Dr. Jayadarie RanatungaConsultant Venereologist

Teaching Hospital/ Ragama

Never ending challenges in life and science

• The success of antiretroviral therapy in controlling HIV replication and restoring immune function was a major breakthrough in the history of medicine

• With time, the recognition of important metabolic complications resulting from the interplay between traditional risk factors for cardiovascular disease, HIV infection, and antiretroviral medications has proved that life and science is a never ending struggle

Interplay

ART

Virus/ Immune system

HOSTGeneticsLifestyle

The main metabolic complications

• Maldistribution of adipose tissue and effects on lipid metabolism

• Cardiovascular complications• Increased risk of diabetes mellitus • Insulin resistance • Effects on liver metabolism• Effects on the kidney • Abnormal bone metabolism

HIV-Related Metabolic Complications

• One syndrome or several? One etiology or multifactorial?

Body fatredistribution

Lipid(cholesterol/triglyceride)abnormalities

BoneMitochondrial toxicity

Abnormal blood sugar (glucose) metabolism

Effects on lipids

• Chronic HIV infection in the absence of antiretroviral therapy is associated with

• Increased triglycerides• Decreased high density lipoprotein• Decreased low density lipoprotein• Enrichment for subtypes of low density lipoprotein

that are particularly atherogenic.

Changes in fat distribution and other related metabolic effects

• HIV-associated lipodystrophy syndrome involves fat redistribution with lipoatrophy due to subcutaneous fat loss (predominantly in the face and lower limbs) and lipohypertrophy related to central fat gain.

• Changes in body shape are associated with low self esteem leading to adherence problems and medication failure.

• Increased CVD risk leading to increased morbidity and mortality

The possible mechanisms

• An increase in visceral adiposity is associated with excess free fatty acids with increased intramyocellular fat content .

• Reduced adiponectin is associated with changes in visceral and subcutaneous fat deposits .

• Adiponectin is synthesized and secreted exclusively by adipose tissue.

The possible mechanisms

• The functional role of adiponectins is not known but thought to be involved in regulation of insulin action

• A reduction in adiponectin and an increase in IL-6 is found in HIV lipodystrophy and in stavudine (d4T)-treated patients.

• It has also been shown that a reduction in adiponectin is associated with visceral obesity and predicts the risk for CVD and Type 2 diabetes.

Intracytoplasmic lipid droplets

Intracytoplasmic lipid droplets

Mallal et al, XIII Int AIDS Conf, Durban 2000

The possible mechanisms of dyslipidemia in HIV patients

• Via increased apolipoprotein E levels

• Increased hepatic synthesis of very low density lipoprotein (VLDL)

• Reduced clearance of triglycerides.

• Due to effects of viral infection itself

• Acute-phase reactants

• Circulating cytokines including IFN-α.

Effects of ART on lipid metabolism

• Drugs within each class of ART may also have different effects on lipid values

• The thymidine analogues, such as d4T, increase triglycerides and LDL cholesterol compared with tenofovir (TDF).

• D4T is also associated with a greater loss of subcutaneous and total fat, a reduction in HDL cholesterol and an increase in insulin resistance.[

Effects of ART on lipid metabolism

• Anomalies of lipid metabolism have been increasingly recognized among HIV-infected people after the introduction of HAART.

• Much of the concern has focused on the adverse consequences of PI therapy.

• Most PIs are shown to increase total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides and reduce HDL cholesterol after 12 months of therapy.

The pathogenesis of increased lipids by PIs

• It is thought to be via the inhibition of 1. Cytoplasmic retinoic acid binding protein 1

(CRABP)-modified and cytochrome P450-3A-mediated synthesis of cis-9-retinoic acid and PPAR-γ heterodimer.

2. This inhibition increases the rate of apoptosis of adipocytes and reduces the rate at which pre-adipocytes differentiate into adipocytes, with the final effect of reducing triglyceride storage and increasing lipid release.

The effects of NRTIs

• The pathogenesis of NRTI lipid alteration is via nucleoside-induced mitochondrial dysfunction resulting from inhibition of mitochondrial DNA polymerase-γ within adipocytes and depletion of mitochondrial DNA which causes apoptosis and decreased adiponectin.

Effects of NNRTIs

• NNRTIs generally produce increases in total cholesterol, triglycerides and LDL cholesterol

• NNRTIs induce a rise in HDL cholesterol, especially nevirapine and efavirenz.

• Nevirapine reduces triglycerides

• Efavirenz causes hypertriglyceridemia

HIV and atherosclerosis

• Evidence shows dilated cardiomyopathy (prevalence 10-30%), infective endocarditis (6-34%), pericardial effusion (11-17%/year) and pulmonary arterial hypertension (0.5%) are all cardiovascular complications associated with HIV prior to HAART.

• Markers of endothelial function, such as von Willebrand factor, tissue plasminogen activator and β2-microglobulin, are all elevated in HIV-infected patients.

HIV and atherosclerosis

• HIV-infected patients have chronic immune

activation and inflammation as a result of the

virus itself, as well as co infection by other

opportunistic pathogens, such as

cytomegalovirus, which may also contribute to

the endothelial damage.

HIV and atherosclerosis

• Endothelial function appears to be important in the early development of atherosclerosis because endothelial cells provide the regulation of vascular tone, thrombogenesis, lipid breakdown, inflammation and vessel growth.

• The addition of HAART may further enhance the damage caused by HIV gp120 by disrupting the actin cytoskeleton of endothelial cells.

Evidence for inflammatory changes associated with HIV

• HIV itself or with ART even there is residual ongoing replication which

continues to activate immune cells.

• Microbial translocation adds to circulating antigen.

• HIV infection leads to CD4+ depletion which mainly happens in the gut

associated lymphoid tissue.

• Th-17 cells, the host defense against bacterial infections are lost and this results

in increase in permeability of the gut membrane causing a leaky gut.

• Microbes and microbial products can translocate and reach the portal and

systemic circulation . Microbial translocation is a cause of chronic immune

activation.

Microbial Translocation in HIV

HIV +

HIV -

Immune responses in HIV

CD4 CD4

T cell

T cell

T cell

Tcell

T cell

T cell

T cell

Viral replication Circulating antigen

Clonal expansion

Antigen Antigen

Microbialtranslocation

?Inability tocontrolmucosaldysregulation

Loss of naïveT cells

HIV

Thymic dysfunctionality

Activation

Inflammation

Non-AIDS-definingco-morbidities

Premature aging

CD57+ t cells

Loss of CD28on T cellsShortening of telomeres

End-stage senescent T cells

Desai S. and Landay A. Curr HIV/AIDS Rep 2010.

Mechanisms involved in increasing risk of CVD

Mechanisms increasing CVD risk

• Uncontrolled HIV replication has been demonstrated to be a significant

independent risk factor for the lipid abnormalities found to be

associated with increased risk for CVD in the general population.

• In HIV-infected patients, these lipid changes have been found to be

statistically associated with lower CD4+T-cell counts and higher viral RNA

levels.

• Increased lipodystrophy and triglycerides, along with reduced high-

density lipoprotein (HDL) cholesterol, is associated with increased risk

for CVD.

The mechanisms for increased CVD risk

• Increasing evidence indicates that HIV itself has a direct effect on endothelial function.

• Endothelial dysfunction in HIV may be caused by cytokines (e.g., TNF-α) secreted in response to mononuclear or adventitial cell activation by the virus.

• Direct effect of the secreted HIV-associated proteins gp120 and tat (a transactivator of viral replication) on endothelial cells.

• The SMART trial has further investigated the relationship of hs-CRP, IL-6, D-dimer and CVD morbidity and mortality.

• In this analysis, the trial demonstrated that elevated baseline levels of hs-CRP, IL-6 and D-dimer were significantly related to CVD.

• These associations remained after adjustment for CVD risk factors and when each of the inflammatory markers and D-dimer were considered jointly.

Cardiovascular complications of HIVSMART: risk of death strongly associated with IL-6 & D-dimer biomarker levels at study entry

Biomarker <25th

percentile(reference)

25th-49th

percentile50th-74th

percentile>75th

percentilep-value

OR (95%CI)

OR (95t% CI)

OR(95% CI)

IL-6(inflammation)

1.0 1.5(0.7-3.1)

3.2(1.3-7.9)

8.3(3.3-20.8)

<0.0001

D-dimer(coagulation)

1.0 3.2(1.1-9.0)

4.0(1.3-12.3)

12.4(4.3-37.0)

<0.0001

Kuller L, et al. PLoS Med 2008

HIV-associated inflammation → T reg response → TGF-β → Collagen deposition → Fibrosis → Reduced IL-7 → Reduced T cell regeneration → Inflammation

CD3+

Collagen 1 +

Desmin +

Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV

infections

These new data suggest that thrombosis and inflammation are

inextricably intertwined in the biology of atherosclerosis in HIV

patients.

Effects of HAART on lipid metabolism and increased

cardiovascular risk

Insulin resistanceType 2 diabetes

DyslipidemiaHigh FFA

Small dense LDLLow HDLHigh TG

HAART

Inflammatory/metabolic organ damage

CVD

HIV?

Inflammation

Peripheral fat lossCentral obesity

NASHNASH

Microbial translocation

Effects on Liver • Direct effect of HIV in the liver may contribute as several

liver cell types can be infected.

• Replication of HIV in hepatic stellate cells is seen by detection of P 24 Ag and HIV mRNA.

• Microbial translocation can lead to inflammation and cause non- cirrhotic portal hypertension.

• Drug induced liver injury ( DILI) is commonly seen among the HIV infected group due to a decrease in surface endoplasmic reticulum ( SER) and P450 activity.

Hepatic Stellate Cell Activation: A Central Event in Liver Fibrosis

Normal LiverActivated HSC with Fibrosis

The HIV, Aging,ART, Liver and Steatosis

HIV(chronic inflam.

state)

ART(mitochondrial

toxicity)

Fibrosis progression

Insulin ResistanceDiabetes, ObesityDyslipidemia

EtOHDrugs

Co-infection w/Hepatitis C

STEATOSIS

Insulin Resistance

• Could be a direct effect of HIV or a adverse effect of ART: Protease inhibitors( Indinavir, Saqunavir, Lopinavir, Ritonavir)

• Compared to 20%patients who are on non PI based regimens 60 to 85% of patients on PI based regimens reported to have insulin resistance.

• Impaired glucose tolerance and overt diabetes reported in 1-7% in patients on PI based HAART

Insulin resistance syndrome or syndrome X

• Co existence of high blood pressure, dysfunctional glucose homeostasis, obesity and dyslipidaemia due to insulin resistance on insulin target organs.

• Increase the risk for diabetes and cardivascular diseases by affecting endothelial function

When to suspect insulin resistance

• Use of PI based ART• Family history• Abdominal obesity (>45 inches in male and

>35 inches in females)• Ethnicity( African Americans, Hispanics, etc)• Low testosterone level• Presence of Acanthosis nigricans

HIV and kidney • Focal segmental glomerular sclerosis and renal failure / HIV-

associated nephropathy (HIVAN),

• Genetic predisposition (MYH9 and APOL1 genes on chro22)

• Hypertension and kidney disease

• Genetic overlap between risk of hypertension, focal segmental glomerulosclerosis (FSGS) and HIVAN

• Genito-urinary: kidney stones related to ART ( Tenofovir, Acyclovir )

Disorders in bone metabolism

Major bone metabolism disorders

• Avascular necrosis

• Osteopenia

• Osteoporosis

Effects of changes in bone metabolism

• Avascular necrosis of the femur and humerusmay occur in the setting of prior corticosteroid use and hyperlipidemia.

• Osteoporosis is defined as a T-score less than -2.5 when measured by DEXA (dual energy x-ray absorptiometry)

• Osteopenia is an intermediate category of reduced bone mineral density (BMD), when the T-score is between -1 and -2.5.

The possible mechanisms • Vitamin D regulates bone metabolism and immunoregulatory

properties

• Low 1,25(OH)2D3 (vitamin D) levels have been associated with low CD4+ counts, immunological hyperactivity and AIDS progression rates.

• A study by Van Den Bout evaluated the effects of ART on vitamin D status in 252 HIV patients, and found that 29% of HIV patients had vitamin D deficiency, with dark skin color being the only multivariate risk factor.

• NNRTI-treated patients demonstrated lower 1,25(OH)2D3 levels and, therefore, may have increased risk for vitamin D deficiency.

ART and bone disorders • It has been demonstrated that, compared with ART-naive patients,

ART-treated individuals have a 2.5-fold increased risk of prevalent reduced BMD.

• In a meta-analysis of 791 PI-treated patients compared with 410 non-PI-treated HIV patients has shown increased risk of a low BMD with PI treatment.

• In a recent study comparing the two fixed dose combinations of ABC-lamivudine (3TC) and TDF-emtricitabine (FTC) it was demonstrated that those participants randomized to the TDF arm had a lower BMD after 96 weeks of treatment, however, no higher incidence of fracture.

HOSTGeneticsLifestyle

Virus/ImmuneSystem

AntiretroviralTherapy (ART)

Relative contributions of each of these factors to the pathogenesis of specific co-morbidities: key to develop strategies for prevention and treatment

What Contributes to the Risk of Co-morbidities in HIV?

What should we do in preventing metabolic complications ?

• Baseline assessment for medical co morbidities and OIs

• Counseling, regular monitoring and life style changes, dietary modifications

• Research on National cohorts as there may be many differences with international cohorts

• Use existing data sources for secondary data analysisART records, clinic databases, mortality registers, laboratory data, data from hospitals

Do prospective research recruiting HIV positive and negative individuals

• Should we go beyond the guidelines and go for

Management of individual cases by early initiation of HAART?

References • Vu CN1, Ruiz- Esponda R, Yang E, Chang E, Gillard B, Pownall HJ, Hoogeveen RC, Coraza I, Balasubramanyam

A, 2013. Altered relationship of plasma triglycerides to HDL cholesterol in patients with HIV/HAART-associated dyslipidemia: further evidence for a unique form of metabolic syndrome in HIV patients. , Volume62, Issue 7, July 2013, Pages 1014–1020,

• The Lancet Infectious Diseases, Volume 13, Issue 11, Pages 964 - 975, November 2013 doi:10.1016/S1473-3099(13)70271-8Cite or Link Using DOI

• International Journal of Vascular Medicine , Volume 2012 (2012), Article ID 201027, 13 pageshttp://dx.doi.org/10.1155/2012/201027Review Article

• Metabolic syndrome in HIV-infected individuals: underlying mechanisms and epidemiological aspects,Adelzon A Paula, Melissa CN Falcão and Antonio G Pacheco* AIDS Research andTherapy 2013, 10:32 doi:10.1186/1742-6405-10-32

• J Infect Dis. 2012 Feb 15;205(4):535-9. doi: 10.1093/infdis/jir788. Epub 2012 Jan 5. Evaluation of HIVprotease inhibitor use and the risk of sudden death or nonhemorrhagic stroke.

• Worm SW1, Kamara DA, Reiss P, Fontas E, De Wit S, El-Sadr W, D'Arminio Monforte A, Law M, PhillipsA, Ryom L, Dabis F, Weber R, Sabin C, Lundgren JD;D:A:D Study Group.

• JAMA. 2014 Jul 23-30;312(4):380-9. doi: 10.1001/jama.2014.8334. ,,Effect of tesamorelin on visceral fatand liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial.

• Stanley TL1, Feldpausch MN1, Oh J1, Branch KL2, Lee H3, Torriani M4, Grinspoon SK1.