Comparison of INSTI vs INSTI

QDMRK SPRING-2

Raffi F. Lancet 2013;381:735-43

Design

Objective– Non inferiority of DTG at W48: % HIV RNA < 50 c/mL by intention to treat,

snapshot analysis (1-sided significance level of 2.5%, lower margin of the 95% CI for the difference = -10%, 90% power)

DTG 50 mg QD + RAL placebo + 2 NRTI**

RAL 400 mg BID + DTG placebo + 2 NRTI**

Randomisation*1 : 1

Double-blind

Randomisation*1 : 1

Double-blind

> 18 yearsARV-naïve

HIV RNA > 1,000 c/mLAny CD4 cell count

No primary resistance in RT or protease

> 18 yearsARV-naïve

HIV RNA > 1,000 c/mLAny CD4 cell count

No primary resistance in RT or protease

*Randomisation (DTG vs RAL) was stratified by HIV RNA (< or > 100,000 c/mL) at screening and NRTI backbone

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

N = 411

N = 411

W48W48 W96W96

SPRING-2

**NRTI backbone (TDF/FTC or ABC/3TC if exclusion of the HLA-B*5701 allele) selected by investigator

DTG + 2 NRTIN = 411

RAL + 2 NRTIN = 411

Median age, years 37 35

Female 15% 14%

HIV RNA (log10 c/mL), median 4.52 4.58

HIV RNA > 100,000 c/mL 28% 28%

CD4 cell count (/mm3), median 359 362

CD4 < 200 per mm3 13% 12%

Hepatitis B / hepatitis C coinfection 2% / 10% 2% / 9%

Dual NRTI on day 1 : TDF/FTC / ABC/3TC 59% / 41% 60% / 40%

Discontinuation by W48 47 (11.4%) 56 (13.6%)

For virologic failure N = 16 N = 24

For adverse event / For liver stopping criteria N = 8 / N = 2 N = 6 / N = 1

Lost to follow-up N = 4 N = 7

Protocol deviation / Withdrew consent N = 13 / N = 4 N = 11 / N = 7

Discontinuation by W96 62 (15%) 79 (19%)

Baseline characteristics and patient disposition

Raffi F. Lancet 2013;381:735-43 ; Raffi F. Lancet Infect Dis 2013; 13:927-35

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

SPRING-2

Response to treatment at week 48

Median CD4/mm3 increase at W48 :+ 230 in both groups

Non-inferiority was also supported by Kaplan-Meier estimates of the proportion of patients without virological failure by week 48

The number of patients who achieved the primary endpoint was similar between subgroups in analyses that combined high and low HIV RNA strata and backbone NRTI

25

50

100

75

87.8 85.4

Adjusted difference(95% CI) =

2.5% (- 2.2 ; 7.1)

89.9 88.4

Adjusted difference(95% CI) =

= 1.6% (- 2.7 ; 5.9)

ITT, snapshot Per protocol

DTG + 2NRTIRAL + 2 NRTI

HIV RNA < 50 c/mL

Primary analysis%

0

Raffi F. Lancet 2013;381:735-43

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

SPRING-2

DTG 50 mg QDN = 411

RAL 400 mg BIDN = 411

Difference in % (95% CI)

DTG – RAL

Number of Responders/Number Assessed

Baseline Plasma HIV-1 RNA

≤ 100,000 c/mL 267 / 297 (90%) 264 / 295 (89%) 0.4 (-4.5, 5.3)

>100,000 c/mL 94 / 114 (82%) 87 / 116 (75%) 7.5 (-3.1, 18.0)

P = 0.236*

Background Dual NRTI

ABC/3TC 145 / 169 (86%) 142 / 164 (87%) -0.8 (-8.2, 6.6)

TDF/FTC 216 / 242 (89%) 209 / 247 (85%) 4.6 (-1.3, 10.6)

P = 0.264*

* Test for homogeneity

HIV-1 RNA < 50 c/mL at week 48 by stratification factors

Raffi F. Lancet 2013;381:735-43

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

SPRING-2

Response to treatment at week 96

25

50

100

75

80.876.4

%

Adjusted difference(95% CI) =

4.5 % (- 1.1 ; 10.0)

83.580.4

Adjusted difference(95% CI) =

3.2 % (- 2.1 ; 8.6)

ITT, snapshot Per protocol

25

50

100

75

78

63

%

> 100,000

HIV-1 RNA (c/mL) NRTI backbone

74 76

DTG + 2 NRTIRAL + 2 NRTI

HIV RNA < 50 c/mL at week 96

0 0

ITT snapshot, by baseline stratification factors

≤ 100,000 TDF/FTC ABC/3TC

82 8286

77

Raffi F. Lancet Infect Dis 2013;13:927-35

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

SPRING-2

Raffi F. Lancet Infect Dis 2013;13:927-35

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

Virologic non-responders (ITT, snapshot) at week 96 by baseline stratification factors

SPRING-2

DTG 50 mg QDN = 411

RAL 400 mg QDN = 411

Baseline HIV-1 RNA < 100,000 c/mL 10/297 (3) 17/295 (6)

Baseline HIV-1 RNA > 100,000 c/mL 12/114 (11) 26/116 (22)

ABC/3TC 10/169 (6) 16/164 (10)

TDF/FTC 12/242 (5) 27/247 (11)

ABC/3TC(N = 169)

TDF/FTC(N = 242)

ABC/3TC(N = 164)

TDF/FTC(N = 247)

Baseline HIV-1 RNA < 100,000 c/mL 6/132 (5) 4/165 (2) 8/125 (6) 9/170 (5)

Baseline HIV-1 RNA > 100,000 c/mL 4/37 (11) 8/77 (10) 8/39 (21) 18/77 (23)

Virologic failure definition– 2 consecutive plasma HIV-1 RNA > 50 c/mL, on or after W24

Criteria for resistance testing– All patients with protocol defined virologic failure (PDVF)– Genotype of RT and integrase on baseline and suspected virologic failure samples

DTG + 2 NRTI , N = 411 RAL + 2 NRTI, N = 411

D0-W48 W48-W96 D0-W48 W48-W96

PDVF 20 (4.9%) 2 28 (6.8%) 1

Integrase genotype results at baseline and time of PDVF

8 2 18 1

Emergent integrase-resistance mutations 0 0 1* 0

Reverse transcriptase genotype results at baseline and time of PDVF

12 2 19 1

Emergent NRTI-resistance mutations 0 0 4* 0

* 1 patient with INSTI mutations (T97T/A, E138E/D, V151V/I, N155H) and NRTI mutations (A62A/V, K65K/R, K70K/E, M184V),1 patient with M184M/I, 1 with M184M/V, 1 with A62A/V

Resistance data at PDVF

Raffi F. Lancet 2013;381:735-43 ; Raffi F. Lancet Infect Dis 2013;13:927-35

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

SPRING-2

DTG + 2 NRTI RAL + 2 NRTIAny adverse event 82% 83%

AE in > 5% of subjects in either group

Nausea 14% 13%

Headache 12% 12%

Nasopharyngitis 11% 12%

Diarrhoea 11% 11%

Upper respiratory tract infection 6% 6%

Dizziness 6% 6%

Pyrexia 5% 5%

Fatigue 5% 4%

Insomnia 5% 4%

Bronchitis 5% 4%

Depression 5% 3%

Pharyngitis 5% 3%

Influenza 3% 5%

Asthenia 3% 5%

Syphilis 2% 5%

Adverse events at week 48

Raffi F. Lancet 2013;381:735-43

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

SPRING-2

DTG + 2 NRTI RAL + 2 NRTIAny serious adverse event N = 29 (7.1%) N = 31 (7.3%)

SAE related to study drug N = 3 N = 5

Aphasia 0 N = 1

Arrhythmia N = 1 0

Convulsion 0 N = 2*

Diarrhoea 0 N = 1

Hepatitis N = 1 0

Hypersensitivity N = 1 N = 1

CPK increased 0 N = 1*

Serious adverse events at week 48

* 1 patient with elevated CPK + convulsion

Safety between W48 and W96– Adverse events leading to discontinuation : 0 for DTG vs 3 for RAL– No serious adverse events related to study drugs

Raffi F. Lancet 2013;381:735-43 ; Raffi F. Lancet Infect Dis 2013; 13:927-35

Graded laboratory toxic effects : rates similar between groups

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

SPRING-2

Raffi F. Lancet Infect Dis 2013;13:927-35

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

Mean change in serum creatinine concentration (µmol/L) from baseline

SPRING-2

Mean change in estimated creatinine clearance (CG formula) at W96 :– - 19.6 mL/min for DTG vs – 9.3 mL/min for RAL

No discontinuations due to renal events through 96 weeks

Baseline 4 8 12 16 24 32 40 48 60 72 84 96

12.3 14.6

4.7 8.2

-20

-10

0

10

20

30

40DTG 50 mg QDRAL 400 mg BID

Conclusion– DTG 50 mg QD was virologically non-inferior to RAL BID,

(both + 2 NRTIs) over 48 and 96 weeks– No INSTI mutations were detected through 96 weeks with DTG– DTG was similar to RAL in terms of safety and tolerability– Low occurrence of adverse events leading to discontinuation :

2% in each group– Between W48 and W96 : few new virologic failures and few

discontinuations for adverse events– No discontinuation due to renal events through 96 weeks – Mean increases in creatinine with accompanying decreases in

estimated glomerular filtration rate • occurred in both study groups by week 4• generally stabilised and did not change up to week 96

Raffi F. Lancet 2013;381:735-43 ; Raffi F. Lancet Infect Dis 2013;13:927-35

SPRING-2 Study: DTG QD + 2 NRTI vs RAL BID+ 2 NRTI

SPRING-2