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Review 1: "Rapid Acquisition and Transmission of Drug Resistance Amongst Beijing Lineage Mycobacterium tuberculosis in Vietnam"

Published onDec 21, 2022
Review 1: "Rapid Acquisition and Transmission of Drug Resistance Amongst Beijing Lineage Mycobacterium tuberculosis in Vietnam"
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key-enterThis Pub is a Review of
Rapid Acquisition and Transmission of Drug Resistance Amongst Beijing Lineage Mycobacterium tuberculosis in Vietnam

AbstractWhole genome sequencing (WGS) and phenotypic drug susceptibility testing was performed on a collection of 2,542Mycobacterium tuberculosis (Mtb)isolates from tuberculosis (TB) patients recruited in Ho Chi Minh City (HCMC), Vietnam, to investigateMtbdiversity, the prevalence and phylodynamics of drug resistance, andin silicoresistance prediction with sequencing data. Amongst isolates tested phenotypically against first-line drugs, we observed high rates of streptomycin [STR, 37.7% (N=573/1,520)] and isoniazid resistance [INH, 25.7% (N=459/1,786)], and lower rates of resistance to rifampicin [RIF, 4.9% (N=87/1,786)] and ethambutol [EMB, 4.2% (N=75/1,785)]. Resistance to STR and INH was predicted moderately well when applying the TB-Profiler algorithm to WGS data (sensitivities of 0.81 and 0.87 respectively), while resistance to RIF and EMB was predicted relatively poorly (sensitivities of 0.70 and 0.44 respectively). Rates of multidrug-resistance [(MDR, 3.9% (N=69/1,786)], and resistance to a number of second-line drugs [Para-aminosalicylic acid (29.6% N=79/267), Amikacin (15.4% N=41/267) and Moxifloxacin (21.3%), N=57/267], were found to be high within a global context. Comparing rates of drug resistance among lineages, and exploring the dynamics of resistance acquisition through time, suggest the Beijing lineage (lineage 2.2) acquiresde novoresistance mutations at higher rates and suffers no apparent fitness cost acting to impede the transmission of resistance. We infer resistance to INH and STR to have arisen earlier, on average, than resistance to RIF, and to be more widespread across the phylogeny. The high prevalence of ‘background’ INH resistance, combined with high rates of RIF mono-resistance (20.7%, N=18/87) suggests that rapid assays for INH resistance will be valuable in this setting. These tests will allow the detection of INH mono-resistance, and will allow MDR isolates to be distinguished from isolates with RIF mono-resistance.

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.



The manuscript by Silcocks et al. presents the results of a large-scale Whole Genome Sequencing study on a collection of over than 2,500 clinical M. tuberculosis strains from patients in Vietnam. Results of the prediction of resistance to first- and second-line anti-TB drug were compared with the phenotypic drug susceptibility testing results.

Although in the Vietnamese population the level of MDR-TB was relatively low, the levels of monoresistance to isoniazid and rifampicin were quite high. This demonstrates the limited feasibility of the widely used in high burden settings Xpert MTB/RIF test. The low rate of agreement between phenotypic and WGS-predicted resistance to second-line drugs reminds us once again about the importance of conducting further studies investigating the mechanisms that underlie resistance to second-line as well as novel and repurposed drugs.

Important findings of the study also include high rates of acquisition and transmission of resistance by strains from Beijing lineage and earlier emergence of resistance to isoniazid and streptomycin than that to rifampicin.

Overall, the results of this study support implementation of WGS-based drug resistance prediction for individualising treatment against TB in Vietnam.

The manuscript provides detailed overview of the work conducted and results are presented in the text as figures and tables, which give a good understanding of the findings. The analysis of M. tuberculosis diversity in the population, prevalence and phylodynamics of drug resistance is comprehensive and adequately planned, conducted and presented. The main claims and conclusions are supported by the data and clearly can be tracked back to the dataset. The reproducibility, compliance with the ethical principles as well as addressing the issues of diversity and inclusion in the study rise no doubts. The findings are mostly in line with the previous reports although the study analyses the patient population in a high TB burden setting which is less studied previously.

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