1. ACTG 5142: First-line Antiretroviral Therapy With Efavirenz Plus NRTIs Has Greater Antiretroviral Activity Than Lopinavir/Ritonavir Plus NRTIs Slideset on: Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358:2095-2106. This program is supported by educational grants from Jointly sponsored by Postgraduate Institute for Medicine and Clinical Care Options, LLC

2. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Background  Combination of 2 NRTIs plus either EFV or LPV/RTV included among “preferred” regimens for first-line ART in current practice guidelines [1,2] –No previous adequately powered, randomized clinical trials comparing efficacy of EFV- and LPV/RTV-based regimens  Some NRTIs associated with lipoatrophy and other toxicities –Possibly avoided by combining LPV/RTV plus efavirenz [3]  Present study compared safety and efficacy of 3 first-line treatment regimens in antiretroviral-naive participants [4] –EFV plus 2 NRTIs –LPV/RTV plus 2 NRTIs –LVP/RTV plus EFV 1. Hammer SM, et al. JAMA. 2006;296:827-843. 2. Department of Health and Human Services. Available at: http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf. Accessed August 18, 2008. 3. Allavena C, et al. J Acquir Immune Defic Syndr. 2005;39:300-306. 4. Riddler SA, et al. New Engl J Med. 2008;358:2095-2106.

3. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Study Design Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. Antiretroviral-naive HIV-infected patients with HIV-1 RNA ≥ 2000 copies/mL (N = 753) EFV 600 mg once daily + 2 NRTIs* (n = 250) LPV/RTV 400/100 mg twice daily + 2 NRTIs* (n = 253) EFV 600 mg once daily + LPV/RTV 533/133 mg twice daily (n = 250) Week 96 Stratified by HIV-1 RNA < or ≥ 100,000 copies/mL, presence or absence of chronic hepatitis infection (B, C, or both), and NRTI selection *NRTIs = 3TC 150 mg twice daily or 300 mg once daily plus either ZDV 300 mg twice daily, d4T extended release 100 mg once daily (participants < 60 kg received 75 mg once daily), or TDF 300 mg once daily.

4. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Eligibility  Inclusion criteria –13 years of age or older –Antiretroviral naive –HIV-1 RNA ≥ 2000 copies/mL within previous 60 days –Compliant with contraceptive use  Exclusion criteria –Previous ART for ≥ 7 days –Previous use of NNRTIs or lamivudine –Peripheral neuropathy ≥ grade 2 –Use of immunomodulators, vaccines, investigational therapies, human growth hormone, or within previous 30 days (exception: prednisone dose < 10 mg) –Drug/alcohol use/dependence affecting adherence –Recent drug-resistant HIV infection –Systemic treatment and/or hospitalization for severe medical illness within previous 14 days Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

5. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Main Findings  Significantly longer time to virologic failure for efavirenz plus 2 NRTIs vs lopinavir/ritonavir plus 2 NRTIs  No significant differences in time to virologic failure with either NRTI-containing regimen vs efavirenz plus lopinavir/ritonavir Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. Time to Virologic Failure EFV + 2 NRTIs vs LPV/RTV + 2 NRTIs EFV + 2 NRTIs vs EFV + LPV/RTV LPV/RTV + 2 NRTIs vs EFV + LPV/RTV Hazard ratio (95% CI) 0.63 (0.45-0.87) 0.86 (0.61-1.21)1.30 (0.95-1.77) P value.006.49.13

6. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Main Findings (cont’d)  Time to virologic failure varied between treatment arms based on baseline HIV-1 RNA levels –Patients with HIV-1 RNA ≥ 100,000 copies/mL –Longer time to virologic failure for EFV plus 2 NRTIs vs LPV/RTV plus 2 NRTIs (P =.01) –Longer time to virologic failure for EFV plus 2 NRTIs vs EFV plus LPV/RTV (P =.02) –Patients with HIV-1 RNA < 100,000 copies/mL –Longer time to virologic failure for EFV plus LPV/RTV vs LPV/RTV plus 2 NRTIs (P =.02)  Time to regimen failure not significantly different between 3 arms –Trend toward longer time to regimen failure in EFV plus 2 NRTIs arm vs LPV/RTV plus 2 NRTIs arm (P =.03) Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

7. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Main Findings (cont’d)  Percentage of patients with HIV-1 RNA < 200 copies/mL or < 50 copies/mL at Wk 96 significantly higher with EFV plus 2 NRTIs vs LPV/RTV plus 2 NRTIs in intent-to-treat analysis where switches included and missing values censored 93 89 86 77 92 83 0 20 40 60 80 100 EFV + 2 NRTIs (n = 250) LPV/RTV + 2 NRTIs (n = 253) EFV + LPV/RTV (n = 250) Patients (%) < 200 copies/mL< 50 copies/mL HIV-1 RNA Levels at Week 96 P =.04 P =.003 Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

8. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Main Findings (cont’d)  All 3 arms demonstrated increased CD4+ cell count with significantly higher increases in LPV/RTV-containing arms Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. EFV + 2 NRTIs (n = 250) LPV/RTV + 2 NRTIs (n = 253) EFV + LPV/RTV (n = 250) 230 287 273 0 50 100 150 200 250 300 350 P =.01 Median CD4+ Cell Count Increase at Week 96 (cells/mm 3 )

9. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Main Findings (cont’d)  Adherence similar between treatment arms  Time to first treatment-limiting toxicity similar between arms  More grade 3/4 laboratory events in EFV plus LPV/RTV arm resulting primarily from hypertriglyceridemia (P <.01 vs either NRTI-containing arm)  Statistically significant differences in median increase in limb fat from baseline between each group –EFV plus NRTIs (+0.05 kg) < LPV/RTV plus NRTIs (+0.7 kg) < EFV plus LPV/RTV (+1.15 kg) (P ≤.01 for each pairwise comparison) Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

10. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Other Outcomes  Genotypic resistance data (180/227 patients with virologic failure) –Incidence of any drug-resistance mutation or 2-class resistance higher in patients with virologic failure on EFV-containing regimens –NNRTI mutations more common when failing on EFV + LPV/RTV vs EFV + 2 NRTIs Riddler SA, et al. N Engl J Med. 2008;358:2095-2106. CharacteristicEFV + NRTIs (n = 250) LPV/RTV + NRTIs (n = 253) EFV + LPV/RTV (n = 250) Virologic failures, n609473 Genotypic assays, n467856 Any mutation (except minor protease mutations), %* 482170 NRTI mutations, %301911 NNRTI mutations, % † 43366 Mutations in 2 drug classes, % ‡ 2617 EFV + LPV/RTV vs LPV/RTV + NRTIs, P <.001; EFV + NRTIs vs LPV/RTV + NRTIs, P =.002. †LPV/RTV + NRTIs vs EFV + NRTIs or EFV + LPV/RTV, P <.001. ‡LPV/RTV + NRTIs vs EFV + NRTIs, P <.001; EFV + NRTIs vs EFV + LPV/RTV, P =.01.

11. clinicaloptions.com/hiv ACTG 5142: Efavirenz vs Lopinavir/Ritonavir in Treatment-Naive Patients Summary of Key Conclusions  Virologic failure significantly more frequent and occurred more rapidly with LPV/RTV plus 2 NRTIs vs EFV plus 2 NRTIs in first-line ART –Virologic efficacy of efavirenz plus LPV/RTV similar to EFV plus 2 NRTIs –In patients with virologic failure, EFV-containing regimens associated with significantly higher rate of any drug resistance and 2-class resistance  CD4+ cell count increases from baseline at 96 weeks significantly higher in LPV/RTV-containing arms vs EFV plus 2 NRTIs arm Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.