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

 Design  Objective –Non inferiority of NVP (combined groups) compared to ATV/r for primary endpoint: % HIV RNA < 50 c/mL at W24, W36 and W48 by intention to treat with non completers equals failures, (2-sided significance level of 5%, lower margin of the 95% CI for the difference = -12%, 80% power) NVP 400 mg QD** + TDF/FTC ATV/r mg QD + TDF/FTC Randomisation* 1:1:1 Open-label > 18 years, ARV-naïve CD4 cell count < 400/mm 3 for males, <250/mm 3 for females Creatinine clearance > 50 mL/min * Randomisation stratified by HIV RNA ( 100,000 c/mL) and CD4 (> or < 50/mm 3 ) at screening ** Lead-in of NVP 200 mg QD for the first 2 weeks N = 193 N = 188 W48W144 ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC NVP 200 mg BID** + TDF/FTC N = 188 Soriano V. Antiviral Therapy 2011;16: ARTEN

NVP QD N = 188 NVP BID N = 188 ATV/r N = 193 Mean age Female19%13%16% HIV RNA (log 10 c/mL), mean5.1 HIV RNA > 100,000 c/mL62.8% 65.8% CD4 cell count (/mm 3 ), mean CD4 < 50 per mm 3 7.4%9.0%6.2% Hepatitis B / hepatitis C coinfection3% / 9%4% / 7%3% / 9% Discontinuation by W4843 (22.9%)56 (29.8%)18 (9.3%) For adverse eventN = 20N = 27N = 5 For lack of efficacyN = 11N = 21N = 3 Lost to follow-upN = 6N = 2N = 4 Other reasonsN = 6 Baseline characteristics and patient disposition ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC Soriano V. Antiviral Therapy 2011;16: ARTEN

Response to treatment at week 48 Mean CD4/mm 3 increase at W48 : for NVP for ATV/r Adjusted difference (95% CI) = 1.9% (-5.9% ; 9.8%) Adjusted difference (95% CI) = - 2.9% (-10.4% ; 4.5%) ITT, NC=FITT, TLOVR NVP (QD + BID) + TDF/FTC ATV/r + TDF/FTC HIV RNA < 50 c/mL Primary analysis (W24, W36 and W48 ) % 0 Treatment response similar for NVP BID (66.5%) and QD (67%) ITT, snapshot : response rate NVP : 67.3% ATV/r : 78.8% difference – 11.1% (95%CI : ; ; P = 0.003) ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC Soriano V. Antiviral Therapy 2011;16: ARTEN

 Adverse events through week 48 NVP QD N = 188 NVP BID N = 188 ATV/r N = 193 Adverse event, any85.9%86.5% Drug-related adverse event34.6%48.7% Discontinuation for adverse event13.6%3.6% Serious adverse event9.6%8.8% Rash Any grade14.9%17.0%12.4% Grade 31.6% 0 Leading to discontinuation3.7%6.4%0 Hepatitis Any grade1.6%2.1%0 Grade %1.6%0 Leading to discontinuation1.6%2.1%0 The majority of rash in NVP groups occurred during the lead-in phase No Grade 4 rashes ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC Soriano V. Antiviral Therapy 2011;16: ARTEN

 Grade 3 and 4 adverse events and liver enzyme increases Combined NVP N = 376 ATV/r N = 193 Drug-related Grade 3-4 AE in > 1% in either group, any Overall9.0%13.5% Increased bilirubin0.3%6.2% Increased ALT1.3%0.5% Jaundice03.1% Hyperbilirubinemia02.6% Rash1.6%0 Hypertriglyceridemia0.3%1.0% Grade 3-4 liver related laboratory abnormalities Grade 3 / Grade 4 ALT3.7% / 3.5%1.6% / 0 Grade 3 / Grade 4 AST4.0% / 2.1%2.1% / 0.5% Grade 3/ Grade 4 total bilirubin1.6% / 1.6%44.6% / 8.8% ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC Soriano V. Antiviral Therapy 2011;16: ARTEN

ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC Podzamczer D. HIV Medicine 2011;12: ARTEN  Mean lipid values at baseline, W48 (LOCF) and change from baseline (LOCF) BaselineW48Change to W48p* Combined NVP (N = 376) ATV/r (N = 193) Combined NVP (N = 376) ATV/r (N = 193) Combined NVP (N = 376) ATV/r (N = 193) Combined NVP vs ATV/r TC (mg/dL) TG (mg/dL) HDL-c (mg/dL) < LDL-c (mg/dL) TC/HDL-c ratio ApoA1 (gL) < ApoB (g/L) ApoB/A1 ratio * ANCOVA controlling for screeening viral load and CD4 cell count

Mean change in lipid parameters (mg/dL) at week 48 (LOCF)  Safety –Incidence of discontinuation due to adverse event: 13.6% NVP vs 3.6% ATV/r –Rash: 16% NVP vs 12.4% ATV/r (discontinuation due to rash : 5.1% vs 0%) –Hepatitis: 1.9% NVP vs 0% ATV/r –Grade 3-4 liver enzyme elevations: 4% NVP vs 1.5% ATV/r –Grade 3-4 hyperbilirubinemia: 3.2% NVP vs 54.4% ATV/r –No cases of Stevens-Johnson, toxic epidermal necrolysis, or death due to liver or skin toxicity ARTEN NVP ATV/r Mean change in TC: HDL ratio at week 48 (LOCF) P = P = TriglyceridesHDL-C P = p < P < LDL-CTotal cholesterol 3.9 Soriano V, Antivir Ther. 2011;16(3): ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC

 Resistance data –Virologic failure : 2 consecutive HIV RNA > 50 copies/mL at least 2 weeks apart NVP QD N = 188 NVP BID N = 188 ATV/r N = 193 Virologic failureN = 20N = 24N = 28 NNRTI resistance mutations Y181C/I/V/SN = 9N = 15- Other NNRTI mutationsN = 5- NRTI resistance mutationsN = 2 M184V/IN = 10N = 150 K65RN = 4N = 80 Protease resistance mutations--0 ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC Soriano V. Antiviral Therapy 2011;16: ARTEN

 Conclusion –NVP demonstrated at week 48 non-inferior antiviral efficacy compared with ATV/r when given along with TDF/FTC, despite more drug-related discontinuations with NVP than ATV/r –NVP BID and QD had similar efficacy and tolerability –The application of the recommended CD4 + T-cell thresholds when initiating first-line NVP therapy probably explain relative low rate of liver enzymes increases and discontinuations for liver toxicity –NVP was associated with a lower atherogenic lipid profile than ATV/r –At virologic failure, there was a high rate of resistance mutations selected by NVP and none with ATV/r ARTEN Study: [NVP (QD or BID) vs ATV/r] + TDF/FTC Soriano V. Antiviral Therapy 2011;16: ARTEN