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AIDS CLINICAL ROUNDS

Stemming the Tide of Cardiovascular Disease in HIV-infected Persons:

Transitioning from OI Prophylaxis to CVD Prevention

Tyler Lonergan, MD Clinical Professor of Medicine

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

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

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

ED and Cath Lab

• Developed 3rd degree AV block, bradycardia in 30-40s. Atropine given and external, trans- cutaneous 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

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

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)

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

Question #3

• Prior to his MI would you have prescribed aspirin? – Yes – No – Uncertain

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

Prevalence of CHD by Age and Gender

Source: National Heart, Lung and Blood Institute

National Health and Nutrition Examination Survey: 2007-2010

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

Meta-analysis: Relative Risk of CHD in HIV vs nonHIV

Islam FM et al. HIV Medicine 2012

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

Age Distribution by Year: Swiss HIV Cohort

Hasse B, et al. CID 2011

Aging of Owen Clinic Patients

Distribution of Owen Clinic Patients by Age Group and Year

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

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

Traditional CVD Risk Factors in HIV vs Non-HIV

Triant VA, et al. J Clin Endocrinol Metab 2007

a statistically significant comparison of HIV and non-HIV proportions, with X2 (P<0.0001)

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

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

Causes and Consequences of HIV-associated Inflammation

S Deeks et al. The Lancet. 2013

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

Mortality attributable to Smoking in PLHIV

• Danish cohort • 2921 HIV+ patients, 10,642 HIV-

controls • Among PLHIV 47.4%, 17.7%,

34.9% were current, former and never smokers and among HIV- controls 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 HIV- controls

Helleberg, M et al. CID 2013

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

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

2003 IDSA/ACTG Dyslipidemia Guidelines for HIV+ Persons

Dube MP, et al. CID 2003

NCEP ATP III Cholesterol Guidelines

http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

NCEP ATP III Guidelines

http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

Consider drug simultaneously with TLC for CHD and CHD equivalents Consider adding drug to TLC after 3 months for other risk categories.

TLC: low saturated fat diet, increase physical activity and weight management

NCEP ATP III Cholesterol Guidelines

http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

Non-HDL goal 30 mg/dL higher than LDL goal

If TG>500 treat TG first

2013 ACA-AHA Cholesterol Guidelines

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

2013 ACC/AHA CV Risk Calculator

http://my.americanheart.org/professional/StatementsGuidelines/PreventionGuidelines/Prevention-Guidelines_UCM_457698_SubHomePage.jsp

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

Friis-Moller N, et al. Eur J Cardiovasc Prev & Rehabil 2010 *http://www.cphiv.dk/TOOLS/DADRiskEquations/tabid/437/Default.aspx

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

3 CVD Risk Models

N Friis Moller et al. 14th European AIDS Conference 2013

5-year CVD risk by Age and Diabetes

N Friis Moller et al. 14th European AIDS Conference 2013

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)

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.

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

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

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

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

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

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

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

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)

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 anti-

cardioprotective effects and increases risk of GIB)

• Avoid use in patients with history of PUD or other risk factors of GIB

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

USPSTF Aspirin for Primary CVD Prevention Guidelines

USPSTF Ann Intern Med 2009;150:396-404

Does not apply to adults taking NSAIDs (4x GIB risk), have upper GI pain or Hx of GI ulcers (2-3x GIB risk)

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

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

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

First MI among Owen Clinic Patients 2012+2013

• 11 patients • All male • Race: 6 W, 3 L, 1 Asian,

1 B • Mean Age: 49 (range: 38-

57), 2<45 yo • 8/11 on ART • Mean CD4: 488 (160-

1253) • 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%)

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

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

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