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Interpretación de Resistencias. De las mutaciones a la clínica.

Interpretación de Resistencias. De las mutaciones a la clínica. Carmen de Mendoza Servicio de Enfermedades Infecciosas Hospital Carlos III, Madrid. M41L & T215Y. History of HIV Drug Resistance. AZT (1986). HAART (1996). Genetic Barrier and Antiviral Potency. Resistance mutations

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Interpretación de Resistencias. De las mutaciones a la clínica.

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  1. Interpretación de Resistencias. De las mutaciones a la clínica. Carmen de Mendoza Servicio de Enfermedades Infecciosas Hospital Carlos III, Madrid.

  2. M41L & T215Y History of HIV Drug Resistance AZT (1986) HAART (1996)

  3. Genetic Barrier and Antiviral Potency Resistance mutations and patterns Cross-Resistance Surveillance Comprehensive Drug Resistance Overview

  4. inhibitory activity • genetic barrier HIV-RNA The equation for ARV success Success of ARV= Potency x Convenience • pill burden • toxicity profile

  5. First - line therapyPlan for Success, but Prepare for Failure - Prove that primary drug resistance are not present. - Choose regimens with proven efficacy, tolerabilityand convenience to support adherence. - Consider the implications of a failing regimen’s resistanceon: • Cross-resistance mutations • The availability of future effective options

  6. Primary Genotypic Resistance Summary Transmission of drug resistance viruses consistently are around 10-15% in HIV infected individuals with recent infection and in newly diagnosed with unknown time of infection

  7. Prevalencia de mutaciones por familias de fármacos en Seroconvertores recientes por VIH en España De Mendoza C, et al. Clin Infect Dis 2005; 41: 1350-4

  8. Resistencia a NRTI Resistencia a NNRTI Multirresistencia 2000 2005 año Tendencias en la transmisión de virus resistentes

  9. Baseline Resistance Predicts Antiviral Response in Clinical Cohort • Retrospective analysis of resistance test results of samples taken from 1969 patients when treatment naive • As expected, baseline mutations associated with reduced response *L100F, K103N, V106A/I, V108I, F116Y, Y181C, G190A/S, M230L. †D30N, G48V, I50V, V82A/L/T, I84V, L90M. ‡P < .001 for reduced response to NNRTI in patients with NNRTI resistance vs no NNRTI resistance. §P = .026 for increased response to NNRTI vs PI in patients with PI resistance. Price H, et al. IAS 2007. Abstract TUPEB043.

  10. Time to Multiclass Resistance % with resistance Long-term risk of developing drug resistance • Risk of developing ARV drug resistance from the UK CHIC Study (n= 4306) • Longitudinal cohort from 6 clinics in London • Started ARV therapy with 2 NRTIs plus a 3rd agent • Overall risk of treatment failure was 38% over 6 years • Risk of accumulation resistance mutations to any drug 27% Phillips et al. AIDS 2005; 19: 487-94

  11. Viral load 1st regimen late 2nd regimen intermediate early Time Accumulation of resistance mutations Increasing Resistance

  12. 1328 No. of patients on HAART 1005 83% 80% No. of patients with plasma HIV-RNA <50 72% 71% 70% 2006 2003 2004 2005 2002 Hospital Carlos IIIARV failure

  13. Resistance mutations at Hospital Carlos III NRTI NNRTI PI De Mendoza et al. ARHR 2007

  14. Study population: 389 HIV patients who had failed PIs and begun PI/r regimens Virological response defined as >1 log drop in HIV RNA at w24.

  15. Resistance is not absolute Susceptible Resistant De Mendoza et al. HIV Clin Trials 2006; 7: 163-71.

  16. Drug Resistance Interpretation • Genotype • Phenotype • Drug Resistance algorithms: • Mutation list • Mutation score for especific drugs based on clinical response • Rega, ANRS, Stanford, geno2pheno, Artificial Neural Networks (ANN), etc.

  17. IAS-USA panel updated 2007

  18. Cosas Nuevas en 2007 • Listado de mutaciones que deben aparecer en los informes de resistencias • Recomendaciones sobre cuando hacer resistencias • Hipersusceptibilidad • Resistencias a nuevos fármacos: RAL, ETV, Maraviroc • Polimorfismos frecuentes en subtipos no-B • Ponderación de cada mutación para cada fármaco

  19. Métodos utilizados en la elaboración de las guías del 2007 • Listado de mutaciones de la IAS-USA 2007 • Stanford University HIV drug resistance database • Celera: PRS for ViroSeq HIV-1 Genotyping software v2.8 • Trugene guideline v.12 • Prevalencia y asociación de mutaciones de resistencia en el fracaso. • Datos de los ensayos clínicos DUET, BENCHMRK y MOTIVATE

  20. Posiciones que deben aparecer recogidas en los informes de resistencias

  21. Inhibidores de la RT Análogos de Nucleosido

  22. Inhibidores de Proteasa

  23. Inhibodores de Fusión, Inhibidores de la Integrasa y Antagonístas de CCR5

  24. Agradecimientos • Grupo de Español de estudio de SCV y Plataforma de Resistencias del RIS: • - Jorge del Romero y Carmen Rodríguez. Centro Sanitario Sandoval, Madrid • Pilar Leiva. Hospital General de Asturias, Oviedo • Antonio Aguilera. Hospital Xeral de Santiago • Jose Pedreira. Hospital Juan Canalejo, La Coruña • Jesús Aguero, Ana Saiz. Hospital Marques de Valdecilla, Santander • José Mª Eiros, Raúl Ortíz de Lejarazu. Hospital Clínico de Valladolid • Federico Garcia. Hospital Clínico San Cecilio, Granada • Isabel Viciana. Hospital Virgen de la Victoria, Málaga • Manolo Leal, Alex Vallejo. Hospital Virgen del Rocio, Sevilla. • Javier Colomina. Hospital de la Ribera, Valencia • Concha Tuset. Hospital General de Valencia • Javier Martínez-Picado, Josep Mª Llibre, Bonaventura Clotet. Hospital Germans Trias i Pujol, Badalona • José Luis Blanco, Josep Mª Gatell. Hospital Clinic, Barcelona. • Melchor Riera, Carmen Vidal. Hospital Son Dureta, Palma de Mallorca. • Francesc Vidal. Hospital Joan XXIII, Tarragona • Estrella Caballero, Esteban Ribera. Hospital Vall d’ Hebrón, Barcelona. • Mª Jesús Pérez-Elias, Carolina Gutierrez, Santiago Moreno. Hospital Ramón y Cajal, Madrid. • Juan Luis Gómez-Sirvent. Hospital • Felix Gutierrez. Hospital de Elche, Elche • Rafael Benito. Hospital Lozano Blesa, Zaragoza • Julián Torre-Cisneros. Hospital Reina Sofia. Córdoba. • Hospital Carlos III: • Sección de Laboratorio: • Angélica Corral • Natalia Zahonero • Carolina Garrido • Eva Poveda • Sección Clínica: • Pablo Labarga • Pilar García Gasco • Pablo Barreiro • Vicente Soriano • Juan González-Lahoz

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