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

Joseph J. Eron Jr., MDProfessor of MedicineUniversity of North Carolina School of MedicineDirector, AIDS Clinical Trials UnitUniversity of North CarolinaChapel Hill, North Carolina

The Evolving Role of Integrase Inhibitors in HIV Therapy

This program is supported by an educational grant from

clinicaloptions.com/hivThe Evolving Role of Integrase Inhibitors in HIV Therapy

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Program Director and Content Planning FacultyJoseph J. Eron Jr., MDProfessor of MedicineUniversity of North Carolina School of MedicineDirector, AIDS Clinical Trials UnitUniversity of North CarolinaChapel Hill, North Carolina

Paul E. Sax, MDClinical Director HIV Program and Division of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts

Kimberly Y. Smith, MDAssociate Professor of Medicine Division of Infectious DiseasesRush University Medical CenterChicago, Illinois


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.

The Evolving Role of Integrase Inhibitors in HIV Therapy

Viral Life Cycle and Mechanism of Action


HIV Viral Life Cycle

Attachmentfusion

Budding

Reverse transcription

Maturation

Integration

Uncoating

Transcription, translation

Assembly


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.

Attachmentfusion

Uncoating

Integraseinhibitors


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

Using Integrase Inhibitors in Treatment-Naive Patients


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


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.

281282

100

80

60

40

20

0

HIV

-1 R

NA

< 5

0 c/

mL

(%

)

0 48 72 96 120 144Wks

RALEFV

Pts at Risk, n281282

276282

280281

281282

277281

280281

86

82

81

79

75

69

281282

192

76

67∆: +9.5% (95% CI: 1.7% to 17.3%;noninferiority P < .001)

24012 216

71

61

277282

279279

24

279282

168

281282


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


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

-1 R

NA

< 5

0 c

/mL

(N

C =

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

8389

0

20

40

60

80

100

RAL 800 mgQD (n = 382)

RAL 400 mgBID (n = 389)

318/382

343/389

∆: -5.7 (95% CI: -10.7 to -0.83;

P for noninferiority = .044)

Wk 48


Elvitegravir/Cobicistat vs EFV or ATV/RTV + TDF/FTC in Treatment-Naive Pts Randomized, double-blind, active-controlled phase III studies


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)


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)

8075

0

20

40

60

80

10088 84

Δ: 3.6% (-1.6 to 8.8)

Δ: 4.9% (1.3 to 11.1)

8482

Wk 96

Δ: 2.7% (-2.9 to 8.3)


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 vs7% 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

10090 87

Δ: 3.1% (-3.2 to 9.4)

8382

Wk 96


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].


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


Dolutegravir vs Currently “Preferred” Regimens in Treatment-Naive Pts Randomized, noninferiority phase III studies


ART-naive ptsVL ≥ 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 ptsVL ≥ 1000 c/mLHLA-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 ptsVL ≥ 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.


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 at Wk 96[2]: 5% (22/411) in DTG arm and 7% (29/411) in RAL arm


– +276 cells/mm3 (DTG) vs+264 cells/mm3 (RAL)

HIV

-1 R

NA

< 5

0 co

pie

s/m

L (

%)

88 85

DTG 50 mg QD (n = 411)

RAL 400 mg BID (n = 411)

0

20

40

60

80

100

8176

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%)


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

-1 R

NA

< 5

0 c/

mL

at

Wk

48 (

%)

8881

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


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


– +210 cells/mm³ in each arm

HIV

-1 R

NA

< 5

0 c/

mL

at

Wk

48 (

%)

9083

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


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


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 > 500K0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 c/

mL

at

Wk

48

by

FD

A S

nap

sho

t A

nal

ysis

(%

)

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/FTCTDF/FTCABC/3TCABC/3TC

*Pooled data from both INSTIs.


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].


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.


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

Switch Studies Involving Integrase Inhibitors


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.


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 48HIV-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

-1 R

NA

< 5

0 c/

mL

(%

)

100

80

60

40

20

0Wk 12

48/48 48/48 38/38*

Wk 24 Wk 48


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.

Using Integrase Inhibitors in Treatment-Experienced Patients


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.


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)


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

Su

bje

cts

(%)

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 2622 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.


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.


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

Su

bje

cts

(%)

VirologicSuccess

VirologicNonresponse

No Wk 48 Data

DTG + OBR (n = 354)RAL + OBR (n = 361)

7164

2028

9 9

Δ: 7.4% (95% CI: 0.7-14.2;P = .03)


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


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 susceptibilityscore 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.


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


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


Raltegravir Summary: Advantages and DisadvantagesAdvantages 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


Elvitegravir Summary: Advantages and DisadvantagesAdvantages 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


Dolutegravir Summary: Advantages and DisadvantagesAdvantages 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

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

http://www.clinicaloptions.com/Integrase2013

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

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