Novel FujiLAM assay to detect tuberculosis in HIV-positive ambulatory patients in four African countries: a diagnostic accuracy study.

BACKGROUND: Development of rapid biomarker-based tests that can diagnose tuberculosis using non-sputum samples is a priority for tuberculosis control. We aimed to compare the diagnostic accuracy of the novel Fujifilm SILVAMP TB LAM (FujiLAM) assay with the WHO-recommended Alere Determine TB-LAM Ag test (AlereLAM) using urine samples from HIV-positive patients. METHODS: We did a diagnostic accuracy study at five outpatient public health facilities in Uganda, Kenya, Mozambique, and South Africa. Eligible patients were ambulatory HIV-positive individuals (aged ≥15 years) with symptoms of tuberculosis irrespective of their CD4 T-cell count (group 1), and asymptomatic patients with advanced HIV disease (CD4 count <200 cells per µL, or HIV clinical stage 3 or 4; group 2). All participants underwent clinical examination, chest x-ray, and blood sampling, and were requested to provide a fresh urine sample, and two sputum samples. FujiLAM and AlereLAM urine assays, Xpert MTB/RIF Ultra assay on sputum or urine, sputum culture for Mycobacterium tuberculosis, and CD4 count were systematically carried out for all patients. Sensitivity and specificity of FujiLAM and AlereLAM were evaluated against microbiological and composite reference standards. FINDINGS: Between Aug 24, 2020 and Sept 21, 2021, 1575 patients (823 [52·3%] women) were included in the study: 1031 patients in group 1 and 544 patients in group 2. Tuberculosis was microbiologically confirmed in 96 (9·4%) of 1022 patients in group 1 and 18 (3·3%) of 542 patients in group 2. Using the microbiological reference standard, FujiLAM sensitivity was 60% (95% CI 51-69) and AlereLAM sensitivity was 40% (31-49; p<0·001). Among patients with CD4 counts of less than 200 cells per µL, FujiLAM sensitivity was 69% (57-79) and AlereLAM sensitivity was 52% (40-64; p=0·0218). Among patients with CD4 counts of 200 cells per µL or higher, FujiLAM sensitivity was 47% (34-61) and AlereLAM sensitivity was 24% (14-38; p=0·0116). Using the microbiological reference standard, FujiLAM specificity was 87% (95% CI 85-89) and AlereLAM specificity was 86% (95 CI 84-88; p=0·941). FujiLAM sensitivity varied by lot number from 48% (34-62) to 76% (57-89) and specificity from 77% (72-81) to 98% (93-99). INTERPRETATION: Next-generation, higher sensitivity urine-lipoarabinomannan assays are potentially promising tests that allow rapid tuberculosis diagnosis at the point of care for HIV-positive patients. However, the variability in accuracy between FujiLAM lot numbers needs to be addressed before clinical use. FUNDING: ANRS and Médecins Sans Frontières.

High rates of culture conversion and low loss to follow-up in MDR-TB patients managed at Regional Referral Hospitals in Uganda.

BACKGROUND: Multi-drug resistant-tuberculosis (MDR-TB) is an emerging public health concern in Uganda. Prior to 2013, MDR-TB treatment in Uganda was only provided at the national referral hospital and two private-not-for profit clinics. From 2013, it was scaled up to seven regional referral hospitals (RRH). The aim of this study was to measure interim (6 months) treatment outcomes among the first cohort of patients started on MDR-TB treatment at the RRH in Uganda. METHODS: This was a cross-sectional study in which a descriptive analysis of data collected retrospectively on a cohort of 69 patients started on MDR-TB treatment at six of the seven RRH between 1st April 2013 and 30th June 2014 and had been on treatment for at least 9 months was conducted. RESULTS: Of the 69 patients, 21 (30.4%) were female, 39 (56.5%) HIV-negative, 30 (43.5%) resistant to both isoniazid and rifampicin and 57 (82.6%) category 1 or 2 drug susceptible TB treatment failures. Median age at start of treatment was 35 years (Interquartile range (IQR): 27-45), median time-to-treatment initiation was 27.5 (IQR: 6-89) days and of the 30 HIV-positive patients, 27 (90.0%) were on anti-retroviral treatment with a median CD4 count of 206 cells/microliter of blood (IQR: 113-364.5). Within 6 months of treatment, 59 (85.5%) patients culture converted, of which 45 (65.2%) converted by the second month and the other 14 (20.3%) by the sixth month; one (1.5%) did not culture convert; three (4.4%) died; and six (8.8%) were lost-to-follow up. Fifty (76.8%) patients experienced at least one drug adverse event, while 40 (67.8%) gained weight. Mean weight gained was 4.7 (standard deviation: 3.2) kilograms. CONCLUSIONS: Despite MDR-TB treatment initiation delays, most patients had favourable interim treatment outcomes with majority culture converting early and very few getting lost to follow-up. These encouraging interim outcomes indicate the potential for success of a scale-up of MDR-TB treatment to RRH.

Study protocol and implementation details for a pragmatic, stepped-wedge cluster randomised trial of a digital adherence technology to facilitate tuberculosis treatment completion.

INTRODUCTION: Low-cost digital adherence technologies (DATs) such as 99DOTS have emerged as an alternative to directly observed therapy (DOT), the current standard for tuberculosis (TB) treatment supervision. However, there are limited data to support DAT scale-up. The 'DOT to DAT' trial aims to evaluate the effectiveness and implementation of a 99DOTS-based TB treatment supervision strategy. METHODS AND ANALYSIS: This is a pragmatic, stepped-wedge cluster randomised trial, with hybrid type 2 effectiveness-implementation design. The trial will include all adults (estimated N=1890) treated for drug-susceptible pulmonary TB over an 8-month period at 18 TB treatment units in Uganda. Three sites per month will switch from routine care (DOT) to the intervention (99DOTS-based treatment supervision) beginning in month 2, with the order determined randomly. 99DOTS enables patients to be monitored while self-administering TB medicines. Patients receive daily automated short message service (SMS) dosing reminders and confirm dosing by calling toll-free numbers. The primary effectiveness outcome is the proportion of patients completing TB treatment. With 18 clusters randomised into six steps and an average cluster size of 15 patients per month, the study will have 89% power to detect a 10% or greater increase in treatment completion between the routine care and intervention periods. Secondary outcomes include more proximal effectiveness measures as well as quantitative and qualitative assessments of the reach, adoption and implementation of the intervention. ETHICS AND DISSEMINATION: Ethics approval was granted by institutional review boards at Makerere University School of Public Health and the University of California San Francisco. Findings will be disseminated through peer-reviewed publications, presentations at scientific conferences and presentations to key stakeholders. TRIAL REGISTRATION NUMBER: PACTR201808609844917.