Concept: Multi-drug-resistant tuberculosis
Treatment of multidrug-resistant tuberculosis (MDR-TB) is complex, lengthy, and involves a minimum of four drugs termed a background regimen (BR), that have not previously been prescribed or that have proven susceptible to patient sputum culture isolates. In recent years, promising new treatment options have emerged as add-on therapies to a BR. The aim of this study was to evaluate the long-term costs and effectiveness of adding the novel or group 5 interventions bedaquiline, delamanid, and linezolid to a background regimen (BR) of drugs for the treatment of adult patients with pulmonary multidrug-resistant tuberculosis (MDR-TB), within their marketing authorisations, from a German healthcare cost-effectiveness perspective.
The treatment of multidrug-resistant tuberculosis (MDR-TB) is currently based upon expert opinion and findings from case series, rather than upon randomised clinical trials (RCTs).
It is often necessary to include WHO Group 5 drugs in the treatment of extensively drug-resistant TB (XDR-TB) and fluoroquinolone-resistant multidrug-resistant tuberculosis (MDR-TB). As clinical evidence about use of Group 5 drugs is scarce, we conducted a systematic review using published individual patient data. We searched PubMed and OvidSP through 7 April 2013 for publications in English to assemble a cohort with fluoroquinolone-resistant MDR-TB treated with Group 5 drugs. Favorable outcome was defined as sputum culture conversion, cure, or treatment completion in the absence of death, default, treatment failure, or relapse. A cohort of 194 patients was assembled from 20 articles involving 12 geographical regions. In descending order of frequency, linezolid was used in 162 (84%), macrolides in 84 (43%), clofazimine in 65 (34%), amoxicillin with clavulanate in 56 (29%), thioridazine in 18 (9%), carbapenem in 16 (8%), and high-dose isoniazid in 16 (8%). Cohort analysis with robust Poisson regression models and random-effects meta-analysis similarly suggested that linezolid use significantly increased the probability (95% confidence interval) of favorable outcome by 57% (10%, 124%) and 55% (10%, 121%), respectively. Defining significant associations by risk ratios ≥ 1.2 or ≤ 0.9, neither cohort analysis nor meta-analysis demonstrated any significant add-on benefit from the use of other Group 5 drugs on outcome of patients treated with linezolid, although selection bias might have underestimated their effects. Our findings substantiated use of linezolid in the treatment of XDR-TB or fluoroquinolone-resistant MDR-TB, and calls for further studies to evaluate the roles of other Group 5 drugs.
The “fitness” of an infectious pathogen is defined as the ability of the pathogen to survive, reproduce, be transmitted, and cause disease. The fitness of multidrug-resistant tuberculosis (MDRTB) relative to drug-susceptible tuberculosis is cited as one of the most important determinants of MDRTB spread and epidemic size. To estimate the relative fitness of drug-resistant tuberculosis cases, we compared the incidence of tuberculosis disease among the household contacts of MDRTB index patients to that among the contacts of drug-susceptible index patients.
For treating multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recommends a regimen of at least four second-line drugs that are likely to be effective as well as pyrazinamide. WHO guidelines indicate only marginal benefit for regimens based directly on drug susceptibility testing (DST) results. Recent evidence from isolated cohorts suggests that regimens containing more drugs may be beneficial, and that DST results are predictive of regimen effectiveness. The objective of our study was to gain insight into how regimen design affects treatment response by analyzing the association between time to sputum culture conversion and both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen.
Owing toGiven the high costs of drugs to treat multi-drug resistant tuberculosis (MDR-TB), the Green Light Committee (GLC) initiative enables TB programs to procure quality-assured drugs at reduced prices. Despite price reductions, internationally quality assured (IQA) drugs can be more expensive than locally procured drugs. There is little evidence to inform decision-makers about whether IQA drugs are more effective than local drugs. This is the first study to compare outcomes between MDR-TB patients treated using IQA, and locally procured drugs in the same hospitals during the same time period.
Kevin Cain and colleagues reflect on the cross border movement of people from Somalia with MDR-TB and the implications for MDR-TB programs in East Africa.
BACKGROUND: 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. METHODS AND FINDINGS: 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]). CONCLUSIONS: 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.
To estimate prevalence of multidrug-resistant tuberculosis (MDR TB) in Harare, Zimbabwe, in 2012, we performed microbiologic testing on acid-fast bacilli smear-positive sputum samples from patients previously treated for TB. Twenty (24%) of 84 specimens were consistent with MDR TB. A national drug-resistance survey is needed to determine MDR TB prevalence in Zimbabwe.
Rapid progress has been made in the development of new diagnostic assays for tuberculosis in recent years. New technologies have been developed and assessed, and are now being implemented. The Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis (MTB) and rifampicin (RIF) resistance, was endorsed by WHO in December, 2010. This assay was specifically recommended for use as the initial diagnostic test for suspected drug-resistant or HIV-associated pulmonary tuberculosis. By June, 2012, two-thirds of countries with a high tuberculosis burden and half of countries with a high multidrug-resistant tuberculosis burden had incorporated the assay into their national tuberculosis programme guidelines. Although the development of the Xpert MTB/RIF assay is undoubtedly a landmark event, clinical and programmatic effects and cost-effectiveness remain to be defined. We review the rapidly growing body of scientific literature and discuss the advantages and challenges of using the Xpert MTB/RIF assay in areas where tuberculosis is endemic. We also review other prospects within the developmental pipeline. A rapid, accurate point-of-care diagnostic test that is affordable and can be readily implemented is urgently needed. Investment in the tuberculosis diagnostics pipeline should remain a major priority for funders and researchers.