Comparing Efficacy of LPV/r QD vs. BID in Combination Therapy

Study M02-418 compared once-daily (QD) and twice-daily (BID) LPV/r in combination with TDF and FTC for HIV treatment. The primary endpoint was achieving HIV RNA

• HIV treatment
• LPV/r
• QD vs BID
• Combination therapy
• Clinical study

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1. Comparison of PI vs PI ATV vs ATV/r LPV/r mono vs LPV/r + ZDV/3TC LPV/r QD vs BID BMS 089 MONARK M02-418 M05-730 A5073 GARDEL ALERT ATADAR KLEAN GEMINI CASTLE ARTEMIS LPV/r + 3TC vs LPV/r + 2 NRTI ATV/r vs FPV/r ATV/r vs DRV/r FPV/r vs LPV/r SQV/r vs LPV/r ATV/r vs LPV/r DRV/r vs LPV/r

2. Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC Design Randomisation 3:2 Open-label N = 115 LPV/r 800/200 mg QD + TDF 300 mg + FTC 200 mg QD Adults > 18 years ARV-na ve or < 7 days prior ART HIV RNA > 1,000 c/mL Any CD4 cell count N = 75 LPV/r 400/100 mg BID + TDF 300 mg + FTC 200 mg QD 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) Johnson MA. JAIDS 2006;43:153-60 M02-418

3. Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC Patient disposition and baseline characteristics LPV/r QD 118 LPV/r BID 78 Randomized, N Treated eligible patients, N 115 75 Mean age, years 39.2 + 11.1 37.7 + 9 Female 19% 25% White/Black/Other 57% / 27% / 16% 51% / 36% / 13% HIV RNA (log10c/mL), median HIV RNA > 100,000 c/mL 4.8 4.6 44% 29% (p = 0.047 vs QD) CD4 cell count (/mm3), median 214 232 CD4 < 200/mm3 44% 47% HBsAg+ and/or HCV Ab+ 17% 20% Discontinuation before W48, n (%) 23 (20%) 22 (29%) For adverse event 14 6 For virologic failure 0 2 Note: LPV/r was administered as soft-gel capsules Johnson MA. JAIDS 2006;43:153-60 M02-418

4. Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC Response to treatment at week 48 Primary efficacy endpoint QD (N = 115) BID (N = 75) p = 0.67 % 100 /mm3 200 196 185 80 160 71 70 65 64 60 120 40 80 20 40 0 0 ITT, NC = F TLOVR Mean CD4 increase 95% CI 95% CI for the difference = - 7; 20 for the difference = - 8; 20 Johnson MA. JAIDS 2006;43:153-60 M02-418

5. Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC Pharmacokinetics and resistance W4 steady-stade LPV PK Genotyping and phenotyping were performed in all specimens with HIV RNA > 500 c/mL from W12 through W48 BID group (N = 24) vs QD (N = 13) Cmaxand AUC24not significantly different Significantly lower Ctroughand Cmin for QD group (p < 0.003) Median Ctrough: 4.37 g/mL for QD vs 6.64 g/mL for BID Median IQ (Ctrough/IC50*) significantly lower for QD group (48.1) vs BID (86.5; p < 0.001) LPV/r QD LPV/r BID Met criteria for resistance testing N = 11 N = 11 * Testing failure ** N = 3 N = 3 Emergence of resistance to LPV/r *** 0 0 TDF 0 0 FTC 2 1 * 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 *Protein-binding adjusted IC50 for wild-type HIV-1 = 0.07 mg/mL Johnson MA. JAIDS 2006;43:153-60 M02-418

6. Study M02-418: LPV/r QD vs BID, in combination with TDF + FTC 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 * Diarrhoea Nausea Vomiting Grade 3-4 laboratory abnormalities * AST > 5 x ULN ALT > 5 x ULN Triglycerides > 750 mg/dL Amylase > 2 x ULN 18 (16%) 10 (9%) 4 (3%) N = 111 5 (5%) 4 (4%) 5 (5%) 8 (7%) 4 (5%) 6 (8%) 3 (4%) N = 74 2 (3%) 2 (3%) 3 (4%) 4 (5%) 0.036 NS NS NS NS NS NS * Occurring in > 3% of patients 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 m2)]: 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. Johnson MA. JAIDS 2006;43:153-60 M02-418

7. 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 Ctrough 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 Johnson MA. JAIDS 2006;43:153-60 M02-418