1. Workshop 4: Il late-presenter Moderatori: G. Ippolito, M. Moroni Discussant: R. Iardino Risposta virologico-clinica e scelta della terapia C. Mussini

2. 760 pazienti/ 125 morti (16%)

3. Kaplan Meier plot showing the cumulative proportion of patients with clinical progression, according to the type of AIDS diagnosis that was present at the time of HIV diagnosis

5. Prognosis of late presenters Adapted from Sterne et al. CROI 2009, Abstract 525 and presentation Based on 24,444 patients from 15 cohort studies 808 deaths and 2366 events in 81,071 person-years of follow-up 0 – 50 51 – 150 151 – 250 0.15 0.10 0.05 0.00 012345 6 Probability of death Years since start of HAART 251 – 350 351 – 450 451 – 550 Years since start of cART 0.40 0.30 0.20 0.10 0.00 012345 6 Probability of AIDS or death

7. EFV vs LPV/RTV in Tx-Naive Pts With CD4+ < 200 in Mexico HIV-1 RNA < 50 copies/mL at Week 48 Madero JS, et al. IAC 2008. Abstract TUAB0104. 0 20 40 60 80 100 016 32 48 Week 82440 Efavirenz (n = 95) LPV/RTV (n = 94) Number of Pts With HIV-1 RNA < 50 copies/mL EFV 29 70 68 67 LPV 8 53 56 50 70.5% 53.2% 0 20 40 60 80 100 HIV-1 RNA < 50 copies/mL (%) 79% 49% 64% 57% P = 0.012 P = 0.15 EFV LPV/RTV n = 42 45 53 49 50 cell/mm 3 > 50 cell/mm 3 EFV met criteria for superiority to LPV/RTV: Δ 17% (CI 95%: 3.5% to 31.0%; P =.017) HIV-1 RNA < 50 copies/mL (%) By BL CD4+ Cell Count

9. STARTMRK: Virologic and Immunologic Efficacy at Week 48 Significantly shorter time to virologic response with RAL vs EFV (P <.001) Significantly greater CD4+ cell count increase with RAL vs EFV +189 vs +163 cells/mm 3 ; Δ: 26 cells/mm 3 (95% CI: 4-47) Lennox J, et al. ICAAC/IDSA 2008. Abstract 896a. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA. Copyright © 2008 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 0 20 40 60 80 100 0163248 Weeks Patients With HIV-1 RNA < 50 copies/mL (%) 248122440 86% 82% RAL n = 281 279 281 279 281 279 278 280 280 EFV n = 282 282 282 282 281 282 280 281 281 Δ: 4% (95% CI: -2 to 10) P <.001 for noninferiority RAL EFV ITT, NC = F

10. Incidence of PcP if CD4 200

11. Incidence of secondary PcP Incidence secondary PCP per 1000 PYFU (95% CI) Proph Events No 1 No 1 No 4 Yes 5 Yes 1 Yes 2 No 5 No 0* No 0* Yes 2 Yes 0* Yes 0* CD4 < 200CD4 > 200 <400 400-9999 >10000<400400-9999>10000 *No events; incidence and lower bound of 95% CI=0.0

12. Proporzione con Disturbi NP Prevalenza di HAND in epoca post-HAART (Studio CHARTER) Letendre et al., 2007

13. Updated CSF Penetration Effectiveness Scores Overall CPE score = sum of following scores for the individual agents ClassificationScoreAgents Good penetrators4IDV/RTV, NVP, ZDV Decent penetrators3ABC, DLV, DRV/RTV, EFV, FPV/RTV, FTC, IDV, LPV/RTV, MVC, RAL Limited penetrators23TC, ATV ± RTV, d4T, ddI, ETR, FPV Poor penetrators1ddC, ENF, NFV, RTV, SQV ± RTV, TDF, TPV Letendre S, et al. CROI 2010. Abstract 172.

14. MONOI: 48 Wk Outcomes With DRV/RTV Monotherapy vs Triple Therapy DRV/RTV monotherapy met criteria for noninferior virologic efficacy vs DRV/RTV + 2 NRTIs at Wk 48 in PP analysis, but not in ITT-E analysis –PP population = all pts from ITT population except pts who d/c tx without virologic failure or SAE (n = 10) or pts withdrawn without virologic failure or SAE (n = 6) Virologic failure in 3 pts (2.7%) on monotherapy vs 0 on standard therapy –Low DRV drug levels noted in 1 pt –No DRV RAMs in any pt with virologic failure –All 3 pts regained HIV-1 RNA < 50 c/mL on reintroduction of 2 NRTIs Virologic Response at Wk 48, %* DRV/ RTV + 2 NRTIs ΔLower Limit of 90% CI PP analysis (n = 204) 94.199.0-4.9-9.0 ITT-E analysis (n = 225) 87.592.0-4.5-11.0 Viremia detected in CSF in 2 of 3 pts with serious CNS disorders on monotherapy arm –Each pt had HIV-1 RNA < 200 c/mL in CSF following reintroduction of NRTIs Katlama C, et al. IAS 2009. Abstract WELBB102. Virologic failure defined as consecutive HIV-1 RNA > 400 c/mL or treatment modification or discontinuation

15. CONCLUSIONI La sopravvivenza del paziente libero da malattia deve essere lobiettivo della TARV. Il successo virologico costituisce un fattore essenziale per la prognosi a lungo termine. La prescrizione di un regime terapeutico deve tener conto anche della penetrazione nei diversi comparti.