NRTI-sparing  SPARTAN  PROGRESS  NEAT001/ANRS 143  MODERN

Stellbrink HJ. IAC 2014, Abs. TUAB0101  Design  Objective –Non inferiority of MVC at W48: % HIV RNA < 50 c/mL by intention to treat, missing, switch, discontinuation = failure, snapshot analysis (lower margin of the 95% CI for the difference = -10%) MVC 150 mg QD + TDF/FTC placebo + DRV 800 mg QD + RTV 100 mg QD TDF/FTC QD + MVC placebo + DRV 800 mg QD + RTV 100 mg QD Randomisation 1 : 1 to tropism assay > 18 years ARV-naïve HIV RNA > 1,000 c/mL CD4 > 100/mm 3 No resistance to DRV, TDF, FTC MODERN Study: MVC QD + DRV/r vs TDF/FTC + DRV/r N = 402 N = 1423 W48W96 MODERN Trofile Phenotypic Assay Genotypic Tropism Assay CCR5 tropic CCR5 tropic Randomisation double-blind, 1 : 1 to treatment N = 402 MVC 150 mg QD + TDF/FTC placebo + DRV 800 mg QD + RTV 100 mg QD TDF/FTC QD + MVC placebo + DRV 800 mg QD + RTV 100 mg QD

MVC + DRV/r N = 396 TDF/FTC + DRV/r N = 401 Median age, years3735 Female9.1%8.5% HIV RNA (log 10 c/mL), mean4.42 HIV RNA > 100,000 c/mL21% CD4 cell count (/mm 3 ), median CD4 < 200 per mm 3 9.5%11% B subtype86.4%88.3% Discontinuation by W48, n (%)73 (18.4%)50 (12.5%) For insufficient response338 For adverse event1918 Lost to follow-up87 Withdrew consent / other6 / 78 / 9 Baseline characteristics and patient disposition Study was terminated early upon recommendation of IDMC MODERN Study: MVC QD + DRV/r vs TDF/FTC + DRV/r MODERN Stellbrink HJ. IAC 2014, Abs. TUAB0101

Response to treatment at week 48 HIV RNA < 50 c/mL at week 48, ITT snapshot Mean CD4+ cell count//mm 3 changes at W48 : MVC = vs TDF/FTC = % Adjusted difference (95% CI) = -9.5 % ( ; -4.2) Adjusted difference (95% CI) = 6.9 % (- 1.3 ; 15) < 100,000 Baseline HIV RNA (c/mL) MVC + DRV/rTDF/FTC + DRV/r 0 ≥ 100, / / / / 215 GenotypePhenotypeOverall MODERN Study: MVC QD + DRV/r vs TDF/FTC + DRV/r MODERN Stellbrink HJ. IAC 2014, Abs. TUAB0101

 Protocol-defined treatment failure (PDTF) criteria : –Decrease in plasma HIV RNA < 1 log 10 from baseline after W4, unless plasma HIV RNA is < 50 c/mL, or –Plasma HIV RNA > 1 log 10 c/mL above the nadir value after W4, or –Plasma HIV RNA ≥ 50 c/mL at any time after W24, or –Plasma HIV RNA ≥ 50 c/mL after suppression to < 50 c/mL on 2 consecutive visits, or –Decrease in plasma HIV RNA < 2 log 10 c/mL from baseline on or after W12, unless plasma HIV RNA is < 50 c/mL (amendment 2), and < 400 c/mL (amendment 3) –All PDTFs required confirmation within 28 days of the initial event MVC + DRV/rTDF/FTC + DRV/r PDTF, n (%)40 (10.1%)13 (3.2%) HIV RNA < 400 c/mL at PDTF27 (68%)10 (77%) Emergence of resistance mutations00 MODERN Study: MVC QD + DRV/r vs TDF/FTC + DRV/r MODERN Stellbrink HJ. IAC 2014, Abs. TUAB0101

MVC + DRV/rTDF/FTC + DRV/r AE in > 5% of subjects in either group Diarrhea21%32% Nasopharyngitis10%12% Upper respiratory tract infection9%8% Rash8%6% Nausea7%11% Fatigue7%10% Cough6%7% Bronchitis6%5% Gastroenteritis5%4% Depression5%7% Insomnia4%6% MalignanciesN = 7 (2%)N = 2 (0.7%) Grade 3-4 laboratory abnormalities ALT1.8%1.3% Total bilirubin0.8%0.2% Creatine kinase3.3%3.5% Cholesterol2.0%1.5%  Treatment-emergent adverse events at week 48 MODERN Study: MVC QD + DRV/r vs TDF/FTC + DRV/r MODERN Stellbrink HJ. IAC 2014, Abs. TUAB0101

 Conclusion –MVC 150 mg QD + DRV/r QD was statistically inferior to TDF/FTC + DRV/r QD in antiretroviral-naïve subjects over 48 weeks Lower rate of virologic suppression IDMC recommended study termination –The majority of failure had HIV RNA < 400 c/mL –There was no treatment-emergent resistance in either arm –Safety was comparable –MVC 150 mg QD in dual therapy with DRV/r QD cannot be recommended as first-line antiretroviral therapy MODERN Study: MVC QD + DRV/r vs TDF/FTC + DRV/r MODERN Stellbrink HJ. IAC 2014, Abs. TUAB0101