1. Sustained Antiretroviral Efficacy of Raltegravir as part of Combination ART in Treatment-Naive HIV-1 infected patients: 96-week data
M. Markowitz1, B.-Y. Nguyen2, E. Gotuzzo3, F. Mendo4, W. Ratanasuwan5, C. Kovacs6, H. Wan2, H. Campbell2, M. Miller2, R. Isaacs2, H. Teppler2, and the Protocol 004 Part II Study Team
1Aaron Diamond AIDS Research Center, New York, NY; 2Merck Research Labs, West Point, PA; 3Hospital Nacionale Cayetano Heredia, Lima, Peru; 4Hospital Nacionale Edgardo Rebagliati, Lima, Peru; 6Maple Leaf Medical Center, Toronto, Canada; 5Siriraj Hospital, Bangkok, Thailand
AIDS 2008, Abstract # TUAB0102

2. In Vitro Activity of Raltegravir (MK-0518)H O - F K +
Potent in vitro activity
IC95 (Mean  SD) = 31 nM  20 nM in 50% NHS
Active against:
Multi-drug resistant HIV-1
CCR5 and CXCR4 HIV-1
HIV-1 resistant to raltegravir remain sensitive to other antiretroviral classes
Additive/synergistic in vitro with NRTIs, NNRTIs, PIs, and enfuvirtide
AIDS 2008, Abstract # TUAB0102

3. Protocol 004: Part II Design
Key inclusion criteria
Susceptible to EFV, TDF, 3TC
No prior ART
HIV RNA ≥ 5000 copies/mL; CD4 ≥ 100 cells/mm3
Hypotheses: Raltegravir (RAL) + TDF/3TC
will be generally well tolerated, with similar antiretroviral activity vs efavirenz + TDF/3TC
Endpoints
HIV RNA, CD4 counts, Adverse experiences
Exploratory: CNS and lipids
Timepoints: 24 wk primary, 48 and 96 wk secondary
48 week data presented AIDS 2007
Current presentation is 96 week update
0-48 wks RAL given at doses of 100, 200, 400 or 600 mg b.i.d.
doses could not be differentiated at 48 wk
After 48 wk, all RAL groups received 400 mg bid
Therefore all RAL data post 48 wk shown as single RAL group (N=160)
AIDS 2008, Abstract # TUAB0102

4. Baseline Characteristics / Patient Status
RAL *
EFV *
# Patients Treated
N = 160
N = 38
Age-mean (yrs) 36
%Male 80 76
%Non-White 69 68
HIV RNA copies/ml** (log10cp/ml)
55266 (4.7)
67554 (4.8)
CD4-mean (cells/ul)
305
280
% with AIDS± 34 37
Discontinuations by Week 96†
22 (14%)
6 (15%)
± Defined as history of clinical diagnosis of AIDS at baseline, * With TDF/3TC, **geometric mean
† : RAL / EFV (# of patients); Lack of efficacy (3/1), AE (3/1), withdrew consent (7/4), Loss-to-follow up (3/0), Other reasons (6/0)
AIDS 2008, Abstract # TUAB0102

5. Using Observed Failure approach:
RAL 94% and EFV 91%
Protocol 004 – 96 weeks Percent of Patients (95% CI) With HIV RNA <400 Copies/mL [Non-Completer=Failure] *
84%
*After Week 48 patients in all RAL groups continued at 400 mg b.i.d.
All patients received TDF/3TC
AIDS 2008, Abstract # TUAB0102

6. *After Week 48 patients in all RAL groups continued at 400 mg b.i.d.
All patients received TDF/3TC *
83%
84%
Protocol 004 – 96 weeks Percent of Patients (95% CI) With HIV RNA <50 Copies/mL [Non-Completer=Failure]
Using Observed Failure approach:
RAL 92% and EFV 91%
AIDS 2008, Abstract # TUAB0102

7. Protocol 004 – 96 weeks Change from Baseline: CD4 and HIV RNA [Observed Failure Approach]*
221
232
-2.30
-2.28
*After Week 48 patients in all RAL groups continued at 400 mg b.i.d.
All patients received TDF/3TC
AIDS 2008, Abstract # TUAB0102

8. Treatment-Emergent Mutations
Group
VF type
RAL
3TC
TDF
EFV
RAL 100
Non-Response ║
V151I, N155H, D232D/N, G163R/G
M184M/I/V
K65K/R
---
Relapse
Y143C†
RAL 200
N155H
M184V
RAL 200/400
Relapse*
Y188L
K103K/N
S230S/N‡
K65R
G190E
Protocol definition of virologic failure: (1) non-response: > 400 copies/ml at week 24 or early discontinuation, (2) virologic relapse; > 400 copies/ml after initial response of < 400 copies/ml, or > 1.0 log10 increase above nadir level. (Percentage of virologic failures in RAL: 6/160 (3.8%), and in EFV: 2/38 (5.3%).
*Failure occurred after Week 48, (--- indicates no mutations), †Mutation developed after patient was a virologic failure
‡S230S/N is a common polymorphism that does not affect raltegravir sensitivity in phenotypic assays. All other mutations listed were associated with reduced drug sensitivity.
║ All four patients with Non-Response achieved >1.0 log10 decrease in HIV RNA at the nadir.
AIDS 2008, Abstract # TUAB0102

9. Protocol 004: 96 week Safety Summary
Overall adverse experience (AE) profiles generally similar between RAL and EFV
Drug-related clinical AEs: RAL (51%) vs EFV (74%)
Neuropsychiatric symptoms*:
Most occurred by 48 wks
13% (RAL) vs 29% (EFV) at wk 48
16% (RAL) vs 32% (EFV) at wk 96
Malignancies†: 1.9% (3/160 pts) for RAL vs. 2.6% (1/38 pts) in EFV
Grade 3 / 4 lab abnormalities uncommon
Neutral effect of RAL on serum lipids
†Cases included: 2 pts with Kaposi’s sarcoma, 1 pt with both basal cell carcinoma and squamous cell carcinoma (SC), 1 pt with both gastrointestinal carcinoma and SC
#Per investigator
*Depression, nightmare, confusional state, suicidal ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, delirium, depressed level of consciousness, hallucination, auditory hallucination, completed suicide, major depression
AIDS 2008, Abstract # TUAB0102

10. Most Common* Drug-Related Adverse Events (96 weeks)
RAL (N=160)
(%)
EFV (N=38)
Diarrhea
6.9
10.5
Nausea
12.5
13.2
Dizziness
8.8
28.9
Headache
23.7
Abnormal Dreams
6.3
18.4
Insomnia
8.1
Nightmares
RAL taken twice daily; EFV taken once daily; both with TDF/3TC.
* Incidence at least 10% in any treatment group; all severity levels included.
AIDS 2008, Abstract # TUAB0102

11. Percent of Patients with Grade 3 / 4† Laboratory Abnormalities
Test
Toxicity
Criteria†
Raltegravir
Efavirenz
(N = 160)
(N = 38) n
(%)
Absolute neutrophil count
<750 cells/µL 1
(0.6)
(0.0)
Fasting LDL cholesterol
≥190 mg/dL 2
(5.3)
Fasting total cholesterol
>300 mg/dL
Fasting triglycerides
>750 mg/dL 3
(7.9)
Alkaline phosphatase
>5 x ULN
Pancreatic amylase
>2 x ULN 4
(2.5)
Lipase
>3 x ULN
(1.3)
Aspartate aminotransferase
(2.6)
Alanine aminotransferase
Creatine kinase
≥10 x ULN 10
(6.3)
No grade 3 or 4 abnormalities were reported in either treatment group for the following parameters: hemoglobin, platelet count, fasting glucose, creatinine, and total bilirubin.
AIDS 2008, Abstract # TUAB0102

12. Effect on Serum Lipids (96 weeks)
Total cholesterol, LDL-cholesterol, triglycerides not increased by raltegravir
Mean change from baseline (mg/dL) at week 96
RAL* (N=160)
EFV (N=38)
Baseline Mean
Mean Change
RAL vs EFV
Cholesterol
166.2
+1.1
168.9
+24.0
P=0.002
LDL-C
103.9
-5.8
108.5
+4.4
P=0.045
HDL-C
38.0
+7.4
37.9
+13.0
P=0.017
Triglycerides
134.7
-10.8
126.1
+13.4
P=0.145
Total: HDL ratio
4.6
-0.7
P=0.689
* All RAL dose groups combined; both groups with TDF and 3TC
AIDS 2008, Abstract # TUAB0102

13. P004 Conclusions
At 96 weeks, RAL had sustained antiretroviral effect similar to 48 week data and to EFV (both with TDF/3TC)
83% vs 84% (RAL vs EFV) with HIV RNA < 50 copies/mL
No new RAL mutations identified after 48 weeks
RAL was generally well tolerated at 96 weeks:
Drug-related AEs appeared less frequent for RAL vs. EFV
RAL had neutral effect on total cholesterol, LDL-C, and triglycerides.
AIDS 2008, Abstract # TUAB0102

14. Acknowledgements – Protocol 004 Study Team
Investigators
M. Markowitz USA
E. Gotuzzo Peru
F. Mendo Peru
W. Ratanasuwan Thailand
C. Kovacs Canada
G. Prada Colombia
J. Morales-Ramirez Puerto Rico
A. Afani Chile
D. Cooper Australia
J. Perez Chile
S. Thitivichianlert Thailand
J. Cortes Colombia
R. Steigbigel USA
M. Bloch Australia
Merck Research
Laboratories
S. Little USA
N. Bodsworth Australia
R. Schwartz USA
C Tsoukas Canada
C. Workman Australia
R. Liporace USA
D. Baker Australia
C. Hicks USA
K. Tashima USA
C. Crumpacker USA
P. Kumar USA
K. Lichtenstein USA
J. Santana-Bagur Puerto Rico
S. Brown USA
H. Teppler
B.-Y. Nguyen
R. Isaacs
H. Wan
J. Chen
H. Campbell
L. Wenning
M. Miller
D. Hazuda
J. Vacca
M. Rowley
V. Summa
M. Iwamoto
R. Danovich
AIDS 2008, Abstract # TUAB0102