PhD defence Isabel Cuella Martin

Supervisors

• Prof. dr. Bouke de Jong (ITM)

• Prof. dr. Leen Rigouts (ITM/University of Antwerp)

• Dr. Jean-Claude Semuto Ngabonziza (Rwanda Biomedical Center) 

Abstract

Tuberculosis (TB) remains one of the world's deadliest infectious diseases, and drug resistance poses an even greater threat to global health. This thesis focuses on rifampicin-resistant tuberculosis (RR-TB) in Rwanda, providing crucial insights that extend beyond the country.

Despite significant progress in RR-TB control in Rwanda, which has achieved a relatively low incidence (0.77 per 100,000 population), high rifampicin (RIF) diagnostic coverage, and high treatment success rates (89% for first-line treatment), critical gaps remain in diagnostic accuracy and overall surveillance of resistance mechanisms.

This thesis revealed a problem with the recommended rapid diagnostic test, Xpert MTB/RIF Ultra. In settings where rifampicin resistance prevalence is low, this test gives false-positive results, mistakenly identifying patients as having RR-TB when they actually don't. This led to unnecessary treatment with toxic, expensive drugs for over half of the patients, particularly those with very low levels of bacteria in their samples. In addition, we found that many testing health facilities struggled with equipment failures and processing delays, highlighting the gap between having advanced technology and implementing it effectively in real-world settings.

To address the diagnostic gap for new drugs, we successfully validated and implemented an accessible and fast method called thin-layer agar (TLA) that can detect resistance to multiple drugs, including bedaquiline. This technique can be performed in BSL2 laboratories, making comprehensive drug resistance testing more accessible in resource-limited settings.

The mapping of RR-TB transmission revealed that resistant strains transmit across administrative boundaries, suggesting that traditional contact tracing methods do not capture some transmission patterns. Finally, we identified cross-border spread of Rwanda's dominant drug-resistant strain to neighbouring countries, demonstrating that RR-TB control cannot succeed through national efforts alone.

These findings emphasize that effectively combating drug-resistant tuberculosis requires combining improved diagnostic tools with better implementation strategies and regional coordination.