Comparison of INSTI vs EFV

1
Comparison of INSTI vs EFV

• STARTMRK
• GS-US-236-0102
• SINGLE

2
Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD

• Design

Randomisation 1 1 Double-blind
W48
W192
EVG/c/FTC/TDF 150/150/200/300 mg QD
EFV/FTC/TDF placebo
N 348
gt 18 years ARV-naïve HIV RNA gt 5,000 c/mL Any
CD4 cell count eGFRgt 70 mL/min
EFV/FTC/TDFQD
EVG/c/FTC/TDF placebo
N 352
Randomisation was stratified by HIV RNA (lt or gt
100,000 c/mL) at screening

• Objective
• Non inferiority of EVG/c/FTC/TDF at W48 HIV
  RNA lt 50 c/mL by intentionto treat, snapshot
  analysis (lower margin of the 2-sided 95 CI for
  the difference -12, 95 power)

Sax PE. Lancet 20123792439-48
3
Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD
Baseline characteristics and patient disposition
EVG/c/FTC/TDF N 348 EFV/FTC/TDF N 352
Mean age, years Mean age, years 38 38
Female Female 12 10
HIV RNA (log10 c/mL), median HIV RNA (log10 c/mL), median 4.75 4.78
HIV RNA gt100,000 c/mL HIV RNA gt100,000 c/mL 34 33
CD4 cell count (/mm3), median CD4 cell count (/mm3), median 376 383
CD4 lt 200 per mm3 CD4 lt 200 per mm3 12 14
Hepatitis B / hepatitis C coinfection Hepatitis B / hepatitis C coinfection 3 / 5 3 / 4
Discontinuation by W48 Discontinuation by W48 10.6 13.1
For lack of efficacy N 5 N 4
For adverse event N 12 N 18
Lost to follow-up N 10 N 12
Non-compliance N 3 N 6
Discontinuation by W96 Discontinuation by W96 15.2 17.3
Discontinuation by W144 Discontinuation by W144 18.4 23
Sax PE. Lancet 20123792439-48 Zolopa A, JAIDS
20136396-100 Wohl DA, JAIDS 201465e118-121
4
Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD
Response to treatment at week 48
Viral suppression was high inboth treatment
arms, for various Subgroups including
patientswith HIV RNA gt 100 000 c/mLat baseline
Mean CD4/mm3 increase at W48 239
(EVG/c/FTC/TDF) vs 206 (EFV/FTC/TDF), P 0.009
Sax PE. Lancet 20123792439-48
5
Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD
Response to treatment at week 96 and week 144
Zolopa A, JAIDS 20136396-100 Wohl DA, JAIDS
201465e118-121
6
Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD
Secondary efficacy outcomes at week 144
EVG/c/FTC/TDF EFV/FTC/TDF
HIV-1 RNA lt 50 c/mL in patients withbaseline HIV-1 RNA lt 100,000 c/mL 81.7 74.2
Adjusted difference 7.6 95 CI 0.1 15.1 Adjusted difference 7.6 95 CI 0.1 15.1 Adjusted difference 7.6 95 CI 0.1 15.1
HIV-1 RNA lt 50 c/mL in patients withbaseline HIV-1 RNA gt 100,000 c/mL 77.1 77.6
Mean CD4/mm3 increase 321 300
Median (IQR) change in creatinine and eGFR at
week 48
EVG/c/FTC/TDF EFV/FTC/TDF P
Creatinine (mmol/l) 13 (5 20) 1 (-6 8) lt 0.001
eGFR (mL/min) - 14.3 (-24.2 -4.3) - 3.0 (-11.2 8.2) lt 0.001
Sax PE. Lancet 20123792439-48 Zolopa A, JAIDS
20136396-100 Wohl DA, JAIDS 201465e118-121
7
Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD

• Virologic failure definition
• Suboptimal virologic response 2 consecutive
  visits with HIV RNA 50 c/mLand lt 1 log10 c/mL
  below baseline at or after week 8,
• Virologic rebound 2 consecutive visits with HIV
  RNA either 400 c/mL after achievingHIV RNA lt50
  c/mL, or gt 1 log10 c/mL increase from nadir,
• HIV RNA 400 c/mL at their last visit (at or
  after week 8)
• Criteria for resistance testing
• Virological failure or HIV RNA gt 400 c/mL at
  study discontinuation (at or after W8 and taking
  study drug)

Resistance data at week 48
EVG/c/FTC/TDFN 348 EFV/FTC/TDFN 352
Analysed for the development of resistance Analysed for the development of resistance Analysed for the development of resistance 14 (4) 17 (5)
Emergent primary integrase mutations Emergent primary integrase mutations 7 -
Emergent reverse transcriptase resistance Emergent reverse transcriptase resistance 8 8
M184V/I K65R NNRTI mutation 8 3 - 2 2 8
Q148R, N 1, N155H, N 1, E92Q, N 7, T66I,
N 1 K103N, N 7, K101E, N 3, V108I, N
1, Y188F/H/K, N 1, G190A, N 1
Sax PE. Lancet 20123792439-48
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Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD
Resistance data at week 144
EVG/c/FTC/TDFN 348 EVG/c/FTC/TDFN 348 EVG/c/FTC/TDFN 348 EVG/c/FTC/TDFN 348 EFV/FTC/TDFN 352 EFV/FTC/TDFN 352 EFV/FTC/TDFN 352 EFV/FTC/TDFN 352
Total D0-W48 W48-W96 W96-W144 Total D0-W48 W48-W96 W96-W144
Emergent resistance, n 10 8 2 0 14 8 2 4
INSTI resistance 9 7 2 0 -
E92Q 7 7 0 0
N155H 3 1 2 0
Q148R 1 1 0 0
T66I 1 1 0 0
NRTI resistance 10 8 2 0 4 2 1 1
M184V/I 10 8 2 0 4 2 1 1
K65R 4 3 1 0 3 2 1 0
NNRTI resistance - 14 8 2 4
K103N 13 7 2 4
Zolopa A, JAIDS 20136396-100 Wohl DA, JAIDS
201465e118-121 White KL. Antiviral Therapy
2015, ePub ahead of print
9
Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD

• Treatment-emergent adverse events leading to
  premature discontinuation of study drugs

EVG/c/FTC/TDF EFV/ FTC/TDF
Total at week 48 Total at week 48 13 (4) 18 (5)
Nausea 1 0
General Disorder 1 3
Liver injury 1 0
Drug hypersensitivity 0 1
Infection 1 2
Neoplasm 1 1
Neuropsychiatric disorder 4 9
Creatinine increased 2 0
Renal failure 2 0
Fanconi syndrome 1 0
Dyspnoea 0 2
Rash, drug eruption 0 4
Other 0 3
Total at week 96 Total at week 96 17 (4.9) 24 (6.8)
Total at week 144 Total at week 144 21 (6.0) 26 (7.4)
Sax PE. Lancet 20123792439-48 Zolopa A, JAIDS
20136396-100 Wohl DA, JAIDS 201465e118-121
10
Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD

• Adverse events occurring in gt 10 of patients in
  either group (W48)

EVG/c/FTC/TDF EFV/FTC/TDF P
Diarrhoea 80 (23 ) 66 (19 ) -
Nausea 72 (21 ) 48 (14 ) 0.016
Upper respiratory tract infection 48 (14 ) 38 (11 ) -
Dizziness 23 (7) 86 (24) lt 0.001
Headache 49 (14 ) 34 (10 ) -
Abnormal dreams 53 (15 ) 95 (27 ) lt 0.001
Insomnia 30 (9) 49 (14 ) 0.031
Depression 33 (9) 39 (11) -
Rash 22 (6) 43 (12) 0.009

• Laboratory test results at week 48

EVG/c/FTC/TDF EFV/FTC/TDF P
Total cholesterol (mmol/L), median change 0.25 0.49 lt 0.001
LDL cholesterol (mmol/L), median change 0.26 0.44 0.001
HDL cholesterol (mmol/L), median change 0.13 0.20 0.001
Graded ALT abnormality 15 34 lt 0.001
Graded AST abnormality 18 31 lt 0.001
Sax PE. Lancet 20123792439-48
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Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD

• Discontinuation for renal event
• EVG/c/FTC/TDF
• 5 between D0 and W48 4/5 patients developed
  signs of tubular toxicity (hypophosphataemia,
  and/or glycosuria, and/or proteinuria
• 2 between W48 and W96 decreased GFR, renal
  failure
• 1 between W96 and W144 creatinine increase,
  without tubulopathy
• EFV/FTC/TDF
• No discontinuation
• Discontinuation for neuropsychiatric event
• EVG/c/FTC/TDF
• 3 before W48, none after
• EFV/FTC/TDF
• 6 before W48, 4between W48 and W96, none between
  W96 and W144
• Discontinuation for rash
• EVG/c/FTC/TDF
• No discontinuation
• EFV/FTC/TDF
• 4 before W48, none between W48 and W144

Sax PE. Lancet 20123792439-48 Zolopa A, JAIDS
20136396-100 Wohl DA, JAIDS 201465e118-121
12
Study GS-US-236-0102 EVG/c/FTC/TDF QD vs
EFV/FTC/TDF QD

• Summary of week 48 results
• EVG/c/FTC/TDF QD is virologically non inferior to
  EFV/FTC/TDF
• Similar virologic reponse of the 2 regimens in
  different subgroups of patients, including those
  high HIV RNA at enrolment
• Discontinuation because of adverse events 4
  vs 5
• Development of major resistance mutations
  occurred in
• 8 patients on EVG/c/FTC/TDF 7 with integrase
  mutations, 8 with NRTI mutations
• 8 patients on EFV/FTC/TDF 8 with NNRTI
  mutations, 2 with NRTI mutations
• Incidence of adverse events was similar except
  for neuropsychiatric adverse events and rash
  (more frequent with EFV/FTC/TDF), and nausea
  (more frequent with EVG/c/FTC/TDF)
• Median increases in creatinine with decreases in
  estimated glomerular filtration rate more
  pronounced with EVG/c/FTC/TDF
• Five patients on EVG/c/FTC/TDF discontinued for
  renal events
• Week 144 results
• Durable efficacy of EVG/c/FTC/TDF, with no new
  renal safety signal and a longer-term safety
  profile that is differentiated from EFV/FTC/TDF

Sax PE. Lancet 20123792439-48 Wohl DA, JAIDS
201465e118-121