1. Cardiovascular Disease in the Setting of HIV Infection
Kathleen Fitch, MSN, FNP-BC
Massachusetts General Hospital and Harvard Medical School
2018 Michigan Clinical Nursing Conference for HIV and STD Care
May 31st, 2018

2. Disclosures
None

3. Learning Goals
Improve understanding of heightened cardiovascular disease (CVD) risk in the setting of HIV
Delineate unique pathophysiology of CVD in the setting of HIV
Understand assessment for and management on CVD in the setting of HIV, including those of an investigative nature
Explore areas of future research
Explore patient education strategies for HIV-associated CVD

4. Outline Epidemiology of CVD in the setting of HIV
Pathophysiology of CVD and HIV
Role of traditional risk factors
Role of inflammation/immune activation
Management of CVD in HIV
CVD risk prediction
CVD prevention/treatment
Novel risk factors
Traditional risk factors

5. Background
In the past several years we have observed many advances in the care for people living with HIV:
Improved treatment
Rapid 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)

6. People Living with HIV are Aging
National Dutch ATHENA cohort with data between
Projected age distribution of PLWH on ART
Median age will increase from ~44 years in 2010 to ~57 years in 2030
Proportion of PLWH over 50 years will increase from 28% in 2010 to 73% in 2030
Smit Lancet ID 2015

7. PLWH will Face Increased Rates of NCDs as They Age
Predicted burden of non-communicable diseases (NCDs) in PLWH modeled for
NCDs include
Cardiovascular disease (hypertension, hypercholesterolemia, myocardial infarction, stroke)
Diabetes
Chronic kidney disease
Osteoporosis
Non-AIDS malignancies (i.e. lung cancer)
Smit Lancet ID 2015

8. Age Related Comorbidities
Aging‐associated non-communicable diseases (NCDs) include:
HTN, MI, PAD, CVA, angina, DM2, COPD, CKD, non-AIDS cancer, fracture/osteoporosis
Schouten CID 2014

9. Outline Epidemiology of CVD in the setting of HIV
Pathophysiology of CVD and HIV
Role of traditional risk factors
Role of inflammation/immune activation
Management of CVD in HIV
CVD risk prediction
CVD prevention/treatment
Novel risk factors
Traditional risk factors

11. HIV and Risk of Acute Myocardial Infarction

12. Rates of Other CV Outcomes in the Setting of HIV
Heart failure
Increased risk in HIV veterans vs. controls
Adjusted HR 1.81
Higher risk associated with HIV viremia
Compared with control women, women with HIV have
Increased rates of cumulative HF hospitalization
Increased HF length of stay
Increased CV mortality
Decreased use of optimal HF pharmacologic therapy
Sudden cardiac death
In San Francisco HIV cohort
230 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)
Butt Arch Intern Med 2011; Janjua JACC 2016; Tseng JACC 2012

13. CVD Mortality in PLWH Morlat AIDS 2014.
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.

14. Mechanisms of HIV-Associated CVD
Antiretroviral Therapy
Early (1900s-early/mid 2000s) understanding of heightened CVD risk in PLWH
Traditional CVD risk factors
Elevated rates observed in HIV
ART?
Select PIs
Abacavir (debated)
Traditional CVD Risk Factors:
hypertension, dyslipidemia, diabetes, visceral adipose tissue/lipodystrophy
CVD
Lifestyle:
smoking, nutrition, substance use
Genetics:
family history
Adapted from Zanni, M et al. Nature Reviews Cardiology 2014

15. Smoking in HIV Heightened rates 85% lifetime history
56% (D:A:D)
54% (SFGH)
47% (US cohort)
69% (French cohort)
85% lifetime history
Significantly higher than people without HIV
Burkhalter 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.

16. Metabolic Abnormalities and CVD Risk Factors are Increased in HIV
*P<0.001
**P<0.05 % ** * ** * * * * *
HIV participants with lipodystrophy are more likely to have impaired glucose tolerance, increased cholesterol, high triglycerides and decreased HDL than controls.
Hadigan CID 2001

17. Body Composition Changes
LIPODYSTROPHY
LIPOHYPERTROPHY
LIPOATROPHY
Nutrition for Healthy Living Cohort :
Lipoatrophy: 35%
Lipohypertrophy: 44%
Combination: 14%
(Jacobson, 2005)
Reduced SAT
(Subcutaneous Adipose Tissue)
Increased VAT (Visceral Adipose Tissue)

18. MI Incidence Increased with ART/PIs
Increased Risk of CVD??
Lipodystrophy
Antiretroviral Therapy
Dyslipidemia
Abnormal Glucose
D:A:D - prospective observational cohort of 33,347 patients
Relative risk of MI 1.16 per year ART exposure
PIs but not NNRTIs conferred increased risk
Note: First generation ART
Friis-Moller NEJM 2007

19. Abacavir and Risk of MI? Unequivocal findings
Since the study in additional analyses have been conducted
5 demonstrated + effect of abacavir on MI
6 have shown no effect of abacavir on MI
MI event rate increases as predicted as risk for CHD risk increases
Within each predicted CHD risk category, MI rates are higher with recent abacavir use
Relative risk greater at lower predicted CHD risk
Sabin Lancet 2008

20. Contemporary ART and CVD Risk
Cumulative 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 dyslipidemia
Limitations:
No adequately powered randomized trial has yet to be conducted
Unclear how NRTIs including abacavir accounted for
Unmeasured confounding
Cannot prove causality
No dose data
No gender-stratified analyses
Clinical implications potentially significant  further randomized controlled trials are needed
More data favors using ART to prolong life and PIs are an important component of the regimen
Tyom et al. Abstract 128LB. CROI 2017; Lundgren Current Opinion 2018.

21. Traditional Risk Factors Do Not Tell the Whole Story
Increased MI risk persists despite accounting for established CVD risk factors and ART use
Traditional risk factors only account for 10-25% of risk in large cohorts
Persistent 40-80% increased risk of MI in PLWH
Persistently increased risk thought to be driven by HIV-specific inflammation and immune activation supported by extensive data
SMART study
Biomarkers of inflammation linked to surrogate markers of CVD
Low CD4 and high HIV viral load linked to CVD events
In treated and suppressed HIV patients
Reduced but persistent inflammation/immune activation and CVD risk

22. HIV and Risk of Acute Myocardial Infarction
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)
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)
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 ).
(Freiberg JAMA IM 2013)

23. Traditional Risk Factors?
Increased Traditional Risk Factors Account for Only a Portion of CVD Risk in HIV
Dyslipidemia
Hypertension
Diabetes
HIV -negative
HIV-positive
Cohort study with 3,851 HIV and 1,044,589 non-HIV patients receiving
longitudinal care in the Partners Health Care System,
DM, HTN, and dyslipidemia, though increased, accounted for 25% of excess risk
Triant JCEM 2007.

24. Shift in Traditional Paradigm to Explain CVD Risk in HIV
SMART Study
Increased CVD event rates in drug conservation (episodic treatment) vs. viral suppression (continuous therapy)
HR for CVD event: 1.57, P=0.05
The SMART Study Group NEJM 2006.

25. Inflammation Might Explain Increased CVD Risk in PLWH
SMART Study
252 participants had a CVD event over follow up
Adjusted HRs for CVD for Q4 vs Q1 were
4.65 for IL-6
2.10 for hsCRP
2.14 for D-dimer
IL-6, hsCRP, and D-dimer are associated with an increased risk of CVD independent of other risk factors
Duprez DA, et al. PLoS One

26. Immune Activation Might Explain Increased CVD Risk in PLWH
162 HIV- infected and 71 HIV-uninfected participants (male and female)
Well matched for traditional CV risks including smoking, with low CVD Risk Scores
sCD163, immune activation marker, was significantly higher in women with HIV
Women with HIV had significantly more noncalcified plaque on CCTA
Fitch JID 2013.

27. Arterial Inflammation and Coronary Plaque Characteristics
Immune activation markers, including markers of monocyte activation (sCD163), are significantly linked to:
Presence of non-calcified, vulnerable plaque
High-risk morphology plaque
Arterial inflammation
Non-HIV
HIV
Burdo JID 2011; Zanni AIDS 2013; Subramanian JAMA 2012

28. CD4 and HIV VL Linked to CVD
CD4 < 500 associated with CVD events independent of CVD risk factors or ART
CD4 <200 independently associated with MI with OR 0f 1.74
HIV VL >100,000 was associated with increased MI risk in univariate analysis but this was not significant in multivariate analysis
Lichtenstein CID 2010; Triant JAIDS 2010.

29. Mechanisms of HIV-Associated CVD
Antiretroviral Therapy
Traditional CVD Risk Factors:
hypertension, dyslipidemia, diabetes, visceral adipose tissue
HIV Associated Factors:
Viral replication, inflammation, immune activation, microbial translocation
CVD
Lifestyle:
smoking, nutrition, substance use
Genetics:
family history
Increase risk
Decrease risk
Adapted from Zanni, M et al. Nature Reviews Cardiology 2014

30. Outline Epidemiology of CVD in the setting of HIV
Pathophysiology of CVD and HIV
Role of traditional risk factors
Role of inflammation/immune activation
Management of CVD in HIV
CVD risk prediction
CVD prevention/treatment
Novel risk factors
Traditional risk factors

31. Current Challenges in Preventing and Treating CVD in HIV
Understanding of mechanisms has not yet translated into tailored clinical interventions
Area of intensive investigation
Intervention must address both traditional and immune-related risk factors
Unclear applicability of general population guidelines
Limitations of HIV-specific guidelines
As of right now, we do not have a strategy uniquely tailored in HIV

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

33. ACC/AHA CVD Risk Guidelines Add Complexity to Risk Prediction in HIV
New ACC/AHA guidelines on CVD risk estimation released in 2013
New CVD risk prediction equation employed (Pooled cohorts equation)
Reports of overestimation of CVD risk in the general population
Goff Circulation 2014.

34. What Do We Know About CVD Risk Prediction in HIV?
3 calculators have been used for CVD risk prediction in HIV
Framingham risk calculator
Not developed for PLWH
Estimates 10 year CVD risk
D:A:D risk calculator
Developed for PLWH
Estimates 5 year CVD risk
Incorporates exposure to IDV, LPV, abacavir
ACC/AHA ASCVD risk calculator
EACH of these calculators tends to underestimate CVD risk in PLWH

35. Comparison of Framingham and ACC/AHA ASCVD Calculators
ACC/AHA ASCVD Risk Calculator
Framingham Risk Calculator
Data collected from 1713 patients in the Partners HIV Cohort
Compared observed versus predicted risk
Observed risk exceeded predicted risk for most deciles
Indicates underestimation of CVD risk
Triant Circulation 2018.

36. Many HIV Patients with Plaque Would not Be Recommended for a Statin by 2013 Guidelines
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 plaque
vs 12% using 2004 ATP III
Future challenges include developing a prediction algorithm specific to HIV to detect those with subclinical atherosclerosis.
Zanni AIDS 2014.

37. Clinical Strategy
Calculate ASCVD risk score and consider the score as lower estimate of risk
Patients with 10-year ASCVD risk score >7.5% merit:
Suppressive ART if not already started
Aggressive CVD risk factor reduction
Strong consideration for statin

38. Paradigm Shift in Role of ART in Relation to CVD Risk in HIV
2010 IAS-USA HIV treatment guidelines
Recommend initiation of ART specifically for patients with HIV CV risk regardless of CD4 count
Endorse aggressive management of modifiable CVD risk factors
2012 DHHS HIV treatment guidelines
Recommend antiretroviral therapy for all HIV-infected individuals
The 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 malignancy
Thompson JAMA 2010; ACCF/AHA/ACP Circulation 2009;

39. Does an Early START Prevent CVD?
Strategic Timing of AntiRetroviral Treatment (START) Study
First RCT to assess rates of events including non-AIDS/CVD by early (CD4 >500) versus deferred (CD4 <350) ART initiation
Early 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, 2015

40. ART and CVD Risk: Strategies
Treat HIV to reduce CVD risk
CVD-related benefit from virologic suppression and immune reconstitution achieved by treating HIV thought to outweigh possible proatherogenic effects of individual medications
Clinical Strategy
Treat HIV to reduce inflammation, immune activation and associated CVD risk
Consider underlying CVD risk when selecting specific drugs, as individual ART may have varying risk
Thompson JAMA 2010

41. Statins in HIV Dyslipidemia in HIV
Prevalent, with higher rates than people without HIV
Distinctive pattern of low HDL and high triglycerides
May 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 factors
Statin in HIV:
Effectively lower LDL
Decrease immune activation
Hadigan CID 2001; Riddler JAMA 2003; Silverberg Ann Int Med 2009; Lo Lancet HIV 2015

42. Statin Effects on CVD Parameters in HIV
Randomized Controlled Trial, 40 participants, no known history of CVD,
40mg atorvastatin vs. placebo for 12 months
Placebo
Atorvastatin
p = 0.009
p < .0001
p = 0.005
Decreased LpPLA2: marker of vascular inflammation
Decreased LDL
Decreasing non-calcified plaque in proximal left anterior descending (LAD) coronary artery in patient on atorvastatin for 12 months.
Lo, Lancet HIV 2015

43. Challenges in Applying ACC/AHA Cholesterol Guidelines to HIV
Dose-adjustment in HIV (with PIs)
Awaiting further study in HIV
Contraindicated in HIV (with PIs)
Stone Circulation 2014

44.
The first large-scale randomized clinical trial to test a strategy for preventing heart-related disease among PLWH
Hypothesis: 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 HIV

45. REPRIEVE Study Design R 7500 participants from 120 sites Eligibility
Intervention
Screening
and
Consent
Pitavastatin
Placebo
Randomization R
Mechanistic
Study
Primary Endpoint
Coronary plaque,
vascular
Inflammation,
immune activation
HIV+ participants, ages with no history of CVD and ASCVD ≤15%
Primary
Endpoint
Clinical
CVD Death MI
Unstable Angina
TIA & Stroke
Arterial Revasc
PAD
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 guidelines
N=7500
Pitavastatin
*moderate intensity statin
*does not interact w/ any ART – no dose adjustment
*net neutral effects on glucose

46. Clinical Strategies
Early patient education to modify lifestyle (keep it simple, address barriers)
Weight maintenance
Diet modification
Smoking cessation
Physical activity
Monitor for dyslipidemia
Check fasting lipids
At HIV diagnosis
Prior to and within 1-3 months after starting or changing ART
Every 6-12 months
Consider starting statin based on ACC/AHA cholesterol guidelines
Consider fibrate if triglycerides >500mg/dL
Dube CID 2003; Aslangul AIDS 2010; Aberg CID 2014

47. Clinical Strategies Diabetes Hypertension
Check fasting glucose or HbA1c at HIV diagnosis, 103 months after starting or changing ART, and every 6-12 months
HbA1c may be used for screening
Consider cutoff 5.8%
HbA1c may underestimate glycemia in HIV
Check HbA1c every 6 months in DM
Hypertension
Check blood pressure annually
Follow existing Hypertension Guidelines for the general population
No HIV-specific guidelines
Consider drug interactions
Use of some calcium-channel blockers contraindicated with PIs
Aberg CID 2014; Lundgren HIV Med 2008

48. Novel Interventions Targeting Inflammation and Immune Activation
ART treatment intensification
Methotrexate
CCR5 antagonists
Rifaximin
Sevelamer
Mesalamine
Pentoxifylline
Hydroxychloroquine
IL-1β inhibition with canakinumab
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 2012

49. Prevention of HIV-Associated CVD
Start
Antiretroviral Therapy
Early
Traditional Risk Factor Modification
Statins
Smoking cessation
Lifestyle
HIV Associated Factors:
Anti-inflammatories
Immune Modulators
Statins
Patient Education/Prevention

50. Implications and Questions
There is a significant impact of CVD in HIV populations that is related to inflammation and immune activation
Current treatment guidelines do not reflect this pathophysiology
Recommended strategies
Treat HIV infection to reduce CVD risk
Build CVD risk assessment into practice—understanding limitations
Educate about traditional CVD risk factors early and manage risk factors aggressively (smoking cessation)
Start appropriate statin if needed
Future questions
How 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?

51. Questions?