Switch to LPV/r monotherapy  Pilot LPV/r  M  LPV/r Mono  KalMo  OK  OK04  KALESOLO  MOST  HIV-NAT 077

 Design Randomisation* 1 : 1 Open-label 205 HIV+ ≥ 18 years On 2 NRTIs + LPV/r > 4 weeks No history of prior virologic failure on PI HIV-1 RNA 6 months N = 103 N = 102 W48 OK04 Study: Switch LPV/r + 2NRTIs to LPV/r monotherapy Pulido F, AIDS 2008;22:F1-9 OK04 W96 * Randomisation was stratified by CD4 cell count (> or ≥ 200/mm 3 ) and months with HIV-1 RNA < 50 c/mL prior to randomisation (< or ≥ 9 months)  Objective –Non inferiority of the monotherapy group in the proportion of patients with therapeutic failure at W48 (per-protocol analysis) ; upper limit of the 95% CI for the difference = 12%, 80% power –Therapeutic failure: 2 consecutive HIV-1 RNA > 500 c/mL (if no resistance at failure and successful viral suppression after reintroduction of 2 NRTIs, not considered as failure) ; change of randomised therapy ; treatment discontinuation ; loss to follow-up LPV/r 400/100 mg bid + continuation of the 2 NRTIs LPV/r 400/100 mg bid

LPV/r + 2 NRTIs* N = 98 LPV/r monotherapy N = 100 Median age, years4241 Female18%22% IV drug user46%43% Prior AIDS44%45% CD4 cell count, median/mm HIV-RNA pre-HAART, median log 10 c/mL Time with HIV-1 RNA < 50 c/mL, median months1719 Discontinuation by W48, n7 (3 for adverse events)4 Treatment received at W48 LPV/r monotherapy LPV/r + 2 NRTIS - N = 88 N = 89 N = 5 Baseline characteristics and patient disposition OK04 Study: Switch LPV/r + 2NRTIs to LPV/r monotherapy OK04 Pulido F, AIDS 2008;22:F1-9 * Most common NRTIs were ZDV + 3TC and d4T + 3TC

Outcome at week 48 OK04 Study: Switch LPV/r + 2NRTIs to LPV/r monotherapy OK04 Pulido F, AIDS 2008;22:F1-9 * Missing data and change of therapy for any reason censored LPV/r + 2 NRTIsLPV/r mono HIV-1 RNA < 50 c/mL % % CI for the difference = ; 3.4 HIV-1 RNA < 500 c/mL 95% CI for the difference = ; % CI for the difference = ; 14 95% CI for the difference = ; N= HIV-1 RNA < 50 c/mL HIV-1 RNA < 50 c/mL 95% CI for the difference = 0.8 ; ITT analysis, switch = failure ITT, TLOVRAbsence of therapeutic failure Observed treatment* 98100

 Therapeutic failures –6 in the monotherapy group 3 were lost to follow-up 1 changed randomised therapy without loss of virologic suppression 1 lost virologic suppression and developed PI resistance 1 lost virologic suppression and failed to achieve suppression after reintroduction of NRTIs –10 in the triple therapy arm 4 were lost to follow-up 3 had confirmed loss of virologic suppression 3 discontinued randomised treatment due to adverse events  Loss of virologic suppression at W48 –3 in the triple therapy group –6 in the monotherapy group: of these 6, 4 resumed baseline NRTIs and regained virologic suppression, 1 had LPV/r resistance, and 1 did not achieve virologic suppression after resuming baseline NRTIs Response to treatment at week 48 OK04 Study: Switch LPV/r + 2NRTIs to LPV/r monotherapy OK04 Pulido F, AIDS 2008;22:F1-9

 Study drug-related adverse events of at least moderate severity –3 in the triple therapy group (diarrhoea, N = 2, insomnia, N = 1), leading to treatment discontinuation –None in the monotherapy group (p = 0.08)  No statistical significant changes from baseline in fasting total cholesterol, HDL cholesterol or triglycerides in both groups  Genotypic analysis in patients with HIV-1 RNA > 500 c/mL –3 in the triple therapy group: PI resistance, N = 1 (mutations 54V, 63P, 71V and 82A) NRTI resistance, N = 1 –11 in the monotherapy group: PI resistance, N = 2 (mutations 10F and 46I in 1 ; mutations 54V, 77I and 82A in 1) NRTI resistance, N = 1  No difference in adherence between the 2 groups Safety, Adverse events, Resistance, Adherence (W48) OK04 Study: Switch LPV/r + 2NRTIs to LPV/r monotherapy OK04 Pulido F, AIDS 2008;22:F1-9

 Conclusions from W48 data –In patients with virologic suppression for more than 6 months on LPV/r + 2 NRTIs, LPV/r monotherapy followed by re-introduction of the NRTIs as required is a therapeutic strategy as effective as continuing triple therapy: non inferiority of monotherapy was demonstrated –The vast majority of patients with loss of virologic suppression on LPV/r monotherapy had no evidence of resistance mutations in the protease gene and were able to resupress and maintain virologic suppression after resumption of baseline NRTIs OK04 Study: Switch LPV/r + 2NRTIs to LPV/r monotherapy OK04 Pulido F, AIDS 2008;22:F1-9

Outcome at week 96 OK04 Study: Switch LPV/r + 2NRTIs to LPV/r monotherapy OK04 * Missing data and reinduction with NRTIs = failure ** Missing data and change of therapy for any reason censored, reinduction with NRTIs = failure Triple therapy N = 98 LPV/r mono N = 100 Still receiving randomised therapy 7677 Therapeutic failure2213 Confirmed HIV-1 RNA > 500 c/mL 56 Reinduction with NRTIsNA12 Lost to follow-up98 Death01 Discontinuation due to AE 8 0 (p=0.003) Arribas J, JAIDS 2009;51: LPV/r + 2 NRTIsLPV/r mono HIV-1 RNA < 50 c/mL % p = ITT* HIV-1 RNA < 50 c/mL p = Observed Treatment** N=98100

Point prevalence of discontinuations and virologic response through 96 weeks LPV/r + 2 NRTIsLPV/r monotherapy OK04 Study: Switch LPV/r + 2NRTIs to LPV/r monotherapy OK04 Arribas J, JAIDS 2009;51: % Weeks % Weeks On study, HIV RNA On study, HIV RNA > 500 On study, HIV RNA < 50 Discontinued  After 2 years of follow-up, proportion of patients rebounding with isolates containing major PI mutations was 2% in each group

OK04 Study: Switch LPV/r + 2NRTIs to LPV/r monotherapy  Conclusions from 96 weeks data –The 96 weeks results support the efficacy and safety of the LPV/r monotherapy strategy –Although episodes of low-level viremia were more frequent in the monotherapy group, there was not an increased risk of resistance development and most of these patients could be virologically resupressed with addition of NRTIs –The toxicity of the LPV/r monotherapy regimen was lower than the toxicity of the triple regimen OK04 Arribas J, JAIDS 2009;51:147-52