Comparison of NNRTI vs PI/r ARV-trial.com Comparison of NNRTI vs PI/r EFV vs LPV/r vs EFV + LPV/r A5142 Mexican Study NVP vs ATV/r ARTEN EFV vs ATV/r A5202 1

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Design Randomisation* 1:1:1 Open-label W96 N = 250 EFV 600 mg QD + 3TC + [d4T XR or TDF or ZDV] > 13 years ARV-naïve HIV RNA > 2,000 c/mL Any CD4 cell count N = 253 LPV/r SGC 400/100 mg BID + 3TC + [d4T XR or TDF or ZDV] N = 250 LPV/r SGC 533/133 mg BID + EFV 600 mg QD * Stratified according to : HIV RNA < or > 100,000 c/mL Chronic hepatitis coinfection (B and/or C) NRTI selection 3TC = 300 mg QD or 150 mg BID, in all patients 2nd NRTI (d4T XR 100 mg BID [75 mg if < 60 kg] or TDF [300 mg QD] or ZDV 300 mg BID) selected by investigator before randomisation Follow-up = 96 weeks after last patient’s enrolment A5142 Riddler SA. NEJM 2008;358:2095-2106 2

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Objectives Time to virologic failure: lack of suppression of HIV RNA by 1 log10 c/mL or rebound before W32, or lack of suppression of HIV RNA < 200 c/mL, or rebound after W32. Confirmation of suspected virologic failure was required within 4 weeks. If confirmation sample was missing, case was included as failure Time to regimen failure: first of either virologic failure or toxicity-related discontinuation of any component of the initial randomized treatment regimen Analyses ITT analyses stratified according to the 3 randomisation factors, including all patients who received at least one dose of study drug If discontinuation for intolerance, follow-up continued for the occurrence of virologic failure If no virologic nor regimen failure, data was censored at last study visit Missing data due to missed evaluations, loss to follow-up, or censoring were ignored Power of 85% to detect a 56% reduction in the risk of virologic failure Power of 90% to detect a 52% reduction in the risk of regimen failure Primary endpoints assessed with Kaplan-Meier (statistical significance of hazard ratios between study groups: p < 0.014) A5142 Riddler SA. NEJM 2008;358:2095-2106 3

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Baseline characteristics Variable EFV + 2 NRTI N = 250 LPV/r + 2 NRTI N = 253 EFV + LPV/r N = 250 All patients N = 753 Median age, years 39 37 38 Female 19% 23% 18% 20% White/Black/Other 40%/38%/22% 35%/46%/19% 35%/41%/24% 36%/42%/22% CD4 count (/mm3), median * 195 190 189 191 CD4 < 200/mm3 51% 54% 52% HIV RNA (log10 c/mL), median * 4.8 4.9 HIV RNA > 100,000 c/mL 36% 37% 42% 38% HBsAg+ or HCV Ab+ 14% 13% Selected NRTI, in addition to 3TC ZDV d4T XR 24% 25% TDF 34% * Mean of 2 measurements obtained at visits before study entry and at entry No significant differences among the study group in baseline characteristics Median follow-up = 112 weeks; 78% of patients completed the protocol. No differences among the study groups in follow-up duration nor reasons for loss to follow-up A5142 Riddler SA. NEJM 2008;358:2095-2106 4

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Probability of no virologic failure (%) All patients Probability of no regimen failure (%) All patients % % 100 100 90 90 80 80 70 70 60 60 p = 0.006 EFV vs LPV/r 50 50 p non significant * = 0,03 EFV vs LPV/r 40 40 EFV + 2 NRTIs EFV + 2 NRTIs 30 LPV/r + 2 NRTIs 30 LPV/r + 2 NRTIs EFV + LPV/r EFV + LPV/r Weeks Weeks 24 48 72 96 120 144 24 48 72 96 120 144 N = 250 210 186 173 142 73 19 250 188 160 142 113 55 13 N = 253 210 185 168 140 74 14 253 193 159 143 116 52 11 N = 250 215 189 181 149 73 17 250 195 169 155 126 59 14 * Level of significance of p value with adjustement for multiple comparisons = 0.014 A5142 Riddler SA. NEJM 2008;358:2095-2106 5

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Probability of no virologic failure (%) HIV RNA > 100,000 c/mL at screening HIV RNA < 100,000 c/mL at screening % % 100 100 90 90 80 80 70 70 p = 0.01 EFV vs LPV/r p = 0.02 EFV vs EFV + LPV/r 60 60 p = 0.02 EFV + LPV/r vs LPV/r 50 50 40 40 EFV + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r 30 30 Weeks Weeks 24 48 72 96 120 144 24 48 72 96 120 144 N = 121 108 96 90 76 40 11 129 102 90 83 66 33 8 N = 128 105 90 81 67 32 6 130 105 95 87 73 42 8 N = 122 102 86 81 66 35 9 128 113 103 100 83 38 9 A5142 Riddler SA. NEJM 2008;358:2095-2106 6

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r HIV RNA < 50 c/mL % 100 89% (95% CI: 84-93) 90 83% (95% CI: 76-88) 80 77% (95% CI: 71-83) 70 60 p = 0.003 EFV vs LPV/r 50 40 Efavirenz + 2 NRTIs 30 Lopinavir/r + 2 NRTIs 20 EFV + LPV/r 10 Weeks 4 8 16 24 32 40 48 56 64 72 80 88 96 N = 250 236 224 212 201 178 N = 253 235 226 217 201 177 N = 250 242 228 217 206 180 A5142 Riddler SA. NEJM 2008;358:2095-2106 7

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Virologic and immunologic outcomes Virologic failure % HIV RNA < 50 c/mL at W96 (95% CI) Median (IQR) CD4 (/mm3) increase at W96 Efavirenz + NRTI 24% 89 (84-93) 230 (142-353) p = 0.01 vs LPV/r or EFV + LPV/r Lopinavir/r + NRTI 37% 77 (71-83) p = 0.003 vs EFV 287 (155-422) Efavirenz + lopinavir/r 29% 83 (76-88) 273 (176-419) Hazard ratios (95% CI) for time to virologic failure or to regimen failure Time to virologic failure Time to regimen failure EFV vs LPV/r 0.63 (0.45-0.87) 0.75 (0.57-0.98) EFV vs EFV + LPV/r 0.86 (0.61-1.21) 0.93 (0.70-1.23) LPV/r vs EFV + LPV/r 1.30 (0.95-1,77) 1.21 (0.93-1.56) Hazard ratios (95% CI) for virologic failure * Female sex 1.38 (1.01-1.89) Black race 1.57 (1.18-2.08) Younger age 1.23 (1.06-1.45) Lower CD4 cell count 1.14 (1.01-1.27) * Multivariable Cox model stratified according to the 3 baseline factors A5142 Riddler SA. NEJM 2008;358:2095-2106 8

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Grade 3 or 4 clinical events or laboratory abnormalities EFV + 2 NRTIs (1) N = 250 LPV/r + 2 NRTIs (2) N = 253 EFV + LPV/r (3) N = 250 p Any new sign or symptom, grade 3 or 4 17% 18% Pain or discomfort 6% 8% Diarrhoea or loose stools < 1% 3% < 0.05 (1 vs 2) Nausea 2% Macules, papules or rash 1% Headache 4% Grade 3 or 4 laboratory abnormality Any abnormality 29% 32% 43% < 0.05 (1 vs 3) < 0.05 (2 vs 3) Creatine kinase > 5 x ULN Neutrophil count < 750/mm3 7% 5% Fasting LDL-cholesterol > 190 mg/dL Fasting triglycerides > 750 mg/dL 14% Hepatic aminotransferase > 5 x ULN Lipase > 2 x ULN 9% Clinical lipoatrophy Toxicity leading to discontinuation of one or more drugs = 18% (no significant difference among the 3 groups) A5142 Riddler SA. NEJM 2008;358:2095-2106 9

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Resistance mutations at the time of virologic failure EFV + 2 NRTIs (1) N = 250 LPV/r + 2 NRTIs (2) N = 253 LPV/r + EFV (3) N = 250 p Virologic failure, N (%) 60 (24%) 94 (37%) 73 (29%) Genotype available, N 46 78 56 > 1 major mutation, N (%) 22 (48%) 16 (21%) 39 (70%) 0.03 (1 vs 3) < 0.001 (3 vs 2) 0.002 (1 vs 2) Any NRTI mutation, N (%) 14 (30%) 15 (19%) 6 (11%) 0.02 (1 vs 3) M184V, N (%) 8 (17%) 13 (17%) 1 (2%) 0.01 (1 vs 3) < 0.01 (3 vs 2) K65R, N (%) 3 (7%) 0.05 (1 vs 2) TAMs *, N (%) 2 (4%) 1 (1%) - Any NNRTI mutation, N (%) 20 (43%) 2 (3%) 37 (66%) K103N, N (%) 11 (24%) 31 (55%) 0.002 (1 vs 3) Major protease mutation **, N (%) Mutation associated with 2 drug classes, N (%) 12 (26%) 4 (7%) < 0.001 (1 vs 2) * 41L, 67N, 70R, 210W, 215Y/F and 219Q/E; ** 30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V, 82A/F/L/S/T, 84V and 90M A5142 Riddler SA. NEJM 2008;358:2095-2106 10

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r ARV-trial.com ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Summary - Conclusions 96-week randomized trial comparing 3 regimens for initial therapy for HIV infection Less virologic failure with EFV + 2 NRTIs than with LPV/r + 2 NRTIs NRTI-sparing regimen of EFV + LPV/r: virologic efficacy similar to EFV + 2 NRTIs but more frequent NNRTI resistance and lipid abnormalities Non-significant trend toward a shorter time to regimen failure with LPV/r + 2 NRTIs as compared with EFV + 2 NRTIs No significant difference among the 3 groups in the time to treatment-limiting toxicity Lower increases in CD4 count with EFV + 2 NRTIs compared to the 2 LPV/r groups Resistance emergence: NRTI resistance frequency not significantly different between EFV + 2 NRTIs and LPV/r + 2 NRTIs; mutations to 2 drug classes significantly more frequent with EFV + 2 NRTIs; EFV + NRTI failure associated with high frequency of NNRTI resistance; failure of LPV/r + 2 NRTIs not associated with LPV resistance This study shows moderate efficacy superiority of EFV + 2 NRTIs as compared with LPV/r + 2 NRTIs for initial therapy of HIV-1 infection Results highlight the complexity of choosing initial therapy with the need to take into considerations many factors, including virologic and immunologic response, tolerability, short-term and long-term toxicity, and the resistance consequences associated with virologic failure A5142 Riddler SA. NEJM 2008;358:2095-2106 11