Rifampicin-Resistant Tuberculosis Control in Rwanda Overcomes a Successful Clone That Causes Most Disease Over a Quarter Century

Background: Rifampicin-resistance (RR) poses an important challenge in tuberculosis (TB) management and control. Understanding the driving factors behind the rising numbers of RR-TB is important for developing appropriate control strategies. Methods: We analysed whole genome sequences of a longitudinal nationwide collection of RR-TB (308 isolates): before RR-TB programmatic management (PMDT; 1991-2005), the early PMDT phase (2006-2013; rifampicin testing for retreatment patients only), and the consolidated phase (2014-2018; rifampicin testing for all patients). We reconstructed transmission clusters based on a 5 SNP cut-off and resistance conferring SNPs and estimated pathogen population dynamics and secondary cases infections using Bayesian methods and multivariable logistic regression to assess predictors of being infected by the dominant clone. Findings: 259 (84.1%) isolates fell into a transmission cluster with 213 (82.2% of clustered and 69.1% of all RR-TB) belonging to a single dominant clone, which we named the “Rwanda rifampicin-resistant clone” (R3clone). The R3clone was estimated to first arise in 1987 with an exponential population growth through the 1990s’, reaching maximum size (~84%) in early 2000s’, with a declining trend since 2014. We showed that patients who had multiple rounds of first-line TB treatment such as unsuccessful category 2 treatment were more likely to generate secondary cases than new TB patients. Interpretation RR-TB in Rwanda is largely transmitted, with decreasing rates of transmission strongly associated with shortening in effective treatment initiation. To our knowledge, our findings provide the first direct evidence supporting the impact of effective programmatic management on the transmission of RR-TB. Funding Statement: Belgian Directorate General for Development Cooperation, ERC grant [INTERRUPTB; no. 311725], EDCTP2 programme grant [no. DRIA2014-326—DIAMA], and InnoR3TB study with financial support from ITM’s SOFI programme supported by the Flemish Government, Science & Innovation. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: The study protocol was approved by the Rwanda National Ethical committee, Kigali, Rwanda (IRB 00001497 of IORG0001100; Ref No·0069/RNEC/2017), the Institutional Review Board of the Institute of Tropical Medicine, Antwerp, Belgium (IRB/AB/AC/062; Ref No.1208/17; 19/03/2018), and the Ethics Committee of the Antwerp University Hospital, Universitair Ziekenhuis Antwerpen Ethische Commissie, Antwerp, Belgium (REG No.B300201836458; 14/05/2018).