Benin Population Diversity of Tuberculosis and Implications

Study Overview
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Brief Summary
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Tuberculosis is a public health problem caused by a microbe. This microbe may differ from one patient to another. The purpose of this study is to know to which extent, each of these various microbes is involved in tuberculosis disease in Benin. This study will also find out whether the type that affects a patient, depends on patient characteristics and whether the difference affects the outcome of the treatment. Finally the study will also help to find out whether diagnostic tests are reliable for all types of the microbe. This information will be used after the study to inform decision making in order to improve tuberculosis control.

Detailed Description
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The overall aim of this study is to determine the population structure of Mycobacterium tuberculosis complex in Benin, and implications for tuberculosis presentation, diagnosis and outcome The primary objective is to compare the characteristics of ancestral lineages of Mycobacterium tuberculosis complex, such as M. africanum West African 1 (Lineage 5), with modern M. tuberculosis in Benin. This study will build on the system of nationwide surveillance already implemented for retreatment patients and recruit in addition a representative random sample of new patients. So for this study sputa from retreatment patients and from a sample of new patients, from the 24 tuberculosis (TB) clinics (Centres de Diagnostic et de Traitement de la Tuberculose) selected all over the country (Benin), will be shipped from TB clinics to the ''Laboratoire de Référence des Mycobactéries'' (LRM), Cotonou (National Reference Laboratory for Mycobacteria, Cotonou) if they consent. All retreatment patients will be recruited into the study and each 4 new patients detected after detection of a retreatment patient will also be recruited into the study. At enrolment, a questionnaire will be used to collect from consenting participants information such as: Participant place of residence (rural or urban as determined by population density); ethnic group; age; sex; Human Immuno-deficiency Virus (HIV) status; Bacillus Calmette Guerin (BCG) vaccine scar... Spoligotype analysis will be used to determine the population structure, as it allows the classification of most Mycobacterium tuberculosis complex isolates in lineages, including strains with single or few copies of IS6110. The external quality evaluation (assurance quality) of the laboratory analyses to be performed at the LRM (National Reference Laboratory for Mycobacteria) in Cotonou, Benin during the study, will be performed by the Institute of Tropical Medicine of Antwerp in Belgium.

Official Title
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Implications of the Population Structure of the Mycobacterium Tuberculosis Complex in Benin for Tuberculosis Presentation, Diagnosis and Outcome

Conditions
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Tuberculosis

Intervention / Treatment
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* Other: No intervention (observational study)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: New or retreatment tuberculosis patients with Acid Fast Bacilli-positive microscopy, Diagnosed in a participating TB clinic of Benin, Aged ≥15 years (Patients aged less than 15 years old will not be included in this study as acid-fast-bacilli microscopy is rarely positive in children) Who has given his/her informed consent (if adult potential participant:≥18 years old) OR who has given his/her assent in addition to the informed consent of his/her legal representative (if potential participant aged 15-<18 years) Exclusion Criteria: Extra-pulmonary TB only, New patient who has started taking the TB treatment drugs. Retreatment patient who has started taking the TB retreatment drugs. Very low sputum quantity (at least 5 milliliters total sputum is acceptable) and potential participant refusing to give more sputum

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| New patients<br>''New tuberculosis patients'' are patients just diagnosed for tuberculosis, and who were never treated for tuberculosis or who are treated for less than 1 month. In total, 1192 new patients will be recruited. | Other: No intervention (observational study)<br> <br> |
| Retreatment patients<br>''Retreatment tuberculosis patients'' are patients just diagnosed for tuberculosis and who were previously treated for tuberculosis (for a duration of 1 month at least). This group includes: patients with treatment relapse, failure and patients who return after default. In total, 298 retreatment patients will be recruited. | Other: No intervention (observational study)<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Lineage | Mycobacterium tuberculosis lineage as determined by the spoligotyping pattern. The lineage will be determined using the specimen collected at participant enrolment. Spoligotyping will be done on sputum, or on culture isolate if failed on sputum and culture is positive. | At enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spoligotype (family) | Mycobacterium tuberculosis spoligotype (family) as determined by the spoligotyping pattern. The lineage will be determined using the specimen collected at participant enrolment. | At enrollment | 
| Treatment failure or success as evidenced by microscopy result (for new and retreatment patients) | Treatment failure will be ascertained at the end of the treatment period using microscopy for detection of acid-fast bacilli in participant' sputa. Treatment failure or success will be measured using microscopy, only for new and retreatment patients. | At Month 6 for new patient; at Month 8 for retreatment patients | 
| Treatment failure or success as evidenced by culture result (for rifampicin resistant patients) | Treatment failure will be ascertained at the end of the 20 months treatment period by culturing sputa from rifampicin resistant participants. | At Month 20 for rifampicin resistant patients | 
| Relapse ascertainment (by questioning and retrospective check of microscopy evidence in TB clinics) | Participants will be called and will be asked whether they have experienced another episode of tuberculosis. This will be retrospectively confirmed in the TB clinic by checking microscopy results for the new episode of tuberculosis. | At Month 18 for new patients; at Month 20 for retreatment patients; at Month 32 for rifampicin resistant patients | 
| Chest X-ray findings | Chest X-ray will be performed in participants to be enrolled in Cotonou and Porto-Novo, the 2 biggest TB clinics and where X-ray is available. | At enrollment | 
| Culture positivity | Isolation of mycobacteria (in vitro mycobacterial growth) in culture | At enrollment | 
| Phenotypic Drug-resistance or susceptibility | Drug resistance as determined using phenotypic drug susceptibility testing on 1st and 2nd line anti-tuberculous drugs | At enrollment (if positive culture) | 
| Genotypic resistance to rifampin (GeneXpert) | Resistance of Mycobacterium tuberculosis to rifampin as determined using the GeneXpert Mtb/Rif test. | At enrollment | 
| (Phenotypic)Type of Mycobacteria (tuberculous or non-tuberculous) | Group of Mycobacteria (tuberculous or non-tuberculous) as determined by the result of phenotypic drug sensitivity testing on para-nitro-benzoic acid | At enrollment (if positive culture) | 
| (Mpt64's)Type of Mycobacteria (tuberculous or non-tuberculous) | Group of Mycobacteria (tuberculous or non-tuberculous) as determined using the Mpt64 antigen test | At enrollment (if positive culture) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, population structure, implications, lineages, spoligotyping, sputum, resistance, culture, diagnostics, outcome, new/retreatment patient