred to a conventional 6m regimen for treatment of drug-susceptible tuberculosis in people with human immunodeficiency virus in South Africa, in terms of short-term and long-term clinical and economic outcomes.Methods: We used the Cost-Effectiveness of Preventing AIDS Complications-International microsimulation model to project outcomes modeled on participants in the OFLOTUB trial. For calibration purposes, we did a base case analysis by applying trial-informed parameters for the 4m/6m regimens, including monthly LTFU during treatment (0.68%/0.83%), average monthly tuberculosis recurrence (0.65%/0.31%), and monthly drug costs (U.S. dollars [USD]25.90/3.70). We then evaluated different scenarios and 4m regimen characteristics, varying key parameters, including LTFU (informed by observational cohort data), recurrence, and cost. We projected outcomes, including 2-year mortality and life expectancy. We conducted a cost-effectiveness analysis, evaluating the incremental cost-effectiveness ratio of a 4m versus 6m regimen.Results: In the base case model analysis, risk of the composite unfavorable outcome in the 4m/6m groups was 19.8%/15.9%, similar to the trial; projected life expectancies were 22.1/22.3 years. In analyses of alternative scenarios and 4m regimen characteristics, a 4m regimen yielded lower risk of the composite unfavorable outcome than the conventional 6m regimen if LTFU increased to greater than 3.5%/mo or if average recurrence after a 4m regimen decreased to less than 0.45%/mo, and it yielded higher life expectancy if LTFU was greater than 3.5%/mo or if recurrence was less than 0.5%/mo. A 4m regimen was not cost-effective in the base case but became cost-effective (incremental cost-effectiveness ratio <USD940/yr of life saved) in two-way sensitivity analysis; for example, if LTFU was greater than or equal to 5.3%/mo and either average recurrence was less than or equal to 0.5%/mo or drug cost was less than or equal to USD15/mo.Conclusions: A novel shortened tuberculosis treatment regimen could improve outcomes such as survival despite conferring a higher recurrence risk, particularly in settings where LTFU is higher than that seen in recent trials.

Pharmacokinetic Evaluation and Local Tolerability of Dry Powder Amikacin Via the Cyclops™ in Patients With Drug Susceptible Tuberculosis

Pharmacokinetic Evaluation and Local Tolerability of Dry Powder Amikacin Via the Cyclops™ in Patients With Drug Susceptible Tuberculosis

Different macrophage polarization between drug-susceptible and multidrug-resistant pulmonary tuberculosis

BackgroundMacrophages play a key role in the infection process, and alternatively activated macrophages (M2 polarization) play important roles in persistent infection via the immune escape of pathogens. This suggests that immune escape of pathogens from host immunity is an important factor to consider in treatment failure and multidrug-resistant tuberculosis (MDR-TB)/extensively drug-resistant tuberculosis (XDR-TB). In this study, we investigated the association between macrophage polarization and MDR-TB/XDR-TB and the association between macrophage polarization and the anti-TB drugs used.MethodsiNOS and arginase-1, a surface marker of polarized macrophages, were quantified by immunohistochemical staining and imaging analysis of lung tissues of patients who underwent surgical treatment for pulmonary TB. Drug susceptibility/resistance and the type and timing of anti-tuberculosis drugs used were investigated.ResultsThe M2-like polarization rate and the ratio of the M2-like polarization rate to the M1-like polarization rate were significantly higher in the MDR-TB/XDR-TB group than in the DS-TB group. The association between a high M2-like polarization rate and MDR-TB/XDR-TB was more pronounced in patients with a low M1-like polarization rate. Younger age and a higher M2-like polarization rate were independent associated factors for MDR-TB/XDR-TB. The M2-like polarization rate was significantly higher in patients who received anti-TB drugs containing pyrazinamide continuously for 4 or 6 weeks than in those who received anti-TB drugs not containing pyrazinamide.ConclusionsThe M2-like polarization of macrophages is associated with MDR-TB/XDR-TB and anti-TB drug regimens including pyrazinamide or a combination of pyrazinamide, prothionamide and cycloserine.

Pharmacokinetic Modeling, Simulation, and Development of a Limited Sampling Strategy of Cycloserine in Patients with Multidrug-/Extensively Drug-Resistant Tuberculosis.

Multidrug-resistant tuberculosis has much poorer treatment outcomes compared with drug-susceptible tuberculosis because second-line drugs for treating multidrug resistant tuberculosis are less effective and are frequently associated with side effects. Optimization of drug treatment is urgently needed. Cycloserine is a second-line tuberculosis drug with variable pharmacokinetics and thus variable exposure when programmatic doses are used. The objective of this study was to develop a population pharmacokinetic model of cycloserine to assess drug exposure and to develop a limited sampling strategy for cycloserine exposure monitoring. Patients with multidrug-/extensively drug-resistant tuberculosis who were treated for > 7days with cycloserine were eligible for inclusion. Patients received cycloserine 500mg (body weight ≤ 50kg) or 750mg (body weight > 50kg) once daily. MW/Pharm 3.83 (Mediware, Groningen, The Netherlands) was used to parameterize the population pharmacokinetic model. The model was compared with pharmacokinetic values from the literature and evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset. Monte Carlo simulations were used to develop a limited sampling strategy. Cycloserine plasma concentration vs time curves were obtained from 15 hospitalized patients (nine male, six female, median age 35years). Mean dose/kg body weight was 11.5mg/kg (standard deviation 2.04mg/kg). Median area under the concentration-time curve over 24h (AUC0-24h) of cycloserine was 888h mg/L (interquartile range 728-1252h mg/L) and median maximum concentration of cycloserine was 23.31mg/L (interquartile range 20.14-33.30mg/L). The final population pharmacokinetic model consisted of the following pharmacokinetic parameters [mean (standard deviation)]: absorption constant Ka_po of 0.39 (0.31) h-1, distribution over the central compartment (Vd) of 0.54 (0.26) L/kg LBM, renal clearance as fraction of the estimated glomerular filtration rate of 0.092 (0.038), and metabolic clearance of 1.05 (0.75) L/h. The population pharmacokinetic model was successfully evaluated with a bootstrap analysis, Monte Carlo simulation, and an external dataset of Chinese patients (difference of 14.6% and 19.5% in measured and calculated concentrations and AUC0-24h, respectively). Root-mean-squared-errors found in predicting the AUC0-24h using a one- (4h) and a two- (2h and 7h) limited sampling strategy were 1.60% and 0.14%, respectively. This developed population pharmacokinetic model can be used to calculate cycloserine concentrations and exposure in patients with multidrug-/extensively drug-resistant tuberculosis. This model was successfully validated by internal and external validation methods. This study showed that the AUC0-24h of cycloserine can be estimated in patients with multidrug-/extensively drug-resistant tuberculosis using a 1- or 2-point limited sampling strategy in combination with the developed population pharmacokinetic model. This strategy can be used in studies to correlate drug exposure with clinical outcome. This study also showed that good target attainment rates, expressed by time above the minimal inhibitory concentration, were obtained for cycloserine with a minimal inhibitory concentration of 5 and 10mg/L, but low rates with a minimal inhibitory concentration of 20 and 32.5mg/L.

High-dose rifapentine with or without moxifloxacin for shortening treatment of pulmonary tuberculosis: Study protocol for TBTC study 31/ACTG A5349 phase 3 clinical trial

IntroductionPhase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen. Methods/DesignS31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority. DiscussionThis phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels.Trial registration:NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1

A Partially-Randomised Phase 3 Trial of Pretomanid, Moxifloxacin and Pyrazinamide in Combination for the Treatment of Drug-Susceptible and Drug-Resistant Pulmonary Tuberculosis

Background: Tuberculosis (TB) is a leading infectious cause of death globally. Current treatment for drug-susceptible (DS-TB) and rifampicin-resistant (RR-TB) infections is lengthy and toxic. Methods: The STAND trial was a partially-randomised, open-label, non-inferiority phase 3 study. Patients ≥18 years with smear positive sputum were eligible. HIV-positive patients with CD4+ counts <100 cells/mm3 were excluded. DS-TB participants were randomised 1:1:1:1 to receive: 200mg pretomanid (P) daily, 400mg moxifloxacin (M) and 1500mg pyrazinamide (Z) for either 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) in combination for 6 months as control. The primary outcome was treatment failure or relapse 12 months after randomisation. The non-inferiority margin for between-group differences was 12 percent. RR-TB participants were allocated to 6Pa200MZ. Recruitment was paused in September 2015 and did not resume. Findings: In total 43 of 56 (76.8%), 46 of 61 (75.4%), 38 of 57 (66.7%), and 52 of 60 (86.7%) DS-TB participants were favourable on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ, and control respectively. The difference in favourable response between control and 6Pa200MZ was 9.9% [95%CI -4.1 to 23.9%]. Ten of 11 (90.9%) RR-TB participants were favourable. Grade 3 or higher adverse events affected 22 of 67 (32.8%) 6Pa200MZ participants, 21 of 71 (29.6%) on 4Pa200MZ, 25 of 65 (38.5%) on 4Pa100MZ, and 19 of 68 (27.9%) on control. Serious adverse events affected 19 of 203 (9.4%) experimental DS-TB participants, 3 of 68 (4.4%) on control, and 3 of 13 (23.1%) RR-TB cases. Ten of 203 (5%) participants on the experimental arms and 2 of 68 (3%) participants on the control arm died, with 2 deaths on the 4MPa200Z arm and one death on the 4MPa100Z arm attributed to hepatotoxicity. Interpretation: The experimental DS-TB treatment did not achieve non-inferiority in this underpowered trial. The role of Pa200MZ in tuberculosis treatment needs to be investigated further. Trial Registration: (Clinicaltrials.gov identifier NCT02342886) Funding Statement: Sponsored by TB Alliance with financial support from the U.K. Department for International Development, Bill and Melinda Gates Foundation, U.S. Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and the Federal Ministry for Education and Research of Germany. Declaration of Interests: The authors declared no conflicts of interest. Ethics Approval Statement: Ethical approval was granted by the national and local ethics committees for the sites participating in the trial.

The pattern of comorbidity and its prevalence among drug-resistant tuberculosis patients at treatment initiation in Lagos, Nigeria.

Multimorbidity is increasingly being recognized as a serious public health concern in the control of both drug-susceptible and drug-resistant tuberculosis (DR-TB). This study assessed the pattern of comorbidities and their prevalence in DR-TB patients at treatment initiation in Lagos, Nigeria. A cross-sectional study was conducted. The baseline laboratory records (human immunodeficiency virus [HIV] status, fasting blood sugar, audiometry, thyroid function tests, serum electrolyte, haemoglobin level and pregnancy test) of DR-TB patients initiated on treatment in Lagos, Nigeria between 1 August 2014 and 31 March 2017 were reviewed. A total of 565 DR-TB patients' laboratory records were reviewed, of which 397 (70.3%) had comorbidities. The proportion with one, two, three and four comorbidities was 60.2%, 29.7%, 8.1% and 2.0%, respectively. Anaemia was the most common (48.1%) comorbid condition, while anaemia and hypokalaemia (7.3%), anaemia and hypothyroidism (6.5%) and anaemia and HIV (5%) were most common among patients with more than one comorbid condition. DR-TB patients with comorbidity were significantly older (34.8±12.3y) than those without comorbidity (32.0±12.8y) (p=0.038). Of the 176 females in the reproductive age group, 8 (4.5%) were pregnant at baseline. The prevalence of comorbidity among DR-TB patients was high. There is a need for the national TB program to expand its DR-TB council of experts and also integrate reproductive health services into DR-TB management in Nigeria.

Cost-effectiveness of a Pharmacogenomic Test for Stratified Isoniazid Dosing in Treatment of Active Tuberculosis.

BackgroundThere is marked interindividual variability in metabolism and resulting toxicity and effectiveness of drugs used for tuberculosis treatment. For isoniazid, mutations in the N-acetyltransferase 2 (NAT2) gene explain >88% of pharmacokinetic variability. However, weight-based dosing remains the norm globally. The potential clinical impact and cost-effectiveness of pharmacogenomic-guided therapy (PGT) are unknown.MethodsWe constructed a decision tree model to project lifetime costs and benefits of isoniazid PGT for drug-susceptible tuberculosis in Brazil, South Africa, and India. PGT was modeled to reduce isoniazid toxicity among slow NAT2 acetylators and reduce treatment failure among rapid acetylators. The genotyping test was assumed to cost the same as the GeneXpert test. The main outcomes were costs (2018 US dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios.ResultsIn Brazil, PGT gained 19 discounted life-years (23 QALYs) and cost $11 064 per 1000 patients, a value of $476 per QALY gained. In South Africa, PGT gained 15 life-years (19 QALYs) and cost $33 182 per 1000 patients, a value of $1780 per QALY gained. In India, PGT gained 20 life-years (24 QALYs) and cost $13 195 per 1000 patients, a value of $546 per QALY gained. One-way sensitivity analyses showed the cost-effectiveness to be robust to all input parameters. Probabilistic sensitivity analyses were below per capita gross domestic product in all 3 countries in 99% of simulations.ConclusionsIsoniazid PGT improves health outcomes and would be cost-effective in the treatment of drug-susceptible tuberculosis in Brazil, South Africa, and India.

Unfavourable treatment outcomes in tuberculosis patients with different vitamin D status and blood glucose levels in a programme setting in China.

Tuberculosis (TB) treatment success rates are high in China, but there are still a considerable number of cases who have unfavourable treatment outcomes (UTO). We aimed to determine the proportion of TB patients with UTO and to assess whether baseline characteristics that included glycaemic status [normal fasting blood glucose (FBG), transient hyperglycaemia and diabetes mellitus (DM)] and vitamin D status were associated with UTO. Prospective cohort study conducted between November 2015 and July 2016 at six clinics within routine TB services in Jilin province, where persons with TB were consecutively recruited. Data analysis was performed using the chi-squared test and multivariate logistic regression. Of the306 recruited TB patients, 96 (31.4%) had smear-positive pulmonary TB, 187 (61.1%) had smear-negative pulmonary TB and 23 (7.5%) had extrapulmonary TB (EPTB). Of these, 95 (31.1%) had normal blood glucose, 83 (27.1%) had transient hyperglycaemia and 128 (41.8%) had DM. 227 (74.2%) patients had vitamin D deficiency/severe deficiency. There were 125 (40.8%) patients with UTO of whom the majority were lost to follow-up (57.6%) or not evaluated (28.8%). UTO was significantly associated with smear-negative pulmonary TB (P=0.009), EPTB (P<0.001) and DM (P=0.007). The proportion of TB patients with UTO increased with smear-negative pulmonary TB, EPTB and DM. TB programmes need to pay more attention to these issues and ensure intensive patient support to those at risk and early detection of DM.

Enhanced tuberculosis clearance through the combination treatment with recombinant adenovirus-mediated granulysin delivery

Rationale: Tuberculosis (TB) remains the leading cause of death among infectious diseases worldwide. Poor compliance of TB patients to the lengthy treatment increases the risk of relapse and leads to the emergence of multidrug-resistant and extensively drug-resistant TB (MDR-TB and XDR-TB). More effective therapies for TB are urgently needed. We hypothesized that granulysin-mediated clearance of M. tuberculosis parasited inside and outside of alveolar macrophages in presumptive infected hosts might enhance the chemotherapeutic efficacy on TB.Methods: Recombinant adenovirus type 5 (rAd5) based therapeutic vaccines rAdhGLi and rAdhGLs (rAds) were respectively developed to express intracellular and extracellular granulysin. The ex vivo bactericidal effects of rAdhGLi and rAdhGLs were evaluated on U937 and RAW264.7 cells. The efficacy of immunotherapy with both rAdhGLi and rAdhGLs on TB SCID mice, or immunotherapy combined with chemotherapy on drug-susceptible TB or MDR-TB mouse models were further evaluated.Results: rAdhGLs, as well as rAdhGLi, showed a direct bactericidal effect on extracellular or intracellular M. tuberculosis H37Rv and MDR-TB clinical strains, respectively. Immunotherapy with a dose of 109 PFU of rAdhGLi and 109 PFU of rAdhGLs demonstrated a more significant bactericidal effect on M. tuberculosis H37Rv infected SCID mice and prolonged their survival periods than rAdhGLi or rAdhGLs alone. More importantly, chemotherapy combined with rAds immunotherapy shortened the chemotherapeutic duration to 4 months on M. tuberculosis H37Rv infected mice and prevented the relapse. Combination of rAds with chemotherapy on MDR-TB mice also more significantly decreased organ bacterial load than their single use.Conclusions: Delivery of granulysin by recombinant adenovirus to the infected lung could enhance the clearance of TB in vivo and might be a promising adjunct therapeutic vaccine for TB and MDR-TB.