Comparison of INSTI vs PI

1
Comparison of INSTI vs PI

• FLAMINGO
• GS-236-0103
• ACTG A5257
• WAVES

2
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD

• Design

Randomisation 1 1 Double-blind
W48
W192
EVG/c/FTC/TDF 150/150/200/300 mg QD
ATV/r TDF/FTC placebo
N 353
gt 18 years ARV-naïve HIV RNA gt 5,000 c/mL Any CD4
cell count eGFRgt 70 mL/min
ATV/r 300/100 mg TDF/FTC QD
EVG/c/FTC/TDF placebo
N 355
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)

DeJesus E. Lancet 20123792429-38
3
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD
Baseline characteristics and patient disposition
EVG/c/FTC/TDF N 353 ATV/r FTC/TDF N 355
Mean age, years Mean age, years 38 39
Female Female 8 11
HIV RNA (log10c/mL), mean HIV RNA (log10c/mL), mean 4.80.61 4.80.62
HIV RNA gt 100,000 c/mL HIV RNA gt 100,000 c/mL 42 40
CD4 cell count (/mm3), median CD4 cell count (/mm3), median 351 366
CD4 lt 200 per mm3 CD4 lt 200 per mm3 15 11
Hepatitis B / hepatitis C coinfection Hepatitis B / hepatitis C coinfection 1 / 5 2 / 3
Discontinuation by W48 Discontinuation by W48 9.3 11.3
For lack of efficacy N 4 N 1
For adverse event N 13 N 18
Lost to follow-up N 7 N 7
Non-compliance N 5 N 5
Discontinuation by W96 Discontinuation by W96 14 15
DeJesus E. Lancet 20123792429-38 Rockstroh
JK, JAIDS 201362483-6
4
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD
Response to treatment at week 48
Viral suppression was high in both treatment
arms, for various subgroups including
patientswith HIV RNA gt 100 000 c/mLat baseline
Mean CD4/mm3 increase at W48 207
(EVG/c/FTC/TDF) vs 211 (ATV/r FTC/TDF)
DeJesus E. Lancet 20123792429-38
5
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD
ARN VIH lt 50 c/ml
DeJesus E. Lancet 20123792429-38
6
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD
Response to treatment at week 96 and week 144
Rockstroh JK, JAIDS 201362483-6 Clumeck N,
JAIDS 201465e121-4
7
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD
Response to treatment at week 144
Secondary outcomes
EVG/c/FTC/TDF ATV/r FTC/TDF
Virologic failure 7.9 7.3
Mean CD4/mm3 increase 280 293
No treatment difference in virologic success for
various subgroups, including patients with HIV
RNA gt 100,000 c/mL at baseline, except for
adherence gt 95 (favoring EVG/c/FTC/TDF)
Mean decrease in bone mineral density
EVG/c/FTC/TDF EVG/c/FTC/TDF EVG/c/FTC/TDF ATV/r FTC/TDF ATV/r FTC/TDF ATV/r FTC/TDF
W48 W96 W144 W48 W96 W144
Lumbar spine - 2.63 - 1.96 - 1.43 - 3.33 - 3.54 -3.68
Hip - 3.06 - 3.16 - 2.83 - 3.88 - 4.19 -3.77
p 0.018
DeJesus E. Lancet 20123792429-38 Rockstroh
JK, JAIDS 201362483-6 Clumeck N, JAIDS
201465e121-4
8
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD

• Virologic failure definition
• Suboptimal virologic response 2 consecutive
  visits with HIV RNA 50 c/mLand lt1 log10 c/mL
  below baseline at or after week 8
• Virologic rebound (2 consecutive visits with HIV
  RNA either 400 c/mL after achieving HIV RNA lt
  50 c/mL, or gt1 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 353 ATV/r FTC/TDFN 355
Analysed for the development of resistance Analysed for the development of resistance Analysed for the development of resistance 12 (3.4) 8 (2.3)
Emergent primary integrase mutations Emergent primary integrase mutations 4, -
Emergent reverse transcriptase resistance Emergent reverse transcriptase resistance 4 0
M184V K65R 4 1 - -
Emergent primary protease mutation Emergent primary protease mutation - 0
Q148R, N 2, N155H, N 1, T66I E92Q
N155H, N 1 1 had also M184V K65R and 2
M184V
DeJesus E. Lancet 20123792429-38
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Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD
Resistance data at week 144
EVG/c/FTC/TDFN 353 EVG/c/FTC/TDFN 353 EVG/c/FTC/TDFN 353 EVG/c/FTC/TDFN 353 ATV/r FTC/TDFN 355 ATV/r FTC/TDFN 355 ATV/r FTC/TDFN 355 ATV/r FTC/TDFN 355
Total D0-W48 W48-W96 W96-W144 Total D0-W48 W48-W96 W96-W144
Emergent resistance, n 8 5 1 2 2 0 0 2
INSTI resistance 6 4 1 1 -
E92Q 2 1 1 0
N155H 2 2 0 0
Q148R 2 2 0 0
T66I 1 1 0 0
T97A 1 0 0 1
NRTI resistance 7 4 1 2 2 0 0 2
M184V/I 7 4 1 2 2
K65R 1 1 0 0 0
Protease mutation - 0
INSTI NRTI resistance, N 3, INSTI NRTI
resistance, N 1
Rockstroh JK, JAIDS 2013 62483-6 Clumeck N,
JAIDS 201465e121-4
10
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD

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

EVG/c/FTC/TDF ATV/r FTC/TDF
Total at week 48 Total at week 48 13 (3.7) 18 (5.1)
Ocular icterus/Jaundice 0 / 0 4 / 2
Gastro-intestinal disorder 4 5
General disorder 3 2
Drug hypersensitivity 1 0
Infection 1 2
Overdose 0 1
Aminotransferase increased 2 0
Creatinine increased 1 0
Nephropathy toxic 0 1
Limb discomfort or rhabdomyloysis 2 0
Neoplasm 1 1
Neuropsychiatric disorder 4 3
Rash, drug eruption 2 4
Other 3 0
Total at week 96 Total at week 96 15 (4.2) 21 (5.9)
Total at week 144 Total at week 144 21 (5.9) 30 (8.5)
DeJesus E. Lancet 20123792429-38 Rockstroh
JK, JAIDS 201362483-6 Clumeck N, JAIDS
201465e121-4
11
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD

• Treatment-emergent adverse events occurring in gt
  10 of patients in either group (week 48)

EVG/c/FTC/TDF ATV/r FTC/TDF
Diarrhoea 77 (22) 97 (27)
Nausea 70 (20) 69 (19)
Upper respiratory tract infection 54 (15) 58 (16)
Headache 53 (15) 44 (12)
Fatigue 50 (14) 45 (13)
Ocular icterus 2 (1) 51 (14)

• Laboratory test results at week 48

EVG/c/FTC/TDF ATV/r FTC/TDF P
Triglycerides (mg/dL), median change 0.09 0.26 0.006
Creatinine (mmo/L), median change (IQR) 11 (5 18) 7 (1 15) lt 0.001
eGFR (mL/min), median change (IQR) - 12.7 (- 21.8 4.3) - 9.5 (- 17.9 0.2) lt 0.001
Graded ALT abnormality 15.3 21.6 0.041
Severe/life threatening bilirubin abnormality 0.6 58.2 lt 0.001
DeJesus E. Lancet 20123792429-38
12
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD
Median change in serum creatinine (mmol/L)
concentration from baseline
Discontinuations due to renal event
EVG/c/FTC/TDF EVG/c/FTC/TDF EVG/c/FTC/TDF ATV/r FTC/TDF ATV/r FTC/TDF ATV/r FTC/TDF
W48 W96 W144 W48 W96 W144
Discontinuation for renal event 2 1 2 1 1 6
Proximal renal tubulopathy 0 0 0 0 0 3
DeJesus E. Lancet 20123792429-38 Rockstroh
JK, JAIDS 2013 62483-6 Clumeck N, JAIDS
201465e121-4
13
Study GS-236-0103 EVG/c/FTC/TDF QD vs ATV/r
FTC/TDF QD

• Summary (W48 results)
• EVG/c/FTC/TDFQD was virologically non inferior to
  ATV/r FTC/TDF
• Similar virologic reponse of the 2 regimens in
  different subgroups of patients, including those
  with high HIV RNA at enrolment
• Discontinuation because of adverse events was
  lower with EVG/c/FTC/TDF 3.7 vs 5.1
• Development of major resistance mutations
  occurred in
• 5 patients on EVG/c/FTC/TDF 4 with integrase
  mutations (3/4 had also NRTI mutations), 1 with
  only RT mutation (M184V)
• none on ATV/r FTC/TDF
• Incidence of adverse events was similar except
  for jaundice/icterus
• Median increases in creatinine with accompanying
  decreases in estimated glomerular filtration rate
  
• occurred in both study groups by week 2
• generally stabilized by week 8 and did not change
  up to week 48
• median change 11 µmol/L vs 7 µmol/L P lt
  0.001

DeJesus E. Lancet 20123792429-38