Section two

1

Lipid Disorders in Persons with HIV
Carl J. Fichtenbaum, MDProfessor of Clinical
MedicineUniversity of Cincinnati College of
Medicine
The International AIDS SocietyUSA
2
Simvastatin Lovastatin are contraindicated with
which of the following regimens

• AZT/3TC Efavirenz
• TDF/FTC Nevirapine
• AZT/3TC Lopinavir/Ritonavir
• AZT/3TC/ABC

3
The New Patient

• 34 y/o man presents for first visit.
• Diagnosed with HIV infection 1 month ago.
• Treatment naïve.
• No other medical problems.
• Smokes cigarettes 1 PPD x 17 years.
• Family history MI in father at age 53.

4
What is your initial workup?

• In addition to the HIV antibody titers, RT-PCR,
  HIV genotype, hepatitis serology, CBC, T-cells,
  liver and renal panels you order
• Fasting lipids and glucose.
• Random lipids and glucose.
• Fasting lipids, glucose and urinalysis.
• Random lipids, glucose and urinalysis.
• Random lipids, glucose, urinalysis and hs-CRP.
• Fasting lipids, glucose, urinalysis and hs-CRP.
• None of the above

5
What would be a typical lipid profile?

• Assume CD4 count235 cells/cu mm and HIV viral
  load57,000 copies/mL.
• TC187 LDL103 TG-252 HDL34.
• TC195 LDL126 TG-134 HDL42.
• TC252 LDL94 TG-275 HDL38.
• TC215 LDL137 TG-196 HDL39.

6
What would be his cardiovascular risk?

• Assume that his blood pressure was 137/82 mmHg.
• 3
• 5
• 7
• 9
• 11

Note Lipids TC187 LDL103 TG-252 HDL34.
7
MACS Cohort Mean Lipid Values Before and After
HIV Infection (Treated and Untreated)
Non-fasting values
Recommended NCEP values
Riddler SA, et al. JAMA. 20032892978-2982.
8
Traditional Factors Are the Biggest Contributor
to Coronary Heart Disease (CHD) in HIV Population
Inactivity, Diet
Cigarette
Smoking
-
-
?
Diabetes
OrangeModifiable. GreenNon-Modifiable.
Metabolic syndrome.
9
INTERHEART Study Multiple Traditional Risk
Factors Confer Synergistic Increases in the Risk
of MI
Evaluated factors associated with MI in 15,000
(MI) patients versus 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. 2004364937-952.
10
Studies on CV risk in HIV-infected and
HAART-treated patients are inconsistent
7. Rickerts V, Eur J Med Res. 2000532933 8.
Lichtenstein K, 13th CROI, Denver 2006, 735 9.
El-Sadr W, et al. 13th CROI, Denver 2006, 106LB
1. Bozzette SA, New Eng J Med. 200334870210 2.
Friis-Møller N, NEJM. 2003 349 1993-2003. 3.
Klein D,13th CROI, Denver 2006, 737 4. Currier
JS, JAIDS. 20033350612
4. Currier JS, JAIDS. 20033350612 5.
Mary-Krause M, AIDS. 200321247986 6. Moore RD,
10th CROI, Boston 2003, 132
11
Estimation of Risk and ATPIII Guidelines

• Framingham Cardiovascular Risk Score
• http//www.nhlbi.nih.gov/health/prof/other/index.h
  tm
• Utilizes following factors
• Age
• Gender
• Total cholesterol
• Smoking status
• HDL
• Systolic blood pressure

12
The Saga Continues

• Your patient returns to discuss antiretroviral
  therapy.
• You suggest he consider smoking cessation.
• You recommend antiretroviral therapy.
• His HIV genotype reveals wild type virus.

13
What would you recommend for this patient?

• Tenofovir/FTC/efavirenz
• Tenofovir/FTC atazanavirritonavir
• Abacavir/3TC efavirenz
• Abacavir/3TC atazanavir
• Tenofovir/FTC lopinavir/ritonavir
• ZDV/3TC atazanavir
• ZDV/3TC efavirenz
• Something else

fixed-dose combination
14
Antiretroviral Effects on Lipids

• Protease inhibitors, Non-Nucleoside RT Inhibitors
  and Nucleoside/Nucleotide RT Inhibitors all have
  effects on lipids.
• No clear changes with entry inhibitors or
  integrase inhibitors to date.
• Most effects are drug specific, not class
  specific.
• Choice of initial therapy is influenced by the
  desire to minimize the risk of atherogenic
  dyslipidemia.

15
Metabolic Effects of Low-Dose Ritonavir in (HIV-)
Healthy Volunteers
RTV 100 mg BID x 14 days 7-Day washout
LPV/r x 14 Days
Shafran SD, et al. HIV Med. 20056421-425.
16
Fast Forward 2 years

• Your patient is well on TDF/FTC/EFZ still
  smoking.
• You note the following despite altered
  dietexercise
• TC245 LDL162 HDL42 TG203.
• Pre-HAART values
• TC187 LDL103 HDL34 TG252.
• His blood pressure is 136/86 mmHg.
• Calculated Framingham Risk Score is 10 with 2
  Risk Factors (Family History Smoking).

17
What do you recommend?

• Atorvastatin 20 mg daily.
• Simvastatin 40 mg daily.
• Rosuvastatin 10 mg daily.
• Pravastatin 40 mg daily.
• Fenofibrate 145 mg daily.
• Gemfibrozil 600 mg BID.
• Something else.

18
LDL Cholesterol Goals and Cutpoints for
Therapeutic Lifestyle Changes (TLC)and Drug
Therapy in Different Risk Categories
19
Comparison of LDL Cholesterol and Non-HDL
Cholesterol Goals forThree Risk Categories
LDL-C Goal (mg/dL)
Risk Category
Non-HDL-C Goal (mg/dL)
lt100
CHD and CHD Risk Equivalent (10-year risk for CHD
gt20
lt130
lt130
lt160
Multiple (2) Risk Factors and 10-year risk lt20
lt160
01 Risk Factor
lt190
Non-HDL-C (atherogenic lipid fraction) TC HDL
20
Therapeutic Lifestyle Changes

• Major Features
• TLC Diet
• Reduced intake of cholesterol-raising nutrients
• LDL-lowering therapeutic options
• Plant stanols/sterols (2 g per day)
• Viscous (soluble) fiber (1025 g per day)
• Weight reduction
• Increased physical activity
• Risk reduction (smoking)

21
Dyslipidemia main treatment options

• Fibrates
• Good for elevated TG
• Decreases MIs in HIV- pts.
• May elevate HDL
• May elevate LDL but ? size
• Main AEs liver, muscles
• Nicotinic acid
• Good for ? HDL, ? TG or ? LDL
• Liver toxicity, insulin resist.
• Fish Oil (Omega-3 FA)
• Good for elevated TG

• Statins
• Good for elevated LDL
• Survival benefit in HIV- pts.
• Anti-inflammatory effects
• Stabilizes endothelial function
• Main AEs liver, muscles
• Cholesterol absorption blocker
• Only useful for elevated LDL
• Use with statin

22
Selected studies of lipid-lowering therapy in HIV
1.Moyle et al. AIDS, 2001151503-8. 2. Henry et
al. Lancet, 1998352 1031-32. 3. Calza et al.
AIDS 200317851-9. 4. Hewitt et al. AIDS,
199913868-9. 5. Caramelli et al. Braz J Infect
Dis, 20015332-8. 6. Miller et al. AIDS
2002162195-2200.
23
ACTG 5087 Treatment of HIV-Associated
Hyperlipidemia
Cholesterol
LDL
HDL
TG
50

• HIV patients with dyslipidemia
• LDL cholesterol gt 130 mg/dL
• and
• Triglycerides gt 200 mg/dL

LDL
HDL
TG
TC
0
Pravastatin (n 86)
Fenofibrate (n 88)
-50
Pravastatin
Fenofibrate
-100

• Endpoint reaching NCEP goal
  (composite for TG/LDL) by
  week 12

-150
Only 1 of fenofibrate and 5 of pravastatin met
NCEP goals
Aberg JA, et al. AIDS Human Retroviruses, 2005
21 757-67
Slide courtesy of Clinical Care Options
24
The sequel that never ends

• Your patient starts on atorvastatin 20 mg daily.
• After 3 months the lipids look better!
• TC193 LDL123 HDL40 TG152.
• 2 months later he complains of aching in his
  calves.
• CPK is normal.

25
What do you do now?

• Continue treatment reassure patient.
• Stop atorvastatin, try rosuvastatin.
• Stop atorvastatin, try fenofibrate.
• Stop atorvastatin, try ezetimibe.
• Stop atorvastatin, try niacin.
• Something else.

26
Statin Myopathy
Hansen KE et al. Arch Intern Med, 2005 165
2671-2676.
27
Case 2

• 43 y/o man with HIV for 15 years.
• Prior PCP, Oral Thrush and CMV retinitis.
• Initial mono dual therapy before HAART.
• Now on salvage regimen of LPV/r, T20, ZDV/3TC
  TDF.
• HIV VL is undetectable and CD4 is 253.
• Smoker with mild hypertension (125/80) that is
  treated.
• You dutifully measure fasting lipids
• TC275 HDL32 LDLNA TG803.
• Non-HDL-C243.
• CV risk score15

28
How would you treat this patient?

• Atorvastatin 20 mg daily
• Fenofibrate 145 mg daily
• Rosuvastatin 10 mg daily
• Pravastatin 40 mg daily
• Gemfibrozil 600 mg BID
• Fish Oil (Omega-3) capsules 3 g BID
• Something else.

29
Heres what happened.

• Start atorvastatin and titrate up to 40 mg daily.
• Lipid levels after 12 weeks on this dose
• You add fenofibrate 145 mg recheck lipids

• TC223 HDL34 LDLNA TG478.
• Non-HDL-C189.

• TC208 HDL35 LDL118 TG275.
• Non-HDL-C173.

30
What do you do now?

• No changes at this time.
• Increase atorvastatin to 60 mg daily.
• Add fish oil 3 gm BID.
• Change atorvastatin to rosuvastatin 40 mg daily.
• Add Ezetimibe 10 mg daily.
• Something else.

31
Follow-up visit in 6 months

• Hes doing well some lipoatrophy not
  progressing.
• No complaints at this time.
• Hes been on atorvastatin 60 mg/d and
  fenofibrate.
• Measure fasting lipids and heres what you find
• TC216 HDL34 LDL111 TG353.
• Non-HDL-C182.

Note last values were TC208 HDL35 LDL118
TG275. Non-HDL-C173.
32
Why are the lipids worse?

• Patient not really fasting.
• Non-compliant with diet.
• Patient went out and had beer night before.
• Stopped taking fenofibrate.
• Progression of lipoatrophy / insulin resistance.
• Biologic and/or inter-specimen variation.
• Something else.

33
Wohl Study Fish Oil (EPADHA) 2 g/day
Maxepa Study N-3 PUFAs 2 g TID (18 EPA / 12 DHA
per gram)
ACTG 5186 Trial Fish Oil (EPADHA) 3 g BID
Fenofibrate 160 mg/d
De Truchis et al. JAIDS, 2007 44 278-85. Wohl
et al. CID, 2005 41 1498-1504. Gerber et al.
13th CROI, 2006 Abstract 146.
34
Ezetimibe 10 mg/d added to Pravastatin
ACTG A5148 Niacin ER 2 gm/d
mg/dL
Median Change at 48 weeks
20
0
-20
-40
-60
-80
-100
-120
-140
-160
-180
TC HDL TG non-HDL-C
Negredo et al. AIDS, 2006 20 2159-64. Dube et
al. Antivir Ther, 2006 11 1081-89.
35
Approximate Maximum Lipid-lowering Effects In
Persons with HIV infection.
36
Know your interactions
37
ACTG A5047- RTQSQV in HIV negatives
??3059
3000
Fichtenbaum CJ et al. AIDS 200216 569-77.
38
Diminished Effects of Lipid-lowering agents
Efavirenz Statins1
Lopinavir/ritonavir Rosuvastatin2
1Gerber JG et al. JAIDS 2005 39 307-12 2Hoody
DW et al. 14th CROI, 2007 Abstract 564.
39
Summary of Drug-Drug Interactions

• Protease inhibitors ? ? AUC of simvastatin,
  lovastatin.
• Contraindicated
• Protease inhibitors ? AUC of atorvastatin
• Use with caution
• Protease inhibitors ? AUC of pravastatin
• May need to increase dose
• NNRTIs ? AUC of simvastatin, atorvastatin,
  pravastatin
• May need to increase dose
• Lopinavir/ritonavir ? AUC but ? effect of
  rosuvastatin
• May need to increase dose

40
Summary

• Assess cardiovascular risk and lipids.
• Inquire about chest pain.
• Encourage healthy lifestyles, risk reduction.
• Choose antiretroviral therapy to minimize risk.
• Lipid-lowering therapy based upon NCEP
  guidelines.
• Watch out for drug-drug interactions.
• Refer to lipid specialist if needed.
• 1 mg/dL ? in LDL means a 1 increase in CV risk
• 1 mg/dL ? in HDL ? CV risk by 2 in men and 3 in
  women