Casablanca 2010 - VIH: Nouvelles stratégies thérapeutiques - Christine Katlama
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Pr Christine Katlama. Une présentation de la 5ème Conférence Francophone VIH/Sida Casablanca du 28 au 31 mars 2010. http://www.vih.org/casablanca2010
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Casablanca 2010 - VIH: Nouvelles stratégies thérapeutiques - Christine Katlama
- 1. VIH Nouvelles Stratégies Thérapeutiques Pr Christine KATLAMA 2010 5° conférence Francophone Casablanca
- 3. Indétectabilité de la charge virale et Reconstitution immunitaire
- 6. 2005 Les années SMART Le non contrôle de la réplication virale est associée à un sur risque de morbidité El-Sadr W.,NEJM 2006, 0 2495 2512 4 1839 1848 8 1441 1434 12 1112 1122 16 915 931 20 733 754 24 569 601 28 449 490 32 375 398 36 297 310 40 178 184 44 34 41 DC VS Nb patients VS 15 10 5 0 DC p < 0,0001 % cumulated events Mois depuis la randomisation
- 7. SMART : Risque de décès associé à une augmentation des marqueurs de l’inflammmation et de la coagulation Marker Un-adjusted Adjusted OR (4 th /1 st ) P-Value OR (4 th /1 st ) P-Value Hs-CRP 2.0 0.05 2.8 0.03 Amyloid A 2.2 0.07 2.6 0.09 Amyloid P 0.7 0.39 1.1 0.84 IL-6 8.3 <0.0001 11.8 <0.0001 D-Dimer 12.4 <0.0001 26.5 <0.0001 F1.2 1.0 0.92 1.2 0.66 *Adjusted for age, race, ART, VL, BMI, Cholesterol, Smoking, Hepatitis, Statins, BP med’s Kuller LH, et al. PLoS Med. 2008;5:e203.doi;10.1371/journal.pmed.0050203
- 8. Persistance de phénomènes délétères malgré le contrôle de la réplication plasmatique Pathogénèse Une nouvelle donne
- 9. Le tractus intestinal, lieu préférentiel de stockage du VIH est associé à une déplétion massive des lymphocytes CD4 et des altérations tissulaires majeures L’intestin représente 50% des reserves du système immunitaire JM. Brenchley, ..AT. Haase,and DC. Douek J Exp. Med. 2004 S Mehandru,………P Racz, and M Markowitz, J Exp. Med. 2004
- 13. Pathogénèse de l’infection VIH VIH Activation immune Inflammation Déficit Immunitaire Risque cardiovasculaire Os Troubles cognitifs Cancers Vieillissement accéléré SIDA HBV/HCV Le VIH est délétère par l’immunodépression et par l’immunoactivation /inflammation
- 14. Plasma HIV RNA Virémie cellulaire CD4+ VIH: un prédateur dangereux Aucune bonne raison de le laisser se répliquer Années
- 19. * XTC= 3TC or FTC Recommendations internationales Quand debuter ? NDLR IAS-USA 2008 CD4 <350 (consider if > 350 in some situations) 2NRTI (ABC/3TC or TDF/FTC + NNRTI (EFV) or PI/r (ATV/r or DRV/r or FPV/r or LPV/r or SQV/ DHHS 2009 CD4 ≤500 A considerer si CD4> 500) Les plus récentes Les plus actuelles ! EACS 2009 CD4 ≤350 A consider si > 350 dans certaines situations OMS/WHO 2009 CD4 ≤350 Une avancée notable !!
- 20. Essai START Quand débuter le traitement ARV ? Gordin et al. IAS 2007, MOSY205 oral presentation Patients HIV+ avec CD4 >500 cp/ ml Traitement précoce Début cART immédiat n=600 pour la phase initiale n=1500 (estimation) pour la fin de l’étude Traitement différé cART débuté quand CD4 <350 cells/ µL or symptomes n=600 pour la phase initiale n=1500 (estimation) pour la fin de l’étude
- 21. ARVs: 2010 Combivir 1,2 , Trizivir 1,2,3 , Kivexa 2,3 , Truvada 4,5 , Atripla 4,5,6 NRTI/NtRTI NNRTI Protease Fusion ZDV 1 Nevirapine Saquinavir Enfuvirtide 3TC 2 Efavirenz 6 Indinavir ddI Etravirine Nelfinavir Inhib Integrase ddC Ritonavir Raltegravir Abacavir 3 Fosamprenavir Tenofovir 4 Lopinavir/r CCR5 FTC 5 Atazanavir Maraviroc Tipranavir Darunavir
- 22. * XTC= 3TC or FTC Recommendations internationales Quand debuter ? Traitement initial 1° choix IAS-USA 2008 CD4 <350 (consider if > 350 in some situations) 2NRTI (ABC/3TC or TDF/FTC + NNRTI (EFV) or PI/r (ATV/r or DRV/r or FPV/r or LPV/r or SQV/ DHHS 2009 CD4 ≤500 (consider if > 500) TDF/FTC +EFV +/ATVr +DRVr + RAL EACS 2009 CD4 ≤350 (consider if > 350 in some situations) 2NRTI (ABC/3TC or TDF/FTC) + +NNRTI (NVP - EFV) +IP /r (ATVr - DRVr LPVr or SQVr) OMS/WHO 2009 CD4 ≤350 2NRTI (AZT/3TC or TDF/XTC*) + NNRTI (NVP or EFV)
- 23. Etude ACTG A5202 : ABC/3TC versus TDF/FTC, associé à EFV versus ATV/r, en traitement de 1 ère ligne – 1 857 patients naïfs CV ≥ 1000 c/ml Pas de restriction sur les CD4 Randomisation 1:1:1:1 stratifiée sur CV < ou > 100 000 c/ml A B C D TDF/FTC qd + Placebo ABC/3TC qd EFV qd ABC/3TC qd + Placebo TDF/FTC qd EFV qd ATV/r qd ATV/r qd TDF/FTC qd + Placebo ABC/3TC qd ABC/3TC qd + Placebo TDF/FTC qd + + + + Suivi jusqu’à ce que le dernier patient inclus ait atteint S96 Daar E, CROI 2010, Abs. 59LB Sans insu Double aveugle
- 27. Nouvelles Molécules antirétrovirales Quel bénéfice ? Mature virus Maraviroc Entry inhibitors Fusion CCR5 receptors Integrase inhibitors Raltegravir PIs Ataza Lopi Darunavir Reverse transcriptase inhibitors Etravirine Rilpivirine
- 31. Initiation ARV Alternative à la trithérapie ARV-Naïve HIV+, any CD4 Randomisation 1:1 qd DRV/r + RAL pills: 4 +1 Minimum F-U: W96 TVD + DRV/r pills: 4 qd ARV-Naïve HIV+, any CD4 Randomisation 1:1 TVD + DRV/r pills: 4 qd qd DRV/r + RAL pills: 4 +1 ARV-Naïve HIV+, any CD4 Randomisation 1:1 TVD + DRV/r pills: 4 qd Minimum F-U: W96 qd DRV/r + RAL pills: 4 +1 ARV-Naïve HIV+, any CD4 Randomisation 1:1 TVD + DRV/r pills: 4 qd NEAT 001/ANRS 143
- 32. MONARK : Monothérapie LPV chez naifs ARN VIH J0 à S48 Delfraissy, AIDS 2008 0% 20% 40% 60% 80% 100% 0 16 32 48 Ayant arrêté < 50 c/mL 0 16 32 48 LPV/r + AZT/3TC LPV/r 0% 20% 40% 80% 0 16 32 48 > 400 c/mL 0 16 32 48 Semaines LPV/r + AZT/3TC LPV/r 50 - 400 Semaines
- 33. Echec 1 Les enjeux du traitement institué
- 37. DARUNAVIR POWER 1 and 2: CV VL < 50 copies/mL at Week 48 (ITT-TLOVR) DRV/RTV 600/100 mg BID * P < .001 vs comparator PI/RTV. 45* 12 46* 10 0 20 40 60 80 100 0 4 8 12 16 20 24 28 32 36 40 44 48 Weeks 1 2 Control Patients With VL< 50 c/mL (%) Not all patients had reached Week 48 at the time of analysis; patients who had not reached Week 48 were censored at their last available visit. Lazzarin A, et al. IAC 2006. Abstract TUAB0104.
- 39. Etravirine DUET study : Efficacité Response (<50 copies/mL) at Week 48 (ITT-TLOVR) CV < 50 c/ml at W48 according to active molecules in OBT (PSS) p<0.0001 61% 40% Patients with viral load <50 copies/mL at Week 48 (%) ( ± 95% CIs) Time (weeks) Placebo + BR (n=604) ETR + BR (n=599) 10 20 30 40 50 60 70 80 90 100 0 2 4 8 12 16 20 24 32 40 48 0
- 41. Comment associer les mol é cules chez les patients avec virus r é sistants ? ETV PI DRV PI CV et resistance + + + ± ETV RAL DRV RAL + or ? ETV Si pas de Résistance NRTIs CV basse + Cible : indétectabilité de la CV
- 42. Les enjeux du traitement Importance du choix du traitement ARV Succès Tolérance à long terme Activation Inflammation Réservoirs Traitement à vie Comorbidités Echec Traitement 2
- 43. Complications liées au VIH et au traitement ART Troubles neuro-cognitifs HIV Risque cardio vasculaire Lipodystrophie Troubles métaboliques Traitement ARV Rein Os PI NRTI PI TDF TDF PI/r NRTI ?
- 44. Alléger le traitement sans réduire la puissance ?
- 46. Lack of potency in patients treated with less than 350 CD4/mm 3 at initiation To be reconsider in easier therapy? NRTI NNRTI alone NNRTI + PI PI MONO RAL+2NRTI + PI Low genetic barrier to resistance Potential option Nonuke Caution with prior use of NNRTI SWITCHMRK Under investigation CC5 Inhibitor Options for alléger le traitement ARV dans un contexte de suppression virologique 2 Potent strategies No data
- 49. MONOI Efficacit é virologique S48 DRV/r DRV/r + NRTIs
- 50. MONOI : Switch Trithérapie pour mono DRV Evolution de la graisse des membres Valantin , Katlama et al CROI 2010 Variation médiane (IQR) de J0 à S48 Trithérapie Monothérapie p Gras des membres (en g) -20 g (-530;+520) +340 g (-40;+1140) p=0.011 p=0.78 p<0.001 En pourcentage -0.26% (-10%;+9%) + 8.3% (-1%;+21%) P<0.001 p=0.87 p<0.001
- 51. MONO PI Un bénéfice indéniable en termes de coût Bithérapie de NRTI : 4200 Euros/an pour AZT/3TC 5000 Euros /an pour ABC/3TC 5800 Euros /an pour TDF/FTC Epargne de toxicité produits de comblements Epargne de classes molécules NRTI encore sensibles Mono PI
- 57. ERAMUNE-01 & 02 ERAMUNE-02 (USA) ERAMUNE-01 (Europe) SCREENING ARM A ARM B 3 ARV + Intensification (raltegravir + maraviroc) + IL-7 Primary Evaluation W -8 D0 Randomization W8 W56 3 ARV + Intensification (raltegravir + maraviroc) SCREENING ARM A ARM B 3 ARV + Intensification (raltegravir + maraviroc) Primary Evaluation W -8 D0 Randomization W8 W56 3 ARV + Intensification (raltegravir + maraviroc) + Vaccine HIV-rAd5
- 59. Roland Tubiana Marc Antoine Valantin Lumi Schneider Ana Canestri Hocine Ait Mohand Cyril Clavel Fabienne Caby B.Autran D.Costagliola V.Calvez AFRAVIH SOLTHIS ESTHER Mali Les miens
Editor's Notes
- Within the quasispecies, positive (Darwinian) selection implies that one or more members of the quasispecies are better suited to a given environment while negative selection eliminates unfit variants In the absence of drug pressure, resistant mutants tend to disappear from the dominant quasispecies as they are outgrown by the fitter wild-type virus. The greater the impact on fitness the more rapid the disappearance
- Within the quasispecies, positive (Darwinian) selection implies that one or more members of the quasispecies are better suited to a given environment while negative selection eliminates unfit variants In the absence of drug pressure, resistant mutants tend to disappear from the dominant quasispecies as they are outgrown by the fitter wild-type virus. The greater the impact on fitness the more rapid the disappearance
- Le Meilleur de … CROI 2010 F. Raffi, J. Reynes, B. Hoen, B. Masquelier et G. Peytavin
- Within the quasispecies, positive (Darwinian) selection implies that one or more members of the quasispecies are better suited to a given environment while negative selection eliminates unfit variants In the absence of drug pressure, resistant mutants tend to disappear from the dominant quasispecies as they are outgrown by the fitter wild-type virus. The greater the impact on fitness the more rapid the disappearance
- Le Meilleur de … CROI 2010 F. Raffi, J. Reynes, B. Hoen, B. Masquelier et G. Peytavin
- The course of HIV disease can be described in virologic, immunologic and clinical parameters. During acute infection there are extremely high levels of virus replication with seeding throughout lymphoid tissues and the brain. This is usually accompanied by a transient decrease in CD4+ lymphocyte count and a self-limited influenza-like illness. These high levels of HIV replication fall abruptly with the development of an immune response to the virus, now thought to be mediated largely by the emergence of cytotoxic CD8+ lymphocytes, rather than by development of neutralizing antibody. After the acute syndrome, there is a prolong period of clinical latency, which previously was thought to also be a period of viral quiescence. In fact, it is now clear that moderately high levels of virus production occur at all stages of disease in most HIV-infected individuals. Measurement of the decay in viremia during the weeks to months after initiation of potent antiretroviral therapy allowed estimation of the daily virus production (up to 10 billion viral particles daily) and of the virus turnover, in which the virus half-life is estimated to be less than 6 hours. Circulating infectious virus titers are much lower than plasma HIV RNA levels, suggesting that the majority of virus particles are defective. The initial CD4+ lymphocyte increases during the weeks after initiating antiretroviral therapy may mostly represent cell redistribution, with increases in total CD4+ lymphocyte number evident within weeks. With progression of disease there is generally increasing levels of plasma viremia and progressive destruction of lymph node architecture and loss of cell-mediate immune response. With low levels of CD4+ lymphocyte count (< 100 cells/mm 2 ) infectious complications become increasingly common. References Ho DD. Rapid turnover of plasma virions and CD4 lymphocytes ih HIV-1 infection. Nature , 1995; 373:123-6. Pantaleo G. HIV infection is active and progressive in lymphoid tissue during clinically latent stage of disease. . Nature , 1993; 362:355-8. Wei X. Viral dynamics in human immunodeficiency virus type 1 infection. Nature , 1995; 373:117-22. Coffin JM. HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy. Science , 1995; 267:483-489. Perelson AS. HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science , 1996; 271:1582-1586.
- Le Meilleur de … CROI 2010 F. Raffi, J. Reynes, B. Hoen, B. Masquelier et G. Peytavin
- Le Meilleur de … CROI 2010 F. Raffi, J. Reynes, B. Hoen, B. Masquelier et G. Peytavin
- CI, confidence interval; EFV, efavirenz; ITT, intent to treat; NC = F, noncompleter equals failure; RAL, raltegravir. Using a noncompleter-equals-failure analysis at Week 48, 86% of participants in the raltegravir arm achieved HIV-1 RNA < 50 copies/mL compared with 82% of participants in the efavirenz arm. These data established that raltegravir was noninferior to efavirenz. As has been shown in other studies, there was a significantly shorter time to virologic response with raltegravir; approximately 50% of participants in the raltegravir arm achieved HIV-1 RNA < 50 copies/mL at 4 weeks compared with < 20% of participants in the efavirenz arm. In addition, at 48 weeks, subjects in the raltegravir arm had a CD4+ cell count increase of 189 cells/mm^3 vs 163 cells/mm^3 in the efavirenz arm. This finding was determined to be statistically different between the 2 arms, although perhaps not clinically significant. For more information, go online to: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Washington%202008/Tracks/First-Line/Capsules/896a.aspx
- NEAT 001/ANRS 143 trial November 10, 2008
- Within the quasispecies, positive (Darwinian) selection implies that one or more members of the quasispecies are better suited to a given environment while negative selection eliminates unfit variants In the absence of drug pressure, resistant mutants tend to disappear from the dominant quasispecies as they are outgrown by the fitter wild-type virus. The greater the impact on fitness the more rapid the disappearance
- Prezista binding within HIV-1 protease Key point Prezista fits neatly into and has a very stable position in the catalytic pocket in the HIV-1 protease enzyme (numbers on figure represent the distance in Å ngstr ö ms between Prezista and the amino acids that make up the protease). Data on file. Tibotec BVBA, Mechelen, Belgium.
- Le Meilleur de … CROI 2009 F. Raffi, J. Reynes B. Hoen, B. Masquelier et G. Peytavin
- Les résultats du groupe &quot;monothérapie Kaletra ® &quot; ne sont pas inférieurs à ceux du bras &quot;poursuite de la trithérapie&quot;
- Now coming to the RESULTS and the PRIMARY END POINT AT W48 - Considering the per protocol population , the rate of virologic success of DRV monotherapy was 94.1% compared to 99% in the triple therapy group; the difference was 4.9% with a lower limit of CI of -9% under the 10% limit allowing therefore to assess the non-inferiority in the efficacy of monotherapy Considering then the intent to treat population , - the rate of success was 92% in the triple therapy arm and 87.5%in the monotherapy ; - While the difference between the 2 arms is very consistent with a 4.5% difference , here the lower limit of CI is 11% which does not allow to assess non inferiority of the monotherapy arm.