Slideset on: Gathe J, da Silva BA, Cohen DE, et al. A once-daily lopinavir/ritonavir-based regimen is noninferior to twice-daily dosing and results in similar safety and tolerability in antiretroviral- naive subjects through 48 weeks. J Acquir Immune Defic Syndr. 2009;50: Study Findings Support Once-Daily Dosing of Lopinavir/Ritonavir Tablets in Treatment-Naive Individuals This program is supported by an educational grant from

clinicaloptions.com/hiv Once-Daily vs Twice-Daily Dosing of LPV/RTV Tablets in Treatment-Naive Individuals Background  Interpretation of previous studies evaluating relative efficacy of once- daily vs twice-daily LPV/RTV complicated by use of now-discontinued SGC formulation (or both SGC and tablets) rather than current tablet formulation [1-3]  Tablet formulation of LPV/RTV has improved convenience  Current study evaluated once-daily vs twice-daily administration of LPV/RTV tablet or SGC formulations in combination with TDF/FTC [4] –LPV/RTV SGC vs tablet compared for first 8 weeks of study only, then all patients received tablet –First study evaluating once-daily LPV/RTV tablets –Week 48 primary endpoint data reported from ongoing 96-week 1. Molina JM, et al. AIDS Res Hum Retroviruses. 2007;23: Mildvan D, et al. CROI Abstract Ortiz R, et al. AIDS. 2008;22: Gathe J, et al. J Acquir Immune Defic Syndr. 2009;50:

clinicaloptions.com/hiv Once-Daily vs Twice-Daily Dosing of LPV/RTV Tablets in Treatment-Naive Individuals Antiretroviral-naive patients with HIV-1 RNA ≥ 1000 copies/mL (N = 664) LPV/RTV SGC* 800/200 mg QD (n = 166) LPV/RTV SGC* 400/100 mg BID (n = 165) LPV/RTV tablets* 400/100 mg BID (n = 166) Week 8 LPV/RTV tablets* 800/200 mg QD (n = 167) Week 48 primary endpoint, current analysis Week 96 *All arms received TDF 300 mg QD plus FTC 200 mg QD. LPV/RTV tablets 800/200 mg QD (n = 333) LPV/RTV tablets 400/100 mg BID (n = 331)

clinicaloptions.com/hiv Once-Daily vs Twice-Daily Dosing of LPV/RTV Tablets in Treatment-Naive Individuals Description of Analysis  Primary efficacy endpoint –HIV-1 RNA < 50 copies/mL at Week 48 using ITT NC = F analysis –Once-daily dosing considered to be noninferior to twice-daily dosing if lower limit of CI for difference in efficacy between the 2 arms > -12%  Primary safety endpoint –Treatment-emergent adverse event of diarrhea through Week 8  Secondary safety endpoints –Moderate/severe study drug–related treatment-emergent adverse events through Week 48 –Grade 3/4 laboratory abnormalities through Week 48 –Treatment-emergent adverse event of diarrhea at Weeks 8 and 48 Gathe J, et al. J Acquir Immune Defic Syndr. 2009;50:

clinicaloptions.com/hiv Once-Daily vs Twice-Daily Dosing of LPV/RTV Tablets in Treatment-Naive Individuals Main Findings  Once-daily dosing of LPV/RTV determined to be noninferior to twice-daily dosing –Difference in response rates: 1% (95% CI: -5% to 8%) Gathe J, et al. J Acquir Immune Defic Syndr. 2009;50: Outcome at Week 48LPV/RTV QD (n = 333) LPV/RTV BID (n = 331) P Value HIV-1 RNA < 50 copies/mL by ITT NC = F analysis, % HIV-1 RNA < 50 copies/mL by observed analysis, % Mean increase in CD4+ cell count, cells/mm

clinicaloptions.com/hiv Once-Daily vs Twice-Daily Dosing of LPV/RTV Tablets in Treatment-Naive Individuals Main Findings  Proportion of patients with HIV-1 RNA < 50 copies/mL comparable between arms across subgroups defined by baseline HIV-1 RNA (< or ≥ 100,000 copies/mL) and baseline CD4+ cell count (< 50, , and ≥ 200 cells/mm 3 )  Comparison of tablets vs SGC formulation after 8 weeks of treatment identified no statistically significant differences in the following –Proportion of patients discontinuing treatment due to gastrointestinal or other adverse events –Incidence of treatment-emergent diarrhea of any and all levels of severity –Proportion of patients with grade 3/4 laboratory abnormalities –Mean change in total cholesterol or triglycerides Gathe J, et al. J Acquir Immune Defic Syndr. 2009;50:

clinicaloptions.com/hiv Once-Daily vs Twice-Daily Dosing of LPV/RTV Tablets in Treatment-Naive Individuals Main Findings  Adverse events and laboratory abnormalities comparable between once-daily and twice-daily dosing groups through Week 48, except for significantly higher proportion of patients with grade 2 hypertriglyceridemia in twice-daily group Gathe J, et al. J Acquir Immune Defic Syndr. 2009;50: Adverse Events/Laboratory Abnormalities Occurring in ≥ 2% of Patients in Either Group Through Week 48,% LPV/RTV QD (n = 333) LPV/RTV BID (n = 331) P Value Grade 2 laboratory abnormalities  Cholesterol (> 239 mg/d L [> 619 m mol/L])21 <.999  Triglycerides (> 399 mg/dL [> 4.51 m mol/L]) Moderate/severe adverse events  Diarrhea  Nausea  Vomiting  Hypertriglyceridemia*22.801

clinicaloptions.com/hiv Once-Daily vs Twice-Daily Dosing of LPV/RTV Tablets in Treatment-Naive Individuals Main Findings  Mean lipid changes greater for twice-daily dosing group, difference only statistically significant for total cholesterol Crum-Cianflone N, et al. AIDS. 2009;23: *P <.044 LPV/RTV QD LPV/RTV BID Total Cholesterol LDL HDLTriglycerides 30 * Mean Change From Baseline to Week 48 (mg/dL) 70

clinicaloptions.com/hiv Once-Daily vs Twice-Daily Dosing of LPV/RTV Tablets in Treatment-Naive Individuals Other Outcomes  Patient disposition during study comparable between once-daily and twice- daily dosing groups –Study discontinuation: 14.7% vs 16.6%, respectively –Discontinuation due to adverse events: 4.8% vs 3%, respectively  Resistance testing conducted on 17 patients with virologic rebound (10 in once-daily group, 7 in twice-daily group) –No PI or TDF resistance mutations identified –3 patients developed M184V mutation  Survey assessing satisfaction with therapy found that 75% to 80% of patients who switched from SGCs to tablets preferred the tablets –Preference for tablets reflected by significant improvements in ease of use (P =.001 for once-daily group; P =.002 for twice-daily group) and patient satisfaction (P <.001 for once-daily group; P =.061 for twice-daily group) following switch from SGCs to tablets Gathe J, et al. J Acquir Immune Defic Syndr. 2009;50:

clinicaloptions.com/hiv Once-Daily vs Twice-Daily Dosing of LPV/RTV Tablets in Treatment-Naive Individuals Summary of Key Conclusions  Once-daily dosing of LPV/RTV tablets noninferior to twice-daily dosing regarding virologic suppression at 48 weeks when combined with TDF/FTC in treatment-naive individuals  Efficacy comparable between once-daily and twice-daily dosing groups regardless of baseline HIV-1 RNA or CD4+ cell count  Safety and tolerability also comparable between once-daily and twice- daily dosing groups –Similar incidence of diarrhea –Increases in total cholesterol significantly higher in patients given twice- daily LPV/RTV  No new PI resistance mutations identified in any patients with virologic rebound Crum-Cianflone N, et al. AIDS. 2009;23:41-50.