2018 Michigan Clinical Nursing Conference for HIV and STD Care - PowerPoint Presentation

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2018 Michigan Clinical Nursing Conference for HIV and STD CareMay 31st, 2018

Cardiovascular Disease in the Setting of HIV Infection

Kathleen Fitch, MSN, FNP-BCMassachusetts General Hospital and Harvard Medical SchoolSlide2

DisclosuresNone2Slide3

Learning GoalsImprove understanding of heightened cardiovascular disease (CVD) risk in the setting of HIVDelineate unique pathophysiology of CVD in the setting of HIVUnderstand assessment for and management on CVD in the setting of HIV, including those of an investigative natureExplore areas of future research

Explore patient education strategies for HIV-associated CVD3Slide4

OutlineEpidemiology of CVD in the setting of HIVPathophysiology of CVD and HIVRole of traditional risk factorsRole of inflammation/immune activationManagement of CVD in HIV

CVD risk predictionCVD prevention/treatmentNovel risk factorsTraditional risk factors4Slide5

BackgroundIn the past several years we have observed many advances in the care for people living with HIV:Improved treatmentRapid initiation of antiretroviral therapy (ART)Decreased rates of AIDS-related deaths (UNAIDS 2013)Increased life expectancy (Legarth JAIDS 2016; Siddiqi

JAIDS 2016)However, as the population with HIV ages, rates of non-AIDS complications (NCDs) such as CVD are increasingly prevalent (Deeks Lancet 2013; Guaraldi CID 2011)5Slide6

People Living with HIV are Aging

National Dutch ATHENA cohort with data between 1996-2010Projected age distribution of PLWH on ART 2010-2030Median age will increase from ~44 years in 2010 to ~57 years in 2030Proportion of PLWH over 50 years will increase from 28% in 2010 to 73% in 2030Smit Lancet ID 20156Slide7

PLWH will Face Increased Rates of NCDs as They Age

Predicted burden of non-communicable diseases (NCDs) in PLWH modeled for 2010-2030NCDs includeCardiovascular disease (hypertension, hypercholesterolemia, myocardial infarction, stroke)DiabetesChronic kidney diseaseOsteoporosisNon-AIDS malignancies (i.e. lung cancer)Smit Lancet ID 2015

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Age Related ComorbiditiesAging‐associated non-communicable diseases (NCDs) include:HTN, MI, PAD, CVA, angina, DM2, COPD, CKD, non-AIDS cancer, fracture/osteoporosis

Schouten CID 20148Slide9

OutlineEpidemiology of CVD in the setting of HIVPathophysiology of CVD and HIVRole of traditional risk factorsRole of inflammation/immune activation

Management of CVD in HIVCVD risk predictionCVD prevention/treatmentNovel risk factorsTraditional risk factors9Slide10

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HIV and Risk of Acute Myocardial Infarction

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Rates of Other CV Outcomes in the Setting of HIVButt Arch Intern Med 2011; Janjua JACC 2016; Tseng JACC 2012

Heart failureIncreased risk in HIV veterans vs. controlsAdjusted HR 1.81Higher risk associated with HIV viremiaCompared with control women, women with HIV haveIncreased rates of cumulative HF hospitalizationIncreased HF length of stayIncreased CV mortalityDecreased use of optimal HF pharmacologic therapy

Sudden cardiac deathIn San Francisco HIV cohort230 deaths; 30 (13% were sudden cardiac death)Sudden cardiac death rate 2.6 per 1,000 PYs (>4.5-fold higher rate than then general population)12Slide13

CVD Mortality in PLWH

Distribution of the underlying cause of death among HIV adults, French national 2000 (n = 964), 2005 (n = 1042) and 2010 (n = 728) surveys, France.

Morlat AIDS 2014. 13Slide14

Mechanisms of HIV-Associated CVD

Adapted from Zanni, M et al. Nature Reviews Cardiology 2014

Traditional CVD Risk Factors:hypertension, dyslipidemia, diabetes, visceral adipose tissue/lipodystrophy Lifestyle: smoking, nutrition, substance use Antiretroviral Therapywww.onhealth.com14Early (1900s-early/mid 2000s) understanding of heightened CVD risk in PLWH

Traditional CVD risk factorsElevated rates observed in HIV

ART?

Select PIs

Abacavir (debated)

Genetics:

family history

CVDSlide15

Smoking in HIVBurkhalter Nicotine Tob Res 2005; Friis-Moller AIDS 2003; Mamary

AIDS Pt Care STDs 2002; Gritz Nicotine Tob Res 2004; Vittecoq AIDS 2003; Saves CID 2003; Lifson AJPH 2010.15

Heightened rates56% (D:A:D)54% (SFGH)47% (US cohort)69% (French cohort)85% lifetime historySignificantly higher than people without HIVSlide16

Metabolic Abnormalities and CVD Risk Factors are Increased in HIV**

****P<0.001**P<0.05Hadigan CID 2001

***%**HIV participants with lipodystrophy are more likely to have impaired glucose tolerance, increased cholesterol, high triglycerides and decreased HDL than controls.

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LIPOHYPERTROPHY

LIPOATROPHY

Nutrition for Healthy Living Cohort :Lipoatrophy: 35%Lipohypertrophy: 44%Combination: 14% (Jacobson, 2005)LIPODYSTROPHY

Increased VAT

(Visceral Adipose Tissue)

Reduced SAT

(Subcutaneous Adipose Tissue)

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Body Composition ChangesSlide18

MI Incidence Increased with ART/PIsD:A:D - prospective observational cohort of 33,347 patientsRelative risk of MI 1.16 per year ART exposurePIs but not NNRTIs conferred increased risk

Note: First generation ARTFriis-Moller NEJM 2007

Antiretroviral TherapyLipodystrophyDyslipidemiaAbnormal GlucoseIncreased Risk of CVD??18Slide19

Abacavir and Risk of MI?Sabin Lancet 2008

19MI event rate increases as predicted as risk for CHD risk increasesWithin each predicted CHD risk category, MI rates are higher with recent abacavir useRelative risk greater at lower predicted CHD risk

Unequivocal findingsSince the study in 2008 11 additional analyses have been conducted5 demonstrated + effect of abacavir on MI6 have shown no effect of abacavir on MISlide20

Contemporary ART and CVD RiskTyom et al. Abstract 128LB. CROI 2017; Lundgren Current Opinion 2018.

20Cumulative use of DRV/r but not ATV/r associated with increased CVD risk Strength of association similar to that of IDV and LPV/r but not modified by dyslipidemiaLimitations:No adequately powered randomized trial has yet to be conductedUnclear how NRTIs including abacavir accounted forUnmeasured confoundingCannot prove causalityNo dose dataNo gender-stratified analysesClinical implications potentially significant  further randomized controlled trials are neededMore data favors using ART to prolong life and PIs are an important component of the regimenSlide21

Traditional Risk Factors Do Not Tell the Whole Story21

Increased MI risk persists despite accounting for established CVD risk factors and ART useTraditional risk factors only account for 10-25% of risk in large cohortsPersistent 40-80% increased risk of MI in PLWHPersistently increased risk thought to be driven by HIV-specific inflammation and immune activation supported by extensive dataSMART studyBiomarkers of inflammation linked to surrogate markers of CVDLow CD4 and high HIV viral load linked to CVD eventsIn treated and suppressed HIV patientsReduced but persistent inflammation/immune activation and CVD riskSlide22

HIV and Risk of Acute Myocardial Infarction

In the VACS cohort, the HR of MI was 1.5 in HIV vs. non-HIV veterans after adjusting for FRS, comorbidities, and substance use (95% CI 1.27-1.72).

(Freiberg JAMA IM 2013)The RR of MI in HIV vs. non-HIV was 1.53 in a large US cohort. After adjusting for traditional risk factors, including age, gender, race, hypertension, diabetes, and dyslipidemia, the RR was 1.75 (P<0.0001). (Triant JCEM 2007)Recent findings from Kaiser Permanente: MI risk from 1996 to 2011 by HIV status. The adjusted MI rate ratio for HIV status declined over time, reaching 1.0 (Klein CID 2015)

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Traditional Risk Factors? Cohort study with 3,851 HIV and 1,044,589 non-HIV patients receiving

longitudinal care in the Partners Health Care System, 1996-2004 DM, HTN, and dyslipidemia, though increased, accounted for 25% of excess risk

DyslipidemiaHypertension DiabetesHIV -negativeHIV-positive

Triant JCEM 2007.

Increased Traditional Risk Factors Account for Only a Portion of CVD Risk in HIV

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Shift in Traditional Paradigm to Explain CVD Risk in HIV

The SMART Study Group NEJM 2006.

Increased CVD event rates in drug conservation (episodic treatment) vs. viral suppression (continuous therapy)HR for CVD event: 1.57, P=0.05 SMART Study24Slide25

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Duprez

DA, et al. PLoS One. 2012.Inflammation Might Explain Increased CVD Risk in PLWH252 participants had a CVD event over follow upAdjusted HRs for CVD for Q4 vs Q1 were4.65 for IL-62.10 for hsCRP2.14 for D-dimerIL-6, hsCRP, and D-dimer are associated with an increased risk of CVD independent of other risk factorsSMART StudySlide26

Immune Activation Might Explain Increased CVD Risk in PLWHFitch JID 2013.

162 HIV- infected and 71 HIV-uninfected participants (male and female)Well matched for traditional CV risks including smoking, with low CVD Risk ScoressCD163, immune activation marker, was significantly higher in women with HIVWomen with HIV had significantly more noncalcified plaque on CCTA 26Slide27

Arterial Inflammation and Coronary Plaque CharacteristicsImmune activation markers, including markers of monocyte activation (sCD163), are significantly linked to:

Presence of non-calcified, vulnerable plaqueHigh-risk morphology plaqueArterial inflammation Burdo JID 2011; Zanni AIDS 2013; Subramanian JAMA 2012HIVNon-HIV

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CD4 and HIV VL Linked to CVD28

CD4 < 500 associated with CVD events independent of CVD risk factors or ART

CD4 <200 independently associated with MI with OR 0f 1.74HIV VL >100,000 was associated with increased MI risk in univariate analysis but this was not significant in multivariate analysisLichtenstein CID 2010; Triant JAIDS 2010.Slide29

Mechanisms of HIV-Associated CVD

Adapted from Zanni, M et al. Nature Reviews Cardiology 2014

Traditional CVD Risk Factors:hypertension, dyslipidemia, diabetes, visceral adipose tissue Lifestyle: smoking, nutrition, substance use Antiretroviral Therapywww.onhealth.com29

Genetics:family history

CVD

HIV Associated Factors:

Viral replication, inflammation, immune activation, microbial translocation

Increase risk

Decrease riskSlide30

OutlineEpidemiology of CVD in the setting of HIVPathophysiology of CVD and HIVRole of traditional risk factorsRole of inflammation/immune activation

Management of CVD in HIVCVD risk predictionCVD prevention/treatmentNovel risk factorsTraditional risk factors30Slide31

Current Challenges in Preventing and Treating CVD in HIVUnderstanding of mechanisms has not yet translated into tailored clinical interventionsArea of intensive investigationIntervention must address both traditional and immune-related risk factors

Unclear applicability of general population guidelinesLimitations of HIV-specific guidelinesAs of right now, we do not have a strategy uniquely tailored in HIV31Slide32

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Dube CID 2003; Lundgren HIV Med 2008; Aberg CID 2014.Slide33

ACC/AHA CVD Risk Guidelines Add Complexity to Risk Prediction in HIV33

New ACC/AHA guidelines on CVD risk estimation released in 2013New CVD risk prediction equation employed (Pooled cohorts equation)Reports of overestimation of CVD risk in the general populationGoff Circulation 2014.Slide34

What Do We Know About CVD Risk Prediction in HIV?3 calculators have been used for CVD risk prediction in HIVFramingham risk calculatorNot developed for PLWHEstimates 10 year CVD risk

D:A:D risk calculatorDeveloped for PLWHEstimates 5 year CVD riskIncorporates exposure to IDV, LPV, abacavirACC/AHA ASCVD risk calculatorNot developed for PLWHEstimates 10 year CVD riskEACH of these calculators tends to underestimate CVD risk in PLWH34Slide35

Comparison of Framingham and ACC/AHA ASCVD Calculators35

Framingham Risk CalculatorACC/AHA ASCVD Risk CalculatorData collected from 1713 patients in the Partners HIV CohortCompared observed versus predicted risk

Observed risk exceeded predicted risk for most decilesIndicates underestimation of CVD riskTriant Circulation 2018.Slide36

Many HIV Patients with Plaque Would not Be Recommended for a Statin by 2013 Guidelines

Zanni AIDS 2014.Future challenges include developing a prediction algorithm specific to HIV to detect those with subclinical atherosclerosis.CHD risk is underestimated by traditional risk scores

108 HIV+ men and women without CVD By 2013 ACC/AHA guidelines, statins would be recommended for only 29% with plaquevs 12% using 2004 ATP III36Slide37

Clinical StrategyCalculate ASCVD risk score and consider the score as lower estimate of riskPatients with 10-year ASCVD risk score >7.5% merit:Suppressive ART if not already startedAggressive CVD risk factor reduction

Strong consideration for statin37Slide38

Paradigm Shift in Role of ART in Relation to CVD Risk in HIV2010 IAS-USA HIV treatment guidelinesRecommend initiation of ART specifically for patients with HIV CV risk regardless of CD4 countEndorse aggressive management of modifiable CVD risk factors

2012 DHHS HIV treatment guidelinesRecommend antiretroviral therapy for all HIV-infected individualsThe recommendation to initiate therapy at CD4 count >500 cells/mm3 is based on growing awareness that untreated HIV infection or uncontrolled viremia may be associated with development of many non-AIDS defining diseases, including cardiovascular disease (CVD), kidney disease, liver disease, neurologic complications, and malignancy38

Thompson JAMA 2010; ACCF/AHA/ACP Circulation 2009; https://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdfSlide39

Does an Early START Prevent CVD?Strategic Timing of AntiRetroviral Treatment (START) StudyFirst RCT to assess rates of events including non-AIDS/CVD by early (CD4 >500) versus deferred (CD4 <350) ART initiationEarly treatment reduced serious illness/death by 53%Greater risk reduction for AIDS events (75%) vs non-AIDS-events (33%)

There was no difference in CVD events between immediate and deferred treatment groups.Was follow up too short to capture CVD events?Cohort too young (mid 30s)/too healthy to capture events?

Insight START Study Group, NEJM, 201539Slide40

ART and CVD Risk: StrategiesTreat HIV to reduce CVD riskCVD-related benefit from virologic suppression and immune reconstitution achieved by treating HIV thought to outweigh possible proatherogenic effects of individual medications

40Thompson JAMA 2010Clinical Strategy

Treat HIV to reduce inflammation, immune activation and associated CVD riskConsider underlying CVD risk when selecting specific drugs, as individual ART may have varying riskSlide41

Statins in HIVDyslipidemia in HIVPrevalent, with higher rates than people without HIVDistinctive pattern of low HDL and high triglyceridesMay be more difficult to treat with statins

Drug interactions with ART Statins are mainstay of treatment and may reduce both traditional and non-traditional risk factorsStatin in HIV:Effectively lower LDLDecrease immune activation41

Hadigan CID 2001; Riddler JAMA 2003; Silverberg Ann Int Med 2009; Lo Lancet HIV 2015Slide42

Statin Effects on CVD Parameters in HIVLo, Lancet HIV 2015

PlaceboAtorvastatin

PlaceboAtorvastatinp = 0.009p < .0001p = 0.005

Randomized Controlled Trial, 40 participants, no known history of CVD,

40mg atorvastatin vs. placebo for 12 months

Decreased LDL

Decreased LpPLA2: marker of vascular inflammation

Decreasing non-calcified plaque in proximal left anterior descending (LAD) coronary artery in patient on

atorvastatin

for 12 months.

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Challenges in Applying ACC/AHA Cholesterol Guidelines to HIV43

Stone Circulation 2014

Dose-adjustment in HIV (with PIs)

Contraindicated in HIV (with PIs)

Awaiting further study in HIVSlide44

www.reprievetrial.org

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The first large-scale randomized clinical trial to test a strategy for preventing heart-related disease among PLWHHypothesis: statins will prevent CVD in HIV-infected patients, among participants at low-moderate risk not meeting current guidelines for clinical use of statins but at risk based on unique features of HIVSlide45

REPRIEVE Study Design

Intervention

ScreeningandConsentPitavastatin

Placebo

Randomization

R

Mechanistic

Study

Mechanistic

Primary Endpoint

Coronary plaque,

vascular

Inflammation,

immune activation

HIV+ participants, ages 40-75 with no history of CVD and ASCVD ≤15%

Primary

Endpoint

Clinical

CVD Death

MI

Unstable Angina

TIA & Stroke

Arterial Revasc

PAD

N=7500

Pitavastatin

*moderate intensity statin

*does not interact w/ any ART – no dose adjustment

*net neutral effects on glucose

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7500 participants from 120 sites

Eligibility

Ages 40-75

No CVD

Not on a statin

Stable ART

Not recommended for statin by 2013 ACC/AHA guidelinesSlide46

Clinical StrategiesEarly patient education to modify lifestyle (keep it simple, address barriers)Weight maintenanceDiet modification

Smoking cessationPhysical activity Monitor for dyslipidemiaCheck fasting lipidsAt HIV diagnosisPrior to and within 1-3 months after starting or changing ARTEvery 6-12 monthsConsider starting statin based on ACC/AHA cholesterol guidelinesConsider fibrate if triglycerides >500mg/dL

46Dube CID 2003; Aslangul AIDS 2010; Aberg CID 2014Slide47

Clinical StrategiesDiabetesCheck fasting glucose or HbA1c at HIV diagnosis, 103 months after starting or changing ART, and every 6-12 monthsHbA1c may be used for screeningConsider cutoff 5.8%

HbA1c may underestimate glycemia in HIVCheck HbA1c every 6 months in DMHypertensionCheck blood pressure annuallyFollow existing Hypertension Guidelines for the general populationNo HIV-specific guidelinesConsider drug interactionsUse of some calcium-channel blockers contraindicated with PIs47

Aberg CID 2014; Lundgren HIV Med 2008Slide48

Novel Interventions Targeting Inflammation and Immune ActivationART treatment intensificationMethotrexateCCR5 antagonistsRifaximin

SevelamerMesalaminePentoxifyllineHydroxychloroquineIL-1β inhibition with canakinumab48

Hatano JAIDS 2012; Gahdhi JAIDS 2012; Stein JAMA 2012; Jones Br J Pharmacol 2011; Cipriani Circulation 2013; Tenorio CROI 2014; Sandler JID 2014; Somsouk CROI 2014; Gupta PLoS One 2013; Paton JAMA 2012Slide49

Prevention of HIV-Associated CVD

Traditional Risk Factor ModificationStatinsSmoking cessation

LifestyleStartAntiretroviral TherapyEarlywww.onhealth.com49Patient Education/Prevention

HIV Associated Factors:

Anti-inflammatories

Immune Modulators

StatinsSlide50

Implications and QuestionsThere is a significant impact of CVD in HIV populations that is related to inflammation and immune activationCurrent treatment guidelines do not reflect this pathophysiologyRecommended strategies

Treat HIV infection to reduce CVD riskBuild CVD risk assessment into practice—understanding limitationsEducate about traditional CVD risk factors early and manage risk factors aggressively (smoking cessation)Start appropriate statin if neededFuture questionsHow is CVD risk most accurately predicted in HIV?What is the role of statins and immunomodulatory agents to reduce CVD risk in HIV?Should HIV be considered a CV risk equivalent?50Slide51

Questions?51