ORCID Profile
0000-0001-7666-3263
Current Organisations
University of Antwerp
,
University of North Carolina at Chapel Hill
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Publisher: Springer Science and Business Media LLC
Date: 08-10-2022
DOI: 10.1186/S13063-022-06793-W
Abstract: Rif icin-resistant tuberculosis (RR-TB) remains an important global health problem. Ideally, the complete drug-resistance profile guides in idualized treatment for all RR-TB patients, but this is only practised in high-income countries. Implementation of whole genome sequencing (WGS) technologies into routine care in low and middle-income countries has not become a reality due to the expected implementation challenges, including translating WGS results into in idualized treatment regimen composition. This trial is a pragmatic, single-blinded, randomized controlled medical device trial of a WGS-guided automated treatment recommendation strategy for in idualized treatment of RR-TB. Subjects are 18 years or older and diagnosed with pulmonary RR-TB in four of the five health districts of the Free State province in South Africa. Participants are randomized in a 1:1 ratio to either the intervention (a WGS-guided automated treatment recommendation strategy for in idualized treatment of RR-TB) or control (RR-TB treatment according to the national South African guidelines). The primary effectiveness outcome is the bacteriological response to treatment measured as the rate of change in time to liquid culture positivity during the first 6 months of treatment. Secondary effectiveness outcomes include cure rate, relapse rate (recurrence of RR-TB disease) and TB free survival rate in the first 12 months following RR-TB treatment completion. Additional secondary outcomes of interest include safety, the feasibility of province-wide implementation of the strategy into routine care, and health economic assessment from a patient and health systems perspective. This trial will provide important real-life evidence regarding the feasibility, safety, cost, and effectiveness of a WGS-guided automated treatment recommendation strategy for in idualized treatment of RR-TB. Given the pragmatic nature, the trial will assist policymakers in the decision-making regarding the integration of next-generation sequencing technologies into routine RR-TB care in high TB burden settings. ClinicalTrials.gov NCT05017324. Registered on August 23, 2021.
Publisher: Microbiology Society
Date: 18-11-2021
Abstract: Improved understanding of the genomic variants that allow Mycobacterium tuberculosis ( Mtb ) to acquire drug resistance, or tolerance, and increase its virulence are important factors in controlling the current tuberculosis epidemic. Current approaches to Mtb sequencing, however, cannot reveal Mtb ’s full genomic ersity due to the strict requirements of low contamination levels, high Mtb sequence coverage and elimination of complex regions. We have developed the XBS (compleX Bacterial S les) bioinformatics pipeline, which implements joint calling and machine-learning-based variant filtering tools to specifically improve variant detection in the important Mtb s les that do not meet these criteria, such as those from unbiased sputum s les. Using novel simulated datasets, which permit exact accuracy verification, XBS was compared to the UVP and MTBseq pipelines. Accuracy statistics showed that all three pipelines performed equally well for sequence data that resemble those obtained from culture isolates of high depth of coverage and low-level contamination. In the complex genomic regions, however, XBS accurately identified 9.0 % more SNPs and 8.1 % more single nucleotide insertions and deletions than the WHO-endorsed unified analysis variant pipeline. XBS also had superior accuracy for sequence data that resemble those obtained directly from sputum s les, where depth of coverage is typically very low and contamination levels are high. XBS was the only pipeline not affected by low depth of coverage (5–10×), type of contamination and excessive contamination levels ( %). Simulation results were confirmed using whole genome sequencing (WGS) data from clinical s les, confirming the superior performance of XBS with a higher sensitivity (98.8%) when analysing culture isolates and identification of 13.9 % more variable sites in WGS data from sputum s les as compared to MTBseq, without evidence for false positive variants when rRNA regions were excluded. The XBS pipeline facilitates sequencing of less-than-perfect Mtb s les. These advances will benefit future clinical applications of Mtb sequencing, especially WGS directly from clinical specimens, thereby avoiding in vitro biases and making many more s les available for drug resistance and other genomic analyses. The additional genetic resolution and increased s le success rate will improve genome-wide association studies and sequence-based transmission studies.
Publisher: Microbiology Society
Date: 26-04-2022
Abstract: Extensively drug-resistant tuberculosis (XDR-TB), defined as resistance to at least isoniazid (INH), rif icin (RIF), a fluoroquinolone (FQ) and a second-line injectable drug (SLID), is difficult to treat and poses a major threat to TB control. The transmission dynamics and distribution of XDR Mycobacterium tuberculosis ( Mtb ) strains have not been thoroughly investigated. Using whole genome sequencing data on 461 XDR- Mtb strains, we aimed to investigate the geographical distribution of XDR- Mtb strains in the Western Cape Province of South Africa over a 10 year period (2006–2017) and assess the association between Mtb sub-lineage, age, gender, geographical patient location and membership or size of XDR-TB clusters. First, we identified transmission clusters by excluding drug resistance-conferring mutations and using the 5 SNP cutoff, followed by merging clusters based on their most recent common ancestor. We then consecutively included variants conferring resistance to INH, RIF, ethambutol (EMB), pyrazinamide (PZA), SLIDs and FQs in the cluster definition. Cluster sizes were classified as small (2–4 isolates), medium (5–20 isolates), large (21–100 isolates) or very large ( isolates) to reflect the success of in idual strains. We found that most XDR-TB strains were clustered and that including variants conferring resistance to INH, RIF, EMB, PZA and SLIDs in the cluster definition did not significantly reduce the proportion of clustered isolates (85.5–82.2 %) but increased the number of patients belonging to small clusters (4.3–12.4 %, P =0.56). Inclusion of FQ resistance-conferring variants had the greatest effect, with 11 clustered isolates reclassified as unique while the number of clusters increased from 17 to 37. Lineage 2 strains (lineage 2.2.1 typical Beijing or lineage 2.2.2 atypical Beijing) showed the large clusters which were spread across all health districts of the Western Cape Province. We identified a significant association between residence in the Cape Town metropole and cluster membership ( P =0.016) but no association between gender, age and cluster membership or cluster size ( P =0.39). Our data suggest that the XDR-TB epidemic in South Africa probably has its origin in the endemic spread of MDR Mtb and pre-XDR Mtb strains followed by acquisition of FQ resistance, with more limited transmission of XDR Mtb strains. This only became apparent with the inclusion of drug resistance-conferring variants in the definition of a cluster. In addition to the prevention of lification of resistance, rapid diagnosis of MDR, pre-XDR and XDR-TB and timely initiation of appropriate treatment is needed to reduce transmission of difficult-to-treat TB.
Location: United States of America
No related grants have been discovered for Annelies Van Rie.