Triage Test for All Oral DR-TB Regimen (TRiAD Study)

A Phase 4 operational study to assess the effectiveness, feasibility, acceptability, and cost effectiveness of the GeneXpert MTB/XDR (Xpert XDR; Cepheid) assay for rapid triage-and-treatment of DR-TB-A multi-centre, multi-country prospective cohort study

The TriAD study is a multi-center, multi-country Prospective Pragmatic Cohort study assessing the effectiveness, feasibility, acceptability, and cost-effectiveness of implementing the Xpert MTB/XDR (Xpert XDR; Cepheid) assay for rapid triage-and-treatment with short, all- oral drug resistant tuberculosis (DR-TB) treatment. The proposed study aims to screen approximately 4800 GeneXpert MTB/RIF or Ultra MTB-positive (irrespective of rifampicin resistance status) patients from 9 study sites in South Africa, Nigeria and Ethiopia to enrol 880 rifampicin resistant (RR) and 400 isoniazid mono-resistant (HR) patients over a period of 12-18 months. The Xpert XDR assay, a rapid genotypic test, will be implemented as a reflex test to detect resistance to isoniazid, fluoroquinolones and second-line injectable agents to provide rapid genotypic susceptibility testing for DR-TB detection. Patients that test positive for Mycobacterium tuberculosis with rifampicin resistance will be enrolled in Cohort 1 (n=880). Patients that test positive for Mycobacterium tuberculosis that are rifampicin susceptible with isoniazid mono-resistance will be enrolled in Cohort 2 (n=400). Results from the Xpert XDR assay will be used to guide selection of appropriate, evidence-based, all-oral DR-TB treatment regimens of shortest possible duration. The tuberculosis molecular bacterial load assay (TB-MBLA) will be used as an adjunct to provide bacillary load monitoring over the course of treatment to assess real-time treatment response. Operational research will provide information about the feasibility, acceptability and cost-effectiveness to inform policies and guidelines for programmatic implementation of the triage-and-treat model.

Eligibility Criteria:
Inclusion Criteria:

1. Ambulant adults ≥ 18 years of age
2. Newly diagnosed PTB patients receiving less than 5 days of treatment since new diagnosis:

   1. Cohort 1: \< 5 days of DR-TB treatment
   2. Cohort 2: \< 5 days of INH mono-resistant TB treatment preceding study entry for the current TB episode, or
3. Sputum positive (smear and or culture) TB patients classified as failing first line treatment
4. Any currently available Nucleic Acid Amplification Tests for drug-resistance detection changes/assay positive for M.tb infection with:

   Cohort 1: at least Rifampicin resistance Cohort 2: Rifampicin susceptible co-occurring with INH, fluoroquinolone, ethionamide or aminoglycoside resistance (detected by Xpert XDR) occurring alone or in combination
5. Capacity to provide informed consent
6. HIV infected and uninfected participants are allowed in the study. Participants already on ART will be allowed in the study provided the ART regimen in use has no contraindications to the proposed TB drug regimen
7. Willing to have samples collected, stored indefinitely, and used for research purposes
8. Able to provide reasonable proof of identity (to satisfaction of study team member) at or prior to enrolment

Exclusion criteria:

1. Has a known severe allergy to any of the BPaL component drugs
2. Has DST showing infection with a strain resistant to any of the component drugs
3. Has TB meningitis, other central nervous system TB, or TB osteomyelitis; or
4. Is pregnant or breastfeeding
5. Is unable to take oral medications
6. Persons with any other medical condition, precluding study participation based on investigator judgement
7. Any co-existing condition that in the opinion of the attending clinician renders the participant unsuitable for participation in the study
8. Co-enrolment in other interventional research studies