Tuberculosis (TB) is still the world’s top infectious killer and drug-resistant TB (DR-TB) poses a global health threat, being among the major contributors to the antimicrobial resistance crisis worldwide. The past years have seen unprecedented step forwards in DR-TB management, especially in treatment. Multiple short (6-9 months), all-oral regimens are currently available for persons sick with tuberculosis resistant to rifampin/multidrug-resistant (RR/MDR-TB). Some of these regimens are also approved for persons with TB with additional resistance to fluoroquinolones (pre-XDR-TB). A rich pipeline of new drugs with novel mechanisms of action studied by large international consortia offers an important transformational potential in TB treatment. Nevertheless, numerous unmet needs remain in the management of DR-TB. Among them, diagnostic and surveillance gaps prevent to 1) gain understanding on the real burden of DR-TB, 2) monitor DR-TB transmission dynamics within countries and at an international level and 3) control the spread of resistant M. tuberculosis strains. Treatment-related toxicity remains a major concern also in novel regimens and can affect adherence and outcomes. Resistance to bedaquiline, the core drug in DR-TB, is on the rise and poses a global health threat. Limited treatment options are available for special groups including pregnant women and children and for persons who are infected with extensively drug-resistant TB (XDR-TB) or with expanded resistance profiles. The large-scale introduction of novel regimens, including drugs for which resistance mechanisms and susceptibility testing is still not available, can contribute to the emergence of resistance and possibly to short durability of novel regimens and drugs. Finally, access to TB care is still restricted in many high-burden, low and middle-income countries, who face catastrophic costs and count the most number of deaths from the disease. In this thesis, we explored three of the above mentioned unmet needs in DR-TB. By analysing whole-genome-sequencing (WGS) surveillance data of the European Centre for Disease Prevention and Control (ECDC) paired with national Italian surveillance data, we tracked the ongoing evolution of a previously reported cross-country cluster of DR-TB, which progressed from a MDR and pre-XDR resistance profile to XDR with additional resistance to pretomanid, highlighting the crucial role of molecular surveillance for DR-TB control. We analysed hepatotoxicity events, their predictors among baseline characteristics and treatment-related effect among three newly WHO-approved bedaquiline-based, 9-month, all-oral regimens studied in the endTB trial (NCT02754765), highlighting the importance of adverse-events monitoring and compliance to clinical standards both in clinical trials and in real-life settings. We analysed the longitudinal acquisition of bedaquiline resistance in a cohort of persons with RR/MDR-TB in South Africa during treatment with a previously-recommended 9-month, all-oral regimen by performing phenotypic and genotypic DST on serial isolates. Persons who returned to care after treatment interruption showed high rates of acquired bedaquiline resistance, highlighting the need to closely monitor adherence and to have a high suspicion of bedaquiline resistance in this group of patients. In summary, our work provides insights into three of the many unmet needs in DR‑TB and highlights the interrelation between them. These findings underscore that effectively addressing DR‑TB demands a comprehensive, multifaceted approach that considers both the individual and the community as a whole.
Exploring unmet needs in drug-resistant tuberculosis: insights on surveillance, treatment toxicity and emerging bedaquiline resistance
SEPULCRI, CHIARA
2026-05-12
Abstract
Tuberculosis (TB) is still the world’s top infectious killer and drug-resistant TB (DR-TB) poses a global health threat, being among the major contributors to the antimicrobial resistance crisis worldwide. The past years have seen unprecedented step forwards in DR-TB management, especially in treatment. Multiple short (6-9 months), all-oral regimens are currently available for persons sick with tuberculosis resistant to rifampin/multidrug-resistant (RR/MDR-TB). Some of these regimens are also approved for persons with TB with additional resistance to fluoroquinolones (pre-XDR-TB). A rich pipeline of new drugs with novel mechanisms of action studied by large international consortia offers an important transformational potential in TB treatment. Nevertheless, numerous unmet needs remain in the management of DR-TB. Among them, diagnostic and surveillance gaps prevent to 1) gain understanding on the real burden of DR-TB, 2) monitor DR-TB transmission dynamics within countries and at an international level and 3) control the spread of resistant M. tuberculosis strains. Treatment-related toxicity remains a major concern also in novel regimens and can affect adherence and outcomes. Resistance to bedaquiline, the core drug in DR-TB, is on the rise and poses a global health threat. Limited treatment options are available for special groups including pregnant women and children and for persons who are infected with extensively drug-resistant TB (XDR-TB) or with expanded resistance profiles. The large-scale introduction of novel regimens, including drugs for which resistance mechanisms and susceptibility testing is still not available, can contribute to the emergence of resistance and possibly to short durability of novel regimens and drugs. Finally, access to TB care is still restricted in many high-burden, low and middle-income countries, who face catastrophic costs and count the most number of deaths from the disease. In this thesis, we explored three of the above mentioned unmet needs in DR-TB. By analysing whole-genome-sequencing (WGS) surveillance data of the European Centre for Disease Prevention and Control (ECDC) paired with national Italian surveillance data, we tracked the ongoing evolution of a previously reported cross-country cluster of DR-TB, which progressed from a MDR and pre-XDR resistance profile to XDR with additional resistance to pretomanid, highlighting the crucial role of molecular surveillance for DR-TB control. We analysed hepatotoxicity events, their predictors among baseline characteristics and treatment-related effect among three newly WHO-approved bedaquiline-based, 9-month, all-oral regimens studied in the endTB trial (NCT02754765), highlighting the importance of adverse-events monitoring and compliance to clinical standards both in clinical trials and in real-life settings. We analysed the longitudinal acquisition of bedaquiline resistance in a cohort of persons with RR/MDR-TB in South Africa during treatment with a previously-recommended 9-month, all-oral regimen by performing phenotypic and genotypic DST on serial isolates. Persons who returned to care after treatment interruption showed high rates of acquired bedaquiline resistance, highlighting the need to closely monitor adherence and to have a high suspicion of bedaquiline resistance in this group of patients. In summary, our work provides insights into three of the many unmet needs in DR‑TB and highlights the interrelation between them. These findings underscore that effectively addressing DR‑TB demands a comprehensive, multifaceted approach that considers both the individual and the community as a whole.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
