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FLAIR: Switch to Long-Acting CAB + RPV Following Oral Induction in ART-Naive Patients Noninferior to Continued DTG/ABC/3TC at Week 48
1. FLAIR: Switch to Long-Acting CAB + RPV Following
Oral Induction in ART-Naive Patients Noninferior to
Continued DTG/ABC/3TC at Week 48
This program is supported by independent educational grants from
Gilead Sciences; Janssen Therapeutics; Merck & Co, Inc; and ViiV Healthcare.
CCO Independent Conference Coverage*
of the 2019 Conference on Retroviruses and Opportunistic Infections;
March 4-7, 2019; Seattle, Washington
*Clinical Care Options (CCO) is an independent medical education organization that provides conference
coverage and other unique educational programs for healthcare professionals.
2. FLAIR: Background
LA ARVs may improve ART tolerability and facilitate adherence
Potent dual ARV regimens may have a role in switch-maintenance strategies for
patients with virologic suppression on 3-drug ART
‒ DTG/RPV approved for use in this setting[1]
LA CAB + RPV under investigation as maintenance therapy
‒ Phase II LATTE-2 found LA CAB IM + RPV IM maintained HIV-1 RNA < 50 copies/mL in
83% to 90% of patients after 160 wks and in 97% to 100% receiving optimized dosing[2]
Current study designed to assess efficacy and safety of switching to LA CAB IM + LA
RPV IM after induction on DTG/ABC/3TC PO vs continuing DTG/ABC/3TC PO in ART-
naive patients[3]
1. DTG/RPV PI. 2. Margolis. Glasgow 2018. Abstr P118. 3. Orkin. CROI 2019. Abstr 140LB. Slide credit: clinicaloptions.com
3. FLAIR: Study Design
Multicenter, randomized, open-label phase III noninferiority trial
Orkin. CROI 2019. Abstr 140LB. NCT02938520. Slide credit: clinicaloptions.com
LA CAB 400 mg IM +
LA RPV 600 mg IM Q4W
(n = 278)
Continue DTG/ABC/3TC PO QD‡
(n = 283)
ART-naive patients with
HIV-1 RNA ≥ 1000 copies/mL,
HBsAg negative,
no NNRTI RAMs*
(N = 629)
*K103N permitted. †Patients with HIV-1 RNA < 50 copies/mL from Wk 16 to Wk 20 continued to maintenance phase. ‡Alternative, non-ABC
NRTIs permitted for intolerance or HLA-B*5701 positivity. §Loading dose: LA CAB 600 mg IM + LA RPV 900 mg IM; regular dosing begun at Wk 8.
CAB 30 mg +
RPV 25 mg PO QD
(n = 283)
Current Analysis
Wk 48Wk 4§
DTG/ABC/3TC
PO QD‡
Induction Phase† Maintenance Phase
Wk 96Day 0
Wk 20
Primary endpoint: HIV-1 RNA ≥ 50 copies/mL at Wk 48 by FDA Snapshot (6% noninferiority margin)
Secondary endpoints: HIV-1 RNA < 50 copies/mL at Wk 48 by FDA Snapshot, resistance at confirmed
virologic failure, safety and tolerability, patient-reported outcomes
4. FLAIR: Baseline Characteristics in ITT-E Population
Orkin. CROI 2019. Abstr 140LB. Slide credit: clinicaloptions.com
Characteristic
LA CAB + LA RPV
(n = 283)
DTG/ABC/3TC
(n = 283)
Total
(N = 566)
Median age, yrs (range) 34 (19-68) 34 (18-68) 34 (18-68)
Age ≥ 50 yrs, n (%) 33 (12) 29 (10) 62 (11)
Female, n (%) 63 (22) 64 (23) 127 (22)
Race, n (%)
White
Black
Other or missing
216 (76)
47 (17)
20 (7)
201 (71)
56 (20)
26 (9)
417 (74)
103 (18)
46 (8)
Median BMI (range) 24 (17-45) 24 (13-47) 24 (13-47)
HIV-1 RNA ≥ 100,000 copies/mL, n (%) 56 (20) 56 (20) 112 (20)
Median BL CD4+ cell count, cells/mm3 (IQR)
< 200 cells/mm3, n (%)
437 (314-609)
16 (6)
452 (321-604)
23 (8)
444 (320-604)
39 (7)
Median Day 1 CD4+ cell count, cells/mm3 (IQR) 624 (473-839) 625 (472-799) 625 (473-818)
HIV/HCV coinfection, n (%) 19 (7) 9 (3) 28 (5)
5. Difference (%)
Difference (%)
FLAIR: Efficacy at Wk 48 in ITT-E Population
Confirmed VF: n = 3 per arm; emergent NNRTI +
INSTI resistance in all CAB + RPV failures (all HIV-1
subtype A1), no resistance in DTG/ABC/3TC failures
Orkin. CROI 2019. Abstr 140LB. Reproduced with permission. Slide credit: clinicaloptions.com
Patients(%)
100
80
40
60
20
0
Virologic
Nonresponse
(≥ 50 c/mL)
Virologic
Success
(< 50 c/mL)
No
Virologic
Data
2.1 2.5
93.6 93.3
4.2 4.2
LA CAB + LA RPV
(n = 283)
DTG/ABC/3TC
(n = 283)
-10% NI
margin
Difference (%)
-3.7
0.4
-10 -8 -6 -4 -2 0 2 4 6 8 10
4.5
-2.8 2.1
-0.4
6% NI
margin
-10 -8 -6 -4 -2 0 2 4 6 8 10
Virologic Outcomes (FDA Snapshot) Adjusted Treatment Difference (95% CI)*
DTG/ABC/3TCLA CAB + LA RPV
DTG/ABC/3TC LA CAB + LA RPV
Key Secondary Endpoint
(HIV-1 RNA < 50 copies/mL)
LA CAB + LA RPV noninferior
to DTG/ABC/3TC
Primary Endpoint
(HIV-1 RNA ≥ 50 copies/mL)
LA CAB + LA RPV noninferior
to DTG/ABC/3TC
*Adjusted for sex, BL HIV-1
RNA (< vs ≥ 100,000 c/mL).
6. FLAIR: Plasma Trough Concentrations by Visit
Plasma concentrations with IM CAB and RPV similar to effective PO regimens
Orkin. CROI 2019. Abstr 140LB. Reproduced with permission. Slide credit: clinicaloptions.com
4 488 12 16 20 24 28 32 36 40 44
Visit (Wk)
0.1
1
10
PlasmaCAB(μg/mL)*
CAB (n = 278)
PA-IC90 (0.166 µg/mL)
4 488 12 16 20 24 28 32 36 40 44
Visit (Wk)
10
100
PlasmaRPV(ng/mL)*
RPV (n = 278)
PA-IC90 (12 ng/mL)
*Median (5th, 95th percentile) concentration–time data.
7. FLAIR: Adverse Events
Orkin. CROI 2019. Abstr 140LB. Slide credit: clinicaloptions.com
AEs, n (%) LA CAB + LA RPV (n = 283) DTG/ABC/3TC (n = 283)
AEs occurring in ≥ 10% of patients
Any event (per patient)
•Nasopharyngitis
•Headache
•Upper RTI
•Diarrhea
246 (87)
56 (20)
39 (14)
38 (13)
32 (11)
225 (80)
48 (17)
21 (7)
28 (10)
25 (9)
Drug-related AEs occurring in ≥ 3% of patients
Any event (per patient)
•Headache
•Pyrexia
79 (28)*
14 (5)
13 (5)
28 (10)
4 (1)
0
Drug-related serious AEs 1 (< 1)† 0
AEs leading to discontinuation 9 (3)‡ 4 (1)§
*94% (74/79) were grade 1/2. †Right knee monoarthritis. ‡Hepatitis B (n = 2); acute hepatitis A, acute hepatitis A/secondary syphilis, hepatitis C,
increased transaminases, injection-site pain, injection-site pain/general discomfort/diarrhea/vomiting, adenocarcinoma of colon (n = 1 each).
§Fatigue/nausea/dizziness, amnesia/disturbance in attention/dysarthria, suicide attempt, renal failure (n = 1 each).
8. FLAIR: Injection-Site Reactions
99% of ISRs were grade 1/2,
88% resolved within 7 days
Orkin. CROI 2019. Abstr 140LB. Reproduced with permission. Slide credit: clinicaloptions.com
*No grade > 3 events reported. †2 additional patients d/c
for injection intolerability.
ISR Incidence Over Time
Characteristic to Wk 72
LA CAB + LA RPV
(n = 283)
Patients receiving injections, n 278
Injections given, n 7704
ISR events, n (%)
Pain
Nodule
Induration
Swelling
Warmth
Grade 3 ISR pain*
2203 (28.6)
1879 (85.3)
86 (3.9)
82 (3.7)
38 (1.7)
38 (1.7)
12 (< 1.0)
Median duration of ISRs, days 3
ISR pain leading to d/c,† n (%) 2 (< 1.0)
ParticipantsWithISRs(%)
Study Wk
100
80
60
40
20
0
4 8 12 16 20 24 28 32 36 40 44 48
71
43 38
32 31 33 29 27 27
34
24 20
9. FLAIR: Patient-Reported Outcomes
Orkin. CROI 2019. Abstr 140LB. Slide credit: clinicaloptions.com
‡Per single question in Wk 48 participant survey.
Drug Delivery Preference
of Patients in CAB + RPV Arm
Patient Satisfaction With
Regimen at Wk 48 vs Oral Induction
HIVTSQc
Mean Total
Score*
Switch to LA
CAB + LA RPV
(n = 263)
Continue
DTG/ABC/3TC
(n = 266)
Wk 48† 29.6 25.5
Population
Preferred Regimen,‡ % (n/N)
Long-Acting IM Daily PO
ITT-E 91 (257/238) 1 (2/238)
Responding
participants
99 (257/259) NA*Scores can range from -33 to +33.
†Difference: 4.1 (95% CI: 2.8-5.5; P < .001).
10. FLAIR: Conclusions
Following 20-wk induction with DTG/ABC/3TC in ART-naive patients, switch to LA
CAB + LA RPV noninferior to continued BL ART at Wk 48
‒ HIV-1 RNA ≥ 50 copies/mL in 2.1% vs 2.5%, respectively
‒ Treatment difference: -0.4% (95% CI: -2.8% to 2.1%)
‒ HIV-1 RNA < 50 copies/mL in 93.6% vs 93.3%, respectively
‒ Treatment difference: 0.4% (95% CI: -3.7% to 4.5%)
‒ Confirmed VF in 1.4% vs 1.1%, respectively
‒ NNRTI + INSTI resistance with all 3 cases in CAB + RPV arm; none in DTG/ABC/3TC arm
In CAB + RPV arm, most drug-related AEs (94%) and ISRs (99%) were grade 1/2
Patient-reported satisfaction significantly higher in CAB + RPV arm
Orkin. CROI 2019. Abstr 140LB. Slide credit: clinicaloptions.com
11. clinicaloptions.com/hiv
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