NEAT 001/ANRS.143 Study: DRV/r + RAL vs DRV/r + TDF/FTC Endpoints

NRTI-sparing SPARTAN PROGRESS RADAR NEAT001/ANRS 143 A4001078 VEMAN MODERN

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Design Randomisation* 1 : 1 Open label W96 > 18 years ARV-na ve N = 401 DRV/r 800/100 mg QD + RAL bid HIV RNA > 1,000 c/mL CD4 < 500/mm3 HBs Ag negative Creatinine clearance > 60 mL/min No resistance mutations DRV/r QD + TDF/FTC QD N = 404 * Randomisation was stratified by country and participation in the viral and immunological dynamics and inflammation sub-study Objective Non inferiority of RAL compared to TDF/FTC : % of participants reaching the primary endpoint by week 96 estimated by the Kaplan-Meier method in intention-to-treat analysis (upper margin of the 2-sided 95% CI for the difference = 9%, 85% power) Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Endpoints Primary endpoint : time to failure, as the first occurrence of any of the following components Virological Change of treatment before W32 because of insufficient virologic response HIV-1 RNA reduction < 1 log10c/ml by W18* or HIV-1 RNA 400 c/ml at W24* HIV-1 RNA 50 c/ml at W32* HIV-1 RNA 50 c/ml at any time after W32* Clinical Death due to any cause Any new or recurrent AIDS defining event** Any new serious non AIDS defining event** All patients followed-up until last patient reached W96, events recorded until end of F-U Major secondary endpoints : safety, changes in CD4 and HIV RNA, genotypic resistance * Confirmed by a subsequent measurement ; ** confirmed by the Endpoint Review Committee Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Baseline characteristics and patient disposition DRV/r + RAL N = 401 DRV/r + TDF/FTC N = 404 Median age, years 37 39 Female 12% 11% HIV RNA (log10c/mL), median HIV RNA > 100,000 c/mL 4.78 4.75 36% 32% CD4 cell count (/mm3), median 340 325 CD4 < 200 per mm3 15% 16% Hepatitis C coinfection 4% 4% Discontinuation by W96 N = 38 N = 22 Discontinuation by end of follow-up N = 53 N = 38 Data were censored at the first date of meeting the primary endpoint, completion of 96 weeks of follow-up, last time the primary endpoint status was known, or date of withdrawal Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Patients who met the primary endpoint DRV/r + RAL N = 401 DRV/r + TDF/FTC N = 404 Total patients meeting primary endpoint during follow-up 77 (19.2%) 61 (15.3%) Change of regimen because of insufficient virologic response < 1 log10c/mL reduction in HIV RNA at W18 1 0 0 0 HIV RNA 400 c/mL at W24 27 28 HIV RNA 50 c/mL at W32 33 22 HIV RNA 50 c/mL after W32 Death 3 1 AIDS event 5 3 Serious non-AIDS event 8 7 If a patient reached more than one component, only the first was taken into account Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Probability of reaching primary endpoint 1.00 DRV/r + RAL DRV/r + TDF/FTC 0.75 0.50 log rank p=0.12 0.25 0 0 8 18 32 48 64 Time (weeks) 80 96 112 128 144 Numbers of patients 400 383 375 346 327 315 306 210 89 11 402 395 393 361 350 340 331 215 90 12 Estimated proportion reaching primary endpoint at W96 RAL: 17.8% vs TDF/FTC: 13.8% Adjusted difference: 4% (95% CI: -0.8, 8.8%) Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Kaplan-Meier estimates of proportion of patients in each group reaching endpoints at W96 Primary and secondary analyses around the primary endpoint Adjusted difference in proportions of failure at W96 (%, 95% CI) DRV/r + RAL (%) DRV/r + TDF/FTC (%) Primary endpoint 4.0 (-0.8 ; 8.8) 17.8 13.8 Without SNAIDS endpoints 3.9 (-0.7 ; 8.6) 16.0 12.1 Without treatment change 3.7 (-1.0 ; 8.5) 17.7 14.0 > 200 copies per mL in place of > 50 copies per mL 5.5 (2.0 ; 9,0) 10.5 5.0 Virological components only 3.6 (-0.9 ; 8.2) 15.5 11.8 Clinical components only 1.5 (-0.6 ; 3.7) 3.9 2.4 Per-protocol analysis 3.2 (-1.3 ; 7.7) 15.8 12.6 Including treatment discontinuation for virological reason Including treatment discontinuation for any reason 4.0 (-0.8 ; 8.9) 17.7 13.6 3.3 (-1.9 ; 8.5) 23.0 19.7 -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 Adjusted difference in proportions of failure at W96 (%, 95% CI) Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Kaplan-Meier estimates of proportion of patients in each group reaching endpoint at W96 Analyses by baseline HIV RNA and CD4 cell count Adjusted difference in proportions of failure at W96 (%, 95% CI) DRV/r + RAL (%) DRV/r + TDF/FTC (%) Baseline HIV RNA < 100 000 copies/mL 0.1 (-3.8 ; 4.0) 7.4 7.3 Baseline HIV RNA > 100 000 copies/mL 9.6 (-0.1 ; 20.1) 36.8 27.3 CD4 cell count < 200 cells/mm3 22.3 (7.4 ; 37.1) 43.2 20.9 CD4 cell count > 200 cells/mm3 1.4 (-3.5 ; 6,3) 13.7 12.3 -5 0 5 10 15 20 25 30 35 40 Adjusted difference in proportions of failure at W96 (%, 95% CI) Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Kaplan-Meier estimates of proportion of patients reaching primary endpoint at W96 according to combined baseline CD4 and HIV RNA Endpoint N % (95% CI) CD4 < 200/mm3 and HIV RNA < 100,000 c/mL (N = 46) DRV/r + RAL 3/23 9.4% 0.4% (-13.7 ; 14.6) DRV/r + TDF/FTC 3/23 9.0% CD4 200/mm3 and HIV RNA < 100,000 c/mL (N = 484) DRV/r + RAL 19/232 7.1% 0% (-3.9 ; 3.9) DRV/r + TDF/FTC 21/252 7.1% CD4 < 200/mm3and HIV RNA 100,000 c/mL (N = 77) DRV/r + RAL 23/37 60.1% 30.3% (13.8 ; 46.8) DRV/r + TDF/FTC 12/40 29.9% CD4 200/mm3and HIV RNA 100,000 c/mL (N = 198) DRV/r + RAL 32/109 26.5% -1.9% (-13.9 ; 10.0) DRV/r + TDF/FTC 25/89 28.4% Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC HIV RNA < 50 c/mL % 100 80 60 40 20 DRV/r + RAL, 89.4% (95% CI : 85.7-92.4) DRV/r + TDF/FTC, 93.3% (95% CI : 90.3-95.6) 0 0 4 8 12 18 24 32 48 64 80 96 Data are proportions (95% CI) based on available viral load data Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Virological failure and emerging resistance mutations per trial arm DRV/r + RAL N = 401 DRV/r + TDF/FTC N = 404 All PDVF 66 52 Total number of patients who met criteria for genotype testing* 36 15 PDVF patients meeting criteria for genotype testing 33 9 Patients without PDVF meeting criteria for genotype testing 3 6 Patients undergoing genotyping 29 13 Major resistance mutations Reverse transcriptase Protease Integrase 6 1 0 5 0 0 0 0 RAL = raltegravir. DRV/r = ritonavir-boosted darunavir. TDF-FTC = tenofovir-emtricitabine PDVF = protocol-defined virological failure *Genotypic testing carried out by local laboratories when patients had a single HIV RNA > 500 copies/mL at or after week 32 up to the end of follow up K65R. N155H Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Emergence of resistance mutations in full data set (confirmed HIV RNA > 50 c/mL or any single HIV RNA 500 c/ml at or after W32) DRV/r + RAL N = 401 DRV/r + TDF/FTC N = 404 Patients meeting criteria for genotypic testing 69 58 61 49 Patients with available genotype ( 1 amplified gene) 17* 0 0 0 0 1 major IAS resistance mutations Reverse transcriptase (NRTI only) Protease Integrase 3/53 (5.7%) 1**/57 (1.8%) 14***/55 (25.5%) * 1 patient had 2 major IAS resistance mutations (1 NRTI + 1 INI) ** L76V *** N155H = 12 ; N155H + Q148R = 1, Y143C = 1 ; HIV RNA at genotypic testing < 200 c/mL : 4/14 Predictor of integrase resistance mutations emergence : baseline HIV RNA, p=0.006, no association with baseline CD4 nor HIV RNA at time of testing Lambert-Niclot S, JAC 2015 (in press) NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Safety Adjusted difference (95% CI) DRV/r + RAL N = 401 DRV/r + TDF/FTC N = 404 5.8% Discontinuation for any reason 14.8% (W96) 9.1% (W96) (2.0 - 10.0) Discontinued after reaching the primary endpoint 36/80 (44%) 8/51 (16%) Discontinuation for treatment-limiting AE 1.5% 2.6% 3.9 /100 patient-year 4.2/100 patient-year AE leading to treatment modification, all grade AE leading to treatment modification, grade 3-4 N = 7 N = 6 10.2/100 patient-year 8.3/100 patient-year Serious adverse events Death 4* 1** 1.3/100 patient-year 1.6/100 patient-year Grade 2-4 rash * melanoma, Burkitt s lymphoma, severe sepsis with organ failure after DRESS, suicide ** morphine overdose Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Laboratory parameters DRV/r + RAL N = 401 DRV/r + TDF/FTC N = 404 p Mean increase from baseline to W96 Total cholesterol (mmol/L) + 0.9 +0.5 < 0.001 HDL-cholesterol (mmol/L) +0.2 +0.1 < 0.001 LDL-cholesterol (mmol/L) +0.5 +0.4 0.021 Estimated creatinine clearance (mL/min) + 0.8 - 4.6 < 0.001 Graded abnormality over 96 weeks Grade 2 creatinine 0 0 Grade 3-4 CK increase 6% 5% - Grade 3-4 ALAT increase 5% 3% 0.036 Conversion mmol/L to g/L : x 0.387 Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy Bone substudy 146 patients : 70 DRV/r + RAL vs 76 DRV/r + TDF/FTC Randomised at same time as the main study Baseline demographic and HIV characteristics similar in the 2 sub-groups History of fractures : 12 % vs 20 % (p = 0.17) Osteopenia/osteoporosis at baseline : 24 in DRV/r + RAL vs 21 in DRV/r + TDF/FTC Compare changes in bone mineral density (BMD) between treatment arms Whole body dual-energy x-ray absorptiometry (DXA) scans assessed BMD of total hip, lumbar spine and femoral neck, at baseline, W48 and W96 Evaluate clinical factors associated with BMD loss Primary endpoint Mean percentage change of BMD in lumbar spine and hip at 48 weeks Secondary endpoints Mean percentage change at 96 weeks Proportion with WHO criteria for osteoporosis/osteopenia Proportion with a Z score < -2 Incidence of fractures Analyses by intent-to-treat exposed approach (ITT-e) Bernardino JI, Lancet HIV 2015; 2:e464-e473 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy Mean % change in femoral neck BMD Mean % change in total hip BMD Baseline W48 55 67 S96 49 59 Baseline W48 55 67 W96 49 58 1 1 n n 0 0 -0.73 -1.41 -1 -1.57 -1.74 -1 -2 p < 0.0001 -2 p = 0.0084 -3 p = 0.0032 -3 -4 p = 0.025 -3.30 -3.45 -4 -5 -3.86 -6 -5.99 DRV/r + RAL DRV/r + TDF/FTC Mean % change in lumbar spine BMD Baseline W48 51 63 W96 48 57 1 n p : p value of mean values between groups 0 -1.00 -0.43 New cases of osteopenia, osteoporosis or Z-score < - 2 : no difference between arms -1 p = 0.046 p = 0.0054 -2 -2.49 -3 -2.80 Bernardino JI, Lancet HIV 2015; 2:e464-e473 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy Covariates associated with change in BMD at W48 (multivariate analysis) Estimate of mean percentage difference (95% CI) p Total hip TDF/FTC + DRV/r (vs RAL + DRV/r) - 2.48 (- 3.79 ; -1.17) 0.0003 BMI (per kg/m2higher) 0.18 (0.00 ; 0.36) 0.054 HIV RNA at baseline (per log10c/mL higher) Lumbar spine - 0.95 (- 2.03 ; 0.13) ns TDF/FTC + DRV/r (vs RAL + DRV/r) - 1.25 (- 2.78 ; 0.28) ns BMI (per kg/m2higher) 0.03 (- 0.19 ; 0.25) ns HIV RNA at baseline (per log10c/mL higher) Femoral neck - 2.06 (- 3.35 ; 0.77) 0.003 TDF/FTC + DRV/r (vs RAL + DRV/r) - 2.01 (- 3.62 ; 0.45) 0.02 BMI (per kg/m2higher) 0.01 (- 0.22 ; 0.25) ns HIV RNA at baseline (per log10c/mL higher) - 1.27 (- 2.58 ; 0.04) 0.06 Sport versus no sport : ns at all sites Bernardino JI, Lancet HIV 2015; 2:e464-e473 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy Bone biomarkers substudy Biomarkers measured on paired samples D0, W48 Bone formation: osteocalcin, bone specific alkaline phosphatase (BSAP), pro-collagen type 1 N pro-peptide (P1NP), osteoprotegerin Bone resorption: serum C terminal collagen crosslinks (CTX-1), receptor activator of NF (RANKL), osteopontin, urine CTX-1/creatinine ratio 25-OH vitamin D, intact PTH Inflammatory markers : IL-1 , IL-6, TNF- Compared to DRV/r + RAL, patients treated with DRV/r + TDF/FTC had significantly greater increases in bone turnover markers Independently of ART regimen used Baseline bone specific alkaline phosphatase, P1NP and osteopontin levels were associated with BMD loss 5 % Bernardino JI, Lancet HIV 2015; 2:e464-e473 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy Median percentage changes in biomarkers at W48 BSAP Osteocalcin P1NP 250 800 DRV/r + RAL DRV/r + TVD 600 200 600 150 p=0.0082 p<0.0001 p=0.0008 400 400 100 200 50 200 0 0 0 N = 38 N = 47 N = 38 N = 45 N = 38 N = 46 Osteoprotegerin Osteopontin CTX-1 1 000 600 6 000 800 p=0.048 p=0.27 p=0.033 400 600 4 000 400 200 2 000 200 0 0 0 N = 38 N = 46 N = 38 N = 46 N = 38 N = 45 PTH RANK-L 25-OH D3 800 600 200 600 p=0.013 p=0.38 p=0.90 400 100 400 200 0 200 0 0 -100 N = 37 N = 46 N = 12 N = 13 N = 38 Bernardino JI, Lancet HIV 2015; 2:e464-e473 N = 45 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC - Bone substudy Loss of BMD 5% at any site greater in the standard group compared to the NtRTI-sparing group At W48 : 29/68 (43%) vs 9/65 (14%) (p=0.0002) At W96 : 34/68 (51%) vs 13/65 (20%) (p=0.0003) Association between baseline biomarkers and changes in BMD 5 % (multivariate analysis) Odds ratio (95% CI) p Spine W48 Bone-specific alkaline phosphatase (BSAP) 9.4 g/L 0.21 (0.045-1.01) * 0.052 Spine W96 Osteopontin 5423 pg/mL 0.21 (0.06-0.84) 0.03 Femoral neck W96 Procollagen type 1 N-propeptide (P1NP) 44.7 ng/mL 4.29 (1.16-15.90) 0.03 Total hip W48 Procollagen type 1 N-propeptide (P1NP) 44.7 ng/mL 12.52 (1.41-111.14) 0.02 Each biomarker was categorised as > versus baseline median value. Data adjusted for baseline HIV RNA, sports, treatment group, and body-mass index. *Not adjusted for sports because model did not converge Bernardino JI, Lancet HIV 2015; 2:e464-e473 NEAT 001 / ANRS 143

Study NEAT 001/ANRS 143: DRV/r + RAL vs DRV/r + TDF/FTC Conclusion Overall, the NtRTI-sparing strategy of DRV/r + RAL, requiring twice daily medication intake, was well tolerated and had comparable efficacy to the once daily standard regimen of DRV/r + TDF/FTC at 96 weeks. DRV/r + RAL was non inferior to DRV/r + TDF/FTC for the composite primary endpoint based on clinical and virological failure Sensitivity analyses around the primary endpoint, as well as secondary analyses, including per-protocol analysis, supported non-inferiority However, prespecified subgroup analyses showed that the NtRTI-sparing strategy was less efficacious than the standard regimen in patients with CD4 cell count < 200/mm3at treatment start Despite a low rate of virological failure in both arms, emergence of resistance mutations was higher in the raltegravir group The final results of this head-to-head phase III strategic study suggest that the dual therapy DRV/r + RAL represents an alternative option to the standard combination of DRV/r + TDF/FTC for first line therapy in patients with CD4 cell > 200/mm3 Raffi F. Lancet 2014;384:1942-51 NEAT 001 / ANRS 143