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  • Writer's pictureCARE Project

Designing patient-tailored therapies for multidrug-resistant tuberculosis

Today in the CARE Partner spotlight are Drs. Jan Heyckendorf and Matthias Merker from Research Center Borstel (Germany).

Please describe your role in the CARE project?

JH: We are leading a work package, which aims to provide better diagnostic tools for personalised therapy for tuberculosis patients. A major concern, especially in Eastern Europe and Russia, is the transmission of multidrug-resistant (or MDR) strains, which are at least resistant against isoniazid and rifampicin, the two most effective anti-tuberculosis drugs we have so far. When a patient is infected with such an MDR strain, the bacterium is most likely also resistant against other drugs and clinicians need to identify an effective drug regimen comprising ideally five different antibiotics.

MM: At this point, we can employ a relatively new molecular technique called next-generation sequencing (NGS) which can interrogate the whole genome of the infecting strain. That means we can read all genes which are implicated in drug resistance mechanisms and we can further infer transmission chains, for instance when we find very closely related strains from two different patients.

What motivated you and your organisation to join CARE?

JH: Matthias and I already had close collaborations earlier in which we successfully combined my clinical background with his expertise in molecular diagnostics. So, we were basically intrinsically motivated to join CARE and to extend our work on the translation of genomics into clinical practice and improve personalized therapies for the most difficult to treat TB patients.

MM: Within CARE, we further had the opportunity together with the colleagues from St. Petersburg and Chisinau to establish MDR-TB cohorts which built the foundation for CARE projects but also for future tuberculosis research. Importantly, both settings belong to the high burden MDR-TB setting worldwide and our cohorts offer a unique opportunity to understand how drug resistance evolves and how MDR strains spread.

Could you tell us more about the research you are doing within CARE?

JH: We are ultimately aiming to provide a tool which can predict drug resistances from the genomes of tuberculosis strains and thus, provide a solid basis for clinicians to design a patient-tailored therapy. Especially in Eastern Europe and the Russian Federation such personalized therapies are key to overcome the current low treatment success rates of around 50% for MDR-TB patients. Due to the Corona crisis, we were unfortunately not able to organize an in-person workshop about the principles of personalized therapies, but we’re in contact with our partners to discuss and analyze the molecular data generated within CARE.

MM: As far as the Corona restrictions allowed, we hosted two colleagues from Chisinau and could already finalize an investigation about MDR-TB patients who received a very promising drug named bedaquiline which was only recently introduced on the market. As you can imagine very little was known about the molecular mechanisms of resistance and which factors may foster the evolution of resistance in patients. We’re confident that we can submit the manuscript still this year and look more deeply into the St. Petersburg cohort soon. With the colleagues from Tübingen and Cologne, we trained and tuned machine learning algorithms, named geno2pheno[TB], that will use bacterial genome sequences in the future to further improve current predictions based on mutations catalogues.

Why is it important to study TB drug resistance and treatment monitoring in your opinion?

JH: We believe that treatment monitoring, especially for patients with MDR-TB, is one of the most important topics to date. Presently, 18-20 months of therapy for all patients regardless of the host’s immunological status or the pathogen’s resistance pattern is probably wrong in most cases. We are working in this field as well in national and international consortia funded by the EU and the German Center for infection research (DZIF).

MM: Concerning drug resistance, you need to know that today one-third of all deaths due to antimicrobial resistances are caused by MDR-TB strains. Overall, researchers estimate that in 2050 we will have more deaths caused by resistant pathogens than we have today from cancer. That makes it of the utmost importance for us to rapidly detect drug resistance genes in patients and understand the evolution of drug resistance in the patient but also on a global scale.

Do you have any plans to implement the research results in the future?

JH: Absolutely, Matthias and I already collaborated in a retrospective analysis, how NGS based resistance predictions and inferred treatment regimens would have performed with the current knowledge databases. And indeed with our algorithm, we would not have given drugs to MDR-TB patients with proven phenotypic resistance. This makes us very confident, that this is one of the most advanced approaches for precision medicine of tuberculosis patients.

MM: We also started this year at the Research Center Borstel in Germany a prospective study which aims to improve the time to diagnosis and to achieve MDR-TB treatment outcomes which are comparable to drug susceptible tuberculosis therapies, so above 90-95% cure rates. Standardization of procedures and knowledge data basis has been also greatly improved the past two years which is important to translate the technique and workflows also to routine diagnostics labs in less developed countries.

What are your expectations from the project and the collaboration within it?

JH: We have great expectations for the geno2pheno[TB] tool which performs already slightly better for many antibiotics than the current “rule-based” approach. However, it requires large datasets for the training of the algorithm and would eventually need a graphical user interface to be utilized by clinicians and microbiologists. An evaluation of geno2pheno[TB] will employ the data generated within CARE and we’re currently seeking for additional funding to further include resistance predictions for bedaquiline for instance, for which data is still only sparsely available.

MM: In that regard, it would be highly desirable that the work of the CARE consortium as a whole will receive further funding. The opportunity to build up cohorts in Eastern Europe and the Russian Federation, where not only TB is thriving but also HIV and Hepatitis, is a unique trademark of CARE and offers multiple research collaborations in the future.

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