Practical Management Strategies for Cardiovascular Risk in HIV

Pablo Tebas, MDAssociate Professor of MedicineUniversity of PennsylvaniaPhiladelphia, Pennsylvania

Pretreatment Assessment for Metabolic Complications in HIV1. Identify Presence of

CHD

MI

Unstable/stable angina

Previous coronary procedures

Myocardial ischemia

2. Identify Presence of CHD Equivalents

Peripheral artery disease

Abdominal aortic aneurysm

Coronary artery disease

Diabetes

3. Medical History

Hypertension

Cigarette smoking

Family history of CHD

Low HDL

Perform fasting plasma glucose and lipid measurements*

Calculate 10-year CV risk

NCEP ATP III final report. Circulation. 2002;106:3143-3421.

*Measurements should be performed yearly after HAART initiation and more frequently if dyslipidemia, glucose intolerance, or diabetes develops.

Framingham Risk Score Used to Estimate 10-Year Cardiovascular Risk

Developed for use in general population

– Thought to be reasonable predictor in HIV-infected population

However, does not include HIV-specific factors

– Immune status

– Increased inflammatory markers

– Insulin resistance

Age:

Sex:

Total cholesterol:

HDL cholesterol:

Smoker:

Systolic blood pressure:

Are you currently on any medication to treat high blood pressure?

Female Male

No Yes

No Yes

National Cholesterol Education Program. Available at: http://hin.nhlbi.nih.gov/atpiii/calculator.asp. Accessed March 10, 2008.

Calculate Your 10-Year Risk

Lipids Management: Are the LDL cholesterol targets

recommended for the general population also appropriate for patients with HIV?

NCEP ATP III Lipid Goals

Risk Category CHD Risk Factors or Equivalents

LDL Goal, mg/dL (mmol/L)

Non-HDL Goal, mg/dL (mmol/L)

Very highHigh risk + recent acute coronary

syndrome, diabetes, smoking, metabolic syndrome*

< 70 (< 1.81) < 100 (< 2.59)

HighCAD or risk equivalent

(10-yr risk > 20%)

< 100 (< 2.59)(optional < 70

[<1.81])< 130 (< 3.37)

Moderately high≥ 2 risk factors +

(10-yr risk 10% to 20%)< 130 (< 3.37) < 160 (< 4.14)

Moderate≥ 2 risk factors +(10-yr risk < 10%)

< 130 (< 3.37) < 160 (< 4.14)

Low 0-1 risk factor < 160 (< 4.14) < 190 (< 4.92)

NCEP ATP III final report. Circulation. 2002;106:3143-3421.Grundy SM, et al. Circulation. 2004;110:227-239.

*Or baseline LDL < 100 mg/dL (< 2.59 mmol/L).

Lipid Goals For HIV-Infected Patients

NCEP lipid goals intended for general population likely appropriate for HIV-infected patients

– Lipid goals established to reduce cardiovascular risk

Contrary to previous findings, data from D:A:D cohort suggest Framingham risk equation may overestimate risk of cardiovascular events in HIV-infected patients

D:A:D equation more accurately predicted CHD outcomes in HIV-infected population

– Incorporates PI exposure as well as conventional CHD risk parameters

Friis-Moller N, et al. CROI 2007. Abstract 808.

Lipids Management: What are the preferred management approaches for patients with HAART-

associated hyperlipidemia? Specifically, what factors should

be considered in deciding whether to switch antiretroviral agents, use

lipid-lowering therapy, or both?

Carr A, et al. AIDS. 2001;15:1811-1822. Moyle G, et al. AIDS. 2001;15:1503-1508. Miller J, et al. AIDS. 2002;16:2195-2200. Doser N, et al. AIDS. 2002;16:1982-1983. Aberg JA, et al. AIDS Res Hum Retroviruses. 2005;21:757-767. Calza L, et al. AIDS. 2005;19:1051-1058.

Managing Dyslipidemia: PI Switch vs Lipid-Lowering Therapy

Metabolic Parameter PI Switch Statin Fibrate

TC -10% to -30% -11% to -45% 0% to -5%

HDL 0% to +3% 0% to +6% 0% to +17%

TG -10% to -25% 0% to -25% -20% to -45%

Insulin sensitivity Variable No change No change

When switching antiretroviral therapy

– Maintenance of virologic suppression is paramount

– Any switch carries some risk of loss of virologic suppression

Lipid-lowering agents

– May avoid risks associated with switch but at the price of polypharmacy

– More commonly used in US; European guidelines suggest lipid-lowering therapy only after dietary modification and switch strategies

NEFA: Change in TC After Switch From PI to ABC, EFV, or NVP

Martinez E, et al. CROI 2006. Abstract 521.

Outcome at 36 Mos NVP(n = 155)

EFV(n = 156)

ABC(n = 149)

Death or progression to AIDS, n 1 5 3

Virologic failure, % 8 11 36

New clinically relevant lipoatrophy, % 29 30 25

Pat

ien

ts W

ith

Fas

tin

g

Ch

ole

ster

ol

≥ 24

0 m

g/d

L

(6.2

2 m

mo

l/L

) (%

)

05

101520253035

0 1 2 3Years

NVP EFV ABC

2124 25

7

21

29

12

2730

17

12

6

*P < .001 for comparison with time of switch.

Mea

n C

han

ge

in F

asti

ng

L

ipid

s (m

g/d

L)

* *

102

41

59

38

0

20

40

60

80

100

120

Baseline (Time of Switch)

Year 3

GS903E: Change in Lipids After Switch From d4T to TDF (Week 144)

Madruga JVR, et al. ICAAC 2007. Abstract H-364.

N = 85

TG TC

*Unboosted ATV, except ATV/RTV used in patients also receiving TDF.

Continue PI (n = 141)Switch to ATV* (n = 278)

P < .0001

-3

-15

-3

P = NS

-1

-40-35-30-25-20-15-10

-505

1015

TC LDL HDL Non-HDL

Mea

n C

han

ge

Fro

m B

asel

ine

to W

eek

48 (

%)

P = NS

-5

-12

-33

9

P < .0001

-3

-18

P < .0001

TG

SWAN: Change in Lipids After Switch From Comparator PI to ATV (Week 48)

Gatell JM, et al. EACS 2005. Abstract PS1/1.

Mallolas J, et al. IAS 2007. Abstract WEPEB117LB.

ATAZIP: Switch From LPV/RTV to ATV/RTV

TG LDL HDLTC

-60

-40

-20

0

20

P < .0001Ch

ang

e at

Wee

k 48

(m

g/d

L)

P < .0001

Continue LPV/RTV

Switch to ATV

Randomized trial of patients on LPV/RTV > 6 months randomized to continue LPV/RTV 400/100 mg BID (n = 127) or switch to ATV/RTV 300/100 mg QD (n = 121)

Lipid-Lowering Therapy vs Switching PI 12-month, open-label study of

130 patients; 60% male; mean age: 39 years

Stable on first HAART regimen randomized to

– PI EFV (n = 34)

– PI NVP (n = 29)

– Add bezafibrate (n = 31)

– Add pravastatin (n = 36)

Pravastatin or bezafibrate significantly more effective in management of hyperlipidemia than switching ART to an NNRTI

Calza L, et al. AIDS. 2005;19:1051-1058.

Lipids Management: What is the optimal approach to

managing a patient with elevated TG but otherwise normal lipids during

boosted PI–based therapy?

Strategies for Managing Hypertriglyceridemia

NCEP ATP III final report. Circulation. 2002;106:3143-3421.

Initial intervention: dietary modifications

Consider antiretroviral switch options

If TG > 500-1000 mg/mL (> 5.65-11.30 mmol/L) and antiretroviral switch not possible, consider fibrates

– Gemfibrozil 600 mg BID or fenofibrate 200 mg QD associated with 20% to 50% decrease in TG in general population

If hypertriglyceridemia remains uncontrolled

– Fish oil (up to 6 g/day) or niacin (0.5 to 2g twice-dialy) can be added

– Niacin associated with flushing and increased insulin resistance

Dietary Prevention of Dyslipidemia

Randomized trial of NCEP diet in adults initiating ART (N = 90)

– 95% on ZDV/3TC

– 75% on EFV

15- to 30-minute session with a dietician every 3 months

Other outcomes

– Reduced fat, calorie intake

– Reduced BMI

– Increased dietary fiber intakeLazzaretti F, et al. IAS 2007. Abstract WEAB303.

Diet Control

Months

100

120

140

160

180

200

220

0 6 12

TC

(m

g/d

L)

406080

100120140160180200220240

0 6 12

TG

(m

g/d

L)

Lipids Management: What drug-drug interactions are important

for HIV patients when choosing lipid-lowering therapy? Which statins can be used safely in patients receiving PIs?

Lipid-Lowering Agents and PIs:Drug-Drug Interactions

*AUC ↑↑↑ with DRV.

FibratesFluvastatin

Pravastatin*Ezetimibe

Fish oil

Use cautiously

Statin + fibrateAtorvastatin

RosuvastatinNiacin

LovastatinSimvastatin

Contraindicated

Low interactionpotential

Aptivus [package insert]; 2005. Carr RA, et al. ICAAC 2000. Abstract 1644. Fitchenbaum CJ, et al. AIDS. 2002;16:569-577. Gerber JG, et al. CROI 2004. Abstract 603. Gerber J, et al. IAS 2003. Abstract 870. Hsue PH, et al. Antimicrob Agents Chemother. 2001;45:3445-3450. Lexiva [package insert]; 2007. Prezista [package insert]; 2006. Reyataz [package insert]; 2007.

Lipids Management: What should be the management approach for the patient with high

cardiovascular risk who does not reach LDL goals after treatment with statins?

Additional Therapy When LDL Goals Are Not Reached With Statins Drug Effects in the

General PopulationComments

Niacin ↓ LDL 5% to 25%↑ HDL 15% to 35%↓TG 20% to 50%

Start with 500 mg; increase progressively to 2000 mg Caution in patients with diabetes or insulin resistance,

gout, or abnormal LFTs Use aspirin to prevent flushing

Fibrates ↓ LDL 5% to 20%↑ HDL 10% to 35%↓ TG 20% to 50%

Most frequently used to treat hypertriglyceridemia Caution in elderly and patients with abnormal LFTs Monitor GI intolerance and cholelithiasis

Ezetimibe ↓ LDL 25%↑ HDL 3%↓ TG 14%

Generally added to a statin In HIV-infected patients, do not use fixed combination

with simvastatin Monitor LFTs

Fish oil ↓ LDL 10% to 20%↑ HDL 4% to 5%↓ TG 20% to 50%

Not all formulations equivalent GI intolerance most frequent adverse effect Usually used in combination with a fibrate or a statin

Fenofibrate vs Pravastatin in HIV-Infected Subjects: ACTG 5087 HIV infected and on ARV > 6 months (n = 174)

LDL > 130 mg/dL (> 3.37 mmol/L) and TG > 200 mg/dL (> 2.26 mmol/L)

– Randomized to

– Fenofibrate 200 mg QD

– Pravastatin 40 mg QD

– Addition of other drug at Week 12 if lipid goal not achieved

– Goal: NCEP composite LDL, HDL, TG targets

4 (7%) on fenofibrate + pravastatin achieved composite NCEP goal

2 (3%) on pravastatin + fenofibrate achieved composite NCEP goal

Sequencing fenofibrate then pravastatin resulted in greater absolute and % TG ↓

Aberg J, et al. AIDS Res Human Retrovirus. 2005;21:757-767.

Ezetimibe for Lipid Management

Open-label, 24-week study of 19 patients with LDL 130 mg/dL ( 3.37 mmol/L) receiving ezetimibe 10 mg/day, pravastatin 20 mg/day, and current antiretrovirals [1]

Significant ↓ in TC and LDL and significant ↑ in HDL at Week 24*

No adverse events noted

1. Negredo E, et al. AIDS. 2006;20:2159-2164. 2. Wohl D, et al. CROI 2007. Abstract 39.

Baseline

P = .011

P = .005

P = .004

250

200

150

100

50

0

Lip

id L

evel

s (m

g/d

L)

TC LDL HDL TG*Subsequent study found that ezetimibe decreased LDL levels by 12% but had no effect on HDL or TG.

Week 24

Treatment of Hypertriglyceridemia With Fish Oil Randomized, controlled trial of high-dose fish oil vs paraffin oil

N = 122 patients with hypertriglyceridemia > 2 g/L on HAART

– Mean baseline TG: 4.5 g/L

Significant efficacy at Week 8

10 patients with TG > 10 g/L given open-label fish oil: 44% ↓ in TG after 8 weeks

– No change in LDL

Week 8 Outcome (ITT) Fish Oil(n = 58)

Paraffin Oil (Control) (n = 62)

P Value

Mean change in TG, % -25.5 +2.0 .0033

Normalized TG, % 22.4 6.5 .126

TG decreased > 20%, % 58.6 33.9 .007

De Truchis P, et al. CROI 2005. Abstract 39.

Metabolic Syndrome and Diabetes: How is “metabolic syndrome” defined in

HIV-infected patients and what is the relevance to this population?

Definition of Metabolic Syndrome

According to the NCEP ATP III, individuals with ≥ 3 of the following have the metabolic syndrome

– Abdominal obesity (waist circumference > 102 cm for men; > 88 cm for women)

– TG ≥ 150 mg/dL (≥ 1.70 mmol/L)

– HDL < 40 mg/dL (< 1.04 mmol/L) for men, < 50 mg/dL (< 1.30 mmol/L) for women

– Blood pressure ≥ 130/≥ 85 mm Hg

– Fasting glucose ≥ 110 mg/dL (≥ 5.55 mmol/L)

NCEP ATP III final report. Circulation. 2002;106:3143-3421.

Metabolic Syndrome in HIV-Infected vs HIV-Uninfected Patients

1. Mondy K, et al. Clin Infect Dis. 2007;44:726-734. 2. Sobieszczyk ME, et al. IAS 2006. Abstract WEPE0147. 3. Jerico C, et al. Diabetes Care. 2005;28:132-137.

Conflicting data on whether metabolic syndrome more prevalent in HIV-infected patients and whether associated with antiretroviral therapy

May also reflect background regional variations in risk

Study, %

Prevalence of Metabolic Syndrome

P ValueHIV-Infected Patients

HIV-Uninfected Controls

US; 471 men and women[1] 26 27 .77

US; 2394 women[2] 33 22 < .001

Spain; 710 men and women[3] 17 N/A --

Metabolic Syndrome and Diabetes: Are the targets for diabetes management forthe general population also appropriate for

patients on antiretroviral therapy?

Targets For Diabetes Management

Parameter Goal

Glycemic control

A1C, % < 7.0

Preprandial capillary plasma glucose, mg/dL (mmol/L) 90-130 (4.99-7,22)

Peak postprandial capillary plasma glucose, mg/dL (mmol/L) < 180 (< 9.99)

Blood pressure, mm Hg < 130/80

Lipids

LDL, mg/dL (mmol/L) < 100 (< 2.59)

TG, mg/dL (mmol/L) < 150 (< 1.69)

HDL, mg/dL (mmol/L) > 40 (> 1.04)

No evidence that targets for HIV-infected population should differ from HIV-uninfected population

American Diabetes Association. Diabetes Care. 2008;31:S12-S54.

Rosiglitazone vs Metformin in HIV-Infected Patients 39 HIV-infected men with lipodystrophy randomized to rosiglitazone 8 mg/day

or metformin 2 g/day for 26 weeks

– Both drugs increased insulin sensitivity

– Metformin associated with fat loss, rosiglitazone with SAT gain

Week 26 Results Rosiglitazone (n = 19) Metformin (n = 20)

Insulin resistance ↓ ↓

SAT ↑ ↓

VAT ― ↓

TG ↑ ↓

TC ― ↓

Adiponectin ↑ ―

Flow mediated vasodilatation ― ↑

van Wijk JP, et al. ICAAC 2005. Abstract H-339.van Wijk JP, et al. Ann Intern Med. 2005;143:337-346.

Cautions When Using Insulin-Sensitizing Agents Patients beginning insulin-sensitizing agents should be

monitored closely due to risk of adverse events

Patients with aminotransferase levels > 2.5 x ULN should avoid glitazones

– Risk of hepatotoxicity

Patients with elevated serum creatinine levels should avoid metformin

– Risk of lactic acidemia

AACTG Metabolic Guides. Available at: http://aactg.s-3.com/metabolic/diabetes.pdf. Accessed March 10, 2008.

Lifestyle Issues: Are dietary and exercise advice

designed to reduce cardiovascular risk in the general population also

appropriate for patients with HIV?

Dietary Intervention to Reduce CVD Risk in HIV-Infected Individuals 51 HIV-infected patients (45 male and 6 female) receiving PI therapy[1]

– High levels of dietary protein (mainly from animal sources) correlated with elevated TC (P < .01), elevated TG(P < .01), and reduced HDL (P < .001)

Diets high in fiber, particularly soluble fiber, associated with higher HDL levels and reduced fat deposition in HIV-infected patients[2]

Randomized study of omega-3 fatty acids in patients receiving HAART[3]

– Patients assigned to receive omega-3 fatty acids plus dietary and exercise counseling vs dietary and exercise counseling alone

– Mean 25.0% decline vs 2.8% increase in fasting TG, respectively after 4 weeks

– However, decrease in TG associated with significant increase in LDL cholesterol

1. Shah M, et al. HIV Med. 2005;6:291-298.2. Hendricks KM, et al. Am J Clin Nutr. 2003;78:790-795.3. Wohl DA, et al. Clin Infect Dis. 2005;41:1498-1504.

Exercise Intervention to Reduce CVD Risk in HIV-Infected Individuals Metformin alone vs metformin with exercise training in

25 HIV-infected patients

– Metformin plus exercise led to significantly improved cardiovascular parameters vs metformin alone

– Waist-to-hip ratios decreased (P = .026)

– Resting systolic blood pressures decreased (P = .012)

– Resting diastolic blood pressures decreased (P = .001)

– Changes in fasting insulin and insulin AUC more significant with metformin and exercise vs metformin alone (P < .05)

Driscoll SD, et al. AIDS. 2004;18:465-473.

Lifestyle Issues: What are the most effective strategies to

support patients who want to quit smoking?

Effective Smoking Cessation Strategies DHHS guidelines on smoking cessation recommend

pharmacotherapy for all patients attempting to quit smoking except those with medical contraindications

– Approved pharmacotherapies: sustained-release bupropion, varenicline, nicotine gum, inhaler, nasal spray, and patch

More intensive intervention strategies significantly more effective than less intensive ones

– Counseling sessions lasting > 3 minutes and > 10 minutes were 1.3-fold and 2.3-fold, respectively, more likely to result in abstinence vs < 3 minutes

– 8 sessions were 2.3-fold more likely to result in abstinence vs 0-1 sessions

– Treatment by various clinician types, individualized counseling, and multiple intervention strategies associated with successful outcomes

Fiore MC. Respir Care. 2000;45:1200-1262.

Lifestyle Issues: Are there data on interactions

between antiretrovirals and drugs that help with smoking cessation

(eg, varenicline tartrate and bupropion)?

Interactions Between Antiretrovirals and Smoking Cessation Drugs Varenicline

– No reported drug interactions with antiretroviral agents since it undergoes minimal metabolism, with 92% being excreted unchanged in the urine

Bupropion

– Metabolized in liver by various CYP450 enzymes, predominantly CYP2B6

– LPV/RTV and bupropion coadministration resulted in significantly decreased exposures and plasma concentrations of bupropion and hydroxybupropion[1]

– Administration of ritonavir alone—most potent CYP3A4 inhibitor—may slow buproprion metabolism[2]

– Patients receiving boosted PIs should be monitored carefully for bupropion lack of efficacy and adverse effects

1. Hogeland GW, et al. Clin Pharmacol Ther. 2007;81:69-75. 2. Hesse LM, et al. Drug Metab Dispos. 2001;29:100-102