Comparison of PI vs PI  ATV vs ATV/r BMS 089  LPV/r mono vs LPV/r + ZDV/3TCMONARK  LPV/r QD vs BIDM M A5073  LPV/r + 3TC vs LPV/r + 2 NRTIGARDEL  ATV/r vs FPV/rALERT  ATV/r vs DRV/rATADAR  FPV/r vs LPV/rKLEAN  SQV/r vs LPV/rGEMINI  ATV/r vs LPV/rCASTLE  DRV/r vs LPV/rARTEMIS

Johnson MA. JAIDS 2006;43: M Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC Adults > 18 years ARV-naïve or < 7 days prior ART HIV RNA > 1,000 c/mL Any CD4 cell count LPV/r 800/200 mg QD + TDF 300 mg + FTC 200 mg QD LPV/r 400/100 mg BID + TDF 300 mg + FTC 200 mg QD N = 75 N = 115 Randomisation 3:2 Open-label  Design  Objective –Primary endpoint: HIV RNA < 50 c/mL at W48 (ITT, NC = F) –Non-inferiority of LPV/r QD vs BID if lower margin of the 95% CI for the difference = - 15% (> 60% power)

Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC LPV/r QDLPV/r BID Randomized, N11878 Treated eligible patients, N11575 Mean age, years Female19%25% White/Black/Other57% / 27% / 16%51% / 36% / 13% HIV RNA (log 10 c/mL), median HIV RNA > 100,000 c/mL44%29% (p = vs QD) CD4 cell count (/mm 3 ), median CD4 < 200/mm 3 44%47% HBsAg+ and/or HCV Ab+17%20% Discontinuation before W48, n (%)23 (20%)22 (29%) For adverse event146 For virologic failure02 Note: LPV/r was administered as soft-gel capsules Patient disposition and baseline characteristics M Johnson MA. JAIDS 2006;43:153-60

Response to treatment at week 48 M Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC QD (N = 115) BID (N = 75) p = 0.67 Mean CD4 increase /mm ITT, NC = FTLOVR Primary efficacy endpoint % % CI for the difference = - 7; 20 95% CI for the difference = - 8; 20 Johnson MA. JAIDS 2006;43:153-60

Pharmacokinetics and resistance LPV/r QDLPV/r BID Met criteria for resistance testing N = 11N = 11 * Testing failure **N = 3 Emergence of resistance to LPV/r ***00 TDF00 FTC21 *Protein-binding adjusted IC 50 for wild-type HIV-1 = 0.07 mg/mL * No specimen in 1 ** Median HIV RNA = 625 c/mL *** Any primary or active site mutation in protease at codons 8, 30, 32, 46, 47, 48, 50, 82, 84, 90, with decrease in phenotypic susceptibility to LPV > 2.5 fold M Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC Genotyping and phenotyping were performed in all specimens with HIV RNA > 500 c/mL from W12 through W48 W4 steady-stade LPV PK  BID group (N = 24) vs QD (N = 13) –C max and AUC 24 not significantly different –Significantly lower C trough and C min for QD group (p < 0.003) –Median C trough : 4.37 µg/mL for QD vs 6.64 µg/mL for BID –Median IQ (C trough /IC 50 *) significantly lower for QD group (48.1) vs BID (86.5; p < 0.001) Johnson MA. JAIDS 2006;43:153-60

Safety and adverse events LPV/r QD (N = 115)LPV/r BID (N = 75)p Adverse events of at least moderate severity related to study drugs * Diarrhoea18 (16%)4 (5%) Nausea10 (9%)6 (8%)NS Vomiting4 (3%)3 (4%)NS Grade 3-4 laboratory abnormalities *N = 111N = 74 AST > 5 x ULN5 (5%)2 (3%)NS ALT > 5 x ULN4 (4%)2 (3%)NS Triglycerides > 750 mg/dL5 (5%)3 (4%)NS Amylase > 2 x ULN8 (7%)4 (5%)NS Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC  Discontinuation for gastro-intestinal adverse events: QD (N = 9) vs BID (N = 2)  1 death in BID group, unrelated to study drugs (adenocarcinoma)  W48 increase: LDL-cholesterol + 14 mg/dL in both groups; HDL-cholesterol: QD + 3 mg/dL vs BID + 6 mg/dL  LDL-cholesterol > 130 mg/dL: 14% at baseline vs 26% at W48 (2 groups combined)  HDL-cholesterol < 40 mg/dL: 58% at baseline vs 42% at W48 (2 groups combined)  GFR (MDRD [mL/min/1.73 m 2 )]: 112 at baseline, 104 at W48 (2 groups combined), p < 0.001, with no differences between groups. 1 case of acute renal failure in each group. * Occurring in > 3% of patients M Johnson MA. JAIDS 2006;43:153-60

Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC  Summary - Conclusion –In previously untreated HIV-1 infected adults, LPV/r soft-gel capsule 800/200 mg QD was non inferior to LPV/r 400/100 mg BID, in combination with TDF + FTC QD –Virologic response rate at W48 (HIV RNA < 50 c/mL) was 70% in the QD group and 64% in the BID group –Immunologic recovery was similar in the 2 treatment arms –There were greater number of discontinuations for adverse events (primarily gastrointestinal) and a significantly higher rate of diarrhoea in the QD group –No significant differences in lipid changes was seen between the 2 groups Most pronounced lipid effect was triglyceride elevation Lipid increases were less than observed with LPV/r + thymidine analogues –Lack of LPV resistance emergence in either group –Lower C trough with LPV/r QD, not associated with reduced virologic response –Limitation of the study: only 60% power to determine non inferiority of LPV/r QD M Johnson MA. JAIDS 2006;43:153-60