ANTIRRETROVIRALES EN VIHSIDA: AYER Y HOY

1. ANTIRRETROVIRALES EN VIH/SIDA:AYER Y HOY JAMES W. GUTIERREZ TUDELA, MD, FACP

3. 1981 Descripci�n del primer caso de SIDA 1985-9 El AZT mostr� beneficio a corto plazo, pero no a largo plazo 1989-95 Era del pesimismo terap�utico 1994�6 Combinaciones de Nucle�sidos 1995 Primer IP, saquinavir 1996-9 Era del entusiasmo terap�utico Se estableci� la Terapia antirretroviral de gran actividad (TARGA o HAART, en ingl�s) Otros IP y el primer INNTR Objetivo del tratamiento: virus no detectable Historia de la Terapia Antirretroviral

4. 1998-01 Era del balance terap�utico Ganancias terap�uticas consolidadas Emergen toxicidades y dificultades a corto y largo plazo Necesidad de opciones de tratamiento: Reg�menes inicial y tratamiento de �rescate�. IP reforzados 2002-09 Nuevas f�rmacos: Inhibidores de fusi�n Antagonistas de los co-receptores de quimioquinas (CCR5) Inhibidores de integrasa Historia de la Terapia Antirretroviral

5. OBJETIVOS DEL TRATAMIENTO

6. RIESGOS Y BENEFICIOS DE INICIAR TEMPRANAMENTE LA TERAPIA ANTIRRETROVIRAL Beneficios Control de la replicacion del VIH Prevencion de la disfuncion inmune progresiva Progresion retardada a SIDA Supervivencia prolongada Riesgo disminuido de morbilidad no relacionada al VIH/SIDA (HIVAN, neoplasias malignas , disfunci�n neurocognitiva , enfermedad cardiovascular ) Resistencia Disminuida a las drogas Riesgo disminuido de algunas toxicidades por ARV Transmision disminuida del VIH Riesgos Reducci�n de la calidad de vida Desarrollo temprano de resistencia a las drogas si la adherencia es pobre Limitaci�n en las futuras elecciones de ART si ocurre resistancia a las drogas Toxicidades inciertas a largo tiempo y duracion de la efectividad Posible transmision de resistancia a las drogas

7. Cu�ndo iniciar la TAR? � DHHS Guidelines, 2009 La TAR deber�a iniciarse en todos los pacientes con historia de SIDA o con CD4 < 350 cells/�L. La TAR deber�a iniciarse, sin relaci�n al conteo de CD4 , en la gestaci�n, Nefropat�a asociada al VIH (HIVAN), coinfecci�n con HBV si est� indicado su tratamiento La TAR se recomienda para pacientes con CD4 entre 350-500 cells/�L Para pacientes con CD4 >500 cells/�L, el Panel estuvo dividido: 50% a favor de empezar el ART (B); el otro 50% lo consider� opcional

8. Cu�ndo empezar la TAR? � WHO Guidelines, 2009 Empezar el tratamiento ART en todos los pacientes con VIH que tengan CD4 < 350 cells/�L sin relaci�n a los s�ntomas cl�nicos. Se requiere el examen de CD4 para identificar si los pacientes con VIH y estad�os cl�nicos 1 o 2 de la OMS necesitan empezar el TAR. Iniciar el tratamiento antirretroviral en todos los pacientes con VIH y que est�n en estad�os cl�nicos 3 o 4 de la OMS, sin relaci�n al conteo de CD4.

9. 2009 US DHHS Guidelines: Recommendations for Initiation of ART in Na�ve Patients As stated. Note addition of percent of panel voting for recommendation.As stated. Note addition of percent of panel voting for recommendation.

10. INDICACIONES PARA INICIO DE LA TERAPIA ANTIRRETROVIRAL CATEGORIA CLINICA Y/O RECOMENDACIONES CONTEO DE CD4 -HISTORIA DE ENFERMEDAD QUE DEFINE SIDA INICIAR TERAPIA -CD4<350 CEL/UL -MUJER GESTANTE -NEFROPATIA ASOCIADA AL VIH -COINFECCION CON HBV CUAN- DO EL TRATAMIENTO PARA HBV ESTA INDICADO

11. ANTIRRETROVIRALES ACTUALES (2010) INHIBIDORES NUCLEOSIDOS DE TRANSCRIPTASA REVERSA Abacavir ABC Didanosina ddI Emtricitabina FTC Lamivudina 3TC Estavudina D4T Zidovudina ZDV, AZT Tenofovir TDF INHIBIDORES NO NUCLEOSIDOS DE TRANSCRIPTASA REVERSA Delavirdina DLV Efavirenz EFV Nevirapina NVP Etravirina ETR INHIBIDORES DE PROTEASA Amprenavir APV Atazanavir ATV Darunavir DRV Fosamprenavir FPV Indinavir IDV Lopinavir LPV Nelfinavir NFV Ritonavir RTV Saquinavir SQV Tipranavir TPV INHIBIDORES DE FUSION Enfuvirtida ENF, T-20 ANTAGONISTAS CCR5 Maraviroc MVC INHIBIDORES DE INTEGRASA Raltegravir RAL

12. AGENTES ANTIRRETROVIRALES 2010 CO-FORMULACIONES DE INTR Y DE ESTOS CON INNTR Zidovudina + Lamivudina (Combivir) Zidovudina + Lamivudina + Abacavir (Trizivir) Lamivudina + Abacavir (Epzicom) Tenofovir + Emtricitabina (Truvada) Tenofovir + Emtricitabina + Efavirenz (Atripla)

13. AGENTES ANTIRRETROVIRALES 2010 CO-FORMULACIONES DE INTR Y DE ESTOS CON INNTR Zidovudina + Lamivudina (Duovir) Zidovudina + Lamivudina + Nevirapina (Duovir-N) Lamivudina + Estavudina + Nevirapina (Triomune)

15. What drug regimens to start � DHHS 2009 DHHS Guidelines for Adults and Adolescents

16. CON QUE REGIMENES EMPEZAR?  WHO 2009 _AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC o FTC + EFV TDF + 3TC o FTC +, NVP

17. TRATAMIENTO INICIAL: Componentes preferidos *Evitar en gestaci�n (1er trimestre) y en mujeres con alto potencial de embarazo Three NNRTIs (namely, delavirdine, efavirenz, and nevirapine) are currently marketed for use. NNRTI-based regimens are commonly prescribed as initial therapy for treatment-na�ve patients. In general, these regimens have the advantage of lower pill burden as compared to most of the PI-based regimens. Use of NNRTI-based regimens as initial therapy can preserve the PIs for later use, reducing or delaying patient exposure to some of the adverse effects more commonly associated with PIs. The major disadvantage of currently available NNRTIs is their low genetic barrier for development of resistance. These agents only require a single mutation to confer resistance, and cross resistance often develops across the entire class. As a result, patients who fail this initial regimen may lose the utility of other NNRTIs and/or may transmit NNRTI-resistant virus to others. Based on clinical trial results and safety data, the Panel recommends the use of efavirenz as the preferred NNRTI as part of initial antiretroviral therapy (AII). The exception is during pregnancy (especially during the first trimester) or in women who are planning to conceive or women who are not using effective and consistent contraception. Nevirapine may be used as an alternative to efavirenz as the initial NNRTI-based regimen.(BII) Close monitoring of liver enzymes and skin rash should be undertaken during the first 18 weeks of nevirapine therapy, particularly, in female patients with CD4+ T-cell count >250 cells/mm3 prior to therapy initiation. Among these three agents, delavirdine appears to have the least potent antiviral activity. As such, it is not recommended as part of an initial regimen. (DII) PI-based regimens (1or 2 PIs + 2 NRTIs) revolutionized the treatment of HIV infection, leading to sustained viral suppression, improved immunologic function, and prolonged patient survival. Since their inception in the mid-1990s, much has been learned about their efficacy as well as some short term and long term adverse effects. To date, eight PIs have been approved for use in the United States. Each agent has its own unique characteristics based on its clinical efficacy, adverse effect profile, and pharmacokinetic properties. The characteristics, advantages, and disadvantages of each PI can be found in Tables 6 & 12. In selecting a PI-based regimen for a treatment-na�ve patient, factors such as dosing frequency, food and fluid requirements, pill burden, drug interaction potential, baseline hepatic function, and toxicity profile should be taken into consideration. A number of metabolic abnormalities, including dyslipidemia, fat maldistribution, and insulin resistance, have been associated with PI use. The eight PIs differ in their propensity to cause these metabolic complications. At this time, the extent to which these complications may result in adverse long term consequences, such as increased cardiac events in chronically-infected patients, is unknown. The potent inhibitory effect of ritonavir on the cytochrome P450 3A4 isoenzyme has allowed the addition of low dose ritonavir to other PIs as a �pharmacokinetic booster� to increase drug exposure and prolong serum half-lives of the active PIs. This allows for reduced dosing frequency and pill burden, and in the case of indinavir, the addition of low dose ritonavir eliminates the need for food restrictions. All these advantages may improve overall adherence to the regimen. The increased trough concentration (Cmin) may improve the antiretroviral activity of the active PIs, which is most beneficial in cases where the patient harbors HIV-1 strains with reduced susceptibility to the PI [61-63]. The major drawbacks associated with this strategy are the potential for increased risk of hyperlipidemia and a greater potential of drug-drug interactions from the addition of ritonavir. The Panel considers lopinavir/ritonavir as the preferred PI for the treatment-naive patient (AII). Discussed below, this recommendation is based on clinical trial data for virologic potency, barrier for virologic resistance, and patient tolerance. However, there are limited data on the comparative efficacy of lopinavir/ritonavir with other ritonavir-boosted regimens. Alternative PIs are listed in Table 5 and discussed below in greater detail and may include atazanavir (BII), fosamprenavir (BII), or nelfinavir (CII) as sole PI, or ritonavir-boosted fosamprenavir (BII), indinavir (BII), or saquinavir (BII). Three NNRTIs (namely, delavirdine, efavirenz, and nevirapine) are currently marketed for use. NNRTI-based regimens are commonly prescribed as initial therapy for treatment-na�ve patients. In general, these regimens have the advantage of lower pill burden as compared to most of the PI-based regimens. Use of NNRTI-based regimens as initial therapy can preserve the PIs for later use, reducing or delaying patient exposure to some of the adverse effects more commonly associated with PIs. The major disadvantage of currently available NNRTIs is their low genetic barrier for development of resistance. These agents only require a single mutation to confer resistance, and cross resistance often develops across the entire class. As a result, patients who fail this initial regimen may lose the utility of other NNRTIs and/or may transmit NNRTI-resistant virus to others. Based on clinical trial results and safety data, the Panel recommends the use of efavirenz as the preferred NNRTI as part of initial antiretroviral therapy (AII). The exception is during pregnancy (especially during the first trimester) or in women who are planning to conceive or women who are not using effective and consistent contraception. Nevirapine may be used as an alternative to efavirenz as the initial NNRTI-based regimen.(BII) Close monitoring of liver enzymes and skin rash should be undertaken during the first 18 weeks of nevirapine therapy, particularly, in female patients with CD4+ T-cell count >250 cells/mm3 prior to therapy initiation. Among these three agents, delavirdine appears to have the least potent antiviral activity. As such, it is not recommended as part of an initial regimen. (DII) PI-based regimens (1or 2 PIs + 2 NRTIs) revolutionized the treatment of HIV infection, leading to sustained viral suppression, improved immunologic function, and prolonged patient survival. Since their inception in the mid-1990s, much has been learned about their efficacy as well as some short term and long term adverse effects. To date, eight PIs have been approved for use in the United States. Each agent has its own unique characteristics based on its clinical efficacy, adverse effect profile, and pharmacokinetic properties. The characteristics, advantages, and disadvantages of each PI can be found in Tables 6 & 12. In selecting a PI-based regimen for a treatment-na�ve patient, factors such as dosing frequency, food and fluid requirements, pill burden, drug interaction potential, baseline hepatic function, and toxicity profile should be taken into consideration. A number of metabolic abnormalities, including dyslipidemia, fat maldistribution, and insulin resistance, have been associated with PI use. The eight PIs differ in their propensity to cause these metabolic complications. At this time, the extent to which these complications may result in adverse long term consequences, such as increased cardiac events in chronically-infected patients, is unknown. The potent inhibitory effect of ritonavir on the cytochrome P450 3A4 isoenzyme has allowed the addition of low dose ritonavir to other PIs as a �pharmacokinetic booster� to increase drug exposure and prolong serum half-lives of the active PIs. This allows for reduced dosing frequency and pill burden, and in the case of indinavir, the addition of low dose ritonavir eliminates the need for food restrictions. All these advantages may improve overall adherence to the regimen. The increased trough concentration (Cmin) may improve the antiretroviral activity of the active PIs, which is most beneficial in cases where the patient harbors HIV-1 strains with reduced susceptibility to the PI [61-63]. The major drawbacks associated with this strategy are the potential for increased risk of hyperlipidemia and a greater potential of drug-drug interactions from the addition of ritonavir. The Panel considers lopinavir/ritonavir as the preferred PI for the treatment-naive patient (AII). Discussed below, this recommendation is based on clinical trial data for virologic potency, barrier for virologic resistance, and patient tolerance. However, there are limited data on the comparative efficacy of lopinavir/ritonavir with other ritonavir-boosted regimens. Alternative PIs are listed in Table 5 and discussed below in greater detail and may include atazanavir (BII), fosamprenavir (BII), or nelfinavir (CII) as sole PI, or ritonavir-boosted fosamprenavir (BII), indinavir (BII), or saquinavir (BII).

18. Tratamiento Inicial : Componentes Alternativos (1) **Debido al grado de hepatoxicidad, nevirapina no deber�a iniciarse en mujeres con CD4 >250cel/mm3 o en hombres con CD4 >400 cel/mm3. Symptomatic, serious, and even fatal hepatic events associated with nevirapine use have been observed in clinical trials and post-marketing reports. These events generally occur within the first few weeks of treatment. In addition to elevated serum transaminases, approximately half of the patients also develop skin rash, with or without fever or flu-like symptoms. Women with higher CD4+ T cell counts appear to be at highest risk. In a recent analysis, a 12-fold higher incidence of symptomatic hepatic events was seen in women (including pregnant women) with CD4+ T cell counts of >250 cells/mm3 at the time of nevirapine initiation when compared to women with CD4+ T cell counts <250 cells/mm3 (11.0% vs. 0.9%). An increased risk was also seen in men with pre-nevirapine CD4+ T cell counts >400 cells/mm3 when compared to men with pre-nevirapine CD4+ T cell counts <400 cells/mm3 (6.3% vs. 1.2%). Most of these patients had no identifiable underlying hepatic abnormalities. In some cases, hepatic injuries continued to progress despite discontinuation of nevirapine [59, 60]. Symptomatic hepatic events have not been reported with single doses of nevirapine given to mothers or infants for prevention of perinatal HIV infection. Based on the safety data described, the Panel recommends that nevirapine may be used as an alternative to efavirenz in adult female patients with pre-treatment CD4+ T cell counts <250 cells/mm3 or adult male patients with CD4+ T cell counts <400 cells/mm3. (BII) In female patients with CD4+ T cell counts >250 cells/mm3 or male patients with CD4+ T cell counts >400 cells/mm3, nevirapine should not be initiated unless the benefit clearly outweighs the risk. (DI) When starting nevirapine, a 14-day lead-in period at a dose of 200mg once daily should be prescribed before increasing to the maintenance dose of 200mg twice daily. Serum transaminases should be obtained at baseline, prior to and two weeks after dose escalation, then monthly for the first 18 weeks. Clinical and laboratory parameters should be assessed at each visit. More detailed recommendations on the management of nevirapine-associated hepatic events can be found in Table 16a. Symptomatic, serious, and even fatal hepatic events associated with nevirapine use have been observed in clinical trials and post-marketing reports. These events generally occur within the first few weeks of treatment. In addition to elevated serum transaminases, approximately half of the patients also develop skin rash, with or without fever or flu-like symptoms. Women with higher CD4+ T cell counts appear to be at highest risk. In a recent analysis, a 12-fold higher incidence of symptomatic hepatic events was seen in women (including pregnant women) with CD4+ T cell counts of >250 cells/mm3 at the time of nevirapine initiation when compared to women with CD4+ T cell counts <250 cells/mm3 (11.0% vs. 0.9%). An increased risk was also seen in men with pre-nevirapine CD4+ T cell counts >400 cells/mm3 when compared to men with pre-nevirapine CD4+ T cell counts <400 cells/mm3 (6.3% vs. 1.2%). Most of these patients had no identifiable underlying hepatic abnormalities. In some cases, hepatic injuries continued to progress despite discontinuation of nevirapine [59, 60]. Symptomatic hepatic events have not been reported with single doses of nevirapine given to mothers or infants for prevention of perinatal HIV infection. Based on the safety data described, the Panel recommends that nevirapine may be used as an alternative to efavirenz in adult female patients with pre-treatment CD4+ T cell counts <250 cells/mm3 or adult male patients with CD4+ T cell counts <400 cells/mm3. (BII) In female patients with CD4+ T cell counts >250 cells/mm3 or male patients with CD4+ T cell counts >400 cells/mm3, nevirapine should not be initiated unless the benefit clearly outweighs the risk. (DI) When starting nevirapine, a 14-day lead-in period at a dose of 200mg once daily should be prescribed before increasing to the maintenance dose of 200mg twice daily. Serum transaminases should be obtained at baseline, prior to and two weeks after dose escalation, then monthly for the first 18 weeks. Clinical and laboratory parameters should be assessed at each visit. More detailed recommendations on the management of nevirapine-associated hepatic events can be found in Table 16a.

19. Tratamiento Inicial : Componentes Aceptables

20. Selecci�n de la combinaci�n dual de INTR Preferido: Tenofovir + emtricitabina (coformulado) Alternativos: Abacavir + lamivudina (coformulado) Zidovudina + lamivudina (coformulado) Aceptables: Didanosina + lamivudina Didanosina + emtricitabina

21. Reg�menes antirretrovirales a base de INTR Reg�menes antirretrovirales no recomendados: Abacavir/zidovudina/lamivudina (coformulado) Zidovudina/lamivudina + Tenofovir Zidovudina + lamivudina + abacavir + tenofovir Antiretroviral Regimens Not Recommended Monotherapy (EII). Single antiretroviral drug therapy does not demonstrate potent and sustained antiviral activity and should not be used. The rare exception, though controversial, is the use of zidovudine monotherapy to prevent perinatal HIV-1 transmission in a woman who does not meet clinical, immunologic, or virologic criteria for initiation of therapy and who has an HIV RNA <1,000 copies/mL [96, 97] (DIII). Most clinicians, however, prefer to use a combination regimen in the pregnant woman for the management of both the mother�s HIV infection and in the prevention of perinatal transmission. Dual nucleoside regimens (DII). These regimens are not recommended because they have not demonstrated potent and sustained antiviral activity as compared to three-drug combination regimens [98]. For patients previously initiated on this treatment who have achieved sustained viral suppression, it is reasonable to continue on this therapy or to add a PI or NNRTI to this regimen (DIII). If the patient is to stay on a 2-NRTI regimen, the plan should be to change to a three or more drug combination if viral rebound occurs. (See Managing the Treatment Experienced Patient: Assessment of Antiretroviral Treatment Failure and Changing Therapy.) 3-NRTI regimen of abacavir + tenofovir + lamivudine (EII). In a randomized trial for treatment na�ve patients, those randomized to a regimen consisting of abacavir + tenofovir + lamivudine had a significantly higher rate of �early virologic nonresponse� when compared to patients treated with efavirenz + abacavir + lamivudine [55]. This combination should not be used as a 3-NRTI regimen in any patient. 3-NRTI regimen of didanosine + tenofovir + lamivudine (EII). In a small pilot study, a high rate (91%) of virologic failure (defined as <2 log reduction of HIV-RNA by week 12) was seen in treatment-na�ve patients initiated on this 3-NRTI regimen [84]. This combination should not be used as a 3-NRTI regimen in any patient. The Panel DOES NOT RECOMMEND the use of the following 3-NRTI regimens as sole antiretroviral combination at any time: � abacavir + tenofovir + lamivudine (EII) � didanosine + tenofovir + lamivudine (EII) The Panel recommends that a regimen containing �tenofovir + didanosine + NNRTI� should not be used as an initial regimen in antiretroviral treatment na�ve patients. This recommendation is based on results from several small observational studies and pilot clinical trials showing a high rate of early virologic failure in treatment-na�ve patients who received this combination as their initial regimen. Emergence of resistant mutations to NNRTIs and to tenofovir and/or didanosine (K65R or L74V mutations) was frequently seen in patients who failed to respond to this combination [1-4]. Of note, patients with high baseline HIV-RNA (> 100,000 copies/mL) and low CD4+ T-cell counts (< 200 cells/mm3) were particularly at risk of early virologic failure. There are not enough data for the combination of tenofovir/didanosine with protease inhibitor in treatment-na�ve patients to assess virologic responses of this regimen, thus, there is no recommendation for or against the use of this combination at this time. Antiretroviral Regimens Not Recommended Monotherapy (EII). Single antiretroviral drug therapy does not demonstrate potent and sustained antiviral activity and should not be used. The rare exception, though controversial, is the use of zidovudine monotherapy to prevent perinatal HIV-1 transmission in a woman who does not meet clinical, immunologic, or virologic criteria for initiation of therapy and who has an HIV RNA <1,000 copies/mL [96, 97] (DIII). Most clinicians, however, prefer to use a combination regimen in the pregnant woman for the management of both the mother�s HIV infection and in the prevention of perinatal transmission. Dual nucleoside regimens (DII). These regimens are not recommended because they have not demonstrated potent and sustained antiviral activity as compared to three-drug combination regimens [98]. For patients previously initiated on this treatment who have achieved sustained viral suppression, it is reasonable to continue on this therapy or to add a PI or NNRTI to this regimen (DIII). If the patient is to stay on a 2-NRTI regimen, the plan should be to change to a three or more drug combination if viral rebound occurs. (See Managing the Treatment Experienced Patient: Assessment of Antiretroviral Treatment Failure and Changing Therapy.) 3-NRTI regimen of abacavir + tenofovir + lamivudine (EII). In a randomized trial for treatment na�ve patients, those randomized to a regimen consisting of abacavir + tenofovir + lamivudine had a significantly higher rate of �early virologic nonresponse� when compared to patients treated with efavirenz + abacavir + lamivudine [55]. This combination should not be used as a 3-NRTI regimen in any patient. 3-NRTI regimen of didanosine + tenofovir + lamivudine (EII). In a small pilot study, a high rate (91%) of virologic failure (defined as <2 log reduction of HIV-RNA by week 12) was seen in treatment-na�ve patients initiated on this 3-NRTI regimen [84]. This combination should not be used as a 3-NRTI regimen in any patient. The Panel DOES NOT RECOMMEND the use of the following 3-NRTI regimens as sole antiretroviral combination at any time: � abacavir + tenofovir + lamivudine (EII) � didanosine + tenofovir + lamivudine (EII) The Panel recommends that a regimen containing �tenofovir + didanosine + NNRTI� should not be used as an initial regimen in antiretroviral treatment na�ve patients. This recommendation is based on results from several small observational studies and pilot clinical trials showing a high rate of early virologic failure in treatment-na�ve patients who received this combination as their initial regimen. Emergence of resistant mutations to NNRTIs and to tenofovir and/or didanosine (K65R or L74V mutations) was frequently seen in patients who failed to respond to this combination [1-4]. Of note, patients with high baseline HIV-RNA (> 100,000 copies/mL) and low CD4+ T-cell counts (< 200 cells/mm3) were particularly at risk of early virologic failure. There are not enough data for the combination of tenofovir/didanosine with protease inhibitor in treatment-na�ve patients to assess virologic responses of this regimen, thus, there is no recommendation for or against the use of this combination at this time.

22. Ventajas y esventajas de Componentes Antirretrovirales en Terapia Inicial: INNTR VENTAJAS Larga vida media Menos toxicidad metab�lica (dislipidemia y resistencia a la insulina) que con reg�menes basados en IP Se preservan opciones de IP y RAL para uso futuro DESVENTAJAS Baja barrera gen�tica a la resistancia - mutaci�n �nica Resistancia cruzada entre la mayor parte de INNTR Rash; hepatotoxicidad Potenciales interacciones con drogas (CYP450)

23. Ventajas y desventajas de Componentes Antirretrovirales en Terapia Inicial : IP VENTAJAS Barrera gen�tica m�s alta a la resistencia La resistencia es rara con falla (IP reforzado) Se preservan opciones de INNTR para uso futuro DESVENTAJAS Complicaciones Metab�licas (maldistribution grasa, dislipidemia, resistancia a la insulina) Intolerancia gastrointestinal, M�s grande potencial para interacciones con drogas (CYP3A4), especialmente con el ritonavir

24. Ventajas y desventajas de Componentes Antirretrovirales en Terapia Inicial : I IN VENTAJAS Respuesta virol�gica no inferior a EFV Menos eventos adversos y cambios lip�dicos que el EFV Menos interacciones que IP o INNTR DESVENTAJAS Menos experiencia en pacientes na�ve que los IP reforzados o INNTR Mas baja barrera gen�tica a la resistencia que los IP reforzados

25. Componentes Antirretrovirales en Terapia Inicial : INTR dual VENTAJAS Columna vertebral de la terapia de combinaci�n Interacciones m�nimas con otros f�rmacos DESVENTAJAS Acidosis l�ctica y esteatosis hep�tica reportada con la mayor parte de INTR (d4T>ddI=ZDV>TDF=ABC+3TC+FTC)

26. SMART: Non-AIDS Event Rates with Continuous vs Deferred/Intermittent ART Significantly more individuals in DC arm developed major CV, renal, or hepatic disease than those in VS arm Significantly more individuals in DC arm experienced grade 4 event or death from any cause than individuals in VS arm

27. START Design Schematic

28. 28 Estimated Hazard Ratios for AIDS or Death Comparison of starting ART in a higher CD4 range versus deferring to a lower CD4 range

29. Initial ART Regimens in START

31. Reg�menes de tratamiento antirretroviral en el Centro M�dico Naval �CMST� (2006) Dos INTR + un IP 1. ZDV + 3TC + IDV 2. ZDV + 3TC + NFV 3. d4T + ddI + NFV Dos INTR + un INNTR 1. d4T + ddI + EFV 2. ZDV + 3TC + EFV Dos INTR + Dos IP 1. d4T + ddI + LPV/r 2. ddI + 3TC + LPV/r

32. Comparaci�n de la eficacia de IDV, NFV y EFV en el Centro M�dico Naval �CMST� (2006) La combinaci�n dual de INTR fueron ZDV + 3TC (60%) y ddI +d4T (40%) El porcentaje de pacientes con RNA-VIH < 400 copias/ml a las 48 semanas fueron: 36% para IDV, 31% para NFV y 54% para EFV El incremento de CD4 sobre la media a las 48 semanas fue de +62 para IDV, +48 para NFV y +83 para EFV.

33. Efectos Adversos : INTR TODOS LOS INTR: Acidosis l�ctica y esteatosis hep�tica (m�s alta incidencia con estavudina) Lipodistrofia (m�s alta incidencia con estavudina) The combined use of didanosine and stavudine as a 2-NRTI backbone can result in a high incidence of toxicities, particularly peripheral neuropathy, pancreatitis, and lactic acidosis [50, 87, 99].This combination has been implicated in several deaths in HIV-1 infected pregnant women secondary to severe lactic acidosis with or without hepatic steatosis and pancreatitis [100]. In general, a combination containing didanosine and stavudine should be avoided unless other 2-NRTI combinations have failed or have caused unacceptable toxicities, and where potential benefits outweigh the risks of toxicities (DIII). The combined use of didanosine and stavudine as a 2-NRTI backbone can result in a high incidence of toxicities, particularly peripheral neuropathy, pancreatitis, and lactic acidosis [50, 87, 99].This combination has been implicated in several deaths in HIV-1 infected pregnant women secondary to severe lactic acidosis with or without hepatic steatosis and pancreatitis [100]. In general, a combination containing didanosine and stavudine should be avoided unless other 2-NRTI combinations have failed or have caused unacceptable toxicities, and where potential benefits outweigh the risks of toxicities (DIII).

34. Efectos Adversos : INTR Abacavir -Reacci�n de hipersensibilidad (HSR) -Rash -Aumento de riesgo de IMA Didanosina* -Intolerancia GI -Pancreatitis -Neuropat�a perif�rica Estavudina* -Neuropat�a perif�rica -Pancreatitis

35. Efectos Adversos : INTR Tenofovir Cefalea Intolerancia GI Insuficiencia renal Zidovudina -Cefalea -Intolerancia GI -Supresi�n de m�dula �sea

36. Efectos Adversos : INNTR Todos los lNNTR: Rash Interacciones medicamentosas Nevirapina �Rash incluyendo S�ndrome de Stevens-Johnson --Hepatotoxicidad (puede ser severa y fatal; riesgo m�s alto en pacientes con mayor conteo de CD4 cuando inician NVP) Efavirenz �Trastornos neuropsiqui�tricos, teratog�nico en primates (Categor�a D del FDA en embarazo) Nevirapine: Symptomatic hepatic events (accompanied by rash in approximately 50% of cases) occur in significantly higher frequency in female patients with pre-nevirapine CD4+ T lymphocyte count > 250 cells/mm3 or in male patients with pre-nevirapine CD4+ T lymphocyte count > 400 cells/mm3. nevirapine may be used as an alternative NNRTI in adult female patients with pre-treatment CD4+ T cell counts <250 cells/mm3 or adult male patients with CD4+ T cell counts <400 cells/mm3. (BII) In female patients with CD4+ T cell counts >250 cells/mm3 or male patients with CD4+ T cell counts >400 cells/mm3, nevirapine should not be initiated unless the benefit clearly outweighs the risk. (DI) When starting nevirapine, a 14-day lead-in period at a dose of 200mg once daily should be prescribed before increasing to the maintenance dose of 200mg twice daily. Serum transaminases should be obtained at baseline, prior to and two weeks after dose escalation, then monthly for the first 18 weeks. Clinical and laboratory parameters should be assessed at each visit. More detailed recommendations on the management of nevirapine-associated hepatic events can be found in Table 16a. Nevirapine: Symptomatic hepatic events (accompanied by rash in approximately 50% of cases) occur in significantly higher frequency in female patients with pre-nevirapine CD4+ T lymphocyte count > 250 cells/mm3 or in male patients with pre-nevirapine CD4+ T lymphocyte count > 400 cells/mm3. nevirapine may be used as an alternative NNRTI in adult female patients with pre-treatment CD4+ T cell counts <250 cells/mm3 or adult male patients with CD4+ T cell counts <400 cells/mm3. (BII) In female patients with CD4+ T cell counts >250 cells/mm3 or male patients with CD4+ T cell counts >400 cells/mm3, nevirapine should not be initiated unless the benefit clearly outweighs the risk. (DI) When starting nevirapine, a 14-day lead-in period at a dose of 200mg once daily should be prescribed before increasing to the maintenance dose of 200mg twice daily. Serum transaminases should be obtained at baseline, prior to and two weeks after dose escalation, then monthly for the first 18 weeks. Clinical and laboratory parameters should be assessed at each visit. More detailed recommendations on the management of nevirapine-associated hepatic events can be found in Table 16a.

37. Efectos adversos: IP Todos los IP: Hiperlipidemia Resistencia a la insulina y diabetes mellitus Lipodistrofia Hepatotoxicidad Aumento de hemorragias en hemof�licos Interacciones medicamentosas

38. Efectos Adversos : IP Atazanavir - Hiperbilirrubinemia -Prolongaci�n del intervalo PR Darunavir -Rash -Hepatotoxicidad Fosamprenavir -Intolerancia GI -Rash Indinavir -Nefrolitiasis -Intolerancia GI

39. Efectos Adversos : IP Lopinavir/ritonavir �Intolerancia GI Nelfinavir -Diarrea Ritonavir �Intolerancia GI -Hepatitis Saquinavir -Intolerancia gastrointestinal Tipranavir � Intolerance GI - Rash -Hiperlipidemia -Toxicidad hep�tica -Casos de hemorragia intracraneal

40. Efectos Adversos : Inhibidores de Fusi�n Enfuvirtida -Reacciones en el sitio de la inyecci�n -Reacci�n de hipersensibilidad -Riesgo incrementado de neumon�a bacteriana

41. Efectos adversos: Antagonistas de CCR5 Maraviroc Interacciones farmacol�gicas Dolor abdominal Infecciones del tracto respiratorio superior Tos Hepatoxicidad S�ntomas musculoesquel�ticos Rash Hipotensi�n ortost�tica

42. Efectos adversos: Inhibidores de integrasa Raltegravir Nausea Cefalea Diarrea Elevaci�n de CPK

43. Complicaciones Metab�licas - Hiperlipidemia: -Hipercolesterolemia y/o - Hipertrigliceridemia -Resistancia a la Insulina: -Hiperglicemia -Hiperinsulinemia y/o -Diabetes mellitus -Lipodistrofia: -Redistribuci�n grasa -Lipoatrofia

45. PROFILAXIS POST-EXPOSICION (PrEP) En PrEP, un sujeto no infectado por el VIH toma medicaci�n antirretroviral diariamente Al tener estas medicaciones en su torrente circulatorio y tracto genital, el VIH puede ser incapaz de establecer una infecci�n.

46. = FTC/TDF (co-formulado emtricitabine + tenofovir) Truvada

47. 6 efficacy studies, up to 13 countries 20,000+ participants

48. Status of ongoing phase II and phase III trials of oral antiretrovirals for HIV prevention

49. The iPrEx Study High Risk MSM Randomized 1:1 Daily Oral PREP FTC/TDF vs Placebo Followed on Drug for: HIV seroconversion Adverse Events (especially renal & liver) Metabolic Effects (Bone, Fat, Lipids) HBV Flares among HBsAg+ Risk Behavior & STIs Adherence If infected Drug Resistance Viral load Immune responses & CD4 Count

51. Darunavir/Ritonavir in First Line Therapy DRV/r vs LPV/r + TDF/FTC in treatment-na�ve pts stratified by HIV-RNA and CD4 count (N=689 randomized 1:1) DRV/r virologic response both non-inferior and superior to LPV/r Lipid and GI adverse events less with DRV/r

52. ATV/r vs. EFVPrimary Virologic Endpoint

53. ATV/r vs. EFVPrimary Safety Endpoint Safety: Overall: EFV vs. ATV/r with ABC/3TC- 40 and 37% EFV vs. ATV/r with TDF/FTC- 31 and 30% EFV with ABC/3TC more cholesterol events EFV more CNS events Safety: Overall: EFV vs. ATV/r with ABC/3TC- 40 and 37% EFV vs. ATV/r with TDF/FTC- 31 and 30% EFV with ABC/3TC more cholesterol events EFV more CNS events

54. ATV/r vs. EFVPrimary Tolerability Endpoint Tolerability: Overall EFV vs. ATV/r with ABC/3TC- 40 and 31% EFV vs. ATV/r with TDF/FTC- 31 and 27% More VF, CNS and rash/hsr/allergic reactions with EFV More non-compliance with meds/visits and jaundice with ATV/rTolerability: Overall EFV vs. ATV/r with ABC/3TC- 40 and 31% EFV vs. ATV/r with TDF/FTC- 31 and 27% More VF, CNS and rash/hsr/allergic reactions with EFV More non-compliance with meds/visits and jaundice with ATV/r

55. 17th Conference on Retroviruses and Opportunistic Infections (CROI)

56. Raltegravir in First Line Therapy RAL vs EFV + TDF/FTC had similar antiviral activity sustained for 96 weeks (N=198 randomized 2:1) Drug-related adverse events were generally less in RAL-treated patients compared to EFV-treated patients

57. Week 192 Outcomes with Raltegravir vs Efavirenz (with Tenofovir + FTC)

58. Week 192 Outcomes with Raltegravir vs Efavirenz (with Tenofovir + FTC)

59. Week 192 Outcomes with Raltegravir vs Efavirenz (with Tenofovir + FTC)

60. Week 192 Outcomes with Raltegravir vs Efavirenz (with Tenofovir + FTC)