Investigators
Study information
- Research Area: Tuberculosis
- Research type: For study 1 and 4, eligible participants must meet the following inclusion criteria:- Having a positive test on Xpert (Mtb) with resistance detected to rifampicin or without susceptibility results (trace call for Xpert Ultra or rifampicin indeterminate), plus an equal number of retreatment patients in Kigali with RS-TB on Xpert - Willing and able to provide written informed consent, or for minors aged 15 and older: assent from these patients and consent from a legal representative.Eligibility criteria for study 2 will be defined based on results from the study 1. This foreseen amendment will be submitted for ethical approval prior to implementation. For study 3, only patients aged 15 years old and above, for whom RR was confirmed at baseline and who started All-Oral MDR-TB treatment regimen in an MDR-TB treatment hospital will be eligible.In study 5, results from DIAMA and study 1 will be complemented retrospectively with nationwide programmatic data from retreatment patients’ diagnostic results. We seek exemption from asking retrospective informed consent from the retreatment patients for the use of the diagnostic results that were generated per routine programmatic guidelines, which diagnostics are similar to what was collected in the DIAMA study from retreatment patients with an Xpert RS-TB result
- Start date: Jan 01, 2021
- End date: Dec 31, 2024
Study aim of the objectives
Rifampicin-resistant (RR) tuberculosis (TB) impedes patient management and TB control. The National TB Programme of Rwanda made its control a priority, resulting in a decline in RR-TB cases notified and its related mortality. However, many challenges remain unsolved. The World Health Organization (WHO) estimated the RR-TB incidence to be fourfold higher than actual notified cases. The rapid qPCR-based assay, Xpert MTB/RIF has been the global frontline (RR-) TB diagnostic, but it does not reliably exclude RR when patients have a very low bacterial burden. Moreover, the improved version with higher sensitivity to detect TB, Xpert Ultra, does not provide a rifampicin result for a significant number of TB patients with a very low bacillary load. A recent RR-TB genomes analysis from Rwanda, between 1991 and 2018, showed that the majority of RR-TB is due to ongoing transmission of one predominant clone, named Rwanda rifampicin-resistant TB clone, ‘R3clone’. However, it was not yet explored the high risk area where the R3clone transmits and which factors favour its spreading. In addition, preceding robust field evidence, the WHO recommended a new All-Oral treatment regimen for RR-TB patients, omitting the second-line injectables. Concern has been raised on whether this could increase the risk of acquiring resistance to the fluoroquinolones and/or new anti-TB drugs like bedaquiline. Besides, susceptibility testing for new anti-TB drugs involved in this All-Oral regimen is still missing in most high burden settings.
In the present study, we firstly aim to verify the WHO estimates of RR-TB burden in Rwanda, and to test the field performance of Xpert Ultra for the accurate detection of rifampicin resistance. Through a novel approach using Bayesian bioinformatic analyses, including the most recent RR-TB isolates, we will estimate the total bacterial population size to infer the actual RR-TB incidence in Rwanda. Secondly, we will identify higher risk RR-TB transmission areas, by R3clone versus other RR strains, as well as factors driving such transmission in Rwanda, important knowledge to improve targeted control efforts. Thirdly, we will optimize the diagnostic flowchart for RR-TB by validating rapid phenotypic drug-susceptibility testing (pDST) on thin layer agar (TLA) for new anti-TB drugs that can be implemented at lower-level laboratory facilities, serving both surveillance for resistance as well as the selection of individual patient’s optimal treatment. Moreover, we will evaluate the impact of the All-Oral regimen on bacterial metabolism and -killing, in comparison with the former RR-TB regimen that included second-line injectables, thus generating insight on the potential strengthening of this new All-Oral treatment regimen. Building further on the DIAgnostics for Multidrug Resistant Tuberculosis in Africa (DIAMA) study, we will retrospectively analyse programmatic results from retreatment patients nationwide. This will allow to test the hypothesis that only a minority of patients who continue to have sputum that is microscopy positive for acid fast bacilli at 5 months of first-line treatment are actually failing treatment with persistently live bacilli. We expect that most of these patients continue to secrete dead bacilli due to a larger bacterial burden at baseline. Lastly, the InnoR3TB study will involve regional collaboration aiming to strengthen evidence-based RR-TB management and control within the Great Lakes region. Such regional efforts for RR-TB control will likely improve individual country programmatic aspects. Together, these findings will pave the way for the next steps towards better RR-TB management as well as reducing its burden in Rwanda, and with extension in the Great Lakes region.
Study setting/Area (Location)
Rwanda (nationwide)
Implementing institution
Rwanda Biomedical Center & University of Rwanda
Department/Division
NRL Division, TB & ORD Division, College of Medicine and Health Sciences
Impact on Policy
The findings of this study will inform TB treatment guidelines