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

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r LPV/r SGC 400/100 mg BID + 3TC + [d4T XR or TDF or ZDV] * Stratified according to :  Design W96 N = 250 N = 253 N = 250 A5142 LPV/r SGC 533/133 mg BID + EFV 600 mg QD 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 Randomisation* 1:1:1 Open-label –3TC = 300 mg QD or 150 mg BID, in all patients –2 nd 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 - HIV RNA 100,000 c/mL - Chronic hepatitis coinfection (B and/or C) - NRTI selection Riddler SA. NEJM 2008;358:

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 log 10 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:

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Variable EFV + 2 NRTI N = 250 LPV/r + 2 NRTI N = 253 EFV + LPV/r N = 250 All patients N = 753 Median age, years Female19%23%18%20% White/Black/Other40%/38%/22%35%/46%/19%35%/41%/24%36%/42%/22% CD4 count (/mm 3 ), median * CD4 < 200/mm 3 51%54%51%52% HIV RNA (log 10 c/mL), median * HIV RNA > 100,000 c/mL36%37%42%38% HBsAg+ or HCV Ab+14%13%14% Selected NRTI, in addition to 3TC ZDV42% d4T XR24%25%24% TDF34% * 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 Baseline characteristics Riddler SA. NEJM 2008;358:

N = ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r N = Riddler SA. NEJM 2008;358: A5142 Probability of no virologic failure (%) All patients Probability of no regimen failure (%) All patients % * Level of significance of p value with adjustement for multiple comparisons = Weeks EFV + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r p = EFV vs LPV/r % EFV + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r Weeks p non significant * = 0,03 EFV vs LPV/r

HIV RNA < 100,000 c/mL at screening ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r A5142 Probability of no virologic failure (%) HIV RNA > 100,000 c/mL at screening EFV + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r EFV + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r N = N = Riddler SA. NEJM 2008;358: Weeks p = 0.02 EFV + LPV/r vs LPV/r % Weeks p = 0.01 EFV vs LPV/r p = 0.02 EFV vs EFV + LPV/r %

% ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r N = A5142 HIV RNA < 50 c/mL Riddler SA. NEJM 2008;358: Efavirenz + 2 NRTIs Lopinavir/r + 2 NRTIs EFV + LPV/r Weeks p = EFV vs LPV/r 89% (95% CI: 84-93) 83% (95% CI: 76-88) 77% (95% CI: 71-83)

Virologic and immunologic outcomes Virologic failure % HIV RNA < 50 c/mL at W96 (95% CI) Median (IQR) CD4 (/mm 3 ) increase at W96 Efavirenz + NRTI24%89 (84-93) 230 ( ) p = 0.01 vs LPV/r or EFV + LPV/r Lopinavir/r + NRTI37% 77 (71-83) p = vs EFV 287 ( ) Efavirenz + lopinavir/r29%83 (76-88)273 ( ) Hazard ratios (95% CI) for time to virologic failure or to regimen failure Time to virologic failureTime to regimen failure EFV vs LPV/r0.63 ( )0.75 ( ) EFV vs EFV + LPV/r0.86 ( )0.93 ( ) LPV/r vs EFV + LPV/r1.30 (0.95-1,77)1.21 ( ) ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Hazard ratios (95% CI) for virologic failure * Female sex1.38 ( ) Black race1.57 ( ) Younger age1.23 ( ) Lower CD4 cell count1.14 ( ) * Multivariable Cox model stratified according to the 3 baseline factors A5142 Riddler SA. NEJM 2008;358:

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 417%18%17% Pain or discomfort6% 8% Diarrhoea or loose stools< 1%3% < 0.05 (1 vs 2) Nausea3%2%3% Macules, papules or rash2%1%3% Headache2%4%1% Grade 3 or 4 laboratory abnormality Any abnormality29%32%43% < 0.05 (1 vs 3) < 0.05 (2 vs 3) Creatine kinase > 5 x ULN3% 6% Neutrophil count < 750/mm 3 4%7%5% Fasting LDL-cholesterol > 190 mg/dL3%1%6%< 0.05 (2 vs 3) Fasting triglycerides > 750 mg/dL2%6%14% < 0.05 (1 vs 3) < 0.05 (1 vs 2) < 0.05 (2 vs 3) Hepatic aminotransferase > 5 x ULN4%6%8%< 0.05 (1 vs 3) Lipase > 2 x ULN9%4%5%< 0.05 (1 vs 2) Clinical lipoatrophy3%1%0< 0.05 (1 vs 3) Toxicity leading to discontinuation of one or more drugs = 18% (no significant difference among the 3 groups) ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r A5142 Grade 3 or 4 clinical events or laboratory abnormalities Riddler SA. NEJM 2008;358:

ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r 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 > 1 major mutation, N (%)22 (48%)16 (21%) 39 (70%) 0.03 (1 vs 3) < (3 vs 2) (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%) (1 vs 2) TAMs *, N (%)2 (4%)1 (1%) 2 (4%) - Any NNRTI mutation, N (%)20 (43%)2 (3%) 37 (66%) 0.03 (1 vs 3) K103N, N (%)11 (24%)0 31 (55%) (1 vs 3) Major protease mutation **, N (%)00 2 (4%) - Mutation associated with 2 drug classes, N (%)12 (26%)1 (1%) 4 (7%) 0.01 (1 vs 3) < (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 Resistance mutations at the time of virologic failure Riddler SA. NEJM 2008;358:

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: