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Comparison of NNRTI vs PI/r

Comparison of NNRTI vs PI/r. EFV vs LPV/r vs EFV + LPV/r ACTG A5142 EFV vs LPV/r Mexican Study NVP vs ATV/r ARTEN EFV vs ATV/r ACTG A5202. A5142. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r. Design. Randomisation* 1:1:1 Open-label. W96.

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Comparison of NNRTI vs PI/r

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  1. Comparison of NNRTI vs PI/r • EFV vs LPV/r vs EFV + LPV/r • ACTG A5142 • EFV vs LPV/r • Mexican Study • NVP vs ATV/r • ARTEN • EFV vs ATV/r • ACTG A5202

  2. A5142 ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r • Design Randomisation* 1:1:1 Open-label W96 EFV 600 mg QD+ 3TC + [d4T XR or TDF or ZDV] N = 250 > 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] LPV/r SGC 533/133 mg BID + EFV 600 mg QD N = 250 • HIV RNA < or > 100,000 c/mL • Chronic hepatitis coinfection (B and/or C) • NRTI selection * Stratified according to : • 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 Riddler SA. NEJM 2008;358:2095-2106

  3. A5142 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) Riddler SA. NEJM 2008;358:2095-2106

  4. A5142 ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Baseline characteristics * 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 Riddler SA. NEJM 2008;358:2095-2106

  5. A5142 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 p non significant * = 0,03 EFV vs LPV/r 50 50 40 40 EFV + 2 NRTIs EFV + 2 NRTIs LPV/r + 2 NRTIs LPV/r + 2 NRTIs 30 30 EFV + LPV/r EFV + LPV/r Weeks Weeks 0 0 0 24 48 72 96 120 144 0 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 Riddler SA. NEJM 2008;358:2095-2106

  6. EFV + 2 NRTIs EFV + 2 NRTIs LPV/r + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r EFV + LPV/r A5142 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 30 30 Weeks Weeks 0 0 0 24 48 72 96 120 144 0 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 Riddler SA. NEJM 2008;358:2095-2106

  7. A5142 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 0 0 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 Riddler SA. NEJM 2008;358:2095-2106

  8. A5142 ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r * Multivariable Cox model stratified according to the 3 baseline factors Riddler SA. NEJM 2008;358:2095-2106

  9. A5142 ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r Grade 3 or 4 clinical events or laboratory abnormalities Toxicity leading to discontinuation of one or more drugs = 18% (no significant difference among the 3 groups) Riddler SA. NEJM 2008;358:2095-2106

  10. ACTG A5142: [(EFV vs LPV/r) + 2 NRTIs] vs EFV + LPV/r A5142 Resistance mutations at the time of virologic failure * 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 Riddler SA. NEJM 2008;358:2095-2106

  11. A5142 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 Riddler SA. NEJM 2008;358:2095-2106

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