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)
HAART(1996)
M41L & T215Y
Genetic Barrierand Antiviral Potency
Resistance mutationsand patterns
Cross-Resistance Surveillance
Comprehensive Drug Resistance Overview
The equation for ARV success
Success of ARV = Potency x Convenience
• pill burden
• toxicity profile
• inhibitory activity
HIV-RNA
• 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% 3% 9% 2002-2003
Garcia-Diaz[4] London 239 4% 2% 1% 7% 2004-2005
Oelte[3] Germany 831 5% 3% 2% 9% 2001-2005
Yerly[5] Switzerland 691 3-12% 0%-7% 0%-5% 8% 1996-2005
Little[7] USA/Australia 1191 3% 11% 3% 13% 2000-2006
Ross[1] USA 1795 4% 6% 3% 10% 2000-2004
Eshleman[2] USA 195 9% 7% 2% 16% 1999-2003
Bennett[8] Chicago 66 15% 12% 3% 25% 2003-2005
Los Angeles 73 14% 11% 2% 20% 2003-2005
Truong[9] SF-STD 54 5% 5% 0 9% 2004
SF-PHI 48 4% 0% 5% 10% 2004
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
12,6
9,9
4,53,4
0
2
4
6
8
10
12
14
16
18
20
Cualquiermutación
NRTI NNRTI IP
Cualquier mutación NRTI NNRTI IP
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
año2000 2005
clinicaloptions.com/hiv
Update on Resistance and Management of Treatment-Experienced Patients
Baseline Resistance Predicts Antiviral Response in Clinical Cohort
Mutations
PI-Based Regimen NNRTI-Based Regimen
nHIV-1 RNA < 500 copies/mL,
% (95% CI) nHIV-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)
Retrospective analysis of resistance test results of samples taken from 1969 patients when treatment naive
As expected, baseline mutations associated with reduced response
Price H, et al. IAS 2007. Abstract TUPEB043.
*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.
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%
0
5
10
15
20
25
30
35
2 years 4 years 6 years
2 clases
3 clases
Time to Multiclass Resistance
% w
ith r
esis
tanc
e
Phillips et al. AIDS 2005; 19: 487-94
Accumulation of resistance mutations
Viralload
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 withplasma HIV-RNA <5070%
71% 72%80%
83%
1005
1328
Resistance mutations at Hospital Carlos III
0
10
20
30
40
50
60
70
80
90
100
1999 2000 2001 2002 2003 2004 2005
D30N M46L G48V I54V V82X I84V L90M
De Mendoza et al. ARHR 2007
42,6
35,2
35,833,3
3730,5 28,7
22,2 18,515,113,813,2
15,817,5
28,2 32,131,131,428,733
32,5
0
10
20
30
40
50
60
70
80
90
100
1999 2000 2001 2002 2003 2004 2005
K103N Y181C >2 NNRTI
0
10
20
30
40
50
60
70
80
90
100
1999 2000 2001 2002 2003 2004 2005
M41L T215Y K65R L74V M184V
NRTI NNRTI
PI
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.
De Mendoza et al. HIV Clin Trials 2006; 7: 163-71.
Susceptible Resistant
Resistance is not absolute
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
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
Agradecimientos