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What is the magic number? Clinical perspective
Andrea De Luca Dipartimento Biotecnologie Mediche
Università di Siena UOC Malattie Infettive
AOU Senese
Outline
• Regimens with reduced number of drugs
• Use in clinical practice
• Evidence from studies
– First-line
– Switch in virosuppressed individuals
59
329
413
719
0
100
200
300
400
500
600
700
800
2006-2008 2009-2011 20012-2013 2014-2016
Number of mono PI or dual PI therapies used according to calendar period of treatment
Jan 2017 Report
Jan 2017 Report
0,7%
5,2% 5,6%
8,4%
1,7%
3,2%
4,7%
2,1%
0%
1%
2%
3%
4%
5%
6%
7%
8%
9%
2006-2008 2009-2011 2012-2013 2014-2016
Proportion of mono/dual PI therapies according to calendar period of starting
Dual
Mono
Monotherapies?
• PI/r monotherapies – Inferior to triple, but very rare resistance selection
– Reinduction + 2NA works
– DRV/r more solid data: inferior with nadir CD4<200
• DTG monotherapy: catastrophe – Inferior and resistance selection
– How to throw away the most precious ARV class
Pt BL 3rd agent
(with F/TDF)
Timing
of Failure
HIV-RNA at
Failure (c/ml)
Integrase Sequence
at Failure
1 RPV W4 71,600 No RAMs
2 EFV W12 678 Not successful
3 RPV W30 3,510 No RAMs
4 RPV W30 1,570 S230R
5 DTG W36 1,440 Not successful
6 RPV W48 4,990 No RAMs
7 NVP W60 3,470 R263K
8 NVP W72 4,180 N155H
• Study prematurely discontinuation due to predefined stopping rule (emergent INSTI resistance)
DTG monotherapy efficacy was inferior by Week 48
DTG as Maintenance Monotherapy For HIV-1
6
Characteristics of Virologic Failures on DTG Monotherapy*
* All CD4 T-cell nadir ≥210 cellsmm3 and >95% adherence (according to clinician)
DOMONO is a multicenter randomised non-inferiority trial comparing
96 patients on DTG 50mg QD monotherapy vs cART
DOMONO
Wijting I, et al. CROI 2017. Seattle, WA. Poster #451LB
Viral Suppression at W48 On-Treatment Analysis
92% 98%
0
20
40
60
80
100
DTG Mono(N=96)
cART(N=152)
p=0.03
% H
IV-R
NA
<2
00
c/m
l
Outcomes in Patients Failing DTG Monotherapy after Switch
7 Blanco JL, et al. CROI 2017. Seattle, WA. Oral #42
International, multi-cohort, retrospective study characterizing resistance of subjects who switched to DTG monotherapy 50 mg QD (n=122)
Virologic Failures (%)
Monotherapy
(N=122)
Bi / Tri-therapy
(N=1,082)
9% (n=11) 6% (n=64)
• 11 subjects in monotherapy arm experienced virologic failures • 45% - first INSTI • 64% - ≥95% adherence • 72% - ≥3 years virologic
suppressed prior to switch
High rate of genotypic resistance selection after DTG monotherapy failure
Summary of available studies: InSTI resistance in 15 of 20
Monotherapy Bi / Tri-therapy
82%
0% 9/11
Resistance Selection (%)
• Median time from VF until genotypic resistance testing: 5 weeks (IQR: 3-14)
• DTG monotherapy VFs led to different mutation pathways (92Q,118R,148X and 155H)
REDOMO: Pathways of Resistance in Subjects Failing DTG Monotherapy
Why mono?
• Less toxic than dual?
– With 3TC/FTC no/minimal added toxicity
• Less resistance selection (with PI/r)
– More resistance selection to 3TC/FTC or other classes?
Dual therapies in naives
Study regimen control n Efficacy outcome
Benefits/Harms
Gardel LPV/r+3TC LPV/r+2NA 416 Non-inferior Less AE
PADDLE DTG+3TC no 20 20/20 <50 cps at 12m
ACTG A5353
DTG+3TC no 120 Includes VL>100K
GEMINI DTG+3TC DTG+TVD 700
Modern DRV/r+MVC QD
DRV/r+TVD 804 Inferior Bone
NEAT001 DRV/r+RAL
DRV/r+TVD 805 Non-inferior, inferior with CD4<200 or VL>100K
Bone, eGFR/InSTI-R selection
Dual RCT in treatment naive: unsuccessful studies
• DRV/r + MVC inferior to 2NA + DRV/r
– Well powered
• ATV/r + MVC inferior to 2NA + ATV/r
– Small, limited power
• ATV/r + RAL inferior to ATV/r + 2NA
– More jaundice, InSTI resistance selection
Maintainance dual ART: completed RCT Study Previous
regimen Study regimen
control n Main Efficacy outcome
Benefits/Harms
ATLAS-M ATV/r+2NA ATV/r+3TC ATV/r+2NA
266 Non-inferior (superior)
eGFR, bone, AE/lipids
SALT Any triple ATV/r+3TC ATV/r+2NA
273 Non-inferior Less AE/lipids
OLE LPV/r+2NA LPV/r+3TC LPV/r+2NA
250 Non-inferior No/lipids
DUAL DRV/r+2NA DRV/r+3TC DRV/r+2NA
257 Non-inferior
PROBE
PI/r+2NA DRV/r+RPV continue 60 Non-Inferior Bone, immune activation/lipids
Multineka LPV/r+2NA LPV/r+NVP LPV/r+2NA
67 Non-inferior
GUSTA Any triple DRV/r+MVC qd cont 133 Inferior AE, Bone, AP
MARCH PI/r+2NA PI/r+MVC bid 2NRTI+MVC bid
cont 395 PI/r+MVC inferior
Maintainance dual ART: completed RCT
Study Previous regimen
Study regimen
control n Main Efficacy outcome
Benefits/Harms
LATTE CAB+2NA CAB+RPV EFV+2NA 243 Non-inferior
SWORD Any triple DTG+RPV continue 1024 Non-inferior Improved bone turnover markers
SPARE LPV+TVD DRV/r+RAL LPV+TVD 58 eGFR urinary b2M improved
Harness Any triple ATV/r+RAL ATV/r+2NA
109 Inferior
KITE 2NA+X LPV/r+RAL continue 60 Non-inferior no/lipids
Dual therapies as maintenance: uncontrolled/observational studies
• Pilot studies:
– DTG+3TC (DOLULAM)
– DTG+3TC pilot, controlled (ANRS LAMIDOL)
• Observational studies – DRV/r + 3TC
– DRV/r + ETR
– DRV/r + RAL
– LPV/r + RAL
– ATV + RAL
– DRV/r+DTG
– RAL + NVP
– RAL + ETR
– DTG + 3TC
– DTG + RPV
– Mixed
ATV/r+3TC: ATLAS-M 96 weeks
Patients free of treatment failure (ITT S=F)
96 weeks free of TF:
Dual therapy 77.4% (95% CI 70.3-84.5)
Triple therapy 65.4% (95% CI 57.3-73.5)
+12%
Favors Triple Favors Dual
-12% +12%
+1.2%
0
+22.8%
Treatment Difference (95% CI)
Efficacy endpoint analyses at 96 weeks
12%
(95% CI 1.2; 22.8)
12.8%
(95% CI 1.9; 23.7)
13.5%
(95% CI 2.7; 24.3) 14.3%
(95% CI 3.4; 25.2)
Causes of treatment failure
ATV/rit+3TC
N=133
ATV/rit+2 NRTIs
N=133 p
Any cause 30 (22.6) 46 (34.6) 0.030
Virological Failure 2 (1.5)* 9 (6.8) 0.060
Adverse events
(potentially treatment-related)i 7 (5.3) 11 (8.3) 0.329
Adverse events
(not treatment related)ii 3 (2.3) 5 (3.8) 0.722
Withdrawal of consent 6 (4.5) 9 (6.8) 0.425
Loss to follow up 10 (7.5) 7 (5.3) 0.452
Other 2 (1.5) 5 (3.8) 0.447
Notes:
i. DT: skin rash (w4), renal colic (w26 and w49), biliary colic (w60), pancreatitis (w62), hypertriglyceridemia (w72), creatinine increase (w75); TT: creatinine increase (w3 and w7), osteopenia (w16), renal colic (w24, w60, w63, w77, w80), drug nephropathy (w43), proteinuria (w84), hyperbilirubinemia (w84).
ii. DT: sudden death (w10 and w78, suspect cardiac events), thyroid carcinoma (w24); TT: spinal disc herniation (w3), pneumonia (w12), abdominal cancer (w48), creatinine increase (w60), lung cancer (w72).
Values are expressed as n (%) * One VF at baseline, before treatment simplification.
Virological failures
ID Visit HIV-RNA
(cp/mL)
CD4
(cells/µL) Comments
Dual therapy arm
40 BL 1.452 904 VF at BL, before treatment simplification. GRT: no resistance.
164 W12 64 606 VF with low VL (64 and 248 cp/mL); after re-intensification with TDF,
subsequent VL 83 cp/mL then <40 cp/mL. GRT: no resistance.
Triple therapy arm
85 W24 16.667 435 No subsequent data, lost to follow-up.
247 W24 7.684 895 Treatment change to elvitegravir/cobicistat/ tenofovir/emtricitabine
with virological suppression. GRT PR: 58E.
137 W36 2.797 626 VL <50 cp/mL without treatment change. GRT: no resistance.
168 W36 1.854 597 VL <50 cp/mL without treatment change. GRT: no resistance.
23 W48 26.720 305 VL <50 cp/mL without treatment change. GRT: no resistance.
107 W48 99.999 349 Subsequently lost to follow up. GRT PR: no resistance.
174 W60 22.572 341 Subsequent follow up not available. GRT PR: no resistance, RT:
101Q, 138A, 179I (intermediate R to ETR, RPV).
230 w84 55 1.137
VF with low VL (55 and 78 cp/mL); treatment change to
abacavir/lamivudine+dolutegravir with virological suppression. GRT
PR: no resistance RT:215S.
78 w96 109 674 No subsequent data, lost to follow-up.
Proportion with clinical adverse events
ATV/rit + 3TC
(N=133) ATV/rit + 2NRTI
(N=133)
Central Nervous System 7 7
Gastrointestinal 15 16
Skin and soft tissues 8 1
Urinary tract 7 15
Respiratory tract 21 14
Infections 34 36
Neoplasm 5 3
Bone 8 14
Other 33 42
Patients with at least one AE 51/133 (38.3%) 52/133 (39.1%)
• Overall clinical AE:
138 in DT
148 in TT
• 8 renal colics
2 in DT
6 in TT
* Values are expressed as n (%).
Evolution of renal function
Bone outcomes at 96 weeks
0.69
2.53
1.77
-2.95
-1.48
0.57
Lumbar Spine Total Hip Femoral neck
Changes in BMD at 96W (%) Dual arm TT arm
p= 0.02
p= ns p= ns
-15.62
-50.91
-23.3
14.7
-2,64
-45.2
-14.1
31.83
PTH Vitamin D Osteocalcin FAO
Bone turnover biomarkers (%)
Dual arm TT arm
p= ns p= ns
p= ns
p= ns
n=73
DT arm: 41
TT arm: 32
DUAL-GESIDA 8014: Dual DRV/RTV + 3TC
vs Triple DRV/RTV + FTC/TDF or ABC/3TC
Randomized, multicenter, open-label, phase IV noninferiority trial
– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (ITT-e, FDA snapshot analysis)
Pulido F, et al. HIV Glasgow 2016. Abstract O331.
Pts with HIV-1 RNA
< 50 copies/mL for
> 6 mos; on triple
therapy* ≥ 2 mos;
HBsAg negative
(N = 257)
Switch to DRV/RTV + 3TC QD
(n = 129)
Continue Previous Triple Therapy*
(n = 128)
Wk 48 Primary endpoint
*Previous triple therapy regimens: DRV/RTV + FTC/TDF or DRV/RTV + ABC/3TC.
Stratified by baseline NRTI
23
Sensitivity analysis
DUAL-GESIDA 8014-RIS EST-45 study: 48 weeks results Observed data: excluding non-virological reasons for failure.
89% 87% 89%
97% 93%
89% 93%
98%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
ITT-e (snapshot) ITT (snapshot) Per-Protocol (snapshot) Observed data
Pro
po
rtio
n o
fpat
ien
ts w
ith
HIV
vir
al
load
<5
0 c
op
ies/
mL
(%)
DUAL TRIPLE
3.4 5.7
3.9 2.4
-11 -10.2 -10.7
-5.8 -3.8
-2.2 -3.4
-1.7
-12
0
12
Dif
fere
nce
(%
) IC
95%
24
Continuous viral load suppression
DUAL-GESIDA 8014-RIS EST-45 study: 48 weeks results
Including all patients who completed 48 weeks of treatment and had viral loads measurements in all visits.
82.5% 82.9%
0%
20%
40%
60%
80%
100%
DUAL TRIPLE
DUAL
TRIPLE
Only patients who had HIV-RNA < 50 copies at week 48. Blip defined as a transitory viral load ≥ 50 copies/mL
Blips
8.9% 4.5%
0.9%
13.2%
2.6% 0.0% 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Single Double Triple
p=0.31 p=0.46 p=0.31
p =0.94
HIV- viral load less than 50 copies/mL in all the visits (%)
25
Resistance testing (attempted in all rebounds with viral loads > 400 HIV-RNA copies/mL)
GROUP Week
HIV-RNA ≥ 50 c/mL week 48
(SNAPSHOT)
1st viral load
2nd viral load
Genotype Mutations
DUAL Baselin
e Yes 80 800 Yes None
DUAL 24 Yes 988 259 Failed
DUAL 32 No 6,805 165 Yes None
TRIPLE 24 No 427 <20 Failed
TRIPLE 24 No 447,557 5,621 Yes V10I, W71T,
D76W
DUAL-GESIDA 8014-RIS EST-45 study: 48 weeks results
DTG + 3TC as Maintenance Therapy
26
ANRS 167 LAMIDOL
Outcomes
• INDUCTION:
• 95% (104/110) eligible for dual therapy†
• MAINTENANCE:
• 97% (101/104) remained suppressed
• 1 virologic failure: W4 with VL 84 c/mL
• 1 therapeutic failure: W40 with blip VL 59 c/mL
• 1 lost to follow-up: W32
Switching to DTG+3TC maintained virologic suppression
in patients without history of virologic failure
INDUCTION DTG + 2 NRTIs (n=110)
MAINTENANCE DTG + 3TC (n=104)
Baseline Week 8 Week 48 & 56
* Subjects were on current ART for a median of 4 years (range: 0.5 - 11.3) † 6 subjects were ineligible for Phase 2: 3 with detectable VL and 3 with AEs (1 serious AE of suicide ideation)†
Inclusion Criteria
• Current: 2 NRTIs + either
NNRTI, PI, or INSTI
• Maximum of 2 previous ART
modifications (simplification or one tolerability switch)
• Suppressed <50 c/ml for ≥2 years with no blips in previous 6 months*
• Wild type virus • CD4 nadir >200 cells/mm3
• >18 years • Normal labs & HBsAg negative
Joly V, et al. CROI 2017. Seattle, WA. Poster #458
3TC+PI/r dual therapies as simplification strategies: resistance at failure 4 randomized controlled studies:
2 ATV/r+3TC (ATLAS, SALT), 96W
1 LPV/r+3TC (OLE)
1 DRV/r+3TC (DUET)
NO EMERGING RESISTANCE MUTATIONS AT FAILURE (1 case of M184V in the 3-drug arm of SALT)
In observational studies: 1 case of resistance to ATV (V32I-M46L-I50L-V82A) (no M184V)
Role of previous M184V in 3TC + PI/r or DTG see Gagliardini R at this meeting
3TC + ATV/r vs DRV/r in clinical practice: see Di Carlo D #51 at this meeting
27
Study Design and Baseline Characteristics*
Identically designed, randomised, multicenter, open-label, parallel-group, non-inferiority studies
28
VL <50 c/mL on INI, NNRTI or PI + 2 NRTIs Inclusion Criteria
—On stable CAR ≥6 months before screening
—1st or 2nd ART with no change in prior regimen
due to VF
—Confirmed HIV-1 RNA <50 c/mL during the 12
months before screening
—HBV negative
1:1
CAR (N=511)
DTG + RPV (N=513)
Screening Early Switch Phase
Day 1 Week 52
DTG + RPV (n=513) CAR (n=511)
Age, mean (SD)
≥50 years
43 (11.1)
29%
43 (10.2)
28%
Female 23% 21%
Race, non-white 18% 22%
CD4+ cell count, cells/mm3 (median)
≤500; >500
611
32%; 68%
638
29%; 71%
Baseline 3rd-agent class : PI; NNRTI; INI 26%; 54%; 20% 27%; 54%; 19%
Baseline TDF use 73% 70%
Duration of ART prior to Day 1, median, months 51 53
* Data pooled across SWORD-1 and SWORD-2. DTG, dolutegrevir; RPV, rilpivirine; CAR, combination antiretroviral therapy
SWORD 1 and 2: Switching to DTG+RPV vs Maintaining CAR
Llibre JM, et al. CROI 2017. Seattle, WA. Oral #44LB
Snapshot Outcomes at Week 48 (Pooled)
29
Virologic outcomes Adjusted treatment
difference (95% CI)*
0
20
40
60
80
100
Virologicsuccess
Virologicnon-response
No virologicdata
HIV
-1 R
NA
<50
c/m
L, %
DTG + RPV (n=513)
CAR (n=511)
95 95
<1 1 5 4
CAR DTG + RPV
-8 -6 -4 -2 0 2 4 6 8
-3.0 2.5
-0.2
*Adjusted for age and baseline 3rd agent.
SWORD 1 and 2: Switching to DTG+RPV vs Maintaining CAR
Percentage-point difference
Llibre JM, et al. CROI 2017. Seattle, WA. Oral #44LB
Snapshot Outcomes at Week 48 (Pooled)
30
Early Switch Phase*
DTG + RPV
n=513
n (%)
CAR
n=511
n (%)
Virologic success 486 (95) 485 (95)
Virologic non-response 3 (<1) 6 (1)
Data in window not <50 c/mL 0 2 (<1)
Discontinued for lack of efficacy 2 (<1) 2 (<1)
Discontinued while VL not <50 c/mL
Change in ART
1 (<1)
0
1 (<1)
1 (<1)
No virologic data 24 (5) 20 (4)
Discontinued due to AE or death1 17 (3) 3 (<1)
Discontinued for other reasons 7 (1) 16 (3)
Missing data during window but on study 0 1 (<1)
* Two deaths in the study, both unrelated to study drug. DTG+RPV Kaposi’s Sarcoma (N=1), CAR Lung cancer (N=1)
Llibre JM, et al. CROI 2017. Seattle, WA. Oral #44LB
SWORD 1 and 2: Switching to DTG+RPV vs Maintaining CAR
Switch From Suppressive ART to DTG + RPV: Safety Outcomes
AE rates generally similar between treatment arms through Wk 52
– Numerically higher rate of drug-related grade 1/2 AEs with switch: 17% vs 2%
– Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1%
No notable change in serum lipid values from baseline to Wk 48 in either treatment arm
Llibre JM, et al. CROI 2017. Abstract 44LB.
Bone-specific
alkaline
phosphatase
Osteocalcin Procollagen 1
N-terminal
propeptide
Bone Turnover Marker
DTG + RPV Baseline ART
0
20
60
40
80
Me
an
(µ
g/L
)
Baseline
Wk 48
15.9 12.9
100 Baseline
Wk 48
16.2 17.1 23.8
19.0 24.0 23.1
53.0 45.6
55.3 54.7
P < .001 P < .001
P < .001
Dual therapies: considerations
• Most solid evidence of efficacy in maintenance therapy – PI/r+3TC – DTG+RPV
• Caveat: PI/r tolerability? • Toxicity benefits of dual vs triple:
– Bone and renal, due to TDF discontinuation – Will TAF avoid the need of dual?
• Reduced costs – Not for all dual therapies
• DTG + 3TC future game changer? – Naive, maintainance – Beyond efficacy, tolerability and costs will still count
