1. Comparison of INSTI vs INSTI
ARV-trial.com
Comparison of INSTI vs INSTI
QDMRK
SPRING-2
ONCEMRK
GS-US
GS-US 1

2. ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
ARV-trial.com
ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
Design
Randomisation*
2 : 1
Double-blind
W48
W96
RAL 1200 mg ** QD +
RAL 400 mg BID placebo
TDF/FTC fdc QD
N = 531
> 18 years
ARV-naïve
HIV RNA > 1000 c/mL
N = 266
RAL 400 mg BID +
RAL mg ** QD placebo
TDF/FTC fdc QD
* Randomisation was stratified by baseline HIV RNA (< or > c/mL) and viral hepatitis co-infection status
** Reformulated RAL 600 mg tablet
Objective
Non inferiority of RAL QD: % HIV RNA < 40 c/mL by ITT, NC=F (lower margin of the 2-sided 95% CI for the difference = - 10%, 90% power)
ONCEMRK
Cahn P. Lancet HIV, 11 Sept 2017 (ePub ahead of print) ; Cahn P, IAS 2017, Abs. TUPLBEB20 2

3. ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
ARV-trial.com
ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
Baseline characteristics and patient disposition
RAL 1200 mg QD, N = 531
RAL 400 mg BID , N = 266
Median age, years 34 35
Female, % 17 12
White, %
56.7
64.7
History of AIDS, %
14.9
10.5
Clade B viral subtype, %
63.1
69.9
HIV RNA (log10 c/mL), median
4.6
HIV RNA > c/mL, %
28.1
28.9
CD4 cell count (/mm3), median
380
416
CD4 < 200 per mm3, % 13
13.9
HBs Ag+ or HCV Ab+, %
2.8 3
Discontinuation by W96, N (%)
64 (12.1)
39 (14.7)
For lack of efficacy
N = 6
N = 3
For adverse event
N = 7
Lost to follow-up / Withdrew consent
N = 14 / N = 18
N = 13 / N = 11
Other reasons
N = 19
ONCEMRK
Cahn P. Lancet HIV, 11 Sept 2017 (ePub ahead of print) ; Cahn P, IAS 2017, Abs. TUPLBEB20 3

4. ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
HIV RNA < 40 c/mL (NC = F ; snapshot), % (95% CI) at W48
Difference QD vs BID = 0.5% (- 4.2 ; 5.2)
Patients with baseline HIV RNA > c/mL: % HIV RNA < 40 c/mL (observed failure):
QD = 86.7% vs BID = 83.8% ; difference = 2.9% (- 6.5 ; 14.1) %
RAL 1200 mg QD + TDF/FTC
RAL 400 mg BID + TDF/FTC
CD4/mm3 increase at W48 (observed failure): QD = vs BID = ; ∆ -2 (- 31 ; 27)
ONCEMRK
Cahn P. Lancet HIV, 11 Sept 2017 (ePub ahead of print)

5. HIV RNA < 40 c/mL (NC = F ; snapshot), % (95% CI) at W96
ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
HIV RNA < 40 c/mL (NC = F ; snapshot), % (95% CI) at W96
Difference QD versus BID = 1.4% (95% CI: to 7.3) %
RAL 1200 mg QD + TDF/FTC
RAL 400 mg BID + TDF/FTC
100 89
81.5 80 88
80.1 60 40 20 4 8 16 24 36 48 60 72 84 96
Weeks
% HIV RNA < 40 c/mL (observed failure approach)
Baseline HIV RNA > c/mL: QD = 84.7% vs BID = 82.9% ; ≠ 1.8% (- 8.2 ; 13.6)
Baseline CD4 ≤ 200/mm3: QD = 79.0% versus BID = 80.0% ; ≠ - 1.0% ( ; 18.6)
CD4/mm3 increase at W (QD) versus (BID)
ONCEMRK
Cahn P, IAS 2017, Abs. TUPLBEB20

6. ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
Virologic failure
Non response: did not achieve HIV RNA < 40 c/mL by W24
Rebound: 2 consecutive measurements of HIV-1 RNA ≥ 40 c/mL at least 1 week apart after initial response of HIV RNA < 40 c/mL
Treatment group
Virologic failure
Resistance testing
(if HIV RNA > 500 c/mL)
RAL 1200 mg QD, N = 531
N = 36 (6.8%)
14/36
Non response, N = 18 / Rebound, N = 18
6/18 ; 8/18
RAL 400 mg BID, N = 266
N = 18 (6.8%)
3 / 18
Non response, N = 9 / Rebound, N = 9
2 / 1
Patients with R emergence
Failure Type / Time / Resistance
Comments
RAL 1200 mg QD, N = 5
Non response/W24
V151I, N155H
M184V
N155H
M184M/I/V
BL HIV RNA > 106, CD4 < 20
L74M, E92Q
Rebound/W16
N155H, I203M
Rebound/W24
No INSTI mutation
V118I, M184M/I/V
Resuppressed < 40 c/mL on treatment
RAL 400 mg BID, N = 0
ONCEMRK
Cahn P. Lancet HIV, 11 Sept 2017 (ePub ahead of print)

7. ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
Resistance data at W96
RAL 1200 mg QD (N = 531)
RAL 400 mg BID (N = 266)
Protocol-defined virologic failure
N = 51 (9.6%)
N = 26 (9.8%)
Non response, N = 18
Rebound, N = 33
Non response, N = 9
Rebound, N = 17
Tested for resistance (genotype if HIV RNA > 500 c/mL)
17/51
8/26
Patients with resistance emergence
6/531 (1.1%)
3/266 (1.1%)
R to INSTI + NRTI
4/531 * (0.75%)
2/266 ** (0.75%)
R to NRTI only
2/531 *** (0.4%)
1/266 **** (0.4%)
* RAL 1200 mg QD: R to INSTI = N155H (N = 1), V151I + N155H (N = 1), L74M, + E92Q (N = 1), N155H + I203M (N = 1) ; R to NRTI = M184V (N = 3), M184M/I/V (N = 1)
** RAL 400 mg BID: R to INSTI: T97A + I203M (N = 1) ; L74I + N155H + I203M (N = 1) ; R to NRTI: M184V (N = 1), M184V + K65R (N = 1)
*** Resistance to FTC
**** Resistance to FTC and TDF
ONCEMRK
Cahn P, IAS 2017, Abs. TUPLBEB20

8. ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
Clinical adverse events at W48, %
RAL 1200 mg QD
N = 531
RAL 400 mg BID
N = 266
Drug-related adverse event
24.5
25.6
Serious adverse event
Drug-related
5.8
0.2
9.4
0.8
Discontinuation of study therapy for AE
Due to drug-related AE
2.3
Deaths
0.4
1 lymphoma
1 tuberculosis
1 AIDS (multiple OI)
Between W48 and W96, only 1 additional patient (in the QD group) discontinued study drug for adverse event (not drug-related)
ONCEMRK
Cahn P. Lancet HIV, 11 Sept 2017 (ePub ahead of print) ; Cahn P, IAS 2017, Abs. TUPLBEB20

9. ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
ARV-trial.com
ONCEMRK Study: raltegravir 1200 mg QD vs 400 mg BID, with TDF/FTC
Conclusion
In HIV-1 treatment-naive patients, RAL1200 mg (two 600 mg reformulated tablets) QD has potent and durable efficacy comparable to RAL 400 mg BID each in combination with TDF/FTC:
Statistically non-inferior antiretroviral activity of RAL 1200 mg QD compared to RAL 400 mg BID, with 88.9% achieving HIV RNA < 40 c/mL at W48 and 81.5% at W96
High and similar rates of virologic suppression, irrespective of baseline HIV RNA
Low frequency of RAL resistance (0.75%) in both treatment groups
Large increases in CD4 count (232 cells/mm3) comparable to RAL 400 mg BID (234 cells/mm3) at W48 (+ 262/mm3 at W96)
RAL 1200 mg QD was generally well tolerated
Overall safety profile similar to RAL 400 mg BID
Reformulated once-daily raltegravir offers a new potent, well tolerated, and convenient option for initial treatment of HIV infection
ONCEMRK
Cahn P. Lancet HIV, 11 Sept 2017 (ePub ahead of print) ; Cahn P, IAS 2017, Abs. TUPLBEB20 9