Resistencia del VIH a los ARvs

Presentación del tema: "Resistencia del VIH a los ARvs"— Transcripción de la presentación:

1 Resistencia del VIH a los ARvs
Simposio 9: Terapia Antirretroviral. Una mirada al futuro Resistencia del VIH a los ARvs Dr. Luis Enrique Soto Ramírez Profesor de Medicina Interna, Infectología y VIH/SIDA Jefe Laboratorio de Virología Molecular Departamento Infectología Instituto Nacional de Ciencias Médicas y Nutrición Coordinador Comité de Atención Integral CONASIDA

2 Resistencia a ARV: Definiciones
Disminución de la susceptibilidad de un virus a un medicamento Resistencia fenotípica Resistencia genotípica Resistencia primaria Resistencia secundaria Resistencia cruzada

3 Mecanismos de falla a ARV
POTENCIA LIMITADA Alts. Farma- cocinèticas Resistencia Pre-existente Pobre Apego Replicación Viral Persistente Desarrollo de resistencia Falla Virológica

4 Consecuencias de la Terapia ARV
Algunos ejemplos: Largo Plazo Corto plazo Reversible Diarrea/Nausea Hiperlipidemia Efectos de SNC Lipodistrofia* * Partially reversible Irreversible Along with the great success of antiretroviral therapy once must consider the many possible negative consequences. These will depend often on the specific drug and patients characteristics. One can consider these in the context of reversible versus irreversible, as well as short –term versus long term consequences In this context one can define drug resistance as a long-term irreversible negative consequence of drug therapy – therefore it is crucial to avoid resistance as much as possible Resistencia Reacciones de Hipersensibilidad: ABC,NVP

5 “La Resistencia es un continuo”
Mutaciones Fold Change Susceptible Resistente Actividad del Medicamento

6 Recomendaciones para el uso de pruebas de resistencia
DHHS, IAS-USA, EACS Infección primaria PEP (Fuente Pt) Crónica(< 2 años) Falla al tratamiento Embarazo Niños Cambiar las referencias a unas mas recientes 6

7 Importancia del las pruebas de resistencia en el diagnóstico y abordaje del VIH
Resistencia primaria Determinar tratamiento de inicio Tipo Respuesta Resistencia secundaria Nucleósidos No Nucleósidos IPs I. Integrasa Falla múltiple

8 Resistencia Primaria % de nuevas infecciones por VIH con resistencias primarias Canada ~8.5%1 UK: ~181† USA: ~10%1 France: ~123‡ Europe:~112* Spain: ~9.51 Mexico: ~7%1 Brazil 0-30% Australia: ~131 Argentina 7-15% 1 XIII IHDRW, Tenerife, June 2004; 2 Wensing AMJ, XII IHDRW, June 2003, #117; 3 Delfraissy JF, Rapport 2004

9 Efecto de la resistencia transmitida sobre el tiempo a supresión virológica

10 Primary Antiretroviral Resistance in Brazil
N/A, Not available; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PR, protease; RT, reverse transcriptase. aMDR, Multi-drug resistant, defined as the presence of drug-resistant mutations for more than one class of antiretroviral drug. AIDS:Volume 18 Supplement 3June 2004pp S9-S13

11 Primary Antiretroviral Resistance in Brazil
Recently acquired infection (%) Long-standing infection (%) NRTIs T215Y/F M184V M41L 22.7 9.1 4.5 21.1 1.7 3.5 NNRTIs 15.7 PIs 13.6 8.1 Cumulative 32 29.2 M C A Sucupira. High Levels of Primary Antiretroviral Genotypic Resistance and B/F Recombinants in Santos SP, Brazil. 676, 11th CROI, San Francisco 2004.

12 Persistence of transmitted resistant virus
Reversion of DR is rare even after 1 year Primary HIV Infection Follow-up (Weeks) Reversions n=101 NNRTI (n=9) NRTI (n=3) PI (n=3) 1 of 10 9-145 None n=1 PI2 156 n=4 MDR3 36-260 None n=24 MDR (n=1) NNRTI (n=1) None Composite slide of data from 4 posters, showing the incidence of reversion to wild type in transmitted resistant virus. 26-156 1. Little SJ, et al. XII Resistance Workshop, Los Cabos 2003, #115; 2. Ravaux I, et al. 2nd IAS, Paris 2003, #822; 3. Brenner B, et al. J Virology 2002; 766:1753; 4. Chan K, et al. AIDS 2003; 17:1256

13 Resistencia secundaria
Slide #5: Epidemiologic Trends: Treatment-Naïve Patients 13

14 Historia de TARV previo y secuenciación
Medicamentos con pasado ITRAN, ITRNN, IPs Necesitan de Genotipo a la falla para determinar su actividad Medicamentos sin pasado Inh Integrasa, CCR5 y fusión Pueden ser usados sin Genotipo

15 Patrones Dicotómicos de Resistencia
AZT o d4T Factores desconocidos Factores desconocidos Factores desconocidos Factores desconocidos Factores desconocidos Factores desconocidos TAMs 1 41L 210W 215Y + 67N TAMs 1 41L 210W 215Y TAMs 1 41L 210W 215Y TAMs 2 67N 70R 219Q TAMs 2 67N 70R 219Q + 215F In the case of zidovudine or stavudine, unknown factors direct the virus toward the 41, 210, 215 pathway in the emergence of TAMs, or toward the alternative pathway that involves 67, 70, and 219. Viruses carrying the combination of mutations tend to have higher levels of zidovudine resistance, are more cross-resistant to other NRTIs, and are less likely to become fully sensitized to zidovudine when the M184V lamivudine resistance mutation is present. Those carrying the cluster of mutations usually show lower levels of zidovudine resistance, are less cross-resistant to other NRTIs, and are more likely to become fully sensitive to zidovudine when the M184V mutation is present. Mas alto nivel de resistencia a AZT Mayor resistencia cruzada a ITRANs Mayor decremento en resistencia con M184V Menor nivel de resistencia a AZT Menor resistencia cruzada a ITRANs Menor decremento en resistencia con M184V 15

16 Efecto de TAMs, NAMs o ZAMs en la respuesta a otros nucleósidos
NARVAL: Brazo de cuidado estándar Respuesta subsecuente < 3TAMs  3TAMs p a (  log10 CV) d4T ABC ddI ddI + 3TC NS Costagliola D. Abstract 7. 3rd European Symposium on the Clinical Implications of HIV Drug Resistance, Frankfurt 2001

17 Response to Tenofovir DF: Effect of TAMs (Gilead 902 & 907)
Miller M, et al. 9th CROI, 2002, Abstract 43

18 Pocos ITRANs activos en pacientes en falla a primer esquema en Malawi
Resistencia a ITRANs en pacientes en falla a primer esquema Pocos ITRANs activos en pacientes en falla a primer esquema en Malawi País Esquema usado/evaluado % TAMs % M184V México n=134 [1] d4T/ZDV + 3TC + EFV 55 58 Vietnam n=136 [2] d4T/ZDV + 3TC + NVP/EFV 72 75 India n=350 [3] 62 71 1. Rodríguez-Diaz R. et al. In Press AIDS 2. Truong Giang L, et al. IAC Abstract TUPDA Vidya M, et al. IAC TUPDA205.

19 GS934: Resistance Development Through Week 144
TDF + FTC (n = 244) ZDV/3TC (n = 243) Patients genotyped, n (%) 19 (8) 29 (12) Wild type, n 6 7 Any resistance, n 13 22 EFV resistance mutations, n 21 M184V/I, n 2 10* TAMs, n K65R, n For more information go to p=0.037 *P = .02 No emergence of K65R during 3 years No emergence of K65R during 3 years Arribas JR, et al. IAS Abstract WEPEB029. Arribas JR, et al. IAS Abstract WEPEB029. 19 19

20 GS 903 (brazoTDF n=299) Desarrollo de K65R, M184V/I & mutaciones relacionadas a EFV en 144 semanas
Shown here is the development of K65R, M184V/I, and EFV-related resistance through Week Note again that only 1 patient developed K65R in the second year of the study, with no patients developing K65R in the third year. 20

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23 Patrones de Resistencia para ITRNN
EFAVIRENZ NEVIRAPINA K103N L100I P225H Y181C K101E G190A RESISTENCIA CRUZADA A ETRAVIRINA

24 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 3 Y181V 3 K101P 2.5 L100I 2.5 Y181C 2.5 Add together M230L 2.5 Total weighted score E138A 1.5 V106I 1.5 G190S 1.5 V179F 1.5 V90I 1 V179D 1 K101E 1 K101H 1 A98G 1 V179T 1 G190A 1 §V179F was never present as single INTELENCE RAM (always with Y181C) 24

25 Patients with confirmed VL HIV-1 RNA <50 copies/mL (%)
Relación entre score genotípico basal y respuesta virológica (<50 copias/mL) a semana 24 Highest response Intermediate response Reduced response 74.4% Response category 52.0% Patients with confirmed VL HIV-1 RNA <50 copies/mL (%) 37.7%  4/13 1/3 3/9 14/27 19/36 11/15 6/11 37/53 115/148 32/59 2/7 1/5 4/9 2/11 N 2008 weighted mutation score for ETR Highest responses occurred with a weighted score of  2 Hatched bars indicate virologic response for the entire category 25

26 Response by total score
TPV weighted score Mutation Weight L10V 1 L24I -2 M36I 2 K43T M46L I47V 6 I50L/V -4 I54A/M/V 3 I54L -7 Q58E 5 T74P L76V V82L/T N83D 4 I84V Response by total score Score Response ≤3 Susceptible >3 – ≤10 Partially susceptible >10 Resistant 32I 33F 47V 71T 84V Increased response Minor mutation Major mutation Scherer et al, EACS 2007 26

27 Score genotípico para Darunavir
TMC114 (Darunavir) related mutations: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S (T74P), L76V, I84V, L89V Different “weight” of these mutations: FC>4 3-4 2-3 <2 50V(4.5) 54M(3.5) 76V(3.5) 84V(3.5) T74P(3.5) 32I(2.5) 33F(2.5) 47V(2.5) 89V(3) 11I(1.5) 54L(1.5) 73S(1.5) Diminished response to Darunavir when 3 or more of these mutations where present at BL Antiviral Therapy 2006; 11: S83

28 Patients with VL <50 copies/mL, % (n)
Combined effect of ETR and DRV RAMs on virological response (<50 copies/mL) Subgroup of patients treated with ETR; not de novo ENF (n=406) ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs >3 3 2 1 [0; 2] [2.5; 3.5] ≥4 59 74 77 83 71 72 64 38 19 24 43 26 53 60 100 80 Patients with VL<50 copies/mL (%) 60 65% <65% 40 20 Patients with VL <50 copies/mL, % (n) ETR RAMs weighted score* [0; 2] [2.5; 3.5] ≥4 DRV RAMs 71 (12/17) 83 (5/6) 60 (3/5) 1 83 (53/64) 72 (21/29) 53 (8/15) 2 77 (41/53) 64 (14/22) 26 (5/19) 3 74 (40/54) 38 (9/24) 43 (9/21) >3 59 (23/39) 19 (4/21) 24 (4/17) *from the list of 17 ETR RAMs (Vingerhoets et al. IHDRW 2008) Haubrich et al. XVII WAC, Mexico 2008

29 Primary protease resistance in naїve patients failing boosted-PIs
0/19 isolates 1 0/23 isolates 2 Kaletra studies 0/5 isolates 3 0/13 isolates 4 0/51 isolates 5 ATV/r BMS-089 0/3 isolates 6 fosAmp/r SOLO 0/32 isolates 7 Drug resistance testing should be performed on patients with detectable viral load (>500–1000 copies/mL). Blood samples should be drawn before the failing regimen is discontinued or within 2 weeks following treatment interruption: Some mutations may disappear rapidly after withdrawal of the drug (eg, M184V after stopping lamivudine) However, mutational pattern may persist unaltered during 2 weeks after TI. Tests should be performed in a certified laboratory, under strict QC and quality assurance standards. Predicting phenotypic resistance from genotypic data has considerable limitations: The phenotypic effect of many combinations of DRMs is not entirely known. Varying interpretations may be reported regarding the level of resistance conferred by a specific mutational pattern. The many possible complex combinations of multiple mutations may limit the usefulness of rule-based approaches or algorithms for interpreting genotypic results. Therapeutic failure may be due to nonvirologic reasons: Resistance testing should always be accompanied by careful questioning of the patient with regard to: Drug history Adherence Toxicities Concomitant medication. Additionally, whenever possible, determination of plasma levels of PI and NNRTI should be performed 4–12 weeks after starting a new ART regimen. In the case of optimal serum levels, aspects such as adherence, drug interactions or incorrect ARTdosing should be investigated. SQV/r GEMINI 0/17 isolates 7 100 200 300 400 Weeks 1 Murphy R. et al., 10th EACS, Dublin, Ireland, Nov. 2005; #P7.9/3; 2 Kempf D, et al. J Infect Dis 2004: 189: 51-60; 3 Feinberg J, et al. XIV IAC, Barcelona, July 2002, # B4445, 4Cahn P, et al. 1st IAS, Buenos Aires, Argentina, July 2001, #779, 5Molina JM. et al., 3rd IAS, Rio de Janeiro, Brazil, #WePe16.7B04; 6Malan N, et al., 13th CROI, Denver, #LB107; 7Gathe JC, et al. AIDS 2004, 18: 29

30 Como explicar la NO resistencia a IPs/r?
Adherencia?? Zona de Presión Selectiva Alta Ptencia de los IPs/r Alta barrera genética Mecanismos alternativos de resistencia Sitios ruptura de gag

31 MONARK Study: LPV/RTV Monotherapy vs LPV/RTV + 2 NRTIs
Antiretroviral-naive, HIV-infected patients with HIV-1 RNA < 105 copies/mL, CD4+ cell count > 100 cells/mm3, and no evidence of resistance at screening (N = 278) LPV/RTV SGC 400/100 mg BID (n = 83) LPV/RTV SGC 400/100 mg + ZDV/3TC 300/150 mg BID (n = 53) Week 24 Week 48 Week 96 Ongoing Primary endpoints HIV-1 RNA < 400 copies/mL at Week 24 HIV-1 RNA < 50 copies/mL at Week 48 Patients underwent genotyping when evidence of suboptimal response was present or at the treating physician’s request SGC, soft-gel capsule. Delaugerre C, et al. HIV Resistance Workshop Abstract 75.

32 MONARK Study LPV/RTV (n = 32) LPV/RTV + ZDV/3TC (n = 7) No change from screening 15 3 Any change in protease gene 17 4 IAS minor PI resistance mutation 5 IAS major PI resistance mutation 32 patients in LPV/RTV arm vs 7 in LPV/RTV + ZDV/3TC arm qualified for genotypic resistance testing Suboptimal response in 7 vs 4 subjects, respectively 5 vs 2 discontinuations 20 vs 1 requests for genotyping 5 patients with major mutations in monotherapy arm L76V mutation in 3 patients All 3 with HIV viral subtype CRF 02 LPV/RTV should be administered with an NRTI backbone to reduce selection for resistance Delaugerre C, et al. HIV Resistance Workshop Abstract 75.

33 Mutaciones Primarias y Secundarias que afectan la Susceptibilidad a RAL
Q148 Pathway Q148 key mutation emerges, associated with secondary mutations Q148H 600 Q148H/G140S Q148K 500 Q148K/E138A 400 Q148K/G140A Fold Change IC50 Q148K/E138A/G140A 300 Q148R 200 Q148R/G140S 100 N155 Pathway N155H key mutation emerges, associated with secondary mutations N155H 70 N155H/L74M 60 N155H/T97A N155H/E92Q 50 Fold Change IC50 40 30 20 10 Hazuda DJ, et al. HIV Resistance Workshop Abstract 8.

34 Raltegravir Resistance Evolution
N155H N155H + Q148H Q148H + others N155H + Q148H Q148H + others Q148H Q148H + others Fransen S, et al. Resist Wkshp Abstract 7.

35 Cambios en la Susceptibilidad FENOTÍPICA a EVG y RAL de mutaciones sitio-dirigidas
Integrase sequenced in patients with virologic failure Site-directed mutants constructed from those data and used to determine susceptibility to EVG, RAL, and 2 antiretroviral controls (TDF and LPV) Fold Change of Mutant Viruses: Single Integrase Mutations Drug T66I E92Q E138K G140S S147G Q148H Q148K Q148R N155H EVG 15 33 0.7 5.0 8.0 6.4 67 118 38 RAL 1.4 6.0 0.9 2.0 1.0 20 34 30 23 TDF 0.8 LPV Fold Change of Mutant Viruses: Clinical EVG Mutation Patterns T66I/ S147G T66I/ E92Q E92Q/ N155H G140S/ Q148H E138K/S147G/Q148R 46 145 166 > 1000 175 2.5 135 1.1 McColl DJ, et al. HIV Resistance Workshop Abstract 9.

36 ARvs recomendados en 212 casos analizados
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37 PDR Surveillance Antivir Ther. 2007; 12(1):107-13
HIV-1 drug resistance genotyping in treatment-naïve subjects using dried whole blood spots Silvia Bertagnolio, Luis Soto-Ramirez, Richard Pilon, Richard Harrigan, Roberto Rodriguez, MonicaViveros, Luis Fuentes, Theresa Mo, Don Sutherland, Paul Sandstrom. Antivir Ther.  2007; 12(1):107-13  Methods: We prospectively collected specimens from newly-diagnosed, treatment-naïve HIV+ subjects in Mexico. Whole blood was spotted onto filter cards, air dried at room temperature and stored with desiccant at 37°C & 85% humidity for 3 months. Genotypes obtained from DBS-extracted nucleic acids using an in-house nested RT-PCR method were compared to genotypes derived from matched plasma.

38 Results of replicate amplifications of DBS extracts where drug resistance mutations were detected in either specimen type. Specimen ID Plasma DBS Mutations from Replicate RT-PCR (n=11) Mutation Detected in DBS A2-0229 M41L L210W 11-M41L 11-L210W 100% A2-0805 K103N Y181CY 8-K103N, 2-K103KN, 1-K103K 9-Y181C, 2-Y181CY 90.9% A2-0916 L90M K70R T215F K219E 11-L90M 11-K70R 11-T215F 11-K219E B5-0054 B5-0042 11-M41ML B1-0015 K103KN V108I 9-K103KN, 2-K103K 7-V108I, 4-V108IV 81.8% B5-0119 V108IV 11-V108V 0% A2-0535 M184M 10-M184M, 1-M184MV 9.1% B4-0050 D67D 6-D67DN, 5-D67D 54.5% DBS replicate genotypes were generated from 3 RT-PCR that served as template for 11 nested PCR, except in the case of B5-054 and B1-0015, where only 2 RT-PCR were used as template. All differences between specimen types were partial discordances (mixed bases). In 1 case, B5-0119, a mixed wild type/mutant was detected in plasma and no mutations were detected in matched DBS sequences. Two specimens, A and B4-0050, were wild type in plasma and found as mixed wild type/ mutant in 9.1% and 54.5% of replicates in DBS, respectively.

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40 Sobreprescripción en base a genotipo
En 30 ocasiones se utilizaron fármacos más potentes de lo requerido según las mutaciones mostradas por el genotipo y la historia de esquemas antiretrovirales previos. Evaluador 1(2.90): 5/35 (14.28%) Evaluador 2 (2.66): 7/35 (20%) Evaluador 3 (2.47): 17/35 (48.5%) Evaluador 4 (2.26): 1/35 (2.85%) Los fármacos ARV más sobre prescritos: Raltegravir 9/30 (30%). Darunavir 8/30 (26.66%) T20: 5/30 (16.66%) Etravirina 5/30 (16.66%) Tipranavir 3/30 (10%)

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42 LA Latin American HIV Resistance Network Bogotá, Colombia Mayo 6, 2010