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

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

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

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

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

*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

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

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

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

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

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

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

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

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