Post on 15-Jul-2022
Dr Roger Philip LeBlanc BSc MDCM FRCPC Clinique OPUS: médecine urbaine
Président et Fondateur Directeur Division médicale ITSS | VIH/SIDA | Recherche
GMF Satellite du DMRG Centre sud Montreal Services des Maladies Virales Chronique CUSM
Professeur Adjoint de l’Université du McGill
LA TRITHÉRAPIE:
QU’EN PENSENT LES EXPERTS?
OÙ EN SOMMES NOUS EN 2018?
Conflits d’interêt potentiels Consultant ponctuel; chercheur ou conférencier
lors d’activités soutenues par les sociétés suivantes : ViiV HealthCare, Merck, Gilead
PLAN: TRITHÉRAPIE EN 2018 1: ÉTUDES NAÏFS GS 1489;GS 1490; DRIVE-AHEAD; AMBER; NAMSAL
2: TRAITEMENT EXPERIMENTÉS: SWITCH GS 1844 GS 1878
DRIVESHIFT; EMERALD
3: COÛTS RELATIFS
4: QUAND? QUI? COMMENT?
5: CONCLUSION
RECREATIONAL
NON-RECREATIONAL
DRUG USE / ABUSE
LOSS OF JOB
SECURITY
LOSS OF BENEFITS
Les études de trithérapie chez les naïfs
Study Design Studies 1489 & 1490: B/F/TAF vs DTG-containing Regimens in Treatment-Naïve Adults
8
Study 14891
HIV-1 RNA ≥500 c/mL
eGFRCG ≥50 mL/min
HLA B*5701 negative
HBV negative
Genotypic sensitivity to FTC, TFV, ABC, 3TC
B/F/TAF qd
DTG/ABC/3TC qd
DTG/ABC/3TC placebo qd
B/F/TAF QD
48 Week 0
1:1
n=314
n=315
Study 14902 HIV-1 RNA ≥500 c/mL
eGFRCG ≥30 mL/min
Genotypic sensitivity to FTC, TFV
B/F/TAF qd
DTG + F/TAF qd
DTG + F/TAF placebo qd
B/F/TAF placebo qd
1:1
n=320
n=325
Primary Endpoint
ABC, abacavir; eGFRCG, estimated glomerular filtration rate by Cockcroft Gault; FTC, emtricitabine; HBV, hepatitis B virus;
HLA, human leukocyte antigen; TFV, tenofovir; 3TC, lamivudine.
1. Gallant J, et al. Lancet 2017;390:2063-72; 2. Sax P, et al. Lancet 2017;390:2073-82.
96 144
Results: Pooled Baseline Characteristics
9
B/F/TAF
n=634
DTG/ABC/3TC
n=315
DTG + FTC/TAF
n=325
Median age, y (range) 32 (18–71) 32 (18–68) 34 (18–77)
Male, % 89 90 89
Race/ethnicity, %
Black or African descent 33 36 31
Hispanic/Latino 25 21 25
Median HIV-1 RNA, log10 copies/mL (Q1, Q3) 4.42 (4.00, 4.88) 4.51 (4.04, 4.87) 4.45 (4.03, 4.84)
HIV-1 RNA >100,000 copies/mL, % 19 16 17
Median CD4 cell count, cells/µL (Q1, Q3) 442 (293, 590) 450 (324, 608) 441 (297, 597)
CD4 count <200 cells/µL, % 13 10 10
HBV coinfection, %* 1 Excluded 2
HCV coinfection, %† 1 1 2
Median eGFRCG, mL/min (Q1, Q3) 122 (104, 143) 123 (107, 144) 121 (103, 145) *Positive HBV surface antigen and/or isolated positive HBV core antigen with HBV DNA ≥20 IU/mL; †Positive hepatitis C
virus (HCV) antibody and HCV RNA ≥15 IU/mL. Q, quartile.
Virologic Response by Visit (FAS) HIV-1 RNA <50 copies/mL, Missing=Excluded Analysis
All arms showed rapid suppression of viremia, with the majority of participants
<50 copies/mL by Week 412-13
10
a
Part
icip
ants
, %
0,
20,
40,
60,
80,
100,
0 12 24 36 48
76.3 90.7 96.3 97.9 98.8 99.1
75.9 91.6 96.1 98.4 98.3 97.7
79.6 89.9 95.3 97.5 98.1 99.3
B/F/TAF
DTG/ABC/3TC
DTG + F/TAF
4 8
Weeks
Virologic Efficacy: HIV-1 RNA <50 copies/mL, Missing=Excluded Analysis Baseline HIV-1 RNA >100,000 copies/mL
Virologic response rates by visit were also rapid and similar between treatment arms in
participants with high baseline VL
11
a
Part
icip
ants
, %
0,
20,
40,
60,
80,
100,
0 12 24 36 48
25.0 69.8 84.2 92.7 96.3 99
30.0 65.3 83.3 95.7 97.9 97.9
24.1 58.5 79.6 88.7 94.3 96.2
B/F/TAF
DTG/ABC/3TC
DTG + F/TAF
4 8
Weeks
Treatment Naïve: Study 1489 Virologically Suppressed: Study 1844
Week Longitudinal Model
Week Longitudinal Model 4 12 48 4 12 48
HIV-SI Bothersome Symptom*
Fatigue/loss of energy
Dizzy/lightheadedness
Nausea/vomiting
Loss of appetite
Sad/down/depressed
Nervous/anxious
Difficulty sleeping
PSQI
Poor sleep quality
Significant Differences in Bothersome Symptoms and PSQI
13
*Only symptoms where ≥2 time points/models showed significance in either study are presented;
No differences between arms
Favors DTG/ABC/3TC
Favors B/F/TAF
= statistically significant (p <0.05) based on adjusted logistic
regression or longitudinal model favoring the B/F/TAF group
D/c for AEs: 1.9% with BIC/FTC/TAF vs 1.6% with DTG + FTC/TAF
Fewer TRAEs with BIC/FTC/TAF vs DTG + FTC/TAF (P = .02)
Grade 3/4 laboratory abnormalities similar between arms
No tubulopathy or d/c for renal AEs in either arm
No difference in lipid changes between arms
GS-1490: Safety Outcomes Through Wk 96
Stellbrink. Glasgow 2018. Abstr O211. Slide credit: clinicaloptions.com
All-Grade AEs, % BIC/FTC/TAF
(n = 320)
DTG + FTC/TAF (n = 325)
P Value
Any AE 88 89 --
Any TRAE 20 28 .02
TRAEs occurring with ≥ 3% frequency
• Nausea 3 5 --
• Diarrhea 3 3 --
• Headache 4 3 --
ZÉRO
DIFFERENCE
Multicenter, randomized, double-blind phase III noninferiority trial[1]
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (noninferiority margin: -10%)[2]
‒ DOR/3TC/TDF vs EFV/FTC/TDF: 84.3% vs 80.8% (difference: 3.5%; 95% CI: -2.0% to 9.0%)
‒ Neuropsychiatric events less frequent with DOR/3TC/TDF
DRIVE-AHEAD: DOR/3TC/TDF vs EFV/FTC/TDF in Treatment-Naive Adults at Wk 96
Slide credit: clinicaloptions.com
Treatment-naive adults with HIV-1 RNA ≥ 1000 copies/mL
and no resistance to study drugs (N = 728)
Current Analysis Wk 96
Primary Analysis Wk 48
Stratified by HIV-1 RNA (> vs ≤ 100,000 copies/mL), chronic HBV or HCV coinfection status
DOR/3TC/TDF 100/300/300 mg QD + EFV/FTC/TDF Placebo
(n = 364)
EFV/FTC/TDF 600/200/300 mg QD + DOR/3TC/TDF Placebo
(n = 364)
Open-label extension for 96 wks
1. Orkin. IDWeek 2018. Abstr LB1. 2. Orkin. Clin Infect Dis. 2018;[Epub].
DRIVE-AHEAD: Virologic Outcomes at Wk 96
Orkin. IDWeek 2018. Abstr LB1. Reproduced with permission. Slide credit: clinicaloptions.com
HIV-1 RNA < 50 copies/mL by Observed Failure Analysis, % (n*)
DOR/3TC/TDF
EFV/FTC/TDF
All participants 83.7 (337) 85.9 (312)
BL HIV-1 RNA, copies/mL ≤ 100,000 > 100,000
86.9 (268) 71.0 (69)
87.5 (248) 79.7 (64)
BL CD4+ cell count, cells/mm3
≤ 200 > 200
65.0 (40)
86.2 (297)
82.1 (39)
86.4 (273)
FDA Snapshot Analysis
Treatment difference: 3.8% (95% CI: -2.4% to 10.0%)
*n refers to total number of participants per subgroup.
100
80
60
40
20
0
77.5 73.6
HIV
-1 R
NA
< 5
0 c
op
ies/
mL
(%)
DOR/3TC/TDF EFV/FTC/TDF
Resistance:
‒ DOR-R in 6 patients (1.6%) in DOR arm vs EFV-R in 13 patients (3.8%) in EFV arm
‒ NRTI-R in 1.4% vs 1.6%, respectively
Small decreases in fasting LDL-C, non–HDL-C with DOR vs increases with EFV
DRIVE-AHEAD: Safety Outcomes Through Wk 96
Less frequent drug-related AEs, AE-related d/c with DOR/3TC/TDF vs EFV/FTC/TDF
Less frequent neuropsychiatric AEs with DOR/3TC/TDF vs EFV/FTC/TDF
Orkin. IDWeek 2018. Abstr LB1. Reproduced with permission. Slide credit: clinicaloptions.com
AE, n (%) DOR/3TC/TDF (n = 364)
EFV/FTC/TDF (n = 364)
Any AE Drug related
321 (88) 116 (32)
339 (93) 236 (65)
Serious AE Drug related
21 (6) 1 (< 1)
30 (8) 4 (1)
AE leading to d/c Drug related Serious Serious drug
related
11 (3) 8 (2) 2 (1)
1 (< 1)
27 (7) 24 (7) 4 (1)
3 (1)
Death 0 2 (1)
Predefined Neuropsychiatric AEs, %
DOR/3TC/TDF (n = 364)
EFV/FTC/TDF (n = 364)
Dizziness 10.2 38.2
Sleep disorders and disturbances
14.0 27.5
Altered sensorium 4.9 8.5
Depression and suicide/self-injury
5.2 7.4
Psychosis and psychotic disorders
0.5 1.4
AMBER: DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF in Treatment-Naive Adults at Wk 96
Multicenter, randomized, double-blind, noninferiority phase III trial[1]
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (FDA Snapshot)(noninferiority margin: -10%)[2]
‒ DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF: 91.4% vs 88.4% (difference: 2.7%; 95% CI: -1.6% to 7.1%; P < .0001)
‒ Less impact on renal, bone markers with DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF
1. Orkin. Glasgow 2018. Abstr O212. 2. Eron. AIDS. 2018;32:1431.
DRV/COBI/FTC/TAF (n = 362)
DRV/COBI + FTC/TDF (n = 363)
Switch to DRV/COBI/FTC/TAF (n = 295)
DRV/COBI/FTC/TAF (n = 335)
Treatment-naive adults with HIV-1 RNA ≥ 1000 copies/mL, CD4+ counts > 50 cells/mm3, genetic susceptibility to DRV,
FTC, TFV, no HBV/HCV infection (N = 725)
Current Analysis Wk 96
Primary Analysis Wk 48
Rollover phase DRV/COBI/FTC/TAF
Database unblinded at Wk 48.
Slide credit: clinicaloptions.com
AMBER: Efficacy at Wks 48 and 96 (FDA Snapshot, ITT)
Slide credit: clinicaloptions.com
4% 3%
4% 8%
DRV/COBI/FTC/TAF (n = 362)
Wk 48
6% 4%
9% 12%
DRV/COBI + FTC/TDF (n = 363)
Wk 48 Wk 96 Wk 96
HIV-1 RNA ≥ 50 c/mL
No virologic data
HIV
-1 R
NA
< 5
0 c
op
ies/
mL
(%)
91 88 85 84
Virologic response at Wk 96 consistent across subgroups
‒ BL VL >/≤ 100,000 copies/mL, BL CD4+ ≥/< 200 cells/mm3, age >/≤ 50 yrs, sex, race
Resistance analysis in 9/15 patients with PDVF with DRV/COBI/FTC/TAF vs 8/19 in control arm through Wk 96
‒ 1 patient with M184V/I in each arm
‒ No evidence of emergent DRV, primary PI, or TFV RAMs
FDA Snapshot Analysis at Wks 48 and 96
0
20
40
60
80
100
Orkin. Glasgow 2018. Abstr O212. Reproduced with permission.
AMBER: Safety at Wks 48 and 96
No d/c for bone, renal, CNS AEs in DRV/COBI/FTC/TAF arm
No Fanconi syndrome or tubulopathy
No clinically relevant effect on eGFR in either arm
Less effects on bone, renal markers with DRV/COBI/FTC/TAF
Similar lipid changes across arms
Orkin. Glasgow 2018. Abstr O212. Reproduced with permission. Slide credit: clinicaloptions.com
AEs in DRV/COBI/FTC/TAF Arm, n (%)
BL to Wk 48 (n = 362)
BL to Wk 96 (n = 362)
Patient-yrs of exposure 323 626
≥ 1 AE, any grade 312 (86) 334 (92)
Study drug-related AEs 128 (35) 142 (39)
Study drug-related AEs in ≥ 5% patients
Diarrhea 33 (9) 34 (9)
Rash 22 (6) 22 (6)
Nausea 20 (6) 20 (6)
Study drug-related grade 3/4 AEs
6 (2) 11 (3)
≥ 1 serious AE 17 (5) 39 (11)
Study drug-related serious AEs
0 1 (< 1)
≥ 1 AE leading to d/c 8 (2) 10 (3)
NAMSAL: DTG- vs EFV 400 mg–Based ART in Treatment-Naive Patients in Cameroon
Multicenter, randomized, open-label phase III noninferiority trial
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (FDA Snapshot)
‒ Noninferiority tested with 10% margin
Cournil. Glasgow 2018. Abstr O342. Slide credit: clinicaloptions.com
ART-naive adults with HIV-1 RNA ≥ 1000 copies/mL
(N = 613)
Wk 48 Primary Endpoint
DTG 50 mg QD + 3TC/TDF (n = 310)
EFV 400 mg QD + 3TC/TDF (n = 303)
Follow-up through 96 wks
Stratified by HIV-1 RNA at screening, site
NAMSAL: Efficacy at Wk 48 (FDA Snapshot)
AEs: DTG 11% vs EFV 400 8%; AIDS-defining events: DTG 8% vs EFV 400 10%
Virologic failure (HIV-1 RNA > 1000 c/mL) observed in 19 pts; emergent resistance in 0/3 DTG failures vs 9/16 EFV 400 failures
Cournil. Glasgow 2018. Abstr O342. Slide credit: clinicaloptions.com
Outcome at Wk 48 DTG + 3TC/TDF
(n = 310) EFV 400 + 3TC/TDF
(n = 303) Treatment Difference DTG - EFV (95% CI), %
HIV-1 RNA < 50 c/mL (virologic success), n (%) 231 (74.5) 209 (69.0) 5.5 (-1.6 to 12.7)
HIV-1 RNA < 200 c/mL/< 1000 c/mL, % 89.0/91.9 83.5/86.5 --
HIV-1 RNA > 50 c/mL (virologic failure), n 62 70 --
D/c for death 6 7 --
D/c other reasons (LTFU, withdrawn) 9 15 --
HIV-1 RNA < 50 c/mL by BL VL, n/N (%)
HIV-1 RNA < 100,000 c/mL 94/103 (91.3) 86/103 (83.5) 7.8 (-1.2 to 16.8)
HIV-1 RNA > 100,000 c/mL 137/207 (66.2) 123/200 (61.5) 4.7 (-4.6 to 14.0)
HIV-1 RNA > 500,000 c/mL 51/93 (54.8) 55/95 (57.9) --
TRITHÉRAPIE: SWITCH
‡
Methods: Figure 1. B/F/TAF Switch Study Designs
29
‡
Results: Figure 2. Virologic Outcome at Week 48 by FDA Snapshot
30
‡
Table 2. Distribution of Baseline HIV-1 Subtypes
31
Number of Participants, n (%)
HIV-1 Subtype B/F/TAFn=405
PI + 2NRTI
n=125
ABC/DTG/3TC
n=138
B 327 (81%) 79 (63%) 99 (72%)
Non-B 27 (7%) 15 (12%) 6 (4%)
A 2 (<1%) 0 0
A1 2 (<1%) 0 0
AE 3 (<1%) 0 3
AG 5 (1%) 5 (4%) 0
C 4 (1%) 6 (5%) 1 (<1%)
Complex 9 (2%) 3 (2%) 2 (1%)
D 1 (<1%) 0 0
F 1 (<1%) 0 0
H 0 1 (<1%) 0
Undetermined 51 (13%) 31 (25%) 33 (24%)
‡
Figure 4. Week 48 Virologic Outcome of B/F/TAF-treated Participants Stratified by Baseline Resistance Category
34
No significant differences in virologic outcome by presence or absence of baseline resistance in the B/F/TAF group were observed.
BL resistance
INTI~10-15%
NNRTI ~18%
IP/r ~5%
INSTI 0%
‡
Table 9. Resistance Development through Week 48
35
Resistance Category
Number of Participants, n (%)
B/F/TAF
n=572
PI + 2NRTI
n=287
ABC/DTG/3TC
n=281
Resistance Analysis Population (RAP) 5 (0.9%) 5 (1.7%) 2 (0.7%)
Data Available for Any Gene (% of RAP) 2 (40%) 5 (100%) 2 (100%)
PR/RT Data Available (% of RAP) 2 (100%) 5 (100%) 2 (100%)
IN Data Available (% of RAP) 1 (20%) 2 (40%) 2 (100%)
Resuppressed HIV-1 RNA <50 c/mL (% of RAP) 2 (40%) 2 (40%) 1 (50%)
Developed Resistance to Study Drugs 0 1 (0.3%) 0
NRTI-R Substitutions Acquired - L74V -
Change Baseline in eGFRCG Through Week 48
36
Study 380-1878: HIV Suppressed Adults Switched from boosted DRV or ATV + 2 NRTIs
p <0.001
–4.3 mL/min
0.2 mL/min
B/F/TAF SBR
Weeks
Media
n (
Q1, Q
3)
eG
FR
CG C
hange fro
m
BL, m
L/m
in
Daar E, ID Week, 2017, Abstract # 67504
‡
‡
Change in eGFR
CG Over Time
Study 380-1844
No discontinuations due to renal AEs and no cases of renal tubulopathy in either arm
*From 2-sided Wilcoxon rank-sum test. 37
‡ Changes in Spine and Hip BMD Through Week 48 Study 380-1844
*From ANOVA model for comparison of B/F/TAF vs DTG/ABC/3TC at Week 48. 38
Percent Change from Baseline in Quantitative Proteinuria at Week 48
39
Study 380-1878: HIV Suppressed Adults Switched from Boosted DRV or ATV + 2 NRTIs
Media
n P
erc
enta
ge C
hange
from
Baselin
e, %
β2M:Cr RBP:Cr UACR
SBR B/F/TAF
Baseline FTC/TDF-Containing Regimen Baseline ABC/3TC-Containing Regimen
-2,1
-17,7
-40,3
9,9
34,9 31,6
-50,
-25,
0,
25,
50,
4,2 5,4
-19,5
1,1
25,8
7,3
-50,
-40,
-30,
-20,
-10,
0,
10,
20,
30,
40,
β2M:Cr RBP:Cr UACR
Daar E, ID Week, 2017, Abstract # 67504
UACR: urine albumin to creatinine ratio; RBP: retinol binding protein to creatinine ratio; β2M:Cr: beta-2-microglobulin to creatinine ratio
‡
Multicenter, randomized, open-label phase III noninferiority trial
Primary endpoint: HIV-1 RNA < 50 copies/mL (FDA Snapshot)
‒ Noninferiority margin: lower bound of 95% CI > -8%
‒ Time point comparisons: Wk 48 in immediate switch arm vs Wk 24 in baseline ART arm (primary); Wk 24 in each arm (secondary)
DRIVE-SHIFT: Switch to DOR/3TC/TDF vs Continuation of Baseline ART in Virologically Suppressed Adults
DOR/3TC/TDF* (n = 447)
Baseline ART†
(n = 223) DOR/3TC/TDF*
(n = 209)
DOR/3TC/TDF* (n = 427)
Adults with HIV-1 RNA < 40 copies/mL, stable ART for ≥ 6 mos with no prior
virologic failure or resistance to study drugs,
and eGFR ≥ 50 mL/min (N = 670)
Wk 48
*DOR/3TC/TDF dosing: 100/300/300 mg QD. †2 NRTIs + RTV- or COBI-boosted PI (ATV, DRV, LPV), EVG/COBI, or NNRTI (EFV, NVP, RPV).
Wk 24
Slide credit: clinicaloptions.com Kumar. IDWeek 2018. Abstr LB2.
DRIVE-SHIFT: Efficacy of Switch to DOR/3TC/TDF at Wks 24 and 48 vs Continued BL ART at Wk 24 (FDA Snapshot)
Kumar. IDWeek 2018. Abstr LB2. Slide credit: clinicaloptions.com
No evidence of treatment-emergent resistance in patients receiving DOR/3TC/TDF
Efficacy Analysis by FDA Snapshot, %
Immediate Switch to DOR/3TC/TDF
(n = 447)
Continued BL ART (n = 223)
Difference Between Arms, % (95% CI)
Wk 24 DOR/3TC/TDF vs Wk 24 BL ART
HIV-1 RNA < 50 copies/mL 93.7 94.6 -0.9 (-4.7 to 3.0)
HIV-1 RNA ≥ 50 copies/mL 1.8 1.8 0 (-2.3 to 2.3)
No virologic data 4.5 3.6 --
Wk 48 DOR/3TC/TDF vs Wk 24 BL ART
HIV-1 RNA < 50 copies/mL 90.8 94.6 -3.8 (-7.9 to 0.3)
HIV-1 RNA ≥ 50 copies/mL 1.6 1.8 -0.2 (-2.5 to 2.1)
No virologic data 7.6 3.6 --
DRIVE-SHIFT: Safety Outcomes Through Wk 48
Switch to DOR/3TC/TDF associated with significantly greater decreases in LDL-C (-16.5 vs -1.9 mg/dL) and non–HDL-C (-24.7 vs -1.3 mg/dL) at Wk 24 vs continued BL ART in patients receiving PI/RTV-based ART at study entry (P < .0001 for both comparisons)
Kumar. IDWeek 2018. Abstr LB2. Slide credit: clinicaloptions.com
AEs, n (%) Immediate Switch to DOR/3TC/TDF
Wks 0-48 (n = 447)
Continued BL ART Wks 0-24 (n = 223)
Late Switch to DOR/3TC/TDF
Wks 24-48 (n = 209)
Any AE Drug related
308 (68.9) 87 (19.5)
117 (52.5) 5 (2.2)
126 (60.3) 29 (13.9)
Serious AEs Drug related
13 (2.9) 2 (0.4)
8 (3.6) 0
4 (1.9) 1 (0.5)
D/c due to AE Drug related
11 (2.5) 7 (1.6)
1 (0.4) 0
4 (1.9) 4 (1.9)
Death 0 0 0
EMERALD: Switch From Suppressive Boosted PI + FTC/TDF to DRV/COBI/FTC/TAF at Wk 96
Multicenter, randomized, open-label phase III noninferiority trial
Primary endpoint: cumulative virologic rebound at Wk 48 (ITT)
‒ Noninferiority margin: upper bound of 95% CI < 4%
‒ Switch to DRV/COBI/FTC/TAF vs continue boosted PI + FTC/TDF: 2.5% vs 2.1% (difference: 0.4%; 95% CI: -1.5% to 2.2%; noninferiority P < .0001)
Adults with HIV-1 RNA < 50 c/mL while receiving boosted PI* +
FTC/TDF; no prior VF on DRV; no DRV RAMs if historical genotype
known (N = 1141)
Rollover to DRV/COBI/FTC/TAF
Immediate Switch to DRV/COBI/FTC/TAF† (n = 763)
Continue Boosted PI + FTC/TDF (n = 378)
Slide credit: clinicaloptions.com Eron. IDWeek 2018. Abstr 1768. Orkin. Lancet HIV. 2018;5:e23.
Late Switch to DRV/COBI/FTC/TAF†
Wk 48 Primary Analysis
Wk 96 Current Analysis
*Eligible boosted PIs: ATV/COBI or RTV, DRV/COBI or RTV, LPV/RTV. †800/150/200/10 mg QD.
Stratified by boosted PI used at screening
EMERALD: Virologic Outcomes in DRV/COBI/FTC/TAF Immediate Switch Arm Through Wk 96 (ITT)
No RAMs to DRV, tenofovir, or FTC and no primary PI RAMs observed post baseline
Slide credit: clinicaloptions.com Eron. IDWeek 2018. Abstr 1768. Reproduced with permission.
FDA Snapshot at Wks 48 and 96
Pat
ien
ts, %
(9
5%
CI*
)
*2-sided exact Clopper-Pearson 95% CI.
Cumulative PDVR BL to Wk 48(n = 763)
BL to Wk 96(n = 763)
VL ≥ 50 c/mL, n (%) Rebounders
resuppressed, n/N
19 (2.5) 12/19
24 (3.1) 14/24
VL ≥ 200 c/mL, n (%) Rebounders
resuppressed, n/N
3 (0.4) 0/3
4 (0.5) 2/4
VL < 50 c/mL VL < 200 c/mL
DRV/COBI/FTC/TAF Wk 48 (n = 763)
DRV/COBI/FTC/TAF Wk 96 (n = 763)
100
80
60
40
20
0
95 91 91 95
EMERALD: Safety Outcomes in DRV/COBI/FTC/TAF Immediate Switch Arm Through Wk 96
Low rates of study drug–related grade 3/4 or serious AEs, AE-related d/c (all ≤ 2%) maintained from Wk 48 to Wk 96
No cases of subclinical proximal renal tubulopathy or Fanconi syndrome through Wk 96
Lipid parameters stable from Wks 48 to 96
Small (median change: ~ -1.0 mL/min) but statistically significant eGFR decrease from BL to Wk 96 (P < .05)
Slide credit: clinicaloptions.com Eron. IDWeek 2018. Abstr 1768.
BMD Outcome BL to Wk 48(n = 164)
BL to Wk 96(n = 173)
Mean percent change in hip BMD, % Proportion with
≥ 3% increase Proportion with
≥ 3% decrease
1.49
21
2
1.85*
29
3
Mean percent change in spine BMD, % Proportion with
≥ 3% increase Proportion with
≥ 3% decrease
1.45
31
8
2.00*
37
9
*P < .001 for within-arm change from BL by paired t-test.
NA-ACCORD Cohort: Weight Gain Following ART Initiation With INSTI- vs PI-/NNRTI-Based Regimens
Analysis of NA-ACCORD cohort of ART-naive adults who started 3-drug regimen with INSTI, PI, or NNRTI from January 2007 - December 2015 (N = 21,867)
Slide credit: clinicaloptions.com Lake. International Comorbidities WS 2018. Abstr ADRLH-71.
Baseline Characteristic NNRTI (n = 10,711)
PI (n = 7063) INSTI (n = 4093) Overall (N = 21,867)
Median age, yrs (IQR) 43 (32-52) 42 (32-50) 41 (30-51) 42 (32-51)
Black race/Hispanic ethnicity, % 40/8 41/9 38/9 40/8
Male sex, % 91 81 87 87
Median BMI (IQR) 25 (23-29) 25 (22-28) 25 (22-29) 25 (22-29)
Median calendar year started ART (IQR) 2010 (2008-2012) 2010 (2008-2011) 2013 (2011-2014) 2010 (2009-2012)
Median CD4+ cell count, cells/mm3 (IQR) 311 (178-451) 251 (107-405) 346 (171-516) 303 (154-451)
Median HIV-1 RNA, copies/mL (IQR) 40,480 (11,198-
120,016) 52,405 (12,830-
169,824) 42,657 (11,939-
144,709) 44,054 (11,796-
139,374)
ART agent, % RAL/EVG/DTG ATV/DRV/EFV
--/--/-- --/--/87
--/--/--
43/35/--
51/37/12
--/--/--
10/7/2
14/11/43
NA-ACCORD Cohort: Predicted and Observed Weight Change
Comparisons of predicted weight change
‒ RAL/DTG vs NNRTI: P < .05
‒ RAL/DTG vs PI: P = NS
‒ EVG vs PI: P = .03
‒ EVG vs NNRTI: P = NS
Comparisons of 2-yr weight change by INSTI
‒ RAL vs EVG: P = .03
‒ RAL vs DTG: P = .42
‒ EVG vs DTG: P = .07
Slide credit: clinicaloptions.com
Outcome INSTI
RAL DTG EVG
2-yr weight change, kg 5.4 5.6 3.4
Lake. International Comorbidities WS 2018. Abstr ADRLH-71.
Mise en garde: La majorité des nouvelles études ont exclus les co-infections VBH VHC; Peu avec des échecs de traitement antérieurs; Adhérence déjà établie; Peu avec plusieurs co-morbidités; Peu de données chez les femmes…la grossesse…la période de la conception. Les patients avec CD4 <200 et CV >100,000 ainsi que ceux avec CD4<50 et CV>500,000 demeurent une préoccupation.
Simplicité: QD INTI INNI IP (cobi ou rtv) INI en double et triple STR
Puissants |Pan-génotypes | Multi-ethniques | Pan-global | Personnes âgées
Diminution | Réversibilité | Stabilisation des «concerns» rénaux, osseux (TAF et sans TAF)
Diminution des «concerns» sur la mitotoxicité des INTI à long termes (TAF ABC FTC 3TC)
Diminution des symptômes SNC avec Doravirine et Bictégrevir
Habilité de surmonter des mutations transmises ou supprimées chez les naïfs et les
patients SWITCH (INTI INNI IP/r)
Favorable: Polypharmacie …Vieillissement…Co-morbidités…Lipides
La majorité des effets indésirables: peu fréquents, largement transitoires
La prise du poids avec les INI: effets secondaires ou reflet de leur innocuité?
EN CONCLUSION (1):
c
Pour nos patients très expérimentés procèder avec prudence…..surtout ceux avec des histoires de mono-; bi- ; “Add-On” et même trithérapies avec les IP 1ere génération…..HLA-B*5701 Status
Nous avons des années d’expérience avec une approche utilisant 3 médicaments en traitement d’initiation chez les naïfs et en traitant ceux avec des échecs antérieurs… Blips? Pénétration des sites sanctuaires? Adhérence moins que 85%…la durabilité? L’épidémie de l’obésité? Les ITTS? La drogue?
La bithérapie semble être une option rationnelle et raisonnable…$$$..mais HBV immunité doit être établie…..prudence avec ceux HBSAg- HBcAb+ HBSAb-
Les patients TND et TD persistent…importance envers des échecs futurs?
EN CONCLUSION (2)
Prix moyen sans assurance pour 30 jours
Evotaz (ATZ+ COBI) 865$
Delstrigo (Dor+3TC+TDF) 863$
Triumeq (ABC+3TC+DTG) 1216$
Descovy (TAF+FTC) 1075$
Juluca (Ril+DTG) 1175$
Odefsey (Ril+ TAF+ FTC) 1485$
Biktarvy (BIC+ TAF+FTC) 1420$
Genvoya (EVG+Cobi+ FTC+TAF) 1625$
Symtuza (DTG+Cobi+FTC+TAF) 1870$
DTG+3TC Pifeltro (Dor) ~500$