Switch to DTG RPV SWORD Study Switch to CAB LA RPV LA IM LATTE2 Study LATTE2 Study switch to cabotegravir LA rilpivirine LA IM Objective Primary HIV RNA lt 50 cmL at W32 of maintenance phase selection of dosing schedule for phase III studies confirmation of dose on ID: 615856
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Slide1
Switch to INSTI + NNRTI
Switch to DTG + RPV
SWORD
Study
Switch to CAB LA + RPV LA IM
LATTE-2 Study
Slide2
LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IM
Objective
Primary: % HIV RNA < 50 c/mL at W32 of maintenance phase: selection of dosing schedule for phase III studies (confirmation of dose on W48 analysis) ; safety
Randomisation
2 : 2
: 1
Q8W: injection every 8 weeks ; Q4W: injection every 4 weeks
CAB 30 mg QD + ABC/3TC(N = 309)
Induction (oral)
Maintenance(if HIV RNA < 50 c/mL at W-4 and Day 1)
CAB 600 mg IM + RPV 900 mg IM Q8W *(N = 115)
CAB 30 mg QD + ABC/3TC QD (oral) (N = 56)
CAB 400 mg IM + RPV 600 mg IM Q4W **(N = 115)
* CAB IM, loading dose 800 mg at D1 and 600 mg at W4 ** CAB IM, loading dose 800 mg at D1
ARV naive> 18 yearsHIV RNA > 1 000 c/mLCD4 > 200/mm3HBs Ag negativeALT < 5 UNLCreatinine clearance> 50 mL/min
addition of
RPV 25 mg QD oral
Induction phase: HIV RNA < 50 c/mL (ITT-E) after 20 weeks = 91.3 % ; discontinuation in 18/309 patients, including 6 for adverse event and 2 for lack of efficacy
Design
LATTE-2
W48
W96
W32
W-20
D1
W-4
Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.
Margolis
DA. Lancet. 2017 Sep 23;390(10101):1499-1510.Slide3
LATTE-2 Study: switch to cabotegravir LA +
rilpivirine
LA IM
Q8W IM
N = 115
Q4W IM
N = 115
Oral CAB
N = 56
Median age, years
35
36
35
Female, %
7
5
18
White / African American, %
81 / 15
82 / 10
70 / 27
CDC Class C, %
< 1
2
0
HIV RNA, log
10
c/mL, median
4.42
4.46
4.29
CD4 cell count (/mm
3
), median
449
499
518
Discontinuation by W48, N (%)For lack of efficacy, NFor adverse event, NWithdrew consent / other4 (3.5%)111 / 111 (9.6%)071 / 36 (10.7%)112 / 2Discontinuation between W48 and W96, NFor adverse event, NWithdrew consent, N101312303
LATTE-2
Baseline characteristics (ITT-maintenance exposed) and patient disposition
Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.Slide4
LATTE-2 Study: switch to cabotegravir LA +
rilpivirine
LA IM
Oral
Intramuscular
Q4W
‒ 10%
+ 10%
12.2
- 4.8
3.7
Difference (95% CI)
0
‒ 10%
+ 10%
11.5
- 5.8
2.8
Q8W
95
4
< 1
94
< 1
5
0
20
40
60
80
100
Virologic success
Virologic
Non response
No virologic data
%
91
45Q8W IM (N = 115)Q4W IM (N = 115)CAB oral (N = 56)LATTE-2Non inferiority of the 2 IM regimens vs oral CABPrimary endpoint: HIV RNA < 50 c/mL at W32 (snapshot analysis, ITT-ME)Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.Slide5
Oral
Intramuscular
Q4W
‒ 10 %
+ 10 %
20.5
- 0.6
10
Difference, % (95% CI)
0
‒ 10 %
+ 10 %
14.4
- 8.4
3.0
Q8W
92
7
< 1
91
< 1
8
0
20
40
60
80
100
Virologic success
Virologic non response
No virologic data
%
89
2
9
Q8W IM
(N = 115)
Q4W IM(N = 115)Oral(N = 56)
W48
W96
94
87
84
4
0
2
2
13
14
Margolis
DA. Lancet. 2017 Sep 23;390(10101):1499-1510.
LATTE-2 Study: switch to
cabotegravir
LA +
rilpivirine
LA IM
HIV RNA < 50 c/mL at W48 and W96 (snapshot analysis, ITT-ME)
11.6
- 7.6
2.0
12.6
- 6.6
2.9
W48
W96
W48
W96
Non inferiority of the 2 IM regimens vs oral CAB, at W48 and W96
Lower performance of Q4W (vs Q8W) at W96 due to more discontinuations for AE (9 vs 1)
Protocol-defined
virologic
failure: 1 in oral arm (no resistance)
,
2 in Q8W arm (emergence of resistance at failure: K103N, E138G, K238T (NNRTI) and Q148R (INSTI) in 1, R269R/G in 1
LATTE-2Slide6
Q8W IM, N = 115
Q4W IM, N = 115
Oral, N = 56
HIV RNA in window
not < 50 c/mL
2
1 patient with HIV RNA 87 c/mL at W96;
1 patient with repeated blips then failure (HIV RNA: 90-151 c/mL between W72-W96)
0
0
Discontinuation for lack
of efficacy
1 (rebound > 400 c/mL at W4)
0
1
Discontinuation for other reason, while HIV RNA
not < 50 c/ml
2
56 c/mL at W4 with injection intolerance ; HIV RNA > 400 c/mL at W48,
physician decision
0
0
Discontinuation for AE
1
9 *, (7/9 before W48)
2 ** (at W36)
Discontinuation for other reason
1
5 ***
6 ****
Missing data during window but on study
0
1
(HIV
RNA
< 40 c/mL at all visits)0Virologic non response and no data in window (snapshot analysis at W96)* Rash, N = 1, liver stopping criteria, N = 1, QT prolongation, N = 1, mesenteric vein thrombosis, N = 1, Churg-Strauss vasculitis, N = 1, epilepsy leading to death, N = 1, psychosis, N = 1, depression, N = 1, hepatitis C, N = 1 ** Acute hepatitis C, N = 1, liver stopping criteria, N = 1*** Withdrawal by subject, N = 3 ; protocol deviation, N = 2**** Withdrawal by subject, N = 5 ; lost to follow-up, N = 1Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IMLATTE-2Slide7
Q8W IM
(N = 115)
Q4W IM
(N = 115)
Oral
(N = 56)
Drug-related adverse events, excluding ISRs
Pyrexia
Headache
Influenza-like illness
Fatigue
3
3
3
2
6
3
3
3
0
4
0
2
Grade 3-4 adverse
event
,
excluding ISRs
Drug-related
11
2 *
16
4 **
72
Serious adverse event (none drug-related)10
10
13
Adverse event leading to withdrawal
272Grade 3 and 4 laboratory abnormalities192921Injection site reactions (ISR) ***D1W8W48W968548373188403028-Adverse events and laboratory abnormalities (ITT, maintenance period D0-W96), %* Influenza-like illness, N = 1, chills and pain, N = 1** Influenza-like illness, N = 1, rash, N = 1, depression, N = 1, QT prolongation, N = 1*** ISR = pain (66%), nodules (8%), swelling( 6%), pruritus (6%), resolved < 7 days: 89%Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.LATTE-2 Study: switch to cabotegravir LA + rilpivirine LA IMLATTE-2Slide8
LATTE-2
LATTE-2 Study: switch to
cabotegravir
LA +
rilpivirine LA IM
Overall injection site reaction incidence,by visit Day 1-Day 96 (% patients with ISR)
Q8W IM
Q4W IM
Q8W IM
Q4W IM
115
115
115115114115
114
113112111112109109112107107
111
105105111
104
Subjects at visit
99% of ISRs were mild (84%) or moderate (15%)
Median duration was 3.0 days in both groups, and 89% resolved within 7 days
Most common ISR events : pain (66%), nodules (8%), swelling (6%) and pruritus (6%)
The number of subjects reporting ISRs decreased over time, from 86% (D1) to 35% (W48) and 30% (W96)
2/230 subjects (< 1%) withdrew as a result of injection reactions (both in Q8W group)
Margolis
DA. Lancet. 2017 Sep 23;390(10101):1499-1510.
Day 1
W4
W8
W12
W16
W20
W24
W28
W32
W36
W40
W44W48
W64
W72
W96
84
88
38
42
46
40
35
46
31
28
57
35
31
38
29
29
50
32
30
37
30
45
31
29
33
31
28
0
20
40
60
80
100
109
103
109
101
110
102Slide9
LATTE-2 Study: switch to cabotegravir LA +
rilpivirine
LA IM
LATTE-2
Pharmacokinetics (mean
+ SD plasma concentration (mg/mL)
Margolis
DA. Lancet. 2017 Sep 23;390(10101):1499-1510.Q4W
Q8W
Cτ, trough concentration ; PA-IC90, protein binding-adjusted 90% inhibitory concentrationQ8W: 7/9 patients with virological
non-response at W48 had RPV Cτ in the lowest 25th quartile
Mean (95% CI)
C
τ at W48
Q8WQ4W
Oral
2.58
(2.4 - 2.8)
1.46
(1.3 - 1.6)
4.47
(3.9 - 5.2)
x times PA-IC
90
16
19
27
Mean (95% CI)
C
τ
at W48
Q8W
Q4W
94.64
(86.6 - 103.4)
64.48
(
60.0 - 69.3)x times PA-IC9085
0
1
4
8
12
16
20
24
28
32
36
40
44
48
Week
0,1
1
10
100
10
100
1 000
0
1
4
8
12
16
20
24
28
32
36
40
44
48
Week
CAB
RPV
PA-IC
90
10 mg PO C
τ
30 mg PO C
τ
PA-IC
90
25 mg PO C
τ
Q4W
Q8WSlide10
LATTE-2 Study: switch to cabotegravir LA +
rilpivirine
LA IM
Patient reported-outcomes
(HIV Treatment satisfaction questionnaire, status version)
Margolis DA. Lancet. 2017 Sep 23;390(10101):1499-1510.
6
5
4
3
2
1
0
Very satisfied
Very dissatisfied
LATTE-2
0
20
40
60
80
100
Q4W
(N = 100)
Q8W
(N = 108)
Oral CAB + ABC/3TC
(N = 46)
76
85
76
21
14
15
4
2
2
< 13IM CAB LA + RPV LA%
Q4W
(N = 100)
Q8W
(N = 108)
Oral CAB + ABC/3TC
(N = 46)
0
20
40
60
80
100
88
89
43
11
10
35
9
7
4
2
< 1
1
IM CAB LA + RPV LA
%Slide11
LATTE-2 Study: switch to cabotegravir LA +
rilpivirine
LA IM
Conclusion
LATTE-2 results successfully demonstrate ability to maintain HIV-1 RNA < 50 c/mL with IM CAB + RPV LA, dosed every 4 or 8 weeksThree subjects met PDVF criteria during maintenance
Q8W (N = 2), oral CAB (N = 1) ; one Q8W subject with emergent RPV and CAB resistance, and one Q8W subject with minor INSTI mutation emergenceInjection tolerabilityMajority of ISRs were grade 1 to 2 pain, with a median duration
of 3 daysFew subjects had an ISR that led to discontinuation, with higher rate in Q4W group
High overall reported satisfactionDose selectionQ4W dosing resulted in lower rates of virologic non-response with similar safety to Q8WQ4W dosing was selected for pivotal phase III studies
LATTE-2Margolis
DA. Lancet. 2017 Sep 23;390(10101):1499-1510.