Simplified regimens: Pros and...
Transcript of Simplified regimens: Pros and...
Simplified regimens: Pros and Cons
Pedro Cahn
Rio de Janeiro, 2018
Treatment Strategies: A long way……
MonotherapyDual therapy
Triple therapy
Mega HAART
STIs
Simplification
Long Acting/Extended Release Regimens
Non daily regimens
PLHIV are aware their treatments have long-term effects
AE, adverse event; PLHIV, people living with HIV.1. Marcotullio S, et al. EACS 2017, poster PE25/9.
Man by Bluetip Design, clock by Three Six Five, dizzy by Gan Khoon Lay, fewer pills by Alex Arseneau, chemical reaction by Maxim Basinski, pills by Daniel DeLorenzo, food by Gregor Cresnar, capsule by Chameleon Design; all from the Noun Project.
0 50 100 150 200 250 300
Reduces long-term effects of HIV medicine on my body
Longer lasting so I can take treatment less often (e.g. monthly injection administered by a doctor/nurse)
Fewer side effects
Can take less HIV medicine and get the same effect
Does not cause a problem with medication I currently take for other illnesses
Fewer pills each day
No food restrictions or requirements
Smaller pill sizes
Weight, %
25.0
21.4
19.3
13.8
9.6
4.7
4.5
1.5
100
• 73% of participants (n = 1,111) sometimes worried about the long-term effects of their HIV medication1
• Reduction of long-term AEs and longer treatment intervals were viewed as more important potential medication improvements than reduction of side effects and pill burden1
Score (100 = average importance)
PLHIV are interested in new antiretroviral approaches, including longer-acting formulations
141
154
6638
514 3
3858
2
13
5
18
0
20
40
60
80
100
120
140
Not at allinterested
Somewhatinterested
Very interested
Res
po
nd
ents
(%
)
How interested would you be in switching to a new treatment that involves…
Two small plastic implants in forearm every 6 months
Two shots in clinic EOM
Single pill QW
EOM, every other month; PLHIV, people living with HIV; QW, every week.Osterman J, et al. CROI 2018, poster 503.
Survey n = 263
HAART: Is it about number of drugs or aboutpotency and safety?
✓ To reduce ARV exposure making treatment safer without sacrificing virologic control
✓ To reduce pill burden/improved patient adherence and quality of life
✓ To reduce drug-drug interactions
✓To reduce cost
✓Potential for longer-term success
✓Downstream options with “spared” class in case of first-regimen failure
Reducing drug burden in HAART: Why would you do that?
✓ Reduced potency?
✓ Less forgivness for missing doses?
✓Reduced penetration in sanctuaries?
✓ More frequent viral load monitoring?
✓Less durability?
✓ Loss of TDF lipid-lowering effect
✓ Contraindicated in HBV coinfection (3TC-based DT)
Reducing drug burden in HAART: Potential disavantages
Dual Therapy: not always good
• LPV/r - EFV• ATV/r - EFV• LPV/r - NVP
Good virological response, but increased rateof side effects
• ATV 300 mg BID + RAL (SPARTAN)• MVC QD + DRV/RTV (MODERN)• DRV/r + RAL (ACTG 5262)• DRV/r + RAL (NEAT 001)*• ATV/r + RAL (HARNESS – switch)• MARAVIROC+ bPI (MARCH -Switch)
* Strata high pVL and/or low CD4
Dual Therapy: Potential Boosted PI Regimens for Initial/Maintenance Therapy
Study Treatment Setting N Regimen Results
NEAT001 Initial 805 DRV/RTV + RALSimilar efficacy as DRV/RTV + FTC/TDF; poor efficacy in pts with high HIV-1 RNA, low CD4+ cell counts
GARDEL Initial 426 LPV/RTV + 3TC Similar efficacy as LPV/RTV + 2 NRTIs
MODERN Initial 813 DRV/RTV + MVC Inferior efficacy vs DRV/RTV + FTC/TDF
SPARTAN Initial 94 ATV + RALSimilar virologic suppression, higher VF and hyperbilirubinemia rates vs ATV/RTV + FTC/TDF
OLE Switch 250 LPV/RTV + 3TC Similar efficacy as continued standard ART
KITE Switch 60 LPV/RTV + RAL Small study; encouraging efficacy
SALT Switch 286 ATV/RTV + 3TC Similar efficacy as ATV/RTV + 2 NRTIs
ATLAS-M Switch 266 ATV/RTV + 3TC Improved efficacy vs ATV/RTV + 2 NRTIs
DUAL-GESIDA Switch 257 DRV/RTV + 3TC Similar efficacy as DRV/RTV + 2 NRTIs
Slide credit: clinicaloptions.comModified from Eron J and Sax P
7 randomised trials of PI/r + RAL versus PI/r + 2NRTIsHIV RNA <50 copies/mL (switch = failure endpoint)
Overall, in 7 randomised trials of 1266 patients, PI/r + raltegravir showed HIV RNA suppressionrates 10% lower than PI/r + 2NRTIs (p=0.008).
However there was evidence for heterogeneity between the trials (p=0.03).
Favours 3-drug
treatment
Favours 2-drug
treatment
Courtesy Andrew Hill
Lamivudine
• Once daily NRTI
• Very well tolerated– Almost no side effects reported
• No drug-drug interactions
• Generic, low cost
• Low genetic barrier, selects M184V or I
• Residual antiviral activity even after selecting the mutation
• Enhances antiviral activity of TDF and ZDV
88.3% 90.3%
83.7%84.4%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
BSL W4 W8 W12 W24 W36 W48 W96DT TT
GARDEL: Viral load <50 copies/mL at weeks 48 and 96 (ITTe)
Week 48(p= 0.171, difference +4.6%
[CI95%: -2.2% to +11.8%])
Week 96(p= 0.165, difference % [CI95%: -2.3%; to 14.1 %])
Pat
ien
ts w
ith
HIV
-1 R
NA
<5
0 c
op
ies/
mL
(%)[1
]
GARDEL: Viral load <50 copies/mL at weeks 48 and 96 (ITTe), baseline VL
> 100,000 copies/mL
87.2%90.7%
77.9%80.7%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
BSL W4 W8 W12 W24 W36 W48 W96
DT TT
Pat
ien
ts W
ith
HIV
-1 R
NA
<
50
co
pie
s/m
L(%
)[1]
W48(p=0.145, difference +9.3% [CI95%: -2.8% to +21.5%])
W96(p=0.163, difference % [CI95%: -3.8% ; 23.7 %])
OLE: Main endpoints
Difference (95% CI)0.05% (-5.3% to + 5.1%)
Difference (95% CI)0.3% (- 8.5 to + 8.3%)
Difference (95% CI)-0.25% (- 8.2 to + 7.6%)
Protocol defined VF: 2 consecutive VL>= 50 copies/ml; VF or any blip: any detectable VL >= 50 copies/ml
97.3% 97.3%
87.3% 87.6%89.8% 90.1%
Protocol defined VF Any blip Protocol defined VF or any blip
Atlas-M: ATV/r + 3TC non-inferior to
ATV/r + 2 N(t)RTI-s
DUAL-GESIDA Switch study: DRV/RTV + 3TC Dual ART Noninferior to Triple ART at Wk 48
• No resistance detected for 2 pts with resistance data in dual arm
• AE rates similar between arms
• D/c for AEs: 0.8% dual vs 1.6% triple ART (P = .55)
Pulido F, et al. HIV Glasgow 2016. Abstract O331.
Pts With 1,
2, or 3
Blips,* %
Dual
ART
Triple
ART
P
Value
1 8.9 13.2 .31
2 4.5 2.6 .46
3 0.9 0 .31
*Defined as transitory HIV-1 RNA ≥ 50
copies/mL in pts with HIV-RNA < 50
copies/mL at Wk 48.
Pts
(%
)
Wk 48 difference: -3.8%
(95% CI: -11.0% to 3.4%)
Dual ART
Triple ART
Virologic
Success
Virologic
Nonresponse
No Virologic
Data at Wk 48
100
80
60
40
20
0
8993
3 28 6
• Stable regimen: DRV/r + TDF/FTC or ABC/3TC ≥ 2 months
• VL < 50 c/mL > 6 months• HBs Ag (-)
ANDES: FDC of DRV/RTV+3TC was non-inferior to SOC DRV/RTV+TDF/3TC at 48 weeks
0
20
40
60
80
100
ITT snapshot(n=145)
ITT snapshot,baseline VL
>100,000copies/mL (n=35)
Observed cases(n=140)
Total 3DR 2DR
∆-1.5%
(95% CI, -0.9; 3.9%)∆-1.4%
(95% CI, -17.2; 14.4)
∆-1.0%
(95% CI, -7.5; 5.6)
Proportion of patients with
plasma HIV-1 RNA < 50 copies/mL
Primary outcome: VL<50
copies/mL at Week 48
n=
136
n=
66
n=
70
n=
32
n=
12
n=
20n=
136
n=
66
n=
70
Pati
ents
, %
Figueroa M, et al. 25th CROI; Boston, MA; March 4-7, 2018. Abst. 489.
Dual Therapy: Potential InSTI-Based Regimens for Initial/Maintenance Therapy
Regimen Treatment Setting Studies
DTG + 3TCInitial
▪ PADDLE (open-label phase IV)▪ ACTG A5353 (phase II)▪ GEMINI 1/2 (randomized phase III)
Maintenance ▪ ASPIRE (randomized phase III)
DTG + RPV Maintenance ▪ SWORD 1/2* (randomized phase III)
DTG + DRV/RTV Maintenance ▪ DUALIS (randomized phase III)
DTG + ATV/RTV Maintenance ▪ DOLATAV (phase II)
DTG + MVC Maintenance ▪ HP-00056162 (single-arm phase III)
RAL + ETR Maintenance ▪ ETRARAL
#W96 SCR BSL DAY 4 DAY 7 W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 W.48 W 96
1 5.584 10.909 383 101 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
2 8.887 10.233 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
3 67.335151.56
9 1.565 1.178 97 53 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
4 99.291148.37
0 3.303 432 178 55 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
5 34.362 20.544 1.292 570 107 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
6 16.024 14.499 1.634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
7 37.604 18.597 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
8 25.071 24.368 1.377Not
done 105 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
9 14.707 10.832 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 SAE
10 10.679 7.978 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 <50
11 50.089273.67
6 68.129 3.880 784 290 288 147 < 50 < 50 < 50 < 50 < 5070/<50
*
12 13.508 64.103 3.296 135 351 84 67 < 50 < 50 < 50 < 50 < 50 < 50 < 50
13 28.093 33.829 26.343 539 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 5014 15.348 15.151 791 198 < 50 61 64 < 50 < 50 < 50 < 50 < 50 < 50 < 50
15 23.185 23.500 4.217 192 < 50 < 50 < 50Not
done < 50 < 50 < 50 < 50 < 50 < 50
16 11.377 3.910 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
17 39.100 25.828 1.970 460 52 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
18 60.771 73.069 2.174 692 156 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50
19 82.803106.32
0 2.902 897 168 76 < 50 < 50 < 50 < 50 < 50 PDVF
20 5.190 7.368 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 <50
Virologic Outcome at Wk 24, n (%)
[Primary endpoint]
Baseline HIV-1 RNA, copies/mL
Total(N = 120)> 100,000
(n = 37)≤ 100,000
(n = 83)
Success (pVL<50
copies/mL)33 (89) 75 (90) 108 (90)
Nonsuccess 3 (8) 2 (2) 5 (4)
No data 1 (3) 6 (7) 7 (6)
Taiwo: CID 2018,
n = 3 with PDVF; n = 1 with emergent M184V and R263RK
ITT-e: 90% < 50 copies/mL at W 48 & 96 Observed data: 95% <50 copies/mLn=1 with PDVF; No mutations detected
Cahn: JIAS 2017
ITT-e: 90% < 50 copies/mL at W 24
a−10% noninferiority margin for individual studies.
GEMINI-1 and -2 Phase III Study Design
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
DTG + 3TC (N=716)
Day
1
Screening
(28 d)
Identically designed, randomized, double-blind, parallel-group,
multicenter, noninferiority studies
DTG + TDF/FTC (N=717)
DTG + 3TC
Week
48
Primary endpoint
at Week 48:
participants with
HIV-1 RNA <50 c/mL
(ITT-E snapshot)a
Double-blind
phase
Open-label
phase
Continuation
phase
CountriesArgentina Australia Belgium
Canada France Germany
Italy Republic of Korea Mexico
Netherlands Peru Poland
Portugal Romania Russian Federation
South Africa Spain Switzerland
Taiwan United Kingdom United States
Week
144
Week
24
Week
96
• ART-naive adults
• VL 1000-500,000 c/mL
1:1
Eligibility criteria• ≤10 days of prior ART
• No evidence of pre-existing viral resistance
based on presence of any major resistance-
associated mutation
• No HBV infection or need for HCV therapy
Baseline stratification factors: plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL) CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3).
GEMINI 1 & 2: Snapshot Analysis by Visit (Pooled)
Cahn et al. AIDS 2018; Amsterdam, the Netherlands.-Abstr TUAB0106LB.
<1
72
87 89
88
93
90 91
0
7085 89
9093
91 93
-20
0
20
40
60
80
100
-4 0 4 8 12 16 20 24 28 32 36 40 44 48
HIV
-1 R
NA
<5
0 c
/mL
%
Study visit
DTG + 3TC (N=716) DTG + TDF/FTC (N=717)
DTG + TDF/FTC DTG + 3TC
-10 -8 -6 -4 -2 0 2 4 6 8 10
-4.4 1.1
-1.7
Adjusted treatment difference (95% CI)a
Percentage-point difference
Pooled analyses supports noninferiority
of DTG + 3TC versus DTG + TDF/FTC
with respect to snapshot in the ITT-E
population (<50 c/mL) at Week 48
-3.9
-1.3
-1.2
DTG + 3TC non-inferior to DTG + TDF/FTC at 48 weeks
Pooled Snapshot Outcomes at Week 48: ITT-E and Per Protocol Populations
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1
RNA (≤100,000 c/mL vs >100,000 c/mL), CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3), and study (GEMINI-1 vs GEMINI-2). bPP, per protocol: population consisted of participants in the ITT-E population except for significant protocol violators, which could
potentially affect efficacy outcomes as determined by the medical monitor prior to database lock.
Virologic outcome Adjusted treatment difference (95% CI)a
DTG + TDF/FTC DTG + 3TC
-10 -8 -6 -4 -2 0 2 4 6 8 10
-4.4 1.1
-1.7
Percentage-point difference
DTG + 3TC is non-inferior to DTG +
TDF/FTC with respect to proportion
<50 c/mL at Week 48 (snapshot, ITT-E
population) in both studies
-1.3
-3.9 1.2
ITT-E
PP
91
36
93
25
93
25
94
14
0
20
40
60
80
100
Virologicsuccess
Virologicnonresponse
No virologicdata
HIV
-1 R
NA
<50
c/m
L, %
ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717)
PPb DTG + 3TC (N=694) DTG + TDF/FTC (N=693)
Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA: Snapshot Analysis
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
91 9394 9392
79
9093
0
20
40
60
80
100
HIV
-1 R
NA
<5
0 c
/mL
, %
Snapshot Analysis
• 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL
DTG + 3TC DTG + TDF/FTC
>100,000≤100,000 >200 ≤200
Baseline HIV-1
RNA, c/mL
Baseline CD4+
cell count, cell/mm3
526
576
531
564
129
140
138
153
605
653
618
662
50
67
51
55
Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and CD4+ Cell Count: Snapshot Analysis
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
91 9394 9392
79
9093
0
20
40
60
80
100
HIV
-1 R
NA
<5
0 c
/mL
, %
Snapshot Analysis
• 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL
DTG + 3TC DTG + TDF/FTC
>100,000≤100,000 >200 ≤200
Baseline HIV-1
RNA, c/mL
Baseline CD4+
cell count, cell/mm3
526
576
531
564
129
140
138
153
605
653
618
662
50
63
51
55
98 9898 9899 9897 100
0
20
40
60
80
100
Wit
ho
ut
TR
DF,
%
TRDF Analysis
566
576
>100,000≤100,000 >200 ≤200
Baseline HIV-1
RNA, c/mL
Baseline CD4+
cell count, cell/mm3
Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and CD4+
Cell Count: Snapshot and TRDF Analysis
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
91 9394 9392
79
9093
0
20
40
60
80
100
HIV
-1 R
NA
<5
0 c
/mL
, %
Snapshot Analysis
• 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL
• Treatment related discontinuation = failure (TRDF) population accounts for confirmed virologic withdrawal (CVW), withdrawal
due to lack of efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined stopping criteria
• DTG + 3TC CD4 <200 Snapshot non-response (n=13): 1 CVW, 3 with VL >50 in window (2 of 3 re-suppressed), 2 discontinued due to AE (TB,
Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART (incarcerated)
• DTG + TDF/FTC < 200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 VL >50 (re-suppressed)
DTG + 3TC DTG + TDF/FTC
>100,000≤100,000 >200 ≤200
Baseline HIV-1
RNA, c/mL
Baseline CD4+
cell count, cell/mm3
553
564
138
140
149
153
642
653
647
662
62
63
55
55
526
576
531
564
129
140
138
153
605
653
618
662
50
63
51
55
Confirmed Virologic Withdrawals Through Week 48: ITT-E Population
GEMINI 1 GEMINI 2 Pooled
Variable, n (%)
DTG + 3TC
(N=356)
DTG +
TDF/FTC
(N=358)
DTG + 3TC
(N=360)
DTG +
TDF/FTC
(N=359)
DTG + 3TC
(N=716)
DTG +
TDF/FTC
(N=717)
CVW 4 (1) 2 (<1) 2 (<1) 2 (<1) 6 (<1) 4 (<1)
Treatment-emergent
resistance
0 0 0 0 0 0
• Low rates of virologic withdrawals were observed at Week 48
Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.
• No treatment-emergent INSTI mutations or NRTI mutations were
observed among participants who met CVW (confirmed virologic
failure) criteria
Confirmed virologic withdrawal criteria is defined as a second and consecutive HIV-1 RNA value meeting virologic non-response or rebound. Virologic non-response is defined as either a decrease in
plasma HIV-1 RNA of less than 1 log10 c/mL by Week 12 with subsequent confirmation unless plasma HIV-1 RNA is <200 c/mL, or confirmed plasma HIV-1 RNA levels ≥200 c/mL on or after Week 24.
Virologic rebound is defined as confirmed rebound in plasma HIV-1 RNA levels to ≥200 c/mL after prior confirmed suppression to <200 c/mL.
.
Virologic outcomes Adjusted treatment difference (95% CI)a
Percentage-point difference
DTG + RPV is non-inferior to CAR with
respect to snapshot in the ITT-E population
(<50 c/mL) at Week 48
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 15 4
CAR DTG + RPV
-8 -6 -4 -2 0 2 4 6 8
-3.0 2.5
-0.2FDA label: For pts who have been virologicallysuppressed for ≥ 6 months and no history of treatment failure and no resistance to DTG or RPV
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
DTG + Rilpivirine is non-inferior to continuingongoing ART in virologically suppressed
patients
• Cabotegravir: InSTIs formulated as PO tablet and for long-acting IM injection
• LATTE-2: phase IIb study in which pts randomized to CAB 400 mg + RPV 600 mg IM Q4W, CAB 600 mg + RPV 900 mg IM Q8W, or CAB 30 mg + ABC/3TC 600/300 mg PO QD after induction/virologic suppression with oral CAB + ABC/3TC (N = 309)
Dual therapy with Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance ART: 96-Wk Results (LATTE-2)
Eron J, et al. IAS 2017. Abstract MOAX0205LB. Margolis DA, et al. Lancet. 2017;[Epub ahead of print].
*HIV-1 RNA < 50 copies/mL.
Few drug-related AEs. At 96 wks, ~ 30% pts receiving IM injection experienced ISR 99% of ISRs mild/moderate /
AEs leading to withdrawal: Pooled Q4W/Q8W IM arms, 4%. PO arm, 2%
~ 88% of pts receiving IM CAB very satisfied to continue present treatment vs 43% receiving PO CAB
VirologicSuccess*
9487
84
40 2 2
13 14
VirologicNon-response
No VirologicData
Pts
, Wk
96
(%
)
100
80
60
40
20
0
IM CAB + RPV Q4W (n = 115)IM CAB + RPV Q8W (n = 115)PO CAB + ABC/3TC (n = 56)
10.0%
-12 -9 -6 -3 0 3 6 9 12 15
20.5-0.6
Q8W IM
Treatment Differences (95% CI)
3.0%
-12 -9 -6 -3 0 3 6 9 12 15
14.4-8.4
Q4W IM
InjectableRilpivirinerequires
cold chain
0
25
50
75
100
DTG+3TC
% <
50
We
ek
40
• 110 Subjects
• No Hx of failure, No Hep B
• 8 week Switch to 2NRTI+DTG
• 40 Weeks FU on DTG/3TC
• 1 x VF (no resistance)
• 4 SAE• Suicidal ideation
• CK elevation post exercise
• Grade 4 Depression
• Acute Hep C
ANRS 167 LamiDol Study DTG/3TC Maintenance
Joly V, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 458.
Dolutegravir Plus Lamivudine for Maintenance of Suppression (ASPIRE)
Taiwo B, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PE8/5.
Virologic Outcomes at Week 48 (FDA Snapshot)
90,9%
2,3%6,8%
88,9%
2,2%8,9%
0,0%
10,0%
20,0%
30,0%
40,0%
50,0%
60,0%
70,0%
80,0%
90,0%
100,0%
HIV RNA <50 cpm HIV RNA >50 cpm No Virologic Data
DTG+3TC Cont ART
N 40 40 1 1 3 4
On Study 44 45 44 45 44 45
HIV-1 infected adults virologically suppressed on any 3-drug ARV regimen.
CD4 nadir > 200 cells/mm3No history
of virologic failure
Dolutegravir Plus Lamivudine for Maintenance of Suppression (ASPIRE)
No resistanceTaiwo B, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PE8/5.
Viral Blips
Treatment Arm Week 0 Week 4 Week 12 Week 24 Week 36 Week 48
HIV RNA (cpm) DTG + 3TC <20 <20 191/<20 <20 <20 <20
AdherenceLast missed dose
(Participant Report)1-2 wks ago
HIV RNA (cpm) Cont ART <20 <20 351/<20 <20 <20 <20
Adherence Last missed dose 1-3 mo
HIV RNA (cpm) Cont ART <20 <20 <20 <20 <20 179/30
Adherence Last missed dose 1-2 wks Past week
HIV RNA (cpm) Cont ART<20
682/<20 <20 <20 <20 <20
Adherence Last missed dose >3 mo
HIV RNA (cpm) Cont ART 2268 50 31 <20 <20 <20
Adherence Last missed dose >3 mo
What’s New? DTG/RPV FDA Approved for Maintenance Therapy
▪ Once-daily single-tablet regimen of DTG and RPV
– First 2-drug STR FDA approved for use as a complete regimen in the US
Slide credit: clinicaloptions.comDTG/RPV [package insert]. November 2017.
Key US Label Information
Indication▪ For pts who have been virologically suppressed for ≥ 6 mos
▪ Pts must have no history of treatment failure and no resistance to DTG or RPV
Administration
requirements▪ Must be taken with a meal
Key DDIs
▪ Separate dose of DTG/RPV and antacid/polyvalent cation–containing
medications
▪ Avoid PPIs (eg, omeprazole, pantoprazole), dexamethasone
Dose
adjustments
▪ None required for pts with mild/moderate renal impairment; in pts with CrCl
< 30 mL/min, increase monitoring for AEs
SWORD Studies: Snapshot Outcomes at Week 48 (Pooled)
Virologic outcomes Adjusted treatment difference (95% CI)a
Percentage-point difference
DTG + RPV is non-inferior to CAR with
respect to snapshot in the ITT-E population
(<50 c/mL) at Week 48
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 15 4
CAR DTG + RPV
-8 -6 -4 -2 0 2 4 6 8
-3.0 2.5
-0.2
aAdjusted for age and baseline 3rd agent.
Switching to DTG+RPV had a neutral effect on lipids, while significantly
improving bone turnover biomarkers
Llibre et al. CROI 2017; Seattle, WA. Abstract 2421.
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
SWORD Study: RPV/DTG: Bone markers
a. P values are from an ANCOVA model adjusting for original ART third-agent class, age, sex, body mass index category, smoking status, and baseline biomarker level.
23,8 24,0
53,0 55,3
15,9 16,219,023,1
45,6
54,7
12,917,1
0
15
30
45
60
Me
an s
eru
m
con
cen
trat
ion
, µ
g/L
Bone-specific
alkaline phosphatase
P<0.001a
Osteocalcin
P<0.001a
Procollagen 1
N-terminal propeptide
P<0.001a
Type 1 collagen
C-telopeptide
P<0.001a
0,66 0,69
0,49
0,63
0,00
0,18
0,35
0,53
0,70
0,88
Me
an s
eru
m
con
cen
trat
ion
, µ
g/L
Baseline Week 48 Baseline Week 48
CARDTG + RPV
Bone Turnover Biomarkers: Change From Baseline to Week 48
Orkin C, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. BPD1/5.
IAS 2017, Abstr THPEB 542
95% pVL < 50 copies/ml(1pt with etravirine resistance
• Cabotegravir: INSTI formulated as PO tablet and for long-acting IM injection
• LATTE-2: phase IIb study in which pts randomized to CAB 400 mg + RPV 600 mg IM Q4W, CAB 600 mg + RPV 900 mg IM Q8W, or CAB 30 mg + ABC/3TC 600/300 mg PO QD after induction/virologic suppression with oral CAB + ABC/3TC (N = 309)
LATTE-2: 96-Wk Results for Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance ART
Eron J, et al. IAS 2017. Abstract MOAX0205LB. Margolis DA, et al. Lancet. 2017;[Epub ahead of print].
*HIV-1 RNA < 50 copies/mL.
Few drug-related AEs. At 96 wks, ~ 30% pts receiving IM injection experienced ISR 99% of ISRs mild/moderate /
AEs leading to withdrawal: Pooled Q4W/Q8W IM arms, 4%. PO arm, 2%
~ 88% of pts receiving IM CAB very satisfied to continue present treatment vs 43% receiving PO CAB
Virologic
Success*
9487 84
40 2 2
13 14
Virologic
Non-
response
No
Virologic
Data
Pts
, W
k 9
6 (
%)
100
80
60
40
20
0
IM CAB + RPV Q4W (n = 115)
IM CAB + RPV Q8W (n = 115)
PO CAB + ABC/3TC (n = 56)
10.0%
-12 -9 -6 -3 0 3 6 9 12 15
20.5-0.6
Q8W IM
Treatment Differences (95% CI)
3.0%
-12 -9 -6 -3 0 3 6 9 12 15
14.4-8.4
Q4W IM
SELECT (A5273): second-line LPV/r + RAL in resource-limited countries
ACTG, AIDS Clinical Trial Groups; NRTI, nucleoside reverse transcriptase inhibitor
*Three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania,
Thailand, and Zimbabwe
Adapted from La Rosa et al. Lancet HIV. 2016 June ; 3(6): e247–e258.
SELECT (A5273): Randomised, open-label, phase 3, non-inferiority study at 15 ACTG research sites in 9 resource-limited countries*
What about InSTIs monotherapy?
• Only tested with DTG
• Mixed results in regards to efficacy
• High rate of resistance selection in the integrase gene in case of VF
• Resistance mutations selected: 92Q; 97A; 118R; 140S; 148 K, R, H; 155H; 230R; 263K, among others 1,2.
• DTG monotherapy should not be used for initial therapy or as a simplification strategy
2 . Blanco Jl et al:Curr Opin Infect Dis 2018
1. Wensing A et al: Topics in Antiviral Medicine (IAS-USA), 2017
DTG Monotherapy after treatment for Primary HIV Infection
• Patients treated during primary HIV infection (within 180 days of acquiring HIV) may have lower reservoir compared to those treated with chronic infection
• Could these patients maintain suppression on DTG monotherapy?• Study design:
• Primary endpoint: Virological response, defined as proportion of patients without virological failure at week 48, or before
N=103
Braun D, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0102B3.
Continuation of cART
Randomization2:1
DTG vs cART
Week 12
Week 12
Week 24
Week 24
Week 36 Week 48
Week 48Week 36Week 2 Week 4 Week 8 Week 16 Week 20
Monotherapy Dolutegravir
DTG Monotherapy after treatment for Primary HIV Infection: Results
• Comparable slight decay of HIV-1 reservoir (cellular HIV DNA) and absence of CSF virus in both groups
• One patient with virologic failure in DTG mono arm (protocol violation - enrolled with chronic HIV and higher HIV reservoir)
• Results suggest that simplification strategies may require stratification for appropriate candidates
Braun D, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0102.
100% 98,50%100% 100%
0%
20%
40%
60%
80%
100%
Pre-protocol Intention-to-treat
Pro
po
rtio
n o
f p
atie
nts
w
ith
vir
olo
gica
lre
spo
nse
[%
]
DTG monotherapyStandard of care therapy (cART)
67/67 32/32 67/68 33/33
Moncay study: switch to DTG monotherapy vs remain on ABC/3TC/DTG
Stable, efficient and well-tolerated DTG/ABC/3TC regimen*
Randomization 1:1(n=158)
DTG 50 mg QD (n=78)
Baseline Week 24 Week 48
DTG/ABC/3TC single tablet QD (n=80)
Screening**
Non-inferiority margin: 12%
* HIV-RNA (pVL) <50 c/mL for >12 months, no AIDS event (except past tuberculosis), nadir CD4 >100/mm3, no mutation to or failure on any INSTI-based regimen** pVL < local threshold (20 to 40 c/mL)
Hocqueloux L, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0103.
Open-label, randomized, controlled trial in 9 reference centers in France
Primary endpoint: proportion with pVL <50 c/mL in ITT, mITT and PP analyses (with a pre-planned non-inferiority margin of 12%);virologic failure (VF) = 2 consecutive pVL >50 c/mL; ITT, missing or switch = failure (M=F)
Secondary endpoints: changes in CD4 count, CD4:CD8 ratio, eGFR, lipids; HIV-DNA and genital sub-studies
96
1 3
94
3 4
0
20
40
60
80
100
Virologicsuccess
Virologicnon-response
No virologicdata
HIV
-1 R
NA
<5
0 c
/mL,
% DTG/ABC/3TC (n=80)
DTG (n=78)
Moncay study: 24 week results
Virologic outcomes (ITT) W24 treatment difference
Virologic success (%) difference
DTG was non-inferior to DTG/ABC/3TC at Week 24 with respect to snapshot in the ITT, mITT and PP population
Hocqueloux L, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0103.
-15 -10 -5 0 5 10 15
TC/DTG arm Risk difference (95% CI)95%
ConfidenceInterval
7/80 (96.3%) [-5 to 10.8]
7/78 (98.7%) [-4.5 to 8.1]
6/77 (98.7%) [-4.5 to 8.8]
DTG better DTG/ABC/3TC better
0
25
50
75
100
0 12 24 36 48
VF-
Fre
e S
urv
ival
(%
)
Time in Weeks
DTG/ABG/3TC arm
DTG armP=0.005 (Log-Rank Test)
Moncay study : extended follow up
• Excess virologic failures in DTG monotherapy arm led to DSMBrecommendation to stop the study
• 2/7 study subjects with virologic failure developed resistance to DTG (1 pt with S147G, N155H, another with R263K)
Hocqueloux L, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0103.
Similar results in DOMONO trial of DTG maintenance monotherapy:
Noninferior virologic suppression atWk 24, unacceptable VF afterward[3
What Data Are Needed to Change the Treatment Paradigm of HIV Therapy?
• Well-designed noninferiority trials vs triple-combination therapy– With a clear definition of treatment success and
failure
• Sufficient number of patients in new strategies• Robust risk assessment (for both the individual
patient and for public health concerns) • Criteria for identification of patients who are
likely to succeed/benefit from new strategies• Assessment of response durability on
experimental arm
Dual therapy: Remaining questions
• How would dual therapy perform in the context of PW, TB co-treatment, Hepatitis B, adolescents, and children?
• What are the pragmatic issues related to having patients on both three-drug and two-drug regimens?
• - How do we balance the financial impact of dual therapy with treatment durability in low-resource settings?
The future of dual therapy
• Reverse –transcriptase inhibition seems to be crucial for DT
• The anchor drug must have high genetic barrier
• DT can be safely prescribed in virologically suppressed patients, with no previous failure
• So far, DT is only considered as alternative option in naive pts
• If the results of ongoing trials are sustainable, a new paradigm for first line treatment and early switch might be generated.
• In the era of Test & Treat, DT could be a first line preferred strategy, with minimal monitoring requirements, leaving future treatment options in case of failure, as only M184V (or NNRTI) mutations would be expected to emerge.
• This could be an important contribution to the 90/90/90 targets.
Thank you for your attention