The role of integrase inhibitors in first line and later antiretroviral therapy.2013

1. Joseph J. Eron Jr., MD
Professor of Medicine
University of North Carolina School of
Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
The Evolving Role of Integrase
Inhibitors in HIV Therapy
This program is supported by an educational grant from

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The Evolving Role of Integrase Inhibitors in HIV Therapy
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3. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Program Director and Content Planning
Faculty
Joseph J. Eron Jr., MD
Professor of Medicine
University of North Carolina School
of Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
Paul E. Sax, MD
Clinical Director
HIV Program and Division of
Infectious Diseases
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Kimberly Y. Smith, MD
Associate Professor of Medicine
Division of Infectious Diseases
Rush University Medical Center
Chicago, Illinois

4. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Disclosures
Joseph J. Eron, Jr., MD, has disclosed that he has served as a
consultant for AbbVie, Bristol-Myers Squibb, GlaxoSmithKline/ViiV,
Gilead Sciences, Merck, Tibotec/Janssen, and Tobira; has received
funds for research support from Bristol-Myers Squibb and
GlaxoSmithKline/ViiV; and has served on the data and safety monitoring
board for Vertex.
Paul E. Sax, MD, has disclosed that he has received consulting fees
from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV,
Janssen, and Merck and funds for research support from Bristol-Myers
Squibb, Gilead Sciences, and GlaxoSmithKline/ViiV.
Kimberly Y. Smith, MD, MPH, has disclosed that she has received
consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences,
GlaxoSmithKline, Janssen, Merck, and ViiV.

5. The Evolving Role of Integrase
Inhibitors in HIV Therapy

6. Viral Life Cycle and
Mechanism of Action

7. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
HIV Viral Life Cycle
Attachment
fusion
Budding
Reverse
transcription
Maturation
Integration
Uncoating
Transcription,
translation
Assembly

8. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
HIV Viral Life Cycle
Currently available integrase inhibitors
 Raltegravir (approved 10/07)
 Elvitegravir* (approved 8/12)
 Dolutegravir (approved 8/13)
Budding
Reverse
transcription
Maturation
Transcription,
translation
Assembly
*Currently available only as part of a coformulated single-tablet regimen.
Attachment
fusion
Uncoating
Integrase
inhibitors

9. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Integrase Inhibitors in DHHS Guidelines
 All 3 integrase inhibitors are now part of preferred first-line
regimens
DHHS Guidelines. February 2013. DHHS Recommendation on INSTIs. October 2013.
Preferred Regimens Alternative Regimens
NNRTI  EFV/TDF/FTC
 EFV + ABC/3TC
 RPV/TDF/FTC or RPV + ABC/3TC
Boosted PI
 ATV/RTV + TDF/FTC
 DRV/RTV + TDF/FTC
 ATV/RTV + ABC/3TC
 DRV/RTV + ABC/3TC
 FPV/RTV + (TDF/FTC or ABC/3TC)
 LPV/RTV + (TDF/FTC or ABC/3TC)
INSTI
 RAL + TDF/FTC
 EVG/COBI/TDF/FTC
 DTG + ABC/3TC
 DTG + TDF/FTC
 RAL + ABC/3TC

10. Using Integrase Inhibitors in
Treatment-Naive Patients

11. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
STARTMRK: Raltegravir vs Efavirenz in
Treatment-Naive Patients
 Randomized, double-blind (through 5 yrs), placebo-controlled, phase III trial
 Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
HIV-infected, treatment-naive
patients with HIV-1 RNA
> 5000 copies/mL and
no resistance to EFV,
TDF, or FTC
(N = 563)
Efavirenz 600 mg QHS + TDF/FTC
(n = 282)
Raltegravir 400 mg BID + TDF/FTC
(n = 281)
Lennox J, et al. Lancet. 2009;374:796-806.
Stratified by HIV-1 RNA (> vs ≤ 50,000 copies/mL)
and viral hepatitis status

12. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
STARTMRK: RAL vs EFV in Treatment-
Naive Patients: 5-Yr Final Report
 RAL noninferior to EFV in HIV-1 RNA < 50 c/mL at Wk 48
(primary endpoint; ITT, NC = F analysis); superior from Wk 192
Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85.
281
282
100
80
60
40
20
0
HIV-1RNA<50c/mL(%)
0 48 72 96 120 144
Wks
RAL
EFV
Pts at Risk, n
281
282
276
282
280
281
281
282
277
281
280
281
86
82
81
79
75
69
281
282
192
76
67
∆: +9.5% (95% CI: 1.7% to 17.3%;
noninferiority P < .001)
24012 216
71
61
277
282
279
279
24
279
282
168
281
282

13. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
STARTMRK: RAL vs EFV in Treatment-
Naive Patients: 5-Yr Final Report
 Efficacy as good as or better
than EFV in all baseline
subgroups tested
 CD4+ cell count at Wk 240:
+374 (RAL) vs +312 (EFV)
 RAL associated with
– Fewer CNS adverse events
(39.1% vs 64.2%; P < .001)
– Fewer drug-related clinical
adverse events (52.0% vs
80.1%; P < .001)
– Fewer discontinuations due to
adverse events (5% vs 9%)
Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85 plus Supplemental Digital Content.
VF and Resistance at Wk 240
RAL
(n = 281)
EFV
(n = 282)
VF, n (%) 55 (19.6) 59 (20.9)
Resistance data
available, n 23 20
INSTI or NNRTI
mutations only, n 1 7
NRTI mutations only, n 3 2
NRTI + (RAL or EFV)
resistance mutations, n 3 3

14. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
QDMRK: RAL QD Inferior to RAL BID at
Wk 48 in Treatment-Naive Patients
 Randomized, noninferiority phase III
trial of RAL 800 mg QD (n = 382) vs
RAL 400 mg BID (n = 389), both with
TDF/FTC[1]
 RAL QD inferior to RAL BID at Wk 48 in
ITT (NC = F) analysis
 Lower RAL trough levels associated
with higher risk of failure in QD arm but
not in BID arm
 More resistance at failure in QD arm
 PK studies of 2 new RAL formulations
administered as 1200-mg once daily
showed promise in healthy patients[2]
1. Eron J, et al. Lancet Infect Dis. 2011;11:907-915. 2. Krishna R, et al. EACS 2013, Abstract PE10/17.
HIV-1RNA<50c/mL
(NC=F)
*Failure included both failure to suppress and rebounders.
Most patients with VF and RAL resistance had
≥ 2 mutations associated with resistance to RAL.
Parameter, n RAL QD
(n = 382)
RAL BID
(n = 388)
Pts with VF* and
HIV-1 RNA > 400 c/mL
30 16
Resistance data available 27 11
FTC resistance only 11 2
Integrase inhibitor and FTC
resistance
9 2
No evidence of resistance 7 7
83
89
0
20
40
60
80
100
RAL 800 mg
QD (n = 382)
RAL 400 mg
BID (n = 389)
318/
382
343/
389
∆: -5.7
(95% CI: -10.7 to -0.83;
P for noninferiority = .044)
Wk 48

15. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Elvitegravir/Cobicistat vs EFV or ATV/RTV
+ TDF/FTC in Treatment-Naive Pts
 Randomized, double-blind, active-controlled phase III studies
 Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438.
Treatment naive;
HIV-1 RNA ≥ 5000 copies/mL;
any CD4+ cell count;
susceptible to TDF, FTC, and EFV, or ATV;
eGFR ≥ 70 mL/min
Study 102[1]
(N = 700)
Study 103[2]
(N = 708)
EVG/COBI/TDF/FTC QD
(n = 348)
EFV/FTC/TDF QD
(n = 352)
EVG/COBI/TDF/FTC QD
(n = 353)
ATV/RTV + TDF/FTC QD
(n = 355)

16. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
EVG/COBI/TDF/FTC Noninferior to
EFV/TDF/FTC Through Wk 144
 EVG/COBI arm noninferior to EFV
arm at Wk 48 primary endpoint[1]
and
through Wk 144[2,3]
– Results consistent across
subgroups: BL HIV-1 RNA,
CD4+ cell count, age, sex, race
– Treatment-related study d/c: 6% in
EVG/COBI arm vs 7% in EFV arm
at Wk 144
 VF: 7% in EVG/COBI arm and 10%
in EFV arm at Wk 144
 Similar CD4+ cell count increase at
Wk 144:
– +321 cells/mm3
(EVG/COBI) vs
+300 cells/mm3
(EFV)
1. Sax PE, et al. Lancet. 2012;379:2439-2448. 2. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-
100. 3. Wohl D, et al. ICAAC 2013. Abstract H-672a.
Wk 48 Wk 144
EVG/COBI/TDF/FTC
(n = 348)
EFV/TDF/FTC
(n = 352)
80
75
0
20
40
60
80
100
88 84
Δ: 3.6%
(-1.6 to 8.8)
Δ: 4.9%
(1.3 to 11.1)
84
82
Wk 96
Δ: 2.7%
(-2.9 to 8.3)

17. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
EVG/COBI/TDF/FTC Noninferior to
ATV/RTV + TDF/FTC Through Wk 144
 EVG/COBI arm noninferior to
ATV/RTV arm at Wk 48 primary
endpoint[1]
and through Wk 144[2,3]
– Results consistent across subgroups:
BL HIV-1 RNA, CD4+ count,
adherence, age, sex, race
 Treatment-related study d/c:
6% in EVG/COBI arm vs
9% in ATV/RTV arm at Wk 144
 VF: 8% in EVG/COBI arm vs
7% in ATV/RTV arm at Wk 144
 Similar CD4+ cell count increase at
Wk 144: +280 cells/mm3
(EVG/COBI)
vs +293 cells/mm3
(ATV/RTV)
1. De Jesus E, et al. Lancet. 2012;379:2429-2438. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr.
2013;62:483-486. 3. Clumeck N, et al. EACS 2013. Abstract LBPS7/2.
EVG/COBI/TDF/FTC
(n = 353)
ATV/RTV + TDF/FTC
(n = 355)
Δ: 3.0%
(-1.9 to 7.8)
Δ: 1.1%
(-4.5 to 6.7)
Wk 48 Wk 144
78
75
0
20
40
60
80
100
90 87
Δ: 3.1%
(-3.2 to 9.4)
83
82
Wk 96

18. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
EVG/COBI/TDF/FTC Adverse Events
Summary
 EVG/COBI vs EFV: fewer CNS, rash events; smaller
increase in TC, HDL-C, and LDL-C (but similar increase in
TC:HDL ratio), similar TG increase; more nausea[1]
 EVG/COBI vs ATV/RTV: less jaundice; similar increase in
TC, HDL-C, and LDL-C; smaller TG increase[2]
 Small, rapid increase in serum creatinine related to
inhibition of tubular secretion of creatinine by COBI
– 0.14 ± 0.13 mg/dL at Wk 48; most change occurs by Wk 2[3]
 4 pts (0.6% of total) developed tubulopathy, likely from
TDF[3]
1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-
2438. 3. TDF/FTC/EVG/COBI [package insert].

19. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
EVG/COBI/TDF/FTC Resistance Summary
 EVG/COBI vs EFV through
Wk 144[1-3]
 EVG/COBI vs ATV/RTV
through Wk 144[4-6]
1. Sax PE, et al. Lancet. 2012;379:2439-2448. 2. Zolopa A, et al. J Acquir Immune Defic Syndr.
2013;63:96-100. 3. Wohl D, et al. ICAAC 2013. Abstract H-672a. 4. De Jesus E, et al. Lancet.
2012;379:2429-2438. 5. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486.
6. Clumeck N, et al. EACS 2013. Abstract LBPS7/2
EVG/COBI
(n = 348)
EFV
(n = 352)
Wk 48 96 144 48 96 144
Resistance
at VF, n 8 +2 +0 8 +2 +4
INSTI
RAMs, n 7 +2 +0
NNRTI
RAMs, n 8 +2 +4
NRTI
RAMs, n 8 +2 +0 2 +1 +1
EVG/COBI
(n = 353)
ATV/RTV
(n = 355)
Wk 48 96 144 48 96 144
Resistance
at VF, n 5 +1 +2 0 +0 +2
INSTI
RAMS, n 4 0 +1
PI RAMs, n 0 +0 +0
NRTI
RAMs, n 3 +1 +2 0 0 +2

20. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Dolutegravir vs Currently “Preferred”
Regimens in Treatment-Naive Pts
 Randomized, noninferiority phase III studies
 Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
ART-naive pts
VL ≥ 1000 c/mL
(N = 822)
DTG 50 mg QD + 2 NRTIs*
(n = 411)
RAL 400 mg BID + 2 NRTIs*
(n = 411)
*Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC.
ART-naive pts
VL ≥ 1000 c/mL
HLA-B*5701-neg
CrCL > 50 mL/min
(N = 833)
DTG 50 mg QD + ABC/3TC QD
(n = 414)
EFV/TDF/FTC QD
(n = 419)
SPRING-2[1]
(active controlled)
SINGLE[2]
(placebo controlled)
DTG 50 mg QD + 2 NRTIs*
(n = 242)
DRV/RTV 800/100 mg QD + 2 NRTIs*
(n = 242)
ART-naive pts
VL ≥ 1000 c/mL
(N = 484)
FLAMINGO[3]
(open label)
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
3. Feinberg J, et al. ICAAC 2013. Abstract H1464a.

21. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
SPRING-2: DTG vs RAL + 2 NRTIs in Naive
Patients
 DTG noninferior to RAL at both
Wk 48 primary endpoint[1]
and
Wk 96[2]
 Treatment-related study d/c:
2% in each arm at Wk 96
 VF atWk 96[2]
: 5% (22/411) in
DTG arm and 7% (29/411) in
RAL arm
 Similar CD4+ cell count
increase at Wk 96:
– +276 cells/mm3
(DTG) vs
+264 cells/mm3
(RAL)
HIV-1RNA<50copies/mL(%)
88 85
DTG 50 mg QD
(n = 411)
RAL 400 mg BID
(n = 411)
0
20
40
60
80
100
81
76
Wk 48 Wk 96
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17.
361/
411
351/
411
333/
411
314/
411
Δ: 4.4%
(-1.1% to 10.0%)
Δ: 2.5%
(-2.2% to 7.1%)

22. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC
in Naive Patients at Wk 48
 DTG superior to EFV at Wk 48
primary efficacy endpoint
 Treatment-related study d/c:
2% in DTG arm vs 10% in EFV
arm
 VF at Wk 48: 4% (18/414) in
DTG arm and 4% (17/419) in
EFV arm
 CD4+ cell count increase at
Wk 48 greater with DTG:
– +267 cells/mm3
(DTG) vs +208
cells/mm3
(EFV)
(P < .001)
HIV-1RNA<50c/mLatWk48(%)
88
81
Δ +7.4%
(95% CI +2.5% to +12.3%; P = .003)
Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.
DTG 50 mg +
ABC/3TC QD
EFV/TDF/
FTC QD
0
20
40
60
80
100
364/
414
340/
419

23. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in
Naive Patients at Wk 48
 DTG superior to DRV/RTV at
Wk 48 primary efficacy
endpoint
– Treatment-related study d/c:
2% in DTG arm vs 4% in
DRV/RTV arm
 VF at Wk 48: < 1% (n = 2) in
each arm
 Similar CD4+ cell count
increase at Wk 48:
– +210 cells/mm³ in each arm
HIV-1RNA<50c/mLatWk48(%)
90
83
Δ +7.1%
(95% CI: +0.9% to +13.2%; P = .025)
Feinberg J, et al. ICAAC 2013. Abstract H1464a.
DTG 50 mg
QD + NRTIs
DRV/RTV
800/100 mg QD
+ NRTIs
217/
242
200/
242
0
20
40
60
80
100

24. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Virologic Suppression at Wk 48 by
Baseline HIV-1 RNA
1. Lennox J, et al. Lancet. 2009;374:796-806. 2. Sax PE, et al. Lancet. 2012;379:2439-2448. 3. DeJesus E, et al. Lancet.
2012;379:2429-2438. 4. Brinson C, et al. CROI 2013. Abstract 554. 5. Feinberg J, et al. ICAAC 2013. Abstract H1464a.
≤ 100,000 c/mL
> 100,000 c/mL
SPRING-2[4]
3020100-20 -10
Difference, % (DTG-RAL) and 95% CI
In favor of RAL In favor of DTG
≤ 100,000 c/mL
> 100,000 c/mL
SINGLE[4]
3020100-20 -10
Difference, % (DTG-EFV) and 95% CI
In favor of DTGIn favor of EFV
Study 102[2]
FLAMINGO[5]
≤ 100,000 c/mL
> 100,000 c/mL
3020100-20 -10
Difference , % (DTG-DRV/RTV) and 95% CI
In favor of DTGIn favor of DRV/RTV
40
≤ 100,000 c/mL
> 100,000 c/mL
Difference, % (EVG/COBI-EFV) and 95% CI
In favor of EFV In favor of EVG/COBI
Study 103[3]
-15 -10 -5 5 10 150
≤ 100,000 c/mL
> 100,000 c/mL
Difference, % (EVG/COBI-ATV/RTV) and 95% CI
In favor of ATV/RTV In favor of EVG/COBI
≤ 100,000 c/mL
> 100,000 c/mL
STARTMRK[1]
3020100-20 -10
Difference, % (RAL-EFV) and 95% CI
In favor of EFV In favor of RAL
-15 -10 -5 5 10 150

25. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Similar Efficacy of INSTIs (RAL or DTG) +
ABC/3TC or TDF/FTC, Even for High BL VL
 In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or
DTG, including with high BL HIV-1 RNA*
Eron J, et al. Glasgow 2012. Abstract P204.
< 100k 100K - < 250K 250K - 500K > 500K
0
20
40
60
80
100
HIV-1RNA<50c/mLatWk48by
FDASnapshotAnalysis(%)
86
n/
N =
88
225/
257
91
306/
335
36/
42
82
72/
88
81
13/
16
76
29/
38
72
13/
18
64
18/
28
Baseline HIV-1 RNA (c/mL)
TDF/FTC
ABC/3TC
*Pooled data from both INSTIs.

26. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Dolutegravir: Adverse Events Summary
 DTG vs RAL[1,2]
– Adverse events similar between
arms
 DTG vs EFV[3]
– CNS events and rash more
common with EFV; insomnia
more frequent with DTG
 DTG vs DRV/RTV[4]
– More diarrhea with DRV/RTV;
more headache with DTG
 DTG associated with small,
rapid increase in serum
creatinine in first 4 wks of tx that
remained stable through Wk 48
(mean change from baseline:
+0.11 mg/dL; range: -0.60 to
0.62 mg/dL)[5]
– Rise in creatinine related to
inhibition of tubular secretion of
creatinine by DTG
– No drug-related
discontinuations due to renal
adverse events
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17.
3. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 4. Feinberg J, et al. ICAAC 2013. Abstract
H1464a. 5. Dolutegravir [package insert].

27. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Resistance Summary
 DTG vs RAL[1,2]
– 0 pts with resistance in DTG arm
– 1 pt with INSTI-R and 4 pts with NRTI-R with RAL at Wk 48;
no additional resistance by Wk 96
 DTG vs EFV[3]
– 0 pts with resistance in DTG arm
– 1 pt with NRTI and 4 with NNRTI resistance in EFV arm
 DTG vs DRV/RTV[4]
– No pts with resistance in either arm
1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Raffi F, et al. IAS 2013. Abstract TULBPE17. 3. Walmsley
S, et al. N Engl J Med. 2013;369:1807-1818. 4. Feinberg J, et al. ICAAC 2013. Abstract H1464a.

28. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Integrase Inhibitors for Initial Therapy:
Conclusions
 While there are many options for initial therapy, regimens
that include an integrase inhibitor have many favorable
characteristics
– All are potent, well tolerated, favorable metabolic profile
– Rates of transmitted (baseline) drug resistance to INSTIs
presumed to be low
– Few drug–drug interactions (RAL, DTG)
– Resistance rarely reported with DTG
– Available as single-pill regimen (EVG)
 Integrase inhibitor–based regimens may be appropriate for
many (if not most) treatment-naive patients

29. Switch Studies Involving
Integrase Inhibitors

30. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Switching Virologically Suppressed
Patients to RAL
 SWITCHMRK-1 and -2[1]
– Switching to RAL inferior to remaining on LPV/RTV-based regimen in pts with
HIV-1 RNA < 50 c/mL for > 3 mos, particularly among those with previous VF
– TC, non–HDL-C, and TG improved in switch pts
 SPIRAL[2]
– Switching from to RAL noninferior to remaining on boosted PI-based regimens
through Wk 48 in pts with HIV-1 RNA < 50 c/mL for ≥ 6 mos
 Switching to RAL significantly improved lipids and TC:HDL-C ratio
 EASIER/ANRS 138[3]
– Switch from ENF to RAL regimens maintained virologic suppression through Wk 48
in patients with multidrug resistance and HIV-1 RNA < 400 c/mL for ≥ 3 mos
1. Eron J, et al. Lancet. 2010;375:396-407. 2. Martinez E, et al. AIDS. 2010;24:1697-1707.
3. Gallien S, et al. J Antimicrob Chemother. 2011;66:2099-2106.

31. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Study 123: Switch From RAL + TDF/FTC to
EVG/COBI/TDF/FTC
 Open-label, multicenter, 48-wk pilot study of switch from RAL + TDF/FTC to
EVG/COBI/TDF/FTC in pts with HIV-1 RNA < 50 c/mL for 6 mos (N = 48)
 Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 12 postswitch
 Secondary endpoints: Safety and tolerability by Wk 24 and Wk 48
HIV-1 RNA < 50 c/mL at Wk 24 and Wk 48 postswitch
 All subjects maintained virologic
suppression at Wks 12 and 24
– 38/38 subjects who reached
Wk 48 at time of report also
suppressed
 TC and LDL-C improved;
no renal AEs
Crofoot G, et al. IAS 2013. Abstract TUPE283.
HIV-1RNA<50c/mL(%)
100
80
60
40
20
0
Wk 12
48/48 48/48 38/38*
Wk 24 Wk 48

32. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Examples of Ongoing INSTI Switch
Studies in Suppressed Pts
 Raltegravir (primarily switches for tolerability)
– TDF-based NRTI + boosted PI → RAL + boosted PI in pts with low BMD
– Boosted PI → RAL in HIV/HCV-coinfected pts to assess effect on fibrosis
progression
– NNRTI or boosted PI → RAL to assess effect on lipids
– LPV/RTV → RAL to assess endothelial recovery
– NRTIs + boosted PI → RAL + boosted PI to assess safety and efficacy of
NRTI-sparing regimen
 Elvitegravir (primarily switches for simplicity)
– Phase IIIb open-label pilot study: RAL + TDF/FTC → EVG/COBI/TDF/FTC
– Phase IIIb open-label study: NNRTI + TDF/FTC → EVG/COBI/TDF/FTC
– Phase IIIb open-label study: Boosted PI + TDF/FTC → EVG/COBI/TDF/FTC
ClinicalTrials.gov.

33. Using Integrase Inhibitors in
Treatment-Experienced Patients

34. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
TRIO Study (ANRS 139): RAL + ETR +
DRV/RTV in Treatment-Experienced Pts
 Multicenter phase II study of DRV/RTV + ETR + RAL (N = 103); addition of
NRTIs, ENF at discretion of physician
– Inclusion criteria: susceptibility to DRV and ETR based on ≤ 3 DRV and
≤ 3 ETR RAMs, respectively
– 59% of pts had < 1 active agent in OBR, as assessed by GSS
 86% of pts reached HIV-1 RNA < 50 c/mL at Wk 48 (95% CI: 79% to 93%)[1]
 Of 100 pts entering extension trial through Wk 96, 88% achieved HIV-1 RNA
< 50 c/mL (95% CI: 82% to 94%)[2]
 Median CD4+ cell count change: +150 cells/mm3
 4 tx-related grade 3/4 AEs reported before Wk 48: recurrent epidermal
necrolysis (n = 1) (study d/c); nephrolithiasis (n = 1); lipodystrophia (n = 1);
muscle spasm (n = 1)
 No further events between Wks 48 and 96
1. Yazdanpanah Y, et al Clin Infect Dis. 2009;49:1441-1449.
2. Fagard C, et al. Acquir Immune Defic Syndr. 2012;59:489-493.

35. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Study 145: Elvitegravir vs Raltegravir in
Treatment-Experienced Patients
 Randomized, placebo-controlled phase III study
Molina J, et al. Lancet Infect Dis. 2012;12:27-35.
HIV-infected pts,
HIV-1 RNA ≥ 1000
copies/mL,
resistance or 6 mos of
exposure to ≥ 2
antiretroviral classes
(N = 702)
Wk 96
*EVG currently unavailable as single agent.
†
EVG dose reduced to 85 mg QD for pts receiving ATV/RTV or LPV/RTV as part of background regimen.
‡
Background regimen to include fully active RTV-boosted PI, selected using resistance testing.
§
Selected from ENF, ETR, MVC, or NRTI. Option of also adding FTC or 3TC for pts with M184V/I.
Wk 48
Elvitegravir 150 mg (or 85 mg) QD*
+
Boosted PI‡
+ Third Agent§
(n = 351)
Raltegravir 400 mg BID +
Boosted PI‡
+ Third Agent§
(n = 351)

36. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Study 145: EVG Noninferior to RAL at Wks
48 and 96
 Similar incidence of
resistance at VF with EVG vs
RAL
– Integrase resistance: 6.6%
vs 7.4%
– OBR resistance: 7.4% vs
7.1%
 Both regimens well tolerated
– Higher rates of diarrhea with
EVG at Wks 48 and 96
– Discontinuations: 3% vs 4%
Elion R, et al. J Acquir Immune Defic Syndr. 2013;63:494-497.
100
80
60
40
20
0
Subjects(%)
Wk 48 Wk 96 Wk 48 Wk 96 Wk 48 Wk 96
Virologic
Response
Virologic
Failure*
Other
59 58
EVG (n = 351)
RAL (n = 351)
48 45
26 29 26 26
22 23 19 19
*VF includes never suppressed, rebound, switch of BR, and
d/c due to lack of efficacy.

Others include death, discontinuation due to AE,
investigator’s discretion, lost to follow-up, pregnancy, protocol
violation, subject noncompliance, withdrawal of consent.

37. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
SAILING: Dolutegravir vs Raltegravir in
ART-Exp’d, Integrase Inhibitor–Naive Pts
 Randomized, double-blind, noninferiority, phase III study
Treatment-experienced,
integrase inhibitor–naive
patients with HIV-1 RNA
> 400 copies/mL and
≥ 2 class resistance
(N = 715)
Dolutegravir 50 mg QD
+ Raltegravir placebo + OBR*
(n = 354)
Raltegravir 400 mg BID
+ Dolutegravir placebo + OBR*
(n = 361)
Stratified by number of fully active background
agents, use of DRV, screening HIV-1 RNA
(≤ vs > 50,000 copies/mL) Wk 48
*OBR comprising at least 1 and no more than 2 active agents.
Cahn P, et al. Lancet. 2013;382:700-708.

38. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
SAILING: Superior Rate of Virologic
Suppression With DTG vs RAL at Wk 48
 Lower incidence of resistance
at VF with DTG vs RAL
– Integrase resistance: 1%
(4/354) vs 5% (17/361);
P = .003
– OBR resistance: 1% (4/354) vs
3% (12/361)
 Both regimens well tolerated
with similar AE profiles
– Grades 2-4: 8% vs 9%
– Discontinuations: 3% vs 4%
 No difference in outcome between
study arms when combined with
fully active DRV/RTV
Cahn P, et al. Lancet. 2013;382:700-708.
100
80
60
40
20
0
Subjects(%)
Virologic
Success
Virologic
Nonresponse
No Wk
48 Data
DTG + OBR (n = 354)
RAL + OBR (n = 361)
71
64
20
28
9 9
Δ: 7.4% (95% CI: 0.7-14.2;
P = .03)

39. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
VIKING-3: Dolutegravir After Failure of
Integrase Inhibitor–Based Regimen
 Phase III single-arm trial
 Mean HIV-1 RNA change from baseline to Day 8
– Overall: -1.4 log10 copies/mL (P < .001)
– No primary integrase resistance mutations at BL: -1.6 log10 copies/mL
– Q148 + ≤ 1 secondary integrase resistance mutation: -1.1 log10 copies/mL
– Q148 + ≥ 2 secondary integrase resistance mutations: -1.0 log10 copies/mL
Nichols G, et al. Glasgow 2012. Abstract O232.
Pts with HIV-1 RNA
≥ 500 c/mL, RAL and/or
EVG resistance, and
resistance to ≥ 2 other
antiretroviral classes*
(N = 183)
Dolutegravir 50
mg BID +
Continue Failing
Regimen
Dolutegravir 50 mg BID +
Optimized Background Regimen With
Overall Susceptibility Score ≥ 1
(ie, ≥ 1 active drug)
Day 8 Wk 24 Wk 48
*Detected at screening or based on historical evidence.
Functional
Monotherapy
Optimized Therapy

40. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
VIKING-3: Efficacy of DTG in
INSTI-Experienced Pts at Wk 48
 24-wk data on full cohort
(N = 183) and 48-wk data on
first 114 pts
 Response rates affected
by baseline INSTI resistance
but not overall susceptibility
score of background regimen
HIV-1 RNA < 50 c/mL at Wk 24
by INSTI Mutation(s), n/N (%)
Overall Susceptibility Score
0 1 ≥ 2 Total
No Q148 4/4 (100) 35/40 (83) 57/70 (76) 96/114 (79)
Q148 + 1 2/2 (100) 8/12 (67) 10/17 (59) 20/31 (65)
Q148 + ≥ 2 1/2 (50) 2/11 (18) 1/3 (33) 4/16 (25)
Outcome, n (%) Wk 24
(n = 183)
Wk 48
(n = 114)
HIV-1 RNA < 50 c/mL at
Wk 24 (snapshot, ITT-E) 126 (69) 64 (56)
Virologic nonresponse 50 (27) 44 (39)
d/c due to AE or death 5 (3) 5 (4)
Nichols G, et al. IAS 2013. Abstract TULBPE19.

41. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Drug–Drug Interactions With Integrase
Inhibitors and Key Drugs
RAL[1,2]
EVG/COBI[1]
DTG[3]
 Rifampin
 Antacids
containing
polyvalent cations
(Ca++, Mg++)
 Antacids
 Benzodiazepines
 Beta blockers
 Calcium channel
blockers
 Erectile dysfunction
drugs
 Inhaled/injectable
corticosteroids
 MVC
 OCPs (norgestimate)
 Rifampin
 Statins
 EFV
 ETR
 FPV/RTV
 Medications containing
polyvalent cations (Ca++,
Mg++), including
laxatives, antacids
 Metformin
 Rifampin
 TPV/RTV
1. DHHS Adult Guidelines. February 2013. 2. Raltegravir [package insert]. 3. Dolutegravir [package insert].
*May be a class effect

42. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Integrase Inhibitors for Treatment-
Experienced Patients: Conclusions
 INSTIs appropriate for many treatment-experienced pts
– For INSTI-naive pts, all INSTIs should be active
– DTG superior to RAL, EVG noninferior to RAL
– For INSTI-experienced pts, DTG superior to RAL
– Cross-resistance between EVG and RAL
 Difficult to use EVG due to current FDC-only regimen, lack of data
combining FDC with other ARVs
 Much clinical experience with RAL as component of new regimens for
pts with NRTI, NNRTI, PI experience
 DTG represents a new option for INSTI-experienced pts
– BID dosing recommended for those with INSTI resistance

43. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Raltegravir Summary:
Advantages and Disadvantages
Advantages Disadvantages
 INSTI with longest track record of
safety and efficacy—approved in
2007
 Noninferior to EFV in initial therapy
at Wk 48 (superior from Wk 192
through Yr 5 final analysis)
 Fewer CNS adverse effects, less
rash, and better lipids than EFV
 Few drug–drug interactions
 No food effect
 Conflicting data on efficacy in switch
strategies
 Integral part of many regimens in
treatment-experienced pts
 Twice-daily dosing
 No FDC available or planned
 Rare CNS, cutaneous, and muscle-
related adverse effects
 Inferior to DTG in treatment-
experienced patients
 Risk of resistance at VF, especially in
treatment-experienced pts
 When VF failure occurs with
resistance, 2-class resistance is
common

44. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Elvitegravir Summary:
Advantages and Disadvantages
Advantages Disadvantages
 Only INSTI currently available as a
1-pill once-daily regimen
 Noninferior to EFV and ATV/RTV in
initial therapy
 Maintains antiviral activity as well as
comparators across HIV-1 RNA and
CD4+ cell count strata
 Fewer CNS adverse effects, less
rash, and better lipids than EFV
 Less jaundice than ATV/RTV
 Appears to be effective switch
regimen for patients on first-line RAL
 Noninferior to RAL in treatment-
experienced patients
 Not recommended for patients with
eGFR < 70 mL/min
 Must be taken with food
 Cobicistat inhibits tubular secretion of
creatinine, increasing Cr levels
 More nausea than EFV
 Risk of resistance at VF, especially in
treatment-experienced patients
 When VF occurs with resistance,
2-class resistance is common
 Many COBI-related drug–drug
interactions
 Currently only available in FDC,
limiting regimen flexibility

45. clinicaloptions.com/hiv
The Evolving Role of Integrase Inhibitors in HIV Therapy
Dolutegravir Summary:
Advantages and Disadvantages
Advantages Disadvantages
 Once-daily administration
 Small mg dose and tablet size
 Noninferior to RAL and superior to
EFV and DRV/RTV
 Maintains comparable or better
virologic activity to EFV, RAL,
DRV/RTV across low and high HIV-
1 RNA
 Fewer CNS and rash events vs EFV
 When VF occurs, no integrase
resistance mutations as yet detected
in treatment-naive patients
 Few drug–drug interactions
 Can be taken with or without food
 Not yet available as part of FDC
 Inhibits tubular secretion of
creatinine, increasing Cr levels
 Relatively little clinical experience
compared with RAL (especially) and
EVG

46. Go Online for More Educational
Content on Integrase Inhibitors!
Interactive Virtual Presentation with faculty commentary and case
studies illustrating the use of integrase inhibitors across the treatment
spectrum
clinicaloptions.com/Integrase2013