Resistance to anti-tuberculosis drugs is a continually growing problem. Multidrug-resistant tuberculosis (MDRTB) is resistance to at least rifampicin and isoniazid, and extensively drug-resistant TB is additional resistance to a fluoroquinolone and a second injectable line drug. Methods currently employed in testing for resistance are inadequate and a contributing factor to the 40-50% MDR-TB treatment success rate. Current drug susceptibility testing methods are slow for most drugs, taking weeks. Rapid molecular methods such as the line probe assays, e.g. Hain GenoType MDRTBplus and sl, provide resistant calls to only a limited number of drugs, and are often less useful in smear negative patients.
Molecular technologies such as sequencing can provide a comprehensive readout of drug resistance and are able to detect resistant populations at very low levels (≤1%), thus enabling individualized therapy. This can be done directly from sputum. Targeted sequencing amplifies regions of genomic DNA associated with resistance prior to sequencing. Rapid analytic software is used to process the raw sequence data, identify resistance causing mutations and provide a readout of clinically relevant information. However, the feasibility, and more importantly the impact, of this approach has not been evaluated in a clinical trial to establish proof of concept.
Aim 1: To conduct a randomised controlled trial to determine the impact of sputum-based targeted sequencing in detecting resistance to second-line TB drugs compared to the current programmatic standard of care (Hain MDRTBplus/sl and adjunct phenotypic drug susceptibility testing) when used to inform of treatment for MDR-TB.
Aim 2: To compare currently available drug resistant sequencing pipelines for diagnostic accuracy, sensitivity, specificity and predictive value as compared to culture based phenotypic drug susceptibility testing.
Aim 3: To compare the feasibility, accuracy, turn-aroundtime, and cost implications of the above-mentioned diagnostic approaches.
Newly diagnosed culture and/or Xpert/MTB Ultra positive pulmonary TB
Rifampicin resistance detected using GeneXpert
Provide written informed consent prior to all trial-related procedures
Male or female aged 18 years and older.
A subject who in the opinion of the investigator is unlikely to cope with regular visits to the trial site either because of travel constraints, or drug or alcohol abuse, or other reason.
Currently on MDR-TB treatment and completed 7 days of treatment.
Any participant with a clinically significant pre-existing medical condition that, in the opinion of the investigator, may be significantly worsened by the patient's participation in the study
Any subject with a Karnofsky score < 50.
Parallel
Targeted sequencing using the GenoScreen Deeplex assay
Diagnostic testTargeted sequencing to be performed on DNA extracted directly from clinical sputum samples using an on-demand strategy to generate a drug resistant profile. Clinicians treating the patients will have access to this and prescribe 5 or more effective drugs to the patients within 14 days of diagnosis.
Impact of targeted genome sequencing to initiate more than or equal to five effective TB drugs within 14 days of diagnosis (reference standard phenotypic DST).
Impact of sputum-based targeted sequencing in detecting resistance to second-line TB drugs using the GenoScreen Deeplex assay compared to the current programmatic standard of care (Hain MDRTBplus/sl and adjunct phenotypic drug susceptibility testing) when used to inform of treatment for MDR-TB.
Feasibility of targeted sequencing to initiate more than or equal to five effective TB drugs within 14 days of diagnosis.
To determine the proportion of patients in the interventional group with a drug-resistant profile and placed on ≥ 5 likely effective drugs within 14 days of rifampicin resistant tuberculosis diagnosis.
Favourable outcome rate
Rate of favourable outcome (cure or treatment complete) in conventional and interventional arms
Rate of treatment failure
Rate of treatment failures in conventional and interventional arm
Culture conversion rates
Culture conversion rates in conventional and interventional arm
Relapse rate
Rate of relapse in conventional and interventional arm
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University of Cape Town
Lead sponsor
University of Stellenbosch
Collaborator
Ospedale San Raffaele
Collaborator
Stichting Katholieke Universiteit
Collaborator
University of Cape Town Lung Institute
Collaborator
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