VIH. novedades terap©uticas

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Presentación realizada por Piedad Arazo Garcés, en el curso de la Jornada Pacientes y Salud: “Foros en el CIBA”. Novedades terapéuticas e importancia del paciente informado, el 12 de noviembre de 2014.

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2. Avances del tratamiento aannttiirrrreettrroovviirraall 3. Avances del tratamiento aannttiirrrreettrroovviirraall 4. Antirretrovirales disponibles en la actualidadNucleoside RTIs Zidovudine (ZDV) Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) Emtricitabine (FTC) Tenofovir DF (TDF)Nonnucleos(t)ide RTIs Nevirapine (NVP) Rilpivirina (RPV) Efavirenz (EFV) Etravirine (ETR)Protease Inhibitors Saquinavir (SQV) Ritonavir (RTV) Indinavir (IDV) Nelfinavir (NFV) Amprenavir (APV) Lopinavir/r (LPV/r) Atazanavir (ATV) Fosamprenavir (Fos-APV) Tipranavir (TPV)Boosters Darunavir (DRV) Ritonavir (RTV)Fusion Inhibitor Enfuvirtide (T-20)CCR5 Antagonist Maraviroc (MVC)Integrase Inhibitors Raltegravir (RAL) Elvitegravir 5. Antirretrovirales acutales y futurosNucleoside RTIs Zidovudine (ZDV) Didanosine (ddI) Zalcitabine (ddC) Stavudine (d4T) Lamivudine (3TC) Abacavir (ABC) Emtricitabine (FTC) Tenofovir DF (TDF) Tenofovir AF (TAF)Nonnucleos(t)ide RTIs Nevirapine (NVP) Rilpivirina (RPV) Efavirenz (EFV) Etravirine (ETR) Doravirine (DRV)Protease Inhibitors Saquinavir (SQV) Ritonavir (RTV) Indinavir (IDV) Nelfinavir (NFV) Amprenavir (APV) Lopinavir/r (LPV/r) Atazanavir (ATV) Fosamprenavir (Fos-APV) Tipranavir (TPV)Boosters Darunavir (DRV) Ritonavir (RTV) Cobicistat* (cobi) Fusion Inhibitor Enfuvirtide (T-20)CCR5 Antagonist Maraviroc (MVC)Integrase Inhibitors Raltegravir (RAL) ElvitegravirDolutegravir* 6. MK-1439 (Doravirine): A New NNRTIMMKK--11443399 2255 mmggDose-Ranging Trial in Treatment-nave Patients 3-fold potency shift vs. common NNRTI-resistance mutantsK103N, Y181C, G190A, E138K(4) Low potential for CNS effects, drug-drug interactions; lowerprotein-binding vs. other NNRTIsMorales-Ramirez J, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 92LB.EEffaavviirreennzzMMKK--11443399 220000 mmggEEffaavviirreennzz96 Week End ofStudy Treatmentfor Part 1MK-1439 SelectedDosePART 1Dose-Ranging~200 patients(~40/group)MMKK--11443399 5500 mmggMMKK--11443399 110000 mmgg24 Week PrimaryTime Point forDose Selection 7. Virologic Response by Screening RNAAd hoc analysis (Week 24), Observed Failure100,000 c/mL 100,000 c/mLAll MK = 86% All MK = 92% All MK = 66% All MK = 94%27 12 13 11 12Copyright 2014 MerckCo. Inc. All Rights Reserved. 8. Virologic Response by Screening RNAAd hoc analysis (Week 24), Observed Failure100,000 c/mL 100,000 c/mLAll MK = 86% All MK = 92% All MK = 66% All MK = 94%27 12 13 11 12Copyright 2014 MerckCo. Inc. All Rights Reserved. 9. La coformulacin de Darunavir pronto serposible 10. Avances del tratamiento aannttiirrrreettrroovviirraall 11. GSK1265744 (744) HIV-1 integrase inhibitor,dolutegravir analogue Oral drug (t = 40 hours) Long-acting SC or IM injection(apparent t 40 days) Good virologic response at 5and 30 mg/day as oral 10-daymonotherapyMargolis et al. CROI 2014; Boston, MA. Abstract 91LB.Spreen et al. HIV Clin Trials. 2013;14:192-203. 12. LATTE Study Design Phase IIb, randomized, multicenter, partially blind, dose-ranging study 744 + NRTI subjects with a W20 HIV-1 RNA 50 c/mL simplified to 744 + RPV at W24HIV ART-naiveHIV-1 RNA 1000 c/mLCD4 200 cells/mm31:1:1:1 RandomizationStratified by VLand NRTI*ABC/3TC or TDF/FTCOral Induction Phase744 10 mg + 2 NRTIs*744 30 mg + 2 NRTIs744 60 mg + 2 NRTIsOral Maintenance Phase744 10 mg + RPV 25 mg744 30 mg + RPV 25 mg744 60 mg + RPV 25 mgEFV 600 mg + 2 NRTIsWeek Primary endpoint: % HIV-1 RNA 50 c/mL at 48 weeks (FDA Snapshot) Intent-to-treat exposed (ITT-E) received at least one dose of Investigational Product (IP) Intent-to-treat maintenance exposed (ITT-ME) received at least one maintenance dose 13. Primary EndpointVirologic Success: HIV-1 RNA 50 c/mL by FDA Snapshot (ITT-E)Induction Phase Maintenance PhaseWeek744 overall response W4882%EFV response W4871%744 overall response W2487%EFV response W2474%Median (IQR) change frombaseline CD4+ cell count(cells/mm3)Week 48744 overall +219 (141,343)EFV +227 (134,369)Proportion, %BL 2 4 8 12 16 24 2628 32 36 40 48Margolis et al. CROI 2014; Boston, MA. Abstract 91LB. 14. Avances del tratamiento aannttiirrrreettrroovviirraall 15. Choice of Initial RegimenTenofovir/emtricitabine (TDF/FTC) ORAbacavir/lamivudine (ABC/3TC)WITHThird agent (NNRTI, boosted PI, or InSTI): Efavirenz OR Atazanavir/r OR Darunavir/r OR RaltegravirThompson et al, JAMA, 2012. 16. A5257 Study Design*HIV-infected patients, 18 yr, with no previous ART,VL 1000 c/mL at US SitesRandomized 1:1:1 to Open Label TherapyStratified by screening HIV-1 RNA level ( vs100,000 c/mL), A5260smetabolic substudy participation, cardiovascular riskRRAALL 440000 mmgg BBIIDD ++FFTTCC//TTDDFF220000//330000mmggQQDDDDRRVV 880000mmggQQDD++RRTTVV 110000mmggQQDD++ FFTTCC//TTDDFF 220000//330000 mmgg QQDDAATTVV 330000mmgg QQDD ++ RRTTVV 110000mmggQQDD++ FFTTCC//TTDDFF 220000//330000 mmgg QQDDStudy Conclusion 96 weeks after final participant enrolledFollow-up continued for 96 weeks after randomization of last subject (range 2-4years) regardless of status on randomized ART600 PACIENTES POR RAMA*With the exception of RTV, all ART drugs were provided by the study 17. ACTG 5257: Failure Comparisons at 96 WeeksVirologic FailureArms Difference 97.5% CI FavorsATV/r vs. RAL 3.4% -0.7%, 7.4% EquivalentDRV/r vs. RAL 5.6% 1.3%, 9.9% EquivalentATV/r vs. DRV/r -2.2% -6.7%, 2.3% Equivalent 18. ACTG 5257: Failure Comparisons at 96 WeeksVirologic FailureArms Difference 97.5% CI FavorsATV/r vs. RAL 3.4% -0.7%, 7.4% EquivalentDRV/r vs. RAL 5.6% 1.3%, 9.9% EquivalentATV/r vs. DRV/r -2.2% -6.7%, 2.3% EquivalentTolerability FailureArms Difference 97.5% CI FavorsATV/r vs. RAL 13% 9.4%, 16% RAL SuperiorDRV/r vs. RAL 3.6% 1.4%, 5.8% RAL SuperiorATV/r vs. DRV/r 9.2% 5.5%, 13% DRV/r Superior 19. ACTG 5257: Failure Comparisons at 96 WeeksVirologic FailureArms Difference 97.5% CI FavorsATV/r vs. RAL 3.4% -0.7%, 7.4% EquivalentDRV/r vs. RAL 5.6% 1.3%, 9.9% EquivalentATV/r vs. DRV/r -2.2% -6.7%, 2.3% EquivalentTolerability FailureArms Difference 97.5% CI FavorsATV/r vs. RAL 13% 9.4%, 16% RAL SuperiorDRV/r vs. RAL 3.6% 1.4%, 5.8% RAL SuperiorATV/r vs. DRV/r 9.2% 5.5%, 13% DRV/r SuperiorCumulative FailureArms Difference 97.5% CI FavorsATV/r vs. RAL 15% 10%, 20% RAL SuperiorDRV/r vs. RAL 7.5% 3.2%, 12% RAL SuperiorATV/r vs. DRV/r 7.5% 2.3%, 13% DRV/r Superior 20. Avances del tratamiento aannttiirrrreettrroovviirraall 21. Elvitegravir/c: Eficacia y seguridad en los estudios 102 y 103en semana 96TDF/FTC/EVG/c (n=701) EFV/TDF/FTC (n=352) ATV/r + FTC/TDF (n=355)80 80 85 81 82 8210080604020 Subgrupo de CD450 (n=30). 11/19 EVGc con xito virolgico. 8 fueron fracasos (todos con CV100 K c/mL, 4 conadherencia subptima. 5/6 EFV con xito virolgico; 1 fracaso (CV100 K c/mL, con adherencia subptima). 5/5 ATV/r + TDF/FTC con xito virolgico.Zolopa A. et al. 20th CROI. Atlanta, 3 6 Marzo 2013. #5537884 86050 a 200 200 a 350 350CD4 (cels/mm3)xito virolgico en semana 96 (%) 22. Dolutegravir (estudio SPRING-2). Anlisis de eficacia a 48 semanas DTG es no-inferior a RAL con un margen del 10%: Diferencia: 2,5%; IC95% (-2,2% a 7,1%). No-inferioridad demostrada con100.000 c/mL 7,5 (-3,1 a 18). No-inferioridad demostrada con TDF/FTC: 4,6 (-1,3 a 10,6) y con ABC/3TC -0,8 (-8,2 a 6,6). Similar recuperacin de CD4 entre DTG y RAL (+230 CD4 a las 48 semanas). Fallo virolgico a 48 semanas: DTG 20 (5%; 1 con CV400); RAL: 28 (7%; 5 con CV400). Resistencias: con DTG: 0 a integrasa, 0 a nuclesidos; RAL: 1 a integrasa, 4 a nuclesidos. Efectos adversos grado 2-4: 6% DTG vs 7% RAL. Abandonos por EA: 2% DTG, vs 2% RAL. Incremento de creatinina (grado 1/2): 2%/0,6% para DTG vs 2%/0% para RAL.Raffi F, et al. IAS 2012. Washington DC. 19 - 27 Julio. #THLBB041009080706050403020100BL Sem 4 Sem 8 Sem 12 Sem 16 Sem 24 Sem 32 Sem 40 Sem 48SemanaProporcin 50 c/mL (%)DTG 50 mg QDRAL 400 mg BIDDTG 88%RAL 85% 23. Snapshot por estrato de randomizacinDTG50 mg QDDRV/r800 mg/100 mg QDen la semana 48A favorDRV/rA favorDTGGlobala n=484 90% 83%HIV-1 RNAbasalb100.000 c/mL100.000 c/mLn=362n=12288%93%87%70%NuclesidosbABC/3TCTDF/FTCn=159n=32590%90%85%81%Estudio FLAMINGO: DTG vs DRV/r en pacientes naveProporcin (IC 95%) de individuos conRNA VIH-1 50 c/mL en el tiempo-snapshot100%90%80%70%60%50%40%30%20%10%DTG: 90%0,9 7,113,2*Diferencia ajustada (DTG-DRV/r) basada en un anlisis estratificado CMH ajustando porHIV RNA basal y los nuclesidos acompaantes.Resultados confirmados en el anlisis por protocolo: 91% DTG vs. 84% DRV/r, (IC):7,4 (1,4 13,3).-40-30-20-10 0 10 20 30 40 50Diferencia en la proporcin (DGT DRV/r)Feinberg J. et al. ICAAC. Denver, 10-13 Septiembre 2013. #1464a0%Proporcin (%)BL 4 8 12 16 24Semanas36 48DTG 50 mg QDDRV/r 800 mg/100 mg QDDRV/r: 83%95% IC para la diferencia*A favorDRV/rA favorDTG-20% -12% 0 20%Test de superioriad: P=0,025Se demostr superioridad global60aDiferencia ajustada (DTG-DRV/r) basada en un anlisis estratificado Cochran-Mantel-Haenszel ajustando por HIV RNA basal y los nuclesidos acompaantes. .bLas diferencias no ajustadas apoyan la no-inferioridad de DTG vs DRV/r en los estratos deHIV-1 RNA basal y de nuclesidos acompaantes. 24. SINGLE Study. Virologic Suppression (HIV-1 RNA 50c/mL; FDA Snapshot)DTG: 80%EFV: 72%Week 96 adjusted difference in response (95% CI):+8.0% (+2.3% to +13.8%); P=0.0064 8 1216 24 32 40 48 60 72 84 96Walmsley et al. CROI 2014; Boston, MA. Poster 543. 25. Resistance Mutations in Individuals Who Met PDVFCriteriaTE = treatment emergent*n=1 with K101E, n=1 with K103N, n=2 with K103K/N, n=1 with G190A and n=1 withK103N + G190A**E157Q/P polymorphism detected with no significant change in IN phenotypicsusceptibilityWalmsley et al. CROI 2014; Boston, MA. Poster 543.MutationDTG + ABC/3TC QD(n=414)EFV/TDF/FTC QD(n=419)NRTI TE major mutations 0 1 (K65R)NNRTI TE major mutations 0 6 (K101E, K103N,G190A)*INI-r TE major substitution 0** 0 26. Avances del tratamiento aannttiirrrreettrroovviirraall 27. Evolucin del tratamiento antirretroviral deinicioDualNRTIs