Tuberculosis contact investigation and short-course preventive therapy among young children in Africa.

SETTING: The largest cities in Benin, Burkina Faso, Cameroon and Central African Republic.OBJECTIVE: To demonstrate the feasibility and document the effectiveness of household contact investigation and preventive therapy in resource-limited settings.DESIGN: Children under 5 years living at home with adults with bacteriologically confirmed pulmonary tuberculosis (TB) were screened using questionnaire, clinical examination, tuberculin skin test and chest X-ray. Children free of active TB were offered preventive treatment with a 3-month rifampicin-isoniazid (3RH) or 6-month isoniazid (6H) regimen in Benin. Children were followed-up monthly during treatment, then quarterly over 1 year. Costs of transportation, phone contacts and chest X-rays were covered.RESULTS: A total of 1965 children were enrolled, of whom 56 (2.8%) had prevalent TB at inclusion. Among the 1909 children free of TB, 1745 (91%) started preventive therapy, 1642 (94%) of whom completed treatment. Mild adverse reactions, mostly gastrointestinal, were reported in 2% of children. One case of incident TB, possibly due to a late TB infection, was reported after completing the 3RH regimen.CONCLUSION: Contact investigation and preventive therapy were successfully implemented in these resource-limited urban settings in programmatic conditions with few additional resources. The 3RH regimen is a valuable alternative to 6H for preventing TB.

Progress in global rollout of new multidrug-resistant tuberculosis treatments.

SETTING: The global multidrug-resistant tuberculosis (MDR-TB) epidemic has grown over the past decade and continues to be difficult to manage. In response, new drugs and treatment regimens have been recommended.OBJECTIVE: In 2017 and again in 2018, the International Union Against Tuberculosis and Lung Disease (The Union) drug-resistant (DR) TB Working Group collaborated with RESIST-TB to implement an internet survey to members of The Union around the world to assess access to these new treatment strategies.DESIGN: A nine-question survey was developed using SurveyMonkey®. The survey was open for participation to all members of The Union registered under the TB Section. Two reminders were sent during each survey. The responses were analyzed taking into account the WHO Region to which the respondent belonged.RESULTS: The 2018 survey showed a global increase in implementation of the shorter (9-month) MDR-TB regimen (from 33% to 56% of respondents, P < 0.001) and an increase in the use of bedaquiline and/or delamanid (from 25% to 41% of respondents, P < 0.001) compared to 2017. There were substantial variations in roll-out between WHO regions.CONCLUSION: These results demonstrate improvement in global implementation of the new treatment strategies over a 1-year period.

Outcome definitions for multidrug-resistant tuberculosis treated with shorter treatment regimens.

To assess whether the revised 2013 World Health Organization (WHO) definitions for multidrug-resistant tuberculosis (MDR-TB) treatment outcomes apply to shorter treatment regimens in low- and middle-income countries and to propose modified criteria. Criteria for 'failure' and 'cure' outcomes were assessed using data on 1006 patients enrolled in an observational study on the standardised 9-11 month shorter MDR-TB regimen in Africa. Absence of conversion in the intensive phase, a WHO criteria for failure, was the worst performing criterion; reversion had low sensitivity and other criteria provided limited added value. Based on our study results, we propose new definitions for 'treatment failure' as treatment termination or the permanent discontinuation of 2 anti-tuberculosis drugs due to 1) positive culture after 6 months of treatment (except for one isolated positive culture) or 2) at least two consecutive grade 2+ positive sputum smears after 6 months of treatment if culture is not available; and for 'cure' as treatment completion without proof of failure AND two consecutive negative cultures taken 30 days apart, one of which should be after 6 months of treatment. The proposed new definitions are applicable to shorter regimens in low- and middle-income countries, and should also work for the newly recommended longer regimens. .

Challenges and opportunities to prevent tuberculosis in people living with HIV in low-income countries.

People living with the human immunodeficiency virus (HIV) (PLHIV) are at high risk for tuberculosis (TB), and TB is a major cause of death in PLHIV. Preventing TB in PLHIV is therefore a key priority. Early initiation of antiretroviral therapy (ART) in asymptomatic PLHIV has a potent TB preventive effect, with even more benefits in those with advanced immunodeficiency. Applying the most recent World Health Organization recommendations that all PLHIV initiate ART regardless of clinical stage or CD4 cell count could provide a considerable TB preventive benefit at the population level in high HIV prevalence settings. Preventive therapy can treat tuberculous infection and prevent new infections during the course of treatment. It is now established that isoniazid preventive therapy (IPT) combined with ART among PLHIV significantly reduces the risk of TB and mortality compared with ART alone, and therefore has huge potential benefits for millions of sufferers. However, despite the evidence, this intervention is not implemented in most low-income countries with high burdens of HIV-associated TB. HIV and TB programme commitment, integration of services, appropriate screening procedures for excluding active TB, reliable drug supplies, patient-centred support to ensure adherence and well-organised follow-up and monitoring that includes drug safety are needed for successful implementation of IPT, and these features would also be needed for future shorter preventive regimens. A holistic approach to TB prevention in PLHIV should also include other important preventive measures, such as the detection and treatment of active TB, particularly among contacts of PLHIV, and control measures for tuberculous infection in health facilities, the homes of index patients and congregate settings.

Insights into drug-resistant tuberculosis treatment: results of The Union DR-TB Working Group Survey, 2017.

The past 4 years have seen the introduction of new regimens and new drugs to treat multidrug-resistant tuberculosis (MDR-TB). To identify implementation trends over time, the DR-TB Working Group of the International Union Against Tuberculosis and Lung Disease (The Union), in collaboration with RESIST-TB, launched an online survey to Union members around the world. Survey results showed substantial diversity in treatment roll-out: 36% of respondents stated that their country is using the 9-month regimen for MDR-TB treatment; 41% are using bedaquiline and delamanid, but not the 9-month regimen; 28% are using both; and 22% of respondents indicated that their country does not currently offer either of these treatment options. Survey respondents also identified specific challenges to the introduction of shorter MDR-TB regimens and new drugs, including access to rapid diagnosis of fluoroquinolone resistance and case management. The results of this survey are intended to help identify research and implementation gaps while highlighting the importance of global implementation of scalable regimens for the treatment of MDR-TB.

Les quatre dernières années ont vu l'introduction de nouveaux protocoles et de nouveaux médicaments dans le traitement de la tuberculose multirésistante (TB-MDR). Dans le but d'identifier les tendances de la mise en œuvre dans le temps, le groupe de travail sur la TB résistante de l'Union Internationale contre la tuberculose et les maladies respiratoires (L'Union), en collaboration avec RESIST-TB, a lancé une enquête en ligne auprès des membres de l'Union autour du monde. Les résultats de l'enquête ont montré une grande diversité dans le lancement du traitement : 36% des répondants ont affirmé que leur pays utilisait le protocole de 9 mois pour le traitement de la TB-MDR ; 41% utilisent la bédaquiline et le délamanide, mais pas le protocole de 9 mois ; 28% utilisent les deux ; et 22% des répondants ont indiqué que leur pays n'offrait actuellement aucune de ces options de traitement. Les répondants ont également identifié les défis spécifiques à l'introduction de protocoles plus courts et de nouveaux médicaments de TB-MDR, notamment l'accès à un diagnostic rapide de la résistance aux fluoroquinolones et la prise en charge des cas. Les résultats de cette enquête sont destinés à contribuer à identifier les lacunes en matière de recherche et de mise en œuvre, tout en mettant en lumière l'importance de la mise en œuvre mondiale de protocoles évolutifs pour le traitement de la TB-MDR.

En los últimos 4 años ha tenido lugar la introducción de nuevos esquemas terapéuticos y nuevos fármacos para el tratamiento de la tuberculosis multirresistente (TB-MDR). Con el propósito de evaluar las tendencias de su aplicación en el transcurso del tiempo, el grupo de trabajo sobre TB farmacorresistente de la Unión Internacional Contra la Tuberculosis y Enfermedades Respiratorias (La Unión), en colaboración con la iniciativa RESIST-TB, emprendió una encuesta en línea dirigida a los miembros de La Unión en todo el mundo. Los resultados pusieron de manifiesto una gran diversidad del despliegue del tratamiento. El 36% de quienes respondieron afirmaba que en su país se utiliza el esquema de 9 meses para el tratamiento de la TB-MDR; el 41% utiliza bedaquilina y delamanid, pero no el esquema de 9 meses; el 28% utilizan ambos; y el 22% de quienes respondieron indicaba que en su país no se ofrece en la actualidad ninguna de estas opciones terapéuticas. Las respuestas a la encuesta revelan también dificultades específicas con la introducción de los esquemas más cortos de tratamiento de la TB-MDR y con los nuevos medicamentos, entre ellas el acceso al diagnóstico rápido de la resistencia a las fluoroquinolonas y el manejo de los casos. Los resultados de esta encuesta tienen por finalidad contribuir a reconocer las lagunas en la investigación y en la ejecución y al mismo tiempo destacar la importancia de la introducción mundial de esquemas ampliables de tratamiento de la TB-MDR.

QTc and anti-tuberculosis drugs: a perfect storm or a tempest in a teacup? Review of evidence and a risk assessment.

Treatment outcome with a short multidrug-resistant tuberculosis regimen in nine African countries.

SETTING: Nine countries in West and Central Africa. OBJECTIVE: To assess outcomes and adverse drug events of a standardised 9-month treatment regimen for multidrug-resistant tuberculosis (MDR-TB) among patients never previously treated with second-line drugs. DESIGN: Prospective observational study of MDR-TB patients treated with a standardised 9-month regimen including moxifloxacin, clofazimine, ethambutol (EMB) and pyrazinamide (PZA) throughout, supplemented by kanamycin, prothionamide and high-dose isoniazid during an intensive phase of a minimum of 4 to a maximum of 6 months. RESULTS: Among the 1006 MDR-TB patients included in the study, 200 (19.9%) were infected with the human immunodeficiency virus (HIV). Outcomes were as follows: 728 (72.4%) cured, 93 (9.2%) treatment completed (81.6% success), 59 (5.9%) failures, 78 (7.8%) deaths, 48 (4.8%) lost to follow-up. The proportion of deaths was much higher among HIV-infected patients (19.0% vs. 5.0%). Treatment success did not differ by HIV status among survivors. Fluoroquinolone resistance was the main cause of failure, while resistance to PZA, ethionamide or EMB did not influence bacteriological outcome. The most important adverse drug event was hearing impairment (11.4% severe deterioration after 4 months). CONCLUSIONS: The study results support the use of the short regimen recently recommended by the World Health Organization. Its high level of success even among HIV-positive patients promises substantial improvements in TB control.

Do active case-finding projects increase the number of tuberculosis cases notified at national level?

OBJECTIVE: To analyse the impact of active tuberculosis case finding (ACF) projects on the number of sputum smear-positive (SS+) tuberculosis (TB) cases notified at national level. METHODS: Case-finding results of the 16 countries that participated in the first wave of the TB REACH project were analysed. Information on the number of SS+ TB cases at national level were taken from the 2014 World Health Organization global tuberculosis report. A segmented linear regression model was used to analyse trends in notification. RESULTS: An increase in SS+ TB cases from 3% to 334% was observed in the areas of intervention of the TB REACH project in almost all countries. There were no significant increases in the number of SS+ TB cases notified at the national level in most countries, except in two countries during the intervention period (Benin and Kenya), and in one country after the intervention period (Somalia). CONCLUSIONS: The TB REACH project had no impact on SS+ TB cases notified at national level in almost all countries during and after the intervention. ACF projects are pilot studies that are often difficult to reproduce at national level due to their high cost and the lack of human resources.

Numbers of tuberculosis cases: dreams and reality.

BACKGROUND: Use of estimated numbers of tuberculosis (TB) cases for planning purposes in some sub-Saharan countries. OBJECTIVE: To document the uncertainties of official World Health Organization estimates and problems encountered in using them for planning. DESIGN: Brief review of the methods used in estimation, using different sub-Saharan countries to illustrate problems. RESULTS: The annual risk of tuberculous infection, used for many years to calculate estimates, is no longer considered a valid method. New methods are based on an assessment of the completeness of TB notification data (the Onion Model) and prevalence surveys of bacteriologically proven pulmonary TB cases; however, these are subject to bias and are very imprecise. Examples from sub-Saharan countries reflect these difficulties and show that official estimates vary substantially, by up to a quarter of the initial values. Donors, particularly the Global Fund, rely on these estimates and push countries to arbitrarily increase planned numbers of notified cases to improve 'case detection rates'. CONCLUSION: Use of estimated numbers to monitor progress in TB control may be counterproductive, costly and risky. It would be much more realistic to accept that low-income countries plan their strategies based on TB notifications rather than on case detection rates that are more dream than reality.

Connectivity of diagnostic technologies: improving surveillance and accelerating tuberculosis elimination.

In regard to tuberculosis (TB) and other major global epidemics, the use of new diagnostic tests is increasing dramatically, including in resource-limited countries. Although there has never been as much digital information generated, this data source has not been exploited to its full potential. In this opinion paper, we discuss lessons learned from the global scale-up of these laboratory devices and the pathway to tapping the potential of laboratory-generated information in the field of TB by using connectivity. Responding to the demand for connectivity, innovative third-party players have proposed solutions that have been widely adopted by field users of the Xpert(®) MTB/RIF assay. The experience associated with the utilisation of these systems, which facilitate the monitoring of wide laboratory networks, stressed the need for a more global and comprehensive approach to diagnostic connectivity. In addition to facilitating the reporting of test results, the mobility of digital information allows the sharing of information generated in programme settings. When they become easily accessible, these data can be used to improve patient care, disease surveillance and drug discovery. They should therefore be considered as a public health good. We list several examples of concrete initiatives that should allow data sources to be combined to improve the understanding of the epidemic, support the operational response and, finally, accelerate TB elimination. With the many opportunities that the pooling of data associated with the TB epidemic can provide, pooling of this information at an international level has become an absolute priority.

High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon.

SETTING: Two specialised multidrug-resistant tuberculosis (MDR-TB) treatment units in Cameroon. OBJECTIVE: To assess outcome and adverse drug events with a standardised 12-month regimen for MDR-TB among second-line drug naïve patients. DESIGN: Prospective observational study of MDR-TB patients treated with a standardised 12-month regimen including gatifloxacin, clofazimine, prothionamide, ethambutol and pyrazinamide throughout, supplemented by kanamycin and isoniazid during an intensive phase of a minimum of 4 months. Progress was monitored monthly until treatment completion and twice over one year after treatment cessation. RESULTS: Eighty-seven potentially eligible patients were lost and never treated due to delayed availability of test results. Among the 150/236 eligible and treated patients, 134 (89%) successfully completed treatment, 10 died, 5 were lost, 1 failed and none relapsed. The patients' mean age was 33.7 years (range 17-68), 73 (49%) were females, 120 (80%) had failed on previous treatment, 30 (20%) were human immunodeficiency virus seropositive, 62 (43%) had a body mass index <18.5 kg/m(2) and 41 (27%) had radiographic involvement of five or six of the six lung zones. The most important adverse drug event was hearing impairment, which occurred in 46 of 106 (43%) patients. CONCLUSIONS: These results add further evidence for the usefulness of shorter, standardised regimens among patients without second-line drug resistance.

Integrating HIV testing and care into tuberculosis services in Benin: programmatic aspects.

SETTING: Between 2005 and 2008, the diagnosis and care of human immunodeficiency virus (HIV) infection and tuberculosis (TB) services were integrated in Benin. RESULTS: The appointment of a TB-HIV Coordinator by the National Tuberculosis Control Programme and quarterly supervisory visits to TB clinics have bolstered the implementation of integrated HIV-TB activities. HIV testing and cotrimoxazole preventive therapy were integrated smoothly into the TB services. The strategy chosen to facilitate access of HIV-positive TB patients to antiretroviral treatment contributed to greater integration over time, but perpetuated, for some, the burden of attending two facilities. CONCLUSION: The integration and decentralisation of TB and HIV care services at national level in Benin resulted in a high uptake of HIV services among TB patients.

Results of rapid and successful integration of HIV diagnosis and care into tuberculosis services in Benin.

SETTING: Benin, where 20 of 54 tuberculosis (TB) clinics caring for 80% of all TB patients began providing integrated human immunodeficiency virus (HIV) care in 2005. OBJECTIVE: To describe the characteristics and TB treatment outcomes of the first cohorts of TB-HIV patients, and to assess programmatic outcomes. METHODS: Retrospective cohort study using data from the TB register and the register of co-infected patients. RESULTS: During the study period, 8368 TB patients were registered, 7787 (93%) were tested for HIV and 1255 (16%) were HIV-positive, including 385 (32%) who already knew their positive status. Most patients (88%) were tested within 15 days of TB diagnosis. Female and young patients were overrepresented among the co-infected. Cotrimoxazole preventive therapy was administered to 1152 patients (95%) during anti-tuberculosis treatment, and antiretroviral treatment (ART) to 469 (42%). The likelihood of receiving ART increased as initial CD4 lymphocyte counts decreased. Fifteen per cent of TB-HIV patients died during anti-tuberculosis treatment. Patients already on ART prior to anti-tuberculosis treatment experienced the worst outcomes. Patients who initiated ART early during anti-tuberculosis treatment or in the timeframe recommended by the guidelines fared the best. CONCLUSION: HIV care has been successfully and sustainably integrated into TB services in Benin. However, ensuring the access of co-infected patients to more favourable treatment outcomes still represents significant challenges.

The burden and outcomes of childhood tuberculosis in Cotonou, Benin.

SETTING: The National Tuberculosis Programme (NTP) and the paediatric ward of the General Hospital (GH), Cotonou, Benin. OBJECTIVE: To describe the burden of tuberculosis (TB), characteristics and outcomes among children treated in Cotonou from 2009 to 2011. DESIGN: Cross-sectional cohort study consisting of a retrospective record review of all children with TB aged <15 years. RESULTS: From 2009 to 2011, 182 children with TB were diagnosed and treated (4.5% of total cases), 153 (84%) by the NTP and 29 (16%) by the GH; the latter were not notified to the NTP. The incidence rate of notified TB cases was between 8 and 13 per 100 000 population, and was higher in children aged >5 years. Of 167 children tested, 29% were HIV-positive. Treatment success was 72% overall, with success rates of 86%, 62% and 74%, respectively, among sputum smear-positive, sputum smear-negative and extra-pulmonary patients. Treatment success rates were lower in children with sputum smear-negative TB (62%) and those with HIV infection (58%). CONCLUSION: The number of children being treated for TB is low, and younger children in particular are underdiagnosed. There is a need to improve the diagnosis of childhood TB, especially among younger children, and to improve treatment outcomes among HIV-TB infected children, with better follow-up and monitoring.

MDR-TB treatment needs in patients previously treated for TB in Cotonou, Benin.

SETTING: Centre National Hospitalier de Pneumo-Phtisi-ologie, Cotonou, Benin. OBJECTIVE: To determine the proportion of individuals needing treatment for multidrug-resistant tuberculosis (MDR-TB) among patients previously treated for TB. DESIGN: A retrospective cross-sectional study of all patients previously treated for TB in Cotonou from 2003 to 2011. RESULTS: Of 956 patients on retreatment, 897 (94%) underwent culture and/or a line-probe assay. For different reasons, 594 (66%) underwent drug susceptibility testing for rifampicin (RMP), of whom 95 (16%) had RMP resistance (68 multidrug-resistance [MDR] and 27 other RMP resistance) and therefore needed treatment for MDR-TB. These represent 39% of patients who failed/relapsed after standardised retreatment, and 20% of those who failed, 19% of defaulters and 11% of relapses after first-line treatment. Residence outside of Benin was associated with a higher risk of RMP resistance (RR 3.13, 95%CI 2.19-4.48, P < 0.01). From 2003 to 2011, the prevalence of RMP resistance decreased from 25% to 5% among patients living in Benin. Human immunodeficiency virus (HIV) prevalence was 25%; no association was found between HIV and RMP resistance. Of patients failing treatment, 48% were fully susceptible, 22% were monoresistant and 8% polyresistant. CONCLUSION: The majority of patients who fail retreatment or first-line treatment in Cotonou do not require empirical treatment for MDR-TB.