The Individualized M(X) Drug-resistant TB Treatment Strategy Study
The Individualized M(X) Drug-resistant TB Treatment Strategy Study
This is a randomized controlled clinical trial comparing treatment success of a gene-derived
 individualized drug-resistant Tuberculosis regimen to a standard Tuberculosis regimen based
 on South African National Tuberculosis guidelines.
When drug resistance is detected by molecular methods such as the Xpert MTB/RIF assay,
 second-line Multi Drug-Resistant (MDR) Tuberculosis treatment is started in the complete
 absence of detailed resistance information. The diagnosis of Multi Drug-Resistant
 Tuberculosis is confirmed only on availability of Line Probe Assay (LPA)/Drug Susceptibility
 Testing (DST) results. Extremely Drug-Resistant (XDR) Tuberculosis is diagnosed by in vitro
 phenotypic resistance to Rifampicin, Isoniazid, fluoroquinolones and injectable second-line
 drugs (i.e., amikacin, kanamycin, or capreomycin). Existing culture based Drug Susceptibility
 Testing provides results after 6-8 weeks. This duration may be further increased by other
 existing laboratory challenges, such as culture contamination.

 Furthermore, initial regimens are often not optimal and sometimes completely ineffective as
 there is a lack of Drug Susceptibility Testing to support them. More importantly, even
 optimal regimens are changed due to patient intolerance of the drug's side effects.

 Whole Genome Sequencing (WGS) has the advantage of determining the complete Deoxyribonucleic
 acid (DNA) sequence of an organism's genome at a single time point. Using this technology,
 genotypic mutations conferring resistance to anti-tuberculosis drugs can be identified. This
 information will assist in identifying not only potential resistant drugs, but also
 susceptible drugs and thus enable a more accurate and appropriate choice of regimen. In
 addition, drugs that will not add value to the treatment outcome, but will increase rates of
 adverse drug reactions, can be eliminated earlier, improving drug-resistant TB treatment
 outcomes.

 In this proposal, we aim to use Mycobacterium Tuberculosis (MTB) whole genome sequencing
 prior to the selection of a drug-resistant tuberculosis treatment regimen and thus provide an
 individualized treatment strategy for drug-resistant tuberculosis. By adopting this method,
 we hope to improve culture negative survival rates at 6 months post treatment initiation .

 This study will include 448 adult patients (age ≥ 18 years) that meet inclusion criteria.
 Patients referred by provincial satellite facilities with microbiological confirmation of
 drug-resistant tuberculosis (e.g. Xpert MTB/RIF assay / Line Probe Assay) to King DinuZulu
 Hospital (KDH) will be recruited. Patients randomized to the control arm will receive
 standard of care (SOC) treatment. Patients randomized to the intervention arm will be given
 an individualized treatment regimen based on whole genome sequencing conducted on
 Mycobacteria Growth Indicator Tube (MGIT) positive sputum samples collected at the screening
 visit.
Inclusion Criteria

 -  Adults ≥ 18 years of age

 -  Pulmonary Tuberculosis

 -  Microbiological confirmation [e.g. GeneXpert Mycobacterium Tuberculosis (MTB) detected
 and Rifampicin (RIF) resistant and / Line Probe Assay (LPA)] of Multi drug-resistant
 tuberculosis (MDR-TB) / Pre-Extremely drug-resistant tuberculosis (Pre-XDR-TB) /
 Extremely drug-resistant tuberculosis (XDR-TB)

 -  Capacity for providing informed consent

 -  HIV status - HIV infected and uninfected patients are allowed in the study:

 -  Patients already on antiretroviral treatment (ART) will be allowed in the study.
 The antiretroviral treatment regimen will be evaluated for any contraindications
 to the drugs used.

 -  HIV infected patients at any CD4 count irrespective of antiretroviral treatment
 commencement and duration will be included in the study

 Exclusion Criteria:

 -  Persons suffering from any serious acute condition.

 -  Any other chronic or clinically significant medical condition that in the opinion of
 the attending clinician would render the patient unsuitable for participation in the
 study.