Tyler Lonergan, MD, of the UC San Diego Owen Clinic, presents "Stemming the Tide of Cardiovascular Disease: Transitioning from OI to CVD Prophylaxis" for AIDS Clinical Rounds at UC San Diego Clinical Professor UC San Diego Owen Clinic

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2. Stemming the Tide of Cardiovascular
Disease in HIV-infected Persons:
Transitioning from OI Prophylaxis to
CVD Prevention
Tyler Lonergan, MD
Clinical Professor of Medicine

3. Case Presentation
• 51 year old male w/ HIV (CD4=406/20%, VL<20 on ART) and HTN
who presented to Owen Clinic complaining of epigastric pain
• Pt experienced extreme dizziness on the night before, while getting
out of the jacuzzi at the gym. It was followed by a dull epigastric
pain, which he suspected to be due to indigestion. The pain
progressed overnight, became sharp in quality, radiated to the L
side of his chest, back, and L arm. It was accompanied by nausea,
non-bloody emesis, and loose stools
• In the following morning, he called the Owen Clinic and scheduled
an appointment to be seen in the afternoon despite their advice to
go to the UCSD Hillcrest ED
• At around 14:30 while standing in line to check into the clinic, he
became weak, lightheaded, diaphoretic, and developed L hand
numbness

4. Case Presentation
• PMHx: HIV Dx 2002 (CD4 nadir 29), Herpes Zoster, LTBI,
hypogonadism, depression/ anxiety, osteoporosis, s/p appy,
HTN, dyslipidemia (TC 197, HDL 37, LDL 109, TG 253)
• Meds: efavirenz, abacavir, lamivudine, testosterone gel,
losartan, paroxetine, alendronate, Vit D, Ca
• ScHx: single, lives alone, homosexual (not sexually active),
smokes 1-2 ppw x 12 years, no etoh or illicit drug abuse
• FmHx: mother MI @ 82 yo; uncle, aunt & GF CVA in late 60s
• PEx: thin, anxious, ill appearing, T: 97.8 , BP: 88/58, HR: 87
HEENT: no icterus, no oral lesions, JVP <5 cm, no lad
CV: RRR, nl s1,2, no m,r,g Lungs: CTAB
Abd: nabs, soft, ttp over epigastric area, no HSM Ext: no
edema
• DDx: PUD, pancreatitis, acute MI
• Sent to ED via ambulance

5. ED Course
• Upon arrival in ED at 16:12,
he was hypotensive at
80s/50s, HR 80s, and had
abnormal ECG. A STEMI
code was called, and cath
lab was emergently
activated. Serum cardiac
markers (CPK, CK-MB and
index, Troponin T) were all
elevated. Heparin bolus
and drip, prasugrel, ASA,
atorvastatin and oxygen
given

6. ED and Cath Lab
• Developed 3rd degree AV block, bradycardia in
30-40s. Atropine given and external, transcutaneous pacing initiated. Pt then went into
VT/VF and was shocked once at 150J and
converted back into sinus bradycardia. Also
received a dose of Amiodarone
• In the cath lab, his RCA was found to be 100%
occluded and 2 DES were placed. He continued
dopamine drip to sustain SBP in the 70s-80s

7. Hospital Course
• Echocardiogram: inferior and posterior wall hypokinesis, EF
48%
• Peak CPK: 6306
• Pressure on the chest, sob, dizziness slowly improved over
the week
• New onset of dry cough morning HD#2. Found to have
pulmonary edema on CXR. Edema resolved w/ diuresis
• Pt was in persistent sinus bradycardia but it slowly
converted to a normal rate over the week
• His hemodynamic status was initially grossly unstable w/
low BP, requiring dopamine infusion for 5 days. Unable to
start BB or ACEI due to borderline BP and bradycardia

8. Question #1
• For this patient which of the following is not a
risk factor for CVD?
–
–
–
–
–
–
–
–
HIV
CD4
Abacavir
Lipids
Age
Smoking
HTN
None of the above (all RFs)

9. Question #2
• Prior to his MI which lipid lowering medication
would you have prescribed?
– Statin
– Niacin
– Fibrate
– Omega 3 Fatty Acids
– None of the above

10. Question #3
• Prior to his MI would you have prescribed
aspirin?
– Yes
– No
– Uncertain

11. Leading Causes of Death among All
Americans Age>9yo, 2009

12. Prevalence of CHD by Age and Gender
National Health and Nutrition Examination Survey: 2007-2010
Source: National Heart, Lung and Blood Institute

13. AMI rates in HIV vs non-HIV VA patients
• More than 80,000
veterans with nearly 6
years of follow-up had
871 acute myocardial
infarctions (AMIs)
• Across 3 decades of age,
mean AMIs per 1000
person-years was
consistently higher for
PLHIV than HIV negative
people
• Hazard ratio was 1.5
after adjusting for
Framingham risk factors,
comorbidities, and
substance use

14. Meta-analysis: Relative Risk of CHD in
HIV vs nonHIV
Islam FM et al. HIV Medicine 2012

15. Increased Rates of other CVD in PLHIV
• Sudden cardiac death
- SF clinic: 4.5 fold increased risk of SCD compared to expected city-wide rate1
• Heart Failure
– VA cohort: compared with HIV-uninfected veterans, those who were HIV infected
had an increased risk of HF (adjusted HR, 1.81). Those with baseline HIV RNA>500
had increased risk of HF while those with baseline or most recent HIV RNA<500 did
not2
• Atrial Fibrillation
– VA Cohort: lower CD4(+) cell count (<200 compared with >350; HR: 1.4) and higher
viral load (>100,000 compared with <500 copies/ml; HR: 1.7) were independently
associated with increased risk of AF. Additional RFs: older age, White race, CAD,
CHF, etoh, proteinuria, reduced kidney function, and hypothyroidism3
• Stroke
– Boston Cohort: HR of ischemic stroke 1.21 in HIV vs non-HIV. Increased HIV RNA
was associated with an increased risk of IS4
– In US from 1997 to 2006 stroke hospitalizations with coexisting HIV infection rose
60% (888 to 1425)5
• PAD6
1 Tseng ZH er al. J Am Coll Cardiol 2012, 2 Butt AA et al. Arch Intern Med 2011, 3 Hsu JC et al. J Am Coll Cardiol 2013,
4 Chow FC et al. JAIDS 2012, 5 Ovbiagele B et al. Neurology 2011, 6 Ye Y et al. JAIDS 2010

17. Age Distribution by Year: Swiss HIV Cohort
Hasse B, et al. CID 2011

18. Aging of Owen Clinic Patients

19. Distribution of Owen Clinic Patients by Age
Group and Year

20. Life Expectancy at Age 20 among Treated
HIV+ North Americans
• Estimate temporal changes
in life expectancy among
HIV+ adults on ART from
2000-2007 in US and
Canada
• 22,937 participants from
NA-ACCORD Cohort
• 1622 deaths; crude
mortality rate 19.8/1000 py
• Life expectancy was lower
for individuals with a history
of IVDU, non-whites, and in
patients with baseline CD4
counts <350 cells/mm3
Samji J, et al. PLOS ONE 2013

21. Causes of Death in PLHIV on ART
• Retrospective
classification of deaths
in 39,272 European
and NA patients who
initiated ART from
1996-2006 and were
enrolled in one of 13
HIV cohort studies
• 1597/1876 deaths a
definitive cause of
death identified
Antiretroviral Therapy Cohort Collaboration CID 2010

23. Traditional CVD Risk Factors in HIV vs Non-HIV
a
statistically significant comparison of HIV and non-HIV proportions, with X2 (P<0.0001)
Triant VA, et al. J Clin Endocrinol Metab 2007

24. Other Risk Factors for CVD in PLHIV
• Low CD4 count:
– HOPS COHORT:
Baseline CD4<500 was an
independent RF for CVE
and risk of CVE attributable
to baseline CD4<500 was
comparable to smoking
and dyslipidemia1
• Detectable Viral load
– SMART TRIAL:
Hazard Ratio for risk of
CVD events for DC vs VS
was 1.57 (95% CI 1.00 –
2.46; P=0.05)2
1Lichtenstein KA, et al. CID 2010, 2Phillips N, et al. Antiviral Therapy 2007

25. Antiretrovirals and MI Risk
• Abacavir:
– Meta-analysis of observational studies indicate increased
risk of MI with <6 months of exposure to abacavir (RR 1.92,
95% CI 1.51-2.42)
– Meta-analysis of RCTs found no association between
abacavir use and MI
• Protease inhibitors:
– Meta-analysis of observational studies found increase in
risk of MI with recent PI exposure (OR 2.13, 95% CI 1.06 –
4.28) and cumulative exposure to indinavir (RR 1.11, 95%
CI 1.05 – 1.17) and lopinavir (RR 1.22 (95% CI 1.01 – 1.47)
– Meta-analysis of RCTs failed to demonstrate an association
between PI use and MI
C Bavinger PLOS One 2013

26. Causes and Consequences of HIVassociated Inflammation
S Deeks et al. The Lancet. 2013

27. Primary Prevention of CHD
• Non-modifiable RF (age, gender, family history)
• Modifiable RF (via lifestyle changes +/- meds)
–
–
–
–
–
–
–
–
–
•
Poor diet
Smoking
Hypertension
Dyslipidemia
Physical inactivity
Obesity
Diabetes mellitus
Heavy alcohol consumption
HIV
Additional adjunctive medication intervention: aspirin

29. Mortality attributable to Smoking in
PLHIV
• Danish cohort
• 2921 HIV+ patients, 10,642 HIVcontrols
• Among PLHIV 47.4%, 17.7%,
34.9% were current, former and
never smokers and among HIVcontrols corresponding rates
were 20.6%, 32.8%, 46.6%
• Among PLHIV relative MR from
CVD in smokers 4.3 higher than
in never smokers
• Excess mortality of smokers is
tripled (17.6 vs 4.8/1000 py) and
population-attributable risk of
death associated with smoking is
doubled (61.5% vs 34.2%) among
HIV+ patients compared to HIVcontrols
Helleberg, M et al. CID 2013

30. Smoking Cessation Reduces
Risk for Cardiovascular Events
• D:A:D Cohort
• More than 27,000
patients had a total of
1778 CVEs or mortality
• Adjusted incidence rate
ratio of CVD in patients
who stopped smoking
decreased from 2.3
within the first year of
stopping to 1.5 after > 3
years compared with
those who never
smoked. Similar trends
were observed for the
MI and CHD endpoints
Petoumenos et al, HIV Medicine 2011

32. Question #4
• Which guidelines do you use to determine
who should go on lipid lowering therapy?
– 2013 ACC-AHA
– NECP ACT III
– IDSA/ACTG
– Other
– Do not use any

33. 2003 IDSA/ACTG Dyslipidemia
Guidelines for HIV+ Persons
Dube MP, et al. CID 2003

34. NCEP ATP III Cholesterol Guidelines
http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

35. NCEP ATP III Guidelines
TLC: low saturated fat diet, increase physical activity and weight management
Consider drug simultaneously with TLC for CHD and CHD equivalents
Consider adding drug to TLC after 3 months for other risk categories.
http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

36. NCEP ATP III Cholesterol Guidelines
If TG>500 treat TG first
Non-HDL goal 30 mg/dL higher than LDL goal
http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

37. 2013 ACA-AHA Cholesterol Guidelines

38. High and Moderate-Intensity Statin Therapy
according to ACC-AHA Cholesterol Guidelines

39. 2013 ACC/AHA CV Risk Calculator
http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

40. D:A:D 5 year Estimated Risk
Calculator*
• BMI, lipodystrophy, TGs, CD4
and VL were assessed and
excluded based on
nonsignificance
• Risk of CHD over 5 year
period:
–
–
–
–
Low (<1%)
moderate (1-5%)
high (6-10%)
very high (>10%)
• DAD model better predicted
CVE than an older FRAM
equation (one used did not
include variable for treated
HTN and had differences in
outcomes measured)
• Not validated externally
*http://www.cphiv.dk/TOOLS/DADRiskEquations/tabid/437/Default.aspx
Friis-Moller N, et al. Eur J Cardiovasc Prev & Rehabil 2010

41. Updated D:A:D risk models
• Additional 80,000 PY of follow-up (total
180,000 PY)
• One outcome only: Global CVD risk
• Based on baseline rather than time-updated
risk parameters (Cox Model)
• Full and Reduced D:A:D models (+/- ARVs)
• Updated Models will be available at
www.CPHIV.DK (updated models still currently
unavailable)
N Friis Moller et al. 14th European AIDS Conference 2013

42. 3 CVD Risk Models
N Friis Moller et al. 14th European AIDS Conference 2013

43. 5-year CVD risk by Age and Diabetes
N Friis Moller et al. 14th European AIDS Conference 2013

44. UpToDate Treatment of Lipids in
Primary Prevention Guidelines
• Counsel all patients to exercise, eat a prudent diet and
lose weight as appropriate
• Calculate pt’s baseline risk for CVE (using FRC) and
treating with statin in pts for whom 20-30% reduction
in events translates into absolute reduction in events
worth costs and burdens of daily therapy
• Do not recommend specific LDL target or calculated CV
risk cutoff to determine use of statin
• If decision made to treat then use moderate statin
dose (eg, pravastatin 40 mg, atorvastatin 20 mg,
rosuvastatin 5-10 mg)

45. UpToDate Cholesterol Guidelines
• Recommend measuring LDL 6 weeks after
starting statin and every 6-12 months thereafter
to assess med adherence only
• Do not recommend monitoring LDL response to
therapy or intensifying dose to achieve any
particular LDL goal
• Do not recommend nonstatin lipid-lowering
therapy in pts who do not tolerate statins or
adding them in pts who do not achieve a
particular LDL level on a statin alone.

46. 2013 Cochrane Review of Statins for
primary prevention of CVD
Incidence of cancers, myalgia, rhabdomyolysis, LFT elevation, renal dysfunction, or arthritis and rates of
adverse events (17%) and stopping treatment (12%) did not differ between statin and placebo groups. An
increase risk of incident of diabetes (RR 1.18 [95% CI, 1.01-1.39], NNT 198) found in 1/2 trials reporting this
outcome. No long term data on health related QOL outcomes.
Taylor F, et al. Cochrane Database Syst Rev. 2013

47. Statin Affects on Inflammatory
Markers in PLHIV
• Retrospective cohort study
• 151 HIV+, dyslipidemic pts on stable ART who
were started on a statin and followed for ≥12 mo
Calza L, et al. HIV Cin Trials 2012

48. Statin Affects on Immune Activation in
PLHIV
• Randomized, double-blind, placebo-controlled crossover trial to
investigate effect of statin on HIV RNA and cellular markers of immune
activation
• 24 untreated HIV+ pt randomized to receive 8 weeks of atorvastatin 80 mg
or placebo daily. After 4-6 week washout phase, participants switched
treatment assignments
Ganesan A, et al. JID 2011

49. Affect of Rosuvastatin on cIMT and lipids in
PLHIV
• 36 adult (30 M) HIV+
pts, mean age 49 yr,
mean duration of ART
38 mo, mean 10 yr
risk of MI 18.5%.
• Rosuvastatin 10
mgdaily x 24 months
• Well tolerated, no
adverse events
Calza L, et al. AIDS Res Hum Retroviruses 2013

50. Association between Statins and Mortality in
PLHIV
• JH HIV Cohort
• 238/1538 pt fully suppressed on ART
were also taking a statin
• 85 deaths (7 on statins)
– 12 cardiovascular (2 on statin)
• Statin use associated with relative
hazard of 0.33 (95% CI: 0.14-0.76;
P=0.0009) of all cause mortality after
adjusting for multiple factors
Moore RD, et al. PloS One 2011

52. Aspirin
• Aspirin has been shown to be effective in the primary and
secondary prevention of AMI in the general population
• No study looking at the effect of aspirin in prevention of
CVD in PLHIV
• Decrease cardiovascular events via:
– Antiplatelet effects
– Increased nitric oxide formation
– Anti-inflammatory effects
• Heightened platelet activation and immune activation in
treated HIV-infected patients were attenuated by 1 week of
aspirin therapy (325 mg loading dose followed by 81 mg
daily)1
1 O’Brien M, et al. JAIDS 2013

53. Aspirin Primary Prevention of CVD
• Pooled data from RCT in general population
suggest aspirin is associated with:
– ~20% relative risk reduction in non-fatal MI
– No significant effect on non-fatal stroke (including
hemorrhagic stroke)
– ~12% relative risk reduction in cancer incidence
– ~50% increase in relative risk of major non-fatal
extracranial bleed
– ~6% reduction in relative risk in overall mortality

54. Estimated Absolute Benefits and Risks
of Aspirin for Primary Prevention
• Daily aspirin use in a thousand 60 yo HIV
negative pts with avg risk (10-20%) for CAD
and malignancy (~12%) over 10 yr period:
– 6 fewer deaths
– 6 fewer cancers
– 17 fewer non-fatal MI
– No significant reductions in non-fatal strokes
– 16 more major bleeding events (IC, GI or other
requiring hospitalization +/- transfusion)

55. Caveats of Aspirin Use
• Low dose as effective as higher dose with
possibly less side effects
• Do not use concurrently with warfarin
• Avoid concurrent use of NSAIDs (reduces anticardioprotective effects and increases risk of
GIB)
• Avoid use in patients with history of PUD or
other risk factors of GIB

56. Guidelines for Aspirin Use
• UTDOL: individualize assessment of patient’s risk for MI,
cancer and bleeding and discuss results with patient to
determine patient’s preference. For individuals age ≥50 yr
without excess bleeding risk, suggest low dose daily aspirin
• ACCP 2012: suggest low-dose aspirin (75-100 mg) daily over
no aspirin therapy for persons ≥50 yr without symptomatic
CVD
• European Society of Cardiology 2012: advise against use of
aspirin in individuals without CVD due to risk of major
bleeding
• USPTF 2009: recommends for men 45-79 yo for MI
prevention and women 55-79 for stroke prevention if
benefits outweigh risks
• No specific guidelines for HIV+ patients

57. USPSTF Aspirin for Primary CVD Prevention Guidelines
Does not apply to adults taking NSAIDs (4x GIB risk), have upper GI pain or
Hx of GI ulcers (2-3x GIB risk)
USPSTF Ann Intern Med 2009;150:396-404

58. Underutilization of Aspirin for primary
prevention of CVD in qualifying PLHIV
• UAB HIV Clinic: 66/397 (17%) patients who
qualified to receive ASA were prescribed it1
• Spanish Cohort: 2/37 patients who met
criteria for aspirin for primary prevention of
CVD were prescribed it2
1 Burkholder GA, et al. CID 2012, 2 Tornero CA, et al. JAIDS 2010

59. Undertreatment of CVD RFs
• Multicenter German Cohort: Almost half of
patients with DM and HTN were untreated. LDL
appropriately treated <50% in patients at
moderate CHD risk and <70% at high risk 1
• VACS: 39% of HIV+ vs 62% of HIV- vets (OR 0.45)
received appropriate lipid lowering therapy2
• HOPS: 81%-87% treated for elevated LDL but only
2-11% for low HDL (NCEP ATP III guidelines) and
46-59% for HTN3
1Reinsch N, et al. Eur J Prev Cardiol 2012, 2 Freiberg MS, et al. J Gen Intern Med 2009
3Lichenstein KA, et al. Preventing Chronic Disease 2013

60. Case: Statin/ASA for primary MI
prevention?
•
•
•
•
PreMI lipids: TC 197, HDL 37, LDL 109, TG 253, nonHDL 160
Traditional RFs: HTN, Smoker, Low HDL, Age
HIV related RFs: CD4<500, abacavir
NCEP ATP III:
– 10-year risk: 16%
– 2+RF, 10-yr risk ≤20%: LDL goal <130, nonHDL goal<160
– At goal LDL, slightly above nonHDL goal, initiate TLC and consider drug
therapy
• ACC/AHA 10-year risk: 12.6%
– Recommend high-intensity statin therapy
• D:A:D 5 year risk: 7.4% (high risk)
• USPSTF Guidelines:
– 10-year risk: 17%
– Recommend aspirin

61. First MI among Owen Clinic Patients
2012+2013
• 11 patients
• All male
• Race: 6 W, 3 L, 1 Asian,
1B
• Mean Age: 49 (range: 3857), 2<45 yo
• 8/11 on ART
• Mean CD4: 488 (1601253)
• Viral Load: 8/11<100
• Mean TC: 188 (126-241)
• Mean HDL: 39 (21-52),
6/11<40
• Mean LDL: 107 (61-175),
3/11<70, x/11<100
• Current Smoker: 6/11
• Hypertension: 4/11
• DM: 2/11
• ACC/AHA Calculator: mean
(range): 7.4% (2.9%-16.2%)
• UTDOL FRAM Calculator:
16.5% (6.7%-33.8%)

62. First MI at Owen Clinic
• Prescribed Aspirin prior to MI: 2/11
– 8/11 met USTSPF criteria
– Of 3 who did not meet criteria:
• 1 calculated risk below threshold
• 2 <45 yr
• Prescribed Statin prior to MI: 1/11
– 4/11 met ACC-AHA criteria
– Of 7 who did not meet criteria:
• 3 had LDL<70
• 4 risk <7.5%
• 10/11 patients had stents
– 8 DES, 2 BMS
– 4 had 1 stent, 6 had 2 stents
• 1 CABG
• All survived MI and are still alive

63. Summary
• Due to advances in ART, the life expectancy of
PLHIV is approaching that of the general
population
• PLHIV are at greater risk for developing CVD due
to HIV-associated inflammation and immune
activation and higher rates of traditional CVD RFs
• Encourage all patients to adopt a healthy life
style
• Treat HIV and identify and manage modifiable
traditional CVD RFs

64. Summary II
• Use of interventions for primary prevention of CVD are underutilized
• Aspirin and statins provide anti-inflammatory and immune deactivation
effects that may provide additional benefits for PLWH
• Current guidelines for use of aspirin and statin therapy for primary
prevention of CVD in the general population use risk calculators that do
not account for the deleterious effect of HIV and therefore likely
underestimate the CVD risk for PLWH
• In 2012 and 2013 most Owen Clinic patients did not meet current
guideline criteria for aspirin or statin use due to young age, low LDL or low
calculated risk prior to their MIs. Consider the following for PLWH:
– account for HIV-related risk factors (e.g, CD4 count, viral load) when
determining risk
– start statins and aspirin at younger ages than currently recommended for
general population
– use statins at lower doses in high risk patients with LDL<70
– use new D:A:D HIV risk calculator when available or if using ACC-AHA
calculator then multiply determined risk by 1.5