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WHO-endorsed tests miss MDR-TB cases
WHO-endorsed tests did not detect a substantial number of multidrug-resistant tuberculosis, or MDR-TB, cases in South Africa that harbor a certain mutation, “resulting in ineffective first-line treatment, continued amplification of drug-resistance, and concurrent silent spread in the community,” researchers said.
“Global roll-out of rapid molecular assays is revolutionizing the diagnosis of rifampicin resistance, predictive of multidrug-resistance, in tuberculosis,” Emmanuel André, MD, PhD, clinical microbiologist at Catholic University of Leuven in Belgium, and colleagues wrote in The Lancet Infectious Diseases. “However, 30% of the multidrug-resistant strains in an eSwatini” —formerly known as Swaziland — “study harbored the Ile491Phe mutation in the rpoB gene, which is associated with poor rifampicin-based treatment outcomes but is missed by commercially molecular assays or scored as susceptible by phenotypic drug-susceptibility testing deployed in South Africa.”
According to André and colleagues, South Africa has been a global leader in the national deployment of two WHO-endorsed rapid molecular assays, the GenoType MTBDRplus version 2.0 (Hain Lifescience) and the Xpert MTB/RIF (Cepheid). These tests, they noted, are complemented by culturing with the BACTEC mycobacteria growth indicator tube 960 automated detection system (Becton, Dickinson and Company). However, according to André and colleagues, the tests only detect about 95% of known rifampicin-resistance mutations in Mycobacterium tuberculosis strains and do not detect rifampicin resistance associated with certain mutations in the rpoB gene located outside the rifampin-resistance-determining region (RRDR).
“Although available data suggest that these and other crucial mutations outside the RRDR might be of low frequency globally, the mutations could be more prevalent regionally,” such as in South Africa, where a recent national drug resistance survey could not detect the potential emergence of MDR-TB isolates harboring these mutations, André and colleagues wrote, raising concerns that they may be silently spreading there.
For their study, André and colleagues screened records of 37,644 M. tuberculosis-positive cultures from four South African provinces sent to a national lab for diagnosis between Jan. 1, 2013, and Sept. 30, 2016, to identify isolates with rifampicin sensitivity and isoniazid resistance according to Xpert MTB/RIF, GenoType MTBDRplus, and BACTEC MGIT 960. Of the 1,823 isolates that met these criteria, they randomly selected and screened 277 for the Ile491Phe mutation with multiplex allele-specific PCR and Sanger sequencing of rpoB. They tested Ile491Phe-positive strains by Deeplex-MycTB (Genoscreen) deep sequencing and whole-genome sequencing to evaluate their patterns of extensive resistance, transmission and evolution.
The researchers identified the Ile491Phe mutation in 37 of 249 samples, reclassifying them as multidrug-resistant. All 37 isolates were additionally identified as genotypically resistant to all first-line drugs. Additionally, six of the isolates harbored four distinct mutations potentially associated with decreased sensitivity to bedaquiline, a successful substitute for second-line injectables. The researchers wrote that whole-genome sequencing revealed “concurrent silent spread” of MDT-TB in South Africa “extending from the eSwatini outbreak and at least another independently emerged Ile491Phe-bearing lineage.”
“Our findings highlight a serious gap in current WHO-endorsed algorithms for capturing all MDR tuberculosis strains. This gap results in inappropriate tuberculosis treatment, amplification of drug resistance, and adverse treatment outcomes,” the authors concluded.
“Our observations highlight the importance for South Africa and other countries to monitor the prevalence and potential increase in frequency of tuberculosis strains bearing rifampicin-resistance mutations outside the RRDR in drug-resistance surveys, without phenotypic preselection for rifampicin resistance. The obtained data will better guide and complement the implementation of available tools. Newer tools such as whole-genome sequencing of the Deeplex-MycTB multitarget assay should be used in such surveys to help to close existing gaps.” – by Caitlyn Stulpin
Disclosures: André reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.