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Evoluzione delle strategie terapeutiche in HIV

Evoluzione delle strategie terapeutiche in HIV. Prof. Adriano Lazzarin Università Vita-Salute San Raffaele, Milano. La scoperta di diversi nuovi farmaci antiretrovirali ci offre l’occasione di porci obiettivi più ambiziosi studiando il modo di ottimizzare il loro impiego nella pratica clinica.

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Evoluzione delle strategie terapeutiche in HIV

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  1. Evoluzione delle strategie terapeutiche in HIV Prof. Adriano Lazzarin Università Vita-Salute San Raffaele, Milano

  2. La scoperta di diversi nuovi farmaci antiretrovirali ci offre l’occasione di porci obiettivi più ambiziosi studiando il modo di ottimizzare il loro impiego nella pratica clinica.

  3. THE REALISTIC PROJECT: the HIV patient’s normalization The FAIRY-TALE eradication

  4. Survival of Patients with CD4 Counts ≥500 cells/mm3 for >5 Years is Similarto the General Population 4 3 Standardisedmortality ratio 2 1 0 0 1 2 3 4 5 6 7 Years with CD4+ count >500 cells/mm3 APROCO and AQUITAINE cohorts Standardized mortality ratio = mortality in HIV-infected patients / mortality in general population Lewden C et al. J Acquir Immune Defic Syndr 2007;46:72–77

  5. HIV/cART/HOST The tangled triangle

  6. Fast progressor Normalization road map: personalization of the HIV individual treatment Efficacious HAART Intermediate progressor Optimized cART Rx LTNP Maintenance of HIV control Elite controller Obtain immune recovery

  7. HIV-RNA <50 copies/mL62% (407/658) CD4 >350cells/uL60% (400/658) Long term TREATED non progressor Infectious Diseases Dept-HSR cohort: 658 pts with at least 20 years of follow-up

  8. Discover new horizons Moving from the • Strenght of the drugs • Weakness of the virus • Resources of the host The goal: achieve the undetectability in all the treated patients

  9. Main principles driving the change • Rx based on ethiopatogenetic approach • Long term treatment strategy to save FDO • Avoid long term toxicity • Optimize the drug combination • Put up the goals of cART

  10. First line cART looking for the dream team Add the best “third” • Atazanavir • Darunavir • Maraviroc • Raltegravir • Rilpivirine • Etravirine

  11. Una marcia in più? The new combo

  12. Safety and Efficacy of Raltegravir-Based Versus Efavirenz-Based Combination Therapy in Treatment-Naïve HIV-1 Infected PatientsSTARTMRK Protocol 0212008 ICAAC/IDSA Abstract H-896a Jeffrey Lennox, Edwin DeJesus, Adriano Lazzarin, Richard Pollard, Jose Valdez Ramalho Madruga, Jing Zhao, Xia Xu, Angela Williams-Diaz, Anthony Rodgers, Mark DiNubile, Bach-Yen Nguyen, Randi Leavitt, and Peter Sklar For the STARTMRK Investigators

  13. Proportion With HIV RNA <50 cp/mL (95% CI) (Non-Completer = Failure) * * *in combination with TDF/FTC

  14. Change From Baseline in CD4 Cell Count (95% CI) (Observed Failure) Diff (95%CI) = 25.8 (4.4, 47.2) * * *in combination with TDF/FTC

  15. Conclusions Compared to EFV + TDF/FTC in treatment-naïve patients given 48 weeks of therapy, RAL + TDF/FTC: • Had potent, durable, and statistically non-inferior efficacy • faster to achieve vRNA suppression <50 cp/mL • Had greater immunological effect, measured by increase in CD4 cell counts • Was better tolerated • significantly fewer overall and drug-related clinical adverse events • significantly lower percentages of patients with CNS adverse experiences • Had minimal effects on serum lipids

  16. Maturevirus Entry inhibitors TNX-355 CCR5 inhibitors CXCR4 inhibitors MK-0518 GS-9137 Proteaseinhibitors 1 2 3 Integrase inhibitors Reverse transcriptase inhibitors PA-457 - First line therapy- Target: newly productively infected cells

  17. The drugs life spent

  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. Potential for PI/r monotherapy? Avoid NRTI-related toxicities mitochondrial metabolic Avoid NNRTIs toxicities Preserve future treatment options Reduce costs PIs are the only class where monotherapy is possible Highest genetic barrier to resistance among available ARVs, including new classes

  20. Risks of PI Monotherapy:Viral Escape and Resistance Study 613 – LPV/r Induction / maintenance OK – LPV/r Simplification MONARK – LPV/r Initial therapy 100% 80% 60% 40% 20% 0% 0 16 32 48 0 16 32 48 64 80 90 0 12 24 36 48 Week Week Week Discontinued On study, HIV RNA >400 c/mL On study, HIV RNA 50–400 c/mL On study, HIV RNA <50 c/mL

  21. Difficilesmettere ! HAART

  22. SMART Study: Persistence of Excess Risk Related to Slower Virologic and Immunologic Improvement CD4 Cell Count HIV RNA <400 Copies/mL January 2006 results Post-resumption of HAART January 2006 results Post-resumption of HAART 84% 82% 648 625 73% 507 425 Patients (%) CD4 Cell Count (cells/mm3) 35% Continuous Treatment Treatment Interruption Continuous Treatment Treatment Interruption El-Sadr W, et al. 15th CROI. Boston, 2008. Abstract 36.

  23. HIV life spent The weakness of mutant virus

  24. CD4 Cell Count and HIV-RNA:2002 – 2007 100000 1200 2 NRTI + PI/r 3TC 1000 10000 800 CD4 Count (cells/mm3) HIV-1 RNA (copies/mL) 1000 600 400 100 200 10 0 Feb-98 Feb-99 Feb-00 Feb-01 Feb-02 Feb-03 Feb-04 Feb-05 Feb-06 Feb-07

  25. Il successo virologico nel MEXP: obiettivo raggiungibile.

  26. New ART Combinations with: Bevirimat, Darunavir, Elvitegravir, Elvucitabine, Etravirine, Maraviroc Raltegravir, Rilpivirine, Vicriviroc.

  27. 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.

  28. At least one from new classes EACS Guidelines • Defer the change if < 2 active drugs • Use 2 or 3 active drugs

  29. Y. Yazdanpanah 1, C. Fagard 2, D. Descamps 3, A.M. Taburet 4, B. Roquebert 3, I. Tschope 2, C. Katlama 5, G. Pialoux 6, C. Jacomet 7, C. Piketty 8, D. Bollens 9, J.-M. Molina 10, G. Chene 2and the ANRS 139 TRIO Trial Group 1 Tourcoing Hospital, Tourcoing, France; 2 INSERM U897, Bordeaux, France; 3 Bichat-Claude Bernard Hosp, Paris, France; 4 Kremlin Bicetre Hosp, Paris, France; 5 Pitie-Salpetriere Hosp, Paris, France; 6 Tenon Hosp, Paris, France; 7 Clermont-Ferrand Hosp, Clermont-Ferrand, France; 8 Georges Pompidou Hosp, Paris, France; 9 Saint-Antoine Hosp, Paris, France; 10 Saint-Louis Hosp, Paris, France High rate of virologic success with raltegravir plus etravirine and darunavir/ritonavir in treatment-experienced patients with multidrug-resistant virus : Results of the ANRS 139 TRIO trial

  30. TRIO-Trials Eligibility criteria • Patients failing cART with HIVRNA > 1000 /mL • No CD4 restriction • Naïve to raltegravir, etravirine and darunavir • With multidrug-resistant virus • ≥3 major PI mutations(IAS list 2006) But susceptible to darunavir (1st Power algorithm) : ≤ 3 mutations among V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V and L89V • ≥3 NRTI mutations (IAS list 2006) • Previous virologic failure on NNRTIs But susceptible to etravirine (1st Tibotec analyses for ETR) <3 NNRTI mutations amongA98G, L100I, K101Q/P/E, K103H/N/S/T, V106A/M, V108I, E138G/K/Q, V179D/E/F/G/I, Y181C/I/V/C/H/L, Y188C/H/L, G190A/C/E/Q/S, P225H, F227C/L, M230I/L, P236L, K238N/T and Y318F 32

  31. Trial Profile 170 patients screened 67 ineligible (67% genotypic criteria, 19% HIV RNA < 1000/ml) 103 patients included all received the study treatment • 2 discontinued • One lost to follow-up • One grade 4 clinical AE 101 patients completedthroughweek 24 33

  32. Optimized background therapy received with raltegravir, etravirine and darunavir % of patients • None 14% • NRTIs 83% • Enfuvirtide 12% (10 /12 wereenfuvirtidenaive) GenotypicSensitivity score of OBT (ANRS algorithm) • 0 20% • 0.5 39% • 1 24% • > 1 17% 34

  33. Results : Proportion of patients with HIV RNA < 50 copies/ml at 24 weeks (missing = failure) 90% (95%CI 85% to 96%) 35

  34. CD4 change from baseline: median and IQR (cells/mm3) + 99 cells/mm3 (32-147) 36

  35. Results of clinical trials in treatment experienced patients with MDR virus Control DRV/r ETR Control Control RAL Control ETR % pts with HIV RNA < 50 cp/ml 131 124 304 308 295 296 454 235 103 37 Lancet 2007, Lancet 2007, N Eng J Med 2008

  36. !

  37. Unprecedented high rate of virologic success with raltegravir, maraviroc & etravirine based antiretroviral regimen in heavily pre-treated HIV-infected patients harboring R5 coreceptor-using virus Alessandro Soria, Francesca Visco, Silvia Nozza, Alba Bigoloni, Giuliana Fusetti, Stefania Salpietro, Nicola Gianotti, Giuseppe Tambussi, Adriano Lazzarin, Antonella Castagna Dept of Infectious Diseases, San Raffaele Scientific Institute, Milan

  38. ISENTRESS CELSENTRI INTELENCE NRTI and PI/r sparing Rx New scenario in rescue therapy

  39. D-M/X4: 44 (X4=2) ND: 10 R5:54 Excluded: 2 Other ARTs: 9 MVC+RTG+2NRTIs: 4 (DUET failures) MVC+RTG+DRV/r: 11 (DRV sensible, ETV not jet available) Rescue therapy including raltegravir, maraviroc & etravirine in multiexperienced failing patients (hSR cohort) SCREENING: 108 MVC+RTG+ETR: 28 (26%) cART-Rx:7 CP BID

  40. Viral load change Median (IQR) decrease of viral load from baseline 0 Baseline W4 W12 W24 W36 W48 -0,5 -1 -1,5 HIV-RNA log10 copies/mL -2 -2,5 -3 -3,5 n=28 n=17 n=22 n=24 n=19 n=12

  41. MVC-RTG-ETR treated MEXP % of undetectable viral load Proportion of subjects with viral load < 50 copies/mL 90% 89% 100% 86% 79% 90% 80% 61% 70% 60% 50% 40% 30% 20% 10% 0% W4 W12 W48 Baseline W24 W36 n=28 n=17 n=22 n=24 n=19 n=12

  42. Main IMMUNOLOGICAL findings in 28 failing HIV-infected four classes failing patients who received maraviroc,raltegravir and etravirine.

  43. Main METABOLIC findings in 28 failing HIV-infected four classes failing patients who received maraviroc, raltegravir and etravirine. (*) Greenhouse-Geisser probabilities on time effect by ANOVA for repeated measures calculated on 24 weeks of follow-up as some patients have not yet reached week 36 or 48. (§) Nosignificant differences between values at week 48 and week 24 for all the considered parameters.

  44. Limits of efficacy of new cART • Genetic barrier of resistance • Archived mutations • Durability

  45. Raltegravir Resistance • Virologic failure was observed in 38/133 (29%) patients receiving raltegravir in double-blind period • 68% of patients with virologic failure had GSS of 0 • Genotype data available for all 38 failures: • Most patients (35/38) failing raltegravir had integrase mutations conferring raltegravir resistance • Integrase mutations were in either of two genetic pathways (N155 or Q148) in 34 of 35 patients • Resistance was typically associated with two or more mutations (31 of 35 patients) • Q148H/G140S was most common (N=13) *From: Hazuda et al, XVI International HIV Drug Resistance Workshop, 2007, Barbados

  46. NNRTI RAMS • 22 NNRTI * RAMS** identified in the 2007 IAS-USA list • An additional 22 NNRTI RAMs identified in the literature and described by Tambuyzer et al. At the 5° European HIV Drug Resistance Workshop • A final list of 44 NNRTI RAMs at 20 RT*** amino acid positions • 37/44 identified associated with an increase in FC to at least one NNRTI when introduced alone in a WT HIV-1/HXB2 backbone by SDM**** (labeled:s)

  47. 96 week Safety & Efficacy Analyses of Raltegravir

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