IAS 2011_ Abstract # WEPDB0102 Sustained Efficacy and Tolerability of Raltegravir after 240 Weeks of Combination ART in Treatment- Naive HIV-1 Infected Patients: Final Analysis of Protocol 004 E. Gotuzzo, B.-Y. Nguyen, M. Markowitz, F. Mendo, W. Ratanasuwan, C. Lu, S. Bhanja, H. Teppler, and the Protocol 004 Part II Study Team Prepared by Merck Sharp & Dohme Limited INFC Date of preparation: February 2013 Prescribing information can be found on the final slide.

IAS 2011_ Abstract # WEPDB0102 2BACKGROUND Raltegravir (RAL), an inhibitor of HIV-1 integrase, is licensed for use in combination regimens for the treatment of HIV infection 1. Week 156 data from Phase III studies in treatment-naïve 2 and treatment-experienced 3 patients have demonstrated potent efficacy and good overall tolerability. Protocol 004 (P004) is a Phase II study of RAL vs efavirenz (both with tenofovir/3TC) in treatment-naïve patients that has demonstrated sustained efficacy and good general tolerability up to Week This poster presents final data from P004, through 240 weeks (5 years) of treatment, including: –Exploratory analysis: relationship between early viral load decline and long-term change in CD4 counts

IAS 2011_ Abstract # WEPDB METHODS

4 Study Design Key inclusion criteria –No prior ART –HIV RNA ≥ 5000 copies/mL and susceptible to EFV, TDF, 3TC –CD4 ≥ 100 cells/mm 3 Dosing: –Weeks 0-48 were dose ranging: RAL given at 100, 200, 400 or 600 mg BD * Doses could not be differentiated at 48 weeks –After Week 48, all RAL groups received 400 mg BD –All RAL data post-48 weeks shown as single group (N=160) * Licensed indicated dose = 400mg BD

IAS 2011_ Abstract # WEPDB Overall Analysis Hypothesis: RAL + TDF/3TC will be generally well tolerated, with antiretroviral activity similar to EFV + TDF/3TC Endpoints: –HIV RNA, CD4 counts, adverse events –Exploratory: change in serum lipids Time points: –Week 24 primary, Weeks 48 and 96 secondary –Weeks 144 and 192 exploratory –Week 240 is the final, end-of-study time point

IAS 2011_ Abstract # WEPDB Exploratory Analysis Rationale: earlier HIV suppression by RAL vs EFV was observed in P004 and P021 5 ; impact of early suppression on long-term outcomes is of interest Relationship between early decrease in vRNA and later increase in CD4-cell count was explored using observed failure (OF) approach –Linear regression model of CD4 cell count at each annual time point through Week 240 included the following among model predictors: Baseline CD4 cell count Week 8 HIV RNA log decrease Treatment group

IAS 2011_ Abstract # WEPDB RESULTS

8 Baseline Characteristics / Patient Status RAL + TDF/3TCEFV + TDF/3TC Baseline Characteristics # Patients TreatedN = 160N = 38 Mean age, yrs36 % Male8076 % Non-White6968 HIV RNA, copies/mL † (log 10 cp/mL) (4.7)67554 (4.8) Mean CD4 count, cells/uL % with AIDS ‡ 3437 Patient Status (Week 240) Completed study116 (72%)26 (67%) Discontinued study44 (27%)12 (31%) Lack of efficacy4 (3%)2 (5%) Adverse event4 (3%)1 (3%) Withdrew consent10 (6%)4 (11%) Lost to follow-up8 (5%)3 (8%) Other reasons18 (11%)2 (5%) † geometric mean, ‡ Defined as history of clinical diagnosis of AIDS at baseline.

IAS 2011_ Abstract # WEPDB * Week 240 (OF approach): RAL 93% EFV 81% Patients with HIV RNA < 400 copies/mL (NC=F † ) * After Week 48 patients in all RAL groups continued at 400 mg BD. All patients received TDF/3TC. † Non-completer equals failure (NC=F) approach treats all discontinuations as failures. 65.8% 71.9%

IAS 2011_ Abstract # WEPDB * Patients with HIV RNA < 50 copies/mL (NC=F † ) Week 240 (OF approach): RAL 89% EFV 77% * After Week 48 patients in all RAL groups continued at 400 mg BD. All patients received TDF/3TC. † Non-completer equals failure (NC=F) approach treats all discontinuations as failures. 63.2% 68.8%

IAS 2011_ Abstract # WEPDB Number of Contributing Patients (NC=F † Approach) † Non-completer equals failure (NC=F) approach treats all discontinuations as failures. Week

IAS 2011_ Abstract # WEPDB Change from Baseline: CD4 and HIV RNA (OF ‡ ) *After Week 48 patients in all RAL groups continued at 400 mg b.i.d. All patients also received TDF/3TC. ‡ Observed Failure (OF) approach: only discontinuations due to lack of efficacy are counted as failures. * Weeks

IAS 2011_ Abstract # WEPDB Treatment-Emergent Mutations in Patients with Virologic Failure Virologic failure occurred in 10 (6%) of RAL patients and 5 (13%) of EFV patients Integrase genotype data available for 8 RAL patients with virologic failure –Known RAL resistance mutations in 3 of 8 (38%): N155H (n=2) and Y143C (n=1) All 3 also resistant to 3TC; one also resistant to TDF –No evidence of RAL resistance in 5 of 8 (62%): 4 had no evidence of resistance to 3TC or TDF One showed resistance to 3TC only

14 Most Common* Drug-Related Adverse Events Since week 192, one new report of abnormal dreams in RAL group; no changes in EFV group. RAL (N=160) % EFV (N=38) % Diarrhoea Nausea Dizziness Headache Abnormal Dreams Insomnia Nightmares010.5 RAL taken twice daily; EFV taken once daily; both with TDF/3TC. * Incidence at least 10% in either treatment group; all intensity levels included.

IAS 2011_ Abstract # WEPDB Grade 3 / 4 Laboratory Abnormalities Grade 3 / 4 † Laboratory Abnormalities Laboratory TestToxicity Criteria † RAL (N=160) % EFV (N=38) % Absolute neutrophil count<750 cells/µL Fasting LDL cholesterol≥190 mg/dL Fasting total cholesterol>300 mg/dL Fasting triglycerides>750 mg/dL Fasting glucose>250 mg/dL Aspartate aminotransferase>5 x ULN Alanine aminotransferase>5 x ULN Alkaline phosphatase>5 x ULN Pancreatic amylase>2 x ULN Lipase>3 x ULN Creatine kinase≥10 x ULN † Division of AIDS grading scale December 2004 ULN – Upper Limit of Normal New events since Week 192: Grade 3 LDL-C (n=2), Grade 3 triglycerides (n=1), and Grade 3 creatine kinase (n=1). No grade 3/4 abnormalities reported for haemoglobin, platelet count, creatinine, or total bilirubin.

16 Serum Lipids: Mean Change from Baseline (mg/dL) at Week 240 RAL* (N=160)EFV (N=38) Baseline Mean Mean Change (SD) Baseline Mean Mean Change (SD) RAL vs EFV Cholesterol (0.95) (0.62) P=0.014 LDL-C (0.82) (0.54) P=0.302 HDL-C (0.26) (0.35) P=0.024 Triglycerides (1.23) (0.62) P=0.213 Total: HDL ratio (1.4) (1.1) P= * All RAL dose groups combined; all patients also received TDF/3TC. Greater increase in total cholesterol and HDL-C in EFV group than in RAL group.

IAS 2011_ Abstract # WEPDB Safety Summary: Week 240 Overall adverse event (AE) profiles generally similar for RAL and EFV –Similar frequencies reported at Weeks and 240 Drug-related clinical AEs –less common with RAL than EFV: 55% vs 76% (p=0.017) Neuropsychiatric symptoms* –Most occurred by Week 48 –At Week 240: 38% for RAL vs 63% for EFV *Abnormal dreams, adjustment disorder with depressed mood, depressed mood, depression, dizziness, insomnia, nightmare, psychotic disorder, somnolence, suicidal ideation, suicide attempt.

IAS 2011_ Abstract # WEPDB Safety Summary (cont.) Malignancies † –3.1% (5/160 pts) in RAL group, none considered drug-related –2.6% (1/38 pts) in EFV group, 1 event (GI carcinoma) possibly drug-related Grade 3 / 4 lab abnormalities uncommon –Similar frequencies reported at Weeks and 240 Minimal effect of RAL on serum lipids † Cases included: in RAL group: 1 pt with B-cell lymphoma, 2 pts with Kaposi’s sarcoma, 1 pt with basal cell carcinoma and squamous cell carcinoma (SC), and 1 pt with non-small cell lung carcinoma; in EFV group: 1 pt with gastrointestinal carcinoma (possibly drug-related) and SC.

19 Exploratory Analysis: Prognostic Factors Associated With CD4 Cell Count at Yearly Time Points Prognostic Factor P-value † Wk 48Wk 96Wk 144Wk 192Wk 240 Baseline CD4 cell count (cells/mm 3 ) < Week 8 HIV RNA decline (log 10 copies/mL) < Treatment Group † p-Value calculated from a linear regression model with CD4 cell count separately at each time point as the dependent variable adjusted for baseline CD4 cell count (c/mm 3 ), Week 8 HIV RNA decline (log 10 copies/mL) and treatment group. Significant predictors for CD4 cell count (at 0.05 critical value) at each time point were: (1) baseline CD4 count and (2) log HIV RNA decline at week 8.

20 CONCLUSIONS RAL + TDF/3TC demonstrated sustained antiretroviral efficacy through 5 years, similar to EFV + TDF/3TC: –HIV RNA <50 cp/mL in 69% of RAL pts vs 63% of EFV pts –CD4 counts continued to increase through 5 yrs in both groups RAL was generally well tolerated over 5 years: –Safety profile similar to Week 144 (3 yrs) and Week 192 (4 yrs) –Drug-related AEs less frequent with RAL than EFV –RAL has minimal effect on LDL-cholesterol and triglycerides In an exploratory analysis, statistically significant predictors for CD4 cell count at each yearly time point were baseline CD4 count and early (week 8) log HIV RNA decline.

21 References (1)ISENTRESS (raltegravir) Prescribing Information, (2)J. Rockstroh et al., 18th Conference on Retroviruses and Opportunistic Infections, Feb 2011, Abstract #K-135. (3)J. Eron et al., 17th Conference on Retroviruses and Opportunistic Infections, Feb 2010, Abstract #K-128. (4)E. Gotuzzo et al., 17th Conference on Retroviruses and Opportunistic Infections, Feb 2010, Abstract #K-127. (5)J. Lennox et al., Lancet 2009;374: