Strategie per ottimizzare il risultato clinico della HAART

1. Strategie per ottimizzare il risultato clinico della HAART Prof. Adriano Lazzarin Università Vita-Salute San Raffaele Milano

2. Break-study (FTC weekly) Soria A. et al, in press

3. BENCHMRK-1 and -2[2] 100 RAL + OBR PL + OBR 80 63%* 60 Patients (%) 40 34% 20 *P < .001 vs PL 0 0 2 4 8 12 16 24 Weeks MOTIVATE 1[3] DUET 1 and 2[1] 100 100 PL + OBR MVC BID + OBR PL + OBR ETR + OBR 80 80 59%* 49%* *P < .0001 vs PL 60 60 Patients (%) Patients (%) 47%* 41% 40 40 20 20 16% 25% *P < .0001 vs PL 0 0 0 4 8 16 24 32 40 48 0 2 4 8 12 16 24 Weeks Weeks Is VL < 50 Achievable in Treatment-Experienced Patients With MDR HIV? 1. Cahn P, et al. ICAAC. 2007. Abstract H-717. 2. Kumar P, et al. EACS 2007. Abstract P7.2/06. 3. Lalezari J, et al. ICAAC 2007. Abstract H-718a.

5. MOTIVATE 1 and 2: Virologic Suppression by LPV/RTV Use, Wk 24 100 100 80 80 60 60 Patients (%) Patients (%) 40 40 20 20 0 0 Placebo + OBR MVC QD + OBR MVC BID + OBR HIV-1 RNA < 400 copies/mL HIV-1 RNA < 50 copies/mL 96.3 87.0 74.1 69.6 60.6 60.0 59.8 50.0 47.9 41.7 26.0 22.0 n = 10 27 23 50 94 127 10 27 23 50 94 127 LPV/RTV First Use LPV/RTV Exp/Resistant LPV/RTV First Use LPV/RTV Exp/Resistant van der Ryst E, et al. IAS 2007. Abstract WEPEB115LB.

6. DUET Week 96: response (VL <50 copies/mL TLOVR) by PSS* 100 etravirine + BR (n=497) Placebo + BR (n=477) 90 p<0.0001 76% 80 p<0.0001 70 61% 59% p<0.0001 60 Patients with VL <50 copies/mL at Week 96 (%) 46% 50 40 29% 30 20 6% 10 5/81 52/181 39/84 117/191 126/215 168/222 0 2 0 1 Number of active background ARVs (PSS) • Patients in the etravirine + BR group achieved consistently higher response rates than patients in the placebo + BR group, irrespective of number of active background agents; the difference was most apparent in patients with no active background agents *DRV considered sensitive if FC 10; ENF counted as sensitive if used de novo; etravirine not included in the PSS calculation; analysis excludes patients who discontinued except for VF Trottier B et al. CAHR 2009. Abstract P148

7. ICI - TRIAL New scenario in rescue therapy: new naive patients Figure 1 – Trend of the virological and immunological parameters Bars represent first and third quartiles.

8. Main safety haematological findings in 28 HIV-1 infected failing pts receiving raltegravir, maraviroc and etravirine alone as salvage therapy. Increase of RBC, WBC and PTL N° after the NUCS step

9. ICI - TRIAL Nozza S et al, submitted

10. ICI - TRIAL Nozza S et al, submitted

11. The Next line of drugs for cART in failing MEXP • Elvitegravir • ViiV 572 • Rilpivirine • Bevirimat • Elvucitabine • New NNRTI, and NRTI • Therapeutic vaxins …but mainly recycling of hold drugs active against revertant virus (NA,PI/r, entry inhibitors)

13. Naive: 2 - Reduce the treatment discontinuation due to SAE

16. Early decrease in CD38 expression on CD4+ cells on MVC IRIS Zone The kinetics of change in the proportion of CD38+ on CD4+T cells and in the density of of CD38+ on CD4+T cells were similar

17. To prevent the disease progression in HIV controlled patients that enough a simplified maintenance Rx?

18. SEMPLIFICATION:a long-term treatment strategy in HIV controller Induction Maintenance strategy 3 drugs required • Which antiviral strength Do we need to maintain full viral suppression • PI/r ? • 2 drugs ? • Others ? 4–5 log drop • Which markers do we use ? • HIV RNA < 50 copies • Viral DNA ? • GSS in DNA ? VL Time Schematic representation; Katlama C, personal communication

19. Boosting PIs alone: for potency and genetic barrier could be an option for monotherapy in maintenance ART

20. MONET: Primary Efficacy Analysis:HIV RNA <50 copies/mL at Week 48, TLOVR, S = F Per Protocol analysis (PP) Intent to Treat analysis (ITT) Primary analysis • 1.6%; lower limit 95%CI: -10.1% • 1%; lower limit 95%CI: -9.9% 100 87.8% 86.2% 85.3% 84.3% 90 80 HIV RNA <50 by Week 48 (%) 70 60 50 40 30 20 10 0 DRV/r + 2NRTI (PP) DRV/r mono (PP) DRV/r + 2NRTI (ITT) DRV/r mono (ITT) N=129 N=123 N=123 N=127 Table EFF 4-5 J. Arribas et al, IAS Conference, Cape Town, SA, 21 July 2009, TUAB106-LB

21. Elite controller: a selected core of LTNP FINDINGS • HIV RNA (ultrasensitive method) is found in all controller (except one). • High levels of proviral DNA and cell based RNA is proven. Under ART HIV negative Before ART Ln

22. HIV- HIV+ Primary HIV Infection of Gut-Associated Lymphoid Tissue (GALT) is the First Pathogenic Event Leading to Substantial CD4+ T cell Destruction and the main source of persistant activation GALT Lymph Nodes Brenchley JM, et al J Exp Med. 2004 Sep 20;200(6):749-59. G. Pantaleo et al., Nature 1994

23. Response to long-term antiretroviral treatment in 47 HIV+ with HIV-RNA < 1 copies/mL and >500 CD4/mcl F. Cossarini et al, ongoing study

24. CD8+ CD38+ T cells decay over time

25. CD8+ HLA-DR+ T Cells decay over time

26. CD38+ cells in HIV-Uninfected and infected subjects after 7 years on treatment

27. HLA-DR+ cells in HIV uninfected and infected subjects after 7 years on treatment

28. CD38+ HLA-DR+ Cells in HIV- uninfected and infected ubjects after 7 years on treatment

29. Conclusions • The study doesn’t show a linear correlation between HIV-1 RNA on treatment and CD38+HLA+ T cells subsets. • HIV-RNA on antiretroviral treatment is therefore not a sufficient stimulus to mantain levels of T cell activation, which does not support the possibility of ongoing rounds of viral replication in the plasma compartment.

30. Most of the virus is in central memory and transitional memory CD4+ T cells Courtesy of Brigitte Autran

31. Not HIV but ……..