1 Prevención y predicción del riesgo cardiovascular en pacientes VIH+Mercedes Manzano García Ramón Morillo Verdugo 28-Enero-2016 Priscilla Y. Hsue, MD: The title of today’s presentation is Cardiovascular Disease in HIV-Infected Patients: Predict It and Prevent It. ©2012 Clinical Care Options, LLC. All rights reserved 1

2 Objetivos Epidemiología de la enfermedad cardiovascular en el contexto del VIH El seguimiento y la evaluación del riesgo de ECV en pacientes VIH+ Papel de los antirretrovirales en el RCV El papel de las estatinas en pacientes VIH+ con riesgo de ECV Papel del farmacéutico ART, antiretroviral therapy; CVD, cardiovascular disease. Priscilla Y. Hsue, MD: I will provide an overview of today’s presentation. We’ll first start with discussing the epidemiology of cardiovascular disease in the setting of HIV infection. We’ll next then move on to assessing cardiovascular disease risks among HIV-infected individuals. Next, understanding markers pertaining to increased cardiovascular risk, and then finally selecting antiretroviral therapy among HIV-infected individuals with elevated cardiovascular disease risk. ©2012 Clinical Care Options, LLC. All rights reserved 2

3 Epidemiología de la enfermedad cardiovascular en el contexto del VIHCVD, cardiovascular disease. Priscilla Y. Hsue, MD: So now let’s move on to the epidemiology of cardiovascular disease in the setting of HIV infection. ©2012 Clinical Care Options, LLC. All rights reserved 3

4 Las tasas de ECV son superiores en pacientes VIH+VIH asociado con un 50% más de riesgo IM después del ajuste de los factores de riesgo tradicionales El aumento del riesgo se mantuvo entre las personas con VIH+ bien tratadas El impacto del VIH sobre el RCV es comparable a los factores de riesgo tradicionales como la HT, DM, y la hiperlipidemia Los factores relacionados con la ECV en el paciente VIH+ incluyen una combinación de factores: entre ellos una mayor prevalencia de riesgos tradicionales (por ejemplo, el tabaquismo) y no tradicionales (por ejemplo, el estrés), los efectos del TAR y el propio VIH ART, antiretroviral therapy; CVD, cardiovascular disease; DM, diabetes mellitus; HTN, hypertension; MI, myocardial infarction. Priscilla Y. Hsue, MD: We know from Freiberg and colleagues’ study with the Veterans’ Affairs Cohort that HIV infection is associated with a 50% increased risk for acute myocardial infarction even after adjustment for traditional risk factors. This increased risk remained even among those with HIV who were well treated and suppressed. And, interestingly, the impact of HIV on cardiovascular risk was comparable to very strong traditional risk factors, including hypertension, diabetes, and hyperlipidemia. And, in fact, mechanistic drivers of cardiovascular disease in HIV may include a combination of traditional risk factors, including smoking, along with nontraditional factors, including antiretroviral therapy, chronic inflammation, and HIV infection itself, along with antiretroviral therapy. Freiberg MS, et al. JAMA Internal Medicine. 2013;173:   ©2012 Clinical Care Options, LLC. All rights reserved 4

5 El vínculo entre el VIH y las enfermedades cardiovascularesTasa de IAM superior en pacientes VIH+ [1] Infección por el VIH es un factor de riesgo para el accidente cerebrovascular isquémico [2] Los hombres infectados por el VIH tienen una mayor prevalencia de placa en las arterias coronarias[1,3] Pacientes VIH+ 100 Pacientes VIH- 80 1000 Personas/año IAM por 60 CVD, cardiovascular disease; MI, myocardial infarction; PY, person-years. Priscilla Y. Hsue, MD: On this slide, we discuss a link between HIV and cardiovascular disease. This is a study looking at patients with myocardial infarction treated in the Boston healthcare system showing that rates of acute myocardial infarction were higher in HIV-infected individuals. And you can see here on this diagram that this increased risk of HIV patients compared to uninfected patients, this higher risk was present at different age brackets, including patients who were very young. Other studies have shown that HIV is a risk factor of ischemic stroke. And using different imaging modalities, investigators have shown that HIV-infected men have a higher prevalence of coronary artery plaque. 40 20 18-34 35-44 45-54 55-64 65-74 Edad (años) 1. Triant VA, et al. J Clin Endocrinol Metab. 2007;92: Chow FC, et al. J Acquir Immune Defic Syndr. 2012;60: Post WS, et al. Ann Intern Med. 2014;160: ©2012 Clinical Care Options, LLC. All rights reserved 5

6 ECV Y MORTALIDAD EN VIH Segunda causa de muerte no VIH en US (~ 15%)[1] y tercera en Europa (~ 8%)[2] Las muertes por ECV oscilan entre el 6% y el 15% en diferentes cohortes[1-4] Las muertes relacionadas con el VIH ha disminuido,sin embargo, la tasa de mortalidad de ECV se ha incrementado[5] Sin embargo, las tasas absolutas de IM y los accidentes cerebrovasculares han disminuido con la reducción de factores de riesgo de ECV, el uso de esquemas de TAR con mejores efectos sobre los lípidos, y las mejoras en la inmunocompetencia[6-9] En US, las personas infectadas por el VIH hospitalizadas por IM: Tienen una alta mortalidad comparada con diferentes cohortes (HR: 1.38; P = .04) Tienen menores tasas de eventos relacionados[10] ART, antiretroviral therapy; CVD, cardiovascular disease; MI, myocardial infarction. Priscilla Y. Hsue, MD: We’re now having a growing body of evidence to show the link between cardiovascular disease and mortality in the setting of HIV. Depending on the cohort, cardiovascular disease is the second nonleading is the second leading  non-HIV cause of death in the US, accounting for 15% of deaths of HIV-infected individuals, and in Europe, it is the third leading non-HIV cause of death. And, in fact, in different cohorts deaths range from 6 to 15%. Interestingly, as HIV-related deaths have decreased, the rate of cardiovascular death has increased. This must be tempered with the fact that the absolute rates of MI and stroke have declined with cardiovascular risk reduction, use of antiretroviral regimens that have better lipid effects, and also improvements in treating immunocompetence. Interestingly, in the United States, a study of ICD-9 codes showed that HIV-infected individuals who were hospitalized for myocardial infarction actually had a higher mortality compared to uninfected individuals, and they were less likely to be referred for procedures, including bypass surgery, angioplasty, and stenting; they were less likely to get antiplatelet-type medications as well. 1. Palella FJ, et al. J Acquir Immune Defic Syndr. 2006;43: Lewden C, et al. J Acquir Immune Defic Syndr. 2008;48: Smith CJ, et al. Lancet. 2014;384: Sackoff JE, et al. Ann Intern Med. 2006;145: Hanna D, et al. CROI Abstract Klein DB, et al. CROI Abstract Klein DB, et al. Clin Infect Dis. 2015;60: Marcus JL, et al. CROI Abstract Marcus JL, et al. AIDS. 2014;28: Pearce D et al AM J Cardiol 2012. ©2012 Clinical Care Options, LLC. All rights reserved 6

7 Las mayores causas comunes de muertes, 1999-2011D:A:D: ECV Disminucion de mortalidad en la nueva era de TAR Las mayores causas comunes de muertes, 100 90 80 70 60 Todas las muertes (%) 50 40 30 ART, antiretroviral therapy; CVD, cardiovascular disease. Priscilla Y. Hsue, MD: This slide shows data from the D:A:D study which involved individuals with HIV infection followed up from 1999 until death, loss of follow-up, or There were similar decreases in death rates over this time period for AIDS-related deaths, deaths from liver disease, and cardiovascular disease deaths; however, non-AIDS cancers increased slightly during this time interval. And after adjustment for factors that changed, including CD4 cell count, there was no decrease in AIDS-related death rate. So in summary, these recent reductions in rates of AIDS-related death are linked with an improvement in CD4 cell count, and the authors hypothesize that the reduced rates of liver disease and cardiovascular disease deaths over time are likely due to improved use of non-HIV–specific intervention, so, for example, using statins or using aspirin. 20 10 Total (N = 3909) (n = 256) (n = 788) (n = 862) (n = 718) (n = 658) (n = 627) SIDA Higado ECV Cáncer sin SIDA Otras Desconocido Smith C, et al Lancet. 2014:384: ©2012 Clinical Care Options, LLC. All rights reserved 7

8 Evolución de ECV con la edad en pacientes VIH+A medida que la población infectada por el VIH continúa envejeciendo, están surgiendo nuevos problemas cardiovasculares TAR continuo Inicio temprano de TAR Pre-TAR TAR 1980 1990 2000 2010 2020 Derrame pericárdico Miocardiopatía dilatada Enf arteria coronaria Enf vascular periférica HT Disfunción diastólica Muerte súbita cardiaca Fibrilación auricular ART, antiretroviral therapy; CVD, cardiovascular disease; HTN, hypertension. Priscilla Y. Hsue, MD: This figure shows the evolution of cardiovascular disease along with an aging HIV- infected population. So I think what’s interesting to note is as our HIV population continues to age and as we change how we treat patients with HIV, different cardiovascular issues are emerging. So, for example, if you look on the left-hand side in the 1980s before antiretroviral therapy was developed, a lot of the case reports were reporting things like pericardial effusion and dilated cardiomyopathy. And on the image below, we show a patient with a pericardial effusion. And then in the mid-1990s where antiretroviral therapy and protease inhibitors are developed, that’s when the reports of myocardial infarction, coronary artery disease, peripheral vascular disease, and pulmonary hypertension were described. And we show here a cardiac catheterization of an HIV patient with significant coronary artery disease. And now in the more contemporary era of HIV when we’re saying that all HIV patients should be on antiretroviral therapy, and in fact patients should initiate this therapy earlier, we’re seeing now reports of kind of a diastolic dysfunction, which is a stiffness of the heart, and also arrhythmic abnormalities, including sudden cardiac death and atrial fibrillation. ©2012 Clinical Care Options, LLC. All rights reserved 8

9 Muerte súbita cardiaca en el paciente VIH+Pacientes VIH+ (n = 2860) en el Hospital General de San Francisco entre 230 muertes; 30 (13%) fueron MSC MSCs representó el 86% de todas las muertes cardiacas (30 of 35) Tasa de MSC VIH+: 2.6/1000 personas-año (> 4 veces la población general) 50 SIDA MSC 40 30 Mortalidad por 100 pacientes/año 20 10 PY, person-years; SCD, sudden cardiac death. Priscilla Y. Hsue, MD: I’d like to elaborate on one of these studies. This is a study reporting higher rates of sudden cardiac death in the setting of HIV infection. This was a study performed at San Francisco General Hospital following HIV-infected individuals between the years of 2000 and There were a total of 230 deaths during this time period, and interestingly 30 of these, which was 13%, were sudden cardiac death, which is more than 4-fold higher than that of the general population. And, in fact, if you look here on the diagram, on the X axis is years and on the Y axis is mortality. AIDS- related deaths are shown in blue, and those are higher as you would anticipate,  but in the red line is sudden cardiac death among our HIV-infected patients. What was interesting is that sudden deaths accounted for the majority of all cardiac deaths, so 30 out of 35 of the HIV-infected individuals. So because sudden cardiac death is our most fatal and dreaded complication from a cardiologist’s point of view, really want to learn more about why this rate of sudden cardiac death is higher in the setting of HIV, and ultimately how do we predict individuals who are at-risk so we can prevent this from happening.  Can’t really eliminate the colors here. We’ll have to adjust the figure 2001 2002 2003 2004 2005 2006 2007 2008 2009 Años ¿Por qué es la tasa de MSC mayor en el VIH? ¿Cómo podemos predecir los individuos en riesgo? ¿Cómo podemos evitar esto? Tseng ZH, et al. J Am Coll Cardiol. 2012;59: ©2012 Clinical Care Options, LLC. All rights reserved 9

10 Inflamación crónica e incremento del RCV de comorbilidades en pacientes VIH+Inf no ttada VIH Pérdida de cel inmunorreguladoras Replicación VIH La pérdida de la integridad de la mucosa intestinal y la translocación microbiana TAR Dismunución de la inflmación crónica pero persistente, la activación inmune, Los marcadores de coagulación elevados Translocación microbiana, y Un mayor riesgo de coinfección ART, antiretroviral therapy; HTN, hypertension. Priscilla Y. Hsue, MD: This next slide is a schematic of the mechanism of underlying chronic inflammation in the setting of HIV and how this contributes to increased risk for comorbidities for HIV-infected individuals. So at the very top we have untreated HIV infection which contributes by a loss of immunoregulatory cells, impact on HIV replication, and also impact on gut mucosal integrity and microbial translocation. All of those factors then contribute to chronic inflammation, immune activation, impact on coagulation, microbial translocation, and risk of coinfection. These issues then interact with traditional risk factors, including dyslipidemia, cigarette smoking, hypertension, and substance use to result in an increase of comorbidities, including cardiovascular disease and other non-AIDS conditions including neurologic disease, and perhaps advance aging which remains controversial. Los factores de riesgo de comorbilidad tradicionales, tales como la dislipidemia, el tabaquismo, la lipodistrofia, HT, la obesidad, el consumo de sustancias Mayor incidencia de comorbilidades y la enfermedad clínica Deeks SG. Annu Rev Med. 2011;62: ©2012 Clinical Care Options, LLC. All rights reserved 10

11 Meses después del inicioD:A:D Enfermedad renal y ECV Kaplan-Meier de progresión de ECV confirmado por niveles basales de eGFR 25 20 Niveles basales (confirmados) de eGFR ≤ 30 > 30 - ≤ 60 > 60 - ≤ 90 > 90 15 Porcentaje con ECV 10 5 CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate. Priscilla Y. Hsue, MD: This is a study that was presented at CROI showing that individuals with differing levels of renal dysfunction—as shown here—have a strong progression to cardiovascular disease as assessed by baseline eGFR. You can see individuals have a very low eGFR less than or equal to 30; this is linked to strong progression to CVD in this cohort. 12 24 36 48 60 72 Meses después del inicio Pacientes bajo seguimiento, n > 90 > 60 - ≤ 90 > 30 - ≤ 60 ≤ 30 24, 24, 22, 20, 18, 15, 13, Ryom L, et al. CROI Abstract eGFR, estimated glomerular filtration rate ©2012 Clinical Care Options, LLC. All rights reserved 11

12 Ajuste del riesgo de IM primario*Bajo recuento de células CD4 + y factores de riesgo tradicionales de ECV predictivo de IM primario Bajos niveles de cel CD4+ predicen de forma independiente IM´s primarios Niveles detectables de HIV-1 RNA asociado a factor de riesgo de IM primario con recuento de cel CD4+ ≥ 350 y ≥ 500 cels/mm3 Los factores de riesgo de ECV tradicionales son importantes predictores de IMs Modelo Ajuste del riesgo de IM primario* Modelos CD4 no ponderados CD4 < 100 1.95 ( ) CD4 < 200 1.69 ( ) CD4 < 350 1.36 ( ) CD4 < 500 1.26 ( ) CD4 y modelos ARN HIV-1 CD4 ≥ 350 Y HIV-1 RNA detectable 1.81 ( ) CD4 ≥ 500 Y HIV-1 RNA detectable 1.61 ( ) ART, antiretroviral therapy; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; IDU, injection drug user; MI, myocardial infarction; MSM, men who have sex with men. Priscilla Y. Hsue, MD: This is data from Drozd and colleagues that was presented at CROI from last year showing that low CD4 count independently predicts myocardial infarctions. And you can see here, the relative risk associated with different CD4 counts. Having a detectable viral load is also associated with a higher risk of myocardial infarction at CD4 counts greater than 350 and greater than 500. And also this study showed that traditional risk factors also are important predictors of myocardial infarction in the setting of HIV. You can see that these models were adjusted for some traditional risk factors as well as HIV features. Drozd DR, et al. CROI Abstract 739. Ajustado por edad, sexo, tabaco, UDI, HSH, la diabetes, el uso de estatinas, la hipertensión tratada, eGFR, TAR. ©2012 Clinical Care Options, LLC. All rights reserved 12

13 Monitorización y evaluación del RCV en paciente VIH+CV, cardiovascular. David A. Wohl, MD: Let’s look at monitoring and assessing cardiovascular risk in people with HIV. ©2012 Clinical Care Options, LLC. All rights reserved 13

14 Evaluación del RCV en pacientes VIH+Clínicos Monitorización de lípidos Evaluación de factores de riesgo tradicionales Factores relacionados con el VIH Investigación Nivel de Ca en arterias coronarias CIMT Marcadores de función endotelial FDG-PET Marcadores de inflamación CIMT, carotid intima-media thickness; CV, cardiovascular; FDG-PET, fludeoxyglucose (18F)-positron emission tomography. David A. Wohl, MD: There are different things that we can use to assess CVD risk and understand the pathogenesis of cardiovascular disease in people with HIV. And the things that we use clinically are different than some of the things that we might use in a research setting. So clinically we know we have a wealth of data from people who don’t have HIV infection—you know, what seems to work and what doesn’t work when trying to assess whether or not a person is at higher risk for getting a heart attack or a stroke. So lipids really are the mainstay; we know that checking cholesterol helps us understand more about a person’s risk of cardiovascular disease than probably any other blood test that’s available right now, and that’s been borne out by decades of research. And there’s no reason that that shouldn’t be operative in people living with HIV. In HIV, we have to build on that. There are traditional risk factors that, again, are operative in both people without HIV and people with HIV that that are clearly markers of risk. So you know those: Those are smoking, sedentary lifestyle, obesity. These are things that we know play a role in cardiovascular disease risk universally. But in people with HIV, there are HIV-related factors as well. And so for this, we have to think carefully about how does this play in because we don’t have decades of data and we don’t have studies of 30 or 40,000 people like we do in the realm of the general population. But we do know that there are some factors that seem to be related to HIV, whether it be HIV itself, and as we’re learning more and more, there could be things that are happening in response to virus, even the even very low levels of virus, and, intriguingly, maybe even some of our medicines. On the research side of things, we have a number of different tools, some of which are used in the clinical realm but are not really completely integrated right now into care. But looking at things like coronary at artery calcium score or carotid intimal thickness, or assessing endothelial function, looking at markers of it or assessing it directly, or PET scanning. And some of these blood markers for inflammation, these are probes; these are things that we’re using to understand more how does cardiovascular risk, you know, become meaningful in people with HIV, and for those who do seem to have a risk for cardiovascular disease, what’s the underpinnings? And so, again, I think it’s important that we differentiate between things that we use in the clinical realm and things that you’ll hear about or that you’ll read about that are really research tools. And we’ll try to make that clear as we go along. CIMT: carotid intima-media thickness; FDG: fludeoxyglucose (18F)-positron emission tomography. ©2012 Clinical Care Options, LLC. All rights reserved 14

15 Compación de calculadoras clínicas del RCVEdad, sexo, tabaquismo, lípidos, presión arterial Características ACC/AHA ECVAS Framingham IM ECV Diabetes ✓ Raza/etnia Deprivación social Tto HTA IMC Antecedentes familiares de ECV/EC prematuras IR Fibrilación auricular Artritis reumatoide ACC/AHA, American College of Cardiology/American Heart Association; ASCVD; atherosclerotic cardiovascular disease; BMI, body mass index; CHD, coronary heart disease; CVD, cardiovascular disease; MI, myocardial infarction. David A. Wohl, MD: So looking at some of these risk assessors or calculators, I think it’s important to try to compare them. In the United States, I’d say the Framingham Risk Calculator historically has been the one that’s been most popular. In other parts of the world, especially in Europe, there are some others that are used more commonly, or just as commonly, reflecting the genesis of those calculators. Framingham, of course, comes from the United States so it is more applicable to our population maybe than to in other places in the world. More recently in 2013, we saw the American College of Cardiology and the American Heart Association come out with their own risk assessor. This one’s a little bit different. It’s a little bit more expansive than the Framingham Risk Calculator, and we’ll talk about that more in detail. The similarities and the differences are nicely demonstrated here where you can see that there are some things that the new calculator is assessing, including race and ethnicity, that Framingham didn’t. Some of the other things are the same: diabetes, hypertension and therapy for hypertension, and certainly smoking. Preiss D, et al. Can J Cardiol. 2015;31: ACC/AHA, American College of Cardiology/American Heart Association; ECVAS: ECV arterioesclerótica. IMC: Índice de masa corporal ©2012 Clinical Care Options, LLC. All rights reserved 15

16 Compación de calculadoras clínicas del RCVEventos ACC/ AHA ECVAS Framingham IM ECV Fatal or no fatal ECVAS ✓ EC, AIT o ACV o muerte por ECV IM Fatal o no fatal ECV Fatal Predición de vida La probabilidad de supervivencia libre de IM o ACV ECVAS fatal o no fatal ACC/AHA, American College of Cardiology/American Heart Association; ASCVD; atherosclerotic cardiovascular disease; CHD, coronary heart disease; CVD, cardiovascular disease; MI, myocardial infarction; TIA, transient ischemic attack. David A. Wohl, MD: Other things that are a little bit different are we get a lifetime assessment, not just a 10-year assessment, in the new calculator compared to Framingham, and even looking at fatal and nonfatal cardiovascular disease. It includes both stroke and heart attack, which I think is really important. So I think the new calculator adds on top of the Framingham. I like it because it’s pretty clear-cut; you enter into the calculator the data that it’s asking for, and it gives you the 10-year risk and the lifetime risk. If it’s a 10-year risk of 7.5% or more, that’s generally going to be an indication for a statin. I think that’s a nice cutoff—it’s pretty clear and it’s defensible. The other thing that I think is important is to understand who this calculator is appropriate for. The guidelines make it really clear that people without cardiovascular disease who are under 40 who don’t have known heart disease, they’re not really appropriate for this calculator. So this calculator guides you through who’s right for it and who’s not right for it because it’s based upon data from a specific group of people who are most likely to be at risk for cardiovascular disease. Preiss D, et al. Can J Cardiol. 2015;31: AIT: Ataque isquémico transitorio; EC: Enf coronaria ©2012 Clinical Care Options, LLC. All rights reserved 16

17 Resultados estimados de ECV en pac VIH+ por calculadoras de riesgo ECVPuntos de riesgo ECV calculados con datos de para los pts de la cohorte Partners HealthCare System[1] Framingham [1] ACC/AHA Calculadora de riesgo ECV[1] 25 20 15 10 5 < 2.5 25 n = 2270 n = 2152 20 Observado Observado 15 Niveles de eventos en 5 años (%) Niveles de eventos en 5 años (%) 10 ACC/AHA, American College of Cardiology/American Heart Association; CVD, cardiovascular disease. David A. Wohl, MD: So how well does it do? There are some data looking at both the Framingham Risk Calculator and the ACC/AHA cardiovascular risk calculator in people with HIV. What you can see here is that it pretty much underpredicts actual events, which is interesting because some people complained about the new calculator overpredicting events and being more aggressive in recommending statins in the general population or in certain general non-HIV–infected cohorts. I will say the new calculator looked a little bit better than Framingham, again maybe because there’s more inputs and it’s a little bit more specific to the race/ethnicity of patients as well. Again, that just means that we may have to tell our patients your risk calculator is saying your risk is X; this is probably an underestimate and your real risk may even be a little bit more than this, and that may help you in your decision making. 5 Predecido Predecido < 2.5 Niveles predictos en 5 años (%) Niveles predictos en 5 años (%) Un estudio de cohortes de pacientes ambulatorios (n = 2392) tuvieron hallazgos similares de riesgo de ECV subestimado (15% a 25%)[2] 1. Regan S, et al. CROI Abstract Thompson-Paul A, et al. CROI Abstract 747. ©2012 Clinical Care Options, LLC. All rights reserved 17

18 Redución de factores de RCV pueden disminuir el RCV en pacientes VIH+ mayores.El tratamiento eficaz de los factores de riesgo modificables, como el tabaquismo, el colesterol y la presión arterial puede reducir significativamente el riesgo de ECV de un individuo Modelo para el cambio en el riesgo relativo de ECV desde dejar de fumar, reducir el colesterol, * o reducción de la PA sistólica en una cohorte de VIH+ sin previa ECV (D: A: D Estudio) 6 Redución de PA sistolica 5 Redución del colesterol 4 Riesgo relativo de ECV 3 Dejar de fumar BP, blood pressure CVD, cardiovascular disease. David A. Wohl, MD: There’s been some modeling that’s looked at how do you reduce cardiovascular risk in people with HIV? And these are data that come from a modeling study that was done in the European D:A:D cohort. This was a very, very large cohort. There’s some differences between an American cohort and a European cohort, and that’s important, but I think there’s really good take homes here. And it shows that doing things like reducing blood pressure or reducing cholesterol does have an effect. And we know that we reduce cholesterol really mainly by using statins; statins are very effective at reducing cholesterol, and we’ve learned more and more about that and their role for reducing cardiovascular disease in people without HIV. The biggest effect, of course, is smoking cessation, and dropping down that risk substantially, and that’s not going to be news to anyone who’s ever taken care of people who have cardiovascular disease risk. If you plug into the calculator someone who’s a smoker and then take away the smoking, the risk drops substantially. And that’s a tool I use in clinic. I will show someone the screen that I’m using to calculate their risk, and then I’ll show them what happens if I say, “Well, let’s make believe for a moment that you quit smoking and your risk just went down from 15% to 6%.” That’s a profound drop and that’s the kind of drop you get. So it’s a motivator and we use it. 2 40 45 50 55 60 65 Edas (años) *Reducida por 1 mmol/L. †Reducida por 10 mm Hg. Petoumenos K, et al. HIV Med. 2014;15: ©2012 Clinical Care Options, LLC. All rights reserved 18

19 Aspirina y ECV Prevención secundaria: Pts con EAC establecida, AIT, Evento CV: dosis de 75 mg-162 mg / día (hasta 325 mg para algunos pts)[1] Beneficio definitivo en IM, accidente cerebrovascular y muerte CV Prevención primaria es menos clara: “Considere mg/día para los pts en mayor riesgo, especialmente aquellos con un riesgo de 10 años de enfermedad coronaria ≥ 10%, cuyo riesgo de sangrado no se incrementa”[2] Reducir riesgo de IM primario No reducción en tasas de accidente cerebrovascular o muerte cardiovascular Balance entre incremento del sangrado frente a su beneficio Aspirina, VIH e IM: estudio en Boston, el uso de la aspirina en el VIH no se asocia con tasas más bajas de IM, pero hubo limitaciones en el estudio[3] CAD, coronary artery disease; CV, cardiovascular; MI, myocardial infarction; TIA/CVA; transient ischemic attack/cerebral vascular event. David A. Wohl, MD: One of the interventions we talked about was statins, and statins are really important. As we know in general health, they’re some of the most prescribed medications in our country and clearly have had a profound impact on coronary and cardiovascular disease morbidity and mortality. Aspirin is also important. And there’s some data that indicate that we are getting much, much better at applying statin therapy to HIV-positive patients, but we’re really lagging behind when it comes to aspirin. Part of that may be there’s some controversy in the general population about when to use aspirin. But it is indicated as a secondary prevention method in patients with established coronary artery disease or people who have had TIAs or a CVA. And the dose should be somewhere around mg per day. Usually, we use about 81 mg. In some patients, the cardiologist may recommend a higher dose—a full dose of 325 mg. There’s been proven definitive benefit for cardiovascular disease, including MI, stroke, and cardiovascular disease death. So what about primary prevention though? So using aspirin, let’s say 81 mg a day, for patients at high risk? So the recommendation right now is that patients who are higher risk, those with a 10-year risk of cardiovascular disease, of coronary heart disease of 10% or more, should be indicated for aspirin as long as they don’t have a higher risk of bleeding. So people who have a bleeding disorder or people who’ve had a gastric ulcer and that has bled, those would be indications that would contraindicate for aspirin therapy. The idea, of course, is that in the right patients, this could reduce the risk of first MI. There has not really been good demonstration of reduction and risk of stroke or cardiovascular disease death, and again there’s always this balance between bleeding vs benefit even at 81 mg. So aspirin, HIV and MI—there is a study going on in Boston. The use of aspirin in HIV was not associated with lower rates of MI, but it was—there were limitations and it was a somewhat small study. So I think this is going to have to be looked at in a bigger way in the future. 1. Smith SC, et al. Circulation. 2006;113: Pearson TA, et al. Circulation. 2002;106: Suchindran S, et al. Open Forum Infect Dis. 2014;1:ofu076. ©2012 Clinical Care Options, LLC. All rights reserved 19

20 El papel de herramientas de análisis de RCV en pacientes VIH+ACC/AHA ECVAS Fácil de usar El análisis puede hacerse utilizando la herramienta en línea o a través de la aplicación móvil Indica si pac no se puede evaluar porque el riesgo es demasiado bajo Proporciona la evaluación de riesgos de 10 años y toda la vida ACC/AHA, American College of Cardiology/American Heart Association; ASCVD; atherosclerotic cardiovascular disease; CV, cardiovascular. David A. Wohl, MD: So overall, I think that it’s important that we assess risk for cardiovascular disease in HIV-positive patients across the spectrum. I think it’s important for us to come to a tool that we can become comfortable with. Again, more and more primary care docs and I think HIV docs are getting used to using the ACC/AHA calculator. It can be done online. On your phone, it can be done through an app. I think it has advantages over the Framingham. Again, it may be a little bit of an underestimate but that’s okay, and I think we can use it to assess our risk in our patients, and we should be applying it now, just based exactly upon what the what the guidelines say for the right patients. You can plug in the numbers and it’ll give you the 10-year risk and the lifetime risk, and that can be very important for your patients. ACC/AHA, American College of Cardiology/American Heart Association ©2012 Clinical Care Options, LLC. All rights reserved 20

21 Papel de los antiretrovirales en el riesgo cardiovascularDavid A. Wohl, MD: I’m going to talk about role of antiretrovirals in cardiovascular disease. ©2012 Clinical Care Options, LLC. All rights reserved 21

22 D:A:D: Incidencia de IM incrementa con la exposición de combinaciones del TARIncidencia de IM por año de exposición al TAR 8 7 6 5 Incidencia por 1000 personas-años 4 3 2 ART, antiretroviral therapy; MI, myocardial infarction. David A. Wohl, MD: So let’s look at some of the data about associations between HIV medications and risk for coronary artery disease or stroke. So D:A:D really put this subject on the map, and that was back in the early 2000s where they came out and showed very nicely that exposure over time to combination HIV therapy—we were really only using pretty much protease inhibitors and NNRTIs at this point when this study was presented—was associated with an increased risk of myocardial infarction over time. Now, importantly, D:A:D doesn’t have a control group. These are all patients with HIV, so there’s no way to say, “Well, what about people without HIV who are in Italy and Spain and the UK and everyone else who contributes to this? What’s their background myocardial infarction rate?” We don’t have that. You have to understand that if you had a control group, there would be some incremental increase in risk of myocardial infarction over time as the cohort gets older, as people are followed. So on top of that, there may be some added risk and that’s what everyone’s trying to understand; what’s the added risk on top of that? But what we saw here is that combination HIV therapy did seem to increase your risk for myocardial infarction over time, and as we learned, the older PIs were really driving this by and large. 1 Nada < 1 1-2 2-3 3-4 > 4 Exposición (años) D:A:D Study. N Engl J Med. 2003;349: ©2012 Clinical Care Options, LLC. All rights reserved 22

23 EAC: Enf Arteria coronariaFactores genéticos de ECV y Eventos cardiácos Estudio observacional de Casos-Control de 24 Cohortes de Pts VIH+ (US, EU, Australia, y Argentina) para evaluar EAC, 571 casos con primeros eventos comparados con controles Eventos CV: IM, angina inestable, angioplastia/stent, Cirugía coronaria por bypass Análisis multivariante TAR actual (incluido ABC) asociado con un riesgo similar para evento cardiaco como factores de riesgo de EAC HT, hipercolesterol, fumador CD4 HIV-1 RNA Indinavir ≥ 1 año de exposición Lopinavir ≥ año de exposición TAR Abacavir exposición actual ABC, abacavir; ART, antiretroviral therapy; CAD, coronary artery disease; HDL, high density lipoprotein; HTN, hypertension. David A. Wohl, MD: We have more data recently from the Magnificent Consortium—again, this is a European cohort, probably overlaps somewhat with the D:A:D cohort. And what’s very interesting here is what you see is that you have traditional risk factors coming into play, so it’s not only just the HIV therapies, but really what trumps a lot of that is the traditional risks that we think about all the time, and that’s on the bottom of the graph. You can see that the odds ratio is much higher for smoking, for being older, for family history—the traditional things that we think about—hypertension, high cholesterol, even past smoking really buries some of these HIV therapy–related factors that are also on this slide. So this is really important. And there’s things we can change and there’s things we can’t change. We can’t change that our patients are getting older or their family history, but we can manage their diabetes. We can manage their cholesterol and their hypertension. We can try to get them to stop smoking, being aggressive as possible with that. And then there’s the HIV factors, and we’re learning more and more about that, as we said, in trying to mitigate any risk that’s added on by our HIV therapy. Bajo HDL HT Alto CLT Fumador antiguo Diabetes Historia familiar de EAC Edad por 5 años Fumador actual 1 2 3 4 Odds Ratio (95% CI) Rotger M, et al. Clin Infect Dis. 2013;57: EAC: Enf Arteria coronaria ©2012 Clinical Care Options, LLC. All rights reserved 23

24 Tratamiento inmediatoEstudio START: Comparación aleatorizada de TAR inmediato vs TAR diferido Tratamiento inmediato CD4+ > 500 cells/mm³ (N = 4685) Aplazar tto hasta cél CD4+ ≤ 350 cells/mm³ Estudio dejó de mayo 2015 debido a un exceso de eventos (86 vs 41) en el grupo de tratamiento diferido Las enfermedades relacionadas con el SIDA más frecuentes entre los participantes en el estudio fueron la tuberculosis pulmonar, el sarcoma de Kaposi y el linfoma no Hodgkin; las enfermedades graves no relacionadas con el SIDA más comunes fueron cáncer, ataque al corazón, y las muertes por diversas causas CV, cardiovascular; TB, tuberculosis. David A. Wohl, MD: One thing that really is becoming clear is that starting HIV therapy earlier rather than later seems to reduce the risk of cancer and heart attacks and heart disease. So the START trial, which was big, randomized, controlled trial of starting patients on HIV therapy with a CD4 cell count above 500 vs deferring that therapy until the CD4 cell count dropped towards 350. That study’s ongoing, but in the second quarter of 2015, we saw that the results from a data safety monitoring board review indicated that there was a clear benefit for starting HIV therapy earlier, and a real risk of waiting to start HIV therapy until the until the CD4 cell count was more like 350. And this played out not only in AIDS- related, but non-AIDS–related events, both fatal and nonfatal events. This was really a remarkable result, given that the population that was enrolled in this very large study was generally very healthy. Their median viral load at entry was about 13,000, so there seemed to be some selection for people who would probably not have endpoints, for people who are relatively well and healthy. And even with that, we see here that there was a clear demonstrable benefit in infectious disease terms and noninfectious disease terms, including cardiovascular disease, of starting therapy earlier. So whatever we might talk about with some risk from D:A:D of one drug vs another or one class vs another, overall starting ART earlier before CD4 depletion is good for your heart. And so the benefits of ART clearly outweigh any risks that are associated with ART vis-à-vis lipids or other mechanisms. NIH. Press release. May 27, 2015. ©2012 Clinical Care Options, LLC. All rights reserved 24

25 ECV en ensayo SMART de TAR inmediato vs TAR diferidoPunto final* Grupo de conservación (N = 2720) Grupo de supresión viral (N = 2752) HR para el Grupo de Conservación vs Grupo supresión viral(95% CI) P Value Participantes con Evento, n Tasa de eventos (por 100 personas- año) Primer punto 120 3.3 47 1.3 2.6 ( ) < .001 Muerte por alguna causa 55 1.5 30 0.8 1.8 ( ) .007 Enf oportunista Serios 13 0.4 2 0.1 6.6 ( ) .01 No serio 63 1.7 18 0.5 3.6 ( ) ECV, renal, o hepatica mayor 65 1.8 39 1.1 1.7 ( ) .009 Fatal o no fatal ECV 48 31 1.6 ( ) .05 Fatal o no fatal enf renal 9 0.2 4.5 ( ) Fatal o no fatal enf hepática 10 0.3 7 1.4 ( ) .46 Evento grado 4 173 5.0 148 4.2 1.2 ( ) .13 Evento grado 4 o muerte por alguna causa 205 5.9 164 4.7 1.3 ( ) .03 Outcomes including CVD (ART Better than no ART) ART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: We already knew a little bit about this from the SMART study. In that trial, patients who are mostly on HIV therapy at entry were randomized to stop their therapy or continue on their therapy, the hypothesis being that continuing on your HIV therapy would be detrimental, that you would have toxicity, including cardiovascular toxicity, from your medications. It turned out stopping HIV therapy was much worse than staying on your HIV therapy, including for end-organ disease like cardiovascular disease. Both of these studies, the START study and the SMART study, these are studies that the randomization assignment was stopped early because of an early difference. So both studies show clearly demonstrable benefits of continuing on ART—starting it early and staying on it. *No sumar el número de eventos individuales de cada tipo al número total debido a que algunos participantes tenían más de 1 evento. El Sadr W, et al. N Engl J Med. 2006;355: ©2012 Clinical Care Options, LLC. All rights reserved 25

26 Teimpor con ABC(meses)Resumen de los análisis que muestran asociación de ABC con riesgo de IM Estudio Diseño estudio Edas, años (rango) Eventos (n) Pts, N TDF Efecto CV ABC Efecto CV Teimpor con ABC(meses) Riesgo de IM (95% CI) D:A:D[1] Cohorte 40 (35-47) IM validado (387) 22,625 No Si ≥ 6 1.70 ( ) D:A:D 2013[2] 39 (33-46) MI (493) 32,663 1.47 SMART[3] ECA 45 (39-51) (19) 2752 Corriente 4.3 ( ) STEAL[4] 45.7 ±8.8 IM (3) 357 96 2.2 QPHID[5] Casos- control 47 (22-67) (125) 7053 6 1.79 ( ) Danish[6] (33-47) (67) 2952 > 6 2.00 ( ) VA (Choi)[7] 48 Evento CV (501) 10,931 1.64 ( ) Swiss[8] Not given (350) 11,625 > 1-6 3.36 ( ) MAGNIFICENT[9] Casos- contro 50 ( ) (571) 571 ( ) NA-ACCORD[10] (301) 16,733 1.33 Swiss HIV Cohort[11] (365) 11,856 2.06 ( ) ABC, abacavir; CC, case-control; CV, cardiovascular; CVD, cardiovascular disease; MI, myocardial infarction; RCT, randomized controlled trial; TDF, tenofovir. David A. Wohl, MD: So what are the data? Well, it’s really, really complicated and here’s the list of those that show an association between abacavir and risk of MI. Some of these are in the context of a smaller, randomized controlled trial, some of these are in large cohorts like the D:A:D cohort or the VA cohort or the Swiss cohort, NA-ACCORD cohort. You can see them here and you can see the risk of an MI is basically we’re talking in in the realm of one and a half to 2-fold. 1. Friis-Moller N, et al. Eur J Cardiovasc Prev Rehabil. 2010;17: Friis-Moller N, et al. Eur J Prev Cardiol. 2015;[Epub ahead of print]. 3. SMART/INSIGHT Study Group. AIDS. 2008;22:F Martin A, et al. Clin Infect Dis. 2009;49: Durand M, et al. JAIDS. 2011;57: Obel N, et al. HIV Medicine. 2010;11: Choi AI, et al. AIDS. 2011;25: Young J, et al. IAS Abstract MOPE Rotger M, et al. Clin Infect Dis. 2013;57: Palella F, et al. CROI Abstract 749LB. 11. Young J, et al. JAIDS. 2015;[Epub ahead of print]. ©2012 Clinical Care Options, LLC. All rights reserved 26

27 Resumen de los análisis que NO muestran asociación de ABC con riesgo de IMEstudio Diseño Estudio Edad, años (rango) Event os (n) Pts, N TDF Efecto CV ABC Efecto CV Tiempo ABC (meses) Riesgo de IM (95% CI) FHDB[1] Casos- Control 47 (41-54) IM (289) 74,958 No No* > 6 1.27ǂ ( ) ALLRT/ ACTG[2] Cohorte 37 (27-50) (36) 5056 No† 72 0.70 ( ) VA[3] 46 (278) 19,424 24 1.18 ( ) FDA[4] Meta- analisis de ECA 36-42 (24) 9868 19 1.02 ( ) ABC, abacavir; CC, case-control; CV, cardiovascular; MI, myocardial infarction; RCT, randomized controlled trial; TDF, tenofovir. David A. Wohl, MD: On this next slide, we see that are some studies that don’t show a risk—there’s not as many—but some of these are pretty powerful as well. So I think it’s really, really confusing and I don’t think that we’re going to have a definitive answer anytime soon. We don’t have a signature pathogenic mechanism that explains this; we don’t know for sure that there’s anything that abacavir is doing to platelets or doing to inflammatory markers, so that makes it a little bit more confusing too. So, again, I don’t think you’re going to get a definitive answer from this module. I don’t think we’re going to be able to answer the question for you. * Todos o la mayoría de los Pts que estaban en tto naive que incluían ABC. † Todos o la mayoría de los Pts que estaban en tto pretratados que incluían ABC. ǂSin ajuste por consumo de cocaína OR: 2.01 ( ). 1. Lang S, et al. Arch Intern Med. 2010;170: Ribaudo HJ, et al. Clin Infect Dis. 2011;52: Bedimo RJ, et al. Clin Infect Dis. 2011;53: Ding X, et al. J Acquir Immune Defic Syndr. 2012;61: ©2012 Clinical Care Options, LLC. All rights reserved 27

28 DHHS Guidelines: Factores a considerar cuando selecionamos un TAR de inicioAl seleccionar un régimen para un paciente individual, debemos considerar unas una serie de características específicas del paciente y del regimen, con el objetivo de proporcionar una potencia, seguridad, tolerabilidad y fácil adherencia para el paciente con el fin de lograr el control virológico ECV es una de varias comorbilidades específicas enumeradas entre aquellos que hay que considerar En Pts con alto riesgo cardiaco intentar evitar regimenes basados en ABC y LPV/RTV - Está asociado con un incremento del riesgo CV en algunos estudios. ABC, abacavir; ART, antiretroviral therapy; CVD, cardiovascular disease; DHHS, US Department of Health and Human Services; LPV, lopinavir; RTV, ritonavir. David A. Wohl, MD: In general, when we look at the guidelines and what they have to say about selecting an initial ART regimen, we know that the overarching goal is to achieve sustained virologic control. The worst thing for a person’s cardiovascular system is uncontrolled viremia with HIV. We know that from the START study and we know that from the SMART study. So continuous viral replication, immune activation, all the bad humors that are elicited by having this virus, that’s not good for your organs, including your heart, including your brain, including your cardiovascular system. So we know that. So the number 1 thing: Drop that viral load and keep it suppressed. Now when we’re choosing among ART, as we said, there could be some different flavors that would help us understand, well, you know, does one lead to a higher risk for lipid abnormalities that I’d have to act on? Or is one, like abacavir, associated in a big question mark with cardiovascular disease? I think incorporating thinking about cardiovascular risk into our decision making for ART is what we’re doing and it makes a lot of sense. Just like we do the same thing for renal disease or bone health, we think about these things as well in the big picture as we’re trying to determine what’s best for our patient. DHHS Adult Guidelines. April 2015 DHHS, US Department of Health and Human Services ©2012 Clinical Care Options, LLC. All rights reserved 28

29 Gesida: Factores a considerar cuando selecionamos un TAR de inicioEs importante valorar de forma individual el momento de inicio del TAR y los FAR que deben formar parte del régimen inicial, sopesando las ventajas e inconvenientes de cada una de las opciones Evitar en pac con RCV alto los siguientes regimenes: - ABC/3TC+DRV/r o DRV/COBI - TDF/FTC+LPV/r - ABC/3TC+LPV/r - 3TC+LPV/r - RAL+LPV/r ¨La asociación de ABC con un incremento en la incidencia de eventos cardiovasculares es muy controvertida¨ ABC, abacavir; ART, antiretroviral therapy; CVD, cardiovascular disease; DHHS, US Department of Health and Human Services; LPV, lopinavir; RTV, ritonavir. David A. Wohl, MD: In general, when we look at the guidelines and what they have to say about selecting an initial ART regimen, we know that the overarching goal is to achieve sustained virologic control. The worst thing for a person’s cardiovascular system is uncontrolled viremia with HIV. We know that from the START study and we know that from the SMART study. So continuous viral replication, immune activation, all the bad humors that are elicited by having this virus, that’s not good for your organs, including your heart, including your brain, including your cardiovascular system. So we know that. So the number 1 thing: Drop that viral load and keep it suppressed. Now when we’re choosing among ART, as we said, there could be some different flavors that would help us understand, well, you know, does one lead to a higher risk for lipid abnormalities that I’d have to act on? Or is one, like abacavir, associated in a big question mark with cardiovascular disease? I think incorporating thinking about cardiovascular risk into our decision making for ART is what we’re doing and it makes a lot of sense. Just like we do the same thing for renal disease or bone health, we think about these things as well in the big picture as we’re trying to determine what’s best for our patient. Documento de consenso de GeSIDA/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana (Actualización enero 2016) ©2012 Clinical Care Options, LLC. All rights reserved 29

30 TAR y efecto en lípidos TDF RAL DTG RPV ETV ABC EFVATV/RTV or ATV/COBI DRV/RTV or DRV/COBI EVG/COBI ABC, abacavir; ART, antiretroviral therapy; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETV, etravirine; EVG, elvitegravir; RAL, raltegravir; RTV, ritonavir. David A. Wohl, MD: When we look across the spectrum of HIV therapies and their effects on lipids, we can see that it ranges quite a bit. So on the one hand, we have TDF which pretty much not only doesn’t have much effect on lipids, but in one study from the ACTG, looks like it actually has lowering effect. And there’s other studies that show this, too, but really definitively nicely adding on TDF can drop your LDL levels. Across the spectrum, we can see that we get through integrase that probably is pretty benign as far as lipids; the NNRTIs which do have effects on lipids, especially efavirenz; the newer NNRTIs, not as much. Abacavir, and I don’t think this is what’s playing into this effect on MI, but we do know that abacavir does increase lipids a little bit—LDL and even triglycerides. And then when you start getting to boosting with cobicistat or ritonavir is where you see the biggest effects, and we know that both triglycerides and LDL cholesterol can go up. The HDL question’s a little bit different. We know that most of these effective regimens will raise HDL, especially the NNRTIs, but even the boosted PIs will raise HDLs a little bit. ©2012 Clinical Care Options, LLC. All rights reserved 30

31 Cambio medio en los parámetros lipídicosACTG 5206: TDF reduce LDL en pts con supresión virológica Estudio piloto doble ciego de alternar TDF y placebo durante 12 semanas en pts (n = 17) con ARN VIH-1 <400 copias / ml≥ 90 días en TAR con 4wk de lavado entre los períodos de tratamiento Dislipidemia: ayuno mg / dL o no HDL mg / dl Variable principal: cambios en el no-HDL de más de 12 semanas de TDF activo menos el cambio de más de 12 semanas de placebo Cambio medio en los parámetros lipídicos No HDL P = .01 CT P < .01 LDL P = .06 HDL P = .91 TG P = .83 0.2 -0.2 -0.4 -0.6 ART, antiretroviral therapy; HDL, high density lipoprotein; LDL, low density lipoprotein; TC, total cholesterol; TDF, tenofovir; TG, triglycerides. David A. Wohl, MD: Here are the data that I mentioned before from the ACTG study showing that TDF does lower LDL cholesterol in patients who are virologically suppressed. You can see nicely the drops in total cholesterol and LDL cholesterol with minimal effects on HDL. TDF Placebo -0.8 -1.0 -1.2 Tungsiripat M, et al. AIDS. 2010;24: ©2012 Clinical Care Options, LLC. All rights reserved 31

32 Cambio de Lípidos basales desde la semana 48 en ECA de primera línea de TAR: Las comparaciones NNRTI70 184 STARTMRK[1] RAL + TDF/FTC 70 EFV + TDF/FTC 60 P = .0002 50 (mg/dL) 34 P < .0001 40 30 21 22 20 13 9 10 -14 CT LDL HDL TG 70 ACTG 5202[2] 60 P < .001 EFV + TDF/FTC EFV + ABC/3TC 50 40 ATV/RTV + TDF/FTC ATV/RTV + ABC/3TC 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; EFV, efavirenz; FTC, emtricitabine; HDL, high density lipoprotein; LDL, low density lipoprotein; RCT, randomized controlled trial; RTV, ritonavir; TC, total cholesterol; TDF, tenofovir; TG, triglycerides. David A. Wohl, MD: Looking at other data, so here we see from the STARTMRK study looking at raltegravir vs efavirenz, both with TDF/FTC, efavirenz, more profound changes in total LDL and even HDL cholesterol and triglycerides, whereas the raltegravir had less of an effect. And then ACTG 5202, here a nice comparison, boosted protease inhibitor with atazanavir and efavirenz as the comparator. This is looking at nucleosides, TDF/FTC or abacavir/3TC. Again, you can see a little bit of an abacavir effect if you look closely here, much more so than the TDF/FTC. And there were differences a little bit between the efavirenz and the boosted PI. But for a long time, people thought that efavirenz was kinder and gentler to lipids and we’ve learned that that’s not the case; it does act a lot like a boosted PI. (mg/dL) 40 P < .001 P < .001 29 P < .001 30 22 24 P = .002 21 P < .001 13 14 15 20 12 13 10 10 8 8 5 10 2 CT LDL HDL TG 1. Lennox J, et al. Lancet. 2009;374: Daar E, et al. Ann Intern Med. 2011;154: ©2012 Clinical Care Options, LLC. All rights reserved 32

33 Cambio de Lípidos basales desde la semana 48 en ECA de primera línea de TAR : PIs vs INSTIs(mg/dL) 30 ACTG 5257[1] ATV/RTV + TDF/FTC RAL + TDF/FTC DRV/RTV + TDF/FTC 20 13 1 15 15 16 -8 10 6 4 -3 6 5 CT LDL HDL TG 40 FLAMINGO[2] 33 -6 (mg/dL) 30 DTG + 2 NRTIs  ART, antiretroviral therapy; ATV, atazanavir; BL, baseline; DRV, darunavir; FTC, emtricitabine; HDL, high density lipoprotein; LDL, low density lipoprotein; RAL, raltegravir; RCT, randomized controlled trial; RTV, ritonavir; TC, total cholesterol; TDF, tenofovir; TG, triglycerides. David A. Wohl, MD: More recent data—so we have another AIDS Clinical Trials Groups study, 5257, that shows really nicely boosted PI with atazanavir vs raltegravir vs darunavir/ritonavir, and some important differences. We can see again the integrase inhibitor having less of an effect on total and LDL cholesterol. HDL responded pretty equally across the 3 arms. Triglycerides higher with the booster, right, with the ritonavir-boosted PIs. Not seeing much, in fact a little bit of a decrease, with the integrase inhibitors. So we know integrase inhibitors are kinder and gentler. FLAMINGO study looking at dolutegravir, just to look at a different integrase inhibitor, vs a boosted PI; again, very similar pattern that we saw with raltegravir where the integrase hardly does anything to the lipids, whereas the boosted PI does. 4 23 DRV/RTV + TDF/FTC 20 14 3 10 2 CT LDL HDL TG -5 1. Ofotokun I, et al. Clin. Infect. Dis. 2015;60: Quercia R, et al. Clin. Drug Invest. 2015;35: ©2012 Clinical Care Options, LLC. All rights reserved 33

34 Ensayo aleatorio de la terapia con estatinas y la progresión de la placa coronariaEnsayo aleatorizado de 12 meses en pts VIH+ en TAR estable con LDL <130 y ≥ 1 placa coronaria Atorvastatina 20 mg ( a 40 mg cada 3 meses) (n = 19) vs Placebo (n = 21) Tto con estatinas reduce la progresión de placas coronarias Reducción del volumen de la placa en general, incluyendo las placas cargadas de lípidos Reducción de placas de morfología de alto riesgo El tratamiento con estatinas es seguro y bien tolerado Progresión descendente e placa anterior proximal de la arteria coronaria con atorvastatina vs Placebo Basal ART, antiretroviral therapy; BL, baseline baseline; LDL, low density lipoprotein. David A. Wohl, MD: So we have some data here. Again, in the realm of HIV, we’re looking at pretty small studies, but they’re intriguing. So this is not to say that this is why you should do something. It’s just saying here’s what we’re figuring out; here’s what we’re understanding about the effects of this really potent, interesting class of medications on people with HIV. So one of the studies that were just presented not long ago in early 2015 was a randomized trial of HIV-positive people; these are all people who are on stable ART and had a low LDL, or at least less than 130, but known coronary plaque. So these people who already we knew had coronary artery disease. And they were randomized to atorvastatin 20 mg—and this was increased over time—vs placebo; small study, this was just a pilot probe study, about 20 people in each arm. Remarkably, I think, statin therapy was shown to reduce the progression of the plaque, so it reduced the overall plaque volume including the lipid-laden part of the plaque, and it reduced the higher-risk morphology, the more vulnerable plaque. And it was pretty profound. In the arm that didn’t get the statin but had placebo, there was actual progression of the plaque. So there’s a story emerging, as I’ll show you in a second, that maybe what statins are doing in people with HIV is helping those who already have some coronary artery disease stabilize this, if not have some regression vs the progression that’s happening in the control arms of these studies. 12 meses Atorvastatina Placebo Lo J, et al. CROI Abstract 136. ©2012 Clinical Care Options, LLC. All rights reserved 34

35 Efectos de Rosuvastatina sobre el espesor capa íntima de la carótida y puntuación del Ca coronarioSATURN-VIH: doble ciego, aleatorizado, controlado con placebo de la rosuvastatina en pacientes VIH+ (N = 147) Cambio medio en CCA en aquellos pac con clasificacion basal Cambio medio en CIMT Cambio medio en CIMT (mm) 4 Cambio medio en CCA 300 3 250 P < .05 2 200 P < .05 1 150 CAC, coronary artery calcium; CCA, common carotid artery; CIMT, carotid intima- media thickness. David A. Wohl, MD: Another study with a similar sort of picture is this study of statins in people with HIV called the SATURN-HIV study. This looks at rosuvastatin. And here what we’re looking at is not only coronary calcium score but also that carotid intimal thickness. And what you’ll see on the left-hand side is a significant difference in the mean change in this CIMT, this carotid intimal thickness, in patients who were randomized to get the rosuvastatin—in this case about 75 patients—vs the control arm of an equal number who got placebo. And while the differences aren’t profound on the graph, they are significant comparing the statin to control group where we saw worsening in the control group and stabilization in the statin group. When you look at people who had underlying coronary disease based upon coronary calcium score, we see again the statin led to some stabilization and lack of progression, where the controls experienced some progression. If you look at people who didn’t have any baseline coronary calcium score, who their score was 0, we didn’t see any benefit of the statin. So, again, a story of maybe this helps mitigate progression of coronary artery disease. More will come out of this; these are small studies. There’s a very large ACTG study looking at a statin and seeing how it affects clinical outcomes in addition to some of these markers. It’s going to be huge: patients long term that will, I think, definitely answer the question. -1 100 -2 50 -3 -4 Estatina Control Control Estatina Longenecker T, et al. CROI Abstract 137. CCA:common carotid artery; CIMT:carotid intima-media thickness. ©2012 Clinical Care Options, LLC. All rights reserved 35

36 Papel del farmacéuticoDavid A. Wohl, MD: I’m going to talk about role of antiretrovirals in cardiovascular disease. ©2012 Clinical Care Options, LLC. All rights reserved 36

37 Interacciones farmacológicas con TAR de primera línea y el tratamiento hipolipemianteAntiretroviral Contraindicados Ajuste de dosis No ajuste de dosis EFV Atorvastatina Simvastatina Pravastatina Rosuvastatina Pitavastatina RPV ATV/RTV ATV/COBI Lovastatina DRV/RTV DRV/COBI EVG/COBI/TDF/ FTC DTG RAL ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir. David A. Wohl, MD: I do think it’s important—we’ve talked a lot about statins—to just recognize that there are drug–drug interactions. This is not that complicated. If you understand what ART does to liver metabolism, you understand this. So we know that the NNRTIs are inducers, right, so they induce metabolism of different drugs. That means that if you give someone a statin, you’re probably going to get less of an effect because it’s going to be metabolized. So we often have to jump the dose up of the statin in order to get the effect we want. Now the contrast is true for, you know, ritonavir and cobicistat, right? These block metabolism, that’s how they work as pharmacological boosters. In that way, if you give a statin you’re going to get a much higher dose. And there are some differences between statins. So like simvastatin and lovastatin, you get much higher levels, dangerous levels. That’s why we tend to use pitavastatin or rosuvastatin or atorvastatin because those are safer, and there’s a much better safety window for those drugs regardless of which ART you’re using. For the integrase inhibitors that are not boosted, so dolutegravir and raltegravir, no interaction at all, safe to use. So really not complicated if you think about inducers of metabolism, of blockers of metabolism, and those that don’t have much effect at all on liver metabolism. DHHS Adult Guidelines. April 2015. ©2012 Clinical Care Options, LLC. All rights reserved 37

38 Modelo de estratificación y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 38

39 Modelo de estratificación y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 39

40 Modelo de estratificación y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 40

41 Modelo de estratificación y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 41

42 Estudio INFAMERICA y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 42

43 Estudio INFAMERICA y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 43

44 Estudio INFAMERICA y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 44

45 Estudio INFAMERICA y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 45

46 Estudio INFAMERICA y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 46

47 Estudio INFAMERICA y RCVART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. El seguimiento farmacoterapéutico intensivo en pacientes con RCV moderado-alto mejora los hábitos de vida y parámetros clínicos de seguimiento a estos pacientes. Conclusiones ©2012 Clinical Care Options, LLC. All rights reserved 47

48 Conclusiones: Gestión del RCV en Pacientes VIH+Tasas de enfermedades cardiovasculares mayores en pts VIH-infectados vs población general El riesgo de ECV puede evaluarse teniendo en cuenta Los factores de riesgo tradicionales Factores relacionados con VIH Comenzar el TAR temprano puede mitigar el riesgo CV a pesar de que ciertos TAR pueden aumentar los niveles de lípidos. Las estatinas han demostrado ser eficaces en la reducción de riesgo CV en pts sin infección por el VIH y deben usarse como se indica en pts infectados por el VIH ART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 48

49 Bibliografía Freiberg MS, et al. JAMA Internal Medicine. 2013;173: Palella FJ, et al. J Acquir Immune Defic Syndr. 2006;43:27-34. Lewden C, et al. J Acquir Immune Defic Syndr. 2008;48: Smith CJ, et al. Lancet. 2014;384: Sackoff JE, et al. Ann Intern Med. 2006;145: Hanna D, et al. CROI Abstract 729 Klein DB, et al. CROI Abstract 737. Klein DB, et al. Clin Infect Dis. 2015;60: Marcus JL, et al. CROI Abstract 741. Marcus JL, et al. AIDS. 2014;28: Pearce D et al AM J Cardiol 2012. Smith C, et al Lancet. 2014:384: Tseng ZH, et al. J Am Coll Cardiol. 2012;59: Deeks SG. Annu Rev Med. 2011;62: Wada NI, et al. AIDS. 2015;29: Duprez DA, et al. PLoS One. 2012;7:e44454. Ryom L, et al. CROI Abstract 742. Drozd DR, et al. CROI Abstract 739. Preiss D, et al. Can J Cardiol. 2015;31: Regan S, et al. CROI Abstract 751. Thompson-Paul A, et al. CROI Abstract 747. Petoumenos K, et al. HIV Med. 2014;15: Smith SC, et al. Circulation. 2006;113: Pearson TA, et al. Circulation. 2002;106: Suchindran S, et al. Open Forum Infect Dis. 2014;1:ofu076. D:A:D Study. N Engl J Med. 2003;349: Rotger M, et al. Clin Infect Dis. 2013;57: NIH. Press release. May 27, 2015. El Sadr W, et al. N Engl J Med. 2006;355: ART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 49

50 Bibliografía Friis-Moller N, et al. Eur J Cardiovasc Prev Rehabil. 2010;17: Friis-Moller N, et al. Eur J Prev Cardiol. 2015;[Epub ahead of print]. SMART/INSIGHT Study Group. AIDS. 2008;22:F17-24. Martin A, et al. Clin Infect Dis. 2009;49: Durand M, et al. JAIDS. 2011;57: Obel N, et al. HIV Medicine. 2010;11: Choi AI, et al. AIDS. 2011;25: Young J, et al. IAS Abstract MOPE070. Rotger M, et al. Clin Infect Dis. 2013;57: Palella F, et al. CROI Abstract 749LB. 11. Young J, et al. JAIDS. 2015;[Epub ahead of print]. Lang S, et al. Arch Intern Med. 2010;170: Ribaudo HJ, et al. Clin Infect Dis. 2011;52: Bedimo RJ, et al. Clin Infect Dis. 2011;53: Ding X, et al. J Acquir Immune Defic Syndr. 2012;61: DHHS Adult Guidelines. April 2015 Documento de consenso de GeSIDA/Plan Nacional sobre el Sida respecto al tratamiento antirretroviral en adultos infectados por el virus de la inmunodeficiencia humana Tungsiripat M, et al. AIDS. 2010;24: Lennox J, et al. Lancet. 2009;374: Daar E, et al. Ann Intern Med. 2011;154: Ofotokun I, et al. Clin. Infect. Dis. 2015;60: Quercia R, et al. Clin. Drug Invest. 2015;35: Stein JH, et al. J Am Coll Cardiol. 2014;63: De Jesus E, et al. Lancet. 2012;379: Gallant JE, et al. J Infect Dis. 2013;208: Gallant JE, et al. AIDS Abstract TUAB0103. Lo J, et al. CROI Abstract 136. Longenecker T, et al. CROI Abstract 137. ART, antiretroviral therapy; CV, cardiovascular; CVD, cardiovascular disease. David A. Wohl, MD: So in conclusion, I think it’s really clear that people with HIV have higher rates of cardiovascular disease—no argument there; they do compared to the general population. The question is why, and I think it has a lot to do with a lot of different things that we spoke about. Maybe there’s some HIV factors. I don’t think ART factors are really operative here; they’re not a driving force. I’m not so sure that there’s residual inflammation. I think it’s largely going to be traditional risk factors; those that we know about and maybe even some of those that are more subtle, such as depression, such as stress, such as discrimination; there’s lots of things that we’re exploring. Cardiovascular disease can be assessed by considering those traditional risk factors that we know about, right, so smoking, sedentary lifestyle, those types of things, and even HIV-related factors. So thinking hard about what are the effects of medicines on lipids particularly, and then the abacavir question which is sort of an outlier. Starting ART early mitigates cardiovascular risk—we know that now even though certain drugs may increase lipids. Even regardless of that effect, we see that ART started earlier is better for your heart. Statins are important; they’ve been shown to be effective in reducing cardiovascular risk in patients without HIV. They should be used just as indicated in people with HIV. We’re exploring more about sort of the salutatory effects of statins as an antiinflammatory and thinking about how that will fit in, but right now I use statins basically like I do in patients who don’t have HIV, and I would follow the guidelines and use the same indications. So hopefully that presents a bigger picture of what’s going on—helps, you know, take all these disparate data help you make decisions that are effective for your patients to reduce their risk of cardiovascular disease over time. ©2012 Clinical Care Options, LLC. All rights reserved 50