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.

A systematic review of endpoint definitions in late phase pulmonary tuberculosis therapeutic trials.

BACKGROUND: Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with pulmonary tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologies METHODS: We conducted a systematic review of trials designed to advance new pulmonary TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: favorable, unfavorable, and not assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described. RESULTS: From 2205 trials in any way related to TB, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of favorable and unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing unfavorable from not assessable events. Death was often interpreted as conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes. CONCLUSIONS: In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across pulmonary TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal. PROSPERO REGISTRATION: PROSPERO CRD42020197993 . Registration 11 August 2020.

Defining a migrant-inclusive tuberculosis research agenda to end TB.

BACKGROUND: Pillar 3 of the End TB Strategy calls for the promotion of research and innovation at the country level to facilitate improved implementation of existing and novel interventions to end tuberculosis (TB). In an era of increasing cross-border migration, there is a specific need to integrate migration-related issues into national TB research agendas. The objective of the present review is to provide a conceptual framework to guide countries in the development and operationalization of a migrant-inclusive TB research agenda. METHODS: We conducted a literature review, complemented by expert opinion and the previous articles in this State of the Art series, to identify important themes central to migration-related TB. We categorized these themes into a framework for a migration-inclusive global TB research agenda across a comprehensive spectrum of research. We developed this conceptual framework taking into account: 1) the biomedical, social and structural determinants of TB; 2) the epidemiologic impact of the migration pathway; and 3) the feasibility of various types of research based on a country's capacity. DISCUSSION: The conceptual framework presented here is based on the key principle that migrants are not inherently different from other populations in terms of susceptibility to known TB determinants, but that they often have exacerbated or additional risks related to their country of origin and the migration process, which must be accounted for in developing comprehensive TB prevention and care strategies. A migrant-inclusive research agenda should systematically consider this wider context to have the highest impact.

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.

Drug-resistant tuberculosis clinical trials: proposed core research definitions in adults.

Drug-resistant tuberculosis (DR-TB) is a growing public health problem, and for the first time in decades, new drugs for the treatment of this disease have been developed. These new drugs have prompted strengthened efforts in DR-TB clinical trials research, and there are now multiple ongoing and planned DR-TB clinical trials. To facilitate comparability and maximise policy impact, a common set of core research definitions is needed, and this paper presents a core set of efficacy and safety definitions as well as other important considerations in DR-TB clinical trials work. To elaborate these definitions, a search of clinical trials registries, published manuscripts and conference proceedings was undertaken to identify groups conducting trials of new regimens for the treatment of DR-TB. Individuals from these groups developed the core set of definitions presented here. Further work is needed to validate and assess the utility of these definitions but they represent an important first step to ensure there is comparability in clinical trials on multidrug-resistant TB.

Results at 30 months of a randomised trial of FDCs and separate drugs for the treatment of tuberculosis.

Study C was an open-label, non-inferiority, randomised controlled trial of fixed-dose combination (FDC) or separate drugs given during the intensive phase of treatment to 1585 patients with smear-positive pulmonary tuberculosis conducted at 11 sites in Africa, Asia and Latin America. Thirty months post-randomisation, the failure/relapse rates in the per protocol population were 7.4% of 591 patients on FDCs and 6.5% of 587 patients on separate drugs; the site-adjusted difference was 0.3% (90%CI -1.8 to 2.3). In the modified intention-to-treat analysis, the corresponding results were respectively 17.9% of 683 and 16.1% of 671; the site-adjusted difference was 2.0% (90%CI -1.2 to 5.2).

Methodological and reporting quality of systematic reviews on tuberculosis.

BACKGROUND: Systematic reviews are used to inform tuberculosis (TB) guidelines. However, there are no data on whether TB systematic reviews are conducted well and reported transparently. METHODS: We searched four databases for reviews published between 2005 and 2010. Methodological quality was evaluated using AMSTAR and quality of reporting was assessed using PRISMA. RESULTS: Of 152 articles, 137 (90%) met the inclusion criteria. Only 3 of 11 AMSTAR quality items were met in most reviews: appropriate methods to combine findings (67%), comprehensive literature search (72%) and presentation of characteristics of included studies (90%). The other eight items were met in 4-53% of the reviews. Only 4% of the reviews disclosed conflicts of interest. The majority of the PRISMA items were reported in more than 60-76% of the reviews. Only nine items were reported in less than 55% of the reviews, the lowest being the full-search strategy (30%), risk of bias across studies in the Methods (27%) and Results (21%) sections, and indication of a review protocol (15%). CONCLUSIONS: Systematic reviews in our survey were well reported but generally of moderate to low quality. Better training, use of reporting guidelines and registration of systematic reviews could improve the quality of TB reviews.

Compassionate use of and expanded access to new drugs for drug-resistant tuberculosis.

Several new classes of anti-tuberculosis agents are likely to become available in the coming decade. Ensuring prompt access to these drugs for patients without other treatment options is an important medical and public health issue. This article reviews the current state of 'compassionate use' and 'expanded access' programs for these new drugs, and identifies several shortcomings that will limit patient access to the drugs. A series of five steps is outlined that will need to be taken by national health bodies, international agencies and non-governmental organizations to prevent undue delays in access to new tuberculosis drugs for patients who could benefit from them. Following these steps can ensure that patients will be able to benefit from access to these drugs, while minimizing the risk of emergence of resistance to the drug.

The ethics of a clinical trial when the protocol clashes with international guidelines.

Due to their nature and complexity, clinical trials often take some time to launch after the protocol has been designed and ethics approval obtained. During this time, there may be changes in international treatment guidelines and recommendations that result in a conflict between study protocol and recommended international best practice. Here, we describe the situation that arose in a pharmacokinetic study on the use of two different doses of rifabutin in patients with human immunodeficiency virus-associated tuberculosis who initiated antiretroviral therapy (ART) with a lopinavir-ritonavir-based regimen in South Africa and Viet Nam. The study protocol specified that ART should be started 10 weeks after the start of anti-tuberculosis treatment. The study in South Africa was approved in June 2008, went ahead as scheduled and was completed in August 2010. The study in Viet Nam was approved in October 2008 and was started in June 2010. A few weeks later, the World Health Organization released their 2010 guidelines for adult ART; one of its strong recommendations (with moderate quality of evidence) was that ART should be started 2-8 weeks after the start of anti-tuberculosis treatment. Emerging scientific evidence also supported this recommendation. The investigators felt that the Viet Nam study protocol was in conflict with recommended international best practice, and the trial was stopped in October 2010. An amended study protocol in which ART was started at 2 weeks was developed and implemented. The ethics issues around this decision and the need to change the study protocol are discussed in this article.

Du fait de la nature et de la complexité des études cliniques, leur mise en œuvre est souvent longue après l'élaboration du protocole et son approbation éthique. Pendant cette période, il peut y avoir un changement des lignes directrices internationales de traitement et des recommandations qui provoquent un conflit entre le protocole et les meilleures pratiques recommandées internationalement. Nous décrivons ici la situation apparue dans une étude pharmacocinétique portant sur l'utilisation de deux doses différentes de rifabutin chez des patients atteints de tuberculose (TB) associée au virus de l'immunodéficience humaine et commençant un traitement antirétroviral (ART) à base de lopinavir-ritonavir en Afrique du Sud et au Viet Nam. Le protocole de l'étude spécifiait de commencer l'ART 10 semaines après le début de la thérapie antituberculeuse. En Afrique du Sud, l'étude a été approuvée en juin 2008, s'est déroulée comme prévu et a été achevée en juin 2010. Au Viet Nam, l'étude a été approuvée en octobre 2008 et a démarré en juin 2010. Quelques semaines après, l'Organisation Mondiale de la Santé a publié ses lignes directrices de 2010 pour l'utilisation de l'ART chez les adultes, dont l'une des vives recommandations (basée sur des données de qualité modérée) était de commencer l'ART entre 2 et 8 semaines après le début du traitement de la TB. L'arrivée de nouvelles preuves scientifiques est aussi venue à l'appui de cette recommandation. Les investigateurs ont eu le sentiment que le protocole d'étude au Viet Nam était en conflit avec les meilleures pratiques internationales et l'étude a été arrêtée en octobre 2010. Un protocole d'étude amendé a été développé et mis en œuvre. Les problèmes éthiques entourant cette décision et la nécessité de changer le protocole sont discutés dans ce papier.

Los ensayos clínicos, dadas sus características y su complejidad, suelen exigir mucho tiempo desde la elaboración del protocolo y la aprobación por parte del comité de ética hasta su realización. Durante este lapso, pueden surgir modificaciones en las recomendaciones y las directrices terapéuticas internacionales, lo cual genera un conflicto entre el protocolo del estudio y las prácticas óptimas recomendadas. A continuación se describe la situación que se presentó en Suráfrica y Viet Nam durante un estudio de farmacocinética sobre el uso de dos dosificaciones diferentes de rifabutina, en pacientes aquejados de tuberculosis (TB) asociada con la infección por el virus de la inmunodeficiencia humana (HIV), quienes habían comenzado el tratamiento antirretrovírico (ART) con un régimen basado en la asociación lopinavir y ritonavir. El protocolo del estudio precisaba que el ART se debía comenzar 10 semanas después de haber iniciado el tratamiento antituberculoso. En Suráfrica, el estudio recibió la aprobación en junio del 2008, comenzó en el tiempo previsto y se completó en agosto del 2010. En Viet Nam, se obtuvo la aprobación del estudio en octubre del 2008 y se comenzó en junio del 2010. A las pocas semanas, la Organización Mundial de Salud publicó sus directrices del ART en los adultos del 2010, una de cuyas recomendaciones más firmes consistía en que el ART se debía iniciar entre 2 y 8 semanas después de haber comenzado el tratamiento antituberculoso (con una calidad probatoria moderada). Algunos resultados científicos de aparición reciente respaldaban igualmente esta recomendación. Los investigadores consideraron que el protocolo del estudio en Viet Nam entraba en conflicto con las prácticas óptimas internacionales recomendadas e interrumpieron su realización en octubre del 2010. Se introdujeron modificaciones al protocolo, según las cuales el ART se comenzaría a las 2 semanas y se puso en práctica el estudio. En el presente artículo se analizan los aspectos éticos en torno a esta decisión y a la necesidad de modificar el protocolo del estudio.

Key issues in the clinical development and implementation of TB vaccines in South Africa.

Significant progress has been made in advancing the development pipeline for a new and more effective TB vaccine with some candidate vaccines now in late stage clinical evaluation. However, progress has been hampered by an incomplete understanding of the components of a protective immune response and limited animal models, rendering the field unable to reliably predict vaccine efficacy earlier in preclinical development, including by evaluation in animal models, and limiting the predictive utility of comparing immunogenic effects across vaccine candidates in phase I/II studies. Consequently, new candidate vaccines have to be evaluated for efficacy in large-scale phase II/III trials using clinical endpoints. Apart from the technical challenges of characterising TB incidence in target populations at high risk of acquiring TB disease and standardising case definitions in order to improve both the sensitivity and more importantly the specificity of trial endpoints, there is an urgency in expanding and supporting the considerable trial infrastructure that will be required to evaluate and ultimately license a new TB vaccine. In the longer term, implementation strategies are dependent on what policy makers most value. Economic analyses will be essential to guide policy and implementation. This paper outlines the gaps and challenges and identifies solutions for effectively developing and efficiently introducing a new TB vaccine.

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.

Operational research for improved tuberculosis control: the scope, the needs and the way forward.

The promotion of research is one of the main components of the World Health Organizations Stop TB Strategy, which includes 'programme-based operational research (OR)' and 'research on introducing new tools into practice'. The importance of OR in improving tuberculosis (TB) control was recognised a long time ago, and historical OR studies have been instrumental in the development of major strategies for TB control. Although a growing number of OR projects are being conducted in the world today, little is known about their results or their likely impact on TB control programmes. As funding organisations increasingly recognise the need for OR, we propose a rational framework to conduct OR, which covers a spectrum from local setting-oriented to international policy guiding research, and determines the relevance, replicability and generalisability of the results. OR in TB control is aimed at 1) improving programme performance; 2) assessing the feasibility, effectiveness and impact of new strategies or interventions on TB control; and 3) collecting evidence to guide policy recommendations on specific interventions. This requires strengthened capacity to plan and conduct OR in low-income countries and appropriate support to conduct both nationally and internationally led OR projects. Suggestions are made for potential steps for improved purpose-driven OR, which may help to improve TB control locally and inform policy recommendations internationally.

Methodological issues in the design of clinical trials for the treatment of multidrug-resistant tuberculosis: challenges and opportunities.

The burden of multidrug-resistant tuberculosis (MDR-TB) is increasing dramatically in the world today, severely hampering global TB control. Treatment of MDR-TB is complex, prolonged, expensive and requires appropriate clinical and laboratory infrastructure. The majority of MDR-TB patients still do not have access to adequate diagnostic services or quality assured second-line drugs, leading to high levels of morbidity and mortality. More effective and efficient MDR-TB treatment with reduced toxicity that could be safely delivered to patients co-infected with human immunodeficiency virus (HIV) is an urgent research priority that could be cost-saving for health systems overall. In this context, understanding how best to design and execute randomised controlled trials to improve MDR-TB treatment has taken on new urgency, to identify the optimal combination(s) of existing and new drugs to assemble in efficient and safe regimen(s), preferably of short duration, that can be easily delivered to patients and safely combined with antiretroviral treatment. In the present report, we address the methodological issues in the design and execution of Phase II and Phase III trials arising from this goal. We suggest that a rational selection of appropriate designs and outcome measures, associated with the application of new diagnostic technology, could overcome many of the methodological and logistical problems. These advances could be key to historic improvements in the treatment of patients suffering from MDR-TB, and perhaps ultimately drug-susceptible TB. As with HIV, clinical trials in patients with drug-resistant disease may provide a quicker and less expensive path to licensure than trials for treatment of drug-susceptible disease.

Diagnosis of tuberculosis in ghana: the role of laboratory training.

OBJECTIVES: The laboratory is considered the cornerstone of tuberculosis (TB) control programme. International review of Ghana's programme in the late nineties identified the laboratory services as the weakest component. Sputum smear microscopy (SSM) being the main method of diagnosing pulmonary TB in Ghana, the training objectives were to: (i) strengthen the knowledge and skills of laboratory personnel on SSM (ii) impart necessary techniques in biosafety and (iii) introduce a Quality Assurance (QA) system in order to strengthen SSM services. METHODS: Personnel were selected for training during a nationwide situation analysis of SSM centres in 2000/2001. Four training sessions on SSM/QA were held between 2001/2004. RESULTS: A total of 80 personnel were trained: 10 regional TB coordinators and 70 laboratory personnel. The participants upon return to their respective regions also organized training within their districts. This approach resulted in another 100 district TB coordinators and 200 laboratory personnel being trained. Improvement in smear preparation, staining and reading ability of the participants were observed during the post-test and subsequent visit to their respective laboratories. The training has led to strengthening of TB laboratory services in the country and has contributed to increase in case detection from 10,745 in 2000 to 11,827 in 2004 and 14,022 in 2008. It was observed during the post-training follow-up and quarterly supervision visits that morale of the personnel was high. CONCLUSION: Continuous training and re-training of laboratory personnel on SSM and QA at regular intervals do play an important role for effective and efficient TB control programme.

Isoniazid preventive therapy for people living with HIV: public health challenges and implementation issues.

Isoniazid preventive therapy (IPT) is recognised as an important component of collaborative tuberculosis (TB) and human immunodeficiency virus (HIV) activities to reduce the burden of TB in people living with HIV (PLHIV). However, there has been little in the way of IPT implementation at country level. This failure has resulted in a recent call to arms under the banner title of the 'Three I's' (infection control to prevent nosocomial transmission of TB in health care settings, intensified TB case finding and IPT). In this paper, we review the background of IPT. We then discuss the important challenges of IPT in PLHIV, namely responsibility and accountability for the implementation, identification of latent TB infection, exclusion of active TB and prevention of isoniazid resistance, length of treatment and duration of protective efficacy. We also highlight several research questions that currently remain unanswered. We finally offer practical suggestions about how to scale up IPT in the field, including the need to integrate IPT into a package of care for PLHIV, the setting up of operational projects with the philosophy of 'learning while doing', the development of flow charts for eligibility for IPT, the development and implementation of care prior to antiretroviral treatment, and finally issues around procurement, distribution, monitoring and evaluation. We support the implementation of IPT, but only if it is done in a safe and structured way. There is a definite risk that 'sloppy' IPT will be inefficient and, worse, could lead to the development of multidrug-resistant TB, and this must be avoided at all costs.

A Phase II study of the sterilising activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.

SETTING: Current treatment for pulmonary tuberculosis (TB) might be shortened by the incorporation of fluoroquinolones (FQs). OBJECTIVES: A Phase II study aimed to assess the sterilising activities of three novel regimens containing FQs before a Phase III trial of a 4-month regimen containing gatifloxacin (GFX). DESIGN: A total of 217 newly diagnosed smear-positive patients were randomly allocated to one of four regimens: isoniazid (INH), pyrazinamide and rifampicin (RMP) with either ethambutol, GFX, moxifloxacin (MFX) or ofloxacin (OFX) for 2 months. At the end of the study, RMP and INH were given for 4 months. The rates of elimination of Mycobacterium tuberculosis were compared in the regimens using non-linear mixed effects modelling of the serial sputum colony counts (SSCC) during the first 8 weeks. RESULTS: After adjustment for covariates, MFX substitution appeared superior during the early phase of a bi-exponential fall in colony counts, but significant and similar acceleration of bacillary elimination during the late phase occurred with both GFX and MFX (P = 0.002). Substitution of OFX had no effect. These findings were supported by estimates of time to conversion, using Cox regression, but there were no significant differences in proportions culture-negative at 8 weeks. CONCLUSIONS: GFX and MFX improve the sterilising activity of regimens and might shorten treatment; their progression into Phase III trials therefore seems warranted.

Identifying barriers to effective tuberculosis control in Senegal: an anthropological approach.

SETTING: Low tuberculosis (TB) cure rates (average 53%) and high treatment default rates (average 28%) were reported in Senegal between 1999 and 2001. OBJECTIVE: To qualitatively evaluate the ability of TB patients to access and complete treatment in Senegal, with a view to helping to develop suitable strategies to improve TB control. METHODS: Anthropological study conducted in a series of public and private, urban and rural health facilities in 2001 and 2002. The qualitative methods used included semi-structured and in-depth interviews of health staff, patients and relatives, focus group discussions, and observations carried in health facilities. RESULTS: Problems were identified at several levels of health care. The main impediments to successful patient outcomes identified were: limited access to TB diagnosis and treatment facilities, poor communication between health personnel and patients, poor quality information provided to patients, poorly applied directly observed treatment, lack of a strategy to trace defaulting patients and limited supervision of the treatment units by the district leadership team. CONCLUSION: The anthropological analysis of patient care is an appropriate means of addressing complex public health problems in disease control and identifying solutions that are acceptable, sustainable and adapted to the local context.

Situation analysis of TB microscopy centres in Ghana.

SETTING: Public health laboratories in Ghana performing tuberculosis (TB) microscopy. OBJECTIVE: To assess the situation of the laboratories in terms of staff strength, technical skills, documentation, biosafety practices, equipment, supplies and disposal systems. DESIGN: Methods used for data collection were interviews using a structured questionnaire, informal observation of laboratory registers, disposal systems and safety measures for sputum handling. RESULTS: Of 114 laboratories visited between 2000 and 2001, 102 (89.5%) were performing TB microscopy. Of the staff working in the laboratories, 9% were medical technologists, 24% laboratory technicians, 37% laboratory assistants and 30% orderlies. Average false-negative and -positive rates were respectively 13% and 14%. Although most of the centres (85.3%) were using the recommended TB laboratory register for recording, in most cases they were not filled in accurately or completely. The majority of the available microscopes had mechanical or optical faults. Availability of other materials for smear preparation and staining ranged from 44% to 82%. The main methods employed for disposal of laboratory waste were burning and burying, but conditions were poor in most of the facilities visited. CONCLUSION: Training of laboratory personnel in TB microscopy and establishment of a quality assurance system are needed in Ghana.

Improving the laboratory diagnosis of TB in Ghana: the impact of a quality assurance system.

SETTING: Greater Accra region, Ghana. OBJECTIVE: To establish a pilot quality assurance (QA) system in sputum smear microscopy and to evaluate its impact. DESIGN: Quarterly supporting visits were paid to participating laboratories between 2000 and 2002. Fifteen examined slides were selected randomly from each laboratory during the visits and blindly re-assessed. Feedback was given promptly to the various laboratories. Training and stakeholder workshops were organised whenever necessary. RESULTS: General improvements in smear preparation and staining as well as the reading ability of the laboratory personnel included in the study were observed. The average marks for specimen quality, staining ability, smear cleanness, thickness, size and evenness increased from 64%, 79%, 69%, 46%, 67% and 60% in the last quarter of 2000 to 81%, 90%, 86%, 79%, 80% and 74%, respectively, 24 months after the establishment of the QA system. Within the same period, the rate of false-positives and -negatives decreased from respectively 14.8% and 20.5% to 0%, and agreements in positivity grade increased from 74% to 95%. The performance of the participating laboratories in keeping the laboratory registers up to date also improved. CONCLUSION: The QA system needs to be extended to the rest of the country.

Humoral response to Mycobacterium tuberculosis antigens in patients with tuberculosis in the Gambia.

OBJECTIVE: To determine and compare the sensitivity and specificity of four common mycobacterial antigens with three RD-1 region antigens in the serological diagnosis of active pulmonary tuberculosis (PTB) in the Gambia. DESIGN: Serum from 300 Gambians (100 with active PTB, 100 of their household contacts, and 100 community controls) was tested using an ELISA method to detect antibodies to seven mycobacterial antigens (three encoded in the RD-1 region [ESAT-6, CFP-10 and Rv3871] and four common [38 kDa, GLU-S, 19 kDa and 14 kDa]). Individuals with active TB were recruited from one of the National Leprosy and TB Control Program clinics in the western region of the Gambia, and neighborhood controls were an age-matched individual living within five houses of the case. RESULTS: The sensitivity of the RD-1 antigens ranged from 34% to 67%, while specificity ranged from 51% to 71%. The sensitivity of the common antigens ranged from 24% to 75% and specificity from 26% to 75%. CONCLUSION: In countries with high rates of TB, such as the Gambia, the clinical utility of serological testing to diagnose active TB remains limited, even with newer antigens encoded in the RD-1 region of Mycobacterium tuberculosis.