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