Reduction of diagnostic and treatment delays reduces rifampicin-resistant tuberculosis mortality in Rwanda

YesSETTING: In 2005, in response to the increasing prevalence of rifampicin-resistant tuberculosis (RR-TB) and poor treatment outcomes, Rwanda initiated the programmatic management of RR-TB, including expanded access to systematic rifampicin drug susceptibility testing (DST) and standardised treatment.OBJECTIVE: To describe trends in diagnostic and treatment delays and estimate their effect on RR-TB mortality.DESIGN: Retrospective analysis of individual-level data including 748 (85.4%) of 876 patients diagnosed with RR-TB notified to the World Health Organization between 1 July 2005 and 31 December 2016 in Rwanda. Logistic regression was used to estimate the effect of diagnostic and therapeutic delays on RR-TB mortality.RESULTS: Between 2006 and 2016, the median diagnostic delay significantly decreased from 88 days to 1 day, and the therapeutic delay from 76 days to 3 days. Simultaneously, RR-TB mortality significantly decreased from 30.8% in 2006 to 6.9% in 2016. Total delay in starting multidrug-resistant TB (MDR-TB) treatment of more than 100 days was associated with more than two-fold higher odds for dying. When delays were long, empirical RR-TB treatment initiation was associated with a lower mortality.CONCLUSION: The reduction of diagnostic and treatment delays reduced RR-TB mortality. We anticipate that universal testing for RR-TB, short diagnostic and therapeutic delays and effective standardised MDR-TB treatment will further decrease RR-TB mortality in Rwanda

Prevalence and drivers of false-positive rifampicin-resistant Xpert MTB/RIF results: a prospective observational study in Rwanda

YesBackground: The Xpert MTB/RIF (Xpert) assay is used globally to rapidly diagnose tuberculosis and resistance to rifampicin. We investigated the frequency and predictors of false-positive findings of rifampicin resistance with Xpert. Methods: We did a prospective, observational study of individuals who were enrolled in a Rwandan nationwide diagnostic cohort study (DIAMA trial; NCT03303963). We included patients identified to have rifampicin resistance on initial Xpert testing. We did a repeat Xpert assay and used rpoB Sanger and deep sequencing alongside phenotypic drug susceptibility testing (pDST) to ascertain final rifampicin susceptibility status, with any (hetero)resistant result overriding. We used multivariable logistic regression to assess predictors of false rifampicin resistance on initial Xpert testing, adjusted for HIV status, tuberculosis treatment history, initial Xpert semi-quantitative bacillary load, and initial Xpert probe. Findings: Between May 4, 2017, and April 30, 2019, 175 people were identified with rifampicin resistance at initial Xpert testing, of whom 154 (88%) underwent repeat Xpert assay. 54 (35%) patients were confirmed as rifampicin resistant on repeat testing and 100 (65%) were not confirmed with resistance. After further testing and sequencing, 121 (79%) of 154 patients had a final confirmed status for rifampicin susceptibility. 57 (47%) of 121 patients were confirmed to have a false rifampicin resistance result and 64 (53%) had true rifampicin resistance. A high pretest probability of rifampicin resistance did not decrease the odds of false rifampicin resistance (adjusted odds ratio [aOR] 6·0, 95% CI 1·0–35·0, for new tuberculosis patients vs patients who needed retreatment). Ten (16%) of the 64 patients with true rifampicin resistance did not have confirmed rifampicin resistance on repeat Xpert testing, of whom four had heteroresistance. Of 63 patients with a very low bacillary load on Xpert testing, 54 (86%) were falsely diagnosed with rifampicin-resistant tuberculosis. Having a very low bacillary load on Xpert testing was strongly associated with false rifampicin resistance at the initial Xpert assay (aOR 63·6, 95% CI 9·9–410·4). Interpretation: The Xpert testing algorithm should include an assessment of bacillary load and retesting in case rifampicin resistance is detected on a paucibacillary sputum sample. Only when rifampicin resistance has been confirmed on repeat testing should multidrug-resistant tuberculosis treatment be started. When rifampicin resistance has not been confirmed on repeat testing, we propose that patients should be given first-line anti-tuberculosis drugs and monitored closely during treatment, including by baseline culture, pDST, and further Xpert testing.The European & Developing Countries Clinical Trials Partnership 2 programme, and Belgian Directorate General for Development Cooperation

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

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

National tuberculosis prevalence surveys in Africa, 2008\u20132016: an overview of results and lessons learned

Objective and methods: Worldwide, tuberculosis (TB) is the leading cause of death from a single infectious agent. In many countries, national TB prevalence surveys are the only way to reliably measure the burden of TB disease and can also provide other evidence to inform national efforts to improve TB detection and treatment. Our objective was to synthesise the results and lessons learned from national surveys completed in Africa between 2008 and 2016, to complement a previous review for Asia. Results: Twelve surveys completed in Africa were identified: Ethiopia (2010\u20132011), Gambia (2011\u20132013), Ghana (2013), Kenya (2015\u20132016), Malawi (2013\u20132014), Nigeria (2012), Rwanda (2012), Sudan (2013\u20132014), Tanzania (2011\u20132012), Uganda (2014\u20132015), Zambia (2013\u20132014) and Zimbabwe (2014). The eligible population in all surveys was people aged 6515 years who met residency criteria. In total 588 105 individuals participated, equivalent to 82% (range 57\u201396%) of those eligible. The prevalence of bacteriologically confirmed pulmonary TB disease in those 6515 years varied from 119 (95% CI 79\u2013160) per 100 000 population in Rwanda and 638 (95% CI 502\u2013774) per 100 000 population in Zambia. The male:female ratio was 2.0 overall, ranging from 1.2 (Ethiopia) to 4.1 (Uganda). Prevalence per 100 000 population generally increased with age, but the absolute number of cases was usually highest among those aged 35\u201344 years. Of identified TB cases, 44% (95% CI 40\u201349) did not report TB symptoms during screening and were only identified as eligible for diagnostic testing due to an abnormal chest X-ray. The overall ratio of prevalence to case notifications was 2.5 (95% CI 1.8\u20133.2) and was consistently higher for men than women. Many participants who did report TB symptoms had not sought care; those that had were more likely to seek care in a public health facility. HIV prevalence was systematically lower among prevalent cases than officially notified TB patients with an overall ratio of 0.5 (95% CI 0.3\u20130.7). The two main study limitations were that none of the surveys included people <15 years, and 5 of 12 surveys did not have data on HIV status. Conclusions: National TB prevalence surveys implemented in Africa between 2010 and 2016 have contributed substantial new evidence about the burden of TB disease, its distribution by age and sex, and gaps in TB detection and treatment. Policies and practices to improve access to health services and reduce under-reporting of detected TB cases are needed, especially among men. All surveys provide a valuable baseline for future assessment of trends in TB disease burden