Diapositive 1

Diapositive 1

Update on the observational study on short MDRTB regimen Valrie Schwoebel The Union GDI meeting, Geneva, 29 April 2015 Basis for current WHO recommendations Individual data on 9,153 MDR-TB cases Lost for follow-up 22.89% Dead 15.21% 53.91% Success Failure 8.00% Ahuja,S.D. et al. PloS Med. 2012 9(8): e1001300. doi:10.1371/journal.pmed.1001300 Treatment results for MDR-TB patients WHO GT Report 2014 Bangladesh 4 Km Gfx Pto H Cfz E Z / 5 Gfx Cfz E Z Treatment outcome 2005-2011 relapse-free treatment success 84.5% (N = 515)

cured completed defaulted died failed relapsed 423 (82%) 12 (2%) 40 (8%) 29 (6%) 7 (1%) 4 (0.8%) No evidence of acquisition of Flq resistance 12,4% FQ resistant among 501 patients tested KJM Aung et al. Int J Tuberc Lung Dis 2014 ;18(10):11801187 Adverse event-free MDR treatment outcome, adjusted for age and sex, Bangladesh, 2005 to June 2011 Adverse event-free probability 1.0 Low level resistance (n=33) 0.9 90.4% 87.7% Susceptible (n=439)

0.8 Death Default Failure Relapse 0.7 S 24 31 1 1 LR 0 2 0 1 HR 0 5 6 2 0.6 High level resistance (n=29) 0.5 0 6

12 18 51.3% 24 30 Months since treatment start 36 42 Niger 65 MDR-TB patients (1 HIV-positive) excluded: pregnant women, diabetics, previous 2nd line > 1 month Treatment: 4 Km Gfx Pto H Cfz E Z / 8 Gfx Cfz E Z Results o 58 (89%) cured o 6 (9%) died o 1 (2%) defaulter No relapse at the 24-month follow-up after cure (49 patients followed-up) 1 patient initially resistant to FQ A. Piubello et al. Int J Tuberc Lung Dis 2014;18(10):11881194 Cameroon 150 MDR-TB patients (20% HIV-positive) 4 Km Gfx Pto H Cfz E Z / 8 Gfx Cfz Pto E Z Results o 134 (89%) success (132 cured + 2 completed) o 10 (7%) died

o 5 (3%) lost to follow-up o 1 (1%) failed No relapse at 12 months follow-up No patient initially resistant to FQ or KMY C. Kuaban et al. Int J Tuberc Lung Dis 2015; 19(5): 517-525 History of the observational study Several international workshops in francophone Africa on programme management of MDR-TB organised by The Union: October 2007, Abidjan, Cote dIvoire, February 2008, Ouagadougou, Burkina Faso : Benin and Cameroon decide to test a 12-month regimen May 2011 : Douala, Cameroon : first preliminary results (+ Niger) March 2012, Yaounde, Cameroon, : 9 countries decide to test the 9-month regimen: 4 Km Mfx Pto H Cfz E Z / 5 Mfx Cfz E Z Bnin, Burkina Faso, Burundi, Cameroun, Central African Rep., Cte d'Ivoire, DR Congo, Niger, Rwanda Study launched in January 2013, after approval from national and Union ethics committees Approved by WHO and drugs can be bought through the GF Observational study in francophone Africa Performed within the framework of the NTP: PMDT approach Initiative 5% / Expertise France (GF money) is funding only the environment of the study: tools, regular assessment visits, meetings Strict daily DOT throughout treatment Tools: patient files, registers, EpiData Country data files verified quarterly by The Union Patient monitoring M0

M1 M2 M3 M4 M5 Clinical Evaluation x x x x x x x x x Sputum Smear x x

x x xx (xx) x Sputum Culture x x x x x Audiogram x Chest X-ray x Hemogram x Serum Creatinine x

x x x x Serum Potassium x x x x x TSH x SGOT, SGTP x ECG* xx Pregnancy test x

HIV test x x M6 M7 M8 M9 x M15 M21 M27 M33 x x x x x x x xx x

x x x x x x x x x x x x x x x x x x Surveillance of adverse events

ANRS scale GRADE 1 Mild abnormality GRADE 2 Moderate abnormality GRADE 3 Severe abnormality GRADE 4 Life-threatening abnormality Abnormality Grade 1 AST (SGOT) (UI/l) 1,25 2,50 x N Hearing loss 20dB 2,50 5,00 x > 5,00 10,00

N xN 45 / day or duration > 1 week 24 h ; IV Infusion required Grade 4 > 10,00 x N > 90dB Hospitalization required (hypovolemic shock) Recruitment at 28 February 2015: 921 RR-TB Country Date first recruitment Number recruited Benin 01-feb.-13 25 Burkina Faso

13jun.-14 32 Burundi 23-may-13 63 Cameroon 01-jan.-13 178 Cte d'Ivoire 28-oct.-13 228 Niger 28-oct.-13 63 CAR 01-dec.-12 35

DRC 05-aug.-13 273 10-jul.-14 24 Rwanda Characteristics of patients 356 included < 01/04/2014 Age Median 34 years ; range 18-80 years BMI Median 18.1 ; range 8.8 29.8 Sexe Female 131 37 % Male

225 63 % New 40 11 % Relapse 90 25 % Failure cat.I treatment 92 26 % Failure retreatment 116 33 % Return after lfu / other 12 3%

Unknown 6 2% Positive 79 22 % Patient category HIV test Preliminary 83% Negativesuccess rate: > 275 Unknown 2 77 % 1% Preliminary results (1) Effectiveness (356 patients included <01/01/2014) Overall 83,1% treatment success Treatment completion Cure Death Loss to follow-up Failure Total

N 48 248 27 24 9 356 % 13.5 69.7 7.6 6.7 2.5 100.0 16,1% deaths in HIV+ vs 5,1% in HIV- patients (p<0,001) Among patients who survived, treatment success did not differ significantly by HIV status Preliminary results (2) Adverse events (356 patients included<1/04/2014) Abnormality Gastric Hepatic Neurologic Renal Hearing loss Grade 1 or 2 Grade 3 or 4 38,5% 1,4% 44,4%

3,9% 19,4% 1,1% 23,3% 1,1% 32.3% 9.8% 9.3% had diminishing dosage of >=1 drug 3.7% had a severe (=grade 4) adverse event during treatment Mostly during 2 first month of treatment More frequently in HIV+ (8.9%) than in HIV- patients (2.2%) Summary Excellent results Still preliminary culture results still lacking Some cases may be re-classified Relapse rate not yet evaluated Influence of flq and kmy resistance not yet evaluated Adverse events mostly mild, except for hearing loss Implementation proves feasible within NTP Lessons learned DOT is probably compulsory to avoid XDR needs a lot of efforts and a strict evaluation Bacteriological follow-up is not easy Monthly cultures are not easy to obtain Quality of culture is not easy to guarantee Other methods should be envisaged : smears, FDA (fluoresceine diacetate). Surveillance of adverse events Clinical surveillance is critical essential for adverse effects : daily surveillance of

hearing by DOT nurse Biological/other examinations may not all be useful if the regimen is to be extended Conclusions and perspectives Inclusions are completed (>1000 at 31 March 2015), but treatment results will not be available before 2016 First results are on line with the excellent results obtained in Bangladesh, Niger and Cameroon The Union is in favour of promoting this regimen in the future Acknowledgements Principal Investigators and their teams Martin Gninafon (Benin) Martial Ouedraogo (Burkina Faso) Thadde Ndikumana (Burundi) Christopher Kuaban (Cameroon) Valentin Fikouma (Central African Republic) Alimata Bakayoko (Cte dIvoire) Souleymane Hassane, Bassirou Souleymane (Niger) Zacharie Kashongwe (DR Congo) Michel Gasana (Rwanda) NTP coordinators National Reference Laboratories SRL : Anvers (A. van Deun), Milan (D. Cirillo) Nadia At-Khaled, Brigitte Gicquel, Jrgen Noeske, Alberto Piubello, Hans L Rieder, Arnaud Trbucq, Nicolas Vziris, Muriel Vray Partners : GF, Action Damien, GIZ, MSF, LPS, Pepfar,

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