Metabolic Complications Metabolic Complications of HIVof HIV

Dr Lou Haenel, JrDr Lou Haenel, Jr

EndocrinologyEndocrinology

12/1012/10

TerminologyTerminology

LipodystrophyLipodystrophy

LipoatrophyLipoatrophy

LipohypertrophyLipohypertrophy

HIVHIV

HAART (Highly Active Anti-Retroviral HAART (Highly Active Anti-Retroviral Therapy)Therapy)

Facial lipoatrophyFacial lipoatrophy

Buffalo HumpBuffalo Hump

Peripheral LipoatrophyPeripheral Lipoatrophy

Body-Fat AbnormalitiesBody-Fat Abnormalities

Reported in 40-50% of ambulatory HIV-Reported in 40-50% of ambulatory HIV-infected patientsinfected patients

Preliminary case definition by DEXA and Preliminary case definition by DEXA and CT imaging not ready for widespread CT imaging not ready for widespread clinical practiceclinical practice

Central fat accumulation tends to be Central fat accumulation tends to be visceral in location visceral in location

LocationLocation

Visceral (Hepatic, Omental)Visceral (Hepatic, Omental)

Buffalo humpBuffalo hump

BreastsBreasts

FacialFacial

NeckNeck

ExtremitiesExtremities

EtiologyEtiology

HIV – Direct virus mediated effectHIV – Direct virus mediated effect

Protease InhibitorProtease Inhibitor

Nucleoside analogue reverse-Nucleoside analogue reverse-transcriptase inhibitorstranscriptase inhibitors

Nonnucleoside reverse transcriptase Nonnucleoside reverse transcriptase inhibitorsinhibitors

Cytokine mediated effect (Adipocytokine)Cytokine mediated effect (Adipocytokine)

PathogenesisPathogenesis

Inhibiting sterol regulatory enhancer- Inhibiting sterol regulatory enhancer- binding protein 1 (SREBP1) mediated binding protein 1 (SREBP1) mediated activation of retinoid X and PPARactivation of retinoid X and PPARλλ

Disruption of adipogenesisDisruption of adipogenesis

Inhibit mitochondrial DNA polymerase Inhibit mitochondrial DNA polymerase alpha (DNA replication)alpha (DNA replication)

TNFTNFαα receptor alteration receptor alteration

Clinical ImplicationsClinical Implications

Physical changesPhysical changes

HypertriglyceridemiaHypertriglyceridemia

Low HDL cholesterolLow HDL cholesterol

Modest increases in LDL cholesterolModest increases in LDL cholesterol

Increased diastolic BPIncreased diastolic BP

Increased Metabolic syndrome profileIncreased Metabolic syndrome profile

Increased cardiovascular riskIncreased cardiovascular risk

Update on Update on LipodystrophyLipodystrophy

Dr. Louis C. Haenel, IV Dr. Louis C. Haenel, IV EndocrinologyEndocrinology

UMDNJ-SOM Volunteer FacultyUMDNJ-SOM Volunteer Faculty

DyslipidemiaDyslipidemia

Cholesterol elevation seen in 27% pts on Cholesterol elevation seen in 27% pts on combination tx (>240 mg/dl)combination tx (>240 mg/dl)

Triglyceride elevation seen in 40% pts Triglyceride elevation seen in 40% pts (>200 mg/dl)(>200 mg/dl)

HDL <35 mg/dl seen in 27%HDL <35 mg/dl seen in 27%

DyslipidemiaDyslipidemia

↑ ↑ small, dense LDL 2small, dense LDL 2

↑ ↑ apolipoprotein Bapolipoprotein B

More atherogenic profileMore atherogenic profile

↑ ↑ free fatty acid levelsfree fatty acid levels

↓ ↓ clearance of VLDLclearance of VLDL

..

Carbohydrate MetabolismCarbohydrate Metabolism

Impaired glucose tolerance seen in more Impaired glucose tolerance seen in more than 35% of HIV infected pts compared to than 35% of HIV infected pts compared to 5% in age and BMI matched controls5% in age and BMI matched controls

DM was 3.1X as likely to develop in HIV DM was 3.1X as likely to develop in HIV pts treated with combination therapy vs pts treated with combination therapy vs control populationcontrol population

PathogenesisPathogenesis

↑ ↑ circulating free fatty acidscirculating free fatty acids

Accumulation of intramyocellular lipidsAccumulation of intramyocellular lipids

Low level of adiponectinLow level of adiponectin

Reduced pparReduced pparαα activity which leads to activity which leads to reducing glucose transport mediated via reducing glucose transport mediated via Glut4 transporterGlut4 transporter

Reduce Beta cell insulin secretionReduce Beta cell insulin secretion

AssessmentAssessment

Before initiating HIV therapy, patients Before initiating HIV therapy, patients should be tested for fasting blood glucose should be tested for fasting blood glucose and cholesterol levelsand cholesterol levels

Rechecked several weeks after change in Rechecked several weeks after change in therapy and yearlytherapy and yearly

Oral glucose tolerance testOral glucose tolerance test

Cardiovascular DiseaseCardiovascular Disease

Diabetes Mellitus is considered a coronary Diabetes Mellitus is considered a coronary risk equivalentrisk equivalentEstablished risk factorsEstablished risk factorsHypertension is seen at higher rates in Hypertension is seen at higher rates in patients in HAART therapy than for age-patients in HAART therapy than for age-matched controlsmatched controlsPI therapy may promote atherosclerosis PI therapy may promote atherosclerosis by ↑ CD-36 dependent cholesterol ester by ↑ CD-36 dependent cholesterol ester accumulation in macrophagesaccumulation in macrophages

Risk Factor ModificationRisk Factor Modification

DyslipidemiaDyslipidemia

HypertensionHypertension

Insulin resistanceInsulin resistance

Sedentary lifestyleSedentary lifestyle

WeightWeight

Family historyFamily history

TobaccoTobacco

Treatment of LipodystrophyTreatment of Lipodystrophy

Change in HAART therapyChange in HAART therapyExerciseExerciseMetforminMetforminThiazolidinedionesThiazolidinedionesLeptin Leptin Recombinant Growth Hormone therapyRecombinant Growth Hormone therapyRecombinant testosterone therapyRecombinant testosterone therapyOral testosterone therapyOral testosterone therapy

Treatment of Metabolic SyndromeTreatment of Metabolic Syndrome

DietDiet

ExerciseExercise

MetforminMetformin

ThiazolidinedionesThiazolidinediones

Additional diabetes mellitus treatment Additional diabetes mellitus treatment strategiesstrategies

Treatment of HypertensionTreatment of Hypertension

Ace inhibitor therapyAce inhibitor therapy

Angiotensin receptor blocker therapyAngiotensin receptor blocker therapy

HydrochlorothiazideHydrochlorothiazide

Beta blocker therapyBeta blocker therapy

Treatment of DyslipidemiaTreatment of Dyslipidemia

Fibric Acid derivatives (Tricor, Lopid)Fibric Acid derivatives (Tricor, Lopid)

Cholesterol absorption inhibitors (Zetia)Cholesterol absorption inhibitors (Zetia)

ThiazolidinedionesThiazolidinediones

Statin therapyStatin therapy PravacholPravachol CrestorCrestor Beware of Lescol, Zocor, MevacorBeware of Lescol, Zocor, Mevacor

Improvement of AppearanceImprovement of Appearance

Surgery Surgery

Liposuction Liposuction

Injectable agentsInjectable agents Polylactic acid (promotes collagen formation)Polylactic acid (promotes collagen formation)