#AIDS2016 High-dose rifampicin TB treatment regimen to reduce 12-month mortality of TB/HIV co-infected patients: The RAFA trial results CS Merle, S Floyd, A Ndiaye, T Galperine, A Furco, BC de Jong, H McIlleron, J Glynn, M Sarr, O Bah-Sow,D Affolabi on behalf of the RAFA team

#AIDS2016 Disclosures & Disclaimer  Corinne Merle has no financial relationships with commercial entities to disclose  No drugs or laboratory tests were donated by commercial companies  The opinions expressed are those of the authors and do not necessarily represent the views of the WHO

#AIDS2016 Context  TB is the infectious leading cause of death among people living with HIV  Current strategy to reduce TB/HIV mortality: optimal management of HIV disease  Despite ARV treatment the mortality is still high  More intensive TB treatment might help to reduce mortality

#AIDS2016 Methods(1) Objective To assess in ARV-naïve TB/HIV patients with CD4 counts >50 cells/mm3 the efficacy in terms mortality at 12 months post randomisation of 3 treatment strategies:  ARV initiation at week 2 with a standard TB treatment,  ARV initiation at week 8 with a standard TB treatment,  ARV initiation at week 8 with high dose rifampicin during the intensive phase of TB treatment (15mg/Kg) and standard TB treatment in the continuation phase. Study design  3 parallel arms, multicentre, open-label RCT  nested pharmacokinetic (PK) study in a sub-sample of patients

#AIDS2016 Methods(2)  Sample size: 260 patients per treatment arm to be recruited  Main inclusion criteria ‐ Adults > 18 yrs ‐ ARV Naïve HIV infected patients ‐ CD4 cells ≥50 cell/mm3 ‐ All type of TB disease with bacteriological or molecular confirmation ‐ written informed consent  Patients were recruited in Benin (Cotonou and Porto-Novo), Guinea (Conakry) and Senegal (Dakar)

#AIDS2016 Methods (3) Primary outcome  Mortality at 12 months after starting TB treatment Visits schedule  Clinical visit and 2 sputum taken: every 2 weeks during 2 months, every months until the end of the TB treatment and every 3 months until the end of the follow-up  Total follow-up per patient : 18 months post randomisation Quality Assurance & control  Monitoring & supervision visits every 2 to 3 months  Clinical Audit after 1 year of recruitment  Internal and external laboratory and data QC in place

#AIDS2016 RAFA project partners National TB and HIV programs (Dakar, Sénégal) Cape Town University, Department of Pharmacology (South Africa) Institute of Tropical Medicine of Antwerpen (Belgium) National TB and HIV programs (Cotonou, Benin) National HIV program and Ignace Deen hospital (Conakry, Guinea) London School of Hygiene & Tropical Medicine (UK) Hôpitaux de Paris (CHU Tenon, France) University College London (UK)

#AIDS patient screened 778 patients randomised (212 Benin, 468 Guinea, 98 Senegal) 258 patients ARV 8 Wks 258 patients High Dose Rif Results: CONSORT diagram 251 Considered for mITT 249 Considered for mITT 9 patients excluded MDR-TB: 6 No TB proof: 2 Other:1 11 patients excluded MDR-TB: 8 Not ARV-naive: 1 Other: 2 27 (10%) Lost to follow-up before 12 M 262 patients ARV 2 Wks 24 (9%) Lost to follow-up before 12 M 24 (9%) Lost to follow-up before 12 M 247 Considered for mITT 11 patients excluded MDR-TB: 8 CD4 count<50: 3

#AIDS2016 ARV 2 WKs (n=251) ARV 8 WKs (n=247) High Dose Rif (n=249) Age (years)mean (IQR) 36 (18-60)36 (18-69)36 (18-65) Femalen (%)122 (49%)104 (42%)113 (45%) BMI < 16n (%)66 (26%)68 (28%)65 (26%) CD4 cell/mm3 [50-100] ]100 – 200] ] ] >350 n (%) 60 (24%) 79 (31%) 76 (31%) 36 (14%) 47 (19%) 84 (34%) 86 (35%) 30 (12%) 52 (21%) 82 (33%) 78 (32%) 37 (15%) Haemoglobinmean (SD) 9.1 (1.8)9.2 (2.0)9.5 (1.9) Smear status Negative or scanty 1+, 2+ or 3+ n (%) 30 (12%) 220 (88%) 26 (10%) 220 (90%) 27 (11%) 220 (89%) Culture or Xpert positiven (%)213 (85%)217 (88%)220 (88%) Zone score (59%)134 (55%)140 (58%) Results: mITT population Baseline (n=747)

#AIDS2016 Results: Overall Mortality (n=747) Treatment armnSurvival 2 M Survival 12 M Survival 18 M HR*CI 95% Arm A – ARV 2 Wks – 1.28 Arm B – ARV 8 Wks / Arm C – HD RIF – 1.21 * Cox regression adjusted on country & interaction factor – B is the reference arm Interaction with CD4 level p=

#AIDS2016 Mortality for patients with less than 100 CD4 (n=159) High Dose Rifampicin ART 2 Weeks ART 8 Weeks Treatment armnSurvival 2 M Survival 12 M Survival 18 M HR*CI 95% Arm A – ARV 2 Wks – 1.37 Arm B – ARV 8 Wks / Arm C – HD RIF – 0.55 * Cox regression adjusted on country & interaction factor – B is the reference arm

#AIDS2016 High Dose Rifampicin ART 2 Weeks ART 8 Weeks Treatment armnSurvival 2 M Survival 12 M Survival 18 M HR*CI 95% Arm A – ARV 2 Wks / Arm B – ARV 8 Wks / Arm C – HD RIF – 0.90 * Cox regression adjusted on country & interaction factor – A is the reference arm Mortality for patients with less than 100 CD4 (n=159)

#AIDS2016 Mortality for patients with more than 100 CD4 (n= 588) Treatment armnSurvival 2 M Survival 12 M Survival 18 M HR*CI 95% Arm A – ARV 2 Wks – 1.49 Arm B – ARV 8 Wks / Arm C – HD RIF – 2.04 * Cox regression adjusted on country & interaction factor – B is the reference arm

#AIDS2016 TB and HIV treatment outcomes (2) Treatment arm ARV 2 Wks ARV 8 Wks High Dose RIF CD4 count (median) 6 months post randomisation months post randomisation HIV Viral Load (% of patient with undetectable VL) 6 months post randomisation77%66%77% 18 months post randomisation75%78% Tuberculosis Smear positive at M224%28%29% Culture positive at M216 %13%16%

#AIDS2016 Hepatotoxicity: ALAT grade, by trial arm ALAT lab results pooled across visits 1-10 a. IRIS & Death b. Grade 3 at visit 3 and normalisation c. DRESS syndrome - B Hepatitis co-infection (grade 3, 4 and death) ALAT NormalGrade 1Grade 2Grade 3Grade 4 n%n%n%n%n% Overall ARV 2Wks a1a ARV 8Wks HD Rif b2b 0.21c1c 0.1

#AIDS2016 Conclusion  More aggressive TB treatment using high dose of rifampicin, in addition to ARV treatment, could reduce TB/HIV mortality among co-infected TB/HIV patients with severe immunocompromised state.  No evidence of an increased risk of hepatotoxicity with higher dosage of rifampicin (15mg/Kg) given daily for 2 months to TB/HIV patients  More explorations are needed to explain more precisely these results and PK/PD results will be important to consider  The results of the RAFA trial provoke an interesting area of further research

#AIDS2016 Acknowledgements Hop. Ignace Deen, Conakry, Guinée : O. Bah-Sow, M. Diallo, B. Bah, F. Bah, S.Barry, MT. Barry, A. Barry Prog. National de lutte anti- TB, Senegal: M. Sarr, NF Ngom, K. Ndiaye, D.Sakho, J. Ngom, F. Ba, A. Seck University of Cape town, SA: H. McIlleron, P. Denti, MT Chirehwa University College London: A. Furco London School of Hygiene & Tropical Medicine, UK: CS. Merle, S.Floyd, K. Branson, J. Glynn, D.Phillips, N. Oubaya, C. Saint-Martin Trial participants Data Monitoring Committee: K Fielding (chair), C Perronne, C T Ndour Funding: EDCTP RAFA TEAM Clinical Trial Manager : A. Ndiaye Clinical Monitor: I. Mbaye Inst. of Tropical Medicine, Belgium: B. de Jong Prog. National de lutte anti-TB, Benin: S. Anagonou, D. Affolabi, S. Diatema, I. Gomina, S Gossa, B. Tanimomo, W.Bekou Hopital Tenon, France: T. Galperine

#AIDS2016 RAFA team