Updateon the observational studyon short MDRTB regimen

Valérie Schwoebel

The Union

GDI meeting, Geneva, 29 April 2015

Basis for current WHO recommendationsIndividual data on 9,153 MDR-TB cases

54%

8%

15%

23%Lost for follow-up

Success

Failure

Dead

Ahuja,S.D. et al. PloS Med. 2012 9(8): e1001300. doi:10.1371/journal.pmed.1001300

Treatment results for MDR-TB patientsWHO GT Report 2014

Bangladesh4 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 423 (82%)– completed 12 (2%)– defaulted 40 (8%)– died 29 (6%)– failed 7 (1%)– relapsed 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):1180–1187

Adverse event-free MDR treatment outcome,adjusted for age and sex, Bangladesh, 2005 to June 2011

Months since treatment start

Adve

rse

even

t-fre

e pr

obab

ility

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42

FailureDefault

Death

Relapse

Susceptible (n=439)

Low level resistance (n=33)

87.7%

51.3%High level resistance (n=29)

S LR HR24 0 0

1 1 2

31 2 51 0 6

90.4%

Niger65 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%) curedo 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 FQA. Piubello et al. Int J Tuberc Lung Dis 2014;18(10):1188–1194

Cameroon150 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%) diedo 5 (3%) lost to follow-upo 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 d’Ivoire,

– 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

• Bénin, Burkina Faso, Burundi, Cameroun, Central African Rep., Côte 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 M6 M7 M8 M9 M15 M21 M27 M33

Clinical Evaluation x x x x x x x x x x x x x x

Sputum Smear x x x x xx (xx) x x x xx x x x x

Sputum Culture x x x x x x x x x x x x x x

Audiogram x       x                  

Chest X-ray x                 x        

Hemogram x                          

Serum Creatinine x x x x x                  

Serum Potassium x x x x x                  

TSH x           x              

SGOT, SGTP x x x x x   x              

ECG* xx                          

Pregnancy test x                          

HIV test x                          

Surveillance of adverse events

Abnormality Grade 1 Grade 2 Grade 3 Grade 4

AST (SGOT) (UI/l)

1,25 – 2,50 x N > 2,50 – 5,00 x N

> 5,00 – 10,00 x N

> 10,00 x N

Hearing loss 20dB<hl<40dB 40dB<hl<70dB 70dB<hl<90dB > 90dB

Vomiting2 – 3 / dayor duration ≤ 1 week

4–5 / dayor duration > 1 week

24 h ;IV Infusion required

Hospitalization required

(hypovolemic shock)

ANRS scale GRADE 1 Mild abnormalityGRADE 2 Moderate abnormalityGRADE 3 Severe abnormalityGRADE 4 Life-threatening abnormality

Recruitment at 28 February 2015: 921 RR-TB

Country Date first recruitment

Number recruited

Benin 01-feb.-13 25

Burkina Faso 13–jun.-14 32

Burundi 23-may-13 63

Cameroon 01-jan.-13 178

Côte d'Ivoire 28-oct.-13 228

Niger 28-oct.-13 63

CAR 01-dec.-12 35

DRC 05-aug.-13 273

Rwanda 10-jul.-14 24

Characteristics of patients356 included < 01/04/2014

Preliminary success rate: > 83%

Age Median 34 years ; range 18-80 years

BMI Median 18.1 ; range 8.8 – 29.8

Sexe Female 131 37 %

Male 225 63 %

Patient category 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 %

HIV test Positive 79 22 %

Negative 275 77 %

Unknown 2 1 %

Preliminary results (1)Effectiveness (356 patients included <01/01/2014)

N %Treatment completion 48 13.5 Cure 248 69.7 Death 27 7.6 Loss to follow-up 24 6.7 Failure 9 2.5 Total 356 100.0

• Overall 83,1% treatment success

• 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 Grade 1 or 2 Grade 3 or 4Gastric 38,5% 1,4%Hepatic 44,4% 3,9%Neurologic 19,4% 1,1%Renal 23,3% 1,1%Hearing loss 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)Thaddée Ndikumana (Burundi)Christopher Kuaban (Cameroon)Valentin Fikouma (Central African Republic)Alimata Bakayoko (Côte d’Ivoire)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 Aït-Khaled, Brigitte Gicquel, Jürgen Noeske, Alberto Piubello, Hans L Rieder, Arnaud Trébucq, Nicolas Véziris, Muriel Vray

Partners : GF, Action Damien, GIZ, MSF, LPS, Pepfar, …