Comparison of INSTI vs EFV STARTMRK GS-US-236-0102 SINGLE.

Comparison of INSTI vs EFV

STARTMRK GS-US-236-0102 SINGLE

Lennox JL. Lancet 2009;374:796-806STARTMRKSTARTMRK

Design

Objective– Non inferiority of RAL vs EFV: % HIV RNA < 50 c/mL by per protocol, non-

completer = failure analysis (lower margin of the 2-sided 95% CI for the difference = - 12%, 90% power)

RAL 400 mg BID + EFV placebo

TDF/FTC fdc QD

EFV 600 mg QD + RAL placebo

TDF/FTC fdc QD

> 18 yearsARV-naïve

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

No resistance toEFV, TDF or FTC

> 18 yearsARV-naïve

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

No resistance toEFV, TDF or FTC

*Randomisation was stratified by baseline HIV RNA (< or > 50,000 c/mL)and viral hepatitis co-infection status

STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC

Randomisation*1 : 1

Double-blind

Randomisation*1 : 1

Double-blind

N = 284

N = 282

W240W240W48W48


RAL EFVRandomized, N 282 284

Treated eligible patients, N 281 282

Median age, years 37 36

Female 19% 18%

White/Black/Other 41% / 12% / 47% 44% / 8% / 48%

HIV RNA (log10 c/mL), median 5.1 5.0

HIV RNA > 100,000 c/mL 55% 51%

HIV RNA > 50,000 c/mL 72% 70%

CD4 cell count (/mm3), median 212 204

CD4 < 50 per mm3 10% 11%

HBsAg+ or HCV Ab+ 6% 6%

Discontinuation by W48 24 (8.5%) 35 (12.4%)

For lack of efficacy N = 4 N = 2

For adverse event N = 8 N = 17

RAL was administered with or without food, EFV on an empty stomach at bedtime,TDF/FTC in the morning with food

STARTMRKSTARTMRK Lennox JL. Lancet 2009;374:796-806

Baseline characteristics and patient disposition

Baseline RAL EFV

RNA < 5 log10 c/mL

RNA > 5 log10 c/mL

92.5%

90.9%

89.1%

89.2%

CD4 > 200/mm3

CD4 < 200/mm3

94.4%

88.3%

92.4%

85.6%

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

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Lennox JL. Lancet 2009;374:796-806

HIV RNA < 50 c/mL at W48(observed-failure analysis)

by baseline factors

Mean CD4/mm3 increase at W48 (observed-failure analysis): 189 (RAL) vs 163 (EFV)(P = 0.0184)

HIV RNA < 50 c/mL

86.181.9

95% CI for the difference

= - 1.9; 10.3

91.6 89.1

Per protocol,observed-failure *

95% CI for the difference

= - 2.6; 7.7

281 282 263 258

25

50

100

75

% Primaryanalysis

RAL EFV

PP, NC = F

N =

RAL EFV PClinical adverse events

Drug-related AE 44.1% 77.0% < 0.0001

Serious drug-related AE 1.4% 1.8% NS

Treatment discontinuation due to AE 3.2% 6.0% NS

Laboratory adverse events

Drug-related AE 5.0% 8.5% NS

Treatment discontinuation due to AE 0 0.4% NS

Clinical drug-related AE of moderate to severe intensity 16% 32% < 0.0001

Headache 4% 5%

Dizziness 1% 6%

Insomnia 4% 3%

Fatigue 1% 3%

Diarrhoea 1% 3%

No difference in incidence in other AE occurring in > 2% of patients

Grade 3 or 4 laboratory abnormality

Fasting LDL-cholesterol > 4.92 mmol/L (190 mg/dl) 1% 4%

Incidence of other abnormalities < 2% and not different between arms

STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Safety at W48


STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Safety: neuropsychiatric symptoms

– At Week 8• CNS-related adverse events had occurred in 10% of RAL patients vs 18%

of EFV patients (P = 0.0149)

• Retrospective sensitivity analysis (additional symptoms): > 1 CNS-related adverse event: 20% vs 52% (P < 0.0001)

• Most symptoms were self-limited

– At Week 48• Cumulative incidence of CNS-related adverse event was significantly

lower in patients on RAL: 14% vs 23% in the main analysis (P = 0.0044); 26% vs 59% in the sensitivity analysis (P < 0.0001)

• These events were generally mild: 62% of RAL vs 79% of EFV

• Only 1 patient, on EFV, discontinued the trial because of CNS-related adverse event


RALN = 281

EFVN = 282

HIV RNA level < 50 c/mL 71.0% 61.3%

Mean CD4/mm3 change from baseline 374 312

Virologic failure (confirmed HIV RNA > 50 c/mL) 19.6% 20.9%

Non response 3.6% 8.5%

Rebound 16.0% 12.4%

Death 5 (1.8%) 5 (1.8%)

Discontinuation 71 (25.2% 98 (34.5%)

Due to lack of efficacy 6 10

Due to clinical AE 14 25

Due to laboratory AE 0 3

Due to other reasons 51 60

Drug-related clinical adverse events 52.0% 80.1%

Cumulative treatment outcome for the entire 5 years study

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Rockstroh JK, JAIDS 2013;63:77-85

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Cumulative Discontinuation Rate due to AE (%)

0

2

4

Log rank P-value = 0,023

6

8

10

12

14

16

18

20

0 16 32 48 60 72 84 96 120 140 168 192 216 240

Weeks

281 272 265 262 255 246 236 231 227 223 217 190

282 272 257 254 245 235 221 213 203 200 196 183

Number at risk

RAL EFV

Baseline RAL EFV

RNA < 5 log10 c/mL

RNA > 5 log10 c/mL

94%

85%

78%

83%

CD4 > 200/mm3

CD4 < 200/mm3

82.5%

88.3%

78.7%

85.6%

HIV-1 B subtype

Non-B subtype

90%

87%

79%

84%

Response to treatment at week 240 (5 years)

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

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HIV RNA < 50 c/mL (observed-failure analysis) by baseline factors

HIV RNA < 50 c/mL

71.0

61.3

Difference (95% CI) = 9.5% (1.7 ; 17.3)

Superiority

89.280.7

Per protocol,observed-failure *

279 279 263 258

25

50

100

75

%Primary analysis

RAL EFV

PP, NC = F

N =

Difference (95% CI) = 8.6% (1.9 ; 15.5)

Superiority

Increases in fasting serum triglycerides, total cholesterol, HDL cholesterol, and LDL cholesterol from baseline were significantly lower at W240 (P < 0.005) in RAL than EFV


RALN = 281

EFVN = 282

Protocol-defined virologic failure confirmed (HIV RNA > 50 c/mL) 55 (19.6%) 59 (20.9%)

Resistance data available (HIV RNA > 400 c/mL) 23* 20

RAL or EFV resistance alone 1 7

RAL or EFV resistance, and NRTI resistance 3 3

NRTI resistance alone 3 2

Cumulative summary of genotypicresistance data for patients with RNA > 400 c/mL at the time of virologic failure out to week 240

* Integrase gene could not be amplified in 5 cases


Rockstroh JK, JAIDS 2013;63:77-85STARTMRKSTARTMRK

Emergence of RAL resistance in 4 patients (1.4%)Sequencing data of the 4 patients with emergence of RAL-associated mutations

– Q148H + G140S,

– Q148R + G140S,

– Y143Y/H + L74L/M + E92Q +T97A,

– Y143R

RAL EFVGastrointestinal disorders

Diarrhea 5.3% 9.9%

Flatulence 3.6% 5.0%

Nausea 8.9% 11.0%

General disorders

Fatigue 4.3% 8.9%

Nervous system disorders

Dizziness 7.8% 35.1%

Headache 9.3% 14.2%

Somnolence 1.1% 7.4%

Psychiatric disorders

Abnormal dreams 6.8% 13.1%

Insomnia 7.5% 8.2%

Nightmare 2.8% 5.3%

Skin and subcutaneous tissue disorders

Rash 1.1% 8.2%

Drug-related adverse events in > 5% in either group over 5 years


Rockstroh JK, JAIDS 2013;63:77-85STARTMRKSTARTMRK

STARTMRK Study: raltegravir vs efavirenz,in combination with TDF/FTC Summary – Conclusion

– At 48 weeks of treatment, RAL was non-inferior to EFV, in combination with TDF/FTC. Virologic non-inferiority of RAL was confirmed through W24. RAL was superior to EFV for virologic outcome at week 240

– RAL + TDF/FTC led to more rapid viral load decline (significantly more patients with HIV RNA < 50 c/mL for weeks 2 to 16)

– Greater increase in CD4 was observed in the RAL group. It was significant from W156

– Upon virologic failure, resistance mutations to RAL was found in few cases

– RAL was associated with significantly fewer overall and drug-related clinical adverse events, and CNS-related adverse events than was EFV

– Mean changes in lipid parameters were smaller for RAL than for EFV– RAL + TDF/FTC is an alternative to EFV + TDF/FTC as a first-line

combination regimen in treatment-naïve HIV-infected patients

STARTMRKSTARTMRK Lennox JL. Lancet 2009;374:796-806; Rockstroh JK, JAIDS 2013;63:77-85

Comparison of INSTI vs EFV STARTMRK GS-US-236-0102 SINGLE.

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