Effectiveness of a Simplified Short Regimen for Multidrug Resistant Tuberculosis in Uzbekistan
Effectiveness of a Simplified Short Regimen for Multidrug Resistant Tuberculosis in Uzbekistan
Multidrug resistant tuberculosis (MDR TB) is a growing problem and few people have access to
 adequate diagnosis and treatment. The current recommended treatment regimen for MDR TB has a
 minimum of 20 months duration with high toxicity. Scale up of MDR TB treatment is associated
 with high default rates, and experience in the Medecins Sans Frontieres (MSF) programme in
 Uzbekistan shows that the current standard treatment greatly limits the ability to scale up
 to meet the high rates of MDR TB in the region.

 Evidence from Bangladesh in 2010 showed that a 9-month short-course regimen could achieve a
 relapse-free cure rate of 88%. Several countries in West Africa started implementing similar
 regimens with similar outcomes. Evidence of effectiveness of this shortened regimen among
 regions with high second line drug use and resistance is still limited.

 The investigators propose an observational study under programmatic conditions to evaluate
 the effectiveness of a shortened course MDR TB regimen in the high MDR/extensively drug
 resistant (XDR) TB prevalence and high second-line drug resistance setting of Karakalpakstan,
 Uzbekistan.
A prospective observational study has been designed. The study regimen is composed of an
 intensive phase of at least 4 months duration of Pyrazinamide (Z) + Ethambutol (E) +
 Isoniazid (H) + Moxifloxacin (Mfx) + Capreomycin (or Kanamycin/Amikacin) (Cm/Km/Am) +
 Prothionamide (Pto) + Clofazimine (Cfz) and a continuation phase of oral drugs
 Z-E-Mfx-Pto-Cfz. Patients will be followed up until the end of treatment and during 12 months
 after treatment completion in order to evaluate the rate of relapse.

 Data will be recorded in patient's clinical files and electronic databases and analyzed with
 Stata 11.0.

 This study is a result of ongoing collaboration of MSF with the Ministry of Health in
 Uzbekistan; results will be shared with the national health authorities, World Health
 Organization and the rest of the scientific community and aim to influence and improve
 treatment and care of patients with MDR TB.
Inclusion Criteria:

 -  New presumptively diagnosed MDR TB patients (adults and children) with Xpert® MTB/RIF
 (rifampicin) or Hain MTBDR (Mycobacterium tuberculosis drug resistance), or confirmed
 with Hain MTBDR plus on positive cultures if initial molecular tests negative or
 confirmed from MGIT (mycobacteria growth indicator tube) culture/DST if initial
 molecular tests negative;

 -  Children (<14 yo) suspected of MDR TB without bacteriological confirmation but
 documented as a close contact of a confirmed MDR TB patient; AND

 -  Informed consent to participate in the study signed by the patient or the responsible
 caretaker for patients <16 years old (as per national legislation).

 Only patients with a history of prior treatment with second line anti-TB drugs for less
 than one month will be eligible for inclusion.

 Patients will be included regardless of HIV status.

 Exclusion Criteria:

 -  Baseline contraindications to any medications of the study regimen medications, where
 benefits of the regimen do not outweigh the risks as judged by treating physician;

 -  Severe renal insufficiency with estimated creatinine clearance of <30 ml/min at
 baseline (calculated with Cockcroft-Gault formula);

 -  Patients with extrapulmonary TB only (without involvement of lung parenchyma)

 -  Patients with documented ofloxacin resistance

 -  Patients with XDR TB (additional resistance to SLD [second line drug] kanamycin (or
 capreomycin) AND ofloxacin);

 -  Patients with resistance to both Km and Cm.

 -  Critically ill and in the judgement of the treating physician unlikely to survive more
 than 1 week (these patients may still be commenced on standard MDR TB treatment
 according to the Karakalpakstan comprehensive TB treatment guidelines)

 -  Has one or more of the following risk factors for QTc prolongation:

 -  A confirmed prolongation of QTc interval (Fridericia formula), e.g., repeated
 demonstration of QTcF (Fridericia correction) interval > 500 ms in the screening ECG
 (i.e., retesting to reassess eligibility will be allowed once using an unscheduled
 visit during the screening phase)