WHO target product profiles for TB preventive treatment.

BACKGROUND: The WHO has developed target product profiles (TPPs) describing the most appropriate qualities for future TPT regimens to assist developers in aligning the characteristics of new treatments with programmatic requirements.METHODS: A technical consultation group was convened by the WHO to determine regimen attributes with greatest potential impact for patients (i.e., improved risk/benefit profile) and populations (i.e., reduction in transmission and TB prevalence). The group categorised regimen attributes as 'priority´ or 'desirable´; and defined for each attribute the minimum requirements and optimal targets.RESULTS: Nine priority attributes were defined, including efficacy, treatment duration, safety, drug-drug interactions, barrier to emergence of drug resistance, target population, formulation, dosage, frequency and route of administration, stability and shelf life. Regimens meeting optimal targets were characterised, for example, as having superior efficacy, treatment duration of ≤2 weeks, and improved tolerability and safety profile compared with current regimens. The four desirable attributes included regimen cost, safety in special populations, treatment adherence and need for drug susceptibility testing in the index patient.DISCUSSION: It may be difficult for a single regimen to satisfy all characteristics so regimen developers may have to consider trade-offs. Additional operational aspects may be relevant to the feasibility and public health impact of new TPT regimens.

TB preventive treatment in high- and intermediate-incidence countries: research needs for scale-up.

BACKGROUND: In 2018, the WHO Member States committed to providing TB preventive treatment (TPT) to at least 30 million people by 2022. However, only 6.3 million people had initiated TPT by the end of 2019. Major knowledge gaps and research needs in diagnosis, treatment and the programmatic management of TPT (PMTPT) require to be addressed urgently.METHODS: In September 2019, a group of stakeholders involved in PMTPT in high TB burden countries met to develop an action agenda to support the global expansion of PMTPT.RESULTS: Barriers at the health system level, and priorities for research to overcome these, were identified for each step of the PMTPT cascade. The need for data on TPT financing, gaps and coverage under national health insurance schemes, as well as the need for mathematical and cost-effectiveness modelling of the impact of TPT on TB incidence and mortality were highlighted. Specific research needs were identified for high-risk populations such as household contacts of any age and people living with HIV, as well as other people at risk.CONCLUSIONS: The meeting facilitated agreement on a set of actions needed to ensure that PMTPT continues to expand to achieve the End TB Strategy targets.

Urgent need to address the slow scale-up of TB preventive treatment in the WHO South-East Asia Region.

In September 2018, all countries made a commitment at the first ever United Nations High-Level Meeting (UNHLM) on TB, to provide TB preventive treatment (TPT) to at least 30 million people at high-risk of TB disease between 2018 and 2022. In the WHO South-East Asia Region (SEA Region), which accounts for 44% of the global TB burden, only 1.2 million high-risk individuals (household contacts and people living with HIV) were provided TPT (11% of the 10.8 million regional UNHLM TPT target) in 2018 and 2019. By 2020, almost all 11 countries of the SEA Region had revised their policies on TPT target groups and criteria to assess TPT eligibility, and had adopted at least one shorter TPT regimen recommended in the latest WHO TPT guidelines. The major challenges for TPT scale-up in the SEA Region are resource shortages, knowledge and service delivery/uptake gaps among providers and service recipients, and the lack of adequate quantities of rifapentine for use in shorter TPT regimens. There are several regional opportunities to address these gaps and countries of the SEA Region must make use of these opportunities to scale up TPT services rapidly to reduce the TB burden in the SEA Region.

The impact of didactic read-aloud action cards on the performance of cannula cricothyroidotomy in a simulated 'can't intubate can't oxygenate' scenario.

Significant benefits have been demonstrated with the use of peri-operative checklists. We assessed whether a read-aloud didactic action card would improve performance of cannula cricothyroidotomy in a simulated 'can't intubate, can't oxygenate' scenario. A 17-step action card was devised by an expert panel. Participants in their first 4 years of anaesthetic training were randomly assigned into 'no-card' or 'card' groups. Scenarios were video-recorded for analysis. Fifty-three participants (27 no-card and 26 card) completed the scenario. The number of steps omitted was mean (SD) 6.7 (2.0) in the no-card group vs. 0.3 (0.5); p < 0.001 in the card group, but the no-card group was faster to oxygenation by mean (95% CI) 35.4 (6.6-64.2) s. The Kappa statistic was 0.84 (0.73-0.95). Our study demonstrated that action cards are beneficial in achieving successful front-of-neck access using a cannula cricothyroidotomy technique. Further investigation is required to determine this tool's effectiveness in other front-of-neck access situations, and its role in teaching or clinical management.

Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Poor treatment outcomes among multidrug-resistant tuberculosis patients in Gomel Region, Republic of Belarus.

SETTINGS: Tuberculosis (TB) health facilities in the Gomel Region, Republic of Belarus-settings with a high burden of multidrug-resistant TB (MDR-TB) and human immunodeficiency virus (HIV) infection. OBJECTIVE: To determine treatment outcomes among MDR-TB patients diagnosed in 2009-2010 and factors associated with unsuccessful outcomes (death, failure and loss to follow-up). DESIGN: Retrospective cohort study involving a review of an electronic patient database maintained under the National Tuberculosis Control Programme. RESULTS: Of 517 patients diagnosed, 78 (15%) did not start treatment. Among 439 patients who started treatment (84% males, median age 45 years, 15% HIV-infected), 291 (66%) had unsuccessful outcomes (35% deaths, 18% treatment failure and 13% lost to follow-up). Multivariate regression analysis showed that patients aged ⩾45 years (aRR 1.2, 95%CI 1.1-1.3), HIV-infected patients and those not receiving antiretroviral therapy (ART) (aRR 1.5, 95%CI 1.4-1.6) and those with a previous history of anti-tuberculosis treatment (aRR 1.2, 95%CI 1.1-1.4) had significantly higher risk of unsuccessful outcomes. CONCLUSION: Treatment outcomes among MDR-TB patients were poor, with high rates of death, failure and loss to follow-up (including pre-treatment loss to follow-up). Urgent measures to increase ART uptake among HIV-infected MDR-TB patients, improved access to second-line anti-tuberculosis drug susceptibility testing and comprehensive patient support measures are required to address this grim situation.

Multidrug-resistant tuberculosis in Uzbekistan: results of a nationwide survey, 2010 to 2011.

Multidrug-resistant tuberculosis (MDR-TB; resistance to at least rifampicin and isoniazid) is a global public health concern. In 2010­2011, Uzbekistan, in central Asia, conducted its first countrywide survey to determine the prevalence of MDR-TB among TB patients. The proportion of MDR-TB among new and previously treated TB patients throughout the country was measured and risk factors for MDR-TB explored. A total of 1,037 patients were included. MDR-TB was detected in 165 treatment-naïve (23.2%; 95% confidence interval (CI) 17.8%­29.5%) and 207 previously treated (62.0%; 95% CI: 52.5%­70.7%) patients. In 5.3% (95% CI: 3.1%­8.4%) of MDR-TB cases, resistance to fluoroquinolones and second-line injectable drugs (extensively drug resistant TB; XDR-TB) was detected. MDR-TB was significantly associated with age under 45 years (adjusted odds ratio: 2.24; 95% CI: 1.45­3.45), imprisonment (1.93; 95% CI: 1.01­3.70), previous treatment (4.45; 95% CI: 2.66­7.43), and not owning a home (1.79; 95% CI: 1.01­3.16). MDR-TB estimates for Uzbekistan are among the highest reported in former Soviet Union countries. Efforts to diagnose, treat and prevent spread of MDR-TB need scaling up.

Multidrug resistance in new tuberculosis patients: burden and implications.

In 2010, 30 countries with anti-tuberculosis drug resistance surveillance data were each estimated to have more than 700 multidrug-resistant tuberculosis (MDR-TB) cases among their notified TB cases. New TB patients comprised a median of 54% (interquartile range 45-67) of the MDR-TB cases. The occurrence of MDR-TB in a new TB patient is a warning sign that MDR-TB is spreading in a community. While MDR-TB case-finding efforts should first prioritize previously treated patients, reaching universal access requires rapidly adding other risk groups, and then all new TB patients. Epidemiological data as presented in this paper can help inform country scale-up plans.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.

The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2-0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6-2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Predictors of sputum culture conversion among patients treated for multidrug-resistant tuberculosis.

OBJECTIVE: To identify predictors of initial sputum culture conversion, estimate the usefulness of persistent positive cultures at different time points in predicting treatment failure, and evaluate different definitions of culture conversion for predicting failure among patients with multidrug-resistant tuberculosis (MDR-TB) in five countries, 2000-2004. METHODS: Predictors of time to conversion were identified using multivariate Cox proportional hazards regression modeling. Receiver operating characteristic curves were plotted to visualize the effect of using different definitions of 'culture conversion' on the balance between sensitivity and specificity. RESULTS: Overall, 1209/1416 (85%) of patients with baseline positive cultures converted in a median of 3.0 months (interquartile range 2.0-5.0). Independent predictors of less likely conversion included baseline positive smear (hazard ratio [HR] 0.60, 95%CI 0.53-0.68), resistance to pyrazinamide (HR 0.82, 95%CI 0.70-0.96), fluoroquinolones (FQs; HR 0.65, 95%CI 0.51-0.83) or thioamide (HR 0.83, 95%CI 0.71-0.96), previous use of FQs (HR 0.71, 95%CI 0.60-0.83), poor outcome of previous anti-tuberculosis treatment (HR 0.69, 95%CI 0.54-0.88) and alcoholism (HR 0.74, 95%CI 0.63-0.87). The maximum combined sensitivity (84%) and specificity (94%) in predicting treatment failure was based on lack of culture conversion at month 9 of treatment, assuming conversion is defined as five consecutive negative cultures. CONCLUSION: Patients with identified risk factors were less likely to achieve sputum culture conversion during MDR-TB treatment.

The impact and cost-effectiveness of strategies to detect drug-resistant tuberculosis.

Drug-resistant tuberculosis (TB) is a serious emerging problem in many low-resource countries. TB control programmes are uncertain of which drug susceptibility tests (DSTs) to use and when to test patients. We predicted the potential cost-effectiveness of different DST strategies, in settings with varying prevalence of drug resistance. Using decision analysis, we assessed the cost-effectiveness of conventional and rapid DSTs for previously diagnosed smear-positive TB cases. Five different time-points were considered for administering DSTs. Different initial drug resistance and HIV scenarios were also considered. All DST scenarios in the wide range of settings considered were found to be cost-effective. The strategy of performing a rapid DST that detects any form of isoniazid (INH) and rifampicin (RIF) resistance for all patients before the initiation of treatment was predicted to be the most cost-effective strategy. In a setting with moderate drug resistance, the cost per disability-adjusted life year gained was as low as US$744. Our findings support the roll-out of rapid drug susceptibility testing at the moment of diagnosis to detect any form of INH and RIF resistance in all countries with moderate or greater burdens of drug-resistant TB.

Frequency and type of microbiological monitoring of multidrug-resistant tuberculosis treatment.

Monthly culture is usually recommended to monitor treatment of multidrug-resistant tuberculosis (MDR-TB). As mycobacterial laboratory capacity is limited in many settings, TB programs need evidence to decide whether monthly cultures are necessary compared to other approaches. We simulated three alternative monitoring strategies (culture every 2 or 3 months, and monthly smears alone) in a cohort of MDR-TB patients in Estonia, Latvia, Philippines, Russia and Peru from 2000 to 2004. This retrospective analysis illustrated that less frequent testing delays confirmation of bacteriological conversion. This would prolong intensive treatment, hospitalization and respiratory isolation, increasing cost and toxicity. After conversion, less frequent testing could delay diagnosis of possible treatment failure.

WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update.

The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting ≥ 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens.