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MARCH Study 1

2. 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

3. 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

4. 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 = to 2.2)
** ≠ : % ; (95% CI = to -5.8)
MARCH
Pett SL. Clin Infect Dis 2016;63:122-32

5. 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: ; 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

6. 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

7. 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
p <
+ 0.34
HDL-cholesterol, mmol/L
+ 0.05
+ 0.04
+ 0.10
LDL-cholesterol, mmol/L
p ≤
+ 0.18
Triglycerides, mmol/L
Lumbar spine, T-score
- 0.05
p = 0.03
p = 0.028
Right hip, T-score
- 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

8. 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

9. 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