Rifampicin is the most potent anti-tuberculosis (TB) drug. Accurate diagnosis of rifampicin resistance (RR) is therefore critical to offer the correct treatment. TB patients who have previously received rifampicin-based treatment (Category 1) are at higher risk of having RR-TB. In Niger, like in the majority of high burden TB countries, such retreatment patients are prioritized for the diagnosis of RR-TB using an Xpert MTB/RIF test, which simultaneously detects TB and its susceptibility to rifampicin. However, Xpert can miss RR-TB and does not test for isoniazid resistance. The recognition of RR conferring rpoB mutations outside the Xpert target in historical strains from Niger warrants screening of retreatment patients with rifampicin-susceptible TB on Xpert for the detection of such rpoB mutations missed by Xpert. We therefore aim to use continuous surveillance in ethanol preserved sputa from a systemati sample of retreatment pulmonary tuberculosis patients to determine the magnitude of initial isoniazid-resistant / rifampicin-susceptible TB and RR missed by Xpert MTB/Rif. The results will inform the optimal diagnostic algorithm in Niger to prevent patients from receiving ineffective treatment. This surveillance will moreover help to resolve another clinical puzzle, an alarming discrepancy between microscopy results showing acid-fast bacilli and Xpert “MTB negative” Xpert results found in retreatment patients nationwide. These results may be explained by Non Tuberculous Mycobacterial (NTM) disease or other (partially) acid fast bacilli such as Nocardia. These patients present with respiratory symptoms but remain without clear diagnosis and treatment since there is no guideline on the management of such patients.The systematic ethanol sampling of baseline samples collected from retreatment patients will also allow us to screen for mycobacteria other than TB as aetiology of the respiratory infection. Currently, a cascade of treatment regimens approach is used in Damien Foundation supported RR-TB programmes. The second-line RR-TB treatment regimen is the fluoroquinolone-based injectablecontaining 9-month “Bangladesh STR”. This regimen is very effective in Niger. While fluoroquinolone is used as core drug in this second-line regimen, bedaquiline safeguarded to serve as core drug for third-line regimens. Outcomes of second-line regimens were previously reported. However few data are available on the outcomes of third-line treatment regimens. In addition, most TB studies report outcomes by regimen, without providing “definitive outcomes” for those requiring a follow-up thirdline treatment, after an unsuccessful second-line treatment. We therefore aim to describe definitive treatment outcomes for the RR-TB cohort, including outcomes of patients unsuccessfully treated with a second-line shorter treatment RR-TB regimen and treated with a third-line RR-TB treatment regimen. For this retrospective study data from Niger will be merged with data from other Damien Foundation supported countries Guinea and Burundi. The fluoroquinolone-based injectable-containing 9-month second-line “Bangladesh STR” achieved successful outcome in RR-TB patients, with few patients experiencing failure and relapse. In 2016, the WHO endorsed this regimen. But, without strong evidence, in its 2020 guidelines the WHO recommends replacing the injectable by bedaquiline, thus using most both powerful second-line antiTB drugs (fluoroquinolone and bedaquiline) together in a single, all-oral regimen. To implement this new regimen WHO also emphasises rapid drug susceptibility tests (DST) to rule out fluoroquinolone resistance before starting this all-oral regimen. However, access to rapid DST for fluoroquinolone is not routinely available in many low-income countries with high TB prevalence, such as Niger. If the WHO-recommended fluoroquinolone- and bedaquiline-containing second-line RR-TB regimen would be used in patients with undetected initial resistance to fluoroquinolones, there is a high risk of acquiring resistance to bedaquiline, thus creating potentially untreatable disease because the options for developing an effective third-line regimen for such patients are scarce. In light of the above considerations, the Niger NTP decided to implement a new second-line all-oral bedaquiline-based RRTB regimen without a fluoroquinolone (4-6 LZD-INHh-BDQ-PTO-CFZ-EMB-PZA/5 BDQ-CFZ-EMB-PZA) under operational research conditions. I will document its safety and effectiveness in a one-arm programmatic low-intervention clinical trial. If this approach proves to be effective, it will also allow to have an effective fluoroquinolone-based injectable-containing third-line RR-TB regimen for patients with unfavourable outcomes (failure or relapse).
|Effective start/end date
|1/01/21 → 31/12/24
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