1. Switch to LPV/r monotherapy  Pilot LPV/r  M03-613  LPV/r Mono  KalMo  OK  OK04  KALESOLO  MOST  HIV-NAT 077

2.  Design  Objective –Non inferiority of the monotherapy group in the proportion of patients with HIV-1 RNA < 50 c/mL in the plasma and treatment failure in the CNS or the genital compartment without modification of treatment (per-protocol analysis) ; lower limit of CI for the difference = - 12%, 80% power –Study was prematurely stopped before full recruitment when 6 patients on monotherapy (none in cART group) demonstrated a virologic failure in blood Continuation current antiretroviral therapy (cART)* LPV/r 400/100 mg bid Randomisation 1 : 1 Open-label Target of 100 HIV+ On cART > 6 months HIV-1 RNA 3 months Baseline determination of HIV-1 RNA in CSF and genital secretions N = 29 N = 31 W96 * Possibility offered to switch to LPV/r monotherapy at W48 delayed switch) MOST Study: Switch to LPV/r monotherapy Gutmann C, AIDS 2010;24:2347-54 MOST

3. MOST Study: Switch to LPV/r monotherapy Continuation of cART N = 31 LPV/r monotherapy N = 29 Mean age, years4642 Female23%34% CDC stage C23%34% CD4 cell count at baseline, median/mm 3 465498 CD4 cell count at nadir, median/mm 3 160 HIV-RNA set point, mean log 10 c/ml4.74.9 ARV at inclusion PI-based74%73% NNRTI-based 23%24% 3 NRTIs 3% Baseline characteristics Gutmann C, AIDS 2010;24:2347-54 MOST

4. MOST Study: Switch to LPV/r monotherapy  Median follow-up: 48 weeks  Virologic failure (2 consecutive plasma HIV-1 RNA > 400 c/mL) occurred in 6/29 patients in the LPV/r monotherapy group, after a median of 12 weeks, vs 0/31 in the continued antiretroviral therapy group  In these 6 failures, the median duration of HIV-1 RNA < 50 c/mL was 50 months ; 5/6 patients had clinical symptoms at the time of failure, all symptoms resolving after treatment switch ; all 6 patients had a nadir CD4 cell count < 200/mm 3  CSF was examined in 45 patients at study termination (25 on LPV/r monotherapy and plasma HIV-1 RNA < 400 c/mL, 5 failing monotherapy and 15 continuing prior ARV therapy with plasma HIV-1 RNA < 50 c/mL) CSF HIV-1 RNA was > 40 c/mL –8/25 patients on monotherapy –none of the 15 patients still on continued treatment (p = 0.01)  No marked elevation of HIV-1 RNA in the genital secretions Outcome Gutmann C, AIDS 2010;24:2347-54 MOST

5. MOST Study: Switch to LPV/r monotherapy SexPre-Treatment CD4 nadir /mm 3 Treatment arm Week on study/on monotherapy HIV-1 RNA plasma, log 10 c/ml HIV-1 RNA CSF, log 10 c/mL Blood failure (HIV-1 RNA > 400 c/mL) 1MaleTDF/FTC/ATV/r57LPV/r mono124.35.1 2FemaleZDV/3TC/LPV/r5Delayed Switch60/124.23.1 3FemaleABC/3TC/LPV/r149LPV/r mono124.15.0 4MaleZDV/3TC/EFV7LPV/r mono243.04.1 5MaleTDF/3TC/LPV/r54LPV/r mono65.0ND 6FemaleTDF/3TC/EFV160LPV/r mono243.03.7 HIV-RNA detectable in CSF Monotherapy arm 1MaleTDF/FTC/LPV/r211Delayed Switch96/48< 1.62.9 2MaleTDF/3TC/ATV/r370Delayed Switch66/182.23.4 3FemaleABC/3TC/LPV/r100LPV/r mono632.34.3 4MaleTDF/3TC/ZDV/EFV130Delayed Switch68/202.13.4 5MaleZDV/3TC/LPV/r120Delayed Switch72/24< 1.62.1 6MaleTDF/FTC/LPV/r20LPV/r mono37< 1.62.4 7FemaleABC/3TC/ZDV/LPV/r220LPV/r mono481.92.5 8FemaleZDV/3TC/LPV/r17LPV/r mono44< 1.61.9 HIV-RNA detectable in CSF Continuation therapy arm 9MaleTDF/FTC/LPV/r20cART at baseline0< 1.61.6 10MaleTDF/FTC/ATV/r126cART at baseline0< 1.61.7 11MaleTDF/3TC/EFV185cART at baseline0< 1.61.9 12MaleTDF/3TC/ATV/r370Delayed Switch48/0< 1.61.6 Patients with treatment failure in blood or detection of elevated HIV-1 RNA in CSF Gutmann C, AIDS 2010;24:2347-54 MOST

6. MOST Study: Switch to LPV/r monotherapy  Conclusions –Maintenance of HIV treatment with LPV/r monotherapy should not be recommended as a standard strategy ; this is particularly evident in patients with a CD4 cell count < 200/mm 3 at nadir –The proportion of patients with detectable HIV-1 RNA in CSF was not only significantly higher on LPV/r monotherapy than on continued combination therapy (32% vs 0% ; p = 0.01), but the difference appears biologically (CSF inflammation) and clinically (acute symptoms) relevant Gutmann C, AIDS 2010;24:2347-54 MOST