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.

Standards for clinical trials for treating TB.

BACKGROUND: The value, speed of completion and robustness of the evidence generated by TB treatment trials could be improved by implementing standards for best practice.METHODS: A global panel of experts participated in a Delphi process, using a 7-point Likert scale to score and revise draft standards until consensus was reached.RESULTS: Eleven standards were defined: Standard 1, high quality data on TB regimens are essential to inform clinical and programmatic management; Standard 2, the research questions addressed by TB trials should be relevant to affected communities, who should be included in all trial stages; Standard 3, trials should make every effort to be as inclusive as possible; Standard 4, the most efficient trial designs should be considered to improve the evidence base as quickly and cost effectively as possible, without compromising quality; Standard 5, trial governance should be in line with accepted good clinical practice; Standard 6, trials should investigate and report strategies that promote optimal engagement in care; Standard 7, where possible, TB trials should include pharmacokinetic and pharmacodynamic components; Standard 8, outcomes should include frequency of disease recurrence and post-treatment sequelae; Standard 9, TB trials should aim to harmonise key outcomes and data structures across studies; Standard 10, TB trials should include biobanking; Standard 11, treatment trials should invest in capacity strengthening of local trial and TB programme staff.CONCLUSION: These standards should improve the efficiency and effectiveness of evidence generation, as well as the translation of research into policy and practice.

Knowledge and attitudes towards TB among healthcare workers in Yogyakarta, Indonesia.

SETTING: Healthcare workers (HCWs) are at an increased risk of TB worldwide. Individual knowledge and attitudes may influence HCW behaviour, and subsequently, TB risk. Indonesia has the second highest case-load globally. OBJECTIVE: To measure TB knowledge and attitudes among a subsection of HCWs in Yogyakarta, Indonesia, and to explore factors associated with knowledge. DESIGN: A cross-sectional study using an online survey targeting all HCW staff was conducted among HCWs from four pre-selected healthcare facilities in Yogyakarta. Descriptive analysis and a multivariable linear regression were undertaken. RESULTS: Of 792 HCWs, 290 (37%) completed the survey; 64% (n = 185) were medical staff, 33% (n = 95) reported previously being tested for active TB and 8% (n = 24) for latent TB. The mean knowledge score was 7.2/11 (SD 1.5): this was higher among medical staff and those with university education (average score increase: 0.53, 95% CI 0.15 to 0.90; and 0.38, 95% CI 0.01 to 0.74, respectively). Participants agreed that free access to TB screening (93%) and treatment (93%) should be available, and 57% of medical and 77% of non-medical staff would take preventive therapy if eligible. CONCLUSION: Participants had practical understanding of TB; however, gaps were identified in knowledge about TB disease progression and prevention. Prevention programmes were viewed positively. We suggest further TB education and engagement programmes for HCWs.

CONTEXTE: Les travailleurs de la santé (HCW) sont exposés à un risque accru de TB dans le monde entier. Les connaissances et les attitudes individuelles peuvent influencer le comportement des HCW et, par conséquent, le risque de TB. L'Indonésie a le deuxième plus grand nombre de cas dans le monde. OBJECTIF: Mesurer les connaissances et les attitudes à l'égard de la TB parmi un sous-groupe de HCW à Yogyakarta, en Indonésie, et explorer les facteurs associés aux connaissances de la TB. MÉTHODE: Une étude transversale a été menée à l'aide d'un sondage en ligne ciblant tous les HCW de quatre établissements de santé présélectionnés à Yogyakarta. Une analyse descriptive et une régression linéaire multivariable ont été effectuées. RÉSULTATS: Sur 792 HCW, 290 (37%) ont répondu à l'enquête ; 62% (n = 181) étaient des membres du personnel médical, 33% (n = 95) ont déclaré avoir déjà été testés pour la TB active et 8% (n = 24) pour la TB latente. Le score moyen de connaissances était de 7,2/11 (SD 1,5) : il était plus élevé parmi le personnel médical et les personnes ayant une formation universitaire (augmentation moyenne du score : 0,53 ; IC 95% 0,11­0,93 et 0,38 ; IC 95% 0,01­0,74, respectivement). Les participants étaient d'accord pour dire que l'accès au dépistage (93%) et au traitement (93%) de la TB devrait être gratuit, et 57% du personnel médical et 77% du personnel non médical suivraient un traitement préventif s'ils étaient éligibles. CONCLUSION: Les participants avaient une compréhension pratique de la TB ; cependant, des lacunes ont été identifiées dans les connaissances sur la progression de la maladie et la prévention de la TB. Les programmes de prévention ont été perçus positivement. Nous suggérons d'autres programmes d'éducation et d'engagement sur la TB pour les HCW.

Adapting active case-finding for TB during the COVID-19 pandemic in Yogyakarta, Indonesia.

The COVID-19 pandemic and response measures, including lockdowns and the reorientation of health services, have disrupted essential health services for other diseases, including TB, HIV and malaria. For TB, reductions in case detection due to the COVID-19 pandemic are projected to result in increased TB transmission, morbidity and mortality. Active case-finding (ACF) for TB using community-based approaches is a potential strategy to offset reductions in TB detection by obviating the need for patients to seek care at a health facility. A number of approaches can be used to conduct TB ACF safely and screen designated target populations while managing the risks of SARS-CoV-2 transmission for staff, individuals and the community. We present a framework of options for and experience of adapting TB ACF services in response to the challenges of COVID-19 in our programme in Yogyakarta, Indonesia. Key changes have included revised prioritisation of target populations focusing on household contacts, reducing case-finding throughput, implementation of additional infection control measures and precautions, and integration of COVID-19 screening among those being screened for TB. Our approach could inform other programmes seeking to adapt TB ACF services to mitigate the negative impact of COVID-19 on TB case detection.

La pandémie de COVID-19 et les mesures de riposte incluant des confinements et une réorientation des services de santé ont perturbé les services de santé essentiels destinés aux autres maladies comme la TB, le VIH et le paludisme. En ce qui concerne la TB, les réductions de la détection des cas dues à la pandémie de COVID-19 devrait entraîner une augmentation de la transmission, morbidité et mortalité de la TB. La recherche active des cas (ACF) de TB grâce à des approches communautaires est une stratégie potentielle visant à compenser pour les réductions de détection de la TB en écartant le besoin pour les patients de solliciter des soins dans un structure de santé. Plusieurs approches peuvent être utilisées pour réaliser l'ACF TB de façon sûre et de dépister des populations cibles désignées tout en gérant les risques de transmission du SARS-CoV-2 pour le personnel, les individus et la communauté. Nous présentons un cadre d'options et d'expériences d'adaptation des services TB ACF en réponse aux défis du COVID-19 dans notre programme à Yogyakarta, Indonésie. Les changements majeurs ont inclus une révision des priorités des populations cibles focalisée sur les contacts domiciliaires ; une réduction de la cadence de la recherche de cas ; la mise en œuvre de mesures supplémentaires de lutte contre l'infection et de précautions ; et l'intégration du dépistage de COVID-19 parmi ceux dépistés pour la TB. Notre approche pourrait informer d'autres programmes voulant adapter les services TB ACF afin d'atténuer l'impact négatif du COVID-19 sur la détection des cas de TB.

TB treatment delay associated with drug resistance and admission at Daru General Hospital in Papua New Guinea.

SETTING: Daru General Hospital, Daru Island, Papua New Guinea, where high rates of tuberculosis (TB) have been reported. Prompt diagnosis and effective treatment are needed for improving TB outcomes and to prevent nosocomial transmission. OBJECTIVE: To assess the time to treatment initiation and the risk factors associated with delayed treatment for patients started on TB treatment at Daru General Hospital from January to September 2017. DESIGN: This was a retrospective cohort study that entailed reviewing the records from treatment, admission, discharge and presumptive TB registers. RESULTS: The study included 360 patients on TB treatment. The median time from presentation to treatment initiation was 7 days [IQR 3-11]. Treatment was started <7 days for 215 patients (60%); however, only 16.2% commenced treatment <2 days. Risk factors for delayed treatment were diagnosis of TB as an inpatient (OR 2.67, 95% CI 1.35-5.28, P = 0.005) and having drug-resistant TB (OR 2.65, 95% CI 1.5-4.68. P = 0.001). CONCLUSION: A high proportion of TB patients commenced treatment <7 days. Inpatient status, DR-TB and lack of microbiological confirmation were associated with delays in treatment initiation. We recommend that programmes monitor the time from presentation to treatment initiation, and propose that a period of >3 days from presentation to treatment initiation be considered as delayed treatment initiation.

The effects of decentralisation of tuberculosis services in the East New Britain Province, Papua New Guinea.

SETTING: The tuberculosis (TB) programmes at the Nonga General Hospital, Rabaul Urban Clinic and Kerevat District Hospital in East New Britain Province, Papua New Guinea. BACKGROUND: In East New Britain, TB care was mainly offered by the General Hospital, resulting in limited community-based care and poor treatment outcomes. In 2016, TB services were decentralised from the provincial to the district level by 1) training health workers, 2) increasing community awareness of TB, and 3) providing a weekly Clinical Outreach (TACO) service. OBJECTIVE: To describe the effect of TACO on the use of TB diagnostic and treatment services from 1 January 2014 to 31 December 2017. DESIGN: This was a retrospective study comparing 2014-2015 (pre-TACO) and 2016-2017 (TACO) cohorts. RESULTS: There was an increase in pre-TACO to TACO cohorts in screened cases (1581 to 2195), total registered TB cases (678 to 824) and registered cases at decentralised sites (209 to 615). Unfavourable treatment outcomes were common (pre-TACO, 46.0% vs. TACO, 40.1%). In multivariable analysis, treatment at a decentralised Basic Management Unit (aOR 0.55, 95%CI 0.42-0.74) was significantly associated with fewer unfavourable outcomes, but treatment outcomes between the pre-TACO and the TACO group were not significantly different. CONCLUSION: Strengthening decentralisation of TB services at the district level increased TB screening and case registration, with similar treatment outcomes.

Challenges in TB diagnosis and treatment: the Kavieng Provincial Hospital experience, Papua New Guinea.

SETTING: The Tuberculosis (TB) Basic Management Unit at Kavieng Provincial Hospital, New Ireland Province, Papua New Guinea. OBJECTIVE: To assess the linkage between laboratory diagnosis and treatment initiation and describe the characteristics and treatment outcomes of TB patients. DESIGN: This was a retrospective cohort study of 1) sputum smear-positive TB patients recorded in the laboratory register, and 2) TB patients recorded in the treatment register in 2015 and 2016. RESULTS: Of the 221 patients registered for TB treatment, 173 (78%) were clinically diagnosed; extrapulmonary TB was common (36% of all patients). Unfavourable treatment outcomes were seen in more than 40% of patients, including death (10%) and loss to follow-up (26%), and were significantly more common in smear-negative vs. smear-positive pulmonary TB patients (RR 1.69 [95%CI 1.02-2.80]). Only 4 (<2%) TB patients had undergone testing for HIV. Twelve (21%) of 58 sputum smear-positive TB patients were not registered as undergoing treatment for TB. CONCLUSION: This study identifies diagnostic and treatment gaps in the TB treatment cascade at the Kavieng Basic Management Unit. The TB programme requires strengthening to address the high proportions of clinically diagnosed TB, of patients not tested for HIV and of loss to follow-up.

Outcomes in children treated for tuberculosis with the new dispersible fixed-dose combinations in Port Moresby.

SETTING: The new child-friendly fixed dose combinations (FDCs) were introduced at Port Moresby General Hospital, Papua New Guinea, in 2016 for the first-line treatment of children (aged <15 years) with tuberculosis (TB) who weighed <25 kg. OBJECTIVE: To describe the characteristics and outcomes for children treated with the new FDCs, and to identify risk factors for unfavourable treatment outcomes. DESIGN: This was a retrospective cohort study of all children treated for TB with the FDCs from August 2016 to August 2017. RESULTS: Of 713 children included, 488 (68%) were diagnosed with pulmonary TB. Only 6 (0.8%) TB cases were bacteriologically confirmed and human immunodeficiency virus (HIV) status was known in 50%. Treatment outcomes were favourable in 425 (60%) children. Of 288 children with unfavourable outcomes, there were 242 (84%) with loss to follow-up (LTFU) and 25 (8.4%) were known to have died. Children who were severely underweight (weight-for-age Z score <-3) on presentation were at greater risk of LTFU compared to children of normal weight on multivariable analysis (aRR 1.3, 95%CI 1.0-1.6, P < 0.05). CONCLUSION: Alternative models of care to decrease LTFU during treatment are needed, including integration with nutritional support. Improving diagnosis through microbiological confirmation of TB and HIV are major challenges to be addressed.

Successful implementation of bedaquiline for multidrug-resistant TB treatment in remote Papua New Guinea.

SETTING: Bedaquiline (BDQ) was introduced in the multi-drug-resistant tuberculosis (MDR-TB) programme in Daru in remote Papua New Guinea in 2015, along with a core package of active drug-safety monitoring (aDSM). OBJECTIVE: To assess interim results and safety of BDQ for the treatment of MDR-TB from 1 July 2015 to 31 December 2017. DESIGN: A retrospective cohort analysis of routine programme data. RESULTS: Of 277 MDR-TB patients, 77 (39%) received BDQ with a total of 8 serious adverse events including 5 (6.5%) deaths, of which 1 (1.3% QTcF prolongation, grade 3) was attributable to BDQ. Of 200 (61%) patients who did not receive BDQ, there were 17 (9%) deaths. Completeness of monitoring for the BDQ group was 90% for >5 electrocardiograms and 79% for ⩾2 cultures. In the interim result indicator analysis at month 6 in the BDQ and non-BDQ groups, there were respectively 0% and 1% lost to follow-up; 6.5% and 8.5% who died; 94% and 91% in care; and 92% and 96% with negative culture among those monitored. CONCLUSION: Early experience in Daru shows BDQ is safe and feasible to implement with aDSM with good interim effectiveness supporting the rapid adoption and scale-up of the 2019 WHO MDR-TB treatment guidelines in the programme and in similar remote settings.

Impact of pyrazinamide resistance on multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan.

SETTING: The World Health Organization (WHO) recommends the inclusion of pyrazinamide (PZA) in treatment regimens for multidrug-resistant tuberculosis (MDR-TB) unless resistance has been confirmed. OBJECTIVE: To investigate the association between PZA susceptibility and MDR-TB treatment outcome among patients treated with a PZA-containing regimen and whether the duration of the intensive phase of the PZA-containing regimen affected treatment outcome. DESIGN: We conducted a retrospective cohort study including all eligible MDR-TB patients starting treatment in 2003-2013 in the TB programme in Karakalpakstan, Uzbekistan. PZA drug susceptibility testing (DST) using liquid culture was performed, and outcomes were classified according to the WHO 2013 definitions. RESULTS: Of 2446 MDR-TB patients included, 832 (34.0%) had an available baseline PZA DST result, 612 (73.6%) of whom were PZA-resistant. We found no association between treatment success and PZA susceptibility (adjusted odds ratio [aOR] 0.86, 95%CI 0.51-1.44, P = 0.6) in patients treated with PZA. Furthermore, among patients with no baseline PZA DST result, no evidence was seen of an association between treatment success and PZA treatment duration (aOR 0.86, 95%CI 0.49-1.51, P = 0.6). CONCLUSION: Treatment of MDR-TB with a standard PZA regimen does not appear to improve treatment outcomes, regardless of PZA susceptibility or duration of treatment.

Treating children for drug-resistant tuberculosis in Tajikistan with Group 5 medications.

BACKGROUND: Management of extensively drug-resistant tuberculosis (XDR-TB) and pre-XDR-TB is challenging, as effective drugs are lacking. Group 5 anti-tuberculosis drugs have an unclear role in the treatment of drug-resistant TB, and in children the efficacy, safety and effects of long-term use are not well described. We present clinical outcomes and adverse effects of a cohort of children with XDR-TB or pre-XDR-TB treated with Group 5 drugs in Tajikistan. METHODS: We conducted a retrospective analysis of eight children treated with one or more of the Group 5 drugs available under the Tajikistan National TB Programme-linezolid, amoxicillin-clavulanate, clofazimine and clarithromycin-given in combination with first- and second-line drugs. Time to sputum culture conversion, clinical outcomes and adverse effects were evaluated. RESULTS: Two children were cured, one completed treatment, four achieved favourable interim outcomes and one died. Adverse effects attributable to linezolid that required drug cessation occurred in one child; adverse effects of the other Group 5 drugs were insignificant or absent, requiring no regimen changes. CONCLUSION: Group 5 drugs can contribute to effective regimens in children with XDR and pre-XDR-TB. With proper monitoring and aggressive management of adverse effects, their safety profile might be acceptable, even in long-term use.

'They prefer hidden treatment': anti-tuberculosis drug-taking practices and drug regulation in Karakalpakstan.

SETTING: The joint Médecins Sans Frontières/Ministry of Health Multidrug-Resistant Tuberculosis (MDR-TB) Programme, Karakalpakstan, Uzbekistan. OBJECTIVE: Uzbekistan has high rates of MDR-TB. We aimed to understand patients' and prescribers' attitudes to anti-tuberculosis drug prescription, regulation and drug-taking behaviour. METHODS: Participants (12 patients, 12 practitioners) were recruited purposively. Data were gathered qualitatively using field notes and in-depth interviews and analysed thematically. FINDINGS: Our analysis highlighted two main themes. First, shame and stigma were reported to increase the likelihood of self-treatment and incorrect use of anti-tuberculosis drugs, most commonly at the initial stages of illness. A health system failure to promote health information was perceived, leading to wrong diagnoses and inappropriate therapies. Motivated by shame, patients hid their condition by resorting to drug treatment options outside the programme, compounding the risk of chaotic management and dissemination of erroneous information through lay networks. Second, positive influences on treatment were reported through patients, practitioners and peers working effectively together to deliver the correct information and support, which acted to normalise TB, reduce stigma and prevent misuse of anti-tuberculosis drugs. CONCLUSION: Effective case finding, patient support and community education strategies are essential. Patients, practitioners and peers working together can help reduce stigma and prevent misuse of anti-tuberculosis drugs.

Identification of patients who could benefit from bedaquiline or delamanid: a multisite MDR-TB cohort study.

BACKGROUND: The World Health Organization recommends adding bedaquiline or delamanid to multidrug-resistant tuberculosis (MDR-TB) regimens for which four effective drugs are not available, and delamanid for patients at high risk of poor outcome. OBJECTIVE: To identify patients at risk of unfavourable outcomes who may benefit from the new drugs. METHODS: Retrospective cohort study of treatment outcomes involving four to five effective drugs for 15-24 months in programmes in Uzbekistan, Georgia, Armenia, Swaziland and Kenya between 2001 and 2011. RESULTS: Of 1433 patients, 48.5% had body mass index (BMI) <18.5 kg/m(2), 72.9% had a high bacillary load, 16.7% were resistant to two injectables, 2.9% were resistant to ofloxacin (OFX) and 3.0% had extensively drug-resistant TB (XDR-TB). Treatment success ranged from 59.7% (no second-line resistance) to 27.0% (XDR-TB). XDR-TB (aOR 8.16, 95%CI 3.22-20.64), resistance to two injectables (aOR 1.90, 95%CI 1.00-3.62) or OFX (aOR 5.56, 95%CI 2.15-14.37), past incarceration (aOR 1.88, 95%CI 1.11-3.2), history of second-line treatment (aOR 3.24, 95%CI 1.53-6.85), low BMI (aOR 2.22, 95%CI 1.56-3.12) and high bacillary load (aOR 2.32, 95%CI 1.15-4.67) were associated with unfavourable outcomes. Patients started on capreomycin rather than kanamycin were more likely to have an unfavourable outcome (aOR 1.54, 95%CI 1.04-2.28). CONCLUSION: In our cohort, patients who may benefit from bedaquiline and delamanid represented up to two thirds of all MDR-TB patients.

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.

Challenges and solutions to implementing drug-resistant tuberculosis programmes for children in Central Asia.

Guidelines for children with drug-resistant tuberculosis (DR-TB) tend to focus on individual patient care; there is little guidance for national tuberculosis programmes (NTPs) on how to plan, implement and integrate DR-TB services for children. In 2013, through the paediatric tuberculosis (TB) programme started by the Tajikistan Ministry of Health and Médecins Sans Frontières in 2011, 21 children became the first to be treated for multidrug-resistant tuberculosis (MDR-TB) in Tajikistan. We describe the challenges encountered in establishing the programme and the solutions to these challenges, and propose a framework to guide the implementation of paediatric DR-TB care. This framework could prove useful for other NTPs in resource-limited settings.

Les directives relatives aux enfants atteints de tuberculose pharmacorésistante (TB-DR) ont tendance à se focaliser sur la prise en charge des patients individuels; il y a par contre peu de directives destinées aux programmes nationaux de lutte contre la TB (PNT) sur la manière de planifier, mettre en œuvre et intégrer les services de TB-DR destinés aux enfants. En 2013, dans un programme de prise en charge de la TB pédiatrique démarré par le Ministère de la Santé et Médecins Sans Frontières en 2011, 21 enfants ont été les premiers à être traités pour TB-MDR (TB multi-résistante) au Tadjikistan. Nous décrivons les défis de la mise en œuvre d'un programme et de leurs solutions et proposons un cadre conceptuel d'aide à la mise en œuvre de la prise en charge de la TB-DR pédiatrique. Notre cadre pourrait s'avérer utile pour d'autres PNT dans des contextes de ressources limitées.

Las directrices sobre el manejo de los niños con diagnóstico de tuberculosis drogorresistente (TB-MDR) suelen centrarse en la atención del paciente individual; existe poca orientación dirigida a los Programas Nacionales contra la Tuberculosis (PNT) en materia de planeamiento, ejecución e integración de los servicios que se ocupan de la TB-DR en los niños. El Ministerio de Salud y Médecins Sans Frontières iniciaron en el 2011 un programa de TB dirigido a los niños y en el 2013, por primera vez, 21 niños recibieron tratamiento contra la TB-MDR (multidrogorresistente) en Tayikistán. En el presente artículo se describen los obstáculos encontrados durante la introducción del programa, las soluciones que se aportaron y se propone un marco de trabajo encaminado a orientar la ejecución de la atención pediátrica de la TB-MDR. Este marco será útil a otros PNT en entornos con recursos limitados.

A bitter pill to swallow: the need for better medications for drug-resistant tuberculosis in children.

The large and growing access gap between the number of children who become sick with drug-resistant tuberculosis (DR-TB) and those who are treated for the disease each year represents a significant health systems failure. While there are multiple reasons why children with DR-TB are not diagnosed and treated, a serious challenge is the medications used to treat the disease. This paper presents three child DR-TB cases who were treated incorrectly; the cases are used to illustrate some of the problems with existing second-line medications. Challenges, including the perception that the drugs are more dangerous than the disease, lack of proper dosing recommendations and formulations, and the high cost of current treatment, all contribute to a perverse situation in which the most vulnerable pediatric patients are provided with a lower standard of care. This situation can be reversed with novel partnerships and training models, pharmacokinetic studies of the relevant drugs, increased collaboration, and dedicated funding, grounded in a rights-based approach to DR-TB in children.

Strategies for reducing treatment default in drug-resistant tuberculosis: systematic review and meta-analysis.

BACKGROUND: Scaling up treatment for multidrug-resistant tuberculosis is a global health priority. However, current treatment regimens are long and associated with side effects, and default rates are consequently high. This systematic review aimed to identify strategies for reducing treatment default. METHODS: We conducted a systematic search up to May 2012 to identify studies describing interventions to support patients receiving treatment for multidrug-resistant tuberculosis (MDR-TB). The potential influence of study interventions were explored through subgroup analyses. RESULTS: A total of 75 studies provided outcomes for 18,294 patients across 31 countries. Default rates ranged from 0.5% to 56%, with a pooled proportion of 14.8% (95%CI 12.4-17.4). Strategies identified to be associated with lower default rates included the engagement of community health workers as directly observed treatment (DOT) providers, the provision of DOT throughout treatment, smaller cohort sizes and the provision of patient education. CONCLUSION: Current interventions to support adherence and retention are poorly described and based on weak evidence. This review was able to identify a number of promising, inexpensive interventions feasible for implementation and scale-up in MDR-TB programmes. The high default rates reported from many programmes underscore the pressing need to further refine and evaluate simple intervention packages to support patients.

Towards the WHO target of zero childhood tuberculosis deaths: an analysis of mortality in 13 locations in Africa and Asia.

SETTING: Achieving the World Health Organization (WHO) target of zero paediatric tuberculosis (TB) deaths will require an understanding of the underlying risk factors for mortality. OBJECTIVE: To identify risk factors for mortality and assess the impact of human immunodeficiency virus (HIV) testing during anti-tuberculosis treatment in children in 13 TB-HIV programmes run by Médecins Sans Frontières. DESIGN: In a retrospective cohort study, we recorded mortality and analysed risk factors using descriptive statistics and logistic regression. Diagnosis was based on WHO algorithm and smear microscopy. RESULTS: A total of 2451 children (mean age 5.2 years, SD 3.9) were treated for TB. Half (51.0%) lived in Asia, the remainder in sub-Saharan Africa; 56.0% had pulmonary TB; 6.4% were diagnosed using smear microscopy; 211 (8.6%) died. Of 1513 children tested for HIV, 935 (61.8%) were positive; 120 (12.8%) died compared with 30/578 (5.2%) HIV-negative children. Risk factors included being HIV-positive (OR 2.6, 95%CI 1.6-4.2), age <5 years (1.7, 95%CI 1.2-2.5) and having tuberculous meningitis (2.6, 95%CI 1.0-6.8). Risk was higher in African children of unknown HIV status than in those who were confirmed HIV-negative (1.9, 95%CI 1.1-3.3). CONCLUSIONS: Strategies to eliminate childhood TB deaths should include addressing the high-risk groups identified in this study, enhanced TB prevention, universal HIV testing and the development of a rapid diagnostic test.