Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and ...duration of treatment with those drugs in patients with multidrug-resistant tuberculosis.
In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion success, failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration.
Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (–0·20, –0·23 to –0·16), levofloxacin (–0·06, –0·09 to –0·04), moxifloxacin (–0·07, –0·10 to –0·04), or bedaquiline (–0·14, –0·19 to –0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses.
Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition.
American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.
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Highlights • Tuberculosis (TB) and multidrug-resistant (MDR)-TB prevention and control are major global health priorities among the communicable diseases. • There are major challenges in TB, MDR-TB, ...and TB/HIV prevention and control in the penitentiary services (prisons). • The authors present the challenges, gaps, and next steps to address these challenges from the perspective of the recently introduced post-2015 End TB Strategy. • The focus of past research has rarely been on the most at-risk populations, such as prisoners, as these neglected populations are more sensitive to research ethics. The authors call for further research with a focus on prisons.
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Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on ...outcomes of the type, number, and duration of drugs used to treat MDR-TB.
Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio aOR: 2.5 95% CI 1.1-6.0), ofloxacin (aOR: 2.5 1.6-3.9), ethionamide or prothionamide (aOR: 1.7 1.3-2.3), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 1.3-3.9), and three or more likely effective drugs in the continuation phase (aOR: 2.7 1.7-4.1). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 1.7-4.3), ofloxacin (aOR: 2.3 1.3-3.8), ethionamide or prothionamide (aOR: 1.7 1.4-2.1), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 1.9-3.9), and three or more likely effective drugs in the continuation phase (aOR: 4.5 3.4-6.0).
In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary.
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•WHO recommends countries monitor the safety profile of new drugs and regimens.•WHO developed the active TB drug safety monitoring and management (aDSM) package.•aDSM data are not yet available ...globally.•A project to prove aDSM feasibility was launched by the Global Tuberculosis Network; 41 centres in 27 countries participated.•309 cases were fully reported as of February 2019 out of 781 cases countries committed to report in 2019.
The World Health Organization launched a global initiative, known as aDSM (active TB drug safety monitoring and management) to better describe the safety profile of new treatment regimens for drug-resistant tuberculosis (TB) in real-world settings. However, comprehensive surveillance is difficult to implement in several countries.
The aim of the aDSM project is to demonstrate the feasibility of implementing national aDSM registers and to describe the type and the frequency of adverse events (AEs) associated with exposure to the new anti-TB drugs.
Following a pilot study carried out in 2016, official involvement of TB reference centres/countries into the project was sought and cases treated with bedaquiline- and/or delamanid-containing regimens were consecutively recruited. AEs were prospectively collected ensuring potential attribution of the AE to a specific drug based on its known safety profile.
A total of 309 cases were fully reported from 41 centres in 27 countries (65% males; 268 treated with bedaquiline, 20 with delamanid, and 21 with both drugs) out of an estimated 781 cases the participating countries had committed to report by the first quarter of 2019.
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WHO estimates that 9 million people developed active tuberculosis in 2013 and 1·5 million people died from it. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis continue to ...spread worldwide with an estimated 480,000 new cases in 2013. Treatment success rates of MDR and XDR tuberculosis are still low and development of new, more effective tuberculosis drugs and adjunct therapies to improve treatment outcomes are urgently needed. Although standard therapy for drug-sensitive tuberculosis is highly effective, shorter, more effective treatment regimens are needed to reduce the burden of infectious cases. We review the latest WHO guidelines and global recommendations for treatment and management of drug-sensitive and drug-resistant tuberculosis, and provide an update on new drug development, results of several phase 2 and phase 3 tuberculosis treatment trials, and other emerging adjunct therapeutic options for MDR and XDR tuberculosis. The use of fluoroquinolone-containing (moxifloxacin and gatifloxacin) regimens have failed to shorten duration of therapy, and the new tuberculosis drug pipeline is sparse. Scale-up of existing interventions with increased investments into tuberculosis health services, development of new antituberculosis drugs, adjunct therapies and vaccines, coupled with visionary political leadership, are still our best chance to change the unacceptable status quo of the tuberculosis situation worldwide and the growing problem of drug-resistant tuberculosis.
...in countries/settings where a formal system of consultation does not exist, specialized staff from MDR-TB reference centres or international organizations usually spend a considerable amount of ...their working time responding to phone or e-mail clinical queries on how to manage M/XDR-TB cases. The vulnerable patient population includes those with chronic lung disease (chronic obstructive pulmonary disease, bronchiectasis and cystic fibrosis) and survivors of previous TB infection among others. ...the ERS/WHO TB Consilium represents an effective instrument to support the WHO End TB Strategy and TB elimination14,15.
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More than 22,000 people attended the 2010 European Respiratory Society conference. Numerous scientific sessions discussed TB themes (e.g., European and global epidemiology, management of ...drug-resistant TB, TB in vulnerable populations, and bacteriological and immunological diagnosis). In particular, several authors emphasized the increasing trend of TB in Europe, highlighting the need for public health programs focused on vulnerable populations: frequently, these populations are infected with drug-resistant strains and their clinical and treatment outcomes could be poor, with the consequence of increasing the risk of ongoing mycobacterial transmission. Other interesting reports were focused on IFN- release assays, which show a good diagnostic performance in different clinical conditions, even though their role needs to be clarified in well-designed analytic studies.
The World Health Organization (WHO) recommends that countries implement pharmacovigilance and collect information on active drug safety monitoring (aDSM) and management of adverse events.The aim of ...this prospective study was to evaluate the frequency and severity of adverse events to anti-tuberculosis (TB) drugs in a cohort of consecutive TB patients treated with new (
bedaquiline, delamanid) and repurposed (
clofazimine, linezolid) drugs, based on the WHO aDSM project. Adverse events were collected prospectively after attribution to a specific drug together with demographic, bacteriological, radiological and clinical information at diagnosis and during therapy. This interim analysis included patients who completed or were still on treatment at time of data collection.Globally, 45 centres from 26 countries/regions reported 658 patients (68.7% male, 4.4% HIV co-infected) treated as follows: 87.7% with bedaquiline, 18.4% with delamanid (6.1% with both), 81.5% with linezolid and 32.4% with clofazimine. Overall, 504 adverse event episodes were reported: 447 (88.7%) were classified as minor (grade 1-2) and 57 (11.3%) as serious (grade 3-5). The majority of the 57 serious adverse events reported by 55 patients (51 out of 57, 89.5%) ultimately resolved. Among patients reporting serious adverse events, some drugs held responsible were discontinued: bedaquiline in 0.35% (two out of 577), delamanid in 0.8% (one out of 121), linezolid in 1.9% (10 out of 536) and clofazimine in 1.4% (three out of 213) of patients. Serious adverse events were reported in 6.9% (nine out of 131) of patients treated with amikacin, 0.4% (one out of 221) with ethionamide/prothionamide, 2.8% (15 out of 536) with linezolid and 1.8% (eight out of 498) with cycloserine/terizidone.The aDSM study provided valuable information, but implementation needs scaling-up to support patient-centred care.
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