ARV-trial.com Switch to MVC MARCH Study 1

MARCH Study: switch to MVC Design Randomisation 1 : 2 : 2 Open-label W48 W96 Adults ≥ 18 years Stable (> 24 weeks) 2 NRTI + PI/r regimen HIV RNA < 200 c/mL CCR5 virus on proviral DNA tropism testing No previous virological failure No resistance to study medications HBs Ag negative N = 82 Continuation of 2 NRTI + PI/r N = 156 2 NRTI + MVC 300 mg BID N = 157 PI/r + MVC 150 mg BID Objective Primary Endpoint: proportion with HIV RNA < 200 copies/mL at W48 Non inferiority of the switch arms vs control, by intention-to-treat, lower margin of the two-sided 95% CI for the difference = - 12 %, 80 % power MARCH Pett SL. Clin Infect Dis 2016;63:122-32

MARCH Study: switch to MVC Baseline characteristics and disposition 2 NRTI + PI/r N = 82 2 NRTI + MVC N = 156 PI/r + MVC N = 157 Mean age, years 43.6 43.7 42.7 Female, % 24 22 CDC, category C, % 25.6 23.1 19.1 Baseline HIV RNA < 50 c/mL, % 96.3 96.8 95.5 Baseline CD4/mm3, mean 635 596 638 Nadir CD4/mm3, mean 258 206 238 ART duration, mean years 6.3 5.7 6.4 Baseline ART, % TDF/FTC ; TDF+3TC ; ABC/3TC ; ZDV/3TC ATV/r ; LPV/r ; DRV/r ; SQV/r 46 ; 16 ; 22 ; 7 33 ; 35 ; 16 ; 11 53 ; 17 ; 12 ; 13 37 ; 21 ; 21 ; 15 53 ; 16 ; 13 ; 11 35 ; 32 ; 13 ; 14 Mean Framingham 10-year CVD risk 6.87 6.84 Discontinuation at W48, N Not on randomised ART Lost to follow-up Withdrew Died 2 1 16 13 17 MARCH Pett SL. Clin Infect Dis 2016;63:122-32

MARCH Study: switch to MVC Virologic Outcomes – W48 Intention to Treat Analysis 100 95.1 91.7 20 40 60 80 % HIV RNA < 50 c/mL HIV RNA < 200 c/mL (primary endpoint) 97.6 93.6 * 77.7 84.1 ** 2 NRTI + MVC 2 NRTI + PI/r PI/r + MVC * ≠ : - 4% ; (95% CI = - 9.0 to 2.2) ** ≠ : - 13.5% ; (95% CI = - 19.8 to -5.8) MARCH Pett SL. Clin Infect Dis 2016;63:122-32

MARCH Study: switch to MVC % with virologic response (HIV RNA < 200 c/mL), by week Hazard ratio for loss of virological response < 200 c/mL over 48 weeks: 2.41 (95% CI: 1.31-4.43 ; p = 0.005) for the MVC + PI/r arm vs control arm 2 NRTI + MVC 2 NRTI + PI/r PI/r + MVC 0.00 1.00 0.25 0.50 0.75 12 24 36 48 60 72 84 96 Week Number at risk 2 NRTI + PI/r 2 NRTI + MVC PI/r + MVC 82 156 157 81 149 151 80 143 137 80 139 134 77 132 123 59 103 98 45 90 65 36 86 54 17 60 36 MARCH Pett SL. Clin Infect Dis 2016;63:122-32

MARCH Study: switch to MVC Emergent resistance in participants with confirmed virologic failure 2 NRTI + PI/r N = 82 2 NRTI + MVC N = 156 PI/r + MVC N = 157 Confirmed virologic failure, N 1 6 18 Successful sequencing, N 5 17 PI and RT genotype R emergence (mutations) N = 1 - K103N N = 5 - M41L, T215E - M184V, K101E, Y181C, G190A - L10I, K65R, V106I - L10I, A71V, M184V - L90M, L10I, A71V, M184M/V N = 7 - L10I - I50V, L10I, L33F/L - A62V, T215S - K20I - E138A - V32A/V Tropism (phenotypic assessment) at failure CCR5 CXCR4 Test failed 4 10 3 4 MARCH Pett SL. Clin Infect Dis 2016;63:122-32

MARCH Study: switch to MVC Changes in immunologic and metabolic parameters and quality of life over 48 weeks Mean change 2 NRTI + PI/r N = 82 2 NRTI + MVC N = 156 PI/r + MVC N = 157 CD4/mm3 increase + 40 + 39 + 29 Total cholesterol, mmol/L + 0.06 - 0.45 p < 0.0001 + 0.34 HDL-cholesterol, mmol/L + 0.05 + 0.04 + 0.10 LDL-cholesterol, mmol/L - 0.27 p ≤ 0.0002 + 0.18 Triglycerides, mmol/L - 0.0795 - 0.4016 + 0.1146 Lumbar spine, T-score - 0.05 + 0.08 p = 0.03 + 0.10 p = 0.028 Right hip, T-score - 0.12 - 0.12 ns + 0.07 p = 0.01 Physical and mental QOL No significant changes vs control p: vs 2 NRTI + PI/r MARCH Pett SL. Clin Infect Dis 2016;63:122-32

MARCH Study: switch to MVC Safety at W48 2 NRTI + PI/r N = 82 2 NRTI + MVC N = 156 PI/r + MVC N = 157 Mean changes in GFR, mL/min -1.96 - 9.54 - 0.69 Discontinuation for adverse event, N 1 4 Serious adverse event, N (%) 8 (9.76) 15 (9.62) 14 (8.92) One myocardial infarction was reported on MVC in a patient with increased CVD risk due to lifestyle and cardiac congenital malformation MARCH Pett SL. Clin Infect Dis 2016;63:122-32

MARCH Study: switch to MVC Conclusion This large international randomised study demonstrates that MVC with a 2-N(t)RTI backbone, in those with R5-tropic virus determined by genotypic tropism testing, is a switch/simplification option for patients virologicaly suppressed on PI/r + N(t)RTI regimens MVC was safe and well tolerated, with favorable impact on lipids and neutral effects on renal function over 48 weeks These data support MVC as a switch option for ritonavir-boosted PIs when partnered with a 2-N(t)RTI backbone, but not as part of N(t)RTI-sparing regimens comprising MVC with PI/r MARCH Pett SL. Clin Infect Dis 2016;63:122-32