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Project
First-line anti TB-drugs revisited
Drug-resistant tuberculosis (DR-TB) continues to be a major challenge in the control of the worldwide TB epidemic.1 In 2015, approximately 3.9% of new and 21% of previously treated TB patients were infected with rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB).2 MDR-TB is characterized by resistance to at least rifampicin (RIF) and isoniazid (INH), the two most powerful first-line drugs of standard TB treatment.2 One of the strategies to oppose DR-TB has been to optimize the use of existing drugs, including first-line drugs. For example, whereas treatment with INH is often ceased when INH resistance has been demonstrated at the generally applied cut-offs, normal or elevated doses of INH continue to be clinically effective at low- and moderate-level resistance, respectively, since the resulting serum levels of the drug exceed minimum inhibitory concentrations (MICs) associated with the respective resistance levels.3-9 We showed that a low number of wellcharacterized, easily detectable mutations in katG and inhA can reliably predict the resistance level of M. tuberculosis to INH (manuscript submitted for publication). In concurrence with previous studies, our results suggested moreover that moderate-level resistance can be overcome by elevated doses of the drug in patients with MDR-TB complicated by baseline fluoroquinolone (FQ, the most important second-line class of drugs) resistance who received the so-called 9-month Bangladesh regimen, which includes moderately high-dose INH.
The 9-month Bangladesh regimen is a standardized FQ-based regimen for the treatment of MDR-TB which shortens treatment duration from 18 months to 9-12 months and increases treatment success from about 50% to 85% compared to previous regimens.6,7 The regimen, developed by Armand Van Deun, is recommended by the WHO since May 2016.10 Whether high-level resistance to INH is associated with treatment failure of the 9-month regimen when including all patients of the Bangladesh MDR-TB cohort and taking into account resistance to other drugs in a multivariate analysis, will be investigated in this PhD project. Included in the project as well, will be the question whether resistance to another first-line drug, pyrazinamide (PZA), is associated with treatment failure. The majority of resistance to PZA results from mutations in pncA. Many mutations in this gene have been described and they are scattered throughout the gene.11,12 Since only a few, rare mutations appear to be not associated with phenotypic resistance, it is assumed that the majority of the others do confer resistance.11,12 However, it is not known what the clinical impact of this resistance is, i.e. whether treatment with PZA should be continued in case of mutations in pncA. WP 1: Do mutations in katG, inhA and pncA predict failure of the 9-month regimen? M. tuberculosis isolates of all patients included in the Bangladesh MDR-TB cohort as well as phenotypic drug resistance results of these isolates are available at ITM. On those isolates that did not have katG, inhA and/or pncA sequencing done, we will carry out the respective line probe assays (LPAs) of NIPRO. The association between molecular/phenotypic resistance and treatment failure will be investigated in a multivariate analysis. Isolates with mutations in both katG and inhA will have extended INH MIC testing done, to verify whether this combination of mutations is indeed associated with high-level INH resistance as was found in the submitted study and with cross-resistance to prothionamide (PTH), another drug in the 9-month regimen.
Another first-line drug to which renewed attention has been paid is RIF. Resistance to RIF is caused by mutations in rpoB. However, not all phenotypic resistance to RIF can be explained by mutations in rpoB.13 Unraveling novel resistance mechanisms would aid better detection of RIF resistance. As part of drug resistance surveillance in Kinshasa, Democratic Republic of Congo (DRC), we found a number of M. tuberculosis isolates that were indeed phenotypically resistant to RIF, but had a wild type rpoB gene. Moreover, the majority of these isolates appeared as a phylogenetic cluster.
The 9-month Bangladesh regimen is a standardized FQ-based regimen for the treatment of MDR-TB which shortens treatment duration from 18 months to 9-12 months and increases treatment success from about 50% to 85% compared to previous regimens.6,7 The regimen, developed by Armand Van Deun, is recommended by the WHO since May 2016.10 Whether high-level resistance to INH is associated with treatment failure of the 9-month regimen when including all patients of the Bangladesh MDR-TB cohort and taking into account resistance to other drugs in a multivariate analysis, will be investigated in this PhD project. Included in the project as well, will be the question whether resistance to another first-line drug, pyrazinamide (PZA), is associated with treatment failure. The majority of resistance to PZA results from mutations in pncA. Many mutations in this gene have been described and they are scattered throughout the gene.11,12 Since only a few, rare mutations appear to be not associated with phenotypic resistance, it is assumed that the majority of the others do confer resistance.11,12 However, it is not known what the clinical impact of this resistance is, i.e. whether treatment with PZA should be continued in case of mutations in pncA. WP 1: Do mutations in katG, inhA and pncA predict failure of the 9-month regimen? M. tuberculosis isolates of all patients included in the Bangladesh MDR-TB cohort as well as phenotypic drug resistance results of these isolates are available at ITM. On those isolates that did not have katG, inhA and/or pncA sequencing done, we will carry out the respective line probe assays (LPAs) of NIPRO. The association between molecular/phenotypic resistance and treatment failure will be investigated in a multivariate analysis. Isolates with mutations in both katG and inhA will have extended INH MIC testing done, to verify whether this combination of mutations is indeed associated with high-level INH resistance as was found in the submitted study and with cross-resistance to prothionamide (PTH), another drug in the 9-month regimen.
Another first-line drug to which renewed attention has been paid is RIF. Resistance to RIF is caused by mutations in rpoB. However, not all phenotypic resistance to RIF can be explained by mutations in rpoB.13 Unraveling novel resistance mechanisms would aid better detection of RIF resistance. As part of drug resistance surveillance in Kinshasa, Democratic Republic of Congo (DRC), we found a number of M. tuberculosis isolates that were indeed phenotypically resistant to RIF, but had a wild type rpoB gene. Moreover, the majority of these isolates appeared as a phylogenetic cluster.
Datum:12 jan 2017 → 12 apr 2023
Trefwoorden:B780-tropische-geneeskunde
Project type:PhD project