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Simposio 9: Terapia Antirretroviral. Una mirada al futuro Dr. Luis Enrique Soto Ramírez Profesor de Medicina Interna, Infectología y VIH/SIDA Jefe Laboratorio.

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Presentación del tema: "Simposio 9: Terapia Antirretroviral. Una mirada al futuro Dr. Luis Enrique Soto Ramírez Profesor de Medicina Interna, Infectología y VIH/SIDA Jefe Laboratorio."— Transcripción de la presentación:

1 Simposio 9: Terapia Antirretroviral. Una mirada al futuro 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 Resistencia del VIH a los ARvs

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

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

4 Consecuencias de la Terapia ARV Corto plazo Largo Plazo Resistencia Reacciones de Hipersensibilidad: ABC,NVP * Partially reversible Diarrea/Nausea Hiperlipidemia Efectos de SNC Lipodistrofia* Reversible Irreversible Algunos ejemplos:

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

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

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 1 XIII IHDRW, Tenerife, June 2004; 2 Wensing AMJ, XII IHDRW, June 2003, #117; 3 Delfraissy JF, Rapport 2004 % de nuevas infecciones por VIH con resistencias primarias USA: ~10% 1 Canada ~8.5% 1 Europe:~11 2 * UK: ~18 1 Mexico: ~7% 1 Australia: ~13 1 France: ~12 3 Spain: ~9.5 1 Argentina 7-15% Brazil 0-30%

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

10 N/A, Not available; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PR, protease; RT, reverse transcriptase. a MDR, 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 Primary Antiretroviral Resistance in Brazil

11 Recently acquired infection (%) Long-standing infection (%) NRTIs T215Y/F M184V M41L NNRTIs015.7 PIs Cumulative M C A Sucupira. High Levels of Primary Antiretroviral Genotypic Resistance and B/F Recombinants in Santos SP, Brazil. 676, 11 th CROI, San Francisco 2004.

12 Persistence of transmitted resistant virus 1. Little SJ, et al. XII Resistance Workshop, Los Cabos 2003, #115; 2. Ravaux I, et al. 2 nd IAS, Paris 2003, #822; 3. Brenner B, et al. J Virology 2002; 766:1753; 4. Chan K, et al. AIDS 2003; 17:1256 n=10 1 NNRTI(n=9) NRTI(n=3) PI(n=3) Primary HIV Infection of 10 Reversions n=1 PI None n=4 MDR None n=2 4 MDR (n=1) NNRTI (n=1) None Follow-up (Weeks) Reversion of DR is rare even after 1 year

13 Resistencia secundaria

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 AZT o d4T Factores desconocidos TAMs 1 41L 210W 215Y TAMs 2 67N 70R 219Q Mas alto nivel de resistencia a AZT Mayor resistencia cruzada a ITRANs Mayor decremento en resistencia con M184V Patrones Dicotómicos de Resistencia Factores desconocidos Menor nivel de resistencia a AZT Menor resistencia cruzada a ITRANs Menor decremento en resistencia con M184V Factores desconocidos TAMs 1 41L 210W 215Y Factores desconocidos TAMs 2 67N 70R 219Q + 215F Factores desconocidos TAMs 1 41L 210W 215Y + 67N Factores desconocidos

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. 9 th CROI, 2002, Abstract 43

18 Pocos ITRANs activos en pacientes en falla a primer esquema en Malawi Pocos ITRANs activos en pacientes en falla a primer esquema en Malawi Resistencia a ITRANs en pacientes en falla a primer esquema PaísEsquema usado/evaluado % TAMs% M184V México n=134 [1] d4T/ZDV + 3TC + EFV 5558 Vietnam n=136 [2] d4T/ZDV + 3TC + NVP/EFV 7275 India n=350 [3] d4T/ZDV + 3TC + NVP/EFV 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 p=0.037 TDF + FTC (n = 244) ZDV/3TC (n = 243) Patients genotyped, n (%) 19 (8) 29 (12) Wild type, n 67 Any resistance, n 1322 EFV resistance mutations, n EFV resistance mutations, n1321 M184V/I, n M184V/I, n2 10* TAMs, n TAMs, n02 K65R, n K65R, n00 *P =.02 Arribas JR, et al. IAS Abstract WEPEB029. No emergence of K65R during 3 years Arribas JR, et al. IAS Abstract WEPEB029. No emergence of K65R during 3 years

20 GS 903 (brazoTDF n=299) Desarrollo de K65R, M184V/I & mutaciones relacionadas a EFV en 144 semanas

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

24 § § Y181I Y181V K101P L100I Y181C M230L E138A V106I G190S V179F V90I V179D K101E K101H A98G V179T G190A § V179F was never present as single INTELENCE RAM (always with Y181C) Score for individual mutations Add together Total weighted score 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)

25 Patients with confirmed VL HIV-1 RNA <50 copies/mL (%) Highest response Intermediate response Reduced response Highest responses occurred with a weighted score of 2 Relación entre score genotípico basal y respuesta virológica (<50 copias/mL) a semana 24 Hatched bars indicate virologic response for the entire category 74.4% 52.0% 37.7% 4/131/33/914/2719/3611/156/1137/53115/14832/592/71/54/92/11N Response category 2008 weighted mutation score for ETR

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

27 TMC114 (Darunavir) related mutations: V11I, V32I, L33F, I47V, I50V, I54L/M, G73S (T74P), L76V, I84V, L89V Different weight of these mutations: FC> <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 Score genotípico para Darunavir

28 Combined effect of ETR and DRV RAMs on virological response (<50 copies/mL) Patients with VL <50 copies/mL, % (n) ETR RAMs weighted score* [0; 2][2.5; 3.5]4 DRV RAMs 0 71 (12/17)83 (5/6)60 (3/5) 183 (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) Patients with VL<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 > [0; 2][2.5; 3.5] % <65% *from the list of 17 ETR RAMs (Vingerhoets et al. IHDRW 2008) Haubrich et al. XVII WAC, Mexico 2008 ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5] ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5] ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5] ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5] ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5] ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5] ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5] ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5] ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5] ETR RAMs weighted score Response at Week 24 (%) DRV RAMs > [0; 2][2.5; 3.5]

29 Primary protease resistance in naїve patients failing boosted-PIs 1 Murphy R. et al., 10 th 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, 4 Cahn P, et al. 1 st IAS, Buenos Aires, Argentina, July 2001, #779, 5 Molina JM. et al., 3rd IAS, Rio de Janeiro, Brazil, #WePe16.7B04; 6 Malan N, et al., 13 th CROI, Denver, #LB107; 7 Gathe JC, et al. AIDS 2004, 18: Weeks 0/32 isolates 7 0/3 isolates 6 0/19 isolates 1 0/51 isolates 5 0/13 isolates 4 0/5 isolates 3 0/23 isolates ATV/r BMS-089 fosAmp/r SOLO Kaletra studies SQV/r GEMINI 0/17 isolates 7

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

31 MONARK Study: LPV/RTV Monotherapy vs LPV/RTV + 2 NRTIs Primary endpoints 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 physicians request Patients underwent genotyping when evidence of suboptimal response was present or at the treating physicians request Delaugerre C, et al. HIV Resistance Workshop Abstract 75. Antiretroviral-naive, HIV-infected patients with HIV-1 RNA < 10 5 copies/mL, CD4+ cell count > 100 cells/mm 3, 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 SGC, soft-gel capsule.

32 MONARK Study 32 patients in LPV/RTV arm vs 7 in LPV/RTV + ZDV/3TC arm qualified for genotypic resistance testing 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 5 patients with major mutations in monotherapy arm - L76V mutation in 3 patients All 3 with HIV viral subtype CRF 02 All 3 with HIV viral subtype CRF 02 LPV/RTV should be administered with an NRTI backbone to reduce selection for resistance LPV/RTV should be administered with an NRTI backbone to reduce selection for resistance Delaugerre C, et al. HIV Resistance Workshop Abstract 75. LPV/RTV (n = 32) LPV/RTV + ZDV/3TC (n = 7) No change from screening 153 Any change in protease gene 174 IAS minor PI resistance mutation 50 IAS major PI resistance mutation 50

33 Mutaciones Primarias y Secundarias que afectan la Susceptibilidad a RAL Fold Change IC Q148H Q148H/G140S Q148K Q148K/E138A Q148K/G140A Q148K/E138A/G140A Q148R Q148R/G140S Q148 Pathway Q148 key mutation emerges, associated with secondary mutations N155 Pathway N155H key mutation emerges, associated with secondary mutations Fold Change IC N155H N155H/L74M N155H/T97A N155H/E92Q 60 Hazuda DJ, et al. HIV Resistance Workshop Abstract 8.

34 Q148H Raltegravir Resistance Evolution N155H + Q148H N155H N155H + 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 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 DrugT66IE92QE138 K G140SS147GQ148HQ148KQ148RN155H EVG RAL TDF LPV Fold Change of Mutant Viruses: Clinical EVG Mutation Patterns DrugT66I/ S147G T66I/ E92Q E92Q/ N155H G140S/ Q148H E138K/S147G/ Q148R EVG > RAL > TDF LPV McColl DJ, et al. HIV Resistance Workshop Abstract 9.

36 ARvs recomendados en 212 casos analizados

37 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): Antivir Ther. 2007; 12(1): 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. PDR Surveillance

38 Results of replicate amplifications of DBS extracts where drug resistance mutations were detected in either specimen type. Specimen ID PlasmaDBS Mutations from Replicate RT-PCR (n=11) Mutation Detected in DBS A2-0229M41L L210W 11-M41L 11-L210W 100% A2-0805K103N Y181CY 8-K103N, 2-K103KN, 1-K103K 9-Y181C, 2-Y181CY 90.9% 100% A2-0916L90M K70R T215F K219E 11-L90M 11-K70R 11-T215F 11-K219E 100% B5-0054M41L11-M41L100% B5-0042M41L11-M41ML100% B1-0015K103KN V108I 9-K103KN, 2-K103K 7-V108I, 4-V108IV 81.8% 100% B5-0119V108IV11-V108V0% A2-0535M184M10-M184M, 1-M184MV9.1% B4-0050D67D6-D67DN, 5-D67D54.5% DBS replicate genotypes were generated from 3 RT-PCR that served as template for 11 nested PCR, except in the case of B 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 f á rmacos m á s potentes de lo requerido seg ú n 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 f á rmacos ARV m á s 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


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