When (new) drugs don’t work: Mozambique Faces Alarming Multidrug-Resistant Tuberculosis Epidemic

Effective diagnostics and treatment of patients affected by MDR-TB are key for TB control. In Mozambique and other African countries, the WHO has recommended a nationwide use of the Xpert MTB/RIF Ultra test as a first line diagnostic test for MDR-TB to guide rapid MDR-TB treatment in line with the latest World Health Organization (WHO) guidelines.

Recently, the WHO recommended a new 6-month oral treatment regimen (BPaLM) composed of bedaquiline, pretomanid and linezolid plus moxifloxacin (in the absence of fluoroquinolone resistance) for the treatment of patients with MDR-TB. Although this regimen holds great promise, the emergence of fluoroquinolone and/or bedaquiline resistance described recently will threaten the success and longevity of the regimen.

In this study, led by scientists from the Research Center Borstel, Leibniz Lung Center and the National Institute of Health (Instituto Nacional de Saúde, INS, Mozambique), researchers used cutting-edge genomic sequencing technology on a set of rifampicin resistant (RR) Mycobacterium tuberculosis (Mtb) strains submitted to the National Tuberculosis Reference Laboratory in Maputo between 2015-2021 to study the transmission and evolution of drug resistant Mtb strains over time.

It has been found, that over 20% of the MDR Mtb strains in Mozambique already exhibit fluoroquinolone. Further, bedaquiline resistance is steadily increasing, from 3% in 2016 to 14% in 2021 among the MDR/RR Mtb strains. The data also indicate a high rate of recent transmission, especially of Mtb strains with high levels of drug resistance, such as pre-XDR or XDR strains.

“The rapid evolution of resistance and the efficient transmission of highly resistant M. tuberculosis strains represent a major threat to TB control in Mozambique and the

neighbour regions” says Prof. Niemann, study coordinator at the Research Center Borstel, and PI at the Leibniz Science Campus EvoLUNG, the Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI) and the German Center for Infection Research (DZIF).

Equally worrisome is the spread of Mtb strains with a particular rifampicin resistance mutation (I491F), which was not detected by Xpert MTB/RIF Ultra and commercially available line probe assays. A large proportion of the I491F strains have a further resistance to bedaquiline, or even combined resistances to bedaquiline and fluoroquinolone. Comparison with strains from South Africa and Eswatini supports the cross border spread of I491F strains, a finding, that needs to be urgently investigated.

“Given the current diagnostic algorithms and treatment regimens, both, the emergence of rifampicin resistance due to I491F strains and bedaquiline resistance in general, may jeopardize efforts to contain the drug resistant TB epidemic in Mozambique” says Dr. Sofia Viegas, lead scientist and deputy general director at INS.

In a more general context, the study raises fundamental points regarding the development and introduction of new anti-TB agents or regimens. In the absence of effective diagnostics and direct translation of results into clinical decisions and resistance-adapted drug regimens, there is a high risk of rapid development of resistance, rendering newly developed medicines ineffective within a short timeframe. The study also calls into question the role of rapid molecular tests such as Xpert MTB/RIF in regions where the prevalence of “diagnostic escape” strains is high. The uncontrolled transmission of MDR Mtb strains in Mozambique and other parts of Africa represents a tremendous challenge for the fight against TB in the 21st century, and underlines the importance of effective diagnosis and TB surveillance based on comprehensive molecular methods such as sequencing technologies.

“Our research focuses on these topics, which we work on in national and international projects. Here, the translation of the basic research results into application is of particular importance” explains Prof. Niemann.

About the Leibniz Association

The Leibniz Association connects 97 independent research institutions that range in focus from natural, engineering and environmental sciences to economics, spatial and social sciences and the humanities. Leibniz Institutes address issues of social, economic and ecological relevance. Because of their importance for the country as a whole, the Leibniz Association Institutes are funded jointly by Germany’s central and regional governments The Leibniz Institutes employ around 20,500 people, including 11,500 researchers. The financial volume amounts to 2 billion euros. (www.leibniz-gemeinschaft.de/en/)

Scientific contact:

Prof. Dr. Stefan Niemann
Forschungszentrum Borstel, Leibniz Lungenzentrum
Parkallee 1, 23845 Borstel
+49 4537 188-7620
sniemann@fz-borstel.de

Press contact:

Britta Weller
Public Relation
Forschungszentrum Borstel, Leibniz Lungenzentrum
Parkallee 1, 23845 Borstel
+49 4537.188-2870
Fax: +49 4537.188-2600
bweller@fz-borstel.de