Comparison of INSTI vs EFV

1
Comparison of INSTI vs EFV

• STARTMRK
• GS-US-236-0102
• SINGLE

2
STARTMRK Study raltegravir vs efavirenz,in
combination with TDF/FTC

• Design

Randomisation 1 1 Double-blind
W240
W48
RAL 400 mg BID EFV placebo
TDF/FTC fdc QD
gt 18 years ARV-naïve HIV RNA gt 5,000 c/mL Any
CD4 cell count No resistance to EFV, TDF or FTC
N 282
EFV 600 mg QD RAL placebo
TDF/FTC fdc QD
N 284
Randomisation was stratified by baseline HIV RNA
(lt or gt 50,000 c/mL) and viral hepatitis
co-infection status

• Objective
• Non inferiority of RAL vs EFV HIV RNA lt 50
  c/mL by per protocol, non-completer failure
  analysis (lower margin of the 2-sided 95 CI for
  the difference - 12, 90 power)

Lennox JL. Lancet 2009374796-806
STARTMRK
3
STARTMRK Study raltegravir vs efavirenz,in
combination with TDF/FTC
Baseline characteristics and patient disposition
RAL EFV
Randomized, N Randomized, N 282 284
Treated eligible patients, N Treated eligible patients, N 281 282
Median age, years Median age, years 37 36
Female Female 19 18
White/Black/Other White/Black/Other 41 / 12 / 47 44 / 8 / 48
HIV RNA (log10 c/mL), median HIV RNA (log10 c/mL), median 5.1 5.0
HIV RNA gt 100,000 c/mL HIV RNA gt 100,000 c/mL 55 51
HIV RNA gt 50,000 c/mL HIV RNA gt 50,000 c/mL 72 70
CD4 cell count (/mm3), median CD4 cell count (/mm3), median 212 204
CD4 lt 50 per mm3 CD4 lt 50 per mm3 10 11
HBsAg or HCV Ab HBsAg or HCV Ab 6 6
Discontinuation by W48 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
Lennox JL. Lancet 2009374796-806
STARTMRK
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STARTMRK Study raltegravir vs efavirenz,in
combination with TDF/FTC
Response to treatment at week 48
HIV RNA lt 50 c/mL at W48(observed-failure
analysis) by baseline factors
Baseline RAL EFV
RNA lt 5 log10 c/mL RNA gt 5 log10 c/mL 92.5 90.9 89.1 89.2
CD4 gt 200/mm3 CD4 lt 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
Mean CD4/mm3 increase at W48 (observed-failure
analysis) 189 (RAL) vs 163 (EFV) (P 0.0184)
Exclusion of discontinuations due to
intolerability or reasons unrelated to treatment
Lennox JL. Lancet 2009374796-806
STARTMRK
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STARTMRK Study raltegravir vs efavirenz,in
combination with TDF/FTC

• Safety at W48

RAL EFV P
Clinical adverse events Clinical adverse events Clinical adverse events Clinical adverse events Clinical adverse events
Drug-related AE 44.1 77.0 lt 0.0001
Serious drug-related AE 1.4 1.8 NS
Treatment discontinuation due to AE 3.2 6.0 NS
Laboratory adverse events Laboratory adverse events Laboratory adverse events Laboratory adverse events 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 Clinical drug-related AE of moderate to severe intensity 16 32 lt 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 gt 2 of patients No difference in incidence in other AE occurring in gt 2 of patients No difference in incidence in other AE occurring in gt 2 of patients No difference in incidence in other AE occurring in gt 2 of patients
Grade 3 or 4 laboratory abnormality Grade 3 or 4 laboratory abnormality Grade 3 or 4 laboratory abnormality Grade 3 or 4 laboratory abnormality Grade 3 or 4 laboratory abnormality
Fasting LDL-cholesterol gt 4.92 mmol/L (190 mg/dl) 1 4
Incidence of other abnormalities lt 2 and not different between arms Incidence of other abnormalities lt 2 and not different between arms Incidence of other abnormalities lt 2 and not different between arms Incidence of other abnormalities lt 2 and not different between arms
Lennox JL. Lancet 2009374796-806
STARTMRK
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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) gt 1 CNS-related adverse event 20 vs
  52 (P lt 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 lt 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

Lennox JL. Lancet 2009374796-806
STARTMRK
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STARTMRK Study raltegravir vs efavirenz,in
combination with TDF/FTC
Cumulative treatment outcome for the entire 5
years study
RALN 281 EFVN 282
HIV RNA level lt 50 c/mL HIV RNA level lt 50 c/mL 71.0 61.3
Mean CD4/mm3 change from baseline Mean CD4/mm3 change from baseline 374 312
Virologic failure (confirmed HIV RNA gt 50 c/mL) Virologic failure (confirmed HIV RNA gt 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 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 Drug-related clinical adverse events 52.0 80.1
Rockstroh JK, JAIDS 20136377-85
STARTMRK
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STARTMRK Study raltegravir vs efavirenz,in
combination with TDF/FTC
Cumulative Discontinuation Rate due to AE ()
Rockstroh JK, JAIDS 20136377-85
STARTMRK
9
STARTMRK Study raltegravir vs efavirenz,in
combination with TDF/FTC
Response to treatment at week 240 (5 years)
HIV RNA lt 50 c/mL (observed-failure analysis) by
baseline factors
Baseline RAL EFV
RNA lt 5 log10 c/mL RNA gt 5 log10 c/mL 94 85 78 83
CD4 gt 200/mm3 CD4 lt 200/mm3 82.5 88.3 78.7 85.6
HIV-1 B subtype Non-B subtype 90 87 79 84
Increases in fasting serum triglycerides, total
cholesterol, HDL cholesterol, and LDL cholesterol
from baseline were significantly lower at W240 (P
lt 0.005) in RAL than EFV
Exclusion of discontinuations due to
intolerability or reasons unrelated to treatment
Rockstroh JK, JAIDS 20136377-85
STARTMRK
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STARTMRK Study raltegravir vs efavirenz,in
combination with TDF/FTC
Cumulative summary of genotypicresistance data
for patients with RNA gt 400 c/mL at the time of
virologic failure out to week 240
RALN 281 EFVN 282
Protocol-defined virologic failure confirmed (HIV RNA gt 50 c/mL) Protocol-defined virologic failure confirmed (HIV RNA gt 50 c/mL) 55 (19.6) 59 (20.9)
Resistance data available (HIV RNA gt 400 c/mL) Resistance data available (HIV RNA gt 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
Integrase gene could not be amplified in 5 cases

• 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

Rockstroh JK, JAIDS 20136377-85
STARTMRK
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STARTMRK Study raltegravir vs efavirenz,in
combination with TDF/FTC
Drug-related adverse events in gt 5 in either
group over 5 years
RAL EFV
Gastrointestinal disorders Gastrointestinal disorders Gastrointestinal disorders Gastrointestinal disorders
Diarrhea 5.3 9.9
Flatulence 3.6 5.0
Nausea 8.9 11.0
General disorders General disorders General disorders General disorders
Fatigue 4.3 8.9
Nervous system disorders Nervous system disorders Nervous system disorders Nervous system disorders
Dizziness 7.8 35.1
Headache 9.3 14.2
Somnolence 1.1 7.4
Psychiatric disorders Psychiatric disorders Psychiatric disorders Psychiatric disorders
Abnormal dreams 6.8 13.1
Insomnia 7.5 8.2
Nightmare 2.8 5.3
Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders
Rash 1.1 8.2
Rockstroh JK, JAIDS 20136377-85
STARTMRK
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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
  lt 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

Lennox JL. Lancet 2009374796-806 Rockstroh JK,
JAIDS 20136377-85
STARTMRK