Multidrug-resistant tuberculosis control in Rwanda overcomes a successful clone that causes most disease over a quarter century

Abstract

Summary background: Multidrug-resistant (MDR) tuberculosis (TB) poses an important challenge in TB management and control. Rifampicin resistance (RR) is a solid surrogate marker of MDR-TB. We investigated the RR-TB clustering rates, bacterial population dynamics to infer transmission dynamics, and the impact of changes to patient management on these dynamics over 27 years in Rwanda.

Methods: We analysed whole genome sequences of a longitudinal collection of nationwide RR-TB isolates. The collection covered three important periods: before programmatic management of MDR-TB (PMDT; 1991-2005), the early PMDT phase (2006-2013), in which rifampicin drug-susceptibility testing (DST) was offered to retreatment patients only, and the consolidated phase (2014-2018), in which all bacteriologically confirmed TB patients had rifampicin DST done mostly via Xpert MTB/RIF assay. We constructed clusters based on a 5 SNP cut-off and resistance conferring SNPs. We used Bayesian modelling for dating and population size estimations, TransPhylo to estimate the number of secondary cases infected by each patient, and multivariable logistic regression to assess predictors of being infected by the dominant clone.

Results: Of 308 baseline RR-TB isolates considered for transmission analysis, the clustering analysis grouped 259 (84.1%) isolates into 13 clusters. Within these clusters, a single dominant clone was discovered containing 213 isolates (82.2% of clustered and 69.1% of all RR-TB), which we named the "Rwanda Rifampicin-Resistant clone" (R3clone). R3clone isolates belonged to Ugandan sub-lineage 4.6.1.2 and its rifampicin and isoniazid resistance were conferred by the Ser450Leu mutation in rpoB and Ser315Thr in katG genes, respectively. All R3clone isolates had Pro481Thr, a putative compensatory mutation in the rpoC gene that likely restored its fitness. The R3clone was estimated to first arise in 1987 and its population size increased exponentially through the 1990s', reaching maximum size (∼84%) in early 2000 s', with a declining trend since 2014. Indeed, the highest proportion of R3clone (129/157; 82·2%, 95%CI: 75·3-87·8%) occurred between 2000 and 13, declining to 64·4% (95%CI: 55·1-73·0%) from 2014 onward. We showed that patients with R3clone detected after an unsuccessful category 2 treatment were more likely to generate secondary cases than patients with R3clone detected after an unsuccessful category 1 treatment regimen.

Conclusions: RR-TB in Rwanda is largely transmitted. Xpert MTB/RIF assay as first diagnostic test avoids unnecessary rounds of rifampicin-based TB treatment, thus preventing ongoing transmission of the dominant R3clone. As PMDT was intensified and all TB patients accessed rifampicin-resistance testing, the nationwide R3clone burden declined. To our knowledge, our findings provide the first evidence supporting the impact of universal DST on the transmission of RR-TB.

Keywords: Mycobacterium tubercuslosis transmission; Rifampicin-resistant tuberculosis control; Tuberculosis in Rwanda; Universal drug-susceptibility testing.

Fig. 1

Study population and clustering results.

Fig. 2

Phylogenetic tree of RR-TB strains in Rwanda. The red leaves show clusters by 12SNP and blue by 5 SNP cut-off. The R3clone is shown in grey box. All branches with bootstrap support below 70% were collapsed into polytomies.

Fig. 3

Bayesian phylogenetic tree of R3clone and associated Skyride plot. Date of emergence of the clone is indicated at the root node. The mean estimate of population size changes is indicated by the solid black line with the High Posterior Density Interval of this estimate in the shaded blue area. The bush-like topology suggests continuous spread as opposed to consecutive single transmission events.

Fig. 4

Number of secondary transmissions per case for 93 selected R3clone isolates grouped by tuberculosis (TB) treatment history. Cat 1: patients diagnosed with rifampicin-resistant TB after failure or relapse to category 1 anti-TB treatment; Cat 2: patients diagnosed with rifampicin-resistant TB after failure or relapse to category 2 anti-TB treatment.