ICAR 2016 INSTI in continuum of care: from engagement to retention in care
M. Zazzi ([email protected])
Siena

Personal fees and travel grants
 Janssen‐Cilag
 Merck Sharp and Dohme
 ViiV Healthcare

Research grants
 Gilead Sciences
 ViiV Healthcare
Reg #1
failure
Reg #2
failure
Reg #3
failure
Reg #?
Complex failure
Challenging salvage
Increasing resistance and exhaustion of treatment options
Reg #1
failure
Reg #2
failure
Reg #3
failure
Reg #?
Most potent & highest genetic barrier regimen FIRST
Complex failure
Challenging salvage
Salvage possible

Adherence  Tolerability
 Convenience, e.g. STR, limited drug‐drug interactions 
Potency  Rapid and strong VL decay
 Effective with difficult patients (high VL, low CD4)

Resistance  Limited transmitted resistance
 High genetic barrier
Adherence 
Adherence  Tolerability
 Convenience, e.g. STR, limited drug‐drug interactions 
Potency  Rapid and strong VL decay
 Effective with difficult patients (high VL, low CD4)

Resistance  Limited transmitted resistance
 High genetic barrier
144‐wk treatment discontinuation % due to adverse events
DTG, SINGLE
EVG, 102 & 103
RAL, STARTMRK
0
2
4
Not for head to head comparison 6
8

INSTI with most prolonged safety track record

BID, no STR currently available

Largest individual pK
variability
Rockstroh, JAIDS 2013
2.8%
4.1%
Adapted from Prinapori, Patient Prefer Adherence 2015
Study 102
Study 103
E/C/
F/TDF
EFV/
F/TDF
E/C/
F/TDF
ATV/r
F/TDF
(n=348)
(n=352)
(n=353)
(n=355)
HIV RNA <50 copies/mL (%)
84*
82
HIV RNA <50 copies/mL (%)
83*
82
CD4 gain (cells/mm3)
295
273
CD4 gain (cells/mm3)
256
261
Change in eGFR (mL/min)
-13.8
-0.8
Change in eGFR (mL/min)
-12.3
-9.5
25
21
19
17
15
1
31
21
20
15
16
14
4
6
Common adverse events (%)
Nausea
Abnormal dreams
Insomnia
Dizziness
Discontinuations due to
adverse events (%)
22
15
11
8
15
28
16
25
5
7
Common adverse events (%)
Diarrhea
Nausea
Upper respiratory infection
Headache
Fatigue
Ocular icterus
Discontinuations due to
adverse events (%)
E/C/F/TDF: elvitegravir/cobicistat/emtricitabine/tenofovir DF.
*Met non-inferiority margin: 12%.
Zolopa A, et al. JAIDS. 2013;63:96-100.
Rockstroh J, et al. JAIDS. 2013;62:483-486.
<1 to 3%
Cruciani, Patient Prefer Adherence 2015
Potency

Adherence  Tolerability
 Convenience, e.g. STR, limited drug‐drug interactions 
Potency  Rapid and strong VL decay
 Effective with difficult patients (high VL, low CD4)

Resistance  Limited transmitted resistance
 High genetic barrier
-1.7
-2
-2.03
-2.5
-1.99
-1.96
300mg BID
300mg BID
100mg BID
400mg BID + RTV
100mg BID
900mg BID
-1.5
50mg QD + RTV
-1
400mg BID
-0.5
50mg QD
Change from BL in HIV RNA (log10)
0
-0.52
-1.19
-1.42
-1.85
-2.46
-3
INTEGRASE INHIBITORS
1. Lalezari J. 5th IAS 2009, Cape Town, abstract TUAB105.
2. DeJesus E. J Acquir Immune Defic Syndr 2006 ; 43:1-5.
3. Markowitz et al. JAIDS Volume 43(5) 15 December 2006 pp 509-515.
4. Sankatsing et al. AIDS 2003, 17:2623–2627.
5. Kilby JM. AIDS Res Hum Retroviruses 2002; 18:685-694.
OTHER ANTIRETROVIRALS
6. Murphy RL. AIDS 2001;15:F1-F9.
7. Fätkenheuer G et al. Nat Med 2005 Nov; 11:1170-1172.
8. Eron JJ, N Engl J Med 1995, 333:1662-1669.
Courtesy of J. Gatell
Lennox, Lancet 2009
Study 102
Study 103
Kulkarni, CROI 2014
Walmsley, NEJM 2013
Molina, LID 2011
INSTI based therapy
VL
NNRTI or PI based therapy
Suppressed VL
Time
VL
Large mutant selection AUC
Suppressed VL
Time
VL
Limited mutant selection AUC
Suppressed VL
Time
VL
Does faster decay mean deeper suppression and/or lower probability of failure?
Suppressed VL
Time
VL rebound



Post hoc cross‐sectional analysis of subjects enrolled in the naive DTG phase III clinical trials, SPRING‐2, SINGLE, and FLAMINGO RVR and SVR were assessed at Weeks 4 and 96, respectively, based on HIV‐1 RNA <50 as determined by FDA Snapshot
Positive (PPV) and negative (NPV) predictive values were calculated;  PPV as the proportion of subjects suppressed at Week 4 who were also suppressed at Week 96,  NPV as the proportion of subjects not suppressed at Week 4 who were also not suppressed at Week 96
Quercia, EACS 2015

PPV and NPV of RVR4 in the DTG based regimens (DBR)
study population were 85%
(95% CI: 82%‐87%) and 29% (95% CI: 24%‐34%), respectively

The PPV of the DBR was numerically higher than for EFV or DRV/r plus 2 nucleosides and similar to that with RAL plus 2 nucleosides

The NPV with RAL was numerically higher than with DBR, reflecting that more DBR subjects without RVR4 ended with SVR96
Achieving VL suppression at week 4 is more predictive of VL suppression at week 96 with DTG than with EFV or DRV Quercia, EACS 2015
48‐wk response rate in patients with <100k and >100k VL
DTG, SINGLE
EVG, 101 & 104
RAL, STARTMRK
0
20
>100k
40
60
<100k
Not for head to head comparison 80
100
48‐wk response rate in patients with <200 and >200 CD4 cells
DTG, SINGLE
EVG, 101 & 104
RAL, STARTMRK
0
20
<200
40
60
>200
Not for head to head comparison 80
100
STARTMRK, week 48
Lennox, Lancet 2009
HIV RNA Subgroup
100
E/C/F/TAF
E/C/F/TDF
94%
91%
CD4 Subgroup
100
87%
89%
86%
89%
93%
91%
80
Patients (%)
Patients (%)
80
60
40
20
0
E/C/F/TAF
E/C/F/TDF
60
40
20
<100,000
(n=670|672)
>100,000
(n=196|195)
Baseline HIV RNA (copies/mL)
E/C/F: elvitegravir/cobicistat/emtricitabine.
TAF: tenofovir alafenamide.
Sax PE, et al. Lancet. 2015;385:2606-2615.
0
<200
(n=112|117)
>200
(n=753|750)
Baseline CD4 (cells/mm3)
HIV RNA Subgroup
100
Dolutegravir 50 mg + ABC/3TC qd
Efavirenz/FTC/TDF qd
90%*
83%
Dolutegravir 50 mg + ABC/3TC qd
Efavirenz/FTC/TDF qd
89%*
83%
76%
60
40
20
0
100
80
Patients (%)
Patients (%)
80
CD4 Subgroup
81%
79%
77%
60
40
20
<100,000
(n=280|288)
>100,000
(n=134|131)
Baseline HIV RNA (copies/mL)
*P=0.003.
Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
0
>200
(n=357|357)
<200
(n=57|62)
Baseline CD4 Count (cells/mm3)
Efficacy‐related discontinuations = failure (ERDF) analysis: only virologic failure or withdrawal due to lack of efficacy were counted as failure
 Pooled analysis of SPRING‐2, SINGLE and FLAMINGO

Granier, CROI 2015
Efficacy‐related discontinuations = failure (ERDF) analysis: only virologic failure or withdrawal due to lack of efficacy were counted as failure
 Pooled analysis of SPRING‐2, SINGLE and FLAMINGO

Granier, CROI 2015
The areas represent the population viral load (PVL, i.e. the sum of log VL from each patient) after first exposure (>= 180 days) to the specific drug class and the PVL after virological failure of the specific drug class
Scherrer, JID 2016
Resistance 
Adherence  Tolerability
 Convenience, e.g. STR, limited drug‐drug interactions 
Potency  Rapid and strong VL decay
 Effective with difficult patients (high VL, low CD4)

Resistance  Limited transmitted resistance
 High genetic barrier
Resistance
TDR
Hurt, AVT 2011
Monogram (Hurt, CID 2013)
ARCA (May 30, 2016)
50
45
40
35
30
% 25
20
15
10
5
0
2009 2010 2011 2012 2013 2104 2015 2016
Warning: it is expected but not verified that IN genotyping was requested in INI exposed patients


Analysis of 339 genotypic resistance test results determined to be from treatment‐naive HIV‐infected pts (from among 1060 total pts) March 2013 to June 2015 at 13 AIDS Healthcare Foundation sites
Overall TDR rate: 24.9%
 2013: 24.2%; 2014: 30.2%; 2015: 15.9%

No cases of transmitted INSTI resistance detected
 TDR rates: NNRTI 16.9%; NRTI 6.5%; PI 4.2%; INSTI 0%


Most frequent mutations: K103N/S 13.0%; L90M 2.7%; Y181C/I/V, M41L, M184V/I 2.1%
TDR prevalence increased with increasing pt age
Volpe, ICAAC 2015

Increased use of INSTI not paralleled by increased INSTI TDR
 Only one case in 1316 (0.1%) with T66I but the sample dates back to 2001
 No cases following clinical introduction of INSTI

Likewise, minor INSTI resistance mutations (e.g. 74M, E92G, T97A, E138K, R263K) also do not increase
Scherrer, JID 2016
10
9
% of cases with INI resistance mutations in drug‐naïve patients (ARCA IN sequences obtained after 2008, N = 398)
8
7
6
5
4
3
2
1
0
66AIK
74M
92Q
97A
118R
121Y
138AK
140AS 143CHR 147G 148HKR 155H
157Q
263K
Non‐polymorphic mutations are red boxed, i.e. there is no case of INI TDR





Anecdotal case in one patient with primary HIV infection 2 years after receiving a second kidney transplant
E157K as a natural polymorphism
Both RAL and DTG fail without selection of additional IN mutations (DRV then suppresses VL)
The E157Q recombinant has stronger strand transfer activity which confers 9‐fold resistance to DTG in a biochemical assay (RAL and EVG not tested)
Warrants confirmation in cell based assays
Danion, JAC 2015

The E157Q clone (NL4‐3 backbone) is not resistant to DTG/RAL
 The effect shown by Danion 2015 must have been strain specific


E157Q increases DTG resistance by R263K
No cases of selection of E157Q and R263K have been reported in the clinic
Anstett, JAC 2016
Resistance
Genetic barrier 
Comparable rates of DRM with EVG and EFV

Minimal NRTI resistance and no PI resistance with ATV/r
Kulkarni, CROI 2014
Comparable incidence of drug resistance in RAL and EVG first‐line treatment studies
(INDIRECT COMPARISON)
Rockstroh, JAIDS 2013
CAUTION: different definitions of virological failure, different proportions of advanced patients, different procedures to collect samples at failure.
Llibre, AIDS Rev 2015
1067 PATIENTS
40 VIROLOGICAL FAILURES 0 RESISTANCE CASES
Raffi F, et al. Lancet 2013;381:735–43
Walmsley S, et al. N Engl J Med 2013;369:1807–18
5Clotet B, et al. Lancet 2014, 383,:2191-2193
Failure without resistance & protection of backbone therapy
Failure with resistance
•2NRTI + Boosted PI
•2NRTI + DTG
•2NRTI + NNRTI
•2NRTI + INI (not DTG)
DTG
RAL
EVG
Relative binding
1.0
0.8
0.6
0.4
INI
koff (s )
Dissociation t1/2 (h)
DTG
2.7 x 10‐6
71
RAL
22 x 10‐6
8.8
EVG
71 x 10‐6
2.7
0.2
0.0
0
10
20
30
40
50
‐1
60
Time (h)
DTG dissociated more slowly from a WT IN‐DNA complex at 37°C compared with RAL and EVG
DTG dissociation was eight times slower than RAL and 26 times slower than EVG
Koff , dissociation rate; t1/2h, half‐life in hours
Adapted from Hightower KE, et al. Antimicrob Agents Chemother 2011;5:4552–9
Hightower, AAC 2011
Study
IN mutation (wk)
DTG FC
RAL FC
EVG FC
Kobayashi 2011
S153FY (12)
2.5
1.3
2.3
Quashie 2012
R263K (20)
G118R (20)
M50I (37)
H51Y (37)
2‐11
10‐20
1.9
1.2
1.1‐1.8
8.2‐20
0.5
1.2
3.3‐21.4
3.1
5.4
2
Seki 2015
E92Q (8)
G193E (8)
1.6
1.3
3.5
1.3
19
1.3



FC derived from different studies on HIV clones
Different selection strategies applied INI comparative studies:  Time to selection longer for DTG than RAL/EVG
 No resistance selection at higher starting dose with DTG as opposed to rapid selection with RAL or EVG

Impairment of viral functions
 Lower integration rate: G118R (Quashie 2013), R263K (Quashie 2012)
 Lower IN‐DNA association: R263K (Quashie 2012)

Inefficient compensation of defects by secondary mutations 





H51Y on R263K (Mesplede 2013)
M50I on R263K (Wares 2014)
E138K on R263K (Mesplede 2014)
E157Q on R263K, partial compensation (Anstett, JAC 2016)
L74M, E92Q, T97A, E157Q, and G163R on N155H/R263K (Anstett, JV 2015)
Additive impairment of replicative capacity with other IN and RT mutations
 R263K plus E92Q, Y143R, Q148R, N155H (Anstett, JV 2015)
 R263K plus M184IV (Singhroy 2015)
 R263K/H51Y plus K65R, L74V, K103N, E138K, M184IV (Pham 2016)

Greatly diminished replication capacity on the part of viruses that might become resistant to DTG when the drug is used in initial therapy 
No compensatory mutation that might restore viral replication fitness to HIV in the aftermath of the appearance of a single drug resistance mutation has yet to be observed

DTG might be able to be used in HIV prevention
and eradication strategies
Wainberg, BMC Med 2013
Oliveira, AIDS 2014
K65R
L74V
K103N
E138K
M184I M184V
0
‐2
‐4
+R263K
‐6
+H51Y +R263K2
‐8
‐10
‐12
Effects of R263K and H51Y/R263K in combination with different RTI substitutions on viral infectivity in TZM‐bl
reporter cells. Expressed luciferase levels were measured at 48 h.p.i. and normalized to relative p24 levels.
Adapted from Pham, Retrovirology 2016
Resistance
Genetic barrier and first‐line LDR
Pt #
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
HIV‐1 RNA, copies/mL
Day 10
Wk 2
Wk 3
Screen
BL
Day 2
Day 4
Day 7
Wk 4
Wk 6
Wk 8
Wk 12
Wk 24
5584
10,909
3701
383
101
71
< 50
< 50
< 50
< 50
< 50
< 50
< 50
8887
10,233
5671
318
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
67,335
151,569
37,604
1565
1178
266
97
53
< 50
< 50
< 50
< 50
< 50
99,291
148,370
11,797
3303
432
179
178
55
< 50
< 50
< 50
< 50
< 50
34,362
20,544
4680
1292
570
168
107
< 50
< 50
< 50
< 50
< 50
< 50
16,024
14,499
3754
1634
162
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
37,604
18,597
2948
819
61
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
25,071
24,368
6264
1377
Not done
268
105
< 50
< 50
< 50
< 50
< 50
< 50
14,707
10,832
Not done
516
202
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
10,679
7978
5671
318
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
50,089
273,676
160,974
68,129
3880
2247
784
290
288
147
< 50
< 50
< 50
13,508
64,103
3496
3296
135
351
351
84
67
< 50
< 50
< 50
< 50
28,093
33,829
37,350
26,343
539
268
61
< 50
< 50
< 50
< 50
< 50
< 50
15,348
15,151
3994
791
198
98
< 50
61
64
< 50
< 50
< 50
< 50
23,185
23,500
15,830
4217
192
69
< 50
< 50
< 50
Not done
< 50
< 50
< 50
11,377
3910
370
97
143
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
39,100
25,828
11,879
1970
460
147
52
< 50
< 50
< 50
< 50
< 50
< 50
60,771
73,069
31,170
2174
692
358
156
< 50
< 50
< 50
< 50
< 50
< 50
82,803
106,320
35,517
2902
897
352
168
76
< 50
< 50
< 50
< 50
< 50
5190
7368
3433
147
56
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
Patients with >100,000 baseline VL
Figueroa, EACS 2015
Resistance
Genetic barrier and switch to LDR 
33 Virally suppressed patients switched to DTG 50mg QD for adverse effects, comorbidities, interactions, archived resistance

At 24 weeks, the therapeutic efficacy of dolutegravir monotherapy was 97% (95% CI 83%‐100%) (ITT non‐
completer=failure)

One patient had low‐level virological failure after 4 weeks (88 copies/mL, and confirmed as 155 copies/mL)


Previous VF to a RAL‐containing regimen without IN‐GRT by the time of this VF HIV DNA genotypic resistance tests detected no integrase mutations at 4 weeks, but 118R was detected in 7% of the integrated‐DNA in PMBC at 24 weeks
There was a positive impact (interactions, improvement of GI symptoms, lipids, Framigham
score) on several of the reasons that motivated switching to DTG monotherapy
Rojas, JAC 2016
Katlama, EACS 2015
Katlama, EACS 2015
Katlama, EACS 2015



Rojas EACS 2015: 32/33 pts maintain VL <50 at week 24
Katlama EACS 2015: 25/28 pts maintain VL <50 at week 24
All 4 pts with virologic failure had history of INSTI use before switch; 1 pt
had previous raltegravir failure but no INSTI resistance
HIV‐1 RNA at VF, c/mL
155[1]
469[2]
291[2]
INSTI Resistance by Timepoint (Detection Source)
Day 0
Wk 4
Wk 12/13
Wk 24
‐
None (DNA)
‐
118R (DNA)* R: DTG EVG RAL?
L74I (DNA)
‐
L74I, E92Q (RNA)
R: EVG RAL
‐
None (DNA)
‐
‐
155H (RNA)
R: EVG RAL
2220[2]
None (DNA)
*118R detected in plasma at week 36
None (RNA)
None (DNA)
E138K / G140A, Q148R (RNA)
R: DTG EVG RAL
1. Rojas J, et al. EACS 2015. Abstract 1108.
2. Katlama C, et al. EACS 2015. Abstract 714.

The same Spanish patient reported by Rojas (EACS 2015, JAC 2016) plus another patient from Canada
 Both pretreated with INSTI (one RAL, one EVG)
 Both with the GGA variant at codon 118 favoring development of AGA → R
 G188R selection within 2 months following switch to DTG monotherapy
G118R favors selection of drug resistance to all the three INSTI
 Genetic polymorphism and monotherapy leading to DTG failure

Brenner, JAC 2016
Brenner, JAC 2016
Brenner, JAC 2016
Codon GGC
GGT GGA** GGG** AGC GAC
All
Barrier* to CGN or AGR (AA = R)
G
2.5
G
2.5
G
1
G
1
S 2.5
D
3.5
‐
‐
AA Cases
%
2282
202
37
8
1
1
2531
90.16
7.98
1.46
0.32
0.04
0.04
100.00
*Barrier calculated as 1 for each transition and 2.5 for each transversion
**40/45 low barrier GGA/GGG variants are found in subtype B
ARCA, accessed May 29, 2016
Brenner, JAC 2016
Switch to
Switch from
CD4 nadir
Last CD4
Years with VL <50
Follow‐up (wks)
Outcome VL <50
199
702
3.7
50
30/31 (97%)
310
768
5.9
32
21/21 (100%)
2‐drug: 14
DTG dual: 31
3‐drug: 15
4‐drug: 2
2‐drug: 6
DTG mono: 21
3‐drug: 15
4‐drug: 0

DTG dual group




8/31 patients had experienced failure with INI regimens
6/31 had detectable VL at the time of switching (66 to 6750 copies/ml)
The single patient with confirmed virological failure had previously failed with RAL and N155H, she admitted to taking half the pills she was prescribed and genotyping revealed additional V72I+F121Y+S147G
DTG mono group

1/21 patients had experienced failure with INI regimens
Gubavu, JAC 201
Resistance
Cross‐resistance & INI sequencing
RAL
EVG
66IAK
92Q
118R
121Y
143CHR
DTG
147G
148HKR
155H
263K
RAL
EVG
DTG
Arrow thickness indicates probability of selection
Dotted arrow indicates selection not seen in vivo with first‐line therapy
S  R
Addition of R263K to E92Q, Y143R, Q148R, N155H decreases strand transfer activity
Anstett, J Virol 2015
Conclusions

INSTI fulfil many or all the prerequisites for excellent first‐line therapy





Tolerability (class feature, 5‐year trial data with RAL)
Convenience (STR for EVG and DTG)
Potency Currently negligible TDR and high genetic barrier (DTG)
In particular, DTG is a favored option in first‐line therapy
 Higher genetic barrier and protection of companion drugs  Unique resistance profile, saving a second‐line INI option (most probably RAL) Fine

Natural resistance
 Actually a key factor to halt drug development (e.g. bevirimat)

Treatment emergent resistance
 No drug is resistance‐free  Genetic barrier and cross‐resistance make the difference

Transmitted resistance
 Function of circulating resistance in transmitters with untreated/uncontrolled infection  Impact of fitness on transmission rate
Interpatient variability: DTG 27%, EVG 32% (compared to reference RAL 53‐220%) Elliot, JAC 2016
Elliot, JAC 2016
Meta-Analysis (2004-2011): Adherence With
Once- and Twice-Daily ART Regimens
Adherence Rates
Favors
Twice-Daily Regimen
Favors
Once-Daily Regimen
Treatment-Naive (n=7 studies)
Number of patients
qd
bid
1677
1393
3.9
(P=0.002)
Stable, Treatment-Experienced (n=9 studies)
Number of patients
qd
bid
1152
740
0.9
(P=0.001)
Failing, Treatment-Experienced (n=3 studies)
Number of patients
qd
bid
677
674
5.3
(P=0.03)
-20
-10
0
10
20
Mean Difference in Adherence Rate (95% CI)
Means of assessing adherence included either pill count or MEMS.
Overall mean difference in adherence rate favored once-daily ART: 2.55 (P=0.0002).
Nachega JB, et al. Clin Infect Dis. 2014;58:1297-1307.
82
Meta-Analysis (2004-2011): Virologic Control With
Once- and Twice-Daily ART Regimens
HIV RNA <50 or <200 Copies/mL
Favors
Twice-Daily Regimen
Favors
Once-Daily Regimen
Treatment-Naive (n=6 studies)
Events/patients
qd
bid
931/1312
898/1270
1.0
(P=0.7)
Stable, Treatment-Experienced (n=9 studies)
Events/patients
qd
bid
953/1163
628/756
1.0
(P=0.9)
Failing, Treatment-Experienced (n=3 studies)
Events/patients
qd
bid
425/688
406/682
1.0
(P=0.4)
0.5
0.7
1
1.5
2
Adjusted Risk Ratio (95% CI)
Means of assessing adherence included either pill count or MEMS.
Overall adjusted risk ratio for HIV RNA <50 or <200 copies/mL: 1.01 (P=0.5).
Nachega JB, et al. Clin Infect Dis. 2014;58:1297-1307.
83
Meta-Analysis (2007-2014): Adherence With
Single- and Multiple-Tablet HIV Regimens
Adherence Rates
Favors
Multiple-Tablet Regimen
Favors
Single-Tablet Regimen
STR Versus MTR (n=5 studies)
Events/patients
STR
MTR
204/260
642/954
2.4
(P<0.001)
STR Versus MTR bid (n=3 studies)
Events/patients
STR
MTR
153/182
264/395
2.5
(P=0.02)
STR Versus MTR (qd) (n=3 studies)
Events/patients
STR
MTR
153/182
323/434
1.8
(P=0.01)
0.1
0.2
0.5
1
2
5
10
Adjusted Odds Ratio (95% CI)
STR: single-tablet regimen; MTR: multiple-tablet regimen.
Adherence events: number of patients meeting specific threshold measure for each study.
Similar results obtained using pill counts for adherence (P<0.001).
Clay PG, et al. Medicine. 2015;94:e1677.
84
Meta-Analysis (2007-2014): Virologic Control With
Single- and Multiple-Tablet HIV Regimens
Efficacy Outcomes (48 Weeks)
Favors
Multiple-Tablet Regimen
Favors
Single-Tablet Regimen
HIV RNA <50 Copies/mL (n=3 studies)
Events/patients
STR
MTR
720/789
329/394
1.1
(P=0.0003)
CD4 Change (cells/mm3) (n=3 studies)
Change/patients
STR
MTR
56/783
58/379
-0.01
(P=0.83)
0.1
0.2
0.5
1
2
5
10
Adjusted Risk Ratio (95% CI)
Mean CD4 change from baseline.
No significant difference between STR and MTR:
Any serious adverse event (OR: 1.0), any grade 3-4 adverse event (OR: 0.77), grade 3/4 laboratory abnormalities (RR: 0.68).
Clay PG, et al. Medicine. 2015;94:e1677.
85
No One Right Option for Everyone:
Limitations of Current First-Line Regimens
Single-Tablet Regimens
• Elvitegravir/cobicistat
– Lower barrier to resistance than dolutegravir
or PIs
– Drug-drug interactions
– 2 co-formulated NRTI options
• Tenofovir AF version generally favored over
tenofovir DF version due to better renal and bone
safety profile
• Dolutegravir
– May have a higher barrier to resistance than
elvitegravir or raltegravir
Multiple-Tablet Regimens
• Raltegravir-based regimens
– Twice-daily administration
– Relatively low barrier to resistance
– Not available as a single-tablet regimen
• Ritonavir-boosted darunavir regimens
– Higher pill count
– Gastrointestinal toxicity
– High genetic barrier to resistance
– Not available as a single-tablet regimen
– 1 co-formulated NRTI option
̶
Abacavir/lamivudine
̶
Only for HLA-B*5701 negative patients
86


Historical: a game of chess Prerequisite to start and stay
 The King = the regimen
 The Queen = the genetic barrier
▪ Do we really know everything about INSTI drug resistance?
▪ The genetic barrier of the drug vs. the regimen
▪ Natural resistance and TDR (the more DTG is used the less will be)
 The Rook = potency  The Bishop = tolerability/convenience
▪ The seduction of less drug therapy
 The Knight = pK (symmetry) 

INSTI in the development of long‐acting drugs Conclusions Laskey, Nat Rev Microbiol 2014
Dow, Infect Dis Ther 2014
How to halt HIV DNA integration • Biochemistry: what’s new/unique with DTG
DTG activity on virus not exposed to RAL/EVG
•
•
•
•
•
Natural susceptibility
In vitro selection experiments In vivo (Drug naïve patients)
In vivo (Drug experienced INI‐naïve patients)
How often are DTG‐selected mutations present in vivo? DTG activity on RAL/EVG selected variants
• In vitro • In vivo (VIKING studies)
HIVdb ANRS REGA algorithms for DTG
Remarks from the virologist
How to halt HIV DNA integration
How to halt HIV DNA integration • Biochemistry: what’s new/unique with DTG
DTG activity on virus not exposed to RAL/EVG
•
•
•
•
•
Natural susceptibility
In vitro selection experiments In vivo (Drug naïve patients)
In vivo (Drug experienced INI‐naïve patients)
How often are DTG‐selected mutations present in vivo? DTG activity on RAL/EVG selected variants
• In vitro • In vivo (VIKING studies)
HIVdb ANRS REGA algorithms for DTG
Remarks from the virologist
This step is inhibited by currently available IN inhibitors
INSTI (integrase strand transfer inhibitors)

Designed to prevent HIV IN/LEDGF interaction in the intasome

Shown to enhance IN multimerization

Unexpected dual mode of action
 Integration  Maturation 
Currently preclinical
Potempa, PNAS 2013
Fantauzzi, HARPC 2013
The oxadiazole group makes RAL activity dependent of interaction with Y143
Linker allowing more stable and deeper position into the pocket vacated by the displaced 3’ end viral DNA
Llibre, AIS Rev 2015
Dierynck, JV 2007
DTG activity on virus not exposed to RAL/EVG
In vitro
How to halt HIV DNA integration • Biochemistry: what’s new/unique with DTG
DTG activity on virus not exposed to RAL/EVG
•
•
•
•
•
Natural susceptibility
In vitro selection experiments In vivo (Drug naïve patients)
In vivo (Drug experienced INI‐naïve patients)
How often are DTG‐selected mutations present in vivo? DTG activity on RAL/EVG selected variants
• In vitro • In vivo (VIKING studies)
HIVdb ANRS REGA algorithms for DTG
Remarks from the virologist

Activity against HIV‐1 subtypes shown for all the three INIs
 IC50 variability within 1 log 
Activity against HIV‐2 shown for all the three INIs
 IC50 similar to or slightly higher than HIV‐1
 INIs are a good option for difficult to treat HIV‐2
 Same major INI resistance mutations as with HIV‐1
▪ However, cross‐resistance between first‐generation INIs and DTG seems higher with HIV‐2 than with HIV‐1

Parameters
Drug concentration →





Starting drug dose
Fold drug concentration increment Starting virus genotype
The longer the time to obtain resistant virus, the highest the genetic barrier
High‐level resistance
Resistance mutations must be confirmed (site‐directed mutagenesis)
Intermediate resistance
Low‐level resistance
Genotypic analysis
Wild type virus
Time →
Seki, CROI 2010
Study
IN mutation (wk)
DTG FC
RAL FC
EVG FC
Kobayashi 2011
S153FY (12)
2.5
1.3
2.3
Quashie 2012
R263K (20)
G118R (20)
M50I (37)
H51Y (37)
2‐11
10‐20
1.9
1.2
1.1‐1.8
8.2‐20
0.5
1.2
3.3‐21.4
3.1
5.4
2
Seki 2015
E92Q (8)
G193E (8)
1.6
1.3
3.5
1.3
19
1.3



FC derived from different studies on HIV clones
Different selection strategies applied INI comparative studies:  Time to selection longer for DTG than RAL/EVG
 No resistance selection at higher starting dose with DTG as opposed to rapid selection with RAL or EVG
DTG
160 nM
RAL
EVG
32 nM
6.4 nM
Seki, AAC 2015
DTG activity on virus not exposed to RAL/EVG
In vivo
SPRING‐21
SINGLE2
FLAMINGO3
N=822
Phase III non‐inferiority, randomised, double‐blind, double‐dummy, multicentre study of:
• DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs
• RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs
N=833
Phase III non‐inferiority, randomised, double‐blind, double‐dummy, multicentre study of:
• DTG (50 mg QD) with ABC/3TC FDC plus EFV/TDF/FTC placebo
• EFV/TDF/FTC (QD) plus DTG and ABC/3TC FDC placebos N=484
Phase IIIb non‐inferiority, randomised, active‐controlled, multicentre, open‐label study of:
• DTG (50 mg QD) + 2 NRTIs
• DRV/r (800/100 mg QD) + 2 NRTIs
3TC, lamivudine; ABC, abacavir; BID, twice daily; FDC, fixed‐dose combination
NRTI, nucleoside reverse transcriptase inhibitor; QD, once daily
1. Raffi F, et al. Lancet Infect Dis 2013;13:927–35
2. Walmsley S, et al. N Engl J Med. 2013;369:1807–18
3. Clotet B, et al. Lancet 2014. Epub ahead of print
SPRING‐21
SINGLE2
DTG
50 mg QD
(N=411)
RAL
400 mg BID
(N=411)
DTG 50 mg
+ABC/3TC QD
(N=414)
EFV/TDF/FTC
QD
(N=419)
22 (5)
29 (7)
25 (6)
25 (6)
IN genotypic results at baseline and time of PDVF
10
19
133
103
INI‐resistant mutations
0
1 (6)*
0¶
0
RT genotypic results at baseline and time of PDVF
14
20
173
123
NRTI‐resistant mutations
0
4 (21)*†
0
1 (K65R)
NNRTI‐resistant mutations
–
–
0
6 (K101E,
K103N, G190A)‡
n (%)
Subjects with PDVF
*One subject had INI‐resistance mutations (T97T/A, E138E/D, V151V/I, N155H) and NRTI‐resistance mutations (A62A/V, K65K/R, K70K/E, M184V)
†M184M/I, A62A/V, M184M/V (each n=1)
¶E157Q/P polymorphism detected with no significant change in phenotypic susceptibility; ‡K101E (n=1), K103N (n=1), K103K/N (n=2), G190A (n=1) and K103N + G190A (n=1)
BL, baseline; c/mL, copies/mL; INI, integrase inhibitor; PDVF, protocol‐defined virologic failure (defined as two consecutive plasma HIV‐1 RNA values of ≥50 c/mL on or after Week 24)
Adapted from
1. Raffi F, et al. Lancet Infect Dis 2013;13:927–35
2. Walmsley S, et al. CROI 2014. Abstract 543
3. ViiV data on file (SINGLE 96‐week Clinical Study Report) PDVF, n (%)1
Treatment‐emergent primary mutations (INI, NRTI, PI)
DTG 50 mg QD
(N=242)
DRV/r 800/100 mg QD
(N=242)
2 (<1)
2 (<1)
0*
0
PDVF was defined as 2 consecutive HIV‐1 RNA values >200 c/mL, on or after Week 24
*One subject in the DTG treatment group had phenotypic resistance to nelfinavir. This subject had secondary PI resistance mutations L10V, I13V, K20R, E35D, M36I, I62I/V, L63T and L89M at baseline and at PDVF2
1. Clotet B, et al. Lancet 2014. Epub ahead of print
2. Feinberg J, et al. ICAAC 2013. Abstract H‐1464a
No treatment emergent resistance mutations in the DTG and DRV arm at 96 weeks
CAUTION: different definitions of virological failure, different proportions of advanced patients, different procedures to collect samples at failure.
Llibre, AIDS Rev 2015
DTG 50 mg QD plus background regimen
(N=354)
• ARV‐experienced,
INI‐naïve adults
• HIV‐1 RNA ≥400 c/mL*
• Resistance to ≥2 classes of ARVs (not incl. INIs)
• Stratified by HIV‐1 RNA (≤ or >50,000), DRV/r use and no. of fully active drugs for background
Screening Visit RAL 400 mg BID plus background regimen
(N=361)
Randomisation (Day 1) Screening period
Interim analysis Week 24
Analysis Week 48 Randomised phase
Primary endpoint: proportion of subjects with HIV‐1 RNA <50 c/mL at Week 48
*With 2 consecutive HIV‐1 RNA ≥400 c/mL, unless screening HIV‐1 RNA >1,000 c/mL
Cahn P, et al. Lancet 2013;382:700‐8 Week 24
Week 48
n (%)
DTG 50 mg QD
(N=354)
RAL
400 mg BID
(N=361)
DTG 50 mg QD
(N=354)
RAL 400 mg BID
(N=361)
PDVF
14 (4)
34 (9)
21 (6)
45 (12)
2/9 (22)†
9/27 (33)
4/17 (24)‡
16/38 (42)
INI mutations* present for patients with determinable genotype/phenotype, n (%)
*INI‐associated resistance mutations: H51Y, T66A, T66I, T66K, L68V, L68I, L74I, L74M, L74R4, E92Q, E92V, Q95K, T97A, G118R, E138A, E138K, E138T, G140A, G140C, G140S, Y143C, Y143H, Y143R, P145S, S147G, Q148H, Q148K, Q148R, V151I, V151L, S153F, S153Y, N155H, E157Q, G163R, G163K, G193E, R263K. IN substitutions listed above in bold were defined from the Stanford database (http://hivdb6.stanford.edu) with a score of >45. Other mutations are secondary IN resistance mutations from the Stanford database detected during INI clinical investigation, or were observed during other clinical investigation or in vitro studies with DTG
†Mutation(s), DTG FC IC : R263R/K, FC IC = 1.12; R263K, FC IC = 1.93
50
50 50
‡Mutation(s), DTG FC IC : R263R/K, FC IC = 1.1; R263K, FC IC = 1.9; E138T/A and T97A, DTG FC IC > max (baseline sample 50
50
50
50
testing showed this patient enrolled with preexisting RAL resistance [Q148] and FC IC50 > max for RAL and DTG); V151V/I, DTG FC IC50
= 0.92 Cahn P, et al. Lancet 2013;382:700–8. Supplementary appendix DTG selected mutations impair HIV replication
Natural occurrence of DTG selected mutations
16
14
12
10
%
8
INI‐naive
6
INI‐treated
4
2
0
M50I H51Y G118R E138K R263K
Not relevant if alone
Source: dbARCA accessed July 5th 2014 (1436 IN sequences)
16
14
12
10
%
8
INI‐naive
6
INI‐treated
4
2
0
M50I H51Y G118R E138K R263K
Not relevant if alone
Source: Stanford HIVdb accessed July 5th 2014 (6219 IN sequences)
DTG activity on RAL/EVG selected variants
How to halt HIV DNA integration • Biochemistry: what’s new/unique with DTG
DTG activity on virus not exposed to RAL/EVG
•
•
•
•
•
Natural susceptibility
In vitro selection experiments In vivo (Drug naïve patients)
In vivo (Drug experienced INI‐naïve patients)
How often are DTG‐selected mutations present in vivo? DTG activity on RAL/EVG selected variants
• In vitro • In vivo (VIKING studies)
HIVdb ANRS REGA algorithms for DTG
Remarks from the virologist
Viruses
WT1,2
T66A1,2
T66I1,2
T66K1,2
E92I1,2
E92Q1,2
E92V1,2
G118S1,2
F121Y1,2
T124A1,2
E138K1,2
G140S1,2
Y143C1,2
Y143H1,2
DTG
1
0.26
0.26
2.3
1.5
1.6
1.3
1.1
0.81
0.95
0.97
0.86
0.95
0.89
3 ≤ FC IC50 < 5
Mean FC IC50
RAL
EVG
1
1
0.61
4.1
0.51
8.0
9.6
84
2.1
8.0
3.5
19
1.4
8.3
1.2
4.9
6.1
36
0.82
1.2
1
0.93
1.1
2.7
3.2
1.5
1.8
1.5
5 ≤ FC IC50 < 10
RAL and EVG‐related single mutation SDMs (site directed mutants) Viruses
Y143R1,2
P145S1,2
Q146R1,2
Q148H1,2
Q148K1,2
Q148R1,2
I151L1,2
S153F1,2
S153Y1,2
M154I ,2
N155H1,2
N155S1,2
N155T1,2
G193E2
DTG
1.4
0.49
1.6
0.97
1.1
1.2
3.6
1.6
2.5
0.93
1.2
1.4
1.9
1.3
Mean FC IC50
RAL
16
0.87
1.2
13
83
47
8.4
1.3
1.3
0.82
11
6.2
5.2
1.3
EVG
1.8
>350
2.8
7.3
>1700
240
29
2.8
2.3
1.1
25
68
39
1.3
10 ≤ FC IC50
1. Adapted from Kobayashi M, et al. Antimicrob Agents Chemother 2011;55:813–21
2. Adapted from Seki T, et al. CROI 2010. Abstract 555 Viruses
WT
T66I/L74M
T66I/E92Q
T66K/L74M
L74M/N155H
E92Q/N155H
T97A/N155H
L101I/S153F
F121Y/T125K
E138A/Q148R
E138K/Q148H
E138K/Q148K
E138K/Q148R
3 ≤ FC IC50 < 5
DTG
1
0.35
1.2
3.5
0.91
2.5
1.1
2.0
0.98
2.6
0.89
19
4.0
Mean FC IC50
RAL
1
2.0
18
40
28
>130
26
1.3
11
110
17
330
110
EVG
1
14
190
120
42
320
37
2.6
34
260
6.7
371
460
5 ≤ FC IC50 < 10
RAL and EVG‐related single mutation SDMs (site directed mutants) Viruses
G140C/Q148R
G140S/Q148H
G140S/Q148K
G140S/Q148R
Y143H/N155H
Q148R/N155H
N155H/G163K
N155H/G163R
N155H/D232N
V72I/F121Y/T125K
L101I/T124A/S153F
E138A/S147G/Q148R
V72I/F121Y/T125K/I151V
Mean FC IC50
DTG
RAL
EVG
4.9
200
485
2.6
>130
>890
1.5
3.7
94
8.4
200
267
1.7
38
16
10
>140
390
1.4
23
35
1.1
17
35
1.4
20
36
1.3
13
58
1.9
1.4
2.0
1.9
27
130
1.2
7.0
37
10 ≤ FC IC50
Adapted from Kobayashi M, et al. Antimicrob Agents Chemother 2011;55:813–21
Dissociative t½ (h)
100
DTG
RAL
EVG
10
1
0.1
IN substitutions
DTG dissociation from IN‐DNA complexes was slower compared with RAL and EVG
The combination of multiple RAL signature substitutions or the accumulation of RAL secondary substitutions are needed to impact on DTG dissociation
Hightower KE, et al. IDRW 2012. Poster 12
DTG
RAL
160 nM
32 nM
6.4 nM
EVG
Seki, AAC 2015
DTG
160 nM
32 nM
6.4 nM
RAL
Seki, AAC 2015
DTG
160 nM
32 nM
RAL
6.4 nM
EVG
Seki, AAC 2015
VIKING1
(Cohort I)
N=27
Phase IIb open‐label, single‐arm multicentre study (Cohort I) of:
• DTG 50 mg QD + OBR (not incl. RAL)
N=24
Phase IIb open‐label, single arm multicentre study (Cohort II) of:
• DTG (50 mg BID) + OBR (not incl. RAL)
• subjects required to have ≥1 fully active ARV for Day 11 optimisation (not required for Cohort I)
INI‐resistant
VIKING1
(Cohort II)
INI‐resistant
VIKING‐32
INI‐resistant
VIKING‐43
INI‐resistant
N=183
N=30
BID, twice daily; BR, background regimen
QD, once daily; OBR, optimised background regimen
Phase III, open‐label, single‐arm, multicentre study of:
• DTG (50 mg BID) + OBR (not incl. RAL)
Phase III, open‐label, placebo‐controlled, multicentre study of:
• DTG 50 mg BID vs. placebo (both plus current failing regimen)
• At Day 8, all subjects received DTG (50 mg BID) + OBR (containing ≥1 fully active ARV)
1. Eron JJ, et al. J Infect Dis 2013;207:740–8 2. Castagna A, et al. J Infect Dis 2014. Epub ahead of print
3. Akil B, et al. EACS 2013. Abstract PE7/3
Subjects achieving primary endpoint* (%)
100
80
23/24 (96%)
21/27 (78%)
60
11/11 (100%)
18/18 (100%)12/13 (92%)
Cohort I (QD)
3/9 (33%)
40
Cohort II (BID)
20
0
1,2
All patients
1
Q148 +≥1
1
Other pathways
The primary endpoint* was achieved by 96% of subjects in Cohort II receiving DTG 50 mg BID and 78% of subjects in Cohort I receiving DTG 50 mg QD1,2
*Primary endpoint: HIV‐1 RNA <400 c/mL and/or ≥0.7 log10 c/mL decline at Day 11
1. Adapted from Eron J, et al. CROI 2011. Abstract 151LB
2. Adapted from Eron J, et al. J Infect Dis 2013;207:740–8
Vavro, CROI 2015
Vavro, CROI 2015
Vavro, CROI 2015
Smith, CROI 2015
Smith, Retrovirology 2015
G118R
F121Y
Malet, JAC 2014
Prevalence of RAL/EVG selected variants decreasing DTG activity
Llibre, AIDS Rev 2015
ARCA (N = 120)
5%
143
27%
41%
148
155
143 and 155
148 and 155
24%
None
2% 1%
Saladini, Clin Microbiol Infect 2012




502 patients failing RAL in France
Previous exposure to median five NRTIs, one NNRTI and three PIs
71% HIV‐1 subtype B Most frequent IN mutations: N155H/S (19.1%), Q148G/H/K/R (15.4%), Y143C/G/H/R/S (6.7%)
61%
Fourati, JAC 2015




502 patients failing RAL in France
Previous exposure to median five NRTIs, one NNRTI and three PIs
71% HIV‐1 subtype B Most frequent IN mutations: N155H/S (19.1%), Q148G/H/K/R (15.4%), Y143C/G/H/R/S (6.7%)
Fourati, JAC 2015
Danion, JAC 2015
NRTI: M41L, D67N, V118I, M184V, L210W, T215Y
NNRTI: K101P, K103N/S, V108I, V179T, V189I
PI: L10F, I13V, K20M, V32I, L33F, M36I, M46L, I54L, K55R, L63P, A71I, G73A, I84V, L90M
INI: R20K, V31I, L45I, L101I, I135V, E157Q, K160Q, V201I, K215N, A265V
INI: + N155H, S119R, S147G, V151I
DTG FC: 1.9
INI: + T97A, E138K DTG FC: 37
INI: + A49P, L68FL , L234V
DTG FC: 63
Hardy, JAC 2014
HIVdb ANRS REGA algorithms for DTG
How to halt HIV DNA integration • Biochemistry: what’s new/unique with DTG
DTG activity on virus not exposed to RAL/EVG
•
•
•
•
•
Natural susceptibility
In vitro selection experiments In vivo (Drug naïve patients)
In vivo (Drug experienced INI‐naïve patients)
How often are DTG‐selected mutations present in vivo? DTG activity on RAL/EVG selected variants
• In vitro • In vivo (VIKING studies)
HIVdb ANRS REGA algorithms for DTG
Remarks from the virologist
Mutations in the Integrase Gene Associated With Resistance to
Integrase Strand Transfer Inhibitors
Dolutegravir
Elvitegravir
Raltegravir
© 2014. IAS–USA
Wensing et al. Top Antivir Med. 2014;22(3):642-650.
Updates, user notes, and references available at www.iasusa.org.
Mutations in the Integrase Gene Associated With Resistance to
Integrase Strand Transfer Inhibitors
Dolutegravir
Missing:
148KR
118R
263K
Elvitegravir
Raltegravir
© 2014. IAS–USA
Wensing et al. Top Antivir Med. 2014;22(3):642-650.
Updates, user notes, and references available at www.iasusa.org.
RESISTANCE
POSSIBLE
RESISTANCE
Too high??
F121Y
V151L
S153Y
POSSIBLE
RESISTANCE
RESISTANCE
RESISTANCE
POSSIBLE
RESISTANCE
RESISTANCE
POSSIBLE
RESISTANCE
Natural polymorphism and consensus in SubB
124A
Main mutations (score ≥10)
148 H 20
148 K 20
148 R 20
151 L 15
263 K 15
51 Y
66 K
92 Q
118 R
138 K
138 A
140 S
140 A
140 C
153 Y
153 F
155 H
10
10
10
10
10
10
10
10
10
10
10
10
31‐60: intermediate resistance
>60: high‐level resistance
Additional penalties for double mutants
148HRK+138AK
148HRK+140SAC
148HRK+163RK
148HRK+74M
148HRK+97A
25
25
5
5
5
Main mutations (score ≥10)
148 H 20
148 K 20
148 R 20
Too high??
V151L
Too low?
F121Y
151 L 15
263 K 15
51 Y
66 K
92 Q
118 R
138 K
138 A
140 S
140 A
140 C
153 Y
153 F
155 H
10
10
10
10
10
10
10
10
10
10
10
10
31‐60: intermediate resistance
>60: high‐level resistance
Additional penalties for double mutants
148HRK+138AK
148HRK+140SAC
148HRK+163RK
148HRK+74M
148HRK+97A
25
25
5
5
5

IN sequences of 216 patients failing therapy containing RAL 
Resistance interpretation systems: ANRS v23, HIVdb v7.0 and Rega v9.1.0, and FDA and EMA package inserts
Theys, CROI 2015
Remarks from the virologist
How to halt HIV DNA integration • Biochemistry: what’s new/unique with DTG
DTG activity on virus not exposed to RAL/EVG
•
•
•
•
•
Natural susceptibility
In vitro selection experiments In vivo (Drug naïve patients)
In vivo (Drug experienced INI‐naïve patients)
How often are DTG‐selected mutations present in vivo? DTG activity on RAL/EVG selected variants
• In vitro • In vivo (VIKING studies)
HIVdb ANRS REGA algorithms for DTG
Remarks from the virologist

Activity across HIV1 subtypes and HIV2
 Feature shared with the other INIs

INI with exceedingly tight binding to target
 Contributes to potency and genetic barrier

Unique resistance profile when used as first INI, decreased activity in <50% RAL‐failing patients  Use as first‐line INI appears to be the best option
 Expect lower response as second‐line INI in the presence of Q148 (plus others mutations) resistance pathway or with the rare G118R and F121Y

Excellent and “resistance‐free” antiviral activity in randomized clinical trials in drug‐naïve patients
 First player in the 2nd generation high‐genetic barrier INI class
 First “bPI‐like” INI (suitable for LDR simplification strategies?)
END

DTG mono/dual
Fall 2015 HIV Update
clinicaloptions.com/hiv
PADDLE: All Pts Virologically Suppressed
by Wk 8 of Dolutegravir + Lamivudine
 Included 4 pts with HIV-1 RNA > 100,000 copies/mL at BL
Pt # Screen
1
5584
2
8887
3
67,335
4
99,291
5
34,362
6
16,024
7
37,604
8
25,071
9
14,707
10
10,679
11
50,089
12
13,508
13
28,093
14
15,348
15
23,185
16
11,377
17
39,100
18
60,771
19
82,803
20
5190
HIV-1 RNA, copies/mL
Day 10 Wk 2
Wk 3
BL
Day 2
Day 4
Day 7
Wk 4
Wk 6
Wk 8
Wk 12
Wk 24
10,909
3701
383
101
71
< 50
< 50
< 50
< 50
< 50
< 50
< 50
10,233
5671
318
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
151,569
37,604
1565
1178
266
97
53
< 50
< 50
< 50
< 50
< 50
148,370
11,797
3303
432
179
178
55
< 50
< 50
< 50
< 50
< 50
20,544
4680
1292
570
168
107
< 50
< 50
< 50
< 50
< 50
< 50
14,499
3754
1634
162
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
18,597
2948
819
61
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
24,368
6264
1377
Not done
268
105
< 50
< 50
< 50
< 50
< 50
< 50
10,832
Not done
516
202
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
7978
5671
318
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
273,676
160,974
68,129
3880
2247
784
290
288
147
< 50
< 50
< 50
64,103
3496
3296
135
351
351
84
67
< 50
< 50
< 50
< 50
33,829
37,350
26,343
539
268
61
< 50
< 50
< 50
< 50
< 50
< 50
15,151
3994
791
198
98
< 50
61
64
< 50
< 50
< 50
< 50
23,500
15,830
4217
192
69
< 50
< 50
< 50
Not done
< 50
< 50
< 50
3910
370
97
143
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
25,828
11,879
1970
460
147
52
< 50
< 50
< 50
< 50
< 50
< 50
73,069
31,170
2174
692
358
156
< 50
< 50
< 50
< 50
< 50
< 50
106,320
35,517
2902
897
352
168
76
< 50
< 50
< 50
< 50
< 50
7368
3433
147
56
< 50
< 50
< 50
< 50
< 50
< 50
< 50
< 50
Figueroa MI, et al. EACS 2015. Abstract 1066. Reproduced with permission.
Fall 2015 HIV Update
clinicaloptions.com/hiv
Switch From Suppressive ART to
Dolutegravir Monotherapy
 Single-arm, 24-wk pilot study
– Primary endpoint: HIV-1 RNA
< 37 c/mL at Wk 24 (ITT, NC=F)
 Eligibility: HIV-1 RNA < 50 c/mL
on ART for ≥ 12 mos
– Switched to DTG 50 mg QD
monotherapy if ≥ 2 of the
following: ART or ARTcomorbidity toxicity, avoidance
of DDIs, or potential loss of
virologic control due to archived
resistance
 Baseline ART: PI (67%), NNRTI
(27%), INSTI (6%)
Reasons for Switch, %
Pts
(N = 33)
Underlying cause
 Comorbidities
97
 DDIs
85
 ART-related AEs
76
 Resistance
48
Immediate cause
 DDIs
39
 GI symptoms
33
 Dyslipidemia
27
 Osteoporosis
18
 High CVD risk
12
 CKD progression
3
Rojas J, et al. EACS 2015. Abstract 1108. Reproduced with permission.
Fall 2015 HIV Update
clinicaloptions.com/hiv
Switch From Suppressive ART to
Dolutegravir Monotherapy

97% of pts maintained virologic suppression at Wk 24[1]

Reasons for switch improved in most pts from BL to 24 wks[1]
– T-scores unchanged in 2 pts with osteoporosis
– In single pt with renal disease, eGFR ↓ from 59 mL/min at BL to 52 mL/min/ at Wk
24; urine protein:creatinine ratio ↓ from 330 to 146 mg/mg
Reason for Switch
Pts at Risk, n
Outcome Improved/ Avoided, n
DDIs
13
13
GI symptoms
11
9
Dyslipidemia
9
9
High Framingham score
3
3

In separate study of switch from suppressive ART to DTG monotherapy, 89%
of pts maintained virologic suppression 24 wks after switch[2]
1. Rojas J, et al. EACS 2015. Abstract 1108. 2. Katlama C, et al. EACS 2015. Abstract 714.
Mix Miller, Infect Drug Res 2015

Retroviral integration is initiated by IN’s recognition of both ends of viral DNA and subsequent removal of two (or three) nucleotides from each of the 3’ ends (3’ processing). 
The target DNA (i.e., chromosomal DNA) captured by IN is cleaved in a staggered fashion via the xposed
hydroxy (OH) groups on the viral DNA ends, and the 3’ end of the viral DNA and the 5’ end of the target DNA is simultaneously linked (strand transfer). 
The 3’ processing and strand transfer steps are reproducible in vitro using recombinant IN, indicating that IN alone suffices to catalyze these steps. However, in infected cells, excision of the mispaired 5’ viral DNA ends and filling in the single‐strand gaps are carried out by yet‐to‐be identified cellular enzymes.
Suzuki, Front Microbiol 2012
RAL1
DTG1
Catalytic loop
F
F
N N
O
N
H
Catalytic loop
H
N
O
O
N
O
OH
S/GSK1349572
O
NH
F
O
O
2
N155
N
N
H
N
O
OH
Raltegravir
2
Comparison of the docked poses of DTG and RAL show clear differences1
DTG has a more streamlined metal‐chelating scaffold compared with RAL, enabling it to lie distal to residue 1431
The architecture of DTG may contribute to its resistance to substitutions1
MOA, mode of action
1. Adapted from DeAnda et al. PLoS ONE 2013;8(10):e77448
2. Hightower KE, et al. Antimicrob Agents Chemother 2011;55:4552–9

Two patients failing with N155H pattern, switched to DTG+TDF+FTC

One with I84V + E92Q + T97A + N155H + 214H
 Complete response

One with I84V + A153G + N155H + Q214H
 Partial response followed by rebound
Trevino, JCV 2015
S153FY
Seki, CROI 2010
DTG
160 nM
RAL
EVG
32 nM
6.4 nM
E92Q/G193E
Seki, AAC 2015
No treatment-emergent
emergent mutations leading to drug resistance have been detected
with DTG 50 mg QD in any clinical trial in treatment-naive subject (total of 1118
patients)1–3

No INI or NRTI mutations were detected through 96 weeks of DTG treatment in subjects from SPRING‐2 (comparator: RAL) or SINGLE (comparator: EFV/TDF/FTC) with available samples at baseline and time of PDVF1



in SPRING‐2 in the RAL arm, 1 (6%) subject with virologic failure had INI treatment‐emergent resistance and 4 (21%) had NRTI treatment‐emergent resistance
in SINGLE in the EFV/TDF/FTC arm, no subject with virologic failure had INI treatment‐emergent resistance and 6 subjects had major NRTI or NNRTI treatment‐emergent resistance2
No INI or NRTI treatment‐emergent mutations were detected through 48 weeks of DTG treatment in subjects from FLAMINGO (comparator: DRV/r) with available samples at baseline and time of PDVF2,3

in FLAMINGO in the DRV/r arm, no subject with virologic failure had PI or NRTI treatment‐emergent resistance3
1. Raffi, Lancet Infect Dis 2013; 2. Walmsley, CROI 2014; 3. Clotet , Lancet 2014.



Day 1: Clade B; PSS=2, GSS=2
Regimen (PSSDay 1): TDF(1) and DRV/r(1)
DTG C0a: Week 4=0.57 µg/mL
HIV‐1 RNA (log10 c/mL)
7
Treatment: DTG 50 mg QD – Subject 1
Plasma HIV‐1 RNA Profile by Visit
PDVF Week 16: 6,446 c/mL
6
5
4
3
Day 1
PDVF
IN mutation
‐
R263R/K
DTG FC IC50
0.96
1.12
RAL FC IC50
1.02
0.94
IN RC 61%
33%
2
PDVF BR: No emergent IAS, nor increased FC IC50
1
0 4 8 12 16
Week
24
32
40
48
60
72
Selected relevant characteristics
• Fluctuating HIV‐1 RNA despite DTG + potent BR
aMean
Week 4 + Week 24 C0 was 0.86 µg/mL
TDF, tenofovir; GSS, genotypic sensitivity score; RC, replication capacity Adapted from
Underwood MR, et al. IDRW 2013. Abstract 21
Day 1: Clade C; PSS=1, GSS=0.75 Regimen (PSSDay 1): TDF(0) and EFV(1)
DTG C0a: Week 4=<0.02 µg/mL (BLOD); Week 24=0.26 µg/mL
Treatment: DTG 50 mg QD – Subject 2
Plasma HIV‐1 RNA Profile by Visit
7
HIV‐1 RNA (log10 c/mL)



PDVF Week 24: 9,367 c/mL
6
5
4
Day 1
PDVF
IN mutation
‐
V260I/R263K
DTG FC IC50
0.92
1.93
2
RAL FC IC50
1.11
1.12
1
IN RC 119%
NR
3
0 4 8 12 16 24 32
Week 40
48
60
72
PDVF BR: Emergent RT G190S; EFV FC IC50 increase
Selected relevant characteristics
• Background regimen: Day 1 TDF (PSS=0) + EFV active
• DTG trough level <0.02 µg/mL (BLOD) indicates dose ≥3 days prior
aMean
Week 4 + Week 24 C0 was 0.86 µg/mL
BLOD, below limit of detection Adapted from
Underwood MR, et al. IDRW 2013. Abstract 21
Strain
IN substitution / FC IC50
DTG
RAL
EVG
NL432a
R263K
1.5
0.8
1.3
HXB2b
RVA
V260I
1.0
0.7
5.3
R263K
2.1
0.6
10.6
V260I/R263K
2.0
0.5
6.3
DTG and RAL retained good activity against the R263K and V260I/R263K mutants
aHeLa‐CD4 cells, 3‐day assay, B‐gal readout.
bMT4 cells, 5‐day assay, cell titer glow readout
Underwood MR, et al. IDRW 2013. Abstract 21
DTG (56 days)1,2
FC IC50 = 1.2–4.1
S153F DTG (84 days)1,2
FC IC50 = 1.2–4.1
S153Y
S153F
DTG (112 days)1,2
FC IC50 = 1.2–4.1
S153Y
S153F
RAL (84 days)1,3,4
FC IC50 = 6 – >138
Q148K
Q148R
E138K/Q148K
E138K/Q148R
G140S/Q148R
N17S/Q148K/G163R
G140C/Q148K/G163R
E138K/Q148K/G163R
E92Q/E138K/Q148K/M154I
N155H/I204T
V151I/N155H
V151I/N155H EVG (56 days)1,3 FC IC50 = 2–497
T66I
E92Q
P145S
Q148K
Q148R
T66K
E92V
P145S
Q146L
Q148R
T66I/V72A/A128T
T66I/E92Q
T66I/Q146L Integrase substitutions observed during passage of wild‐type HIV‐1 IIIB strain in the presence of DTG, RAL or EVG; list excludes
polymorphisms Mutations in bold indicate those seen in clinical trials
All substitutions observed during DTG passage had low level impact on DTG susceptibility (FC IC50 ≤ 4.1)1,2
FC IC50, fold change in 50% inhibitory concentration
S153FY
1. Adapted from Sato A, et al. IAS 2009. Poster WEPEA097
2. Data on file (Global Data Sheet)
3. Kobayashi M, et al. Antiviral Research 2008;80;213–22
4. Kobayashi M, et al. Antimicrob Agents Chemother 2011;55:813–21
R263K
G118R
Quashie, JV 2012
R263K
Quashie, JV 2012
R263K slightly decreases viral infectivity
R263K
HIV‐1 (pNL4‐3) integration is diminished in the presence of the R263K mutation
R263K decreases IN‐DNA binding activity
Quashie, JV 2012
R263K
Mesplede, Retrovirology 2013
Effects of the E138K and R263K mutations on HIV integration. Alu‐mediated qPCR
quantification of integrated HIV DNA in primary human PBMCs infected with WT NL4.3 and with viruses containing the E138K, R263K and E138K/R263K mutations for 72 h. Results were normalized for β‐globin gene content and expressed relative to the signal detected for WT, arbitrarily set at 100%. Error bars indicate mean ± SEM. NS, not significant. **Statistically significant differences (unpaired t‐test, P < 0.001).
R263K
Mesplede, AAC 2014
R263K
Singhroy, AAC 2015
R263K
Wares, Retrovirology 2014
M50I does not compensate for the reduction in HIV replication associated with R263K. Effects of the M50I and R263K mutations on HIV infectivity in TZM‐bl cells
Wares, Retrovirology 2014
R263K
Mesplede, Retrovirology 2013
EC50 values were obtained from cell culture assays and IC50 values were obtained from assays using recombinant IN proteins
G118R
F121Y
Munir, AAC 2014
G118R
F121Y
Munir, AAC 2014
Replication capacity of wild‐
type and mutant viruses. Replication capacity was determined by comparing levels of RT activity in
culture supernatants between mutated and wild‐
type viruses at 72 h
postinfection. Error bars represent SEM.
G118R
Bar‐Magen, JV 2011
Strand transfer activity
3’ processing activity
LTR DNA binding 
G118R impacts the strand transfer step by diminishing the ability of integrase‐LTR complexes to bind target DNA

The addition of H51Y and E138K to G118R partially restores strand transfer activity by modulating the formation of integrase‐LTR complexes through increasing LTR DNA affinity and total DNA binding, respectively

Unique mechanism, in which one function of HIV integrase partially compensates for the defect in another function
G118R
Quashie, AAC 2013
Comparative strand transfer activities of purified HIV‐
1 WT integrase and variant integrase proteins of CRF02_AG, subtype C, and subtype B origins
G118R
Quashie, JV 2015
DTG
RAL
EVG
Subtype‐specific susceptibility of WT and variant integrase proteins to clinically relevant INSTIs.
G118R
Quashie, JV 2015
Emerging mutations in integrase
detected by genotyping viruses containing INSTI resistance‐
associated mutations that were grown under DTG pressure for 30 weeks
Anstett, JV 2015
VIKING
Adult subjects with HIV‐1
Current or historic RAL failures with evidence of RAL resistance
Resistance to ≥2 other ARV classes
ART optimised on Day 11 (OBR)
Efficacy and safety of DTG assessed at Week 24
VIKING (Cohort I; N=27)
DTG 50 mg QD + current ART (not incl. RAL)
Results formed rationale for regimen of DTG to be used in VIKING Cohort II and VIKING‐3
VIKING (Cohort II; N=24)
DTG 50 mg BID + current ART (not incl. RAL)
≥1 fully active ARV for Day 11 optimisation
Results formed rationale for regimen of DTG to be used in VIKING‐3
Eron J, et al. J Infect Dis 2013;207:740–8
Change from baseline in HIV‐1 RNA 0
–0.5
–1.0
–1.5
–2.0
–2.5
DTG 50 mg QD
–3.0
0.5
1
2
4
8
16
32
Change from baseline in HIV‐1 RNA Baseline DTG FC in IC50 relative to WT virus
0
–0.5
–1.0
–1.5
–2.0
–2.5
DTG 50 mg BID
–3.0
0.5
1
2
4
8
16
32
Baseline DTG FC in IC50 relative to WT virus
Q148 + 1
Q148 + 2
Mixture
N155
Y143
Other integrase mutations
Adapted from Eron J, et al. CROI 2011. Abstract 151LB
Main eligibility criteria:
• HIV‐1 RNA ≥500 c/mL
• Screening or documented historic evidence of resistance to RAL and/or EVG, and resistance to ≥2 ARV classes other than INIs
Functional monotherapy phase
DTG 50 mg BID and continue failing ART regimen
Optimised phase
DTG 50 mg BID
+
OBR with OSS ≥1
Screening period
up to a maximum of 42 days
Screening visit ~Day ‐35 OSS, overall susceptibility score, determined by Monogram Biosciences net assessment
Day 1
Day 8
Week 24 analysis
Week 48 analysis
Castagna A, et al. J Infect Dis 2014. Epub ahead of print
IN mutation group
N
Day 8 response1
Median decline in HIV‐1 RNA Full responsea
(log10 c/mL) N (%)
Week 24 response1
N
<50 c/mL, N (%)
No Q148
122
‐1.65
112 (92%)
72
57 (79%)
Q148 + 1b
35
‐1.10
25 (71%)
20
9 (45%)
Q148 + ≥2b
20
‐0.74
9 (45%)
9
1 (11%)
aFull
response: decline in HIV‐1 RNA >1 log10 c/mL or <50 c/mL at Day 8
bL74I, E138A/K/T and G140A/C/S
Adapted from Vavro C, et al. IDRW 2013. Abstract 29
Subjects with HIV‐1 RNA
<50 c/mL at Week 24 (%)*1
100
98/120
120/161
(75%)
(82%)
80
14/25
(56%)
60
40
1/9
(11%)
20
0
≤4
>4 to 10
>10
Total
DTG FC IC50 at baseline
• In a separate analysis to estimate DTG phenotypic cut‐offs, DTG FCs in IC50 of <9.45, 9.45 to <25.99 and >25.99 were estimated as full, intermediate and no response cut‐offs, respectively2
• 87% of subjects with baseline DTG FC IC50 <9.45 achieved full response at Day 8, and 69% of subjects with baseline DTG FC IC50 <9.45 had <50 c/mL at Week 242
• However, univariate response by baseline DTG phenotype grouping does not account for other factors and is not meant to represent definitive clinical susceptibility breakpoints for DTG1
*Virologic outcome population (N=161) used for baseline resistance analysis to minimise confounding factors of antiviral response
1. Nichols G, et al. IAS 2013. Abstract TULBPE19
2. Vavro C, et al. IDRW 2013. Abstract 29
Codon
Any
97
138
148
140
155
74
92
157
147
143
PDVF genotypic
population (n=39),* n (%) 22 (56)
10 (26)
9 (23)
6 (15)†
4 (10)
4 (10)
3 (8)
2 (5)
1 (3)
1 (3)
1 (3)
Genotype at PDVF
T97T/A, T97A
E138A, E138E/K, E138K
Q148H, Q148Q/H, Q148Q/R/K
G140G/S, G140S
N155H
L74L/M/V, L74L/M, L74I
E92E/Q
E157E/Q
S147G
Y143Y/H
Emergent mutations were at well‐characterised IN resistance‐associated positions
18/22 (82%) subjects harboured Q148 pathway virus at baseline or historically
*39/45 subjects with paired baseline and PDVF samples
†3 subjects with historic Q148H: 2 with Q148H at screening but not baseline; one with Q148R at baseline and Q148Q/R/K at PDVF
Adapted from Vavro CL, et al. EUDRW 2014. Abstract O_10
Q148 + 1
N=7
Q148H + G140S + T97T/A (n=3)
Q148H + G140S + E138K
Q148H + G140S + E138K + E92E/Q
Q148H + G140S + E138E/A + T97A
Q148H + G140S + E138K + T97A
Q148H + G140S
Q148 + ≥2
N=6
Q148H + G140S + E157Q
Q148H + G140S + E138T/A + G193E
Historic* Q148
N=5
DTG Treatment
Q148H + G140S + E138T/K/A
Q148H + G140S + E138T/K/A + E157E/Q
Q148H + G140S + E138T + T97A
Q148H + G140S + E138T + N155H
Q148H + G140S + E157Q + N155H
Q148Q/R/K + G140A + E138A + G193E
Q148Q/H + G140G/S + E138T/A + G193E + L74L/M + T97T/A
Q148H + G140G/S + E138E/K + T97T/A + E92E/Q
Q148H + G140S + E138A + T97T/A
Q148H + G140S + E138A + T97T/A
Q148Q/H + G140S + E138E/K
Q148Q/H + G140S + N155H
Q148H
Emergent mutations shown in bold
*Historic includes subjects with screening Q148 but not at baseline Vavro CL, et al. EUDRW 2014. Abstract O_10
Main eligibility criteria:
• HIV‐1 RNA ≥1000 c/mL
• Experiencing virologic failure on an INI‐containing regimen
• Resistance to ≥2 ARV classes + INIs
• Stratification by presence of Q148 + ≥2 INI resistance‐
associated mutations
Screening Visit
Screening period
DTG 50 mg BID + remaining components of failing regimen (N=14)
DTG 50 mg BID plus OBR (OSS ≥1)
(N=30)
Placebo + remaining components of failing regimen
(N=16)
Randomisation (Day 1) Randomisation phase
Day 8
Analysis Week 24
Analysis Week 48 Open label phase
Primary endpoint: change in HIV‐1 RNA from baseline to Day 8
Akil B, et al. EACS 2013. Abstract PE7/3 Baseline INI mutation group
VIKING‐4
DTG 50 mg BID
VIKING‐4
PBO
VIKING‐3
DTG 50 mg BID
n
Meana (SE)
n
Meana (SE)
n
Mean
13b
‐1.06 (0.17)
16
‐0.03 (0.26)
182
‐1.43 (0.61)
n
Mean (SD)
n
Mean (SD)
n
Mean (SD)
No Q148
5
‐1.43 (0.75)
9
‐0.03 (0.33)
126
‐1.59 (0.51)
N155
2
‐1.13 (0.97)
4
0.11 (0.36)
33
‐1.43 (0.51)
Y143
2
‐1.74 (0.95)
4
‐0.01 (0.10)
28
‐1.70 (0.42)
Q148 + 1c
6
‐0.87 (0.59)
6
‐0.05 (0.18)
36
‐1.15 (0.54)
Q148 + ≥2c
3
‐0.90 (0.76)
1
0.09
20
‐0.92 (0.81)
Overall
aMean
adjusted baseline plasma HIV‐1 RNA, baseline DTG FC in IC50, OSS of failing regimen and the interaction between DTG FC in IC50
and treatment. bOne out of 14 subjects in the DTG 50 mg BID arm had no result for baseline DTG FC in IC50 and was excluded from the calculation of the mean adjusted change from baseline in plasma HIV‐1 RNA. cG140A/C/S, E138A/K/T, L74I
As in VIKING‐3, baseline INI mutations impacted on DTG antiviral response in VIKING‐4
Akil B, et al. EACS 2013. Abstract PE7/3 ARV‐experienced, INI‐resistant subjects (Cohort I: DTG 50 mg QD + OBR; N=27 and Cohort II: DTG 50 mg BID + current ART; N=24)1
• At Day 11, a higher response rate was observed in Cohort II compared with Cohort I.1 Additionally, all 11 subjects in Cohort II with Q148+ secondary mutations responded (compared with 3/9 in Cohort I)2
• In Cohort I, a strong correlation was observed between change from baseline in plasma HIV‐1 RNA and baseline FC IC50 in susceptibility to DTG. The same trend was seen in Cohort II, but to a lesser extent2
• INI resistance emergence during therapy occurred in <15% of all subjects, and the mutations that emerged were previously described RAL‐associated mutations. As yet there is no in vivo evidence of emergence of novel mutations that result in a substantial decrease in DTG susceptibility1
ARV‐experienced, INI‐resistant subjects (DTG 50 mg BID + OBR; N=183)3,4
• Three IN genotypic groups were derived based on differential impact on DTG antiviral response: “No Q148,” “Q148 + 1” and “Q148 + ≥2”. The best antiviral responses (at Day 8, Week 24 and Week 48) were seen in the “No Q148” group.3 Response rates at Week 24 and Week 48 were higher in the subgroup of subjects with No Q148 mutation at baseline versus those with Q148 and secondary mutations at baseline3,4
• PDVF was detected in 22% of subjects at Week 48. Limited resistance evolution was seen and only previously identified INI‐associated mutations were identified4
VIKING‐4
ARV‐experienced, INI‐resistant subjects (DTG 50 mg BID vs. placebo + current ART; N=30)5
• At Day 8, subjects receiving DTG 50 mg BID had a significantly greater reduction in HIV‐1 RNA compared with subjects receiving placebo
• As in VIKING‐3, baseline DTG fold change in IC50 and INI mutations impacted on DTG antiviral response
1. Eron J, et al. J Infect Dis 2013;207:740–8; 2. Eron J, et al. CROI 2011. Abstract 151LB; 3. Castagna A, et al. J Infect Dis 2014. Epub ahead of print; 4.Vavro CL, et al. EUDRW 2014. Abstract O_10; 5. Akil B, et al. EACS 2013. Abstract PE7/3

How to halt HIV DNA integration  Biochemistry: what’s new/unique with DTG

DTG activity on virus not exposed to RAL/EVG






DTG activity on RAL/EVG selected variants




Natural susceptibility
In vitro selection experiments In vivo (Drug naïve patients)
In vivo (Drug experienced INI‐naïve patients)
How often are DTG‐selected mutations present in vivo? In vitro In vivo (VIKING studies)
HIVdb ANRS REGA algorithms for DTG
Remarks from the virologist