1. Comparison of INSTI vs EFV
ARV-trial.com
Comparison of INSTI vs EFV
STARTMRK
GS-US
SINGLE 1

2. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
ARV-trial.com
STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
Design
Randomisation*
1 : 1
Double-blind
W48
W240
> 18 years
ARV-naïve
HIV RNA > 5,000 c/mL
Any CD4 cell count
No resistance to
EFV, TDF or FTC
N = 282
RAL 400 mg BID + EFV placebo
TDF/FTC fdc QD
N = 284
EFV 600 mg QD + RAL placebo
TDF/FTC fdc QD
*Randomisation was stratified by baseline HIV RNA (< or > 50,000 c/mL)
and viral hepatitis co-infection status
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)
STARTMRK
Lennox JL. Lancet 2009;374: 2

3. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
ARV-trial.com
STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
Baseline characteristics and patient disposition
RAL
EFV
Randomized, N
282
284
Treated eligible patients, N
281
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%
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
STARTMRK
Lennox JL. Lancet 2009;374: 3

4. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
ARV-trial.com
STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
Response to treatment at week 48
HIV RNA < 50 c/mL
86.1
81.9
95% CI for the difference
= - 1.9; 10.3
91.6
89.1
Per protocol,
observed-failure *
= - 2.6; 7.7
281
282
263
258 25 50
100 75 %
Primary analysis
RAL
EFV
PP, NC = F
N =
HIV RNA < 50 c/mL at W48 (observed-failure analysis)
by baseline factors
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%
Mean CD4/mm3 increase at W48 (observed-failure analysis):
189 (RAL) vs 163 (EFV)
(P = )
* Exclusion of discontinuations due to intolerability or reasons unrelated to treatment
STARTMRK
Lennox JL. Lancet 2009;374: 4

5. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
ARV-trial.com
STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
Safety at W48
RAL
EFV P
Clinical adverse events
Drug-related AE
44.1%
77.0%
<
Serious drug-related AE
1.4%
1.8% NS
Treatment discontinuation due to AE
3.2%
6.0%
Laboratory adverse events
5.0%
8.5%
0.4%
Clinical drug-related AE of moderate to severe intensity
16%
32%
Headache 4% 5%
Dizziness 1% 6%
Insomnia 3%
Fatigue
Diarrhoea
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)
Incidence of other abnormalities < 2% and not different between arms
STARTMRK
Lennox JL. Lancet 2009;374: 5

6. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
ARV-trial.com
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 = )
Retrospective sensitivity analysis (additional symptoms): > 1 CNS-related adverse event: 20% vs 52% (P < )
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 = ); 26% vs 59% in the sensitivity analysis (P < )
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
STARTMRK
Lennox JL. Lancet 2009;374: 6

7. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
Cumulative treatment outcome for the entire 5 years study
RAL N = 281
EFV N = 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%)
Discontinuation
71 (25.2%
98 (34.5%)
Due to lack of efficacy 6 10
Due to clinical AE 14 25
Due to laboratory AE 3
Due to other reasons 51 60
Drug-related clinical adverse events
52.0%
80.1%
STARTMRK
Rockstroh JK, JAIDS 2013;63:77-85 7

8. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
Cumulative Discontinuation Rate due to AE (%) 2 4
Log rank P-value = 0,023 6 8 10 12 14 16 18 20 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
257
254
245
235
221
213
203
200
196
183
Number at risk
RAL
EFV
STARTMRK
Rockstroh JK, JAIDS 2013;63:77-85 8

9. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
ARV-trial.com
STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
Response to treatment at week 240 (5 years)
HIV RNA < 50 c/mL
71.0
61.3
Difference (95% CI)
= 9.5% (1.7 ; 17.3) Superiority
89.2
80.7
Per protocol,
observed-failure *
279
263
258 25 50
100 75 %
Primary analysis
RAL
EFV
PP, NC = F
N =
= 8.6% (1.9 ; 15.5)
 Superiority
HIV RNA < 50 c/mL (observed-failure analysis) by baseline factors
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%
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
* Exclusion of discontinuations due to intolerability
or reasons unrelated to treatment
STARTMRK
Rockstroh JK, JAIDS 2013;63:77-85 9

10. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
Cumulative summary of genotypicresistance data for patients with RNA > 400 c/mL at the time of virologic failure out to week 240
RAL N = 281
EFV N = 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
NRTI resistance alone 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
STARTMRK
Rockstroh JK, JAIDS 2013;63:77-85 10

11. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
Drug-related adverse events in > 5% in either group over 5 years
RAL
EFV
Gastrointestinal disorders
Diarrhea
5.3%
9.9%
Flatulence
3.6%
5.0%
Nausea
8.9%
11.0%
General disorders
Fatigue
4.3%
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%
Skin and subcutaneous tissue disorders
Rash
STARTMRK
Rockstroh JK, JAIDS 2013;63:77-85 11

12. STARTMRK Study: raltegravir vs efavirenz, in combination with TDF/FTC
ARV-trial.com
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
STARTMRK
Lennox JL. Lancet 2009;374: ; Rockstroh JK, JAIDS 2013;63:77-85 12