TERAPIA ANTIRETROVIRAL

1. TERAPIA ANTIRETROVIRAL Juan Villena Vizcarra HNGAI UNMSM

3. VIH bajo microscopio electrónico Se observan el core central y la envoltura

5. Evolución reciente de la TARV La terapia antiretroviral de alta actividad continúa evolucionando rápidamente. Los conceptos y fármacos que se utilizaban entre 1995 y 2000 son diferentes en la actualidad. Se ha reconocido que no es posible curar la infección con los fármacos actualmente disponibles. Se han reconocido las limitaciones y efectos de largo plazo de los medicamentos. Se ha ganado experiencia en el uso de los tratamientos

6. Evolución reciente de la TARV Principales diferencias se refieren a: Criterios de inicio de terapia: evolución a inicio menos precoz y según nivel de deterioro inmunológico Uso de medicamentos disponibles con ventajas farmacocinéticas (menos tomas al día, menor número de pastillas) y mejor perfil de toxicidad o probable mayor durabilidad de efecto

7. Evolución reciente de la TARV Incremento de acceso a terapia en países de menor desarrollo relacionado a uso de medicamentos fuera de patente e iniciativas internacionales. No necesariamente por incremento del gasto público (¿financiamiento a largo plazo?)

8. TRATAMIENTOS DE PRIMERA LINEA Preguntas fundamentales como cuál es el mejor tratamiento o si la terapia tiene que ser permanente aun no tienen respuesta. El grueso de estudios son de 1-2 años de seguimiento. Poca información con estudios prolongados.

9. TRATAMIENTOS DE PRIMERA LINEA Las opciones de primera línea están fuertemente influenciadas por la realidad económica. Consenso sobre importancia del primer esquema: durabilidad (potencia) vs. simplicidad/tolerabilidad (adherencia)

10. TRATAMIENTOS DE PRIMERA LINEA INTR “tradicionales” como AZT + 3TC (Glaxo), o la asociación D4T + DDI (Bristol) tienden a caer en desuso fente a nuevas opciones como las combinaciones FTC + TDF (Truvada, Gilead) o ABC + 3TC (Epzicom, Glaxo), que se pueden tomar 1 vez al día, parecen ser menos tóxicas y permiten mejor secuenciación para esquemas de rescate.

11. TRATAMIENTOS DE PRIMERA LINEA Son combinaciones más costosas y aun no están disponibles en mercados más pequeños. D4T + 3TC no disponible en combinación por diferente origen (Bristol vs. Glaxo)

12. TRATAMIENTOS DE PRIMERA LINEA Análogamente, IPs “tradicionales” son de difícil uso por su alto número de pastillas y tomas, o requerimientos adicionales. Ejs. Indinavir 2 tid, nelfinavir 5tid, saquinavir 6 tid, ritonavir bid. Nuevos IPs como atazanavir (Reyataz, Bristol) o lopinavir (Kaletra, Abbott) son más utilizados.

13. TRATAMIENTOS DE PRIMERA LINEA IPs antiguos vienen siendo reformulados para facilitar su toma y mantener competitivo el mercado: nelfinavir de 250 a 625, amprenavir (12 tab/d) a fosamprenavir (4 tab/d), saquinavir 200 a 500 Uso de ritonavir como potenciador ha influenciado en el alza de su precio.

14. TRATAMIENTOS DE PRIMERA LINEA En Latinoamérica se utilizan productos fuera de patente de diferentes fármacos. Pero en general nevirapina fuera de patente o efavirenz son preferidos por su menor costo.

15. TRATAMIENTOS DE PRIMERA LINEA 1995-2000: AZT+3TC+IDV D4T+ DDI + NFV 2001-2003: ABC + 3TC + AZT EFV + 2INTR LPV/r + 2INTR

16. TRATAMIENTOS DE PRIMERA LINEA 2004 (países desarrollados): FTC+TDF (Truvada) + ATZ (Reyataz) toma día, 3 tabletas 2004 (países subdesarrollados): D4T+3tC+NVP (Triomune): 2 tomas día, 2 tabletas

17. PERSPECTIVA FUTURA Corto plazo: 1 tab 1 vez día en planes de preparación (requiere acuerdos comerciales, pero va a ocurrir) Países en desarrollo seguirán usando actuales combinaciones, no hay aparentes cambios en políticas de precios para productos más recientes Productos no originales vienen ganando mayor reconocimiento a medida que aparecen estudios de bioequivalencia, clínicos y el programa de certificación de la OMS se consolida

18. PERSPECTIVA FUTURA Mediano plazo: Identificación de durabilidad de efecto de fármacos

19. TRATAMIENTOS DE RESCATE “Rescate” se aplica a modificación de esquema luego de fracaso de tratamiento por falta de respuesta. Modificaciones debidas a intolerancia o efecto adverso no son considerardas en esta categoría cambio de AZT por D4T en anemia, cambio de IP a EFV por diagnóstico de tuberculosis

20. TRATAMIENTOS DE RESCATE La posibilidad de éxito terapéutico disminuye en el esquema de rescate, por lo que es necesario disponer de mecanismos para optimizarlo: Alternativas terapéuticas (limitadas en países de menor desarrollo, ej. no hay tenofovir en Perú y abacavir es sumamente costoso)

21. TRATAMIENTOS DE RESCATE La posibilidad de éxito terapéutico disminuye en el esquema de rescate, por lo que es necesario disponer de mecanismos para optimizarlo: Estudios de resistencia (igualmente no disponibles en muchos países y muy costosos). Su real utilidad ha sido incluso cuestionada

22. TRATAMIENTOS DE RESCATE Para mejorar los rescates se requiere de nuevas opciones como INNTR sin resistencia cruzada o fármacos con nuevo blanco farmacológico como los inhibidores de fusión. Estos nuevos productos aun están en desarrollo y son o serán costosos, lo que contribuye a complicar el manejo en nuestros países.

23. TRATAMIENTOS DE RESCATE En general se considera preferible mantener un tratamiento, aun cuando no tenga eficacia óptima debido a que el virus “salvaje” tiende a ser más virulento que el virus mutante, con lo que la progresión de la enfermedad es más lenta (Grant, NEJM 2002). Esto siempre que el regimen utilizado sea tolerable y no se asocie a otras complicaciones.

24. CONCLUSIONES La terapia antiretroviral continúa evolucionando y se ven modificaciones recientes que generalmente representan mejoras (uso más racional, mejor conocimiento de efectos a largo plazo, mayores alternativas, mayor facilidad para tomar). Aun se está lejos de conseguir una cura, pero se dispondrá de tratamientos más sencillos y seguramente algo más eficaces para la primera línea. Los rescates irán mejorando igualmente de manera progresiva. Los países de menor desarrollo mantienen un retraso importante para acceder a los nuevos avances.

25. INFECCION POR VIHEVOLUCION DE LAS ESTRATEGIAS DE TRATAMIENTO

27. INHIBICION DEL METABOLISMO DEL PRIMER PASO Y LA DEPURACION HEPATICA MEJORAN LOS NIVELES DE LA DROGA

28. C max : TOXICIDAD. Cmin : EFICACIA

29. POTENCIACION DE INHIBIDORES DE PROTEASA RESULTA EN: INCREMENTO DE EXPOSICION A LOS IP Cvalle QUE EXCEDE A LA CI50 o CI95 POR UN MARGEN CONSIDERABLE Cvalle QUE PERMITE EFECTO ANTIRETROVIRAL CONTRA LOS VIRUS RESISTENTES (LA RESISTENCIA ES RELATIVA, NO ABSOLUTA) PARA ALGUNOS IPs: POTENCIACION DEL Cmax (SQV, ABT-378) POTENCIACION t1/2 (APV, IDV, ABT-378) BENEFICIOS Y TOXICIDADES A LARGO PLAZO

30. MEJOR EFECTO FARMACOCINETICO (POTENCIA, DURABILIDAD/RESISTENCIA) ? CANTIDAD DE FARMACOS MEJOR TOLERANCIA ? FRECUENCIA DE DOSIS ? RESTRICCIONES ? COSTOS

31. COMO PODEMOS MEJORAR LOS RESULTADOS EN LA TERAPIA DE LOS PACIENTES ?

35. El Ciclo de Vida del VIH-1 The Life Cycle of HIV-1 The binding of HIV-1 to a susceptible cell is the initial step in the HIV-1 life cycle.1 Binding is accomplished between the surface glycoprotein (gp) 120 env molecule on the HIV-1 particle and the CD4+ molecule on the cell. (Other factors have been shown to play a role in this binding process. Those factors are discussed in a later slide.) Following cytoplasmic penetration of the virus core, the viral genomic RNA is released. Next, reverse transcriptase converts the single-stranded RNA molecule to a double-stranded DNA molecule that is integrated into the host cell genome.1 The proviral DNA replicates with the host genes. The production of viral messenger RNA (mRNA) and other RNA molecules permits the subsequent synthesis of viral proteins. The proteins are assembled into new HIV-1 particles and are released at the cell membrane 1. Folks and Hart. In: DeVita et al, eds. AIDS: Etiology, Diagnosis, Treatment and  Prevention. 4th ed. Lippincott-Raven Publishers; 1997:29-43.The Life Cycle of HIV-1 The binding of HIV-1 to a susceptible cell is the initial step in the HIV-1 life cycle.1 Binding is accomplished between the surface glycoprotein (gp) 120 env molecule on the HIV-1 particle and the CD4+ molecule on the cell. (Other factors have been shown to play a role in this binding process. Those factors are discussed in a later slide.) Following cytoplasmic penetration of the virus core, the viral genomic RNA is released. Next, reverse transcriptase converts the single-stranded RNA molecule to a double-stranded DNA molecule that is integrated into the host cell genome.1 The proviral DNA replicates with the host genes. The production of viral messenger RNA (mRNA) and other RNA molecules permits the subsequent synthesis of viral proteins. The proteins are assembled into new HIV-1 particles and are released at the cell membrane 1. Folks and Hart. In: DeVita et al, eds. AIDS: Etiology, Diagnosis, Treatment and Prevention. 4th ed. Lippincott-Raven Publishers; 1997:29-43.

36. INDICACIONES PARA INICIAR TERAPIA ANTIRRETROVIRAL PACIENTE SINTOMATICO (MUGUET O FIEBRE PERSISTENTE) O CON CRITERIOS DE SIDA PACIENTE ASINTOMATICO CON CELULAS CD4 MENOR DE 200, INDEPENDIENTE DE CV

37. CRITERIOS PARA INICIAR TERAPIA ANTIRRETROVIRAL PACIENTES ASINTOMATICOS CON CD4 ENTRE 200 Y 350 CON CARGA VIRAL MAYOR DE 55000 COPIAS (PCR) LOS PACIENTES ASINTOMATICOS CON CD4 MAYOR DE 350 NO DEBEN TENER CARGA VIRAL Y PUEDEN SER OBSERVADOS.

38. RESPUESTA TERAPEUTICA ADECUADA DE LA CARGA VIRAL CAIDA DE 0.5 A 0.75 LOG10 ENTRE LA SEGUNDA Y OCTAVA SEMANA NIVEL INDETECTABLE USUALMENTE ENTRE LA SEMANA 12 Y 16 LA CARGA VIRAL DEBE SER INDETECTABLE A LOS 6 MESES DE TRATAMIENTO

39. RESPUESTA TERAPEUTICA ADECUADA DE LAS CEL. CD4 FASE 1 : ELEVACION RAPIDA, AUNQUE MODERADA, DE LOS LINFOCITOS CD4 DE MEMORIA (REDISTRIBUCION) FASE 2 : A PARTIR DEL TERCER MES, ELEVACION LENTA DE LINFOCITOS CD4 VIRGENES (RECONSTITUCION INMUNE)

40. RESPUESTA TERAPEUTICA 20% DE LOS PACIENTES TIENE RESPUESTA DISCREPANTE EN ESOS CASOS EL CRITERIO PRINCIPAL SERA LA CARGA VIRAL

41. INHIBIDORES NUCLEOSIDOS DE LA TRANSCRIPTASA REVERSA ZIDOVUDINA (ZDV O AZT) DIDANOSINA (DDI) ZALCITABINA (DDC) ESTAVUDINA (D4T) LAMIVUDINA (3TC) ABACAVIR (ABC) EMTRICITAVINA (FTC)

42. INHIBIDORES DE PROTEASA SAQUINAVIR RITONAVIR INDINAVIR NELFINAVIR LOPINAVIR/r AMPRENAVIR (FOSA) ATAZANAVIR DARUNAVIR TIPRANAVIR

43. INHIBIDORES NO NUCLEOSIDOSDE TRANSCRIPTASA REVERSA EFAVIRENZ NEVIRAPINA DELAVIRDINA

44. OTRAS DROGAS ANTIRRETROVIRALES INHIBIDORES NUCLEOTIDOS DE LA TRANSCRIPTASA REVERSA: - ADEFOVIR - TENOFOVIR HIDROXIUREA

46. ESQUEMAS ANTIRRETROVIRALES ALTERNATIVOS COLUMNA A COLUMNA B -ABACAVIR -DDI + 3TC -AMPRENAVIR -ZDV + DDC -DELAVIRDINA -NEVIRAPINA -NELFINAVIR -LOPINAVIR/r -RITONAVIR -SAQUINAVIR (GEL BLANDO) TRATAMIENTO: A + B

47. ESQUEMAS GENERALMENTE NO RECOMENDADOS -HIDROXIÚREA COMO PARTE DEL ESQUEMA ANTIRRETROVIRAL -RITONAVIR + INDINAVIR -RITONAVIR + NELFINAVIR

48. ESQUEMAS NO RECOMENDADOS -CUALQUIER MONOTERAPIA -DDC + DDI -DDC + D4T -DDC + 3TC -D4T + ZDV -SAQUINAVIR COMO GEL DURO

49. Curso de la infección por VIH

50. CARGA VIRAL PLASMÁTICA Mide la cantidad de RNA-VIH en sangre Los resultados de la prueba se expresan como el número de copias de RNA-VIH por mL de plasma. Pueden variar de menos de 50 copias por mL a varios millones de copias por mL.

51. CARGA VIRAL PLASMÁTICA Los niveles de carga viral se correlacionan directamente con el tiempo de progresión de la enfermedad A menor carga viral, es mayor el tiempo que se requiere para la progresión de la enfermedad, y por tanto mayor supervivencia.

52. Diagnóstico de infección aguda Probabilidad de transmisión Progresión de la enfermedad Monitoreo de la Terapia

53. Mas eficaz con menos pastillas

54. Blancos terapeuticos:transcriptasa reversa

55. El Ciclo de Vida del VIH-1 The Life Cycle of HIV-1 The binding of HIV-1 to a susceptible cell is the initial step in the HIV-1 life cycle.1 Binding is accomplished between the surface glycoprotein (gp) 120 env molecule on the HIV-1 particle and the CD4+ molecule on the cell. (Other factors have been shown to play a role in this binding process. Those factors are discussed in a later slide.) Following cytoplasmic penetration of the virus core, the viral genomic RNA is released. Next, reverse transcriptase converts the single-stranded RNA molecule to a double-stranded DNA molecule that is integrated into the host cell genome.1 The proviral DNA replicates with the host genes. The production of viral messenger RNA (mRNA) and other RNA molecules permits the subsequent synthesis of viral proteins. The proteins are assembled into new HIV-1 particles and are released at the cell membrane 1. Folks and Hart. In: DeVita et al, eds. AIDS: Etiology, Diagnosis, Treatment and  Prevention. 4th ed. Lippincott-Raven Publishers; 1997:29-43.The Life Cycle of HIV-1 The binding of HIV-1 to a susceptible cell is the initial step in the HIV-1 life cycle.1 Binding is accomplished between the surface glycoprotein (gp) 120 env molecule on the HIV-1 particle and the CD4+ molecule on the cell. (Other factors have been shown to play a role in this binding process. Those factors are discussed in a later slide.) Following cytoplasmic penetration of the virus core, the viral genomic RNA is released. Next, reverse transcriptase converts the single-stranded RNA molecule to a double-stranded DNA molecule that is integrated into the host cell genome.1 The proviral DNA replicates with the host genes. The production of viral messenger RNA (mRNA) and other RNA molecules permits the subsequent synthesis of viral proteins. The proteins are assembled into new HIV-1 particles and are released at the cell membrane 1. Folks and Hart. In: DeVita et al, eds. AIDS: Etiology, Diagnosis, Treatment and Prevention. 4th ed. Lippincott-Raven Publishers; 1997:29-43.

56. ANTIRETROVIRALES APROBADOS

57. Inhibidores de transcriptasa reversa

58. Viread (tenofovir) Analogo nucleotido Nucleosido fosforilado Una tableta al dia Mas potente que el nucleosido promedio Bien tolerado Hay que vigilar: funcion renal Interacciones de medicamentos

59. Emtriva (emtricitabine) Una tableta al dia Pocos efectos secundarios (similar a 3TC) Mutaciones similares al 3TC (184) Pero, fabricado por la misma compania (Gillead) que el Viread Tableta combinada en proceso

60. Capravirine No-nucleosido Funciona apesar de resistencia a los demas K103N Efectos gastrointestinales Todavia en estudios clinicos

61. Inhibidores de proteasa indinavir Crixivan nelfinavir Viracept ritonavir Norvir saquinavir Fortovase, Invirase amprenavir Agenerase lopinavir/r Kaletra

62. IP que aumentan con ritonavir Lopinavir (Kaletra) Saquinavir (Fortovase, Invirase) Indinavir (Crixivan) Amprenavir (Agenerase)

63. Reyataz (atazanavir) Inhibidor de proteasa Una vez al dia (2 pastillas) Menos efecto sobre los lipidos Se puede aumentar con ritonavir Mutaciones unicas (? Multi-resistencia) Hay que vigilar: hiperbilirrubinemia

64. tipranavir Inhibidor de proteasa Dos veces al dia dos capsulas/ 2 ritonavir BID Efectos secundarios gastrointestinales Puede tolerar varias mutaciones parecido a Kaletra

65. Inhibidores de fusion

66. enfuvirtide (Fuzeon, T-20)

67. Fuzeon (enfuvirtide) Muy eficaz en uso combinado Inyeccion sub-cutanea Reacciones cutaneas son comunes No son severas

68. Nuevos Antiretrovirales y en Desarrollo The viral life cycle is illustrated on this slide along with the targets for novel antiretrovirals currently in clinical development. The cycle begins with viral entry followed by reverse transcription, integration, maturation, and budding. TNX-355 is an entry inhibitor that will be discussed in this presentation. CCR5 antagonists, another subgroup of entry inhibitors, will also be discussed further. Although there has been some interest in trying to develop CXCR4 antagonists, there are currently no candidates in late clinical development, so this group will not be addressed in this presentation. Data concerning the integrase inhibitors, raltegravir and elvitegravir, will be explored. Maturation inhibitors, although they are not included in this presentation, are a class with a novel target that may be an option in the future for people who are highly treatment experienced.The viral life cycle is illustrated on this slide along with the targets for novel antiretrovirals currently in clinical development. The cycle begins with viral entry followed by reverse transcription, integration, maturation, and budding. TNX-355 is an entry inhibitor that will be discussed in this presentation. CCR5 antagonists, another subgroup of entry inhibitors, will also be discussed further. Although there has been some interest in trying to develop CXCR4 antagonists, there are currently no candidates in late clinical development, so this group will not be addressed in this presentation. Data concerning the integrase inhibitors, raltegravir and elvitegravir, will be explored. Maturation inhibitors, although they are not included in this presentation, are a class with a novel target that may be an option in the future for people who are highly treatment experienced.

69. Bloqueantes de Entrada  Let’s start with the entry inhibitors.Let’s start with the entry inhibitors.

70. Inhibidores de entrada VIH-1 This slide displays the different steps involved in viral entry. This process begins with the binding of HIV gp120 to a CD4+ cell followed by a conformational change that allows the V3 loop of gp120 to interact with the chemokine coreceptors, either CCR5 or CXCR4. A conformational change then occurs that facilitates fusion. The first entry inhibitor to be approved, enfuvirtide, is a fusion inhibitor. In this presentation, I will talk about some of the drugs that have been developed to target both CD4 and CCR5.This slide displays the different steps involved in viral entry. This process begins with the binding of HIV gp120 to a CD4+ cell followed by a conformational change that allows the V3 loop of gp120 to interact with the chemokine coreceptors, either CCR5 or CXCR4. A conformational change then occurs that facilitates fusion. The first entry inhibitor to be approved, enfuvirtide, is a fusion inhibitor. In this presentation, I will talk about some of the drugs that have been developed to target both CD4 and CCR5.

71. Ventajas y Desventajas Potenciales de los Inhibidores de Entrada Ventajas Work early in virus life cycle May function in prevention or postexposure Lack of cross-resistance with existing drug classes Lack of “cellular resistance” Chemokine antagonist entry inhibitors bind cellular targets There are potential advantages and disadvantages of entry inhibitors. Obviously, these drugs work on a very early step in the viral life cycle and thereby have the potential to be used as prevention in certain postexposure settings. Moreover, there should be a lack of cross-resistance with existing drug classes as these drugs interact with different targets. This will be especially beneficial for patients who are resistant to NRTIs, NNRTIs, and PIs because these drugs are expected to be active in these patients. Chemokine antagonist entry inhibitors bind cellular targets rather than viral targets, which may offer some advantages as well. Among the disadvantages of entry inhibitors include the fact that their targets, including gp120, are highly variable, which could be an obstacle to therapy. Inhibition of cellular targets may cause mechanism-related toxicities, and we do not fully understand what the potential implications of this may be. There is potential for the virus to alter coreceptor usage and the implications of this remain unknown, as well. For example, the virus may bypass the CCR5 receptor in patients receiving CCR5 antagonists and start to use the CXCR4 receptor. Lastly, the mode of delivery for some of these drugs may be problematic: TNX-355 is delivered via intravenous infusion and enfuvirtide, an entry inhibitor that is already in use, is administered via subcutaneous injection.There are potential advantages and disadvantages of entry inhibitors. Obviously, these drugs work on a very early step in the viral life cycle and thereby have the potential to be used as prevention in certain postexposure settings. Moreover, there should be a lack of cross-resistance with existing drug classes as these drugs interact with different targets. This will be especially beneficial for patients who are resistant to NRTIs, NNRTIs, and PIs because these drugs are expected to be active in these patients. Chemokine antagonist entry inhibitors bind cellular targets rather than viral targets, which may offer some advantages as well. Among the disadvantages of entry inhibitors include the fact that their targets, including gp120, are highly variable, which could be an obstacle to therapy. Inhibition of cellular targets may cause mechanism-related toxicities, and we do not fully understand what the potential implications of this may be. There is potential for the virus to alter coreceptor usage and the implications of this remain unknown, as well. For example, the virus may bypass the CCR5 receptor in patients receiving CCR5 antagonists and start to use the CXCR4 receptor. Lastly, the mode of delivery for some of these drugs may be problematic: TNX-355 is delivered via intravenous infusion and enfuvirtide, an entry inhibitor that is already in use, is administered via subcutaneous injection.

72. TNX-355 Bloqueante de entrada VIH-1 Activo contra virus CCR5- y CXCR4-tropico vitro[3] The first drug to be discussed is TNX-355, which blocks HIV viral entry. This drug is in the early stages of development. TNX-355 has an interesting mechanism of action as it is a humanized monoclonal antibody and recognizes a unique epitope in the second extra cellular domain of the CD4 receptor. TNX-355 does not compete with the location in which the HIV envelope gp120 binds with the CD4 receptor, but TNX-355 binding results in a conformational change in CD4 that prevents a conformational event that it is necessary for infection to occur. The exact mechanism of action is not completely known. Phase II randomized trial data in triple class–experienced patients demonstrate a 0.5-0.8 log10 copies/mL reduction in HIV-1 RNA for those who received this drug with an optimized background regimen vs those who received an optimized background regimen alone. TNX-355 appears to be active against viruses that use both the CCR5 and CXCR4 chemokine coreceptors.The first drug to be discussed is TNX-355, which blocks HIV viral entry. This drug is in the early stages of development. TNX-355 has an interesting mechanism of action as it is a humanized monoclonal antibody and recognizes a unique epitope in the second extra cellular domain of the CD4 receptor. TNX-355 does not compete with the location in which the HIV envelope gp120 binds with the CD4 receptor, but TNX-355 binding results in a conformational change in CD4 that prevents a conformational event that it is necessary for infection to occur. The exact mechanism of action is not completely known. Phase II randomized trial data in triple class–experienced patients demonstrate a 0.5-0.8 log10 copies/mL reduction in HIV-1 RNA for those who received this drug with an optimized background regimen vs those who received an optimized background regimen alone. TNX-355 appears to be active against viruses that use both the CCR5 and CXCR4 chemokine coreceptors.

73. Antagonistas de Coreceptor  The antiretrovirals furthest along in clinical development include the chemokine coreceptor antagonists. In fact, maraviroc, one of these medications was recently recommended for approval by an advisory committee of the FDA. The antiretrovirals furthest along in clinical development include the chemokine coreceptor antagonists. In fact, maraviroc, one of these medications was recently recommended for approval by an advisory committee of the FDA.

74. Uso de Coreceptor por Variantes VIH-1 This schematic demonstrates the mode of action for HIV via certain chemokine coreceptors. On the far left is X4 virus, which primarily uses the CXCR4 coreceptor. CXCR4 chemokine coreceptors are primarily located on T-cell tumor lines as well as primary lymphocytes in peripheral blood.The R5 virus is located on the far right. These viruses are defined by the use of the CCR5 chemokine coreceptor, which is present on monocytes and macrophages as well as primary lymphocytes. In the middle of the schematic are those viruses designated as X4/R5 dual-tropic viruses that are actually able to use either one of these chemokine coreceptors. The terms syncytium-inducing (SI) and nonsyncytium-inducing (NSI) viruses were used before the identification of chemokines as secondary receptors. Syncytium-inducing viruses were isolated from the blood of patients that demonstrated the ability to induce syncytia in T-cell tumor lines. We now know that this ability correlates highly with the use of the CXCR4 coreceptor. The NSI viruses, on the other hand, are able to infect cells but do not induce syncytia. These viruses are now known to use CCR5. This schematic demonstrates the mode of action for HIV via certain chemokine coreceptors. On the far left is X4 virus, which primarily uses the CXCR4 coreceptor. CXCR4 chemokine coreceptors are primarily located on T-cell tumor lines as well as primary lymphocytes in peripheral blood.The R5 virus is located on the far right. These viruses are defined by the use of the CCR5 chemokine coreceptor, which is present on monocytes and macrophages as well as primary lymphocytes. In the middle of the schematic are those viruses designated as X4/R5 dual-tropic viruses that are actually able to use either one of these chemokine coreceptors. The terms syncytium-inducing (SI) and nonsyncytium-inducing (NSI) viruses were used before the identification of chemokines as secondary receptors. Syncytium-inducing viruses were isolated from the blood of patients that demonstrated the ability to induce syncytia in T-cell tumor lines. We now know that this ability correlates highly with the use of the CXCR4 coreceptor. The NSI viruses, on the other hand, are able to infect cells but do not induce syncytia. These viruses are now known to use CCR5.

75. CCR5 Antagonistas en desarrollo Maraviroc Vicriviroc DSMB, data and safety monitoring board; EFV, efavirenz. There are 2 CCR5 antagonists moving forward in later stages of clinical trials. Phase III data on maraviroc in treatment-experienced patients with the R5 virus have been presented. Limited efficacy has been seen in patients with dual/mixed viruses, and these data will be discussed later in the presentation. There is also a phase III study of maraviroc in treatment-naive patients with R5 virus that is currently under way. The once-daily arm of maraviroc was discontinued due to decreased efficacy in comparison to efavirenz. However, the twice-daily arms of the trial are ongoing. A second CCR5 antagonist in development is vicriviroc. Phase IIb data from studies in treatment-experienced patients with R5 virus have been presented. Phase IIb studies in treatment-naive patients were stopped by the data and safety monitoring board because of decreased efficacy vs efavirenz-based therapy. Although the reason for this has yet to be defined, it may be partly related to dosage and other study design issues. The concerns are being addressed for future studies.DSMB, data and safety monitoring board; EFV, efavirenz. There are 2 CCR5 antagonists moving forward in later stages of clinical trials. Phase III data on maraviroc in treatment-experienced patients with the R5 virus have been presented. Limited efficacy has been seen in patients with dual/mixed viruses, and these data will be discussed later in the presentation. There is also a phase III study of maraviroc in treatment-naive patients with R5 virus that is currently under way. The once-daily arm of maraviroc was discontinued due to decreased efficacy in comparison to efavirenz. However, the twice-daily arms of the trial are ongoing. A second CCR5 antagonist in development is vicriviroc. Phase IIb data from studies in treatment-experienced patients with R5 virus have been presented. Phase IIb studies in treatment-naive patients were stopped by the data and safety monitoring board because of decreased efficacy vs efavirenz-based therapy. Although the reason for this has yet to be defined, it may be partly related to dosage and other study design issues. The concerns are being addressed for future studies.

76. Inhibidores de Integrasa  Now I will talk about the other exciting new class of drug, the integrase inhibitors. Now I will talk about the other exciting new class of drug, the integrase inhibitors.

77. Rol de Integrasa de VIH PIC, preintegration complex. The role of integrase in the viral life cycle is instrumental in the integration of proviral DNA into the host DNA chromosome. The integrase inhibitors currently available are strand-transfer inhibitors. Since integrase is a unique novel target, these drugs will presumably be active against viruses that may be resistant to other classes of drugs.PIC, preintegration complex. The role of integrase in the viral life cycle is instrumental in the integration of proviral DNA into the host DNA chromosome. The integrase inhibitors currently available are strand-transfer inhibitors. Since integrase is a unique novel target, these drugs will presumably be active against viruses that may be resistant to other classes of drugs.

78. Inhibidores de Integrasa Raltegravir Metabolizado por glucoronidación No se espera interacción con CYP450 Dosis BID Elvitegravir Metabolizado por CYP3A4 Interactiones posibles con otras drogas metabolizadas por CYP Requiere ritonavir para PK óptimo Dosis QD cuando se coadministra con ritonavir The 2 integrase inhibitors that are the furthest in clinical trial development are raltegravir (formerly MK-0518) and elvitegravir (formerly GS9137). Currently, phase III trials of raltegravir in treatment-naive and treatment-experienced patients are under way. Elvitegravir is in phase II development for treatment-experienced patients.The 2 integrase inhibitors that are the furthest in clinical trial development are raltegravir (formerly MK-0518) and elvitegravir (formerly GS9137). Currently, phase III trials of raltegravir in treatment-naive and treatment-experienced patients are under way. Elvitegravir is in phase II development for treatment-experienced patients.

79. ¿Cuándo usar estas nuevas clases de drogas ? The question remains: How will we use agents from new classes of drugs? The question remains: How will we use agents from new classes of drugs?

80. ¿Cuándo usar bloqueantes de Entrada? Por ejemplo TNX-355, por tener actividad contra virus X4 y R5: útil en virus resistentes a los agentes usuales, y virus resistentes a otros inhibidores de entrada TNX-355 será indicado por infusión EV; Aún no se definió el esquema de dosificación Este agente es probable sea empleado en pacientes con enfermedad avanzada y virus altamente resistente Se debe considerar su empleo en terapia directamente observada Mas activa en regimenes con = 2 agentes activos IV, intravenously. How might we use TNX-355? It is likely to have activity against both X4 and X5 viruses as well as viruses that are resistant to current agents or resistant to other entry inhibitors. TNX-355 will be given as an intravenous infusion, and the dosing schedule is still being investigated. The use of this drug will certainly be limited to patients with advanced disease and those with a highly resistant virus who need new options. Potential as a directly observed therapy might be of interest. TNX-355 will be most active in those who have other active agents as part of their optimized regimen.IV, intravenously. How might we use TNX-355? It is likely to have activity against both X4 and X5 viruses as well as viruses that are resistant to current agents or resistant to other entry inhibitors. TNX-355 will be given as an intravenous infusion, and the dosing schedule is still being investigated. The use of this drug will certainly be limited to patients with advanced disease and those with a highly resistant virus who need new options. Potential as a directly observed therapy might be of interest. TNX-355 will be most active in those who have other active agents as part of their optimized regimen.

81. ¿Cuándo usar antagonistas de CCR5 ? Su uso inicial para pacientes con terapia previa Virus D/M o X4 son detectables en estadios avanzados de enfermedad y tratamiento. Los pacientes vírgenes es menos posible que tengan virus D/M o X4 No se ha definido aún su eficacia en el tratamiento de pacientes vírgenes Costo para uso general no se ha determinado Mas activo en regimenes con = 2 agentes activos D/M, dual/mixed tropic. Regarding CCR5 antagonists, the initial use will be in treatment-experienced patients. This is the treatment group that has been studied most to date, and one of the CCR5 antagonists, maraviroc, may be approved on the recommendation of the advisory committee by summer 2007. Candidates for therapy will include patients with the advanced stages of disease who are more likely to have detectable, dual/mixed-tropic, or X4 virus. Therefore, these patients are less likely to respond to therapy. Individuals who are treatment naive, on the other hand, are less likely to have a dual/mixed-tropic or X4 viral population, and one could argue that they have a better chance of success with this therapy, although further investigation is needed. The cost and availability of an assay for general use has not been determined. Once this is accomplished, these drugs will be more effective, especially when used with other highly active agents.D/M, dual/mixed tropic. Regarding CCR5 antagonists, the initial use will be in treatment-experienced patients. This is the treatment group that has been studied most to date, and one of the CCR5 antagonists, maraviroc, may be approved on the recommendation of the advisory committee by summer 2007. Candidates for therapy will include patients with the advanced stages of disease who are more likely to have detectable, dual/mixed-tropic, or X4 virus. Therefore, these patients are less likely to respond to therapy. Individuals who are treatment naive, on the other hand, are less likely to have a dual/mixed-tropic or X4 viral population, and one could argue that they have a better chance of success with this therapy, although further investigation is needed. The cost and availability of an assay for general use has not been determined. Once this is accomplished, these drugs will be more effective, especially when used with other highly active agents.

82. Cuándo podemos usar los Inhibidores de Integrasa BID, twice daily; RTV, ritonavir. Integrase inhibitors will initially be used for treatment-experienced patients because the largest data sets involved this population of patients. Studies with treatment-naive individuals are under way. The preliminary data, however, certainly suggest that there may be a role of this class of drugs for treatment-naive patients. Unlike CCR5 antagonists, there appear to be no specific considerations that argue for earlier or later therapy. This class should be effective regardless of when it is used. Dosing issues may affect its use as initial therapy. For example, raltegravir, the drug that is farthest along in clinical development, is now dosed twice daily. Once-daily options are still favored in the earlier stages of disease and throughout treatment. Although elvitegravir is a once-daily drug and can be given with ritonavir, the implications of this must be considered as treatment-naive patients would receive low-dose ritonavir alone without other PIs. We have no experience with this particular situation, and it must be explored in the future. Again, consistent with our principles, the class of drugs will be most active when used in conjunction with other active drugs. Therefore, we need to be strategic when thinking about the introduction of novel drugs into our treatment regimens. It is crucial to save as many active drugs as possible and to combine these with new drugs, hopefully enabling us to achieve full suppression even within our most treatment-experienced patients. This, after all, is the goal that has been put forth in the DHHS and IAS-USA guidelines.BID, twice daily; RTV, ritonavir. Integrase inhibitors will initially be used for treatment-experienced patients because the largest data sets involved this population of patients. Studies with treatment-naive individuals are under way. The preliminary data, however, certainly suggest that there may be a role of this class of drugs for treatment-naive patients. Unlike CCR5 antagonists, there appear to be no specific considerations that argue for earlier or later therapy. This class should be effective regardless of when it is used. Dosing issues may affect its use as initial therapy. For example, raltegravir, the drug that is farthest along in clinical development, is now dosed twice daily. Once-daily options are still favored in the earlier stages of disease and throughout treatment. Although elvitegravir is a once-daily drug and can be given with ritonavir, the implications of this must be considered as treatment-naive patients would receive low-dose ritonavir alone without other PIs. We have no experience with this particular situation, and it must be explored in the future. Again, consistent with our principles, the class of drugs will be most active when used in conjunction with other active drugs. Therefore, we need to be strategic when thinking about the introduction of novel drugs into our treatment regimens. It is crucial to save as many active drugs as possible and to combine these with new drugs, hopefully enabling us to achieve full suppression even within our most treatment-experienced patients. This, after all, is the goal that has been put forth in the DHHS and IAS-USA guidelines.