EXPERT MEETING

METABOLIC SYNDROME IN HIV

PATIENTS
IKA PRASETYA WIJAYA
CARDIOLOGY DIVISION
INTERNAL MEDICINE DEPARTEMENT
FACULTY OF MEDICINE, UNIVERSITAS INDONESIA

PDPAI MEETING 2016

 What is Metabolic Syndrome?

• A group of conditions/factors that increase risks of heart

disease and other acute or chronic medical conditions. All
of the conditions outlined below put the person at risk for
cardiovascular disease and premature death.
 Quiz:
What does this have to do with Metabolic Syndrome?
Hint…..
 Diagnosis of Metabolic Syndrome = 3 or more of the
following:
Prothrombotic state (a predisposition Insulin resistance as identified by
to venous or arterial thrombosis type 2 diabetes, impaired fasting
which is the formation or presence of glucose or impaired glucose tolerance
a clot within a blood vessel)

Abdominal obesity (picture in next Body mass index over that

slide) recommended for your height

Elevated triglycerides (normal<150; Elevated fasting blood glucose (>100)

elevated, cause for concern >200)

Low HDL (“good”) cholesterol High blood pressure (>120/80)

(men<40; women<50 is problematic)
Abdominal Obesity
 At Risk for Metabolic Syndrome
Weight gain/obesity (central Taking second generation anti-
obesity – waist line greater than psychotics, and other medications that
include some mood stabilizers: Abilify,
40 inches in men and 35 inches Clozaril, Zyprexa, Invega, Seroquel,
in women) Geodon, etc.

BMI > 25 High LDL (“bad cholesterol”) and Low

BMI= (Wt / h*h)*703 HDL (“good cholesterol”)

High blood pressure (above Ethnicity-African or Mexican American

120/80)

Family history of diabetes Increased age

Tobacco use Heavy alcohol use

Stress Sedentary life-style

High fat diet

Ethnic specific values for waist circumference
Country / Ethnic group Waist circumference
Europids* Male 94 cm
In the USA, the ATP III values ( 102 cm male;
88 cm female) are likely to continue to be Female 80 cm
used for clinical purposes
South Asians Male 90 cm
Based on a Chinese , Malay and Asian-Indian Female 80 cm
population
Chinese Male 90 cm
Female 80 cm
Japanese** Male 90 cm
Female 80 cm
Ethnic South and Central Americans Use South Asian recommendations until
more specific data are available
Use European data until more specific
Sub-Saharan Africans
data are available

EMME ( Arab) populations Use South Asian recommendations

until more specific data are available
Characteristic features of the IDF definition

- Single, universally accepted

- Simple to use clinically
- Clear cut-off points, considering different ethnic
groups
- Central obesity is the core, and waist circumference
is the proxy .
- Open to additional criteria for research , and
- Open to areas for further studies
 Prevention and Treatment
of Metabolic Syndrome
• Lifestyle management – a program of weight loss and exercise
• Tobacco cessation
• Limiting alcohol consumption
• Changes in dietary habits, including eating a heart-healthy diet
• Medication to help lower blood pressure, improve insulin
metabolism, improve cholesterol and increase weight loss
• Weight-loss surgery (bariatric surgery) to treat morbid obesity
in individuals for whom conservative measures have failed.
 Case 1

• Laki-laki, 62 tahun
• Masuk RS dengan sesak nafas sejak 1 hari
SMRS
• Riwayat Darah Tinggi dan Kencing manis
• Pengacara dan ada riwayat berganti pasangan
• Diketahui menderita HIV sejak 6 bulan lalu
dan diberi ART
 Case 1
• Obesitas
• TD 160/80 mmHg, HR 100 x/menit, RR 24
x/menit
• JVP meningkat
• Ronkhi basah halus dikedua lapang paru
• Edema tungkai minimal
• GDS = 230 mg/dL
 Case 1: Masalah
• Gagal Jantung
• Obesitas
• DM tp 2
• Hipertensi
• HIV +
 Case 1: Pertanyaan
A. Cardiovascualr disease akibat HIV
B. Cardiovascular disease akibat penyakit yang
sudah ada sebelumnya
C. CVD akibat HIV dan terapinya
D. CVD akibat tatalaksana yang tidak adekuat
terhadap HIV
 Case 1: Jawaban
A. Cardiovascualr disease akibat HIV
B. Cardiovascular disease akibat penyakit yang
sudah ada sebelumnya
C. CVD akibat HIV dan terapinya
D. CVD akibat tatalaksana yang tidak adekuat
terhadap HIV
 Case 1: lanjutan
• Jika kolesterol yang bersangkutan :
• Kolesterol Total : 189 mg/dL
• LDL : 110 mg/dL
• HDL : 35 mg/dL
• Trigliserida : 350 mg/dL

• Terapi apa yang dianjurkan?

 Case 1: Jawaban
A. Simvastatin dan fenofibrat
B. Fluvastatin dan fenofobrat
C. Pravastatin dan fenofibrat
D. Rosuvastatin dan fenofibrat
E. Atorvastatin dan fenofibrat
 Case 1: Jawaban
A. Simvastatin dan fenofibrat
B. Fluvastatin dan fenofobrat
C. Pravastatin dan fenofibrat
D. Rosuvastatin dan fenofibrat
E. Atorvastatin dan fenofibrat
 Case 2
• Laki-laki, 33 tahun
• Riwayat HIV dengan ART sejak 10 tahun lalu
• Riwayat terapi ART
• Saat ini kontrol teratur tanpa keluhan
 Case 2
• Lingkar perut 92 cm
• TD 130/90 mmHg
• GD puasa: 120 mg/dL
• GD 2 jam pp : 180 mg/dL
• Kolesterol total: 175 mg/dL
• Trigliserida: 275 mg/dL
 Case 2: Masalah
• HIV/AIDS dalam terapi ART
• Sindrom Metabolik
 At Risk for Metabolic Syndrome
Weight gain/obesity (central Taking second generation anti-
obesity – waist line greater than psychotics, and other medications that
include some mood stabilizers: Abilify,
40 inches in men and 35 inches Clozaril, Zyprexa, Invega, Seroquel,
in women) Geodon, etc.

BMI > 25 High LDL (“bad cholesterol”) and Low

BMI= (Wt / h*h)*703 HDL (“good cholesterol”)

High blood pressure (above Ethnicity-African or Mexican American

120/80)

Family history of diabetes Increased age

Tobacco use Heavy alcohol use

Stress Sedentary life-style

High fat diet

Ethnic specific values for waist circumference
Country / Ethnic group Waist circumference
Europids* Male 94 cm
In the USA, the ATP III values ( 102 cm male;
88 cm female) are likely to continue to be Female 80 cm
used for clinical purposes
South Asians Male 90 cm
Based on a Chinese , Malay and Asian-Indian Female 80 cm
population
Chinese Male 90 cm
Female 80 cm
Japanese** Male 90 cm
Female 80 cm
Ethnic South and Central Americans Use South Asian recommendations until
more specific data are available
Use European data until more specific
Sub-Saharan Africans
data are available

EMME ( Arab) populations Use South Asian recommendations

until more specific data are available
Risk factors CVD HIV+ vs HIV-
HIV-neg men
HIV-pos men
HIV-neg women
HIV-pos. women

Dyslipidaemia

Smoking

Insulin
resistance

Kaplan R, et al. CID 2007.

 Comorbidity distribution

Schouten J et al. World AIDS Conference July 2012;

* updated May 2013 (personal communication, Reiss P)
Cardiovascular Complications
Outline
• Epidemiology
• Risk factors
– host
– virus-host
– ART
• Prevention
• Key messages
• Conclusions
SMART - major CVD, hepatic or renal disease
No. of patients Relative risk
Endpoints with events (95% CI)
1.7
Major CVD, hepatic
or renal disease 104
1.6

CVD, fatal or non-fatal 79

Hepatic disease, fatal 1.4

or non-fatal 17
Renal disease, fatal 4.5
or non-fatal 11

0.1 1 10
Favours DC Favours VS ►
►
El-Sadr W, et al. SMART. NEJM 2006
 Cardiovascular complications of HIV
SMART: risk of death strongly associated with IL-6 & D-dimer biomarker
levels at study entry

Biomarker <25th 25th-49th 50th-74th >75th p-value

percentile percentile percentile percentile
(reference)

OR OR OR
(95%CI) (95t% CI) (95% CI)

IL-6 1.0 1.5 3.2 8.3 <0.0001

(inflammation) (0.7-3.1) (1.3-7.9) (3.3-20.8)

D-dimer 1.0 3.2 4.0 12.4 <0.0001

(coagulation) (1.1-9.0) (1.3-12.3) (4.3-37.0)

Kuller L, et al. PLoS Med 2008

Untreated HIV infection and
CVD pathogenesis: a proposed model

Baker J and Lundgren J. Eur Heart J 2011

Cardiovascular Complications
Outline
• Epidemiology
• Risk factors
– host
– virus-host
– ART
• Prevention
• Key messages
• Conclusions
Cardiovascular complications of HIV
ART and myocardial infarction

MI incidence according to duration of ART exposure

Friis-Moller N, et al. D:A:D. NEJM 2003.
Cardiovascular complications of HIV
MI risk disease by ARV exposure in D:A:D

ART exposure and MI risk in

D:A:D

Worm S, et al. D:A:D. JID 2012.

 Untreated HIV infection and
CVD pathogenesis: a proposed model

Baker J and Lundgren J. Eur Heart J 2011

 Treated HIV infection and
CVD pathogenesis: a proposed model
ART Insulin resistance

Baker J and Lundgren Eur Heart J. 2011

 Case continued
• Fasting lipid panel
• Total cholesterol = 320 mg/dL
• Triglycerides= 870 mg/dL
• HDL cholesterol = 32 mg/dL
• LDL cholesterol: could not be calculated
What intervention(s) would you recommend
to improve his lipid profile?

A. Discontinue lopinavir/ritonavir,
substitute atazanavir
B. Discontinue d4T, substitute tenofovir
C. Ask his employer to replace the donuts
in the vending machine with granola
D. Start simvastatin
E. Start gemfibrozil
F. Nothing needs to be done; dyslipidemia
associated with HIV/ART is not
associated with an increase in CAD
 HIV/ART Toxicities:
Dyslipidemia
• Decreased levels of HDL & LDL (especially HDL) and elevated
triglycerides seen in HIV-infected patients prior to introduction of
ART
• Most protease inhibitors have been associated with marked
elevations in triglycerides and LDL but little effect on HDL levels
• NNRTIs and stavudine also associated with dyslipidemic effects
• HIV infection and PI-based ART each associated with pro-
atherogenic profile dyslipidemia
• Substantial evidence that PI-based ART increases risk of coronary
artery disease (CAD)2-4

1. Schambelan M et al. JAIDS 2002; 31(3):257-75. 3. 11th CROI, 2004, Abstract 736.
2. 11th CROI, 2004, Abstract 739. 4. 11th CROI, 2004, Abstract 737.
 Incidence of Myocardial Infarction According to the Duration of
Exposure to Combination Antiretroviral Therapy

The DAD Study Group, N Engl J Med 2003;349:1993-2003

Risk Factors for MI in patients on ART: DAD

Risk Factor Relative Risk of MI*

Use of ART (per additional year) 1.26**

Age (per additional 5 yrs) 1.38
Male Sex 1.99
Current or former smoker 2.17
Prior history of CAD 5.84
* Multivariate analysis
** revised to 1.17 on further follow-up

The DAD Study Group, N Engl J Med 2003;349:1993-2003

 ART- associated Dyslipidemia:
Treatment

• Often improves with removal of offending

agents from regimen

• Treatment with fibrates and/or statins often

indicated

• Beware of drug interactions, risk of myositis

 Switch ART regimen or initiate lipid-
lowering pharmacotherapy?

Trend of mean plasma triglyceride levels of 130 evaluable patients

switched from protease inhibitor to nevirapine (arm A) or efavirenz (B), or
treated with pravastatin (C) or bezafibrate (D), at baseline and after 3, 6, 9
Calza L et al. AIDS 2005: 19(10), 1051-8.
 Switch ART regimen or initiate lipid-
lowering pharmacotherapy?

Trend of mean plasma total cholesterol levels of 130 evaluable patients

switched from protease inhibitor to nevirapine (arm A) or efavirenz (B), or
treated with pravastatin (C) or bezafibrate (D), at baseline and after 3, 6, 9, and
12 months of follow-up.
Calza L et al. AIDS 2005: 19(10), 1051-8.
 Lipid-Lowering Agents and ARV Therapy:
Potentially Dangerous Drug Interactions
Agent Recommendation
Pravastatin No dose adjustment
Atorvastatin Dose titration
Lovastatin Avoid
Simvastatin Avoid
Gemfibrozil
No dose adjustment
Fenofibrate
No dose adjustment
Niacin
Associated with insulin resistance
Bile sequestrants
Avoid
Dube MP et al. Clin Infect Dis 2000;31:1216-24.
 What intervention(s) would you
recommend to improve his lipids?
A. Discontinue lopinavir/ritonavir,
substitute atazanavir
B. Discontinue d4T, substitute tenofovir
C. Ask his employer to replace the donuts
in the vending machine with granola
D. Start simvastatin
E. Start gemfibrozil
F. Nothing needs to be done, as studies
have failed to document an increase in
CAD in patients on ART