new arvs, new strategies - virology...
TRANSCRIPT
Outline
• New ARVs• TAF/FTC/Bictegravir Bictarvy (February 2018)• TAF/FTC/c/DRV Symtuza (July 2018)• Doravirine/3TC/TDF Delstrigo (August 2018)
• New strategies• Dual therapy DTG/3TC. Dovato (April 2019)
• Initial• Maintenance
• Drugs for MDR patients• Ibalizumab Trogarzo (March 2018)• Fostemsavir
• Future drugs*• Cabotegravir/Rilpivirine IM• PRO 140• Islapravir
▪ Design
▪ Objective– Non inferiority of BIC/F/TAF at W48: % HIV RNA < 50 c/mL by intention to treat,
snapshot analysis (lower margin of the 2-sided 95.002% CI for the
difference= -12%, 95% power)
BIC/F/TAF QD
DTG/ABC/3TC placebo QD
DTG/ABC/3TC QD
BIC/F/TAF placebo QD
Randomisation*1 : 1
Double-blind
> 18 years, ARV-naïve HIV RNA > 500 c/mLAny CD4 cell count
HLA B*5701 negativeeGFR ≥ 50 mL/min
HBs Ag negativeNo resistance to
FTC/3TC, TDF or ABC
Study GS-US-380-1489: BIC/F/TAF QD vs DTG/ABC/3TC QD
N = 315
N = 314
W48 W144
* Randomisation was stratified by HIV RNA (< 100 000 c/mL, 100 000-4000 000 c/mL or > 100 000 c/mL),
CD4 (< 50/mm3, 50-199/mm3 or ≥ 200/mm3) at screening and geographic region (USA vs non-USA)
BIC/F/TAF: 50/200/25 mg, as STR
Gallant J. Lancet. 2017 Nov 4;390(10107):2063-2072 ; Wohl DA Lancet HIV 2019 ; 6:e355-63
BICTARVY
Virologic outcome at week 48
DTG/ABC/3TC BIC/F/TAF
0 ‒ 12% + 12%
3.6- 4.8
- 0.6
Difference (95 % CI)BIC/F/TAFDTG/ABC/3TC
92.4
1.06.7
93.0
2.5 4.4
0
20
40
60
80
100
HIV RNA
< 50 c/mL
HIV RNA
≥ 50 c/mLNo data
%
▪ Met criteria for resistance testing (HIV RNA ≥ 200 c/mL)– BIC/F/TAF: 1 vs DTG/ABC/3TC: 4
– No resistance emergence
▪ Mean CD4 increase at W48– BIC/F/TAF: + 233/mm3
– DTG/ABC/3TC: + 229/mm3
▪ HIV RNA < 50 c/mL (per-protocol)‒ BIC/F/TAF: 99.3%
‒ DTG/ABC/3TC: 98.6%
Study GS-US-380-1489: BIC/F/TAF QD vs DTG/ABC/3TC QD
Gallant J. Lancet. 2017 Nov 4;390(10107):2063-2072
▪ Design
▪ Objective– Non inferiority of E/C/F/TAF at W48: % HIV RNA < 50 c/mL by intention to
treat, snapshot analysis (lower margin of the 95% CI for the difference = -10%)
D/C/F/TAF QD
D/C + F/TDF placebo
D/C + F/TDF QD
D/C/F/TAF placebo
Randomisation*1:1
Double-blind
HIV+ AdultsARV-naïve
HIV RNA > 1 000 c/mLCD4 cell count > 50/mm3
eGFR > 50 mL/min
* Randomisation was stratified by HIV RNA (< or ≥ 100 000 c/mL) and CD4 cell count (< or ≥ 200/mm3)
** Patients were switched to open-label D/C/F/TAF after unblinding that occurred at various time after W4
AMBER Study: D/C/F/TAF QD vs D/C + F/TDF QD
N = 363
N = 362
W96W48
Eron J. AIDS 2018 ;32:1431-42
D/C/F/TAF QD
D/C/F/TAF QD **
Median duration of exposure (weeks) : D/C/F/TAF = 96.1 ; D/C + F/TDF = 73.1 ; D/C/F/TAF deferred switch = 22.3
SYMTUZA
▪ Resistance analysis– Virologic failures with paired genotypes (baseline and failure with HIV
RNA ≥ 400 c/mL), N = 9 [7 D/C/F/TAF + 2 D/C + F + TDF]:
1 patient with emergence of M184I/V (D/C/F/TAF)
Virologic outcome at W48 (ITT, snapshot)
-10 -8 -6 -4 -2 0 2 4 6 8 10
2.7
7.1 - 1.6
Adjusted difference, % (95% CI)
Favours
D/C/F/TAF
Favours
D/C + F/TDF
66
D/C/F/TAF (N = 362)D/C + F/TDF (N = 363)
91.4
4.4 4.1
88.4
3.38.3
0
20
40
60
80
100
HIV RNA
< 50 c/mL
HIV RNA
≥ 50 c/mLNo data
%
AMBER Study: D/C/F/TAF QD vs D/C + F/TDF QD
Eron J. AIDS 2018 ;32:1431-42
▪ Design
▪ Objectives– Non inferiority of DOR at W48: % HIV RNA < 50 c/mL by intention to treat,
snapshot analysis (lower margin of the 95% CI for the difference = - 10%,
90% power)
– Superiority of DOR for neuropsychiatric adverse events by W48
DOR 100 mg/3TC/TDF QD + placebo
EFV/FTC/TDF + placebo
Randomisation*1 : 1
Double-blind
* Randomisation was stratified by HIV RNA (< or > 100 000 c/mL) at screening and chronic hepatitis B or C
N = 364
N = 364
W48 W96
DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF
> 18 yearsARV-naïve
HIV RNA > 1 000 c/mLAny CD4 cell count
eGFR (CG) ≥ 50 mL/minNo primary resistance
to DOR, EFV, NRTI
DOR/3TC/TDF : 1 tablet QD as STR
Orkin C. Clin Infect Dis. 2019 ;68:535-44
DELSTRIGO
EFV DOR
0 ‒ 10% + 10%
9.0-2.0
3.5
Difference (95 % CI)EFV/FTC/TDF (N = 364)
84
115
81
10 9
0
20
40
60
80
100
Virologic
response
Virologic
non-responseNo data
DOR/3TC/TDF (N = 364)%
58
Primary endpoint: HIV RNA < 50 c/mL at W48 (ITT, snapshot)
▪ CD4 increase at W48 (ITT, NC = F)– DOR: + 198/mm3
– EFV: + 188/mm3
▪ HIV RNA < 50 c/mL at W48 (observed failure approach)‒ Baseline HIV RNA ≤ 100 000 c/mL: DOR: 90.6% vs EFV: 91.1 %
‒ Baseline HIV RNA > 100 000 c/mL: DOR: 81.2 % vs EFV: 80.8 %
DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF
Orkin C. Clin Infect Dis 2019; 68: 535-44
DHHS[1] IAS-USA[2] EACS[3] WHO[4]
▪ BIC/FTC/TAF▪ DTG/3TC/ABC▪ DTG + FTC/(TAF or TDF)▪ RAL + FTC/(TAF or TDF)
▪ BIC/FTC/TAF▪ DTG/3TC/ABC▪ DTG + FTC/TAF
▪ BIC/FTC/TAF▪ DTG/3TC/ABC▪ DTG + FTC/(TAF or TDF)▪ RAL + FTC/(TAF or TDF) ▪ RPV/FTC/(TAF or TDF)▪ DRV(COBI or RTV) +
FTC/(TAF or TDF)
▪ DTG + (3TC or FTC)/TDF
How these new drugs fit in the current guidelines?How should they be used?
▪ Recommendations may differ based on baseline HIV-1 RNA, CD4+ cell count, CrCl, eGFR, HLA-B*5701 status, HBsAg status, bone mineral density, and pregnancy status or intent
1. DHHS ART. Guidelines. October 2018. 2. Saag. JAMA. 2018;320:379. 3. EACS. 2019. 4. WHO ART. December 2018.
• One of the
options for
“most” patients
starting ART
• Is an option for patients
with comorbidities
• May become popular if
the weight signal is
better than INSTIs/TAF
• Rapid initiation in
people with
adherence concerns
BICTARVYSYMTUZADELSTRIGO
▪ Design
▪ Primary endpoint– 2 parallel studies (GEMINI-1 and GEMINI-2), each with a combined
number of 710-720 patients and similar endpoint
– Proportion of patients with HIV RNA < 50 c/mL at W48, ITT-E analysis,
snapshot algorithm ; non-inferiority if lower margin of a one-sided 97.5% CI
for the difference = - 10%, 90% power
DTG + 3TC
DTG + TDF/FTC
Randomisation *1 : 1
Double-blind
HIV+ ≥ 18 yearsARV-naïve
HIV RNA 1 000-500 000 c/mLNo HBV co-infection
No major HIV resistance mutationsN = 717
N = 716
W96
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
* Randomisation stratified by HIV RNA (≤ or > 100 000 c/mL) and CD4 (≤ or > 200/mm3)
Cahn P. Lancet. 2019; 393(10167):143-155
DOVATO
GEMINI-1 and -2 Studies:Virologic Outcomes at Week 96
Cahn P, et al. J Int AIDS Soc. 2019;22(suppl 5):103. Abstract WEAB0404LB.
Pati
en
ts (
%)
HIV RNA <50 Copies/mL at Week 96 (ITT)
0
20
40
60
80
100
Overall (ITT)(n=716/717)
86%90%
≤100K(n=576/564)
Non-InferiorityMaintained
Difference (%):-3.4 (-6.7, 0.0)
>100K(n=140/153)
Baseline HIV RNA (copies/mL)
>200(n=653/662)
≤200(n=63/55)
Baseline CD4 Count (cells/mm3)
87%90%
84% 86%
68%
90%88% 87%
Dolutegravir + 3TC Dolutegravir + F/TDF
GEMINI-1 and -2 Studies:Pooled Resistance and Safety Outcomes at Week 96
• No treatment-emergent INSTI or NRTI mutations in
either arm
• Safety and tolerability profile was similar between
both arms
• Dolutegravir + 3TC versus dolutegravir + F/TDF
– Confirmed virologic withdrawals: <1% in both arms
– Significantly smaller changes in renal markers
– Significantly less severe change in bone markers (serum
bone-specific phosphatase, serum osteocalcin, serum
procollagen-1 N-terminal propeptide, serum type 1
collagen C-telopeptide)
• 96-week data support the use of dolutegravir + 3TC
as a potential option for initial treatment in select
patients
Cahn P, et al. J Int AIDS Soc. 2019;22(suppl 5):103. Abstract WEAB0404LB.
Safety Outcomes at Week 96
Dolutegravir
+ 3TC
(n=716)
Dolutegravir
+ F/TDF
(n=717)
Discontinuations due to
adverse events (%)
3 3
Adverse events (%)
Serious
Drug-related
Most common
Diarrhea
Headache
Nasopharyngitis
9
20
12
11
10
9
25
13
12
16
Change in renal markers
GFR-cystatin C (mL/min)
Creatinine (µmol/L)
GFR-creatinine (mL/min)
11*
12†
-15*
9
15
-18
*P<0.001 and †P<0.005 versus dolutegravir + F/TDF.
Underwood M, CROI 2019, Abs. 490
Time to HIV RNA < 40 c/mL with target not detected (Kaplan-Meier )
All participants
DTG + 3TC (N = 716)
DTG + TDF/FTC (N = 717)
0 4 8 1216 24 36 48 60 72
0
0.2
0.4
0.6
0.8
1.0 77 %
73 %
Weeks
Baseline HIV RNA < 100 000 c/mL
0 4 8 1216 24 36 48 60 72
0
0.2
0.4
0.6
0.8
1.080 %
79 %
Weeks
(N = 576)
(N = 564)
Baseline HIV RNA > 100 000 c/mL
0 4 8 1216 24 36 48 60 72
0
0.2
0.4
0.6
0.8
1.0
64 %
52 %
Weeks
(N = 140)
(N = 153)
GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line
TANGO Study: Dolutegravir/3TC inTreatment-Experienced Patients on Stable TAF-Based ART
van Wyk J, et al. J Int AIDS Soc. 2019;22(suppl 5):102-103. Abstract WEAB0403LB.
Phase 3
Open-labelTreatment-experiencedStable TAF-based ART
(HIV RNA <50 copies/mL)No HBVNo prior virologic failure or
NRTI or INSTI resistance
Randomization1:1
Continue TAF-Based ART(n=372)
Switch to Dolutegravir/3TC(n=369)
Week 0 48 96 144
Primary EndpointVirologic Failure (ITT)
(4% non-inferiority margin)Virologic failure: includes changing background therapy component,
discontinued due to lack of efficacy, or HIV RNA ≥50 copies/mL by week 48.Baseline demographics:
Male: 92%.Age: 39-40 years.Black: 15%.CD4 count:
Mean: 682-720 cells/µL.<350 cells/µL: 9%.
Duration of ART: 34 months.3rd ART class:
INSTI (79%), NNRTI (13%), boosted PI (8%).
TANGO Study:Treatment Outcomes With Dolutegravir/3TC at Week 48
• Switching to dolutegravir/3TC was non-inferior to
continuing TAF-based regimen
– Virologic failure
– HIV RNA <50 copies/mL
• No emergent resistance after switching to
dolutegravir/3TC
• Both treatment arms were well tolerated (switching
to dolutegravir/3TC versus continuing TAF-based
regimen)
– Discontinuations due to drug-related adverse events:
2% versus <1%
– Any serious adverse events: 6% versus 4%
(none were treatment related)
– Weight increase: 0.8 kg in both arms
van Wyk J, et al. J Int AIDS Soc. 2019;22(suppl 5):102-103. Abstract WEAB0403LB.
Pati
en
ts (
%)
Virologic Outcomes at Week 48
0
20
40
60
80
100
HIV RNA≥50 Copies/mL
<1% <1%
7%
93% 93%
7%
HIV RNA<50 Copies/mL
No VirologicData
Switch to DTG/3TC (n=369) Continue TAF-based regimen (n=372)
Difference (%):-0.3 (-1.2, 0.7)
Can we use dual therapy in all naive?Some questions remain
• Rapid start?
• Transmitted M184V?
• Women with childbearing potential?
• Opportunistic infection/TB?
• HIV-1 RNA level and CD4+ cell count?
• HIV-1 RNA > 500,000 copies/mL?
• CD4+ cell count < 200 cells/mm3?
• Hepatitis B coinfection?
• 3TC as sole agent with anti-HBV activity associated with considerable risk of HBV antiviral resistance
DHHS ART. October 2018.
Trial Design, Enrollment, and Outcomes.
Emu B et al. N Engl J Med 2018;379:645-654
N Engl J Med 2018; 379:645-654
BRIGHTE: Fostemsavir in Heavily Treatment–Experienced Adults With Multidrug Resistant HIV▪ Wk 96 analysis of randomized, double-blind phase III trial in heavily treatment–experienced adults
experiencing failure of current ART with confirmed HIV-1 RNA ≥ 400 c/mL
‒ At BL: median HIV-1 RNA, 4.6 log10 c/mL; median CD4+ cell count, 80 cells/mm3; AIDS history, 86%
Slide credit: clinicaloptions.com
Randomized Cohort1-2 remaining ARV classes
(≥ 1 fully active§approved agent/class), cannot construct viable regimen with
remaining agents(n = 272)
*Blinded. †Day 8 adjusted by Day 1. ‡Open-label. §No evidence of resistance; patient eligible for, tolerant of, willing to receive the ARV. ║Measured from start of open-label tx. Study conducted until another option, rollover study, or approved ARV available.
Primary EndpointMean Δ in HIV-1 RNA,†
log10 c/mL (95% CI)
-0.79 (-0.88 to -0.70)
-0.17 (-0.33 to -0.01)
Day 9
FTR 600 mg BID + Failing Regimen*
(n = 203)
Placebo + Failing Regimen*
(n = 69)
FTR 600 mg BID + OBT‡
FTR 600 mg BID + OBT‡
Treatment ∆: -0.63
Nonrandomized CohortNo remaining ARV classes and no
fully active§ approved agents(n = 99)
FTR 600 mg BID + OBT‡ (investigational agents allowed)
Day 1
Lataillade. IAS 2019. Abstr MOAB0102. Pialoux. IAS 2018. Abstr THPEB045.
Day 8 Wk 96‖
BRIGHTE: ITT-E Virologic Response Through Wk 96
Lataillade. IAS 2019. Abstr MOAB0102. Reproduced with permission.
Randomized Cohort (n = 272)
Nonrandomized Cohort (n = 99)
HIV
-1 R
NA
< 4
0 c
op
ies/
mL
(%)
*Snapshot analysis excluded baseline data. 1 patient had BL HIV-1 RNA < 40 copies/mL.
100
80
60
40
20
0
Baseline* Wk 24 Wk 48 Wk 72 Wk 96
53 54 5360
37 38 35 37
Outcome at Wk 96, n (%)Randomized
Cohort(n = 272)
Nonrandomized Cohort(n = 99)
HIV-1 RNA < 40 copies/mL 163 (60) 37 (37)
HIV-1 RNA ≥ 40 copies/mL▪ Data in window not below
threshold▪ D/c for lack of efficacy▪ D/c for other reason while
not below threshold▪ Change in ART*
81 (30)33 (12)10 (4)17 (6)21 (8)
43 (43)15 (15)
3 (3)6 (6)
19 (19)
No virologic data▪ D/c due to AE or death▪ D/c for other reasons▪ Missing data during
window
28 (10)15 (6)8 (3)5 (2)
19 (19)14 (14)
4 (4)1 (1)
▪ Mean change from BL to Wk 96 in CD4+ count, cells/mm3: randomized cohort, 205; nonrandomized cohort, 119
▪ In the randomized cohort, mean CD4+/CD8+ cell ratio increased from BL (0.2) to Wk 96 (0.443)Slide credit: clinicaloptions.com
BRIGHTE: Safety Through Wk 96
Slide credit: clinicaloptions.comLataillade. IAS 2019. Abstr MOAB0102.
Cumulative Safety Outcomes Through Wk 96, n (%)
Randomized Cohort(n = 272)*
Nonrandomized Cohort(n = 99)
All Treated Patients(N = 371)
Any event 249 (92) 98 (99) 347 (94)
▪ Any grade 2-4 AE 216 (79) 87 (88) 303 (82)
▪ Drug-related grade 2-4 AEs 57 (21) 22 (22) 79 (21)
▪ Any grade 3/4 AE 78 (29) 49 (49) 127 (34)
▪ Any serious AE 92 (34) 48 (48) 140 (38)
▪ Drug-related serious AE 9 (3) 3 (3) 12 (3)
▪ Any AE leading to d/c 14 (5) 12 (12) 26 (7)
▪ Any CDC class C event 23 (8) 15 (15) 38 (10)
▪ Death 12 (4) 17 (17) 29 (8)†
*Includes patients initially randomized to placebo. Data are from initiation of open-label fostemsavir.†AIDS-related events or acute infections, n = 18 (1 case of IRIS considered treatment-related); occurring after study d/c, n = 5.
In summary
▪ It has been a busy year of new drug approvals
▪ First line therapy “for most patients with HIV” is clear (caveats: women of childbearing potential, weight gain issues). Are two drugs an option?
▪ New drugs and new formulations continue to be developed
▪ We will have better options in the future for the MDR patient
▪ The future is intermittent therapy (cabotegravir, ED, bNAbs, Capsid antagonists…)