Performance-based technical support for drug-resistant TB responses: lessons from the Green Light Committee.

Drug-resistant tuberculosis (DR-TB) constitutes a global threat and a major contributor to deaths related to antimicrobial resistance. Despite progress in DR-TB detection and treatment over the last decade, huge gaps remain in treatment coverage, access to quality care and treatment outcome. Global Fund investments have been critical to scaling up the existing and new diagnostic tools, treatment coverage and people-centred service delivery. The United Nations General Assembly (UNGA) high-level meeting represents unprecedented opportunities to accelerate towards addressing DR-TB. Established in 2000 and funded by the Global Fund since 2009, the Green Light Committee (GLC) mechanism has evolved from project approval to providing demand-based technical assistance to countries to scale up response to DR-TB based on their need and priorities. Lessons learnt from the GLC mechanism over 10 years demonstrate that a result-based, systematic and accountable technical assistance model to support scale-up of DR-TB response is critically important. Meeting the UNGA declaration targets requires major scale-up of current efforts and new tools, and hence the need for predictable, consistent and sustained technical support to countries, including through the regional GLC mechanism. The application of the principles and processes of this model could be adapted and replicated to design a similar performance-based and quality-assured technical support mechanism.

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

The background and rationale for a new fixed-dose combination for first-line treatment of tuberculosis in children.

In 2010, the World Health Organization revised the recommendations for the treatment of tuberculosis (TB) in children. The major revision was to increase isoniazid, rifampicin and pyrazinamide dosages according to body weight in children. The recommendations for higher dosages are based on consistent evidence from 1) pharmacokinetic studies suggesting that young children require higher dosages than adolescents and adults to achieve desired serum concentrations; and 2) observational studies reporting that the higher dosages would not be associated with increased risk of toxicity in children. However, national tuberculosis programmes faced unforeseen challenges in implementing the revised recommendations. The main difficulty was to adapt the revised dosages for the treatment of children with drug-susceptible TB using available fixed-dose combinations (FDCs). A more suitable FDC for the intensive and continuation phases of treatment has now been developed for planned implementation in 2015. This paper explains the background and rationale for the development of a new FDC tablet for children with drug-susceptible TB.

Adoption of revised dosage recommendations for childhood tuberculosis in countries with different childhood tuberculosis burdens.

BACKGROUND AND OBJECTIVE: In 2010, the World Health Organization (WHO) published revised dosage recommendations for the treatment of tuberculosis (TB) in children. The aim of the survey was to assess whether countries adopt these new dosage recommendations, as well as to identify challenges in the management and treatment of childhood TB. In addition, countries were asked to provide 2010 surveillance data on childhood TB. DESIGN: A survey questionnaire was developed and broadly disseminated to National Tuberculosis Programmes or people with close links to them. RESULTS: Among the 34 countries that responded to the survey, the proportion of total national TB caseload reported in children in 2010 ranged from 0.67% to 23.6%. The data on new cases reported to this survey varied from data provided to the WHO global TB database. Most countries had childhood TB guidelines in place, and half had adopted the new dosage recommendations. Countries reported a number of challenges related to the implementation of the new recommendations and general management of childhood TB. CONCLUSIONS: Despite the adoption of the new dosage recommendations, their implementation is complicated by the lack of appropriate fixed-dose combinations. In addition, accurate and consistent estimates of the global burden of childhood TB remained a major challenge. Technical assistance and support to countries is needed to improve childhood TB activities.

Speaking the same language: treatment outcome definitions for multidrug-resistant tuberculosis.

SETTING: Globally it is estimated that 273000 new cases of multidrug-resistant tuberculosis (MDR-TB, resistance to isoniazid and rifampicin) occurred in 2000. To address MDR-TB management in the context of the DOTS strategy, the World Health Organization and partners have been promoting an expanded treatment strategy called DOTS-Plus. However, standard definitions for MDR-TB patient registration and treatment outcomes do not exist. OBJECTIVE: To propose a standardized set of case registration groups and treatment outcome definitions for MDR-TB and procedures for conducting cohort analyses under the DOTS-Plus strategy. DESIGN: Using published definitions for drug-susceptible TB as a guide, a 2-year-long series of meetings, conferences, and correspondence was undertaken to review published literature and country-specific program experience, and to develop international agreement. RESULTS: Definitions were designed for MDR-TB patient categorization, smear and culture conversion, and treatment outcomes (cure, treatment completion, death, default, failure, transfer out). Standards for conducting outcome analyses were developed to ensure comparability between programs. CONCLUSION: Optimal management strategies for MDR-TB have not been evaluated in controlled clinical trials. Standardized definitions and cohort analyses will facilitate assessment and comparison of program performance. These data will contribute to the evidence base to inform decision makers on approaches to MDR-TB control.

Encouraging outcomes in the first year of a TB control demonstration program: Orel Oblast, Russia.

SETTING: Orel, Russia. OBJECTIVE: To evaluate outcomes of tuberculosis (TB) patients treated in the first year of a TB control demonstration project using a revised strategy of directly observed treatment, short-course (DOTS). Standard methods recommended by World Health Organization (WHO) were adapted to include mycobacterial cultures. DESIGN: Retrospective cohort analysis of TB patients diagnosed between October 1999 and September 2000. RESULTS: Among 749 TB patients, 65% had bacteriologic confirmation of pulmonary TB, 31% were diagnosed clinically, and 4% had extra-pulmonary TB. Most (92%) had no previous TB treatment, but 8% were identified as retreatment cases. Of all patients, 41% had new sputum smear-positive TB. No patients were HIV-infected. Multidrug-resistant (MDR) TB levels were 3% among new and 17% among retreatment patients. Among new smear-positive patients, treatment success was 79% (72% cure, 7% completion); remaining outcomes were 8% failure, 3% default, 8% death, and 1% transfer. Success rates for new culture-positive and clinically diagnosed patients were 81% and 91%, respectively. CONCLUSION: Despite historical differences, successful implementation of the revised TB strategy in Russia is possible. Treatment success rates were high, suggesting WHO targets of 85% cure for smear-positive patients is attainable. Obstacles include drug resistance and elevated death rates among smear-positive patients.

Frequency of recurrence among MDR-tB cases 'successfully' treated with standardised short-course chemotherapy.

SETTING: Ivanovo Oblast, Russian Federation, 300 km north-east of Moscow, where a pilot DOTS TB control programme was implemented in October 1995. OBJECTIVE: To determine the frequency of TB recurrence among MDR (multidrug-resistant) patients who achieved treatment 'success' on standard short-course chemotherapy. METHODS: All patients with MDR tuberculosis, defined as resistance to at least isoniazid and rifampicin, who were declared 'cured' or 'treatment completed', were identified using the district register and traced whenever possible. Eligible patients underwent medical examination and, if necessary, chest radiography, sputum smear examination, culture and susceptibility testing. If the patient had died, the relatives were interviewed to try to determine the reasons for death. RESULTS: Of 18 patients eligible for analysis, five (27.8%) were documented to have recurrence (two of seven patients resistant to HRSE, one of five patients resistant to HRS and two of six patients resistant to HR). Patients receiving the Category I regimen were more likely to relapse than those receiving the Category II regimen (40% vs. 12.5%). The median time to relapse was 8 months; 2.46 recurrences were observed in 100 person-months (3.17 in category I and 1.3 in Category II patients). CONCLUSIONS: The frequency of TB recurrence among MDR-TB patients declared 'cured' after short-course chemotherapy is high. Improvements in treatment success, after removal of programme-related pitfalls in the treatment delivery process, must incorporate methods for early detection of MDR, along with adequate treatment regimens including second-line drugs. Culture-based bacteriological confirmation at the end of treatment is recommended.

Tuberculosis control in the Caucasus: successes and constraints in DOTS implementation.

SETTING: The pilot projects for tuberculosis (TB) control, supported by the World Health Organization (WHO) and based on the WHO recommended control strategy, directly-observed treatment, short-course (DOTS) in the Caucasian countries (Armenia, Azerbaijan, Georgia). OBJECTIVE: To evaluate the results 2 years after the implementation of the pilot projects. METHODS: Analysis of data on case detection, sputum conversion and treatment outcome reported quarterly to the WHO from the Ministries of Health in each country. RESULTS: Since the establishment of the project, 1330, 764 and 4866 new cases and relapses, respectively, of TB have been detected in the pilot areas of Armenia, Azerbaijan and Georgia. In Armenia and Azerbaijan, respectively 46% and 57% of all cases were smear positive, whilst in Georgia, the corresponding figure was only 12%. After 3 months' treatment, 93% of new smear-positive patients had become smear-negative. The sputum conversion rate for relapses and other retreatment cases (failure, treatment interrupted) was 85%. In Armenia, 78.1% of new smear-positive patients were treated successfully (cured or completed treatment). The corresponding percentages for Azerbaijan and Georgia were 87.9% and 59.6%. Treatment success rates among retreatment cases was generally low, at respectively 46%, 64%, and 35%, in Armenia, Azerbaijan, and Georgia. CONCLUSION: The results of the implementation of the WHO TB control pilot projects in Armenia, Azerbaijan and Georgia suggest that the DOTS strategy is feasible in emergency situations in general, and in the Caucasus in particular.

Cost-effectiveness analysis of tuberculosis control policies in Ivanovo Oblast, Russian Federation. Ivanovo Tuberculosis Project Study Group.

Many of the current tuberculosis control programmes in the Russian Federation are based on costly strategies which are underfunded and use long, individualized treatment regimens. This article compares, using a cost-effectiveness analysis, the new WHO strategy implemented in the Ivanovo Oblast (case-finding among symptomatic patients (SCF) and shorter regimens) and the old strategy (active screening of the asymptomatic population (ACF) and longer regimens). The cost per case cured was calculated at different levels of cure rate (45-95%) using three scenarios to describe the new WHO strategy (use of WHO-recommended regimens and three options at increasing rates of admission) and a fourth scenario to describe the old strategy (all patients admitted for the whole treatment and longer regimens). The cost per case detected was determined by calculating the following: yield of the new and old strategy (number of examinations necessary to diagnose one case); cost of the diagnostic process; multiplying yield per cost according to the three scenarios describing the new WHO strategy and a fourth scenario describing the old strategy. In the Ivanovo Oblast the cost per case cured, at 85% cure rate level, ranged from US$ 1197 (new strategy, scenario 1 without food) to US$ 6293 (old strategy, scenario 4) the cost per case detected ranged from US$ 1581 (new strategy, scenario 1) to US$ 4000 (old strategy, scenario 4). Significant savings can result from shifting towards the new WHO strategy. Decision-makers and health administrators should be responsible for re-investing the financial and human resources mobilized by the adoption of cost-effective strategies within the TB control programme.

Standardized tuberculosis treatment outcome monitoring in Europe. Recommendations of a Working Group of the World Health Organization (WHO) and the European Region of the International Union Against Tuberculosis and Lung Disease (IUATLD) for uniform reporting by cohort analysis of treatment outcome in tuberculosis patients.

Consensus-based recommendations have been developed by a Working Group of the World Health Organisation (WHO) and the International Union Against Tuberculosis and Lung Disease (IUATLD) on uniform reporting of tuberculosis (TB) treatment outcome data in countries in Europe. The main purpose of treatment monitoring is to find out how many of the potential infectious TB patients notified were declared cured at the end of treatment. Following the uniform case definitions as defined in 1996, emphasis is placed on cohort analysis of definite cases of pulmonary TB. The Working Group recommends using a minimal set of six mutually exclusive categories of treatment outcome: cure, treatment completed, failure, death, treatment interrupted, and transfer out. More detailed subsets may be chosen. Treatment outcome is expressed as a percentage of the total number of cases notified. Analysis should be separate for new and retreatment cases. Treatment outcome data have to be collected at the local level and passed on to regional and national authorities on an ongoing basis. Evaluation of treatment results becomes, preferably, an inbuilt component of national monitoring of programme performance. Because of the long duration of treatment, it is recommended that analysis is carried out in the first quarter of the calendar year that follows a full year after the last patient was enrolled. Feedback is essential. Treatment outcome results should become an inseparable part of the annual report on tuberculosis.

[Cost benefit of detection and treatment patients with tuberculosis in Ivanovo region, Russian Federation]. / Stoimost' vyiavleniia i lecheniia bol'nykh tuberkulezom v Ivanovskoi oblasti Rossiiskoi Federatsii.

To execute the tuberculosis control programme in the Ivanovo Region, the authors calculated the cost of detection of a tuberculosis case at patients' referrals to a therapeutical-and-prophylactic institution for medical aid and during prophylactic X-ray fluographic examinations and the cost of tuberculosis cure while treating the patient at a hospital in the intensive treatment phase (2-3 months) and in the outpatient setting or at a day hospital by the intermittent method in the continued treatment phase. The costs calculated were compared with those obtained by early approaches. The cost of detection of a tuberculosis case was 1580.8 for referrals in 1996 and 4000 for X-ray fluographic prophylactic examinations. The costs of hospital tuberculosis cure (85% cure rates) only in the intensive treatment phase (for 2-3 months) and outpatient intermittent treatment (for 2-4 months) with and without meals were 2415.34 and 2142.17 respectively. If the efficiency is equal, the introduction of new approaches to organizing the detection and treatment tuberculosis cases may save 3877.7 for each cured tuberculosis case and 2419.2 for each patient detected.

Tuberculosis control in Kyrgyzstan--an opportunity.

Tuberculosis incidence and mortality rates are rising steeply, reflecting economic hardship and the deterioration of the health infrastructure. The human and technical resources needed to reverse this trend are on hand, but cannot be used effectively without an adequate financial input. The cost of controlling tuberculosis now is modest compared with the cost of allowing it to increase.