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

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

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

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

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

Primary Genotypic Resistance Summary Author Region No. of Patients NRTI NNRTI PI Any Years Wensing[6] Europe 1083 5% 3% 9% 2002-2003 Garcia-Diaz[4] London 239 4% 2% 1% 7% 2004-2005 Oelte[3] Germany 831 2001-2005 Yerly[5] Switzerland 691 3-12% 0%-7% 0%-5% 8% 1996-2005 Little[7] USA/Australia 1191 11% 13% 2000-2006 Ross[1] USA 1795 6% 10% 2000-2004 Eshleman[2] 195 16% 1999-2003 Bennett[8] Chicago 66 15% 12% 25% 2003-2005 Los Angeles 73 14% 20% Truong[9] SF-STD 54 2004 SF-PHI 48 0% 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

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

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

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 Mutations PI-Based Regimen NNRTI-Based Regimen n HIV-1 RNA < 500 copies/mL, % (95% CI) None 354 68 (63.5-73.2) 1113 80 (77.6-82.3) NNRTI* 36 61 (46.1-74.7) 60 57‡ (43.2-69.4) Major PI† 26 50 (32.7-67.3) 39 80§ (66.0-89.4) For more information about this study, see the Capsule Summary at: http://www.clinicaloptions.com/HIV/Conference%20Coverage/Sydney%202007/Tracks/Treatment-experienced/Capsules/TUBEB043.aspx *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.

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% Time to Multiclass Resistance % with resistance Phillips et al. AIDS 2005; 19: 487-94

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

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

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

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.

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

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.

IAS-USA panel updated 2007

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

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

Posiciones que deben aparecer recogidas en los informes de resistencias

Inhibidores de la RT Análogos de Nucleosido

Inhibidores de Proteasa

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

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