Comparison of INSTI vs INSTI QDMRK SPRING-2. Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK Design Objective –Non inferiority of RAL QD: % HIV

Comparison of INSTI vs INSTI

QDMRK SPRING-2

Eron JJ, Lancet Infect Dis 2011;11:907-15QDMRKQDMRK

Design

Objective– Non inferiority of RAL QD: % HIV RNA < 50 c/mL by ITT, NC=F

(lower margin of the 2-sided 95% CI for the difference = - 10%, 90% power)

RAL 400 mg BID + RAL 800 mg QD placeboTDF/FTC fdc QD

RAL 800 mg QD + RAL 400 mg BID placeboTDF/FTC fdc QD

> 18 yearsARV-naïve

HIV RNA > 5,000 c/mLAny CD4 cell count

No resistance toTDF or FTC

> 18 yearsARV-naïve

HIV RNA > 5,000 c/mLAny CD4 cell count

No resistance toTDF or FTC

*Randomisation was stratified by baseline HIV RNA (< or > 100,000 c/mL)and viral hepatitis co-infection status

QDMRK Study: raltegravir QD vs BID, with TDF/FTC

Randomisation*1 : 1

Double-blind

Randomisation*1 : 1

Double-blind

N = 386

N = 389

W96W96W48W48

RAL BID RAL QDRandomised and received treatment, N 388 382

Median age, years 38 38

Female 18% 23%

White/Black/Other 70% / 15% / 16% 72% / 13% / 15%

HIV RNA (log10 c/mL), median 4.8 4.9

HIV RNA > 100,000 c/mL 38% 37%

CD4 cell count (/mm3), median 278 285

CD4 < 200 per mm3 26% 23%

HBsAg+ or HCV Ab+ 6% 7%

Discontinuation by W48 25 (6.4%) 42 (11.0%)

For lack of efficacy N = 5 N = 18

For adverse event N = 2 N = 3

Lost to follow-up N = 7 N = 7

Other reasons N = 11 N = 14

Baseline characteristics and patient disposition



Baseline RAL BID RAL QD

RNA < 5 log10 c/mL

RNA > 5 log10 c/mL

91.9%*

84.2%

89.1%*

74.3%

CD4 > 200/mm3

CD4 < 200/mm3

91.6%

80.8%

87.0%

70.8%

HIV-1 B subtype

Non-B subtype

90.3%

96.3%

88.5%

90.9%

Response to treatment at week 48

* Exclusion of discontinuations due to intolerability or reasons unrelated to treatment

HIV RNA < 50 c/mL at W48(NC=failure analysis)

by baseline factors

Mean CD4/mm3 increase at W48 (observed-failure analysis): + 196 (RAL BID) vs + 210 (RAL QD)

* 95% CI for the difference = - 8.3 ; 2.7



HIV RNA < 50 c/mL

88.983.2

95% CI for the difference=( - 10.7 ; -0.8)

91.086.6

Per protocol,observed-failure*

95% CI for the difference

= (- 9.0 ; 0.2)

386 382 377 367

25

50

100

75

% Primary analysis

RAL BID RAL QD

ITT NC = F

N =0

RAL BID RAL QDClinical adverse events

Drug-related AE 24.2% 26.4%

Serious drug-related AE 0.5% 0.3%

Treatment discontinuation due to AE 1.0% 1.0%

Laboratory adverse events

Drug-related AE 2.3% 1.3%

Treatment discontinuation due to AE 0 0.3%

Moderate to severe adverse events of any cause 48% 45%

Diarrhoea 4% 4%

Headache 4% 3%

Depression 2% 3%

Vomiting 3% 2%

Grade 3 or 4 laboratory abnormality in > 2% of patients in either group

Fasting LDL-cholesterol > 190 mg/dL (4.9 mmol/L) 2.0% 1.4%

Creatine kinase 5.4% 3.9%

ALT / AST 3.4% / 3.4% 2.9% / 1.8%

Safety at W48



Virologic failure: definition– Non-response = never achieved 2 consecutive HIV RNA < 50 c/mL by week

24 or at time of premature study discontinuation– or rebound = after an initial response, confirmed HIV RNA > 50 c/mL

Emergence of resistance in virologic failure RAL BIDN = 388

RAL QDN = 382

Protocol-defined virologic failure 35 (9%) 53 (14%)

Non-response 14 22

Rebound 21 31

Assessed for emergence of resistance mutations * 16 30

No result available (technical issue) 2 2

Raltegravir resistance mutations + M184I/V 2/12 9/27

M184I/V alone 4/13 11/28

No resistance 8/14 8/28

* Genotyping was done only in patients with HIV RNA > 400 c/mL

2/2 (RAL BID) and 7/9 (RAL QD) patients who had emergence of RAL resistance had baseline HIV RNA > 100 000 c/mL




Pharmacokinetic Data– Trough raltegravir concentrations were more than six times higher with

twice-daily dosing than they were with once-daily dosing– Although an association between trough RAL concentrations and

efficacy was evident in the once-daily group, no clear threshold could be identified


Conclusion– At 48 weeks of treatment, RAL QD was not non-inferior to RAL BID,

in combination with TDF/FTC– Virologic failure was more common with once-daily dosing especially

in patients with baseline HIV RNA > 100 000 c/mL– More patients in the once-daily group than in the twice-daily group had

resistance emergence to both RAL and FTC at the time of virological failure

– Patients in the once-daily group with low pharmacokinetic values and high baseline viral loads were at particular risk of treatment failure

– Despite a high response rate, RAL at 800 mg QD cannot be recommended in place of twice-daily dosing for first-line antiretroviral therapy



Documents

Comparison of INSTI vs INSTI QDMRK SPRING-2. Eron JJ, Lancet Infect Dis 2011;11:907-15 QDMRK Design Objective –Non inferiority of RAL QD: % HIV