The European & Developing Countries Clinical Trials Partnership (EDCTP) Knowledge Hub: developing an open platform for facilitating high-quality clinical research.

There is stark global inequity in health research in terms of where studies happen, who leads the research and the ultimate beneficiaries of the results generated. Despite significant efforts made, limited research ideas are conceptualised and implemented in low-resource settings to tackle diseases of poverty, and this is especially true in sub-Saharan Africa. There is strong evidence to show that the barriers to locally led research do not vary largely between disease, study type and location and can be largely solved by addressing these common gaps. The European & Developing Countries Clinical Trials Partnership (EDCTP) was established in 2003 as a European response to the global health crisis caused by the three main poverty-related diseases HIV, tuberculosis and malaria. EDCTP has established a model of long-term sustainable capacity development integrated into clinical trials which addresses this lack of locally led research in sub-Saharan Africa, supporting the development of individual and institutional capacity and research outputs that change the management, prevention and treatment of poverty-related and neglected infectious diseases across Africa. In recognition of emergent data on what the barriers and enablers are to long-term, sustainable capabilities to run studies, EDCTP formed a new collaboration with The Global Health Network (TGHN) in September 2017, with the aim to make a set of cross-cutting tools and resources to support the planning, writing and delivery of high-quality clinical trials available to research staff wherever they are in the world, especially those in low- and middle-income countries (LMICs) via TGHN platform. These new resources developed on the 'EDCTP Knowledge Hub' are those identified in the mixed method study described in this commentary as being key to addressing the gaps that the research community report as the most limiting elements in their ability to design and implement studies. The Knowledge Hub aims to make these tools freely available to any potential health research team in need of support and guidance in designing and running their own studies, particularly in low-resource settings. The purpose is to provide open access to the specific guidance, information and tools these teams cannot otherwise access freely. Ultimately, this will enable them to design and lead their own high-quality studies addressing local priorities with global alignment, generating new data that can change health outcomes in their communities.

Rapid molecular diagnostics of tuberculosis resistance by targeted stool sequencing.

BACKGROUND: Stool is an important diagnostic specimen for tuberculosis in populations who struggle to provide sputum, such as children or people living with HIV. However, the culture of Mycobacterium tuberculosis (M. tuberculosis) complex strains from stool perform poorly. This limits the opportunity for phenotypic drug resistance testing with this specimen. Therefore, reliable molecular methods are urgently needed for comprehensive drug resistance testing on stool specimens. METHODS: We evaluated the performance of targeted next-generation sequencing (tNGS, Deeplex® Myc-TB) for the detection of mutations associated with M. tuberculosis complex drug resistance on DNA isolated from stool specimens provided by participants from a prospective cohort of patients treated for tuberculosis in Eswatini (n = 66; 56 with and 10 participants without M. tuberculosis complex DNA detected in stool by real-time quantitative PCR), and an independent German validation cohort of participants with culture-confirmed tuberculosis (n = 21). RESULTS: The tNGS assay detected M. tuberculosis complex DNA in 38 of 56 (68%) samples; for 28 of 38 (74%) samples, a full M. tuberculosis complex drug resistance prediction report was obtained. There was a high degree of concordance with sputum phenotypic drug susceptibility results (κ = 0.82). The ability to predict resistance was concentration-dependent and successful in 7/10 (70%), 18/25 (72%), and 3/21 (14%) of samples with stool PCR concentration thresholds of > 100 femtogram per microliter (fg/µl), 1 to 100 fg/µl, and < 1 fg/µl, respectively (p = 0.0004). The German cohort confirmed these results and demonstrated a similarly high concordance between stool tNGS and sputum phenotypic drug susceptibility results (κ = 0.84). CONCLUSIONS: tNGS can identify drug resistance from stool provided by tuberculosis patients. This affords the opportunity to obtain critical diagnostic information for tuberculosis patients who struggle to provide respiratory specimens.

Vikela Ekhaya: A Novel, Community-based, Tuberculosis Contact Management Program in a High Burden Setting.

BACKGROUND: The prevention of tuberculosis (TB) in child contacts of TB cases and people living with human immunodeficiency virus (HIV) is a public health priority, but global access to TB preventive therapy (TPT) remains low. In 2019, we implemented Vikela Ekhaya, a novel community-based TB contact management program in Eswatini designed to reduce barriers to accessing TPT. METHODS: Vikela Ekhaya offered differentiated TB and HIV testing for household contacts of TB cases by using mobile contact management teams to screen contacts, assess their TPT eligibility, and initiate and monitor TPT adherence in participants' homes. RESULTS: In total, 945 contacts from 244 households were screened for TB symptoms; 72 (8%) contacts reported TB symptoms, and 5 contacts (0.5%) were diagnosed with prevalent TB. A total of 322 of 330 (98%) eligible asymptomatic household contacts initiated TPT. Of 322 contacts initiating TPT, 248 children initiated 3 months of isoniazid and rifampicin and 74 children and adults living with HIV initiated 6 months of isoniazid; 298 (93%) completed TPT. In clustered logistic regression analyses, unknown HIV status (adjusted odds ratio [aOR] 5.7, P = .023), positive HIV status (aOR 21.1, P = .001), urban setting (aOR 5.6, P = .006), and low income (aOR 5.9, P = .001) predicted loss from the cascade of care among TPT-eligible contacts. CONCLUSION: Vikela Ekhaya demonstrated that community-based TB household contact management is a feasible, acceptable, and successful strategy for TB screening and TPT delivery. The results of this study support the development of novel, differentiated, community-based interventions for TB prevention and control.

Situating trade-offs: Stakeholder perspectives on overtreatment versus missed diagnosis in transition to Xpert MTB/RIF Ultra in Kenya and Swaziland.

Implementing new diagnostics in public health programs can involve difficult trade-off decisions between individual patient benefits and public health considerations. Such decision-making processes are often not documented and may not include engagement of affected communities. This paper examines the perspectives of stakeholders on the trade-off between over-treatment and missed diagnosis captured during decision-making workshops on the transition from use of Xpert MTB/RIF to diagnose tuberculosis to Xpert MTB/RIF Ultra in Kenya and Swaziland. Xpert MTB/RIF Ultra has an overall increase in sensitivity but a decrease in specificity when compared to its predecessor. We conducted a qualitative study using four focus group discussions with a total of 47 participants and non-participant observation. The analysis reveals how participants deemed Xpert MTB/RIF Ultra's reduced specificity vis-à-vis its increased sensitivity to be an acceptable trade-off. The way participants assessed this trade-off was shaped by their experiences with the general uncertainty of all diagnostic tests, alternative testing options, historical evolution of diagnostic practices, epidemiological factors and resource constraints. In assessing the trade-off community and individual benefit and harm was frequently discussed together. Qualitative research on stakeholder engagement activities for diagnostic development and implementation can identify everyday experiences and situate assessments and perspectives of key stakeholders and as such aid in decision-making, improving implementation as well as patient outcomes. Further research is needed on the intended and unintended consequences of such engagement activities, how findings are being incorporated by decision-makers, and the impact on programmatic implementation.

Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.

Decreased risk of HIV-associated TB during antiretroviral therapy expansion in rural Eswatini from 2009 to 2016: a cohort and population-based analysis.

OBJECTIVES: This paper assesses patient- and population-level trends in TB notifications during rapid expansion of antiretroviral therapy in Eswatini which has an extremely high incidence of both TB and HIV. METHODS: Patient- and population-level predictors and rates of HIV-associated TB were examined in the Shiselweni region in Eswatini from 2009 to 2016. Annual population-level denominators obtained from projected census data and prevalence estimates obtained from population-based surveys were combined with individual-level TB treatment data. Patient- and population-level predictors of HIV-associated TB were assessed with multivariate logistic and multivariate negative binomial regression models. RESULTS: Of 11 328 TB cases, 71.4% were HIV co-infected and 51.8% were women. TB notifications decreased fivefold between 2009 and 2016, from 1341 to 269 cases per 100 000 person-years. The decline was sixfold in PLHIV vs. threefold in the HIV-negative population. Main patient-level predictors of HIV-associated TB were recurrent TB treatment (adjusted odds ratio [aOR] 1.40, 95% confidence interval [CI]: 1.19-1.65), negative (aOR 1.31, 1.15-1.49) and missing (aOR 1.30, 1.11-1.53) bacteriological status and diagnosis at secondary healthcare level (aOR 1.18, 1.06-1.33). Compared with 2009, the probability of TB decreased for all years from 2011 (aOR 0.69, 0.58-0.83) to 2016 (aOR 0.54, 0.43-0.69). The most pronounced population-level predictor of TB was HIV-positive status (adjusted incidence risk ratio 19.47, 14.89-25.46). CONCLUSIONS: This high HIV-TB prevalence setting experienced a rapid decline in TB notifications, most pronounced in PLHIV. Achievements in HIV-TB programming were likely contributing factors.

OBJECTIFS: Ce document évalue les tendances des notifications de la tuberculose (TB) à l'échelle des patients et de la population lors de l'expansion rapide du traitement antirétroviral à Eswatini, où l'incidence de la TB et du VIH est extrêmement élevée. MÉTHODES: Les prédicteurs et les taux de TB associée au VIH à l'échelle des patients et de la population ont été examinés dans la région de Shiselweni à Eswatini de 2009 à 2016. Les dénominateurs annuels à l'échelle de la population obtenus à partir des données de recensement projetées et des estimations de la prévalence obtenues à partir d'enquêtes de population ont été combinés avec des données de traitement de la TB à l'échelle individuel. Les prédicteurs de la TB associée au VIH à l'échelle du patient et de la population ont été évalués à l'aide de modèles de régression logistique multivariée et binomiale négative multivariée. RÉSULTATS: Sur 11.328 cas de TB, 71,4% étaient coinfectés par le VIH et 51,8% étaient des femmes. Les notifications de TB ont été réduites de 5,0 fois entre 2009 et 2016, passant de 1.341 à 269 cas par 100.000 personnes-années. Le déclin était de 6,0 fois chez les PVVIH contre 3,0 fois dans la population négative pour le VIH. Les principaux prédicteurs de la TB associée au VIH à l'échelle des patients étaient les traitements antituberculeux récurrents (rapport de cotes ajusté [aOR] 1,40; intervalle de confiance à 95% [IC]: 1,19 à 1,65), un statut bactériologique négatif (aOR: 1,31; 1,15 à 1,49) et manquant (aOR: 1,30; 1,11 à 1,53) et le diagnostic au niveau des soins de santé secondaires (AOR 1,18; 1,06 à 1,33). Par rapport à 2009, la probabilité de contracter la TB a diminué pour toutes les années, de 2011 (aOR: 0,69; 0,58 à 0,83) à 2016 (aOR: 0,5; 0,43 à 0,69). Le prédicteur le plus prononcé de la TB à l'échelle de la population était le statut VIH-positif (rapport de risque d'incidence ajusté: 19,47; 14,89 à 25,46). CONCLUSIONS: Ce contexte de prévalence élevée de la TB-VIH a connu un déclin rapide du nombre de notifications de TB, plus prononcé chez les PVVIH. Les réalisations dans la programmation VIH-TB étaient probablement des facteurs contributifs.

Leveraging tuberculosis case relative locations to enhance case detection and linkage to care in Swaziland.

BACKGROUND: In Swaziland, as in many high HIV/TB burden settings, there is not information available regarding the household location of TB cases for identifying areas of increased TB incidence, limiting the development of targeted interventions. Data from "Butimba", a TB REACH active case finding project, was re-analyzed to provide insight into the location of TB cases surrounding Mbabane, Swaziland. OBJECTIVE: The project aimed to identify geographical areas with high TB burdens to inform active case finding efforts. METHODS: Butimba implemented household contact tracing; obtaining landmark based, informal directions, to index case homes, defined here as relative locations. The relative locations were matched to census enumeration areas (known location reference areas) using the Microsoft Excel Fuzzy Lookup function. Of 403 relative locations, an enumeration area reference was detected in 388 (96%). TB cases in each census enumeration area and the active case finders in each Tinkhundla, a local governmental region, were mapped using the geographic information system, QGIS 2.16. RESULTS: Urban Tinkhundla predictably accounted for most cases; however, after adjusting for population, the highest density of cases was found in rural Tinkhundla. There was no correlation between the number of active case finders currently assigned to the 7 Tinkhundla surrounding Mbabane and the total number of TB cases (Spearman rho = -0.57, p = 0.17) or the population adjusted TB cases (Spearman rho = 0.14, p = 0.75) per Tinkhundla. DISCUSSION: Reducing TB incidence in high-burden settings demands novel analytic approaches to study TB case locations. We demonstrated the feasibility of linking relative locations to more precise geographical areas, enabling data-driven guidance for National Tuberculosis Programs' resource allocation. In collaboration with the Swazi National Tuberculosis Control Program, this analysis highlighted opportunities to better align the active case finding national strategy with the TB disease burden.

Prognostic indicators in the World Health Organization's algorithm for seriously ill HIV-infected inpatients with suspected tuberculosis.

BACKGROUND: Criteria for the 2007 WHO algorithm for diagnosing tuberculosis among HIV-infected seriously ill patients are the presence of one or more danger signs (respiratory rate > 30/min, heart rate > 120/min, temperature > 39 °C, and being unable to walk unaided) and cough ≥ 14 days. Determining predictors of poor outcomes among HIV-infected inpatients presenting with WHO danger signs could result in improved treatment and diagnostic algorithms. METHODS: We conducted a prospective cohort study of inpatients presenting with any duration of cough and WHO danger signs to two regional hospitals in Cape Town, South Africa. The primary outcome was all-cause mortality up to 56 days post-discharge, and the secondary outcome a composite of any one of: hospital admission for > 7 days, died in hospital, transfer to a tertiary level or tuberculosis hospital. We first assessed the WHO danger signs as predictors of poor outcomes, then assessed the added value of other variables selected a priori for their ability to predict mortality in common respiratory opportunistic infections (CD4 count, body mass index (BMI), being on antiretroviral therapy (ART), hypotension, and confusion) by comparing the receiver operating characteristic (ROC) area under the curve (AUC) of the two multivariate models. RESULTS: 484 participants were enrolled, median age 36, 66% women, 53% had tuberculosis confirmed on culture. The 56-day mortality was 13.2%. Inability to walk unaided, low BMI, low CD4 count, and being on ART were independently associated with poor outcomes. The multivariate model of the WHO danger signs showed a ROC AUC of 0.649 (95% CI 0.582-0.717) for predicting 56-day mortality, which improved to ROC AUC of 0.740 (95% CI 0.681-0.800; p = 0.004 for comparison between the two ROC AUCs) with the multivariate model including the a priori selected variables. Findings were similar in sub-analyses of participants with culture-positive tuberculosis and with cough duration ≥ 14 days. CONCLUSION: The study design prevented a rigorous evaluation of the prognostic value of the WHO danger signs. Our prognostic model could result in improved algorithms, but needs to be validated.

Optimizing Tuberculosis Diagnosis in Human Immunodeficiency Virus-Infected Inpatients Meeting the Criteria of Seriously Ill in the World Health Organization Algorithm.

Background: The World Health Organization (WHO) algorithm for the diagnosis of tuberculosis in seriously ill human immunodeficiency virus (HIV)-infected patients lacks a firm evidence base. We aimed to develop a clinical prediction rule for the diagnosis of tuberculosis and to determine the diagnostic utility of the Xpert MTB/RIF assay in seriously ill HIV-infected patients. Methods: We conducted a prospective study among HIV-infected inpatients with any cough duration and WHO-defined danger signs. Culture-positive tuberculosis from any site was the reference standard. A priori selected variables were assessed for univariate associations with tuberculosis. The most predictive variables were assessed in a multivariate logistic regression model and used to establish a clinical prediction rule for diagnosing tuberculosis. Results: We enrolled 484 participants. The median age was 36 years, 65.5% were female, the median CD4 count was 89 cells/µL, and 35.3% were on antiretroviral therapy. Tuberculosis was diagnosed in 52.7% of participants. The c-statistic of our clinical prediction rule (variables: cough ≥14 days, unable to walk unaided, temperature >39°C, chest radiograph assessment, hemoglobin, and white cell count) was 0.811 (95% confidence interval, .802-.819). The classic tuberculosis symptoms (fever, night sweats, weight loss) added no discriminatory value in diagnosing tuberculosis. Xpert MTB/RIF assay sensitivity was 86.3% and specificity was 96.1%. Conclusions: Our clinical prediction rule had good diagnostic utility for tuberculosis among seriously ill HIV-infected inpatients. Xpert MTB/RIF assay, incorporated into the updated 2016 WHO algorithm, had high sensitivity and specificity in this population. Our findings could facilitate improved diagnosis of tuberculosis among seriously ill HIV-infected inpatients in resource-constrained settings.

Effectiveness and safety of standardised shorter regimens for multidrug-resistant tuberculosis: individual patient data and aggregate data meta-analyses.

We assessed the effectiveness and safety of standardised, shorter multidrug-resistant tuberculosis (MDR-TB) regimens by pooling data from observational studies.Published studies were identified from medical databases; unpublished studies were identified from expert consultation. We conducted aggregate data meta-analyses to estimate pooled proportions of treatment outcomes and individual patient data (IPD) meta-regression to identify risk factors for unsuccessful treatment in patients treated with 9- to 12-month MDR-TB regimens composed of a second-line injectable, gatifloxacin/moxifloxacin, prothionamide, clofazimine, isoniazid, pyrazinamide and ethambutol.We included five studies in which 796 out of 1279 (62.2%) individuals with confirmed MDR-TB (98.4%) or rifampin-resistant TB (1.6%), and not previously exposed to second-line drugs, were eligible for shorter regimens. 669 out of 796 participants were successfully treated (83.0%, 95% CI 71.9-90.3%). In IPD meta-regression (three studies, n=497), failure/relapse was associated with fluoroquinolone resistance (crude OR 46, 95% CI 8-273), pyrazinamide resistance (OR 8, 95% CI 2-38) and no culture conversion by month 2 of treatment (OR 7, 95% CI 3-202). Two participants acquired extensive drug resistance. Four studies reported grade 3 or 4 adverse events in 55 out of 304 (18.1%) participants.Shorter regimens were effective in treating MDR-TB; however, there is uncertainty surrounding the generalisability of the high rate of treatment success to less selected populations, to programmatic settings and in the absence of drug susceptibility tests to key component drugs.

BUTIMBA: Intensifying the Hunt for Child TB in Swaziland through Household Contact Tracing.

BACKGROUND: Limited data exists to inform contact tracing guidelines in children and HIV-affected populations. We evaluated the yield and additionality of household contact and source case investigations in Swaziland, a TB/HIV high-burden setting, while prioritizing identification of childhood TB. METHODS: In partnership with 7 local TB clinics, we implemented standardized contact tracing of index cases (IC) receiving TB treatment. Prioritizing child contacts and HIV-affected households, screening officers screened contacts for TB symptoms and to identify risk factors associated with TB. We ascertained factors moderating the yield of contact tracing and measured the impact of our program by additional notifications. RESULTS: From March 2013 to November 2015, 3,258 ICs (54% bacteriologically confirmed; 70% HIV-infected; 85% adults) were enrolled leading to evaluation of 12,175 contacts (median age 18 years, IQR 24-42; 45% children; 9% HIV-infected). Among contacts, 196 TB cases (56% bacteriologically confirmed) were diagnosed resulting in a program yield of 1.6% for all forms of TB. The number needed to screen (NNS) to identify a bacteriologically confirmed TB case or all forms TB case traced from a child IC <5 years was respectively 62% and 40% greater than the NNS for tracing from an adult IC. In year one, we demonstrated a 32% increase in detection of bacteriologically confirmed child TB. Contacts were more likely to have TB if <5 years (OR = 2.0), HIV-infected (OR = 4.9), reporting ≥1 TB symptoms (OR = 7.7), and sharing a bed (OR = 1.7) or home (OR = 1.4) with the IC. There was a 1.4 fold increased chance of detecting a TB case in households known to be HIV-affected. CONCLUSION: Contact tracing prioritizing children is not only feasible in a TB/HIV high-burden setting but contributes to overall case detection. Our findings support WHO guidelines prioritizing contact tracing among children and HIV-infected populations while highlighting potential to integrate TB and HIV case finding.

Upholding Tuberculosis Services during the 2014 Ebola Storm: An Encouraging Experience from Conakry, Guinea.

SETTING: Ten targeted health facilities supported by Damien Foundation (a Belgian Non Governmental Organization) and the National Tuberculosis (TB) Program in Conakry, Guinea. OBJECTIVES: To uphold TB program performance during the Ebola outbreak in the presence of a package of pre-emptive additional measures geared at reinforcing the routine TB program, and ensuring Ebola infection control, health-workers safety and motivation. DESIGN: A retrospective comparative cohort study of a TB program assessing the performance before (2013) and during the (2014) Ebola outbreak. RESULTS: During the Ebola outbreak, all health facilities were maintained opened, there were no reported health-worker Ebola infections, drug stockouts or health staff absences. Of 2,475 presumptive pulmonary TB cases, 13% were diagnosed with TB in both periods (160/1203 in 2013 and 163/1272 in 2014). For new TB, treatment success improved from 84% before to 87% during the Ebola outbreak (P = 0.03). Adjusted Hazard-ratios (AHR) for an unfavorable outcome was alwo lower during the Ebola outbreak, AHR = 0.8, 95% CI:0.7-0.9, P = 0.04). Treatment success improved for HIV co-infected patients (72% to 80%, P<0.01). For retreatment patients, the proportion achieving treatment success was maintained (68% to 72%, P = 0.05). Uptake of HIV-testing and Cotrimoxazole Preventive Treatment was maintained over 85%, and Anti-Retroviral Therapy uptake increased from 77% in 2013 to 86% in 2014 (P<0.01). CONCLUSION: Contingency planning and health system and worker support during the 2014 Ebola outbreak was associated with encouraging and sustained TB program performance. This is of relevance to future outbreaks.

Multicenter Noninferiority Evaluation of Hain GenoType MTBDRplus Version 2 and Nipro NTM+MDRTB Line Probe Assays for Detection of Rifampin and Isoniazid Resistance.

Less than 30% of multidrug-resistant tuberculosis (MDR-TB) patients are currently diagnosed, due to laboratory constraints. Molecular diagnostics enable rapid and simplified diagnosis. Newer-version line probe assays have not been evaluated against the WHO-endorsed Hain GenoType MTBDRplus (referred to as Hain version 1 [V1]) for the rapid detection of rifampin (RIF) and isoniazid (INH) resistance. A two-phase noninferiority study was conducted in two supranational reference laboratories to allow head-to-head comparisons of two new tests, Hain Genotype MTBDRplus version 2 (referred to as Hain version 2 [V2]) and Nipro NTM+MDRTB detection kit 2 (referred to as Nipro), to Hain V1. In phase 1, the results for 379 test strains were compared to a composite reference standard that used phenotypic drug susceptibility testing (DST) and targeted sequencing. In phase 2, the results for 644 sputum samples were compared to a phenotypic DST reference standard alone. Using a challenging set of strains in phase 1, the values for sensitivity and specificity for Hain V1, Hain V2, and Nipro, respectively, were 90.3%/98.5%, 90.3%/98.5%, and 92.0%/98.5% for RIF resistance detection and 89.1%/99.4%, 89.1%/99.4%, and 89.6%/100.0% for INH resistance detection. Testing of sputa in phase 2 yielded values for sensitivity and specificity of 97.1%/97.1%, 98.2%/97.8%, and 96.5%/97.5% for RIF and 94.4%/96.4%, 95.4%/98.8%, and 94.9%/97.6% for INH. Overall, the rates of indeterminate results were low, but there was a higher rate of indeterminate results with Nipro than with Hain V1 and V2 in samples with low smear grades. Noninferiority of Hain V2 and Nipro to Hain V1 was demonstrated for RIF and INH resistance detection in isolates and sputum specimens. These results serve as evidence for WHO policy recommendations on the use of line probe assays, including the Hain V2 and Nipro assays, for MDR-TB detection.

Diagnostic accuracy of a rapid urine lipoarabinomannan test for tuberculosis in HIV-infected adults.

OBJECTIVE: In settings of high HIV prevalence, tuberculosis control and patient management are hindered by lack of accurate, rapid tuberculosis diagnostic tests that can be performed at point-of-care. The Determine TB LAM Ag (TB LAM) test is a lateral flow immunochromatographic test for detection of mycobacterial lipoarabinomannan (LAM) in urine. Our objective was to determine sensitivity and specificity of the TB LAM test for tuberculosis diagnosis. DESIGN: Prospective diagnostic accuracy study. SETTING: Hospital and outpatient settings in Uganda and South Africa. PARTICIPANTS: HIV-infected adults with tuberculosis symptoms and/or signs. METHODS: Participants provided a fresh urine specimen for TB LAM testing, blood for mycobacterial culture, and 2 respiratory specimens for smear microscopy and mycobacterial culture. MAIN OUTCOME MEASURES: For the TB LAM test, sensitivity in participants with culture-positive tuberculosis and specificity in participants without tuberculosis. RESULTS: A total of 1013 participants were enrolled. Among culture-positive tuberculosis patients, the TB LAM test identified 136/367 (37.1%) overall and 116/196 (59.2%) in the group with CD4 ≤100 cells per cubic millimeter. The test was specific in 559/573 (97.6%) patients without tuberculosis. Sensitivity of the urine TB LAM test plus sputum smear microscopy was 197/367 (53.7%) overall and 133/196 (67.9%) among those with CD4 ≤100. CD4 ≤50 [adjusted odds ratio (AOR), 6.2; P < 0.001] or 51-100 (AOR, 7.1; P < 0.001), mycobacteremia (AOR, 6.1; P < 0.01) and hospitalization (AOR, 2.6; P = 0.03) were independently associated with a positive TB LAM test. CONCLUSIONS: In HIV-positive adults with CD4 ≤100, the TB LAM urine test detected over half of culture-positive tuberculosis patients, in <30 minutes and without the need for equipment or reagents.

Diagnostic features associated with culture of Mycobacterium tuberculosis among young children in a vaccine trial setting.

OBJECTIVES: To identify diagnostic features associated with culture of Mycobacterium tuberculosis (MTB), the standard for tuberculosis (TB) diagnosis, to inform clinical end point definitions for new TB vaccine trials. METHODS: Children <2 years of age (n = 1445) were screened and investigated for TB during a Bacille Calmette Guerin vaccine trial in South Africa. Standardized clinical, radiologic, and microbiologic data were collected, including paired gastric lavage and induced sputum for MTB liquid culture. Adjusted odds ratios (AORs) were calculated using a multivariate logistic regression model. RESULTS: Adjusted odds of positive MTB culture increased by 90% with history of wheezing (AOR, 1.9) and by 4% with each 1-mm increase in Mantoux diameter (AOR, 1.04). Odds of positive MTB culture doubled if the chest radiograph was suggestive of pulmonary TB (AOR, 2.16) and more than tripled if lower chest retraction was observed clinically (AOR, 3.37). Fever, night sweats, and presence of lymphadenopathy were negatively associated with MTB culture (AOR: 0.5, 0.62, and 0.2, respectively). Persistent cough, weight loss, and failure to thrive were not significantly associated with MTB culture in this study population. CONCLUSIONS: Wheezing and lower chest retraction, consistent with intrathoracic airway obstruction; chest radiography suggestive of pulmonary tuberculosis; and Mantoux diameter were predictive of positive MTB culture. These variables should be considered for inclusion in composite clinical end point definitions for infant TB vaccine trials. Several clinical features, commonly used for TB diagnosis in older children, were not associated with positive MTB culture among children younger than 2 years.