DTG-Based Regimens Are Active
in INI-Naive Patients With a
History of NRTI Resistance
Jim Demarest,1 Mark Underwood,2 Marty St Clair,2
David Dorey,3 Steve Almond,3 Robert Cuffe,4
Dannae Brown,5 Garrett Nichols6
1ViiV
Healthcare, Global R&D, Research Triangle Park, NC, USA; 2GlaxoSmithKline,
Clinical Virology, Research Triangle Park, NC, USA; 3GlaxoSmithKline, Clinical Statistics,
Mississauga, Canada; 4ViiV Healthcare, Statistics, London, United Kingdom;
5ViiV Healthcare, Medical Affairs, Abbotsford, Australia; 6GlaxoSmithKline,
Infectious Disease R&D, Research Triangle Park, NC, USA
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Introduction
• Dolutegravir (DTG, Tivicay) has exhibited potent antiviral
efficacy in Phase 3 studies of more than 1800 integrase
inhibitor (INI)-naive patients1-4
• All subjects were screened for resistance
• Individuals with resistance were excluded from treatment naïve
studies
• Baseline resistance was used as inclusion criteria and to select
background regimens in SAILING
• Here we present post-hoc analyses of virologic failure by
background regimen and baseline resistance in SAILING
1. Raffi et al. Lancet. 2013;381:735-743. 2. Walmsley et al. N Engl J Med. 2013;369:1807-1818.
3. Clotet et al. Lancet. 2014;383:2222-2231. 4. Cahn et al. Lancet. 2013;382:700-708.
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Potent and Durable Efficacy in Treatment-Naive
Subjects Across the DTG Phase III Program
Study
SPRING-2 (Wk 96)1
SINGLE (Wk 96)2
FLAMINGO (Wk 48)3
Regimen
DTG +
2 NRTI
RAL +
2 NRTI
DTG +
ABC/3TC
EFV/TDF/FTC
DTG +
2 NRTI
DRV/r +
2 NRTI
<50 c/mL,a
n/N (%)
332/411
(81%)
314/411
(76%)
331/414
(80%)
302/419
(72%)
217/242
(90%)
200/242
(83%)
PDVF,b
n (%)
22 (5%)
29 (7%)
25 (6%)
25 (6%)
2 (<1%)
2 (<1%)
aFDA
Snapshot algorithm. bProtocol-defined virologic failure.
• DTG demonstrated statistical superiority in SINGLE and
FLAMINGO in a pre-specified analysis
• In DTG treated individuals:
• No treatment-emergent resistance through 96 weeks in SPRING-2 and
SINGLE
• No treatment-emergent resistance through 48 weeks in FLAMINGO
1. Raffi et al. Lancet Infect Dis. 2013;13:927-935. 2. Walmsley et al. CROI 2014, Boston, MA. Abstract 543.
3. Clotet et al. Lancet. 2014;383:2222-2231.
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
SAILING: DTG Superior to RAL in TreatmentExperienced, INI-Naive Adult Subjects
• HIV RNA ≥400 c/mL
• Resistant to ≥2 classes
of ARVs
• Background regimen =
1-2 agents, at least 1
fully active
DTG 50 mg QD plus
background regimen
(n=354)
Week 48
<50 c/mL
71%
P=0.03
RAL 400 mg BID plus
background regimen
(n=361)
64%
• Significantly less resistance at PDVF with DTG vs RAL at Wk 48
• Emergent genotypic/phenotypic resistance:
• INI: DTG (4/354, 1%) vs RAL (17/361, 5%) p=0.003
• Background: DTG (4/354, 1%) vs RAL (12/361, 3%)
Cahn et al. Lancet. 2013;382(9893):700-708.
Protocol-defined virologic failure (PDVF), defined as plasma HIV-1 RNA decrease <1 log10 c/mL (unless <400 c/mL by
week 16 or HIV-1 RNA ≥400 c/mL on or after week 24) or virological rebound (plasma HIV-1 RNA ≥400 c/mL after
confirmed HIV-1 RNA <400 c/mL or >1 log10 c/mL increase above any nadir of ≥400 c/mL); BR, background regimen.
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Response by DRV/r Use: Baseline Strata
(SAILING, Week 48 Analysis)
Virologic Response (<50 c/mL)
Responders/Total n, (%)
Baseline
Stratification
DTG
(n=354)
RAL
(n=361)
Difference
(95% CI)
DRV/r Use
No
143/214 (67%) 126/209 (60%) 6.5% (-2.6 to 15.7)
Yes, with primary
PI mutations
58/68 (85%)
50/75 (67%)
18.6% (5.0 to 32.2)
Yes, without
primary
PI mutations
50/72 (69%)
54/77 (70%)
-0.7% (-15.4 to 14.1)
Cahn et al. Lancet. 2013;382:700-708. Supplemental Appendix.
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Protocol-Defined Virologic Failure in Subjects by Type
of Background Regimen (SAILING, Week 48 Analysis)
DTG
n with PDVFa/N
(%)
RAL
n with PDVFa/N
(%)
21/354 (6)
45/361 (12)
0/32
7/32 (22)
PI-containing background regimens
18/300 (6)
36/305 (12)
Other background regimens
3/22 (14)
2/24 (8)
Overall
NRTI-only background regimens*
*All received 2 NRTI with exception of one subject on DTG (received only 1 NRTI)
a
Protocol-defined virologic failure (PDFV), defined as plasma HIV-1 RNA decrease <1 log10 c/mL (unless <400
c/mL by week 16 or HIV-1 RNA ≥400 c/mL on or after week 24) or virological rebound (plasma HIV-1 RNA
≥400 c/mL after confirmed HIV-1 RNA <400 c/mL or >1 log10 c/mL increase above any nadir of ≥400 c/mL).
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
No PDVF for DTG Subjects Receiving Only NRTIs
Regardless of Number of Active NRTIs
(SAILING, Week 48 Analysis)
DTG
n with PDVF/N
RAL
n with PDVF/N (%)
0/32
7/32 (22)
2 fully active NRTIsa
0/16
3/19
1 fully active NRTIs
0/12
4/13
0 fully active NRTIs
0/1
-
Missing phenotype
0/3
-
NRTI-only background regimens
a
Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if
upper and lower exist).
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
No PDVF for DTG Subjects with M184V Detected
and Receiving 3TC or FTC Plus a Second NRTI
(SAILING, Week 48 Analysis)
DTG
n with PDVF/N
RAL
n with PDVF/N
0/13
4/12
Fully active
0/10
4/12
Reduced susceptibility
0/1
NA
Missing phenotype
0/2
NA
0 TAMs
0/10
3/10
1 TAMs
NA
1/1
≥2 TAMs
0/3
0/1
M184V patients who received 3TC/FTC
plus a second NRTI
Activity of second NRTI by phenotypea
In presence/absence of TAMs
a
Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if
upper and lower exist). TAM, thymidine analogue mutation.
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Lower PDVF Incidence for DTG Subjects with TAMs
Than for Subjects on RAL (SAILING, Week 48 Analysis)
DTG
n with PDVF/N (%)
RAL
n with PDVF/N (%)
10/164 (6)
17/166 (10)
3/24
1/19
+ third agent (PI)
2/19
1/15
+ third agent (MVC)
0/1
0/2
+ third agent (NNRTI)
1/3
0/2
+ third agent (NRTI)
0/1
-
All patients with TAMs
TAMs + less than fully active 2nd
agent NRTI of ABC, TDF, AZT, or ddIa
NRTI = 3TC or FTC
NRTI = Other
0/1
-
-
-
aFully
active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if
upper and lower exist). TAM, thymidine analogue mutation.
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Lower PDVF Incidence for Subjects Receiving DTG + PI/r
Versus Those on RAL + PI/r (SAILING; Week 48 Analysis)
PI-containing background regimensa
1 fully active PI
DRV/rb
LPV/r
Other
0 fully active PI
Missing phenotype
DTG
RAL
n with PDVF/N (%)
n with PDVF/N (%)
18/300 (6)
18/289 (6)
36/305 (12)
32/295 (11)
6/130 (5)
6/93 (6)
6/66 (9)
12/145 (8)
9/90 (10)
11/60 (18)
0/7
0/4
3/8
1/2
a
Fully active based on phenotype as per Monogram Biosciences’ PhenoSense assay (using lower cut-off if
upper and lower exist).
b DRV also determined as fully active by genotype (Stanford): 6/102 (6%) vs 11/126 (9%).
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Conclusions
• Treatment-naive subjects
• No resistance detected to DTG or to the 2 NRTIs (ABC/3TC or
TDF/FTC) through 96-week (SPRING-2, SINGLE) or 48-week
(FLAMINGO) follow-up
• Treatment-experienced, INI-naive subjects (SAILING; 48 Week)
• No observed virologic failures in this limited set of subjects
receiving DTG + 2 NRTIs, even without full backbone activity
• Further studies with larger numbers of subjects and longer
follow-up are required to confirm these findings
• The resistance profile for DTG will be defined further by use in
clinical practice and additional clinical trials
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Acknowledgments
• Patients and their supporters
• DTG study investigators
• Study teams and colleagues at ViiV Healthcare and GSK
• These studies were sponsored by ViiV Healthcare
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Backup
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia
Resistance Testing in Phase III Studies of DTG
• Samples from baseline and PDVF detection were evaluated for resistance,
regardless of plasma HIV-1 RNA (Monogram Biosciences)
• No plasma was stored from confirmatory (unscheduled) visit
• VL at confirmatory visit tends to decrease with adherence counselling
Viral load
at PDVF:
SPRING-2
HIV RNA >50 c/mL
HIV RNA >400 c/mL*
PDVF
Detection
PDVF
Confirmation
PDVF
Detection
PDVF
Confirmation
DTG
22/22
22/22
6/22
1/22
RAL
29/29
29/29
4/29
5/29
* The assay for RT/PRO and IN is only validated for HIV RNA >400 c/ml
• Ongoing studies will store samples to allow future analysis
Demarest et al. IAC 2014; Melbourne, Australia. Abstract TUAB0104.
20th International AIDS Conference; July 20-25, 2014; Melbourne, Australia