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

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Presentation on theme: "Evoluzione delle strategie terapeutiche in HIV Prof. Adriano Lazzarin Università Vita-Salute San Raffaele, Milano."— Presentation transcript:

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/mm 3 for >5 Years is Similar to the General Population Lewden C et al. J Acquir Immune Defic Syndr 2007;46:72–77 Standardized mortality ratio = mortality in HIV-infected patients / mortality in general population APROCO and AQUITAINE cohorts Standardised mortality ratio Years with CD4+ count >500 cells/mm 3

5 HIV/cART/HOST The tangled triangle

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

7 HIV-RNA <50 copies/mL 62% (407/658) CD4 >350 cells/uL 60% (400/658) Long term TREATED non progressor Infectious Diseases Dept-HSR cohort: 658 pts with at least 20 years of follow-up

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

10 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

11 First line cART looking for the dream team  Atazanavir  Darunavir  Maraviroc  Raltegravir  Rilpivirine  Etravirine Add the best “third”

12 Una marcia in più? The new combo

13 Safety and Efficacy of Raltegravir-Based Versus Efavirenz-Based Combination Therapy in Treatment-Naïve HIV-1 Infected Patients STARTMRK Protocol 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

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

15 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 * *

16 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

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18 TNX-355 CCR5 inhibitors CXCR4 inhibitors PA-457 MK-0518 GS-9137 Entry inhibitors Reverse transcriptase inhibitors Mature virus Protease inhibitors Integrase inhibitors First line therapy - Target: newly productively infected cells

19 The drugs life spent

20 SEMPLIFICATION: a long-term treatment strategy in HIV controller Time VL InductionMaintenance 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 ? Schematic representation; Katlama C, personal communication

21 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

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

23 Difficile smettere ! HAART

24 SMART Study: Persistence of Excess Risk Related to Slower Virologic and Immunologic Improvement Patients (%) HIV RNA <400 Copies/mL 82% January 2006 results Post-resumption of HAART Continuous Treatment Interruption El-Sadr W, et al. 15 th CROI. Boston, Abstract % 35% 73% CD4 Cell Count (cells/mm 3 ) 625 January 2006 results Post-resumption of HAART Continuous Treatment Interruption CD4 Cell Count

25 HIV life spent The weakness of mutant virus

26 CD4 Cell Count and HIV-RNA: 2002 – 2007 CD4 Count (cells/mm 3 ) HIV-1 RNA (copies/mL) 3TC2 NRTI + PI/r Feb-98Feb-99Feb-00Feb-01Feb-02Feb-03Feb-04Feb-05Feb-06Feb

27 Il successo virologico nel MEXP: obiettivo raggiungibile.

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

29 Is VL < 50 Achievable in Treatment- Experienced Patients With MDR HIV? 1. Cahn P, et al. ICAAC Abstract H Kumar P, et al. EACS Abstract P7.2/ Lalezari J, et al. ICAAC Abstract H-718a. 34% 63%* Weeks Patients (%) *P <.001 vs PL BENCHMRK-1 and -2 [2] RAL + OBR PL + OBR MVC BID + OBRPL + OBR 47%* 16% Weeks MOTIVATE 1 [3] 25% 49%**P <.0001 vs PL Patients (%) Weeks Patients (%) *P <.0001 vs PL DUET 1 and 2 [1] ETR + OBRPL + OBR 59%* 41%

30 EACS Guidelines  At least one from new classes  Defer the change if < 2 active drugs  Use 2 or 3 active drugs

31 Madrid, 07/09/07 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 2 and 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

32 ANRS 139 TRIO Trial – Mexico TRIO-Trials Eligibility criteria Patients failing cART with HIV RNA > 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 (1 st 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 among A98G, 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

33 ANRS 139 TRIO Trial – Mexico 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 completed through week 24

34 ANRS 139 TRIO Trial – Mexico 2008 Optimized background therapy received with raltegravir, etravirine and darunavir % of patients None14% NRTIs83% Enfuvirtide12% (10 /12 were enfuvirtide naive) Genotypic Sensitivity score of OBT (ANRS algorithm) 0 20% % 1 24% > 1 17% 34

35 ANRS 139 TRIO Trial – Mexico Results : Proportion of patients with HIV RNA < 50 copies/ml at 24 weeks (missing = failure) 90% (95%CI 85% to 96%)

36 Madrid, 07/09/07 36 CD4 change from baseline: median and IQR (cells/mm 3 ) + 99 cells/mm 3 (32-147)

37 ANRS 139 TRIO Trial – Mexico Results of clinical trials in treatment experienced patients with MDR virus DRV/r Lancet 2007, Lancet 2007, N Eng J Med 2008 Control % pts with HIV RNA < 50 cp/ml ETRControl ETR ControlRALControl

38 !

39 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

40 NRTI and PI/r sparing Rx  I SENTRESS  C ELSENTRI  I NTELENCE New scenario in rescue therapy

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

42 Median (IQR) decrease of viral load from baseline -3, , ,5 -0,5 0 BaselineW4 W12W24 HIV-RNA log 10 copies/mL Viral load change n=28 n=17n=22n=24 W36 W48 n=19n=12

43 Proportion of subjects with viral load < 50 copies/mL 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Baseline W4W12 W24 MVC-RTG-ETR treated MEXP % of undetectable viral load n=28 n=17 n=22n=24 86% n=19n=12 W36 W48 90% 79% 89% 61%

44 Baseline (N=28) Week 12 (N=28) Week 24 (N=28) Week 36 (N=20) Week 48 (N=13) CD4 cells/µL254 (76-399) 399 ( ) 492 ( ) 546 ( ) 554 ( ) CD4%14.0 ( ) 17.5 ( ) 20.5 ( ) 21.7 ( ) 21.4 ( ) CD4/CD8 ratio0.21 ( ) 0.33 ( ) 0.42 ( ) 0.46 ( ) 0.40 ( ) HIV-RNA log 10 copies/mL 4.16 ( ) 1.69 ( ) 1.69 ( ) 1.69 ( ) 1.69 ( ) Main IMMUNOLOGICAL findings in 28 failing HIV-infected four classes failing patients who received maraviroc,raltegravir and etravirine.

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46 Baseline (N=28) Week 12 (N=28) Week 24 (N=28) Week 36 (N=20) Week 48 (§) (N=13) p-value (*) Cholesterol (mg/dl) 178 ( ) 174 ( ) 187 ( ) 185 ( ) 188 ( ) Col HDL (mg/dl)39 (34-46) 50 (40-53) 45 (39-51) 39 (34-52) 42 (33-47) Col LDL (mg/dl)114 (82-129) 94 (71-118) 109 (84-129) 117 (99-123) 119 ( ) Triglycerides (mg/dl) 137 (95-191) 111 (81-149) 112 ( ) 109 (79-207) 124 (84-463) Fasting glucose (mg/dl) 86 (76-91) 94 (86-103) 85 (80-100) 88 (83-99) 86 (83-96) (*) 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. (§) No significant differences between values at week 48 and week 24 for all the considered parameters. Main METABOLIC findings in 28 failing HIV-infected four classes failing patients who received maraviroc, raltegravir and etravirine.

47 Limits of efficacy of new cART  Genetic barrier of resistance  Archived mutations  Durability

48 ICAAC 2007, ABS # H-713 Raltegravir Resistance Virologic failure was observed in 38/133 (29%) patients receiving raltegravir in double-blind periodVirologic 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: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)Q148H/G140S was most common (N=13) *From: Hazuda et al, XVI International HIV Drug Resistance Workshop, 2007, Barbados

49 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)

50 96 week Safety & Efficacy Analyses of Raltegravir

51 (MVC-RTG-ETR combination) Lights  Efficacy  Immune reconstitution  Tolerability Shadows  Convenience  Costs  Lack of informations on: IRIS long term toxicity durability salvage therapy in failing patients CNS efficacy Incidence of neoplasias

52 The “rescue therapy” in failing patients  Elvitegravir  Rilpivirine  Bevirimat  Elvucitabine  New NNRTI  New NRTI Next line drugs for cART  PI/r revertant HIV  T20 revertant HIV recicling

53 The resources of the host T cells: the double crossers

54 Problems to be solved Residual replication of HIV in the reservoirs Continuous immune activation Easier HIV transmission on CD4/CCR5+cells Persistance of HIV replication Depletion of CD4+ memory cells

55 Factors Linked to Impaired CD4+ T-cell Reconstitution More advanced HIV-1 infection at HAART initiation Higher levels of CD8+ T-cell activation at HAART initiation Older age at HAART initiation potentially secondary to impaired thymic function Higher levels of collagen deposition, fibrosis and activation-induced damage to lymphoid tissue Persistent CD4+ T-cell activation and turnover after HAART initiation – independent of plasma HIV-1 RNA level Insufficient suppression of HIV-1 RNA while on HAART Variation in genes encoding CCR5 (the major HIV co-receptor), and CCL3L1 its most potent HIV-suppressive ligand

56 Each 10% Increase in Activated CD8+ T-cells is Associated with a Mean of 70 Fewer CD4+ T Cells Gained on Therapy Hunt et al. JID 2003;187(10):1534–43

57 57 Why Might CCR5 Inhibition Protect CD4s in the Context of HIV Disease? Maraviroc may block the migration of CCR5+ cells into tissues thereby increasing the number of CD4+ cells in circulation and/or preventing their killing by HIV in tissues Maraviroc may block cellular activation and cytokine expression by preventing signaling through this receptor... ……CD4 recovery only a consequence of antiviral efficacy?

58

59 CD4+ Cell Count Increases in 16 Phase 2 and 3 Clinical Studies of ARVs in Treatment-Experienced Patients Wilkin T et al. CROI 2008; poster 800 CCR5 antagonists (vicriviroc, maraviroc) Other ARVs (etravirine, enfuvirtide, raltegravir, darunavir, tipranavir) Size of circle represents sample size CD4 count (cells/mm 3 ) Proportion of patients with HIV-RNA <50 copies/mL at Week 24

60 CD4+ Cell Count Rises in MOTIVATE 1 and 2 Patients According to Suppression to HIV-1 RNA <50 Copies/mL Median change from baseline in CD4+ count (cells/mm 3 ) 59* 43* PBO + OBT (N=140) MVC QD + OBT (N=162) MVC BID + OBT (N=159) Never achieved HIV-1 RNA <50 copies/mL MOTIVATE 1& 2 – Week 48 * for different effect of treatment over time; combined MVC arms vs PBO * p< * 125* PBO + OBT (N=68) MVC QD + OBT (N=251) MVC BID + OBT (N=267 ) Achieved HIV-1 RNA <50 copies/mL at least once * p<0.05 All treated patients with valid baseline and on-treatment measurements (LOCF) Asmuth D, et al. XVII International AIDS Conference 2008 ; Poster TUPE0050h

61 Significantly Greater and Faster Increases in CD4+ Cell Count Were Observed in Patients Receiving MVC Compared to EFV Lazzarin A, et al. 48th Annual ICAAC/IDSA 46th Meeting 2008; Poster H-1248 Time (Weeks) EFV + CBV (n=361) MVC + CBV (n=360) Median change in CD4+ T-cell count from baseline (cells/mm 3 ) 122 cells/mm cells/mm 3 p =0.004 for the difference in treatment effect over time MERIT – Week 48; LOCF

62 Risultati: recupero immunologico Mediana della variazione di CD4/mm 3 p=0.004p=0.02

63 Results in a patient failing at week 24: PT # MVC, RTG, ETR

64 DON’T MISS THE CHANCE the Halley comet appears in the sky every 76 years.


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