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Nuove strategie e nuovi approcci terapeutici nel trattamento dell’infezione da HIV

Nuove strategie e nuovi approcci terapeutici nel trattamento dell’infezione da HIV. Giuliano Rizzardini Ospedale L. Sacco Milano. Outline. Alcuni obiettivi raggiunti, le sfide aperte ed i dati utili nella gestione dei pazienti complessi Gli strumenti del futuro prossimo

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Nuove strategie e nuovi approcci terapeutici nel trattamento dell’infezione da HIV

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  1. Nuove strategie e nuovi approcci terapeutici nel trattamento dell’infezione da HIV Giuliano Rizzardini Ospedale L. Sacco Milano

  2. Outline • Alcuni obiettivi raggiunti, le sfide aperte ed i dati utili nella gestione dei pazienti complessi • Gli strumenti del futuro prossimo • Uno sguardo sul futuro “remoto”

  3. Outline • Alcuni obiettivi raggiunti, le sfide aperte ed i dati utili nella gestione dei pazienti complessi • Gli strumenti del futuro prossimo • Uno sguardo sul futuro “remoto”

  4. Cosa abbiamo raggiunto? • Oggi, un regime ART efficace puo’ essere tanto semplice da essere una sola pillola da assumere prima di dormire. • L’utilizzo della terapia antiretrovirale nei paesi in via di sviluppo si è espanso dopo il 2000 che si stima che attualmente vi siano più di 5 milioni di soggetti HIV infetti nei paesi a risorse limitate che assumono la ART con un beneficio clinico simile a quello dei paesi occidentali. • L’aspettativa di vita di una persona HIV positiva trattata in modo appropriato è aumentata da 10.5 anni nel 1996 a 22.5 anni nel 2005, ed è ora vicina a quella della popolazione generale

  5. Su cosa stiamo lavorando? • Aderenza, tossicità, interazioni farmacologiche e resistenza rimangono un problema,specialmente in popolazioni svantaggiate • Alcuni gruppi di pazienti, inclusi i TD, non hanno fino ad ora beneficiato appieno della ART a causa di numerosi fattori concomitanti (accesso alle cure, aderenza, coinfezioni e comorbidità, problemi psichiatrici) • Dopo 20 anni di ART, alcune domande rimangono ancora aperte: • Quando e come iniziare la terapia? • Quando e come cambiare la terapia? • Quali strategie per prevenire le resistenze?

  6. Verso un inizio di terapia più precoce

  7. A mechanistic rationale for starting therapy as early as possible • Untreated HIV disease is associated with increased T cell activation/inflammation and these markers predict disease • Treatment dramatically reduces but does not normalize levels inflammation • Inflammation on HAART predicts disease • The degree of residual inflammation during HAART is determined in part by CD4 nadir (strong effect < 200, less clear effect > 350) From SG. Deeks, MD, at Atlanta, GA: March 2, 2010, IAS–USA

  8. HIV infection may result in accelerated immunologic aging Desai and Landay, Current HIV/AIDS Reports 2010 From SG Deeks, MD, at Atlanta, GA: March 2, 2010, IAS–USA.

  9. Alla ricerca della soglia dei CD4: Linee guida e RCT • START study: Piu’ di 4000 naive con CD4 >500 cellule/ul • - Pazienti randomizzati a iniziare la terapia subito o ad attendere il raggiungimento della soglia di 350/ul • Follow-up per i seguenti eventi: • Eventi severi AIDS definenti • eventi clinici non AIDS definenti • decesso • Arruolamento in corso, risultati attesi entro il 2015.

  10. PLOS one Jun 2010

  11. Nuove diagnosi di infezione da HIV e numero di pz in HAART

  12. Nuove diagnosi di infezione da HIV: casi attesi e reali (1996 – 2009)

  13. Half (50%) of individuals who initiated therapy discontinuedor changed their initial regimen within the first2 years. Individuals initiating using an NNRTI-based regimen were more likely to achieve virologic suppression(HIV-1 RNA 500 copies/ml) than those initiating using a boosted protease inhibitor-based regimen

  14. THE latest dispatch from the war on AIDS brings good news. At 5.25m, the number of people in poor and middle-income countries who were being treated for HIV infection at the end of 2009 was up 30% from the end of 2008. Eight countries achieved coverage of 80% or better and 21 others covered more than half of those in need. Though the new figure still represents only about a third of those who could benefit, the rate of increase is impressive. The news is doubly welcome, too, because it is now agreed that treatment, which has the effect of making people less infective, is an important way of stopping the spread of HIV as well as being desirable in itsown right. Sep 2010

  15. Outline • Alcuni obiettivi raggiunti, le sfide aperte ed i dati utili nella gestione dei pazienti complessi • Gli strumenti del futuro prossimo • Uno sguardo sul futuro “remoto”

  16. Il panorama terapeutico nel tempo

  17. Comparisons at w96 in randomised controlled studies * § § difference confirmed in High VL subgroup *superiority

  18. La sfida nei pazienti con multipli fallimenti

  19. Accostamenti alternativi e strumenti per il prossimo futuro

  20. Esperienza H Sacco “Dual Study” • Prospective observational cohort of multi experieced patients with very limited options starting a NUC sparing dual therapy including RAL+ 3 rd agent • 3 rd agent choice based on historical mutations pattern and last genotype at failure • Patients must be failing their current treatment to be included • Data on VL, biochemistry, CD4 cells count collected and descriptive analysis performed

  21. Dual results: baseline characteristics • 26 patients included in the analysis • Minimum follow-up: 70 weeks • Co- administered drugs • PI (DRV/r =18, LPV/r= 1, ATV/r= 4, ATV= 1) • NNRTI (EFV = 2).

  22. Baseline characteristics • Median HIV-1 RNA 4.65 log10, (range 3,01 – 5,66) • Median CD4+ cell count 352 cells/mm3 (range: 24 – 1064). • Patients had been exposed to a median of 8 previous antiretroviral regimens (range 5-12). • Median number of NRTI associated mutations: 6 (range 3-8), for NNRTI was 1 (range 1-4) and for PIs was 6 (range 0-13). • Patients were never fully-resistant to the chosen PIs or NNRTI (GSS = 0.5-1). • In the subgroup of 24 PI-treated patients, 17 had at least one major IAS protease mutation (median 3, range 1-5), and 11 at least one relevant darunavir (DRV) -mutation

  23. Efficacy results • At week 24 all patients (100%) reached an HIV RNA load of <50 copies/ml and maintained viral suppression until week 70 and for the entire observation period for those followed longer. • Two subjects experienced a transient ‘blip’ in virus (127 and 113 RNA copies/mL, respectively) and re-suppressed promptly • At week 4, 21/26 patients (80,7%) reached full viral suppression (< 50 copies HIV-1 RNA/mL). • The mean CD4+ cell count increased from 352/mm3 (range 24 – 1064 cells/) to 529/mm3 at week 70 (range 187-1106) (p <0.001).

  24. … in pazienti con soppressione virologica • Switch da PI a RAL: bene nello studio SPIRAL, attenzione all’efficacia del backbone (Switchmrk) • NUC Sparing regimens (RAL+PI): numerose segnalazioni di successo terapeutico, no all’uso di RAL+ATV senza booster (DDI) • Monoterapie: per molti, ma non per tutti (risultati discordanti per LPV/r e ATV/r), incoraggianti i risultati su DRV/r negli studi MONET e MONOI

  25. Strategie gestionali per la prevenzione dell’accumulo di resistenze

  26. Outline • Alcuni obiettivi raggiunti, le sfide aperte ed i dati utili nella gestione dei pazienti complessi • Gli strumenti del futuro prossimo • Uno sguardo sul futuro “remoto”

  27. Nuovi farmaci in sviluppo

  28. HIV Cure: Definitions • Complete eradication of all replication competent virus (“sterilizing cure”) • Is this remotely possible? • How can this be proven? • Long-term health in absence of therapy (“functional cure”) • Cancer model (remission) • Definition: no readily detectable virus in absence of therapy for prolonged periods • Natural model: “elite” controllers

  29. Dinisio PNAS 09, McMahon CID 10; Gandhi IAS 09 From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.

  30. HAART Intensification • In most (but not all) studies, treatment intensification is not associated with measurable changes in plasma HIV RNA levels, immune activation, or HIV-specific responses • Dinoso PNAS 09; Gandhi IAS 09; McMahon CID 10; Hatano CROI 10 • In other studies using more precise measures of replication, an effect of intensification may be evident, but this does not affect plasma HIV RNA levels • Buzon, CROI 10, Yukl CROI 10 • Ongoing viral replication is not likely to be a major cause of persistent viremia, but it is possible that low-level virus replication persists and that this virus will remain a barrier to eradication

  31. Why can’t we cure HIV with ARV DrugsWhere is the virus and how is it maintained in the face of “suppressive” therapy? • Residual replication • Sanctuaries; drug penetration • Efficacy, cell type differences • Persistent HIV expression • Replication competent? • Immune disfunction? Latently infected cells Inflammation Homeostatic Proliferation These are not mutually exclusive mechanisms; will multiple approaches be required?

  32. Can HIV be Purged from Latent Reservoir? Increased DNA transcription direclty (HDAC inhibitors, including SAHA) vs. indirectly (IL2, OKT3) under fully suppressive HAART BMT (CCR5), gene therapy, HIV vaccine Richman et al, Science, 2009 From S Deeks, MD, at Chicago, IL: April 19, 2010, IAS–USA.

  33. Eradication Strategies • Stimulate HIV expression from latently infected cells • HDAC and other approaches to remodel chromatin • Specific HIV induction • Immune modulators • Target infected cells with low level replication • Inhibit cellular activation • Direct cytotoxic therapy • Gene therapy approaches • Transplantation approaches • Replacement of bone marrow with HIV resistant donor • Heller et al., 2009 • NOT widely applicable • ARV discontinuation • Clinical success will require surveillance

  34. Eradication Studies (1st Generation) • HDAC inhibitors and other activations of DNA transcription • Valproic acid failed to accelerate HIV decay (Lerman Lancet 05; Siliciano JID 07) • Suberoylanilide hydroxamic acid (SAHA) (Contreras JBC 09) • Prostratin (Korin JV 02) • T cell activation • IL-2 failed to accelerate viral decay (Chun JEM 98, Lafeuilade JAIDS 01, others) • OKT3 (anti-CD3 antibody) (Kulkosky JID 02, Van Praag J Clin Imm 01) failed to accelerate decay, and caused significant toxicity

  35. Eradication Studies (2nd Generation) • Gene therapy approaches • Gene modified HIV specific T cells (Deeks Molecular Med 02) • CCR5 excision (Sangamo) • Anti-sense methods (VIRxSYS) • Practical concerns regarding gene therapy • Stem cell versus T cell therapies • Partial versus full ablation • Bone marrow transplant • Therapeutic vaccines

  36. Potential HIV-1 Latency Activation Therapies • Histone deacetylase (HDAC) inhibitors • Class I-selective: SAHA, others (MRL) • Non-selective: Trichostatin A (TSA), valproic acid (VPA) • NF-kB activators • Prostratin, PMA, TNF • Akt/HEXIM-1 modulators • Hexamethylbisacetamide (HMBA) • Histone methyltransferase (HMT) inhibitors • DZNep: targets Ezh2 (trimethylates H3-K27/H4-K20) • Chaetocin: targets su(var)3-9 (methylates H3-K9) • Jak/Stat pathway • IL-7

  37. Non-mechanism based screening can identify novel HIV-1 activators ~ 1.5 million compounds (MRL Library) LTR-bGal HTS ~ Confirmed 104 compounds (not known HDACIs) NFAT-BLA Jurkat cell assay ~ 92 compounds that did not activate T-cell HDAC activity assay (novel HDACIs) ~ 83 compounds with potential novel mechanism of Toxicity Chemical attractiveness Further chacterization eg ACH-2, J1.1, primary cells, ex vivo

  38. Clinical implications of new findings in HIV basic research • The need for new antiretroviral medications that are effective against drug resistant HIV variants: • Silencing RNA screens are being used to identify host-cell factors important during the HIV replication cycle. These cellular factors could be ideal targets for future HIV drugs. As opposed to targeting viral genes, cellular factors are more stable and thus, less likely to engender drug resistance. • Optimal time to initiate antiretroviral therapy: • Starting an antiretroviral regimen while the CD4 count is relatively high is costly and potentially leads to a large number of adverse drug effects from the lifelong therapy. By contrast, beginning treatment when the CD4 count is low leads to an unacceptable risk for opportunistic infections. Assays for specific genetic markers may help discriminate patients who should have antiretroviral therapy started early rather than later in infection. • Controlling HIV replication without lifelong antiretroviral therapy: • Currently, patients must strictly adhere to a lifelong antiretroviral regimen to control HIV replication. Newer strategies aimed at blocking the expression of a functional CCR5 receptor and/or excising the integrated HIV proviral genome may lead to the control of HIV replication in the absence of antiretroviral drugs HIV Ther Jul 010

  39. Disclaimer Servizio scientifico offerto alla Classe Medica da MSD Italia S.r.l.Questa pubblicazione riflette i punti di vista e le esperienze dell’autore [o degli autori] e non necessariamente quelli della MSD Italia S.r.l. Ogni farmaco menzionato deve essere usato in accordo con il relativo riassunto delle caratteristiche del prodotto fornito dalla ditta produttrice. 01-13-RTG-2010-IT-4769-AV

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