Expanding Xpert MTB/RIF Ultra® and LF-LAM testing for diagnosis of tuberculosis among HIV-positive adults admitted to hospitals in Tanzania and Mozambique: a randomized controlled trial (the EXULTANT trial).

INTRODUCTION: Tuberculosis (TB) is an important cause of morbidity and mortality among people living with HIV (PLHIV). Current WHO-recommended strategies for diagnosing TB among hospitalized PLHIV rely on symptom screening and disease severity to assess eligibility for urine lipoarabinomannan lateral flow (LF-LAM) and molecular testing. Despite these recommendations, autopsy studies show a large burden of undiagnosed TB among admitted PLHIV. The EXULTANT trial aims to assess the impact of an expanded screening strategy using three specimens (sputum, stool, and urine) for TB diagnosis among PLHIV admitted to hospitals in two high HIV and TB burden African countries. METHODS: This is a multicenter, pragmatic, individually randomized controlled trial conducted across eleven hospitals in Tanzania and Mozambique. Participants in the intervention arm will be tested with Xpert MTB/RIF Ultra® from expectorated sputum, stool, and urine samples, with additional urine LF-LAM testing in the first 24 h after hospital admission, irrespective of the presence of the symptoms. The control arm will implement the WHO standard of care recommendations. Hospitalized adults (≥ 18 years) with a confirmed HIV-diagnosis, irrespective of antiretroviral (ART) therapy status or presence of TB symptoms will be assessed for eligibility at admission. Patients with a pre-existing TB diagnosis, those receiving anti-tuberculosis therapy or tuberculosis preventive treatment in the 6 months prior to enrolment, and those transferred from other hospitals will not be eligible. Also, participants admitted for traumatic reasons such as acute abdomen, maternal conditions, scheduled surgery, having a positive SARS-CoV2 test will be ineligible. The primary endpoint is the proportion of participants with microbiologically confirmed TB starting treatment within 3 days of enrolment. DISCUSSION: The EXULTANT trial investigates rapid implementation after admission of a new diagnostic algorithm using Xpert MTB/RIF Ultra® in several non-invasive specimens, in addition to LF-LAM, in hospitalized PLHIV regardless of TB symptoms. This enhanced strategy is anticipated to detect frequently missed TB cases in this population and is being evaluated as an implementable and scalable intervention. TRIAL REGISTRATION: Trial reference number: NCT04568967 (ClinicalTrials.gov) registered on 2020-09-29.

Characteristic SNPs defining the major multidrug-resistant Mycobacterium tuberculosis clusters identified by EuSeqMyTB to support routine surveillance, EU/EEA, 2017 to 2019.

BackgroundThe EUSeqMyTB project, conducted in 2020, used whole genome sequencing (WGS) for surveillance of drug-resistant Mycobacterium tuberculosis in the European Union/European Economic Area (EU/EEA) and identified 56 internationally clustered multidrug-resistant (MDR) tuberculosis (TB) clones.AimWe aimed to define and establish a rapid and computationally simple screening method to identify probable members of the main cross-border MDR-TB clusters in WGS data to facilitate their identification and track their future spread.MethodsWe screened 34 of the larger cross-border clusters identified in the EuSeqMyTB pilot study (2017-19) for characteristic single nucleotide polymorphism (SNP) signatures that could identify and define members of each cluster. We also linked this analysis with published clusters identified in previous studies and identified more distant genetic relationships between some of the current clusters.ResultsA panel of 30 characteristic SNPs is presented that can be used as an initial (routine) screen for members of each cluster. For four of the clusters, no unique defining SNP could be identified; three of these are closely related (within approximately 20 SNPs) to one or more other clusters and likely represent a single established MDR-TB clade composed of multiple recent subclusters derived from the previously described ECDC0002 cluster.ConclusionThe identified SNP signatures can be integrated into routine pipelines and contribute to the more effective monitoring, rapid and widespread screening for TB. This SNP panel will also support accurate communication between laboratories about previously identified internationally transmitted MDR-TB genotypes.