Comparative Neuropsychiatric Profile of Dolutegravir and Efavirenz After 48w

in Treatment Naive Patients: Data From ING114467 SINGLE Study

S. Moreno,1 P. Viciana,2 M. G�rgolas,3 V. Soriano,4 D. Podzamczer,5 F. Guti�rrez,6

M. Pe�aranda,7 J. Berenguer,8 A. Antela9 on behalf of the SINGLE study team

1H. Ramon y Cajal, Madrid, Spain; 2H. Virgen del Rocio, Seville, Spain; 3H. Fundaci�n Jim�nez D�az, Madrid, Spain; 4H. Carlos III, Madrid, Spain; 5H. Bellvitge, Barcelona, Spain; 6H. General de Elche &

UMH, Alicante, Spain; 7H. Son Espasses, Palma de Mallorca, Spain; 8H. Gregorio Mara��n, Madrid, Spain; 9Complejo Universitario Santiago de Compostela, La Coru�a, Spain

6th International Symposium of Neuropsychiatry and HIV

May 9-10, 2013

Study sponsored by ViiV Healthcare

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 2Study sponsored by ViiV Healthcare

• Dolutegravir (DTG, S/GSK1349572) is a new integrase inhibitor with a 14-hour plasma half-life that enables once-daily dosing without pharmacokinetic boosters.1,2 Regulatory review of DTG for the treatment of HIV-1 infection in adults and adolescents is ongoing globally.

• DTG 50 mg once daily was non-inferior to twice-daily raltegravir 400 mg at 48 weeks in na�ve patients, both in combination with coformulated TDF/FTC or ABC/3TC, in SPRING-2 study.3

• Atripla is a first-line antirretroviral therapy in HIV-infected na�ve patients. CNS toxicity is the most common reason for Atripla discontinuations.4

• Both approved integrase strand transfer inhibitors, raltegravir and elvitegravir, have shown non-inferiority in terms of efficacy and better CNS and psychiatric tolerability compared with Atripla.5,6

Introduction

1. Min S, Song I, Borland J, et al. Antimicrob Agents Chemother. 2010;54(1):254-258; 2. Powderly WG. J Antimicrob Chemother. 2010;65(12):2485-2488; 3. Raffi F, et al. Lancet 2013; 381: 735–43; 4. Scourfield A, et al. AIDS 2012, 26:1399–1401 5. Lenox et al Lancet 2009; 374: 796–806; 6. Sax PE et al. Lancet 2012; 379: 2439–48.

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 3Study sponsored by ViiV Healthcare

Study Design

Primary endpoint: Proportion with HIV-1 RNA <50 c/mL at Week 48, FDA snapshot analysis, -10% noninferiority margin with prespecified tests for superiority

Secondary endpoints:Tolerability, long-term safety, immunologic, health outcome and viral resistance

HIV+ ART-naiveVL ≥1000 c/mL

HLA-B*5701 negativeCreatinine clearance >50 mL/min

Stratified by Baseline plasma HIV-1 RNA and CD4 cell count Atripla QD + DTG + ABC/3TC FDC Placebo

DTG 50 mg + ABC/3TC FDC QD+ Atripla (ATR) Placebo

Week 96Randomization Week 48Primary analysis

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 4Study sponsored by ViiV Healthcare

Baseline Characteristics

DTG 50 mg +ABC/3TC QD

(N=414)Atripla QD

(N=419)Total

(N=833)

Age (y), median 36 35 35

Female (%) 16% 15% 16%

African American/African heritage (%) 24% 24% 24%

CDC class C (%) 4% 4% 4%

HIV-1 RNA (log10 c/mL), median 4.67 4.70 4.68

>100,000 32% 31% 32%

CD4+ (cells/mm3) median 335 339 338

<200 14% 14% 14%

200 to <350 39% 38% 39%

350 to <500 32% 31% 31%

≥500 15% 17% 16%

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 5Study sponsored by ViiV Healthcare

Subject Disposition

12% Subjects Withdrawn (N=51)

Adverse eventSuspected HSR

10 (2%)2 (<1%)

Lack of efficacy(Virologic failure)

14 (3%)

Protocol deviation 7 (2%)

Lost to follow-up 14 (3%)

Investigator discretion 1 (<1%)

Withdrew consent 5 (1%)

Randomized and Treated(N=414)

Randomized and Treated(N=419)

20% Subjects Withdrawn(N=84)

Adverse eventSuspected HSR

42 (10%)4 (<1%)

Lack of efficacy(Virologic failure)

13 (3%)

Protocol deviation 7 (2%)

Lost to follow-up 9 (2%)

Investigator discretion 2 (<1%)

Withdrew consent 11 (3%)

88% Continued (N=363)

80% Continued (N=335)

Randomized DTG + ABC/3TC 50 mg QD (N=422)

(N=422)

Randomized Atripla QD(N=422)

Screened(N=1090)

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 6Study sponsored by ViiV Healthcare

Proportion (95% CI) of Subjects <50 c/mL (FDA Snapshot)

• DTG 50 mg + ABC/3TC QD was statistically superior to Atripla at Week 48 (primary endpoint).• Subjects receiving DTG + ABC/3TC achieved virologic suppression faster than Atripla; median

time to HIV-1 RNA <50 c/mL of 28 days (DTG + ABC/3TC) versus 84 days (Atripla), P<0.0001.

Week

Atripla (ATR) QD

DTG 50 mg + ABC/3TC QD

BL 2 4 8 12 16 24 32 40 48

0

10

20

30

40

50

60

70

80

90

100

Prop

orti

on (%

) of s

ubje

cts

<50

c/m

L H

IV-1

RN

A

DTG + ABC/3TC: 88%

ATR: 81%

Week 48 difference in response (95% CI): +7.4% (+2.5% to +12.3%); P=0.003

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 7Study sponsored by ViiV Healthcare

Significant at prespecified level of 4%

DTG 50 mg + ABC/3TC QD Atripla QDAdj

uste

d m

ean

chan

ge fr

om B

asel

ine

CD4+

cel

l cou

nt (c

ells

/mm

3 )

300

250

200

150

100

50

04 8 12 16 24 32 40 48

Week

Week 48 difference in response (95% CI): 59 (33 to 84); P<0.001

DTG + ABC/3TC 267 cells/mm3

ATR 208 cells/mm3

Absolute Change From Baseline in CD4+ Cell Count Repeated Measures Mixed Model Analysis

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 8Study sponsored by ViiV Healthcare

Most Common Adverse Events (≥10%)

Adverse Event

DTG 50 mg + ABC/3TC QD(N=414), %

Atripla QD(N=419), %

Any event 369 (89) 387 (92)

Dizziness 37 (9) 148 (35)

Abnormal dreams 30 (7) 72 (17)

Insomnia 64 (15) 43 (10)

Headache 55 (13) 56 (13)

Fatigue 54 (13) 50 (12)

Diarrhea 72 (17) 75 (18)

Nausea 59 (14) 57 (14)

Nasopharyngitis 62 (15) 60 (14)

Upper respiratory tract infection 36 (9) 43 (10)

Rash 14 (3) 58 (14)

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 9Study sponsored by ViiV Healthcare

Select Adverse Events

DTG 50 mg+ ABC/3TC QD

(N=414), %Atripla QD(N=419), %

Subjects with events leading to withdrawal 10 (2) 42 (10)*

Serious drug-related – any event 1 (<1)** 8 (2)^

Fatal AEs 0 2(<1)�

*Atripla: Most commonly reported events were CNS, gastrointestinal and rash

**DTG + ABC/3TC: 1 drug hypersensitivity

^Atripla: 4 psychiatric, 2 drug hypersensitivity, 1 cerebral vascular accident, 1 renal failure�Deaths: n=1 primary cause of death judged unrelated to study drug but complicated by renal failure judged possibly related to ATR, n=1 not related to ATR (pneumonia)

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 10Study sponsored by ViiV Healthcare

Events Leading to Withdrawal by Key Subgroups

0

2

4

6

8

10

12

14

16

SPRING2 SINGLE SPRING2 SINGLE

Perc

enta

ge o

f Sub

ject

s (%

)

DTG + ABC/3TC

7/280

TDF/FTC/EFV

30/288 3/134 12/131

TDF/FTC/EFV

DTG + ABC/3TC

0

2

4

6

8

10

12

14

16

SPRING2 SINGLE SPRING2 SINGLE

Perc

enta

ge o

f Sub

ject

s (%

)

DTG + ABC/3TC

6/220

TDF/FTC/EFV

23/221 4/194 19/198

DTG + ABC/3TC

TDF/FTC/EFV

0

2

4

6

8

10

12

14

16

SPRING2 SINGLE SPRING2 SINGLE

Perc

enta

ge o

f Sub

ject

s (%

)

DTG + ABC/3TC

9/284

TDF/FTC/EFV

27/28 1/98 11/99

DTG + ABC/3TC

TDF/FTC/EFV

0

2

4

6

8

10

12

14

16

SPRING2 SINGLE SPRING2 SINGLE

Perc

enta

ge o

f Sub

ject

s (%

)

T�tulo del eje

DTG + ABC/3TC

4/67

TDF/FTC/EFV

9/63 6/347 33/35

DTG + ABC/3TC

TDF/FTC/EFV

0

2

4

6

8

10

12

14

16

SPRING2 SINGLE SPRING2 SINGLE

Perc

enta

ge o

f Sub

ject

s (%

)

DTG + ABC/3TC

9/361 38/37 1/53 4/44

DTG + ABC/3TC

TDF/FTC/EFV TDF/FTC/

EFV

<50 years ≥50 years

Age

White AA/AH

Race

Female Male

Sex

≤100,000 c/mL >100,000 c/mL

Baseline HIV-1 RNACD4

<350 cells/mm ≥350 cells/mm

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 11Study sponsored by ViiV Healthcare

Predefined Adverse Events: Neuropsychiatric AEs of Interest

System Organ ClassPreferred Term

DTG 50 mg+ ABC/3TC QD

(N=414), %Atripla QD(N=419), %

Difference inpercentage

(95% CI)

Fisher'sexact

P value

Any event 169 (41) 260 (62)Nervous system disorders

91 (22) 196 (47) -24.8 (-31.0, -18.6) <0.001

Dizziness 37 (9) 148 (35) -26.4 (-31.7, -21.0) <0.001Headache 55 (13) 56 (13) -0.1 (-4.7, 4.5) 1.000Somnolence 9 (2) 23 (5) -3.3 (-5.9, -0.7)

Psychiatric disorders 120 (29) 158 (38) -8.7 (-15.1, -2.3) 0.008Insomnia 64 (15) 43 (10) 5.2 (0.7, 9.7) 0.029Abnormal dreams 30 (7) 72 (17) -9.9 (-14.3, -5.5) <0.001Nightmare 9 (2) 17 (4) -1.9 (-4.2, 0.5)Sleep disorder 6 (1) 11 (3) -1.2 (-3.1, 0.7)Depression 23 (6) 26 (6) -0.6 (-3.8, 2.5)Depressed mood 3 (<1) 7 (2) -0.9 (-2.4, 0.5)Anxiety 14 (3) 27 (6) -3.1 (-6.0, -0.1)

Only AEs of interest occurring in at least 2% of subjects in either group are presented. P value only derived if more than 10% of subjects in either group experienced this AE.

6th International Symposium of Neuropsychiatry and HIV; May 9-10, 2013; Barcelona, Spain 12Study sponsored by ViiV Healthcare

• DTG 50mg+ABC/3TC is superior to Atripla with respect to snapshot (<50 c/mL) at Week 48• 88% on DTG were virologically suppressed (<50 c/mL) vs 81% on Atripla • 95% CI: (2.5%, 12.3%), lower end above pre-specified -10% non-inferiority limit• DTG 50mg+ABC/3TC statistically superior to Atripla in CD4 change from baseline

• DTG + ABC/3TC safety & tolerability generally favorable vs Atripla

• Fewer rash and discontinuations due to AEs

• Lower rate of liver chemistry elevations

• DTG + ABC/3TC was associated with lower rate of CNS events, than efavirenz.

Conclusions