Enfrentando las resistencias antivirales del VIH en la práctica clínica

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  • In summary the risks of keeping a patient on a failing regimen include:
    accumulating resistance mutations resulting in a loss of treatment options
    decreasing CD4 cell counts
    clinical disease progression resulting in increased morbidity and ultimately death.
  • To understand why mutations can apparently disappear we need to understand how resistance testing works. Current resistance tests have a lower limit of detection of ~10-20%, in other words a mutant must be present within the quasispecies at a prevalence of >10-20% to be detectable. Mutants present at lower levels are undetectable by routine methods, hence the false impression that resistance has “disappeared”
  • Finally, a few considerations about transmitted drug resistance. We have discussed the dynamics of resistant mutants during treatment and seen that mutants selected during therapy disappear rapidly once therapy is interrupted
    Transmitted resistant mutants however behave differently and can persist for long periods in the absence of drug pressure. This cartoon explain the proposed model. HIV transmission leads to an infection which is initially highly homogenous. If the virus transmitted is resistant the infection will become established with a homogenously resistant virus. There is no wild-type virus that can rapidly out compete the resistant mutant. For the wild-type to occur the resistant mutants is required to back mutate, a process that is rather slow due to the fact that the transmitted virus is genetically constrained
    Reversion does occur gradually over time, but the resistant mutants will persist as minority species and archived resistance, with the potential for a long-lasting impact
  • L74V increases ZDV and TDF susceptibility
    M184V/I increase susceptibility to ZDV, TDF, and d4T
  • Evolution of resistance also leads to growing cross-resistance
    Among the NRTIs, there is complete cross-resistance between 3TC and FTC and considerable cross resistance can occur among the other NRTIs TDF, ABC, ZDV, d4T and ddI
    Among the NNRTIs EFV and NVP there is complete cross resistance. Whether the new NNRTI TMC125 (Etravirine) will provide a durable sequencing option in patients with resistance to these drugs remains to be convincingly demonstrated.
    Among the PIs, cross-resistance requires usually the accumulation of multiple mutations
    For the Entry Inhibitors, there is no cross-resistance between T20, which inhibits gp41-mediated fusion, and Maraviroc, which blocks virus interaction with the coreceptor CCR5
    Among the Intergrase Inhibitors, current data indicate that there is at least partial cross-resistance between the Merck product (Raltegravir) and the Gilead product (Elvitegravir) in current advanced development/early clinical use
  • Pyrophosphate can also be an acceptor
    Antagonised by M184V, K65R, L74V
  • Some form of resistance can also be beneficial. In this old study of patients treated with 3TC monotherapy, after the initial viral load drop a rebound was observed coinciding with the emergence of lamivudine resistance. Yet, despite high level resistance to the drug, the viral load did not rebound to pre-treatment levels, but was maintained ~0.5 log10 copies/ml lower than at baseline
  • Starting from the set of 44 NNRTI RAMs, the TMC125 RAMs were identified based on the methods described in the previous slides.
    - 26 mutations were present in at least 5 patients (so, this means that 18 of the 44 were present in less than 5 patients).
    - 13 of these 26 mutations were associated with a response that was at least 25% lower than the reference response: V90I, A98G, L100I, K101E, K101P, V106I, V179D, V179F, Y181C, Y181I, Y181V, G190A, and G190S.
  • POWER studies: Virological response according to baseline DRV/r RAMs
  • Based on data from the previous slides, we examined contributing factors for the decreased virologicalal response: was it the presence of a particular TMC125 RAM of merely the number of TMC125 RAMs?
    Data in these graphs show that a decreased virologicalal response is only observed with multiple concomitant TMC125 RAMs.
    The left graph shows data for Y181C, the right graph for G190A.
    The first bars are the reference response (in the subgroup of patients without detectable NNRTI mutations). The red bars represent the virologicalal response in patients that have Y181C (left) or G190A (right), either alone (Y181C + 0), or with additional TMC125 RAMs (Y181C + 1, 2, 3, or 4).
    The virologicalal response in patients with Y181C, without other TMC125 RAMs but with other NNRTI mutations, is comparable to that in patients without detectable NNRTI mutations.
    The virologicalal response in patients with Y181C + 1 additional TMC125 RAM is lower than the reference response but above the 25% threshold.
    Only in the patients with Y181C + 2 or more additional TMC125 RAMs (total number of TMC125 RAMs = 3 or more), the virologicalal responses are decreased below the 25% threshold.
    Similar results are shown for G190A.
    This clearly shows that a combination of a certain number of specific mutations is needed to observe a reduced virologicalal response to TMC125.
  • Based on data from the previous slides, we examined contributing factors for the decreased virological response: was it the presence of a particular TMC125 RAM of merely the number of TMC125 RAMs?
    Data in these graphs show that a decreased virological response is only observed with multiple concomitant TMC125 RAMs.
    The left graph shows data for Y181C, the right graph for G190A.
    The first bars are the reference response (in the subgroup of patients without detectable NNRTI mutations). The red bars represent the virological response in patients that have Y181C (left) or G190A (right), either alone (Y181C + 0), or with additional TMC125 RAMs (Y181C + 1, 2, 3, or 4).
    The virological response in patients with Y181C, without other TMC125 RAMs but with other NNRTI mutations, is comparable to that in patients without detectable NNRTI mutations.
    The virological response in patients with Y181C + 1 additional TMC125 RAM is lower than the reference response but above the 25% threshold.
    Only in the patients with Y181C + 2 or more additional TMC125 RAMs (total number of TMC125 RAMs = 3 or more), the virological responses are decreased below the 25% threshold.
    Similar results are shown for G190A.
    This clearly shows that a combination of a certain number of specific mutations is needed to observe a reduced virological response to TMC125.
  • UTILIZE was an observational study at 40 US sites that examined clinician use of resistance testing in treatment-experienced patients failing a PI-based regimen. Patients randomised to either genotype or combined genotype and phenotype
  • Prevalence is from all phase 2 and 3 trials
    UPAMs 33, 82, 84, 90
  • 73S replaced by 74P
  • V11I V32I L33F I47V I50V I54L/M T74P L76V I84V L89V
    *24I, 50L/V, 54L, 76V
    L10V
    M36I
    K43T
    M46L
    I47V
    I54A/M/V
    Q58E
    T74P
    V82L/T
    N83D
    I84V
  • Phenotypic data from Monogram
    Minimal correlation between DRV resistance and ATV or TPV resistance
    More of a correlation with LPV, but there is a higher correlation with APV resistance. The latter is not surprising given the structural similarities between the two drugs
  • Weighing the mutations associated with a diminished response to PREZISTA/r
    Key point
    Different mutations were associated with different increases in FC values, based on multiple regression analyses of the 1,405 screening samples from the POWER 1, 2 and 3 studies.
    De Meyer S, Vangeneugden T, Lefebvre E, et al. Phenotypic and genotypic determinants of resistance to TMC114: pooled analysis of POWER 1, 2 and 3. 15th International HIV Drug Resistance Workshop; Sitges, Spain; June 13–17, 2006. Abstract 73.
  • TITAN: DRV/r Versus LPV/r: Treatment-experienced, LPV-naïve
  • >16 to >20
    +3 to -10
  • Assessments
    Follow-up visits were recommended at Weeks 4 and 12, and every 12 weeks thereafter
    Lab assessments of viral load and CD4 count were performed locally and reported electronically
    Only serious adverse events (AEs) and AEs leading to discontinuation were collected
  • BENCHMRK, Blocking Integrase in Treatment Experienced Patients With a Novel Compound Against HIV-1: Merck; GSS, genotypic susceptibility score
    For patients with GSS = 1, 4 ART agents represented at least 80% of the active agents in OBT: darunavir (52%, 52% in raltegravir and placebo groups, respectively), enfuvirtide (8%, 16%), tenofovir (12%, 6%), and tipranavir (11%, 11%).
    Rates of virologic suppression also greater with RAL vs placebo when analyzed by baseline PSS
    Similar results when assessing PSS by number of fully active drugs and by number of fully or partially active drugs
  • OBR, optimized background regimen; PSS, phenotypic susceptibility score; RAL, raltegravir
  • N42S polymorphyms seen in 15% of naïve persons
  • [Click] once to run HIV infection animation
    CCR5 has a specific conformation that permits binding and infection by HIV
    Then [click] to run antagonist animation
    However, when a CCR5 antagonist such as 873140 is bound, CCR5 is allosterically changed.
    Then [click] to run Inhibition of HIV infection animation
    This new conformation does not allow suitable interaction with HIV.
    END OF SLIDE SET
  • [Click] once to run HIV infection animation
    CCR5 has a specific conformation that permits binding and infection by HIV
    Then [click] to run antagonist animation
    However, when a CCR5 antagonist such as 873140 is bound, CCR5 is allosterically changed.
    Then [click] to run Inhibition of HIV infection animation
    This new conformation does not allow suitable interaction with HIV.
    END OF SLIDE SET
  • Lewis and colleagues reported at the 16th International HIV Drug Resistance Workshop in Barbados a detailed analysis of select individuals that entered CCR5 antagonist clinical trials with R5 only virus who then experienced virologic failure with the emergence of CXCR4-utilizing strains. They performed clonal and phylogenic analyses at entry as well as during the course of therapy and assessed tropism for many clones over time. The example in this slide demonstrates that although at baseline the predominant virus did not use CXCR4 and the Trofile assay readout was R5-only, there were minority species that were dual/mixed (D/M) and even X4 only. They showed that these CXCR4-utilizing clones were enriched for on therapy at the time of follow-up visit when the primary readout of the Trofile assay was for detectable D/M virus. In this patient, like others they demonstrate that when selection pressure was removed with the discontinuation of the CCR5 antagonist, the majority population did appear to return to primarily one that did not use the CXCR4 coreceptor. Other select patients studied demonstrated the same findings. In contrast, in some cases they did not identify minority species of CXCR4-utilizing virus at baseline. However, phylogenic analyses of the CXCR4-using viruses that emerged on therapy suggested that they were not closely related to the original R5 population and thus more likely to have emerged from a pre-existing population that was missed both on routine testing of blood as well as clonal analyses. Together, these findings are supportive of the fact that most CXCR4-utilizing virus pre-exists at low levels and are selected for with therapy rather than a CCR5-only utilizing virus mutating and/or adapting to use CXCR4. The clinical implications of these findings and their relevance to the use of CCR5 antagonists will need further exploration.
  • Yazdanpanah Y et al (THABO406)
    Obj/ENDPT: primary: To assess the 24wk efficacy (VL<50) of a regimen containing RAL, ETR and DRV/r in treatment-experienced pts with MDR. Secondary: VR at wk 48 and 96, safety and tolerability, immunologic response, Drug interactions.
    Methods: This phase II trial enrolled treatment-experienced HIV+ patients with plasma VL >1000 copies who were naïve to the investigational drugs (RAL and ETR and DRV), had a hx of VF while on NNRTI and ≥3 major PI mutations (IAS list 06’), ≥3 NRTI mutations and ≤3 darunavir (V11I, L33F, I47V, I54L/M, G73S, L76V, I84V and L89V) and susceptible to ETR (≤3 NNRTI mutations amoung 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, M230I/L, P238N/T and Y318F), documented by a genotypic at initial screening. Backbone regimens included NRTI and/or enfuvirtide whenever possible.
    Results: 103 patients (170pts screened; 67 ineligible based on genotypic criteria and VL) from 04/2007 to 08/2007. Among these patients, 44% had a hx of AIDS-defining events. Median number of mutations was 4 for PIs (primary mutations), 2 for DRV (%pts with 0/1/2/3 DRV mutations: 4/31/30/35), 1 for NNRTIs (%pts with 0/1/2/3 ETR mutations: 34/31/31/3) and 5 for NRTIs. (in addition to BL characteristics on slide) with a median genotypic sensitivity score=0.5 (0:20%, 0.5: 39%, 1:24%, >1:17%). 14 pts had ENF as part of their regimen (12 were ENF-naïve). 57 pts (55%) had VL<50 at wk 4 and 91 patients (88%) had VL<50 at wk 12. At week 24, 93 patients (90%; 95%CI: 85 to 96) had VL <50 copies/ml and 98 patients (95%) had VL<400 copies/ml.
    10/103 had VL>50 at wk 24: 1 lost to f/u, 1d/c, 3 VL>400, 2pts had VL>50 but not <400, and 3pts were <50, but not confirmed at wk 32). Median CD4 increase was +99 cells. One patient d/c’d the investigational arm (grade 4 AE [skin rash]) and one pt lost to f/u. AEs: 1 rash (pt dc’d tx), 1 nephrolithiasis, 4 creatinine kinas elevations (>10xULN) (all returned to normal without tx d/c), 1 GGT elevation (>10xULN) (in HCV co-infected pt with intermittent GGT fluctuation, no d/c required)
    Genotypic analysis of resistance among failing pts and drug-drug interactions still under ongoing analysis and not reported at conference.
    **The ETR EAP program had similar results to TRIO among 2074 patients treated in the US; Observed response rates at Week 24 (VL<75 copies/mL) exceeded 60% and were generally similar across subgroups of investigator-selected regimens.****
  • Enfrentando las resistencias antivirales del VIH en la práctica clínica

    1. 1. Enfrentando la Resistencia en la Practica Clínica Dr. Jaime Andrade Villanueva Unidad de VIH Hospital Civil de Guadalajara México
    2. 2. Falla a Tratamiento y Resistencia Factores del Huésped •CVp •Inmunidad •Genéticos Baja exposición a ARV •Adherencia •PK •Activación de droga •Penetracion de droga Pobre potencia de ARV Replicación viral persistente Presión/ARVs Selección, emergencia y evolución de Resistencia a ARVs Infección con virus resistentes
    3. 3. • • • • Acumulación de resistencia y resistencia cruzada Acumulación de mutaciones en el mismo genoma viral Enriquecimiento de virus resistentes minoritarios Evolución de variantes virales Evolución hacia alta resistencia y alto fitness
    4. 4. Riesgos de mantener un paciente en un régimen en falla virológica Acumulación de mutaciones de resistencia y perdida de opciones de tratamiento Disminución de CD4+ Progresión de la enfermedad
    5. 5. • Manejar TARAA de primera línea bien • Actuar tempranamente si la carga viral es detectable con terapia • Prohibir resistencia acumulante • Continuar un régimen en falla puede ser deletéreo • Reservar casos que no cuenten con >2 fármacos totalmente activos • Selección juiciosa de los fármacos de mantenimiento • Mantener por el periodo mas corto posible • Interpretación de experto de patrones de resistencia complejos • Prohibir monoterapia funcional
    6. 6. La incidencia de viremía de bajo nivel es mas frecuente que viremía de alto nivel Nivel de RNA de HIV-1p durante el seguimiento, % Estudios de Cohorte (N = 4447) Persistentemente < 50 copias/mL 71.2 ≥ 1 determinacion de > 50 copias/mL 28.8 ≥ 1 determinacion de > 1000 copias/mL 6.7 van Sighem A, et al. J Acquir Immune Defic Syndr. 2008;48:104-108.
    7. 7. Manejo de Falla Virológica  La decisión de cambiar un régimen de tratamiento debe tomar en cuenta :  El resto de las opciones de tratamiento  El nivel de falla basado sobre cinética de la carga viral y CD4+ (disminución del fitness viral)  Historia previa de tratamiento, incluyendo patrones de resistencia, tolerabilidad y adherencia  La elección del tratamiento debe estar basada sobre el numero de drogas activas en cada clase (Test de resistencia genotípica)
    8. 8. Frecuencia de Mutaciones Detectado por métodos de Rutina Detectado por métodos ultrasensibles Fondo natural
    9. 9. Virus Resistentes 20-30% Virus Wild-type Presión Por ARVs
    10. 10. Presión Por ARVs Resistencia Transmitida por Drogas (RTD) Estable después de la transmisión Reversión gradual con el tiempo, frecuentemente incompleta Persistencia con especies de baja frecuencia Persistencia en células infectadas latentemente Transmision Tasa de Reversion: Rapida: K70R, M184V, T215Y Intermedia: D67N, Y181C, T215S, K219N Lenta: M41L, T69DN, G190S, L210W, T215LCE, K219Q en TR y I84V, L90M en PR
    11. 11. Falla a ARV 2009: Nuevas Opciones Terapeuticas Falla Primera Segundatercera Multiple Opciones Muchas Algunas Pocas Metas CVp CVp/CD4+ CD4+ Accion Adaptar o switch Esperar o switch Lo mejor de ti
    12. 12. Historia del Caso • 261/09, Masculino de 49 años de edad. • Fecha del Dx de VIH 1993 • Larga historia de Terapia ARV, regular adherencia • Sin Co-infección con Hepatitis B o C • AST y ALT normales. • Nadir de CD4+ 267 (17%) 04/10/01
    13. 13. Historia de Terapia Antirretroviral Fecha Régimen CVp Resultado 03/96 – 11/97 ddI/Rivabirina 62,000 copias/mL Falla Virológica 11/97 – 05/99 SAQ/d4T 20,000 copias/mL Falla Virológica 05/99 – 11/01 IDV/d4T/NEV 11/01 – 02/06 AMP/r/d4T/ABA 02/06- 07/06 1100 copias/mL Falla Virológica 1100 copias/mL Falla Virológica LPV/r/fAMP/EFV/3TC 2000 copias/mL Falla Virológica 07/06-10/06 r/fAMP/EFV/3TC 1600 copias/mL Falla Virológica 10/06-04/07 r/fAMP/ddI/3TC 1700 copias/mL Falla Virológica 04/07-12/08 TPV/fAMP/ddI/3TC 12/08-05/09 TPV/r/TFD/FTC <50 copias/mL 3300 copias/mL CD4+ 306 cel/mL Falla Virológica Falla Virológica
    14. 14. 261/09 : Resultado de 3 Pruebas de Resistencia Genotípica 10I, 32I, 13V, 33F, 47V, 54M, 63P, 71V, 90M gp41 Proteasa Transcriptasa Reversa 41L, 67N, 69D, 70R, 184V 210W 215Y, 219Q 98G, 103N, 190A
    15. 15. Diseñando el Nuevo Régimen • ITRANs • IPs • ITRNNs • Inhibidores de la Entrada • Inhibidores de Integrasa
    16. 16. Resistencia a Antirretrovirales Disponibles ARVs Resistencia Barrera Genética ITRANs Completa Irrelevante ITRNNs 3 Mutaciones Baja IPs 9 Mutaciones Alta Etravirina 2 Mutaciones Media Ninguna Irrelevante Maraviroc >75 % Probabilidad de R5 Baja? Raltegravir Ninguna Baja T20
    17. 17. Resistencia a ITRANs Transcriptasa Reversa ZDV d4T 41L, 67N, 69D, 70R, 210W, 215Y M184V Resultado Neto Resistencia Parcial Alto Nivel de Resistencia ddI ABC TDF 3TC FTC
    18. 18. Potencial Resistencia Cruzada • ITRANs significativa a completa • ITRNNs completa para NVP y EFV • IPs crece con incremento de mutaciones para DRV y TPV • Inh. de Entrada completa para MRC y VRC • Inh. de Integrasa completa para RAL y ELV
    19. 19. Mecanismos Bioquímicos de Resistencia a ITRANs : Primer Desbloqueador • Mutaciones tales como la T215Y promueve la remoción hidrolitica de la cadena- terminal del ITRAN y esto posibilita la reanudación de la síntesis de DNA. • La remoción hidrolitica requiere un donador pirofosfato, el cual en muchas células es ATP (b) • Antagonizada por K65R, L74V, M184V P P a) P P P b) P P P P P P P P P P P P P P P P P P P P P P P P P Gotte, J Virol 2000
    20. 20. Inhibidores de Transcriptasa Reversa Análogos de nucleosidos  Los posibles beneficios de continuar ITRANs en presencia de resistencia puede derivar de: • Susceptibilidad residual de la droga • Costo en el fitness de la resistencia • Efectos de Hipersusceptibilidad
    21. 21. Reducción de la CVp durante Monoterapia Cambio promedio en HIV-1 RNA (log copias/ml) con Lamivudina (NUCA3001) 0.5 0.0 -0.5 -1.0 Emergencia de M184V -1.5 -2.0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Semana Eron, N Eng J Med 1995
    22. 22. Que hacer para Seleccionar un ITRNN ? Determinantes de Susceptibilidad • Fenotipo – Fold-changes – Cut-offs • Genotipo – Patrón de Mutaciones – Numero de Mutaciones – “Peso” de las Mutaciones • Correlación con Niveles de ARV • Efectos de Hipersusceptibilidad • Efectos en el Fitness viral
    23. 23. Cut-offs para interpretación de resistencia Bajo cut-off = Nivel de resistencia mas allá de la cual la respuesta inicia a caerse Respuesta Cut-off superior = Nivel de resistencia mas allá de la cual la respuesta clínica esta perdida Zona de Respuesta intermedia Resistencia
    24. 24. Mutaciones de resistencia asociadas a Etravirina V90I A98G L100I K101E K101P K101Q K103H K103N K103S K103T V106A V106I V106M V108I E138G E138K E138Q V179D V179E V179F V179G V179I Y181C Y181I Y181V Y188C Y188H Y188L V189I G190A G190C G190E G190Q G190S H221Y P225H F227C F227L M230I M230L P236L K238N K238T Y318F • 44 Mutaciones a ITRNN inicialmente estudiadas • 26 Mutaciones a ITRNN estuvieron presentes en ≥ 5 pacientes • 13 Mutaciones predicen respuesta a ETV Vingerhoets, IHDRW 2007
    25. 25. Estudios DUET 1 y 2 : Respuesta virológica de acuerdo a las RAMs basales a ETV RAMs a ETV % pacientes con <50 copias/ml 80 V90I L100I V179D/F Y181C/I/V 40 K101E/P V106I 60 A98G G190A/S 20 0 0 1 2 3 4 5 Numero de RAMs a ETV Pts (%) = 40 30 16 8 5 0.9 Vingerhoets, IHDRW 2007
    26. 26. Susceptibilidad Fenotípica cut-offs: ETV Cut-off inferior Cut-off Superior FDA Label 3 13 Antivirogram (Virco) 3 13 Virtual Phenotype (Virco) 1.6 27.6 PhenoSense (Monogram) 2.9* *Biological cut-off
    27. 27. Score de Peso a ETV 2008 : Clasificación de mutaciones Mutacion Y181C Y181V K101P L100I Y181C M230L E138A V106I G190S V179F V901 V179D K101E K101H A98G V179T V190A Peso 3 3 2.5 2.5 2.5 2.5 1.5 1.5 1.5 1.5 1 1 1 1 1 1 1 Respuesta por score total Score Respuesta ≤2 Susceptible >2 – ≤4 Parcialmente susceptible >4 Resistente Altas respuestas se presentan con un Score de peso ≤2
    28. 28. Pesos relativos – Mutaciones para Etravirina 2008 Mutation Y181I Y181V K101P L100I Y181C M230L E138A V106I G190S V179F V90I V179D K101E K101H A98G V179T G190A ETR FC in the subset of HIV-1 clinical isolates with 1 ETR RAM (n=1,619), regardless of the Prevalence (%) presence of other NRTI or in the panel of NNRTI RAMs* 4,248 HIV-1 Q1–Q3 n clinical isolates Median § 1.5 0.9 2.6 8.4 32.0 1.1 2.5 4.4 3.7 0.7 6.8 2.1 9.9 2.2 9.5 0.6 23.3 42.0 10.4 22.3 6.7 4.4 4.3 2.9 2.6 0.8 – 2.0 1.7 1.5 1.1 1.0 0.9 0.8 34 28 65 264 552 20 44 63 32 0 97 33 24 8 127 2 226 23.2–129.7 3.9–60.6 5.6–42.9 2.7–17 2.1–11.6 2.7–10.5 1.4–10.6 1.4–5.2 0.6–1.7 – 0.8–3.6 1.0–4.7 0.8–2.5 0.6–2.8 0.5–1.9 0.7–1.2 0.5–1.5 ETR FC in Effect on FC in linear a single SDM model 12.5 17.4 6.2 1.8 3.9 3.4 2.0 NA 0.2 0.1 1.5 2.6 1.7 1.3 2.5 0.8 0.8 High High High Medium Medium High Medium Low Low Medium Low Low Low Low Low Low Low Weight factor 3 3 2.5 2.5 2.5 2.5 1.5 1.5 1.5 1.5 1 1 1 1 1 1 1 *Median (Q1–Q3) FC for all isolates was 3.0 (1.1–9.3); V179F was never present as single ETR RAM (always with Y181C) §
    29. 29. Pacientes con CV confirmada <50 copiass/mL a las 24 semanas (%) Respuesta con mutaciones específicas contra ETR: 80 80 Y181C 60 60 40 40 20 G190A 20 0 Placebo Pacientes (n) 414 0 +0 +1 +2 +3 +4 Otras mutaciones para ETR 23 36 26 17 8 Placebo +4 +0 +1 +2 +3 Otras mutaciones para ETR 414 18 46 25 17 9 Se excluyeron los pacientes que recibieron ENF naïve Vingerhoets J, et al. 11th EACS, Spain 2007. Poster 7.3/05
    30. 30. Pacientes con CV confirmada <50 copiass/mL a las 24 semanas (%) Respuesta con mutaciones específicas contra ETR: K101E 100 A98G 100 80 80 60 60 40 40 20 20 0 0 Placebo K101E K101E K101E K101E K101E +0 +1 +2 +3 +4 Otras mutaciones para ETR Pacientes (n) 414 3 9 19 16 6 A98G Placebo + 0 A98G +1 A98G +2 A98G +3 A98G +4 Otras mutaciones para ETR 414 21 9 10 11 8 Se excluyeron los pacientes que recibieron ENF naïve Vingerhoets J, et al. 11th EACS, Spain 2007. Poster 7.3/05
    31. 31. 261/09 : Determinación del score genotípico con peso relativo para Etravirina • Weight for each mutation added together = total weighted score • No single mutation confers a reduced response (≥4) Score for individual mutations Y181I Y181V K101P L100I Y181C M230L E138A V106I G190S V179F V90I V179D K101E K101H A98G V179T G190A § 3 3 2.5 2.5 2.5 2.5 1.5 1.5 1.5 1.5 1 1 1 1 1 1 1 Add together Total weighted score 1+1 =2 V179F nunca se presentó sola, siempre con Y181C §
    32. 32. Relación entre score genotípico basal y respuesta virológica (<50 copias/mL) a semana 24 Alta repuesta Respuesta intermedia Respuesta reducida Pacientes con CVp confirmada HIV-1 RNA <50 copias/mL (%) Respuesta por categoria 74.4% 52.0% 37.7% ≥ N 115/148 37/53 6/11 11/15 32/59 2/7 19/36 1/5 14/27 3/9 4/9 4/13 1/3 2/11 Peso de las mutaciones a Etravirina 2009  Alta respuesta ocurre con un score de peso ≤ 2 Hatched bars indicate virologic response for the entire category
    33. 33. Pacientes con CVp <50 copias/mL a Semana 48 (ITT-TLOVR) Etravirina + BR (n=599) Placebo + BR (n=604) 100 Respuesta (%) ± 95% CIs 90 80 70 61% 60 50 40% 40 30 p<0.0001* 20 10 0 0 2 4 8 12 16 20 24 32 40 48 Tiempo (semanas) • 61% de pacientes en el grupo de Etravirine alcanzaron cargas virales indetectables confirmadas (<50 copias/mL) comparado con 40% en el grupo placebo *Modelo de regresion logistica Trottier et al, CAHR, 2008. P167
    34. 34. Cambio promedio en la cuenta de células CD4+ del basal (células/mm3) ± SE Cambio en la cuenta de células CD4 del basal a Semana 48 (ITT; NC=F) Etravirina + BR (n=599) 150 Placebo + BR (n=604) 125 +98 100 75 +73 50 25 p=0.0006* 0 –25 0 2 4 8 12 16 20 24 32 40 48 Tiempo (semanas) *modelo ANCOVA Trottier et al, CAHR, 2008. P167
    35. 35. 261/09: Resultado de Test de Resistencia Genotípica Transcriptasa Reversa 41L, 67N, 69D, 70R, 184V 210W 215Y, 219Q 98G, 103N, 190A 41L 67N 69D 70R 184V 210W 215Y  219Q AZT 15 15 5 0 -8 15 35 15 TFV 12 5 5 8 -8 12 20 0 ABA 12 8 5 0 12 12 20 0 ddI 12 8 20 0 5 12 20 0 3TC 4 0 5 0 60 4 4 0 EFV ETR 98G 5 5 103N 190A 60 10 Interpretación por el Sistema Stanford Score AZT 110 D4T 97 Nivel de Resistencia: ABA 69 ddI 77 Bajo TFV 54 3TC 77 Intermedio FTC 77 EFV 105 Alto NEV 130 ETV 30 40 15
    36. 36. Que hacer para Seleccionar un IP? Determinantes de Susceptibilidad • Fenotipo – Fold-changes – Cut-offs • Genotipo – Patrón de Mutaciones – Numero de Mutaciones – “Peso” de las Mutaciones • Correlación con Niveles de ARV • Efectos de Hipersusceptibilidad • Efectos en el Fitness viral
    37. 37. La Barrera genética de los IPs in vitro Aumento en la concentración del IP seleccionado 450 TMC114 (R41T, K70E) 400 TPV (L33V, M46L, V82T) ATV (L10F, V32I, M46I, I62V, A71V, I84V, N88S) 350 LPV (L10F, L23I, M46I, I50V, I54V, L63P, V82A) APV (L10F, V32I, L33F, M46I, I47V, I50V) 300 NFV (L10F, D30N, R41K, K45I, M46I, V77I, I84V, N88D) SQV (G48V, A71V, G73S, I84V, L90M) 250 200 RTV (G16E, M46I, V82F, I84V) 150 100 50 0 0 100 300 500 700 900 1100 Tiempo (días) De Meyer, Antimicrob Agents Chemother 2005; De Meyer, IHDRW 2006
    38. 38. La relativa barrera genética de los IPs reforzados in vivo NFV SQV/r, IDV/r ATV/r LPV/r, FPV/r TPV/r, DRV/r Superior • • • • •
    39. 39. UTILIZE: Susceptibilidad Genotípica a IPs en el Tratamiento de Pacientes Experimentados % sensitive • 139/236 (59%) TPEs que fallaron a un IP tenían evidencia de resistencia a IPs • 28% resistencia a todos los IPs • 27% sensibles a solo uno de TPV o DRV 100 90 80 70 60 50 40 30 20 10 0 58 55 27 TPV R / DRV S = 12% TPV S / DRV R = 15% 22 20 19 17 8 TPV DRV FPV IDV LPV ATV SQV NFV Baxter et al, ICDTHI 2008
    40. 40. UTILIZE: Susceptibilidad a TPV por uso previo de IPs Susceptibilidad a TPV en pacientes con resistencia genotípica (n=139/236) o Fenotípica (n=69/236) al menos un IP IPs Previos Susceptibilidad Genotípica a TPV (n=139) Susceptibilidad Fenotípica a TPV * (n=69) 1–2 83% 90% 3–4 60% 71% ≥5 36% 52% Total 58% 79% *incluidos susceptibilidad total y parcial Piliero et al, ICDTHI 2008
    41. 41. Desarrollo de un score de “peso de mutaciones” a TPV Meta • Desarrollar un score para predecir respuesta virológica a TPV/r basado en el genotipo Enfoque • Evolución del score genotípico sobre el tiempo incorporando datos nuevos y refinamiento de análisis • El score de “peso de mutaciones” refleja que : – Algunas mutaciones tienen un mayor impacto en respuesta que otros – Algunas mutaciones están asociadas con mejor respuesta Scherer et al, EACS 2007
    42. 42. Mutaciones de resistencia a TPV y score de Peso • Mutaciones de Resistencia a TPV 1 L I K K M I I Q 10 13 20 33 35 36 43 46 47 54 58 V V M R V • L E M H 69 T V N I 74 82 83 84 F G I T L V A E M V K P L D V T I Q T L V N I Score de peso de las mutaciones a TPV 2 L L M K M I I 10 24 43 46 47 50 54 58 74 76 82 83 84 V I 36 I T L V L A E V M V L P V L D V T Incremento en la respuesta Mutacion menor Mutacion mayor 1. SmPC, July 2008; 2. Scherer et al, EACS 2007
    43. 43. Score Genotípico de Peso a TPV Mutaciones Mayores Mutaciones Menores Mutacion Peso Prevalencia Mutacion Peso Prevalencia 47V 6 14.0% 84V 2 30.1% 74P 6 3.4% 36I 2 52.2% 82L/T 5 4.7% 43T 2 13.6% 58E 5 15.7% 10V 1 12.9% 83D 4 1.4% 46L 1 20.8% 54A/M/V 3 63.7% Mutaciones con peso de= 0 Mutaciones asociadas con mejor respuesta Mutacion Peso Prevalencia 54L -7 7.1% 50L/V -4 7.1% Resistencia parcial: > 3 ≤ 10 24I -2 15.5% Resistencia: ≥ 11 76V -2 8.4% 13V, 20M/R/V, 30N, 33F, 35G, 69K Susceptible : ≤ 3 Scherer, Euro Res 2008
    44. 44. Score de Peso a TPV : Clasificación de mutaciones Mutacion Peso L10V L24I M36I K43T M46L I47V I50L/V I54A/M/V I54L Q58E T74P L76V V82L/T N83D I84V 1 -2 2 2 1 6 -4 3 -7 5 6 -2 5 4 2 Respuesta por score total Score Respuesta ≤3 Susceptible >3 – ≤10 Parcialmente susceptible >10 Resistente Incremento en la respuesta Mutacion menor Mutacion mayor Scherer et al, EACS 2007
    45. 45. 261/09 : Determinación del score genotípico con peso relativo para TPV • Suma del peso de cada una de las mutaciones= Score total • Hay mutaciones que confieran una respuesta reducida (≥6) Score para mutaciones individuales L10V 1 L24I -2 M36I 2 K43T 2 M46L 1 I47V - I50L/V 6 3 I54L -7 Q58E 5 L76V Score Total -4 I54A/M/V T74P Sumar - 6 -2 V82L/T 5 N83D 4 I84V 2 47V (6), 54M (3) =9
    46. 46. Susceptibilidad Fenotípica cut-offs: TPV/r Cut-off inferior Cut-off Superior FDA Label 3 10 Antivirogram (Virco) 3 10 1.5 7 2 8 Virtual Phenotype (Virco) PhenoSense (Monogram)
    47. 47. Mutaciones de resistencia asociadas a Darunavir Un SSG derivado del estudio POWER identifico 11 mutaciones en 10 Posiciones1 En una actualización posterior el reemplazo de T74P por G73S mejoro el modelo2 V V L I I I T L I L 11 32 33 47 50 54 74 76 84 89 I I F V V LoM P V V V Adapted from SmPC, July 2008; 1. De Meyer et al, ARHR 2008; 2. De Meyer et al, EHDRW 2008
    48. 48. Darunavir/r • Datos nuevos confirman mas MARs a DRV • Parcial pero no completa superposición con MARs con TPV Mejoras esperadas: • Peso de Mutaciones • Score de mutaciones adicionales? • Aplicabilidad del Score en varios escenarios clínicos.
    49. 49. TPV y DRV: Superposición parcial de mutaciones de resistencia que predicen respuesta virológica Tipranavir1 L10V M36I K43T M46L I54A/V Q58E H69K V82L/T N83D Darunavir2 I47V I54M T74P I84V V11I V32I L33F I50V I54L L76V L89V Adapted from 1. ASmPC, July 2008 and 2. SmPC, July 2008
    50. 50. Resistencia a IPs en pacientes altamente Experimentados fallando a un régimen conteniendo DRV 100% 80% 60% 40% 20% 0% BL F IDV BL F NFV Susceptible BL F SQV/r BL F ATV/r BL F FPV/r Posible resistencia BL F LPV/r BL F TPV/r BL F DRV/r Resistencia n=25; media de 5 regimenes previos conteniendo IPs. BL = basal; F = falla Delaguerre C et al. AIDS 2008;22:1–5
    51. 51. Peso de las Mutaciones a DRV 11I 32I 33F 47V 50V 54M 54L 74P 76V 84V 89V Stanford 4 10 5 12 20 12 12 5 12 12 4 http://hivdb.stanford.edu/
    52. 52. Impacto en la Resistencia Score genotípico a DRV/r I50V I54M L76V I84V V32I L33F I47V V11I I54L G73S L89V
    53. 53. Peso de la mutaciones asociadas con una disminución de la respuesta a Darunavir/r* Incremento estimado en FC Mutaciones <2 2a3 3a4 >4 V11I I54L G73S L89V V32I L33F I47V I54M L76V I84V I50V T74P –T74P was the only newly identified mutation, resulting in the following 2007 DRV RAMs: V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V and L89V *Determined by multiple regression analyses of the 1,405 screening samples from the POWER 1, 2 and 3 studies De Meyer S, et al. 15th IHDRW 2006. Abstract 73
    54. 54. Susceptibilidad Fenotípica cut-offs: DRV/r Cut-off Inferior FDA Label 2 7 Cut-off Superior 30 Antivirogram (Virco) 10 40 Virtual Phenotype (Virco) 10 106.9 PhenoSense (Monogram) 10 90
    55. 55. Mutaciones Emergentes en Falla a DRV/r Pacientes con experiencia previa a Ips (n=54 Fallas virológicas) • Mutaciones emergentes mas comunes: V32I , L33F, I54M/L, I84V, L89V • Otras mutaciones emergentes: • V11I, M46I/L, I47V/A, I50V, G73S, L76V, V82A/F/T/S/L, L90M Pacientes experimentados a IPs en el estudio TITAN (n=28 Fallas virológicas)2 1. V11I, G16E, V32I, I47V, N83D* 2. L76V* 3. V32I, T74P* 4. I47V, L76V, V82I* *samples with increased DRV FC relative to baseline 5. L10I 6. L63P, A71I/T 7. I93L 1. Lambert-Niclot, AAC 2007; 2. De Meyer, CROI 2008
    56. 56. 261/09 : Determinación del score genotípico con peso relativo para DRV • Suma del peso de cada una de las mutaciones= Score total • No hay mutaciones que confieran una respuesta reducida (≥10) Score para mutaciones individuales I50VI I54M L76V I84V T74P V32I L33F I47V V11I I54L G73S l89V 4.5 4.5 3.5 3.5 3.5 3.5 2.5 2.5 2.5 1.5 1.5 1.5 1.5 Sumar Score Total 32I (2.5), 33F (2.5), 47V (2.5), 54M (3.5) = 11
    57. 57. 261/09 : Resultado de Test de Resistencia Genotípica 10I, 32I, 13V, 33F, 47V, 54M, 63P, 71V, 90M Protease 101 13V 32I 33F 54M 47V 63P DRV 0 0 15 5 20 10 0 TPV 0 0 5 10 15 15 0 71V 90M 0 6 0 6 Interpretación por el Sistema Stanford ATV DRV FPV IDV Score 58 56 119 66 Nivel de Resistencia: Bajo LPV NFV SQV TPV 58 104 54 51 Intermedio Alto
    58. 58. Efecto combinado del FC a ETR y DRV en la respuesta virológica (<50 copias/mL, TLOVR) a las 24 semanas Respuesta a las 24 S. (%) • 100 76 80 60 41 20 20 0 0 ETR FC ≤3 ≥65% <65% 50 53 40 Pacientes con CV <50 copias/mL (%) 61 65 Subgrupo de pacientes tratados con ETR; sin uso naïve de ENF (n=406) 3< ETR FC ≤13 0 DRV FC ≤10 10< DRV FC ≤40 DRV FC >40 ETR FC >13 ETR FC Pacientes con CV <50 copias/mL, % (n) DRV FC FC ≤3 3< FC ≤13 FC >13 FC ≤10 76 (133/175) 61 (30/49) 50 (19/38) 10< FC ≤40 65 (37/57) 41 (7/17) 20 (3/15) FC >40 53 (19/36) 0 (0/8) 0 (0/7) Schapiro, EHDRW 2008
    59. 59. Efecto combinado de RAMs ETR y DRV en la respuesta virológica (<50 copias/mL) • Subgrupo de pacientes tratados con ETR; sin uso naïve de ENF (n=406) Respuesta a las 24 S. (%) 100 82 100 80 78 60 63 50 35 29 27 0 0 1 2 No. de RAMs ETR 3 ≥65% <65% 40 45 27 Pacientes con CV <50 copias/mL (%) 57 56 60 20 0 67 67 75 71 73 40 93 78 30 0 17 >3 3 2 1 0 No. de RAMs DRV >3 No. of ETR RAMs* Pacientes con CV <50 copias/mL, % (n) No. of DRV RAMs 0 0 1 2 3 >3 1 2 3 >3 78 (7/9) 82 (36/44) 73 (30/41) 78 (31/40) 63 (17/27) 67 (8/12) 71 (27/38) 75 (18/24) 50 (12/24) 35 (8/23) 100 (3/3) 93 (13/14) 56 (9/16) 45 (9/20) 27 (3/11) 67 (2/3) 57 (4/7) 29 (2/7) 60 (3/5) 27 (3/11) 0 (0/1) 40 (2/5) 17 (1/6) 30 (3/10) 0 (0/5) *From the list of 13 ETR RAMs. Vingerhoets J, et al. IHDRW 2007. Abstract 32
    60. 60. Efecto combinado de RAMs ETR y DRV en la respuesta virológica (<50 copias/mL) • 83 83 71 Response at Week 24 (%) 60 40 59 20 0 43 38 19 ≥65% <65% 53 64 74 80 Pacientes con CV <50 copias/mL (%) 60 72 77 100 Subgrupo de pacientes tratados con ETR; sin uso naïve de ENF (n=406) 0 26 1 2 24 3 No. de DRV RAMs >3 [0–2] [2.5–3.5] ≥4 Score de peso de RAMs ETR Score de peso de las RAMs ETR * Pacientes con CV <50 copias/mL, % (n) No. of DRV RAMs [0–2] 0 1 2 3 >3 [2.5–3.5] ≥4 71 (12/17) 83 (53/64) 77 (41/53) 74 (40/54) 59 (23/39) 83 (5/6) 72 (21/29) 64 (14/22) 38 (9/24) 19 (4/21) 60 (3/5) 53 (8/15) 26 (5/19) 43 (9/21) 24 (4/17) *From the revised list of 17 ETR RAMs. Vingerhoets J, et al. IHDRW 2008. Abstract 24
    61. 61. Efficacy, Safety and Tolerability of Etravirine With and Without Darunavir and/or Raltegravir in Treatment-Experienced Patients: Preliminary Analysis of TMC125-C214 Early Access Program (EAP) in the US William Towner, MD; Zachary Haigney, BA; Michael G Sension, MD; Michael Wohlfeiler, MD, JD; Joseph Gathe, MD;Jonathan S Appelbaum, MD; Paul Bellman, MD; Christine Marion, BS; Raymond Pecini, PharmD; Robert Ryan, MS; James Witek, MD 1Kaiser Permanente-Infectious Diseases, Los Angeles, CA, USA; 2Quest Clinical Research, San Francisco, CA, USA; 3North Broward Hospital District,Ft. Lauderdale, FL, USA; 4 Wohlfeiler, Piperato and Associates LLC, N. Miami Beach, FL, USA;5Therapeutic Concepts, Houston, TX, USA; 6Community Research Initiative of New England, Boston, MA, USA; 7Office of Paul Bellman, MD, New York, NY, USA; 8Kenmar Research Institute, LLC,Los Angeles, CA, USA; 9Tibotec, Therapeutics, Bridgewater, NJ, USA; 10Tibotec, Inc., Yardley, PA, USA
    62. 62. Baseline Demographics and Disease Characteristics
    63. 63. Treatment Regimens Background ARVs other than N(t)RTIs and ritonavir used in ≥10% of patients • • • • All patients received ETR 200mg bid plus an investigator-selected BR RAL and maraviroc became available through expanded access in January and July of 2007, respectively, and were allowed Background ARVs could be changed at any time at investigator’s discretion ENF was used in 15% of patients overall
    64. 64. Observed Virologic Response Rates (<75 copies/mL) at Wks 12 and 24
    65. 65. Uso de TPV con nuevos Agentes Clase de ARV Nombre Combinación con TPV/r ITRNN Etravirina1 AUC12h  76% Inhibidor de CCR5 Maraviroc2 Inhibidor de Integrasa Raltegravir3 Inhibidor de Integrasa Elvitegravir4    1. Schöller et al, CROI 2006; 2. Celsentri® SmPC; 3. Isentress® SmPC; 4. Mathias et al, JAIDS 2008
    66. 66. BENCHMRK: Tipranavir y raltegravir Proporción de pacientes con CVp <50 copias/mL a Sem 48 100 % pacientes 90 80 Raltegravir + TPV/r* in OBT Placebo + TPV/r* in OBT 73 Cambios en cuenta de CD4 (mm3) del basal a semana 48: RAL+TPV/r* en OBT: +114 70 60 Placebo + TPV/r* en OBT: +56 50 40 40 30 20 10 0 Total n= 52 20 *Sensibles por prueba genotípica Cooper et al, NEJM 2008
    67. 67. Uso de DRV con nuevos Agentes Clase de ARV Nombre ITRNN Efavirenz* ITRNN Etravirina1 Inhibidor de CCR5 Maraviroc2 Inhibidor de Integrasa Raltegravir3 Inhibidor de Integrasa Elvitegravir4 * Precaucion con sintomas al SNC por Combinación con DRV/r AUC12h  13% Cmax  15%     aumento en Cmax (15%); AUC (21%) y Cmin (17%) de EFV 1. Schöller et al, CROI 2006; 2. Celsentri® SmPC; 3. Isentress® SmPC; 4. Mathias et al, JAIDS 2008
    68. 68. Percent of Patients with HIV RNA <50 copies/mL at Week 96 by Baseline HIV RNA and CD4 Cell Count  Subgroup Subgroup % of Patients Percent of Patients N 425 219 Total Baseline HIV RNA copies/mL >100,000 28 153 75 ≤100,000 62 272 144 Baseline CD4 cells/mm3 ≤50 60 34 Virologic failures carried forward 54 11 69 31 65 35 0  70 36 72 36 >200 13 72 35 >50 and ≤200 47 20 40 Raltegravir + OBT Raltegravir + OBT 60 80 100 Placebo + OBT Placebo + OBT Steigbigel RT et al CROI 2009 Abstract K-103 571b
    69. 69. Percent of Patients with HIV RNA <50 copies/mL at Week 96 by Selected ARTs in OBT  Subgroup n % of Patients N Subgroup Percent of Patients 425 219 Total 62 28 Enfuvirtide Darunavir de unavir + + 39 19 de Only + - 42 23 vir Only - + virtide Darunavir 69 42 - 189 91 63 74 43 71 40 56 19 0 20 40 Raltegravir + OBT + : First use in OBT - : Not used in OBT  79 Raltegravir + OBT Virologic failures carried forward. 60 80 100 Placebo + OBT Placebo + OBT Steigbigel RT et al CROI 2009 Abstract K-103 571b
    70. 70. BENCHMRK 1 & 2: RNA VIH-1 < 50 c/mL a Semana 48, Global y por GSS* Subgrupo n Total Pacientes (%) 443 228 RAL + OBR 64 34 Placebo + OBR GSS: 0 112 65 1 166 92 2 158 68 ≥3 158 68 *Virologic failures carried forward. 45 3 67 37 62 52 0 20 Cooper DA, et al. N Engl J Med. 2008;359:355-365. 40 60 77 71 80 100
    71. 71. BENCHMRK 1 & 2: RNA VIH-1 < 50 c/mL a Semana 48 por PSS* Basal PSS n 0 65 44 1 137 69 2 221 108 ≥3 313 153 *Virologic failures carried forward. Pacientes (%) RAL + OBR 51 2 Placebo + OBR 61 29 71 39 61 0 20 Cooper DA, et al. N Engl J Med. 2008;359:355-365. 40 60 71 80 100
    72. 72. Raltegravir: Falla Virológica y resistencia • Falla virológica a Raltegravir] – Generalmente asociada con N155H o Q148H/K/R, en combinación con ≥ 1 otra mutación en la integrasa • Combinaciones mejoran la capacidad de replicación e incrementan los niveles de resistencia. – N155H y Q148H/K/R sola: similar grado de resistencia • Q148H/K/R + mutaciones secundarias generan mas resistencia que N155H + mutaciones secundarias. • N155H es remplazada con el tiempo por Q148H/G140S[2] • Potencial tercera mutación primaria en la integrasa : Y143C/R 1. Johnson VA, et al. Topics HIV Med. 2008;16:62-68. 2. Fransen S, et al. HIV Resist Wkshp 2008. Abstract 7.
    73. 73. Inhibidores de la Entrada: Enfuvirtida • Rápida emergencia de resistencia durante falla virológica. • Mutaciones simples mutaciones dobles y triples • Las mutaciones claves de resistencia están en los codones 36-45 de HR-1 – Otras: L33T, N126K, S138A • Poco beneficio virológico de continuar con la terapia • Ciertas mutaciones, especialmente en el codón 38, asociada con mejoría en la cuenta de CD4+ a pesar de falla virológica.
    74. 74. Falla Inicio de Tratamient o R5 R5 Suspensión Tratamiento D/M D/M D/M D/M 0 R5 D/M X4 Nonfunctional clone D/M 100 200 D/M R5 R5 300 Tiempo desde la primera administración (días) • Lewis M, et al. HIV Resistance Workshop 2007. Abstract 56. Análisis filogenéticos y clonal en 20 pts (16 MVC, 4 placebo) sugieren virus/M predominantemente de poblaciones preexistentes – Las implicaciones clínicas quedan sin estar completamente definidas
    75. 75. Cuantas ARVs activos son Necesarios? Combined Analysis: BENCHMRK-1 and -2[1,2] n Total 443 228 Active Drugs in OBR (n) n 35 0 51 56 64 34 GSS of OBR: 0 112 65 1 166 92 ≥2 Patients With < 50 c/mL at Week 24 (%) Patients With < 50 c/mL at Week 48 (%) 158 68 45 3 67 1 37 59 0 20 40 100 90 80 70 60 50 40 30 20 10 0 Subgroup Combined Analysis: MOTIVATE 1 and 2[3,4] 60 44 130 134 2 59 88 104 75 80 100 RAL + OBR Placebo + OBR 1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789. Adapted with permission of Merck & Co., Inc., ≥ 3 Whitehouse Station, New Jersey, USA, Copyright © 2008 Merck & Co., Inc. All Rights Reserved. 3. Nelson M, et al. CROI 2007. Abstract 104aLB. 4. Lalezari J, et al. CROI 2007. Abstract 104bLB. 64 132 121 3 Placebo + OBR MVC QD + OBR 18 29 MVC BID + OBR 9 43 43 19 52 53 55 61 58 DRK/BA/27.2.09
    76. 76. 261/09 • Se espera alto nivel de resistencia a todos los ITRANs, ITRNNs de primera generación e IPs por historial de terapia ARV y por Genotipo. • Sugerencia: 1. DRV/r, ETR, T20, RAL • CD4+ predice virus R5, Trofile® ? . Pero en este momento no se hace necesario uso de Maraviroc (PAE)
    77. 77. ANRS 139 TRIO trial Open-label, non-comparative, 100 multicenter study (n=101)  24 weeks RAL + ETR + DRV+RTV; 80 primary endpoint HIV RNA <50 c/mL 60 Inclusion 90%  Failing combination therapy, no CD4+ 40 (95% CI, 85% to 96%) restriction  MDR but susceptible to DRV 20 and ETR (38% pts had ≥3 DRV mutations) 0 Results 0 2 4 8 12 16 20 24 Time (weeks)  Baseline HIV RNA 4.0 log c/mL, 10 CD4+ 255 cells/mm3, median ART 10 pt (10%) did not reach primary endpoint: duration 13 years • 1 lost to F/U  OBT (as per investigator) • 1 D/C all ARV – 14% none, 83% NRTI, 12% ENF • 3 HIV RNA >400 c/mL  Only one discontinued due to • 2 HIV RNA 50–400 c/mL adverse event (rash/fever) • 3 HIV RNA <50 c/mL but not yet confirmed Patients with HIV RNA <50 c/mL (%, 95% CI)  Yazdanpanah Y, et al. XVII IAC, Mexico City 2008, #THAB0406 DRK/BA/27.2.09
    78. 78. Sumario • Nuevos ARVs han mejorado las opciones para pacientes altamente experimentados. • Es posible alcanzar supresión virológica duradera en muchos de estos pacientes. • En PETs, ≥2 agentes completamente activos deben ser combinados • Tener en cuenta la barrera genética y el potencial de resistencia cruzada de opciones disponibles.
    79. 79. Conclusiones: • • • • Usa las drogas que tengas Pero úsalas inteligentemente El objetivo es alcanzar <50 copias/mL Usa siempre pruebas de resistencia o consejo de expertos • Plan para el éxito pero también prepararse para falla. • NO PIENSES QUE TU SABES TODO • Varias Mentes piensan mejor que una!

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