HIV Lipodystrophy Jisun Oh PGY-2 Internal Medicine University of Western Ontario Endocrinology Half Day 2006.12.13.

HIV Lipodystrophy

Jisun OhPGY-2 Internal Medicine

University of Western OntarioEndocrinology Half Day

2006.12.13

Objectives

• HIV Lipodystrophy– Clinical Relevance– Clinical Manifestations– Pathophysiology– Treatment

Clinical Relevance

HIV: A Worldwide Problem

*UNAIDS

Drug (abbreviations) Brand name Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) Abacavir (ABC) Ziagen® Didanosine (ddI) Videx®, Videx® EC Emtricitabine (FTC) Emtriva® Lamivudine (3TC) Epivir® Stavudine (d4T) Zerit® Tenofovir (TDF) Viread®* Zalcitabine (ddC) Hivid® Zidovudine (ZDV, AZT) Retrovir®

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Delavirdine (DLV) Rescriptor® Efavirenz (EFV) Sustiva® Nevirapine (NVP) Viramune®

Protease inhibitors (PIs) Amprenavir (APV) Agenerase® Atazanavir (ATV) Reyataz® Darunavir (DRV) Prezista® Fosamprenavir (FPV) Lexiva® Indinavir (IDV) Crixivan® Lopinavir/ritonavir (LPV/r) Kaletra Nelfinavir (NFV) Viracept® Ritonavir (RTV) Norvir®

Saquinavir (SQV) Fortovase®, Invirase®

Tipranavir (TPV) Aptivus®

Fusion inhibitor

Enfuvirtide (T-20) Fuzeon®

Prevalence of PI-related Dyslipidemia

• NOT an UNCOMMON issue – ~50%

• 47% of PI recipients at one clinic1

• 57% of PI recipients2

– LDL: 19%– TG: 44%– LDL + TG: 37%

*1Henry K, Lancet 1998, 2Behrens G, AIDS 1999

Cases

Case: Ms. TH

• 38F, HIV+ since ’86, HAART since ‘93

• Significant FHx of CAD, current smoker, +metabolic syndrome

• Lipodystrophy: new since HAART

• Dyslipidemia: new since HAART– TC 4.94, TG 5.11, HDL 0.80– Started on Ezetrol 10 mg daily

Questions

• What kinds of metabolic changes are associated with antiretroviral therapy in HIV?– Pathophysiology?

• What is Ms. TH’s risk of developing CVD?– Should her dyslipidemia be treated?

• To what targets?

Case: Mr. GM

• Mr. GM– 41M, HIV + since 1991– ++Opportunistic infections

• CMV retinitis, oral candidiasis

– Mega-HAART treatment: • d4T, DDI, Kaletra, Amprenavir, Sustiva• CD4 155 (improved), viral load 67 (improved)






Fusion inhibitor


Mr. GM

0

5

10

15

20

25

30

35

1 2 3 4 5 6 7

TG

TC

HDL

JanMar

May June

July4 yrs

Ezetrol

Lipidil + Dietary

Questions

• Does Mr. GM’s lipid profile present a significant risk?– Long term outcomes?

• What are the best treatment options for his dyslipidemia?– Interactions with HAART

Clinical Manifestations

HIV Lipodystrophy

• Changes in fat distribution often associated with metabolic abnormalities– Insulin resistance– Hyperglycemia– Dyslipidemia– C peptide > 2.5 mmol/L– Lipoatrophy

• Loss of subcutaneous fat (Limbs, Face, Buttocks)

– Lipohypertrophy• Abdomen (Visceral Fat, Buffalo Hump, Breast enlargement)

+/- prominence leg/arm veins

Lipodystrophy Syndrome(s)

Fat atrophy

Fat accumulation

Lipidabnormalities

Dysregulation of glucose metabolism

Facial Lipoatrophy

*UpToDate Images

Facial Lipoatrophy

*google images

Facial Lipoatrophy

www.emedicine.com

Bemasconi AIDS Reader 1999; CFAR Thailand Study

Facial Lipoatrophy

Dorsocervical Fat Pad

www.mediscan.co.uk

Prominent VeinsProminent Veins

Carr CID 2000; CFAR Thailand study

www.virusmyth.net

Carr CID 2000; CFAR Thailand study

Abdominal Visceral Fat Accumulation

Hegele, R

Fat redistribution

Fat atrophy

Hegele, R

HIV Partial Lipodystrophy

Hegele, R

Pathophysiology

HIV Dyslipidemia

• Dyslipidemia of Chronic Infection– Initially: HDL, LDL, and TC– More advanced disease: TG

• Dyslipidemia specific to antiretrovirals, specifically PI’s (Protease Inhibitors)– TG, TC, LDL

Pathophysiology

• Dyslipidemia secondary to HIV infection– Typical of dyslipidemia observed in chronic

infections– Interferon-α: natural course of HIV

• clearance, production TG• ?direct vs indirect effects on lipid metabolism

– TNF (acute phase reactant)• only during opportunistic infections• May exacerbate TC, HDL, LDL

Pathophysiology

• PI-associated HIV Dyslipidemia– Not fully understood– Multiple mechanisms likely involved

• Structural Similarities (CRABP-1 and LRP)• CYP 3A inhibition• Direct stimulation hepatic TG synthesis• Mitochrondrial alterations• Genetic Predisposition

CRABP-1

• Structural similarity– Catalytic region of HIV-1 protease– Cytoplasmic retinoic acid-binding protein type

1 (CRABP-1) – PI binds to CRABP-1 instead of viral protease

• Reduced RXR-PPARγ activity: increased apoptosis, diminished peripheral adipocyte proliferation

• Peripheral lipoatrophy, hyperlipidemia

LRP

• Structural similarity– Catalytic region of HIV-1 protease– Low-density lipoprotein-receptor-related

protein (LRP)– PI binds to LRP-LPL complex

• Inhibits FFA cleavage from TG: promotes FFA accumulation in peripheral adipocytes

– LDL and VLDL

Increased Hepatic TG Synthesis

• PIs may directly stimulate hepatic TG synthesis– Several PIs upregulate mRNA production for

key enzymes in TG biosynthetic pathway

Mitochondrial Alterations

• HAART (multiple NRTIs) inhibits mitochondrial DNA polymerase γ mitochondrial DNA depletion

mitochondrial respiratory chain dysfunction reduced cell energy production

– Abnormalities in adipocytes• Lipodystrophy syndrome• Hyperlipidemia

Genetic Predisposition

• Apo CIII gene– Association between TG (with HDL) and

several polymorphisms• Variations at -455 and -482 associated with

VLDL and HDL• Carriers of -455 variant 30% lower HDL levels• Plasma lipid concentrations increase according to

# variant alleles

Rationale for Treatment

Why It Matters

Psychosocial• Self-esteem

• Stigmatization• Mood disorders• Adherence with ART

Clinical• Pain

– Neck– Lower back– Breast

• Breathing problems• Umbilical hernia• GERD• Adherence with ART

Cardiovascular Complications

• Introduction of HAART has changed the natural history of HIV disease– Notable extension of life expectancy– Chronic and manageable disease– Prolonged metabolic alterations

• ?affect on long-term prognosis and outcome of HIV-infected persons

• Well known cardiovascular risk factors– Dyslipidemia, Insulin Resistance, Overt Diabetes Mellitus

Metabolic Changes

• CV disease takes time to develop

• The older one is, the more important CHD becomes

▲

CV Risk

Risk HIV disease

progression

Why It Matters: MI in HIV Study Event N Comment

HOPS*1 21 MI 5,672 Risk of MI PI vs no PI

German2 29 MI 4,993 Risk of MI prior HAART

Johns Hopkins3

43 CHD 2,671 Risk of CHD HIV+ vs HIV–

French4 49 MI 19,975 on PI

Risk of MI on PI vs HIV–

CA Medicaid5

N/A 28,513 Risk of CHD with ART in 18–33 yr olds, but not older individuals

Kaiser6 65 MI 4,408 Risk of MI HIV+ vs HIV–No greater risk on PIs

D:A:D*7 126 MI 23,468 Risk with HAART

VA8 1,207 CHD 36,766 risk of MI in HAART era

1. Holmberg 9th CROI, Seattle, 2002, #698; 2. Rickerts Eur J Med Res 2000;5:329; 3. Moore 10th CROI, Boston, 2003 #132; 4. Mary-Krause 8th CROI, Chicago, 2001, #657; 5. Currier 4th Int Workshop on Adverse Events and Lipodystrophy, San Diego, 2002; 6. Klein et al. 10th CROI, Boston, 2003 #747; 7. Friis-Møller ibid, #130; 8. Bozzette NEJM 2003

D:A:D Study, NEJM 2003

26% relative risk increase MI / yr over first 4~6 yrs

Friis-Møller, NEJM, 2003

Approach to Management


• Search for secondary contributory causes– Hypothyroidism– Chronic liver disease– Chronic renal failure– Diabetes Mellitus– Familial Hypercholesterolemia– Obesity– Alcohol Abuse


• Search for secondary contributory causes– Medications

• Beta Blockers• Diuretics• Steroid Derivatives• Oral Contraceptives• Hormonal Treatment

Treatment of Dyslipidemia

Treatment of Dyslipidemia

• Lifestyle Interventions

• Switching Antiretrovirals

• HMG CoA-Reductase Inhibitors

• Fibrates

• Niacin

• Alternative Treatments

Guidelines

• “For the purposes of initiating therapy for dyslipidemia, the Panel recommends that the NCEP guidelines should generally be followed for HIV-infected patients. Of note, the new NCEP guidelines now include a category termed CHD “risk equivalents,” which include diabetes mellitus, other atherosclerotic disease, and multiple risk factors that confer a 10-year risk of CHD of >20%. Because of the high risk of CHD in these groups, these individuals should be treated as aggressively as those with established CHD.”*

*Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486-97.

Guidelines

• “When TG levels exceed 200 mg/dL, calculation of non-HDL-C should be performed and considered a secondary target for intervention.”

• “In addition, the high frequency of low HDL-c in persons with HIV warrants attention.”

*Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the NCEP Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285:2486-97.

Lifestyle Interventions

• Diet & Exercise– Thorough trial of non-drug therapies

• Efficacy may be limited– TC by 11%, TG by 21% (Henry K, Lancet, 1998)

– Competing dietary needs frequently identified• Need to lean muscle mass but lipid level

– Dietary options often limited• Prominent GI symptoms in advanced HIV

Dietary Intervention

• Recent Brazilian abstract– Randomized trial: 47 patients new to HAART

• Control: general guidelines on dietary education• Intervention: above + nutritional follow-up every 3

months based on NCEP-ATPIII

– Direct Dietary Orientation prevented the development of dyslipidemia at 6 months

• Extended to 1 year*R. Lazzaretti, 2006, AIDS Conference, Toronto

Lifestyle Interventions

• Treat/Control Other Modifiable Cardiovascular RF’s– Smoking– Glycemic Control in DM– Hypertension

PI-Related Dyslipidemia

• VLDL >> IDL, HDL no change

• TG

• Ritonavir > Amprenavir/Nelfinavir> Indinavir/Saquinavir > Atanavir

• Atanavir associated with minimal/no significant dyslipidemia

• (Mobius, J Acquir Immune Defic Syndr 2005 & Cahn, J Int Assoc Physicians AIDS Care, 2004)






Fusion inhibitor


Switching Antiretrovirals

• Ensure no compromise in control of HIV infection when switching medications


• Switching to a less dyslipidemic PI– Atazanavir

• Not associated with significant TG, TC, LDL• Simplifies treatment (once daily dosing)• No impact on viral load, CD4 count• Nelfinavir Atazanavir

•(Mobius, J Acquir Immune Defic Syndr 2005 & Cahn, J Int Assoc Physicians AIDS Care, 2004)

NNRTI-Related Dyslipidemia

• Associated with dyslipidemia– TC, LDL– BUT HDL, TG– Lesser degree than PIs


• Switching PI for Abacavir1

– Improved lipid profile– No change CD4 counts, viral load

• Stavudine Tenofovir2

– Sustained improvement of dyslipidemia– Significant reduction of cardiovascular risk– Differences amongst various NNRTIs

• dyslipidemia

1. Keiser, BMC Infect Dis 2005. 2. Llibre, AIDS 2006.






Fusion inhibitor


Statins

• First line therapy for hypercholesterolemia in general population

• Considerable evidence to demonstrate benefits in reducing CHD risk– 1° and 2° prevention

Statins

• Generally, studies show modest efficacy with good tolerability

• Potential for interaction with HAART medications level statin– CYP 3A4-metabolized medications:

• PIs and NNRTIs• Most statins• Cyclosporine, erythromycin, itraconazole, oral

anticoagulants

Statins in HIV Dyslipidemia Agent Considerations

Lovastatin (Mevacor®)

Simvastatin (Zocor®)

Extensively metabolized by CYP3A4; toxicity likely when combined with PIs.

Fluvastatin (Lescol®) Metabolized by CYP2C9; interaction with nelfinavir likely.

Cerivastatin (Baycol®)

Off market

Atorvastatin (Lipitor®)

Some CYP3A4 metabolism; small amount of anecdotal and research experience in HIV. Modest increases in AUC when coadministered with ritonavir-saquinavir.

Pravastatin (Pravachol®)

No significant p450 interactions; primarily renal excretion. Minimally decreased AUC when coadministered with ritonavir-saquinavir.

Dube. Clin Infect Dis. 2000; 31:1216-24.

Relative Safety with 3A4 Inhibitors

Simvastatin Lovastatin

Fluvastatin

Pravastatin

Rosuvastatin

Atorvastatin

Statin and HAART Interactions

• Fluvastatin metabolized by CYP 2C9

• Pravastatin not significantly metabolized by CYP enzyme system– Lower risk of interactions with HAART– Reasonable to recommend low dose as 1st

line treatment for HAART-related dyslipidemia• Pravastatin 10 mg daily • Fluvastatin 20 mg daily

Statins: Recent Studies

no effects TC, TG-homocysteine,

Study Event N= Comment

Pravastatin 40 mg 1 1º: TWAUC2 º: total & regional body fat, fasting lipids, glucose, insulin, markers CV risk @ 16 wks

33 +subcutaneous fat-homocysteineNo significant effects TC, TG

Statins, Fibrates, Dual Therapy2

Lipid parameters @ 70 wks

103 TC: -7S/14F/22D%TG: -21S/40F/42D%

Statins, Fibrates3 Fasting lipids at 1 yr 106 Statin: -34.8% (TG) -25.2% (TC)Fibrate: -40.7% (TG), -21.9% (TC)

Rosuvastatin4 TG/TC @ 24 wks 16 TG -30.1%, TC 21.7%

Combination Fenofibrate and Pravastatin5

LDL/HDL/TG/non-HDLc @ 48 wks

174 Substantial improvements, but unlikely to meet guidelines

Fibrates vs Statin6 TG/TC @ 3 and 12 months

245 TG: significant improvementsTC: only significant at 3 months

1.Mallon, AIDS 2006. 2. Aberg, AIDS Res Hum Retrovir 2005. 3.Visnergarwala, J Infect 2004. 4. Calaz, AIDS 2005. 5.Benesic, Infection 2004. 6. Bonnet, HIV Med 2004.

TC

0

2

4

6

8

10

12

baseline 10mg

mm

ol\

L

8.04+2.15 6.67+1.5617.1% decrease

Ezetimibe in Antiretroviral Dyslipdemia

*R Hegele, unpublished data


TG

0

2

4

6

8

10

12

baseline 10mg

mm

ol\

L

5.90+3.41 4.39+3.16

25.6% decrease



HDL

0

0.5

1

1.5

2

2.5

baseline 10mg

mm

ol\

L

1.17+0.54 1.27+0.53

8.7% increase



LDL

0

1

2

3

4

5

6

7

8

baseline 10mg

mm

ol\

L

3.47+3.03 2.98+0.9713.94% decrease


Fibrates

• Well established tolerability and efficacy profile in mixed hyperlipidemia and TG

• Favorable but moderate effect on serum lipids, well tolerated

• Similar efficacy as statins in dyslipidemia

• Concomitant use of statins and fibrates cautioned– Risk of skeletal muscle toxicity

Fibrates

• Comparisons between fibrates– Gemfibrozil

• Safe, but moderate efficacy (questionable clinical significance)1

– Fenofibrate• Improves clinical atherogenic profile

– -40% TG, -14% TC, -21% apoCIII, -17% apoB, -17% non-HDLc

– +15% HDL, +11% apoA1

1. Miller, AIDS 2002. 2. Badiou, Atherosclerosis 2004.

Niacin

• Effective therapy for hypertriglyceridemia• Use has been cautioned in PI-related

dyslipidemia– Flushing, cutaneous rash, pruritis, insulin resistance

• One study with extended release Niacin1

– Significant decreases in TC (14%), TG (34%), non-HDL c (19%)

– No significant decrease in LDL or HDL– Insulin resistance was an issue– Well tolerated with good safety profile

• Most side effects gone with ASA 325 mg daily

1. Gerber, Clin Infect Dis 2004.

Niacin• Acipimox

– Nicotinic acid analogue, potent inhibitor of lipolysis

– Recent study evaluating apicimox use in HIV patients with TG

• Contributory factors to dyslipidemia: Insulin resistance, ++lipolysis, ++ FFAs

• FFAs (-68%), -lipolysis, improved insulin sensitivity, modest but significant –TGs

• Potential clinical utility of apicimox in HIV dyslipidemia

*Hadigan C, JCEM 2006

Fish Oil

• Mixed results with various studies• TGs (19.5%)• Associated LDL (22%) over 16 wks• Contribution of fish oil to LDL unclear• Whether this negates benefits of TG unclear• PEE (polyunsaturated ethyl esters) vs fibrates

– Fibrates>PEE TG

• Further investigation warranted

*Woods, Nutr Clin Care 2005, Wohl, CID 2005.

TTA

• Tetradecylthioacetyl acid– Potential lipid lowering and immuno-

modulatory properties

• Small study (n=10)– TTA + dietary intervention may be therapeutic

approach– Larger efficacy of dietary intervention than

previously reported studies– -TNFα levels

*Fredrikson, Eur J Clin Invest 2004.

Leptin

• 1 randomized, double-blinded, placebo controlled study (n=7)– Effect of r-metHu leptin on metabolic

abnormalities evaluated• Improves insulin resistance, fasting insulin levels,

HDL, truncal fat mass

• Future studies warranted to further explore mechanisms and therapeutic role

*Lee J, JCEM 2006.

Treatment of Lipodystrophy

• Lipoatrophy

• Lipohypertrophy

Lipoatrophy

• Medical Management

• Surgical Management


• Use of thymidine analogue NRTIs strongly associated with lipoatrophy

• Stavudine>zidovudine• Epidemiological studies & clinical trials• Stavudine/Zidovudinealternative nucleoside analog agents

– Modest gains in limb fat

– Use of PIs + NRTIs may accelerate lipoatrophy• Observational data• PINNRTI or Abacavir

– 36% increase limb fat at 2 years

• (Mallal, AIDS 2000)

Prevention

• Randomized, double blind comparison in antiretroviral naïve patients– Stavudine vs tenofovir (+efavirenz & lamivudine)

• Tenofovir group: normal limb fat @ 133 weeks• Stavudine group: significant decline lower limb fat mass in

nearly 50% of patients• No baseline assessments done

• Open label– Tenofovir/emtricitabine vs Zidovudine/lamivudine

+Efavirenz• Primary endpoint virologic efficacy (@ 48 weeks)• Subset analysis: total limb fat less by DEXA in Zidovudine

group

*Carr, Jama 2002. Martin, AIDS 2004.

Thiazolidinediones

• Visceral Fat, Insulin Sensitivity in congenital forms of (non-HIV) lipodystrophy – Rosiglitazone for HIV-associated lipoatrophy

• Data conflicting, remains investigational• Improvements in insulin sensitivity, but TC, TG• Possible limb fat

*Sustinen, Ann Intern Med 2004.

Uridine

• Pyrimidine nucleoside

• Protects adipocytes from adverse effects of thymidine analogues

• NucleomaxX® increases uridine levels– Sugar cane derived dietary supplement– Preliminary results of small, randomized trial

suggests favorable effects on limb fat• Larger, randomized trial underway

*Sustinen, Abstract, 2005.

Leptin

• Pilot study– Improvement in fasting insulin levels, insulin

resistance, and HDL levels, truncal fat mass

*Lee J, JCEM 2006.

Surgical Approaches

• Various injectable fillers to fill in space vacated by facial lipoatrophy– Permanent: purified silicone oil,

polymethylmethacrylate, polyalkylamide, polytetrafluoroethylene (non-FDA approved)

– Temporary: poly-L-lactic acid (PLLA/SculptraTM)- used in dissolvable sutures/dental implants, non-FDA approved: bovine/human collagen, hyaluronic acid, autologous fat

• 50 patients: mean dermal thickness by U/S– 7 mm at 96 weeks

*Sustinen, Curr Opin Infect Dis 2005.

Before

After*UpToDate Images

Before 15 months7 months

‘Hamster Syndrome’: hypertrophy of fat transferred to face

“Hamster Syndrome”

*Google Images

Lipohypertrophy

• Exercise

• Medical Therapy

• Surgical Interventions

Exercise

• Safe & potentially useful in patients with abdominal fat accumulation

• Limited efficacy data

• Individualized, supervised, aerobic training program– Preferential loss of visceral fat and

improvements in TC, TG and HDL at 4/12

*Thoni, Diabetes Metab 2002.

Metformin

• Randomized Placebo Controlled Trial– Metformin 500 mg bid x 3 months in HIV

patients with central obesity and hyperinsulinemia

• Improved insulin sensitivity, reduced visceral and subcutaneous abdominal fat, improved markers of fibrinolysis

• Cannot be recommended to reduce truncal fat in non-diabetic patients

– Risk/benefit ratio not well defined

• Avoid in patients who predominantly have moderate to severe lipoatrophy

*Hadigan, JAMA 2000

Growth Hormone and Related Drugs

• Phase II trials rhGH (recombinant human GH/Serostim®)

• visceral and subcutaneous abdominal fat

• LDL, HDL

• Side effects– Fluid retention, arthralgias, myalgias, carpal

tunnel syndrome, diabetes mellitus

*Schambelan, Ann Intern Med 1996

*Engelson, J Acquir Immune Defic Syndr 2002.

Surgical Approaches

• Suction assisted lipectomy (liposuction) for dorsocervical fat accumulation– Recurrent fat accumulation

• Reduction mammoplasty for breast enlargement


• Clear associations between fat accumulation and specific antiretroviral agents less apparent

Conclusions

• HIV lipodystrophy is an important clinical problem– QOL Issues affecting treatment compliance– Increased risk of medical complications

• Dyslipidemia in HIV should be treated aggressively– Antiretroviral efficacy, resistance, side effects

• Future studies and analyses will help further define optimal treatment of HIV dyslipidemia

Thank You!!

For your attention

HIV Lipodystrophy Jisun Oh PGY-2 Internal Medicine University of Western Ontario Endocrinology Half Day 2006.12.13.

Documents

pathophysiology slide

haart slide

ldl slide

r slide

improved slide

unaids slide

daily slide

clinical relevance slide