Cardiovascular Complications

1

Metabolic ComplicationsA Case-based Discussion
of Treatment Strategies for Dyslipidemia and
Insulin Resistance
Judith A. Aberg, MDAssociate Professor of
MedicineNew York University Medical Center
2
Question 1A patient has the following lipid
profileTotal cholesterol 230 mg/dLLDL
unable to calculateMDL 29 mg/dLTriglycerides
694 mg/dLThe initial drug of choice after diet
and exercise is

• Atorvastatin
• Fenofibrate
• Simvastain
• Ezetimibe

3
Which of the following traditional risk factors
has the most impact on cardiovascular risk in
HIV patients?

• Age
• Gender
• Lifestyle modification (diet and exercise)
• Smoking
• Family history

4
Cardiac Risk Factors

• Cardiac risk factors
• Increased age
• Sex (males are at higher risk)
• Smoking
• Elevated LDL-C cholesterol
• Low HDL-C cholesterol
• Hypertension
• Presence of diabetes (or risk equivalent)
• How to define cardiac risk and need for
  intervention
• Persons with 2 or more risk factors are at
  increased risk of CHD.
• Risk assessment tools can be used to calculate
  percent CHD risk

Wilson et al. Circulation. 1998971837-1847.
hin.nhlbi.nih.gov/atpiii/calculator.asp.
5
CVD Risk Assessment AlgorithmsTools to Predict
the 10-Year Risk of an Individual Having an MI

• Input ranges for PROCAM
• Age 35-65 years
• LDL-C 75-250 mg/dL
• HDL-C 25-75 mg/dL
• TG 50-400 mg/dL
• Systolic BP 100-225 mmHg

• Input ranges for Framingham
• Age 20-99 years
• TC 130-320 mg/dL
• HDL-C 20-100 mg/dL
• Systolic BP 90-200 mmHg

PROCAM Study men only
1. Wilson et al. Circulation. 1998971837-1847
2. Assmann et al. Circulation. 2002105310-315
6
INTERHEART Study In the general population,
multiple traditional risk factors confer
synergistic increases in the risk of MI
Evaluated factors associated with MI in 15,000
(MI) pts vs. 15,000 case controls
Odds ratio (99 CI)
HTN(3)
PS
Risk factor (adjusted for all others)
Smksmoking DMdiabetes mellitus
HTNhypertension Obesabdominal obesity
PSpsychosocial RFrisk factors.
gt90 of total risk can be attributed to these
factors
Yusuf S, et al. Lancet 2004 36493752
7
Traditional factors are the biggest contributor
to coronary heart disease (CHD) in HIV population
Inactivity, diet
Cigarette
smoking
-
-
?
Diabetes
Orange Modifiable Green Non-modifiable
Metabolic syndrome
8
DAD Study Is the Framingham Risk Estimation
Valid in HIV-Infected Patients?
Observed and predicted MI rates according to ART
exposure (DAD Study n23,468)
8
Incidence of MIs is low 345 over 94,469
patient-years follow-up (3.7/1,000 patient-years)
7
Observed rates
6
5
Best estimate of predicted rates
Rates per Thousand Patient-Years
4
3
2
1
0
lt1
1-2
2-3
3-4
4
None
N8890
N10,574
N5292
N6805
N9050
N5973
Duration of cART exposure (years) n ART
exposure
Law et al. HIV Med. 20067218-230.
9
Estimating CVD Risk Summary

• It is possible to estimate the risk for CVD
  disease using mathematical algorithms based on
  outcomes of large cohorts with long-term
  follow-up.
• The total estimated risk is influenced by the
  calculated non-HDL cholesterol, age, gender,
  blood pressure, smoking status, and other
  factors.

10
Case One

• A 52 year old Hispanic man, with HIV infection
  diagnosed last month CD4 238 and VL 62K
• Baseline lipids TC 162, TG 468, HDL 24
• LDLc TC HDL (0.20 x TG)
• LDL 44
• Other Cardiac RF tobacco, father died of MI at
  age 56, SBP 147, not on BP meds

11
IDSA Practice Guidelines for Evaluation and
Management of Dyslipidemia in HIV-Infected
Patients
Obtain fasting lipid profile, prior to starting
ARVS and within 3 to 6 months of starting new
regimen
Count number of CVD risk factors profile and
determine level of risk. If 2 risk factors,
perform a 10-year risk calculation.
Intervene for modifiable nonlipid risk factors
such as diet and smoking
If above the lipid threshold based on risk group
despite vigorous lifestyle interventions,
consider altering ARV therapy or lipid-lowering
drugs
LIPID-LOWERING DRUG THERAPY
Serum LDL cholesterol above threshold, or TG 200
mg-500 mg/dL with elevated non-HDL
cholesterol STATIN
Serum TG gt500 mg/dL FIBRATE
Adapted from Dube M, et al. Clin Infect Dis.
200337613-627.
12
Based on the Case Study, What Is Your Best Guess
at his Framingham Risk?

• 0-5 low risk
• 6-10 medium risk
• 11-15 high risk
• 16-20 high risk
• gt20 high risk

13
What is his initial Framingham risk score?
18

0
5
10
15
20
25
30
low risk moderate risk high risk
hin.nhlbi.nih.gov/atpiii/calculator.aspy
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Case genotype shows a K103N and you decide to
start with TDF, FTC, and LPV/r.

• 4 weeks later
• CD4 is 319 and VL 6457 copies/ml
• Fasting lipid panel reflected below
• Establishing realistic lipid goals for the
  patient (NCEP Guidelines)

15
Hypertriglyceridemia is Independently Associated
with CVD
RR Relative Risk
Cullen et al. The American Journal of Cardiology
Volume 86, Issue 9 , 1 November 2000, Pages
943-949
16
Decision Point you recommend diet and exercise.
After 4 weeks, there is no change to the lipid
profile so you

• Order Direct LDL to determine if LDL elevated
  before prescribing lipid lowering agents
• Start lipid lowering therapy with a statin
• Start lipid lowering therapy with a TG lowering
  agent
• Switch his boosted lopinavir to boosted atazanavir

17
5087 LDL assay comparison

• The Direct Enzymatic Assay overestimates LDL
  Risk of Over Treatment
• The Friedewald underestimates LDL Risk of not
  prescribing treatment when clinically indicated
• Must use ultracentrifugation method to determine
  LDL if TG gt500 BUT better to treat TG first and
  then determine if LDL elevated

18
Drugs Used in the Treatment of Dyslipidemias

• Statins
• Inhibit intrinsic production of cholesterol
• Risk of interaction with PIs
• Risk of skeletal muscle and hepatic toxicities
• Fibrates
• Augment lipoprotein lipase activity (? VLDLs)
• Lower TG levels, Increase HDL
• Concomitant use with statins may increase risk of
  muscle and hepatic toxicities
• Others
• Bile acid sequestrants, ezetimibe, nicotinic
  acid, etc

19
Lipid-lowering therapy overview

• Fibric acids
• LDL ?, TG ??, HDL ?
• Side effects dyspepsia, gallstones, myopathy

• Statins
• LDL ??, TG ?, HDL?
• Side effects myopathy, ? liver enzymes

• Ezetimibe
• LDL ?, TG ?, HDL ?
• Side effects ? liver enzymes, diarrhea

• Omega-3 fatty acids
• LDL ??, TG ? ?, HDL ??
• Side effects GI, taste

• Nicotinic acid
• LDL ? ?, TG ?, HDL ??
• Side effects flushing, hyperglycemia,
  hyperuricemia, upper GI distress, hepatotoxicity

• Bile acid sequestrants
• LDL ?, TG ??, HDL?
• Side effects GI distress/ constipation, ?
  absorption of other drugs

20
Cardiovascular Risk Factors and HAART
Interventions

• Stop smoking
• Treat hypertension
• Encourage appropriate diet and exercise
• Specific interventions for dyslipidemia
• Change antiretroviral therapy
• Lipid-lowering drugs
• Statins
• Fibrates
• Niacin

21
Changes in Lipids NFV to ATV
Murphy, 2003. 10th CROI, abstr 555 Wood R. J
Acquir Immune Defic Syndr. 2004 Jun
136(2)684-92.
22
SWAN Final 48-week lipid results of switch to
ATV
Week 48 lipid changes

• N419 randomized to change PI to ATV vs.
  continue current PI RTV (CPI)
• 91 switched to unboosted ATV
• 9 ATV RTV (where TDF used)
• Conclusions
• Significant decreases in TC and TG seen upon
  switching to primarily unboosted ATV
• No significant changes seen in HDL or LDL
• Impact on CVD risk not assessed

plt0.0001
250
plt0.0001
200
pNS
150
Lipid value (mg/dL)
100
pNS
50
0
HDL
LDL
TG
TC
Lipid parameter
Gatell JM, et al. 10th EACS, Dublin 2005, PS1/1
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Lipid lowering agents and PIsDrug interactions
AUC ??? with darunavir
1. Fichtenbaum CJ, et al. AIDS. 2002 1656977
2. Hsu A, et al. AAC. 2001 45344550 3.
Gerber J, et al. 2nd IAS 2003, 870 4. Carr RA,
et al. 40th ICAAC, Toronto, 2000. 1644 5.
Telzir Package Insert 2003 6. Gerber JG, et al.
11th CROI. 2004. 603 7. Reyataz Package
Insert 2005 8. Aptivus Product Label 2005
24
HOPS Cohort Incidence of MI and lipid-lowering
agent use by year
MI incidence per 1000 pt-yrs, by year
Indidence MI/1000 pt-yrs
0
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2004
2005
2003
Use of lipid-lowering agents associated with
lower CVD risk in HIV patients with
hyperlipidemia
Lichtenstein K, et al. 13th CROI, Denver 2006,
735
25
ACTG 5087 Efficacy and safety of fenofibrate vs.
pravastatin in HIV subjects
NCEP III Composite response (LDL/HDL/TG)

• HIV ARV gt6 mo (N174)
• LDL gt130 and TG gt200
• Open-label 48-week trial
• Randomized to
• Fenofibrate 200 mg QD (n88) or
• Pravastatin 40 mg QD
• Addition of other drug at wk 12 if goal not
  achieved
• Goal NCEP Composite LDL, HDL, TG
• Conclusion Sequencing fenofibrate before
  pravastatin resulted in greater absolute and
  percent TG decrease

Percent

P0.04 for dual arm comparison
Aberg J, et al. AIDS Res Human Retrovirus 2005
21 75767
26
ACTG 5186 Fish Oil and Fenofibrate
Mean (SD) of fasting serum triglycerides (ITT)
Step 1
694
665

• Subjects randomized to receive open- label fish
  oil or fenofibrate for 8 weeks. (n100)
• Fish oil capsules 3 g b.i.d. with meals
• Each 1 g capsule contains 500 mg EPA plus 310 mg
  of DHA (Advanced Nutritional Technology, Inc)
• Fenofibrate 160 mg q.d.

362
338
Serum triglycerides (mg/dL)


Pre-fish oil
Post-fish oil
Pre-fenofibrate
Post-fenofibrate
Mean (SD) of fasting serum triglycerides (ITT)
Step 2
280
369
377
414

279

279

Conclusion The combination of fish oil and
fenofibrate was well tolerated and resulted in a
further decrease in fasting serum triglycerides
above that provided by either single agent.
Single Drug
Fish oilFeno
Group A
Group A combo
Group B
Group B combo
Group A Fish Oil then add Fenofibrate Group B
Fenofibrate then add Fish Oil.
Fitchenbaum, et al AACTG CROI 2006, Denver
Abstract 146
27
ACTG A5148 Long-acting niacin in treatment of
hyperlipidemia in HIV patients

• Open-label 48-wk study in N33 HIVs
  hyperlipidemia
• gt4 weeks of HAART
• CD4 488 cells/mm3
• 97 had HIV RNA lt50 copies/mL
• Niacin dose
• Week 0-4 lead-in period
• Week 4-8 500 mg/day
• Week 8 1000 mg/day
• Subsequently increased based on tolerability
• Long-acting niacin safe and effective for
  hyperlipidemia
• Modest, but limited, effects on glucose

Plt0.001. P0.002 P0.009.
Dube MP, et al. Antivir Ther. 2006 111081-1089.
28
Greater improvement in lipid levels observed with
LLAs vs. switching PI therapy
Mean plasma TGs
350

• 12-month, open-label study (N130) 60 male
  mean age 39
• Stable on first HAART regimen but with mixed
  hyperlipidemia Randomized to
• A PI ? NVP (n29)
• B PI ? EFV (n34)
• C Add pravastatin (n36)
• D Add bezafibrate (n31)
• Conclusion
• Pravastatin or bezafibrate significantly more
  effective in management of hyperlipidemia than
  switching ART to an NNRTI

300
250
200
mg/dL
150
100
50
0
0
3
6
9
12
Months
Mean cholesterol
300
250
200
mg/dL
150
100
50
0
0
3
6
9
12
Months
Calza L, et al. AIDS 2005 1910518
29
DAD Study Lipid changes when either starting
lipid-lowering therapy (LLT) or switch from a PI
to NNRTI

• Prospective, 12-month study (N1,892)
• LLT (N221) switch (N208), control (N1,463)
  control)
• At 12 months
• Both LLT and switching were better than control
  for all parameter
• LLT had more pronounced decreases in total
  cholesterol and LDL-C than switching
• Switching had better increases in HDL-C
• LLT and switching had similar benefit on TC/HDL-C
  ratio and triglycerides

12-Month Change in Lipid Profile
Control Switch LLT
Change (mmol/L)
Total Cholesterol
LDL-C
TG
HDL-C
TCHDL-C Ratio
Van der Valk M, et al. 8th ICDTHIVI. Glasgow,
2006. PL12.2.
30
My approach Case 1

• Would not order Direct LDL
• Would not use Statin as do not know what the LDL
  is. Sequencing of agents may be important
• Would start with a TG lowering agent first
• Would not switch as pt had elevated TG prior to
  starting LPV/r and there are limited data on this
  type of switch

31
Case study Fibrate-lowering treatment

• Patient agrees to go on fenofibrate at week 12
• After 12 weeks of fenofibrate therapy at week 24,
  lipid panel is drawn and results are as follows
• Friedewald Equation LDL TC HDL TG/5

32
What is his Framingham risk score, after 12 weeks
of fenofibrate?
15
Week 24 TC 198 HDL 31 LDL 107 TG 302
0
5
10
15
20
25
30
low risk moderate risk high risk
hin.nhlbi.nih.gov/atpiii/calculator.aspy
33
What would have happened to his Framingham CVD
risk if he had quit smoking?
Risk Factor
Units
Gender
male or female
M
Age
years
52
Total cholesterol
mg/dL
198
HDL
mg/dL
31
Systolic blood pressure
mmHg
118
Treatment for hypertension (only if SBP gt120)
N
yes or no
N
Current smoker
yes or no
7
Week 24 TC 198 HDL 31 LDL 107 TG 302
0
5
10
15
20
25
30
low risk moderate risk high risk
hin.nhlbi.nih.gov/atpiii/calculator.aspy
34
What if he had stopped smoking prior to any other
interventions?
Risk Factor
Units
Gender
male or female
M
Age
years
52
Total cholesterol
mg/dL
162
HDL
mg/dL
24
Systolic blood pressure
mmHg
147
Treatment for hypertension (only if SBP gt120)
yes or no
N
N
Current smoker
yes or no
18
TSs baseline risk
8
risk d/c smoking only
0
5
10
15
20
25
30
low risk moderate risk high risk
hin.nhlbi.nih.gov/atpiii/calculator.aspy
35
Remember all health aspects

• A fasting blood sugar was obtained and found to
  be 134 mg/dL !!!!!!

36
American Diabetic Association Definitions
37
Impact of various PIs on glucose and glucose
disposal rate
1. Noor MA, et al. AIDS. 200115F11-F18. 2.
Dubé MP, et al. J Acquir Immune Defic Syndr.
200127130-134. 3. Behrens G, et al. AIDS.
199913F63-F70. 4. Martinez E, et al. AIDS.
199913805-810. 5. Walli RK, et al. Eur J Med
Res. 20016413-421. 6. Noor MA, et al. AIDS.
200216F1-F8. 7.Dubé MP, et al. Clin Infect
Dis. 200235475-481 .8.Sension M, et al. Antivir
Ther. 20027L26. 9.Noor MA, et al AIDS.
2004182137-2144. 10. Lee G.A., et al.
Clinical Infectious Disease 2006 Sep
143(5)658-60. Epub 2006 Jul 26
38
To improve control of FBS

• Start rosiglitazone
• Start metformin
• Start sulfonylurea
• Switch LPVr to NVP
• Switch LPVr to boosted atazanavir
• Stop ART and observe off meds

39
ACTG 5082Tolerability of Metformin vs
Rosiglitazone CROI 2006

• Both rosi and met ? insulin. Rosi ? LDL and ? HDL
• Stringent toxicity monitoring and dose reduction
  algorithms
• 12/26 of patients in metformin group underwent
  dose reduction/premature discontinuation of study
  drug (diarrhea most common etiology elevated
  lactate gt 2.0 X ULN uncommon)
• 4/25 of patients in the rosiglitazone group
  underwent dose reduction/premature
  discontinuation of study drug
• Jan 5, 2006 FDA warning rosiglitazone and
  rosiglitazone/metformin associated with macula
  edema reversible when meds discontinued

40
Use of Insulin-Sensitizing Agentsin HIV Infection

• Thiazolidinediones (TZDs)
• - ? Subcutaneous fat 2310 ? VAT 2181
• - ? leg subcutaneous fat improved insulin
  sensitivity2
• ? insulin levels no effect on SAT or VAT3
• ? Subcutaneous fat, ? 2-OGTT 34 mg/dL6
• Metformin
• - ? insulin and visceral fat4,5
• ? waist circumference weight loss5
• ? waist circumference, SAT, VAT, TAT, ? 2-OGTT 20
  mg/dL but 32 GI AEs6
• Metformin thiazolidinedione in HIV
• - not much data potential for drug interactions

1 Gelato et al., 2002 2 Hadigan et al 2003 3
Sutinen et al, 2003 4St Marc et al, 2002 5
Hadigan et al 2000 6van Wijk , 2005
41
Case Points

• Diet, exercise and Smoking Cessation. BP and
  glucose control
• Sequencing of lipid lowering therapy may be
  important
• If LDL increased use statin first
• If TG gt400 use fibrate, fish oil or niacin
  first once TG lt400, measure LDL by Friedewald to
  determine next step
• In this patient now with TG 342 and LDL 107 LDL
  is primary target.
• Preferable to use a statin
• Aware of potential drug interactions with a PI

42
My approach to control BS

• Prefer to use insulin sensitizing agent
• Rosi may be better tolerated than metformin
• Warning of macula edema with rosi and adverse
  effect on lipids
• ?Increase lactic acidosis with d4T and metformin
• Would not use NVP as he had K103N at baseline
• Would not stop ART/Implications of CHD
• Unclear if switch would work

43
Smoking Cessation Non-Pharmacologic

• Interventions
• Identify reasons for quitting
• Discuss options
• Set a quit date chosen by the patient
• Set up a support system
• Identify rationalizations
• Define slip vs. relapse
• Identify alternatives for cravings
• Provide reliable sources of information
• Refer to local smoking cessation programs

44
Nicotine replacement therapy
Walgreens.com
45
Oral Agents
1 BetterPills.com 2 Chantixhelps.com
46
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