Cardiac Manifestations of HIV Patients

NON INVASIVE

CARDIAC WORK UP OF

HIV POSITIVE

PATIENTS

Ponangi Udaya Prashant

Consultant, GLOBAL Hospitals, Hyderabad

Email: [email protected]

J.J GROUP OF HOSPITALS DISSERTATION SUBITTED FOR THE DEGREE OF D.M. CARDIOLOGY

EXAMINATION (BRANCH II),

UNIVERSITY OF MUMBAI

May 2008,

INTRODUCTION

HIV aptly called plague of modern era has spread throughout the world

in matter of few decades and is now a global pandemic, with cases reported

from virtually every country. According to the Centres for Disease Control and

Prevention (CDC), the case definition of AIDS is (1) HIV-infected individuals

who have <200 CD4 T lymphocytes/µL or (2) HIV-infected individuals who

have the presence of specific opportunistic infections like Pneumocystis carinii

pneumonia, Kaposi’s sarcoma Cytomegalovirus disease, and pulmonary

tuberculosis1. Around 42 million people are now living with HIV/ AIDS

worldwide2. In 2003 alone, there were 5 million new cases of the infection

worldwide and 3 million deaths from AIDS, making it the 4th leading cause of

mortality3, 4. An estimated 5.7 million people lived with HIV infection in India in

2005, which is more than in any other country in the world. Out of these, total

1.2 million patients were suffering from severe form of the disease, AIDS,

giving an adult prevalence rate of 0.91%5.

There are certain peculiarities of HIV infection. Besides being the most

dreaded infectious disease at present, it differs a lot from other viral diseases.

With the exception of few viruses, most viral infections usually last from

several days to weeks during which development of specific adaptive

immunity along with innate immunity clears virus from the body. However HIV

infection is unique in that once the virus establishes in the body it succeeds in

escaping the immune mediated clearance and hence it is virtually never

eliminated from the body completely. Rather a chronic or persistent infection

develops that persists with varying degrees of viral replication, which is a

hallmark of this disease. 2 Some of the HIV-infected adults are known to have

cardiac involvement in the form of diseases of the pericardium, myocardium

and the endocardium. Although pathogenesis of cardiac involvement in HIV

infection is uncertain; autoimmunity, autonomic dysfunction and abnormal

ventricular growth have been proposed as the possible mechanisms3,

The 2 to 5 yr prevalence of symptomatic heart failure ranges from 4 to

28 percent suggesting prevalence of 5 million cases of symptomatic HIV

related heart failure6. Before the advent of antiretroviral therapy (ART),

clinically significant cardiac disease was unusual in the HIV-infected

population and was detected in most cases only at autopsy. After the

introduction of HAART in 1996, the death rate from AIDS has decreased

dramatically7. Use of new anti retroviral therapies has provided these patients

an opportunity to live longer and healthier life. However, increasing the

longevity of life in HIV patients has uncovered many late manifestations of the

disease. Cardiovascular complication is one of these late manifestations of

HIV and is therefore becoming more prevalent. Infection with HIV is one of

the leading causes of acquired heart disease and specifically of symptomatic

heart failure. In 1996, the estimated prevalence’s of a significant cardiac

morbidity and mortality among HIV-positive patients was 6%–7% and 1%–5%,

respectively8 When HIV-infected patients were examined by

echocardiography in the late 1980s, cardiac abnormalities were detected

more often than would be expected from clinical symptoms and physical

examination.9 Echocardiography studies showed pericardial effusion as the

commonest cardiac manifestation40,41,42, but other studies showed

asymptomatic cardiac dysfunction to be more prevalent 34,35,36. The effect of

various HAART regimes on long term cardiovascular complications like

dyslipidemia, accelerated atherosclerosis is still not known. Few studies were

carried out using exercise stress testing to evaluate silent myocardial

ischaemia (SMI) in asymptomatic HIV patients treated with HAART and the

prevalence was found to be 11%14

Although most conditions are clinically quiescent, most often masked

by superimposed secondary infections, some may have fatal outcomes. For

example Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study,

showed that patients receiving HAART had somewhat higher risk of

myocardial infarction than would be predicted by the Framingham risk

equation10. Furthermore, the risk of cardiac events also appears to be higher

in patients with uncontrolled viremia and worse immunosuppresion. As

patients with HIV infection are living longer, they are also at risk of developing

coronary atherosclerosis. Cardiac complications are often overshadowed by

associated more sinister opportunistic infections and malignancies in HIV

patients. Therefore there is paucity of data regarding cardiac manifestations in

HIV, AIDS patients and influence of long term HAART .

History and clinical examination of HIV patients with cardiac disease is

often unrevealing. Even X-ray and ECG are less sensitive in identifying all

cardiac diseases in such patients and they are also non-specific3. Hence

other tests like Echocardiography, stress test and serum lipid profiles have

emerged as convenient, cost effective, sensitive and non-invasive methods

for studying cardiac affection in patients of HIV/AIDS. From an

epidemiological standpoint, well-designed longitudinal studies are warranted

to properly assess the natural history of cardiovascular and metabolic

abnormalities in the HIV-infected population.

AIMS AND OBJECTIVES

1) Find out various echocardiography, stress test and lipid abnormalities

in clinically stable patients with HIV infection/ AIDS.

2) Demonstrate the use of echocardiography, stress test and serum lipid

levels in detecting asymptomatic cardiac diseases in HIV/AIDS

patients.

3) Effect of HAART on cardiovascular complications in HIV patients.

MATERIALS AND METHODS

This study was carried out on 96 HIV patients, selected randomly from

those attending ART Centre, JJ Hospital Mumbai, and satisfied the selection

criteria of our study. The study was conducted over a period of 1 year from

November 2006 to October 2007

Inclusion criteria

1. Patients of HIV infection diagnosed by at least two positive HIV

ELISA tests or one HIV ELISA and one Western Blot test.

2. Age 15 years and above.

3. Those attending JJ ART centre as out patients.

Exclusion criteria

1. Patients with known structural cardiac disease.

2. Patients suffering from life threatening opportunistic infections,

malignancies and those who are morbidly ill, debilitated and

bedridden due to severe AIDS condition.

The nature of the study was explained to the patients and an informed

consent was taken. A detailed history was taken including that of the risk

factors for HIV infection and the history relevant for the cardiovascular

diseases.

Patients were specifically asked for cardiovascular risk factors like

history of diabetes, hypertension, smoking, family history of early ischaemic

heart disease.

Cardiac symptoms were sought regarding angina on exertion or at rest,

dyspnoea at exertion, orthopnoea, PND, palpitations, giddiness, syncope and

symptoms of congestive heart failure.

Patients were divided into 3 groups depending upon duration of HIV

illness

♦ < 1 year

♦ 1 –5 years

♦ 5 years.

A thorough clinical examination performed on each patient and findings

recorded as per proforma.

Antibodies against HIV 1 & 2 were tested using ELISA method.

Subjects with single positive HIV ELISA were subjected to either repeat

ELISA or Western blot analysis, for confirmation, depending on patients’

affordability. Patients with at least 2 positive HIV ELISA or one positive HIV

ELISA and one positive western blot were considered to be having HIV

infection.

Routine haematological and biochemical investigations were performed

on each patient. Patients were also investigated for particular diseases as

directed by their clinical presentation other than those of cardiovascular

system.

CD4 count testing was performed on all HIV positive patients by flow

cytometry.

Clinically classified into A, B or C according to 1993 CDC Atlanta

revised classification system for HIV infection and expanded AIDS

surveillance for adults1.

A: Asymptomatic, Acute HIV or PGL

B: Symptomatic not `A` or `C` conditions

C: AIDS – indicator conditions.

CLINICAL STAING ACCORDING TO CD4 COUNTS1:

Stage 1 = CD4 count >500.

Stage 2 = CD4 count 200-499.

Stage 3 = CD4 count <200.

CLINICAL CATEGORIES:

CD4 T CELL

CATEGORIES

A

ASYMPTOMATIC,

ACUTE HIV or

PGL

B

SYMPTOMATIC,

NOT ‘A’ or ‘C’

CONDITIONS

C

AIDS-

INDICATOR

CONDITIONS

> 500/µL A1 B1 C1

200-499/µL A2 B2 C2

< 200/µL A3 B3 C3

Chest X ray in PA view and standard 12 lead electrocardiograms were

obtained for all the patients. Chest roentgenogram was interpreted as normal,

cardiac abnormality, pulmonary abnormality or both. Cardiothoracic ratio of

more than 50% was taken as criteria for diagnosing cardiomegaly on X ray.

ECG was studied for abnormalities in rate, rhythm, P wave, QRS complex, T

wave and U wave. PR interval, QT & RR interval abnormalities and ST

segment deviations were looked for.

ECHOCARDIOGRAPHY:

We used SEIMENS ACCUSON Sequoia C 520 Ehocardiography

machine with 3.5 and 5.0 MHz transducers. Transthoracic echocardiography

done with subjects in left lateral decubitus position.

Detailed echocardiography was done as per convention using standard

2D imaging, M mode, Colour, Pulse and Continuous Doppler. The patients

were evaluated for left and right ventricular systolic function in the form of

fractional shortening and ejection fraction. Left and right ventricular

dimensions recorded and compared with normal values for age and sex21.

Other abnormalities like diastolic dysfunction, valvular abnormalities, PAH,

vegetations, effusions are specifically looked for

ECHOCARDIOGRAPHIC CRITERIA21

Following Echocardiographic Criteria were used for diagnosis of respective

cardiac conditions

• Dilated cardiomyopathy

Global LV hypokinesia with LV end systolic diameter >55mm and fractional

shortening <28% or ejection fraction <55

Mild: 54 - 45%

Moderate: 44 – 30%

Severe: < 30%

• Borderline LV systolic dysfunction

LV end systolic diameter <55mm and fractional shortening <28% or

ejection fraction <55%

• Isolated RV dysfunction

-RV larger than LV on standard echo views or RV mean basal diameter

>2.8 cm and RV fractional change <30% then RV dysfunction present.

Mild: 31 – 25%

Moderate : 24 – 18%

Severe : < 17%

• LV diastolic dysfunction

- On M mode, motion of the anterior mitral leaflet showing

diminished excursion and

- reduced E/A ratio

• Pericardial effusion

Diagnosed as echo free space between visceral and parietal

pericardium.

1. Small effusion- max. pericardial space < 10mm

2. Moderate effusion- max. pericardial space 10 to 20mm

3. Large effusion- max. pericardial space >20mm

• Pulmonary hypertension

Pulmonary artery systolic pressure by TR jet more than 30 mmHg.

Mild : 30 – 50 mmHg

Moderate : 50 – 70 mmHg

Severe : > 70 mmHg

COMPUTERISED STRESS TEST:

The computerised cardiac stress test was done on Schiller CS 200

Tread mill machine using Bruce protocol.

The test is terminated when

• Absolute indications :

o Drop in SBP of greater than 10 mm Hg from baseline blood

pressure, despite an increase in workload, when accompanied

by other evidence of ischemia

o Moderate-to-severe angina

o Increasing nervous system symptoms (eg, ataxia, dizziness,

near-syncope)

o Subject's desire to stop

o Sustained ventricular tachycardia

o ST elevation (>1 mm) in leads without diagnostic Q waves (other

than V1 or aVR)

The classic criteria for visual interpretation of positive stress test

findings are J-point (defined as the junction of the point of onset of the ST-T

wave and normally at or near the isoelectric baseline of the ECG) and ST80

(defined as the point that is 80 ms from the J point) depression (flattening or

downsloping) of 0.1 mV (1 mm) in 3 consecutive beats.

LIPIDS:

After 12 hours of overnight fasting blood was collected for lipid profile

and analysis was done in standard laboratory using liquid chromatography

method

According to NCEP ATP III69 lipid goals, present studied population

based on age sex distribution and o clinical evaluation of cardiovascular risk

profile they were considered to be in low risk group with 0 – 1 risk factors and

dyslipidemia defined when following lipid abnormalities were detected.

♦ Total cholesterol >240 mg/dl

♦ LDL Cholesterol >160 mg/dl

♦ HDL Cholesterol <40 mg/dl

♦ VLDL Cholesterol >35 mg/dl

♦ Triglycerides >200 mg/dl

♦ LDL/HDL ratio 2.5 to 3.5

Statistical analysis were done using SPSS software.

REVIEW OF LITERATURE

Newly discovered infecting organisms are brought in contact with

humans either through animals or through changing environment. Human

Immunodeficiency Virus (HIV) is one of such recently discovered viruses,

which pose threat to whole mankind. First identified in March 1981 when

several rare cases of aggressive Kaposi sarcoma and Pneumocystis carinii

pneumonia reported in young homosexual men in US, disease was called

Gay related immuno deficiency (GRID) or acquired immunodeficiency disease

(AID), 12. The cause of AIDS is a virus that scientists isolated in 198313. The

virus was at first named HTLV-III/LAV (human T-cell lymphotropic virus-type

III/lymphadenopathy- associated virus) by an international scientific

committee. This name was later changed to HIV (human immunodeficiency

virus).

Two types of HIV are currently recognized: HIV-1 and HIV-2.

Worldwide, the predominant virus is HIV-1. Both types of virus are transmitted

by sexual contact, through blood, and from mother to child, and they appear

to cause clinically indistinguishable AIDS. However, HIV-2 is less easily

transmitted, and the period between initial infection and illness is longer in the

case of HIV2. Currently at least 10 genetically distinct subtypes of HIV-1 are

identified within the major group (group M) containing subtypes A to J. In

addition, group O (Outliers) contains a distinct group of very heterogeneous

viruses. These subtypes are unevenly distributed throughout the world. For

instance, subtype B is mostly found in the America, Japan, Australia, the

Caribbean and Europe; subtypes A and D predominate in sub-Saharan Africa;

subtype C in South Africa and India; and subtype E in Central African

Republic, Thailand and other countries of southeast Asia. Subtypes F (Brazil

and Romania), G and H (Russia and Central Africa), I (Cyprus), and group O

(Cameroon) are of very low prevalence. In Africa, most subtypes are found,

although subtype B is less prevalent2.

The History of HIV/AIDS in India

In 1986, India’s first cases of HIV were diagnosed among sex workers

in Chennai, Tamil Nadu. In 1987 a National AIDS Control Programme was

launched to co-ordinate national responses. Its activities covered surveillance,

blood screening, and health education.16. By the end of 1987, out of 52,907

who had been tested, around 135 people were found to be HIV positive and

14 had AIDS. Most of these initial cases had occurred through heterosexual

sex, but at the end of the 1980s a rapid spread of HIV was observed among

injecting drug users in Manipur, Mizoram and Nagaland - three north-eastern

states of India bordering Myanmar (Burma). 16

By this stage, cases of HIV infection had been reported in every state

of the country.15 Throughout the 1990s, it was clear that although individual

states and cities had separate epidemics, HIV had spread to the general

population. Increasingly, cases of infection were observed among people that

had previously been seen as ‘low-risk’, such as housewives and richer

members of society. In 1992 the government set up NACO (the National AIDS

Control Organization), to oversee the formulation of policies, prevention work

and control programmes relating to HIV and AIDS.

Since the detection of first case of HIV in 1986 in India, epidemic of the

disease has led to a sharp increase in the number of cases. An estimated 5.7

million people lived with HIV infection in India in 2005, 16 this gives an adult

prevalence rate of 0.91% for AIDS in India. As of July 2005, 92% of all

nationally reported AIDS cases have been found in 10 of the 38 States Union

Territories. The greatest numbers were in Maharashtra and Gujarat in the

west; Tamil Nadu and Andhra Pradesh in the south; and Manipur and West

Bengal in the northeast. A 2006 NACO report revealed 124995 people

suffering from AIDS syndrome with 88245 males and 36750 females16. Of

which 5,500 cases are below 15 years age. According to UNAIDS/WHO,

between 270,000 and 680,000 Indians died of AIDS in 2005.The statistics for

AIDS cases may be a poor guide to the severity of the epidemic, as in many

situations a patient will die without HIV having been diagnosed, and with the

cause of death attributed to an opportunistic infection, such as tuberculosis

HIV Virus

HIV1 and HIV2 are RNA viruses of family Retroviridae belonging to

subfamily Lentiviridae. HIV1 is the commonest among these and contains

several subtypes. Electron microscopy reveals that HIV is an eicosahedral

structure containing numerous spikes formed by 2 major proteins Gp120 and

Gp41.

REPLICATION: -

Retroviruses have unique replication cycle whereby their genetic

information is encoded by RNA rather than DNA. They contain RNA

dependent DNA polymerase (a reverse transcriptase) that directs synthesis of

DNA from viral genome. Hence named retroviruses.2, 17

The replication cycle of retroviruses proceeds in 2 phases:

First phase: Viral entry into cytoplasm after binding to specific cell surface

receptorCD4 and co-receptors CXCR4 and CCR5. Once the virus is

internalised its RNA is released from nucleocapsid and is reverse transcribed

into proviral DNA. This proviral DNA integrates randomly into host DNA.

Second phase: includes synthesis and processing of viral genomes, m-RNAs

and proteins using host cell machinery. The virions are assembled and

extruded from cell surface by budding. Important coding regions of viral

genome are gag, pol and env 2.

PATHOGENESIS

The hallmark of HIV disease is a profound immunodeficiency resulting

primarily from progressive deficiency of helper T cells. This subset of T cells

has a surface molecule CD4, which serves as a primary cellular receptor for

HIV. HIV infected CD4+ T cells undergo destruction and/ or immunologically

dysfunctioned by a number of mechanisms. When the number of T cells

declines below a certain level, the patient is at high risk of developing a

variety of opportunistic diseases.17

DIAGNOSIS AND MONITORING HIV:

Earliest method developed for screening of HIV antibodies was HIV

Elisa in 1985.

Today several direct and indirect tests are being used for the diagnosis

of HIV infection.2

1. HIV Elisa- standard screening test can be used for detection of both

HIV1 and 2 antibodies. Extremely sensitive test. (Sensitivity >99.5%)

2. HIV Western blot- most commonly used confirmatory test.

Has high specificity.

3. P24 antigen capture assay- detects viral protein p24 in HIV infected

patients. Most useful during window period (before development of HIV

sp. Antibodies) and acute HIV syndrome.

4. HIV RNA assay- determines number of copies of HIV RNA per milliliter

of Serum. Used for screening and establishing diagnosis. Also

helpful in determining need for therapy and monitoring

efficacy of therapy. CD4+ T cell count- correlates with disease

severity. Used for determining need for therapy and monitoring

efficacy of therapy.

CLINICAL MANIFESTATIONS

The clinical features of HIV infection range from acute HIV syndrome

to asymptomatic stage to full blown AIDS.

Acute HIV syndrome:

Within 3 to 6 weeks of primary HIV infection, many patients develop a

clinical syndrome of varying severity called acute HIV syndrome. Features

may include fever, pharyngitis, lymphadenopathy, rash etc. it correlates with

burst of plasma viremia. Symptoms may persist from one to several weeks 2

Asymptomatic stage:

Represents the duration between initial infection to the stage of clinical

disease. Although the duration of this stage may have lot of variation it

averages about 10 yrs.

Even though the patient is asymptomatic the disease is constantly

progressing as evidenced by fall in CD4 count and rise in plasma viremia.

Symptomatic stage:

Symptoms of HIV disease can appear at anytime during the course of

HIV infection. Generally, the spectrum of disease that one observes changes

as the CD4 counts declines. The more severe and life threatening

complications of HIV infection occur in patients with very low CD4 counts. A

diagnosis of AIDS is made in anyone with HIV infection and a CD4 count less

than 200/µl. The causative agents of secondary infections in HIV/AIDS are

characteristically opportunistic organisms such as P.carinii, atypical

mycobacteria etc. However non-opportunistic common bacterial and

mycobacteria pathogens frequently affect HIV patients. Approximately 60% of

deaths among AIDS patients are as a direct result of an infection other than

HIV. Multiple organ system involvement is observed in patients with

symptomatic HIV.

Respiratory, cardiovascular, neurological, gastrointestinal and

hepatobiliary, renal and genitourinary, endocrine, rheumatologic,

hematopoietic, dermatologic diseases are common presenting illnesses in

these patients.

Defining AIDS

The case definition of AIDS has undergone several revisions over

years. The current CDC (Centre for Disease Control and prevention)

classification system for HIV infected adolescents and adults categorizes

persons on the basis of clinical conditions associated with HIV infection and

CD4+ T lymphocyte counts. The system is based on three ranges of CD4+ T

lymphocyte counts and three clinical categories. Using this system, any HIV

infected individual with CD4 count <200/µl has AIDS by definition.

1993 REVISED CLASSIFICATION SYSTEM FOR HIV INFECTION AND

EXPANDED AIDS SURVEILLANCE CASE DEFINITION FOR ADULTS 1

CLINICAL CATEGORIES :

CD4 T CELL CATEGORIES

A ASYMPTOMATIC,

ACUTE HIV or PGL

B SUMPTOMATIC

NOT ‘A’ or ‘C’ CONDITIONS

C AIDS-

INDICATOR CONDITIONS

> 500/µL A1 B1 C1

200-499/µL A2 B2 C2

< 200/µL A3 B3 C3

HIV infected patients under classifications – A3,B3, C1, C2, C3 are

defined as AIDS cases CD4 count <200/microlitre is defined as AIDS

regardless of presence pf symptoms or opportunistic infections .

1993 AIDS surveillance case definition CDC Atlanta:

Category A 1 or more of following

Category B Category C (AIDS indicator conditions)

1. Asymptomatic HIV infection.

2. Progressive Generalised Lymphadenopathy

3. Acute primary HIV infection

1. Bacillary angiomatosis

2. Vulvovaginal candidiasis, oral candidiasis

3. Cervical dysplasia, cervical carcinoma insitu.

4. Constitutional symptoms > 1 month

5. Oral hairy leukoplakia

6. Herpes zoster- 2 distinct episodes more than one dermatome

7. Idiopathic thrombocytopenic purpura

8. Listerosis

9. Pelvic inflammatory disease

10. Peripheral neuropathy

1. Candidiasis of the bronchi, trachea or lungs.

2. Esophageal candidosis 3. Coccodiomycosis – disseminated or

extra pulmonary 4. Cryptococcosis – Extra pulmonary 5. Cryptosporidiosis – chronic intestinal

(> one month) 6. Cytomegalovirus disease (other than

lung spleen and nodes) 7. Cervical cancer – invasive 8. CMV retinitis 9. HIV related encephalopathy 10. Herpes simplex – chronic ulcer,

bronchitis, pneumonia or esophagitis 11. Histoplasmosis – disseminated or

extra pulmonary 12. Isosporiasis – disseminated or extra

pulmonary 13. Kaposi `s sarcoma 14. Burkits lymphoma 15. Immunoblastic lymphoma 16. Primary brain lymphoma 17. MAIC, M. kansasi infection –

(disseminated or extra pulmonary) 18. M . tuberculosis 19. Mycobacterium other species or

unidentified species – (disseminated or extra pulmonary)

20. Recurrent pneumonia 21. Progressive multifocal

leukoencephalopathy 22. Salmonella septicemia – recurrent

Indications for starting Anti Retroviral Therapy1, 26

1. Acute HIV syndrome

2. Chronic HIV infection

A) Symptomatic disease

B) Asymptomatic disease

i. CD4+ T cell count < 350/µL or decreasing

ii. HIV RNA > 50,000 copies/ml or increasing

3. Post exposure prophylaxis

PRINCIPLES OF THERAPY OF HIV INFECTION: 18

1. Ongoing HIV replication leads to immune system damage and

progression to AIDS.

2. Plasma HIV RNA levels indicate magnitude of HIV replication. CD4+ T

cell counts indicate current level of immune system competence.

3. Maximum suppression of viral replication is the goal of therapy.

4. Effective therapeutic strategies involve simultaneous initiation of

antiretroviral drugs in combination according to optimum schedule and

dosages.

Compliance is an important part of maximal efficacy of a treatment

regimen.

ANTIRETROVIRAL DRUGS: 2, 19

ANTIRETROVIRAL DRUGS AND REGIMENS

Current antiretroviral drugs comprise four classes

I) Nucleoside/nucleotide reverse transcriptase inhibitors: zidovudine,

lamivudine, emtricitabine, stavudine, didanosine, zalcitabine, abacavir,

tenofovir

II) Non-nucleoside reverse transcriptase inhibitors: efavirenz, nevirapine,

delavirdine

III) Protease inhibitors: amprenavir/fosamprenavir, atazanavir, indinavir,

lopinavir/ritonavir, nelfinavir, saquinavir, tipranavir, ritonavir (not commonly

used as the sole protease inhibitor in an antiretroviral regimen, but often used

in low doses to “boost” the levels of other protease inhibitors).

IV) Fusion inhibitors, of which only enfuvirtide is approved by the US Food

and Drug Administration (FDA).

Commonly used abbreviations for antiretroviral drugs

S = stavudine

A = zidovudine

N = nevarapine

L = lamivudine

E = efavirenze

HAART regimes commonly used

SLN

ALN

SLE

ALE

Highly active antiretroviral therapy “Highly active” antiretroviral therapy

(HAART) is a term used to distinguish aggressive multidrug regimens from

earlier, less potent ones. Currently, antiretroviral therapy (ART) and HAART

both refer to any potent combination of agents that can reduce the plasma

HIV level to less than can be detected by polymerase chain reaction or b-DNA

assay. These regimens most often consist of a protease inhibitor or non-

nucleoside reverse transcriptase inhibitor in addition to a “backbone” of two

nucleoside reverse transcriptase inhibitors.

ECHOCARDIOGRAPHY :

Echocardiography is the use of ultrasound to examine the heart. It is a

safe, non invasive and painless technique.20

ECHOCARDIOGRAPHY:

Two-dimensional echocardiography was first demonstrated in the late

1950s, with real-time mechanical systems and, in the early 1960s, with

intracardiac probes. Transesophageal echocardiography followed, in the late

1960s. Stop-action two-dimensional echocardiography enjoyed a brief vogue

in the early 1970s. It was, however, the demonstration by Bom in Rotterdam

of real-time two-dimensional echocardiography using a linear transducer array

that revolutionized and popularized the subject. Then, the phased array sector

scanner, which had been demonstrated in the late 1960s by Somer in Utrecht,

was applied to cardiac studies from the mid-1970s onwards. Satomura had

demonstrated the use of the ultrasonic Doppler effect to detect tissue motion

in Osaka in the mid-1950s and the technique was soon afterwards applied in

the heart, often in combination with M-mode recording. The development of

the pulsed Doppler method in the late 1960s opened up new opportunities for

clinical innovation20.

NORMAL VALUES FOR AN ADULT:20, 21

Left ventricular internal diameter (end systolic) LVIDs- 2.0- 4.0 cms

Left ventricular internal diameter (end diastolic) LVIDd 3.5- 5.6 cms

Left ventricular wall thickness

Diastolic-septum 0.6- 1.0 cms

Diastolic-posterior wall 0.6- 1.0 cms

Systolic-septum 0.9- 1.8 cms

Systolic-posterior wall 0.9- 1.8 cms

Left ventricular fractional shortening,FS 28- 45%

Left ventricular ejection fraction, LVEF 55- 80%

Left atrial diameter 2.7- 3.8 cms

Aortic root diameter 2.0-4.0 cms

Right ventricular diameter (systolic-diastolic) 0.7-2.3 cms

ECHOCARDIOGRAPHIC FINDINGS21, 22

In some common heart conditions associated with HIV/ AIDS

1) Dilated cardiomyopathy and systolic dysfunction

Characterized by

A) dilatation of cardiac chambers, specially LV

B) reduced wall thickness

C) reduced wall motion, global hypokinesia

D) intra cardiac thrombus

M-mode and 2D echo show, increased LVIDs &LVIDd;

decreased LVEF&FS; reduced motion of IVS & LVPW.

Doppler studies may show functional mitral or tricuspid

regurgitation.

REFERENCE LIMITS AND PARTITION VALUES OF LEFT VENTRICULAR

SIZE21

Women Men

Variable Reference

Range

Mildly

Ab-nomal

Mod-erately

Ab-normal

Severly

Ab-normal

Reference

Range

Mildly

Ab-normal

Moderately

Ab-normal

Severly

Ab-normal

LV diastolic diameter cm

3.9-5.3 5.4-5.7 5.8-6.1 >6.2 4.2-5.9 6.0-6.3 6.4-6.8 >6.9

LVIDD/BSA

Cm/m2

2.4-3.2 3.3-3.4 3.5-3.6 >3.7 2.4-3.3 3.2-3.4 3.5-3.6 >3.7

LVIDD/ height

Cm/m

2.5-3.2 3.3-3.4 3.5-3.6 >3.7 2.4-3.3 3.4-3.5 3.6-3.7 >3.8

REFERENCE LIMITS AND VALUES PARTITION VALUES OF LEFT

VENTRICULAR FUNCTION21

Women

Men

Variable Refere

nce

Range

Mildly

Ab-nmal

Moderat

ely

Ab-

normal

Severly

Ab-

normal

Reference

Range

Mildly

Ab-normal

Moderately

Ab-

normal

Severly

Abnorm

al

Endocardial

fractiona

shortening %

27-45 22-26 17-21 <16 25-43 20-24 15-19 <14

Ejection

fraction %

>55 45-54 30-44 <30 >55 45-54 30-44 <30

2) Myocarditis

have similar features as dilated cardiomyopathy

3) Right ventricular dysfunction

Characterized by dilated or hypokinetic RV. If RV is of the same

size as or larger than LV in all views, it is abnormal.

REFERENCE LIMITS AND PARTITION VALES OF RIGHT VENTRICLAR

SIZE AND FUNCTION AS MEASURED IN THE APICAL FOUR-CHAMBER

VIEW21

Variable Reference

Range

Mildly

Abnormal

Moderately

Abnormal

Severely

Abnormal

RV basal diameter cm

2.0-2.8 2.9-3.3 3.4-3.8 >3.9

RV fractional change %

32-60 25-31 18-24 <17

4) Pulmonary hypertension

Characterized by abnormal increase in pulmonary artery pressure

above 30/20 mmHg.

Doppler study showing PASP by TR jet of mean>20mmHg at rest

and>30mmHg during exercise.

2D echo features-dilated Pulmonary artery (pulmonary artery

diameter>aortic Diameter), RV dilatation/ hypertrophy, RA enlargement,

abnormal IVS motion. M-mode shows abnormal M- mode of pulmonary valve

leaflets with absent A waves, dilated RV with normal LV and abnormal IVS

motion.

5) Pericardial effusion- abnormal collection of excessive fluid in pericardial

space. M-mode reveals an echo free space seen below posterior wall of LV or

above the anterior wall of RV. In 2Decho, effusion is seen as an echo free

space surrounding heart. It can be diffuse or locculated

Minimal pericardial effusion : <10 mm

Moderate pericardial effusion : 10 - 20

Large pericardial effusion: >20 mm

6) Cardiac tamponade is seen as large volume of pericardial effusion with

Diastolic collapse of RA&/or RV. Patient will also have hemodynamic

compromise like resting tachycardia, feeble pulses with pulses paradoxus

7) Constrictive Pericarditis:

Echocardiographic features are

i) thickened pericardium

ii) calcified pericardium

iii) abnormal septal motion, especially end diastolic

iv) abnormal LV filling pattern

v) LV expands only in early diastole

vi) Mid and late diastolic flattening of LVPW motion

vii) Restrictive pattern on Doppler study20,22

STRESS TEST:

HISTORY :

Feil and Seigel23 first noticed the significance of cardiovascular

exercise stress testing in 1928; they reported ST and T changes following

exercise in 3 patients with chronic stable angina. Hellerstein et al introduced

stress testing as a method of evaluating work capacity of cardiac patients.

The following year, Master and Oppenheimer introduced a standardized

exercise protocol to assess functional capacity and hemodynamic response24.

Bruce in 1956 reported a work test performed on a treadmill and established

guidelines that would group patients into NYHA I – IV.

.

Exercise stress testing, which is now widely available at a relatively low

cost, is currently used most frequently to estimate prognosis and determine

functional capacity, to assess the probability and extent of coronary disease,

and to assess the effects of therapy. Ancillary techniques, such as metabolic

gas analysis, radionuclide imaging, and echocardiography, can provide further

information that may be needed in selected patients, such as those with

moderate or prior risk26.

Exercise physiology

The initiation of dynamic exercise results in increases in the ventricular heart

rate, stroke volume, and cardiac output due to vagal withdrawal and

sympathetic stimulation. Also, alveolar ventilation and venous return increase

as a result of sympathetic vasoconstriction. The overall hemodynamic

response depends on the amount of muscle mass involved, exercise

efficiency, conditioning, and exercise intensity.

In the initial phases of exercise in the upright position, cardiac output is

increased by an augmentation in stroke volume mediated through the use of

the Frank-Starling mechanism and heart rate. The increase in cardiac output

in the later phases of exercise is due primarily to an increase in ventricular

rate.

During strenuous exertion, sympathetic discharge is maximal and

parasympathetic stimulation is withdrawn, resulting in autoregulation with

generalized vasoconstriction, except in the vital organs (cerebral and coronary

circulations).

Venous and arterial norepinephrine release from sympathetic postganglionic

nerve endings is increased, and epinephrine levels are increased at peak

exertion, resulting in an increase in ventricular contractility. As exercise

progresses, skeletal muscle blood flow increases; oxygen extraction

increases as much as 3-fold; peripheral resistance decreases; and systolic

blood pressure (SBP), mean arterial pressure, and pulse pressure usually

increase. Diastolic blood pressure (DBP) remains unchanged or may increase

or decrease by approximately 10 mm Hg. The pulmonary vascular bed can

accommodate as much as a 6-fold increase in cardiac output, with only

modest increases in pulmonary arterial pressure, pulmonary capillary wedge

pressure, and right atrial pressure; this is not a limiting determinant of peak

exercise capacity in healthy subjects.

The maximum heart rate and cardiac output are decreased in older

individuals, related in part to decreased beta-adrenergic responsiveness.

Maximum heart rate can be calculated by subtracting the patient's age (y)

from 220 (has a standard deviation of 10-12 beats per minute [bpm]). The

age-predicted maximum heart rate is a useful measurement for safety

reasons and as an estimate of the adequacy of the stress to evoke inducible

ischemia. A patient who reaches 80% of the age-predicted maximum is

considered to have a good test result, and an age-predicted maximum of 90%

or better is considered excellent27.

In the postexercise phase, hemodynamics returns to baseline within

minutes of discontinuing exercise. The return of vagal stimulation is an

important cardiac deceleration mechanism after exercise and is more

pronounced in well-trained athletes but blunted in patients with chronic

congestive heart failure. Intense physical work or important cardiorespiratory

impairment may interfere with achievement of a steady state, and an oxygen

deficit occurs during exercise. The oxygen debt is the total oxygen uptake in

excess of the resting oxygen uptake during the recovery period26

STRESS TESTING PROTOCOL REQUIREMENTS23

The test is conducted using standard Bruce Protocol27

STAGE SPEED mph

METS GRADE CUMULATIVE TIME in min

1 1.7 4.6 10 3 2 2.5 7.0 12 6 3 3.4 10.1 14 9 4 4.2 10.3 17 12 5 5.0 14.9 18 15 6 5.5 20 18 7 6.0 22 21

The test is conducted in three minute stages; The Bruce protocol starts

at a Functional Class 2 workload (4.6 METS of work, a speed of 1.7 mph and

a grade of 10 degrees). Each 3 minutes the workload is increased by a

combination of increasing the speed and the grade of the treadmill. Stage 2

reaches a FC1 activity with a speed of 2.5 mph and a grade of 12 degrees.

The protocol continues until one of several endpoints is reached. These

include a true positive or negative test, hypo or hypertension, fatigue,

dyspnoea, certain arrhythmias, or gait problems

Contraindications to exercise stress testing23,27

The following contraindications are from the AHA/ACC guidelines published in

1997.

• Absolute contraindications

o Acute myocardial infarction (within 2 d)

o Unstable angina not previously stabilized by medical therapy:

Appropriate timing of tests depends on the level of risk of

unstable angina as defined by the Agency for Health Care Policy

and Research Unstable Angina Guidelines.

o Uncontrolled cardiac arrhythmias causing symptoms or

hemodynamic compromise

o Symptomatic severe aortic stenosis

o Uncontrolled symptomatic heart failure

o Acute pulmonary embolus or pulmonary infarction

o Acute myocarditis or pericarditis

o Acute aortic dissection

• Relative contraindications: Relative contraindications can be

superseded if the benefits of exercise outweigh the risks.

o Left main coronary stenosis

o Moderate stenotic valvular heart disease

o Electrolyte abnormalities

o Severe arterial hypertension: In the absence of definite

evidence, the committee suggests an SBP of greater than 200

mm Hg and/or a DBP of greater than 110 mm Hg.

o Tachyarrhythmias or bradyarrhythmias

o Hypertrophic cardiomyopathy and any other forms of outflow

tract obstruction

o Mental or physical impairment leading to an inability to exercise

adequately

o High-degree atrioventricular (AV) block

Acutely ill patients such as those with infections, hyperthyroidism or severe

anaemia.

Patients with locomotor problems.

Severe symptomatic aortic stenosis.

The test is reported in metabolic equivalents (METs) of exercise. A MET

refers to the resting volume oxygen consumption per minute (VO2) for a 70-

kg, 40-year-old man. One MET is equivalent to 3.5 mL/min/kg of body weight.

The standard Bruce protocol, starts at 1.7 mph and 10% grade (5 METs).

The Bruce protocol has 3-minute periods to allow achievement of a steady

state before workload is increased. Stage 1 is 1.7 mph at 10% grade (5

METs). Stage 2 is 2.5 mph at 12% grade (7 METs). Stage 3 is 3.4 mph at

14% grade (9 METs)27.

Interpretation

Interpretation should include exercise capacity and clinical,

hemodynamic, and ECG response. The occurrence of ischemic chest pain

consistent with angina is important, particularly if it forces termination of the

test. The classic criteria for visual interpretation of positive stress test findings

are J-point (defined as the junction of the point of onset of the ST-T wave and

normally at or near the isoelectric baseline of the ECG) and ST80 (defined as

the point that is 80 ms from the J point) depression of 0.1 mV (1 mm) or more

and/or an ST-segment slope within the range of ±1 mV/s in 3 consecutive

beats25.

HEART DISEASE IN HIV

BACKGROUND:

Cardiac involvement in AIDS was first reported in 1983 in a

postmortem description of a 24 year old woman of Haitian origin with multiple

complications of AIDS, including Kaposi’s sarcoma involving the entire

anterior cardiac wall without pericardial effusion.28 Subsequently, cardiac

involvement in patients with HIV infection has been described in multiple

necropsy, clinical, and echocardiographic series. Almost any agent that can

cause disseminated infection in patients with AIDS may involve the

myocardium, but clinical evidence of cardiac disease is usually overshadowed

by manifestations in other organs, primarily the brain and lungs. Thus, the

number of patients with AIDS and cardiac involvement at necropsy greatly

exceeds the number with significant cardiac disease during life. Estimates of

prevalence vary widely from 28–73%38 according to the screening methods

selected. Although exact data are unavailable, conservative estimates derived

from European and US series indicate cardiac morbidity and mortality in HIV

patients of 6–10% and 1–9%39, respectively.

INCIDENCE:

The 2-5 year incidence of symptomatic heart failure in HIV infected

patients ranges from 4%- 28% in various studies.4,5 It suggests that there are

4- 5 million cases of HIV related symptomatic heart failure worldwide.6

Among HIV infected children up to 10 years of age, 25% die due to

chronic cardiac disease and 28% develop serious cardiac events after an

AIDS defining illness.31

LEFT VENTRICULAR SYSTOLIC DYSFUNCTION AND DILATED

CARDIOMYOPATHY

INCIDENCE:

The incidence of left ventricular systolic dysfunction in HIV population is

different in different studies. It ranges from none to seventy percent among

various studies and the difference depends on the echocardiographic

criteria.45

• The first evidence that HIV can be associated with cardiomyopathy

was reported by Cohen and colleagues in 1986.32

• Himelman and colleagues reported 71 patients with HIV infection out

of which 8(11%) had LV dilatation and poor contraction; 4 had

evidence of congestive heart failure.33

• In 1988, a study conducted by Corello and colleagues, 41% patients

had LV hypokinesia which was the commonest abnoemality found in

HIV patients echocardiograpically and this is associated with left

ventricular wall thinning, dilatation and failure.34

• In a prospective study conducted by Herskowitz and colleagues35, 69

AIDS patients were randomly selected to be followed up for a mean

period of 11 months by serial 2D Echo.

At the entry into the study, 10 out of 69(14.5%) already had global LV

hypokinesia. Of the remaining 59, 11 subsequently developed global

LV dysfunction with incidence of 1.5 persons / 100 person months.

Among 21 patients, 20 were clinically silent and 1 had congestive

heart failure.

• In another 4 yr observational study of 296 HIV patients by Curie PF et

al, 44(15%) were found to have dilated cardiomyopathy; 13(4%) with

isolated RV dysfunction and 12(4%) with borderline LV dysfunction.

Dilated cardiomyopathy was strongly associated with CD4 count

<100/µl.36

• LV dysfunction is a common consequence of HIV infection in children.

In a study of 205 children infected with HIV by maternal fetal

transmission, the prevalence of decreased LV function was 5.7%. 2

year cumulative incidence was 15.3%.4

PATHOGENESIS:

Wide variety of possible etiologic agents has been postulated in HIV

related cardiomyopathy. These are HIV myocardial infection, opportunistic

infections, viral infections, autoimmune response to viral infection, cardio

toxicity from therapeutic/ illicit drugs, nutritional deficiencies, cytokine over

expression and many others.

Myocarditis-

Dilated cardiomyopathy can be related to a direct action of HIV on myocardial

tissue or to proteolytic enzymes or cytokine mediators induced by HIV.39, 40

Autopsy and biopsy results have revealed only scant/ patchy inflammatory cell

infiltrates. Toxoplasma gondi, coxackie B virus, EBV, CMV, adenovirus and

HIV have been found in myocytes of biopsy specimens.41

Cytokine Alterations42, 41-

HIV infection increases production of TNF α which

1. alters intra cellular calcium homeostasis

2. increases nitric oxide production

3. increases TGF β

4. causes endothelin 1 upregulation

COURSE OF DISEASE:

Patients with asymptomatic LV dysfunction (fractional shortening<28%;

global hypokinesia) may have transient disease. In one study, 3 out of 6

patients of global LV hypokinesia had normal reading after a mean of 9

months. The three with persistently depressed LV function died within 1

year.43

PROGNOSIS:

Mortality in HIV patients with dilated cardiomyopathy is high

independent of CD4 count, age, sex and risk groups. Median survival to AIDS

related death was 101 days in patients with LV dysfunction whereas it was

472 days in patients with normal heart at a similar stage of infection.36

Isolated RV dysfunction or borderline LV dysfunction did not place

patients at any increased risk36.

Rapid onset congestive heart failure has a grim prognosis in HIV

infected adults and children. More than 50% of patients died within 6-12

months of presentation. Chronic onset heart failure may respond well to

medical therapy.37

THEARAPY:

Treatment is same as for non ischemic cardiomyopathy with diuretics,

digitalis, ACE inhibitors, aldosterone antagonists and beta blockers. As

medical therapy is begun, serial echo studies are to be done at 4 monthly

interval.38 Patients not responding or worsening within 2 weeks of initiation of

medical therapy should be considered for biopsy. Endomyocardial biopsy may

reveal lymphocytic infiltrates suggesting Myocarditis or treatable opportunistic

infections, permitting aggressive th




nts not responding or worsening within 2 weeks of initiation of



infections, permitting aggressive therapy of underlying pathogen.




nts not responding or worsening within 2 weeks of initiation of



erapy of underlying pathogen.38

PERICARDIAL EFFUSION

Pericardial effusion is the most common cardiovascular complication of

HIV infection. Prior to the introduction of highly active antiretroviral therapy

(HAART), the frequency of this complication was estimated to be between 5%

and 46% , with an incidence of 11%–17% per year3

Pericarditis in HIV-infected patients may present with large effusions or

cardiac tamponade.39. Although spontaneous resolution of pericardial effusion

has occurred in as many as 42% of those affected, the 6-month mortality rate

among HIV positive patients with pericardial effusion (62%) is higher than that

among HIV-positive patients without that complication (7%). 39 HIV infected

patients with pericardial effusion generally have a lower CD4 counts than

those without an effusion marking more advanced disease. It is one of the

most common clinical cardiac involvement in AIDS patients. In HIV-positive

patients in whom cardiac tamponade develops, mycobacterial infection is the

most common cause worldwide (44%) followed by malignancy (16%) and

other bacterial infection (11%)39

INCIDENCE:

In autopsy series, it has been reported in as few as 3% of autopsies by

Wilkins et al to as much as 36.9% of autopsies as reported by Lewis and

colleagues.40

In echocardiographic series, variable no of HIV patients had pericardial

involvements in various studies.

• In Corallo and associates series41, 39 out of 102 HIV patients (38%)

had pericardial effusion.

• In Monsurez and colleagues series42, 21% had pericardial effusion.

• Steffen and colleagues43 did a prospective study of 151 patients with

echocardiography out of which 29(19%) had pericardial effusion.

• The 5 yr PRECIA study (prospective evaluation of cardiac involvement

in AIDS) 44 selected 231 patients of HIV (59 subjects with asymptomatic

HIV, 62 with AIDS related complex, 74 with AIDS) 16 of whom

developed pericardial effusion. 3 already had effusion on enrolment, 13

developed subsequently; 12 of these 13 had AIDS.44 80% of them had

small pericardial effusion (max pericardial space<10 mm at the end

diastole) and 87% were asymptomatic. Incidence of pericardial effusion

was 11% per year in patients with AIDS.

CAUSES: Causes of pericardial effusion in HIV individuals are37,

i) Infections

Viral

a) HIV

b) Ebstein-Barr virus

c) Herpes virus

d) Coxsackie virus

e) Cytomegalovirus

Parasitic : Toxoplasma gondii

Mycobacterial :

a) M tuberculosis

b )M kanassi

c) M avium-intracellulare

d) M fortuitum

Fungal

a) Asperillosis

b) Candida

c) Histoplasmosis

d) Cryptococcus

Bacterial

a) Salmonella

b) Staphylococcus

c) Enterococcus

d) Chlamydia

e) Nocordia

f) Listerosis

g) Pseudomonas

h) Klebsiella

i) Streptococcus

Tumours

a) Lymphoma

b) Kaposi sarcoma

c) Adenosarcoma

COURSE OF DISEASE AND PROGNOSIS:

Effusion markedly increases mortality e.g. in PRECIA study, pericardial

effusion nearly tripled the risk of death among AIDS patients.44 2 out of 16

patients developed cardiac tamponade. Effusion spontaneously resolved in

42% of the patients.44

MONITORING AND THERAPY:

Screening echocardiography is recommended in HIV infected

individuals regardless of the stage of the disease.38 Patients should undergo

pericardiocentesis if they have pericardial effusion with signs of tamponade.

Patients with pericardial effusion should be evaluated for possible treatable

conditions like tuberculosis and malignancy. HAART should be considered if

therapy has not been started. Repeat echocardiography is recommended

after 1 month of initial diagnosis.3,38

INFECTIVE ENDOCARDITIS

Injection drug users are at a greater risk than general population for infective

endocarditis, chiefly of the right sided heart valves. Surprisingly HIV patients

may not have higher incidence of endocarditis than people with similar risk

behaviors. However HIV patients may have difference in the clinical picture

than general population.45

• HIV patients are more prone to salmonella endocarditis than

immunocompetent persons because they are more likely to have

salmonella bacteremia.

• HIV patients respond better to IV antibiotics.

• HIV patients are less likely to have damaged heart valves due to lack

of immunity.

CAUSATIVE ORGANISMS:

Common organisms associated with endocarditis in HIV patients

include staphylococcus aureus, salmonella sp. Fungal endocarditis due to

aspergillus fumigatus, candida species and Cryptococcus neoformans are

more common in IV drug abusers.

Fulminant causes of infective endocarditis with high mortality can occur

in late stages of AIDS.46

PROGNOSIS AND THERAPY:

Fulminant courses of infective endocarditis with high mortality can

occur in late stages of AIDS patients with poor nutritional status and severely

compromised ability to fight infection, but several cases have been

successfully treated with antibiotic therapy.

Operative indications for HIV infected patients with infective

endocarditis include

• Hemodynamic instability

• Failure to sterilize cultures after appropriate intravenous

antibiotics

• Severe valvular destruction in patients with reasonable life

expectancy2

NON BACTERIAL THROMBOTIC ENDOCARDITIS

Non-bacterial thrombotic endocarditis (or marantic endocarditis)

involves large friable, sterile vegetations that form on cardiac valves. These

lesions are associated with DIC and systemic embolization. Lesions are

rarely diagnosed ante mortem. Clinically relevant emboli occur in about 42%

of cases.3

However no cases found in prospective series. Marantic endocarditis

should be suspected in any patient with systemic embolization. Yet it should

be considered rare in AIDS patients.

ISOLATED RV DISEASE

Isolated RV hypertrophy with or without RV dilatation is relatively

uncommon in HIV infected individuals. It is generally related to pulmonary

diseases that increase pulmonary vascular resistance. Possible causes

include multiple bronchopulmonary infections, pulmonary arteritis due to HIV

disease, microvascular pulmonary emboli caused by thrombus or

contaminants in injected drugs3,48.

PULMONARY HYPERTENSION

Primary pulmonary hypertension has been described in

disproportionate number of HIV infected individuals. It is estimated to occur in

0.5% of hospitalized AIDS patients.47 Plexogenic pulmonary arteriopathy

characterized by remodeling of pulmonary vasculature with intimal fibrosis

and replacement of normal endothelial structure was frequently demonstrated

in lung histology. All these patients had clear lung fields on examination, chest

radiographs and normal perfusion scans.

Pulmonary hypertension is often explained by lung infections, venous

thromboembolism or LV dysfunction.

In a study conducted by Hilario Nunro et al., of 82 patients with HIV

associated pulmonary arterial hypertension, pulmonary hypertension was the

direct cause of death in 72% of cases48. Survival rates of overall population, at

1,2 and 3 yrs were 73, 60 and 47% respectively. Survival was significantly

lower in patients with NYHA functional class III and IV at presentation. The

results of the study suggest that patients with severe HIV infection, associated

pulmonary hypertension should be considered for long term epoprostenol

therapy.49

VASCULITIS

Vasculitis is being reported more often in HIV infected patients.50 It

should be suspected in patients with

• Fever of unknown origin

• Unexplained multisystem disease

• Unexplained arteritis/ myositis

• Glomerulonephritis

• Peripheral neuropathy

• Unexplained gastrointestinal, cardiac or CNS ischemia

Successful immunomodulatory therapy, chiefly with steroids has been

described.

ACCELERATED ATHEROSCLEROSIS

Accelerated atherosclerosis has been observed in young HIV infected

individuals without traditional coronary risk factors.51-52 Significant coronary

lesions were discovered at autopsy in HIV positive patients who died

unexpectedly. Cytomegalovirus was present in 2 of 8 patients and hepatitis B

in 2 of 8 patients. Premature cerebrovascular disease is common in AIDS

patients. An estimated 8% prevalence of stroke was observed in HIV infected

patients.52

Coronary artery disease and ischemic heart disease have been

reported in patients with HIV infection. Both the prevalence of ischemic heart

disease and the mortality associated with apparently are increased among

HIV-positive patients54. The increased prevalence could be, at least in part,

related to an improvement in the overall survival of HIV-positive patients,

especially since the introduction of HAART. The origins of the disease appear

to be multifactorial and related to the higher incidence of infection with

herpesvirus, cytomegalovirus, or HIV-1, as well as to the inclusion in HAART

of protease inhibitors, which have been reported to produce lipodystrophy,

hyperlipidemia, and hyperglycemia55. In a retrospective analysis of data from

the Frankfurt HIV cohort, which included almost 5000 patients, a fourfold

increase in the annual incidence of myocardial infarction among HIV-infected

patients was found after the establishment of HAART with protease inhibitors,

compared with the incidence among patients who underwent treatment before

the institution of56. Histopathologic examination of coronary arteries generally

reveals eccentric atheromatous and fibrous plaques, with variable degrees of

chronic inflammation and accelerated arteriosclerosis. Unusual proliferation of

smooth muscle cells with abundant elastic fibres, as well as diffuse and

circumferential involvement of the coronary arteries without any intervening

healthy segments, also have been reported57. To assess these manifestations

by non invasive methods the present study is performed

Silent Ischaemia in AIDS patients :

Numerous studies have shown that a silent ischemic

electrocardiographic response to an exercise test is a powerful predictor of

major coronary events, including sudden cardiac death, in clinically healthy

populations. In asymptomatic men in their fourth and fifth decades,

prevalences of SMI of 5% have already been documented. However, SMI is

more frequent in populations at high risk for coronary disease such as

patients with diabetes, in whom the prevalence of SMI ranges from 10% to

15%, and in patients with familial hypercholesterolemia58.

In their study on exercise testing for detecting Silent Myocardial

Iscahemia in HIV patients Duong et al found that central fat accumulation, age

and cholestrol levels were the factors most strongly associated with a positive

exercise test result, whereas duration of HIV illness, duration of HAART

therapy or use protease inhibitors did not influence positive stress test

result14.

AUTONOMIC DYSFUNCTION

Clinical signs of autonomic dysfunction in HIV infected patients include

syncope, presyncope, diminished sweating, diarrhoea, bladder dysfunction

and impotence. In one study, it was shown that autonomic dysfunction was

more pronounced in AIDS patients. Patients with HIV associated nervous

system disease had the greatest abnormalities in autonomic dysfunction.60

CARDIOVASCULAR MALIGNANCY

Malignancy affects many AIDS patients, generally in the later stages of

disease. Cardiac malignancy is usually metastatic disease. Kaposi’s sarcoma

is associated with human herpes virus 8 and affects up to 35 percent of AIDS

patients particularly homosexuals. Autopsy studies found that 28 percent of

HIV infected patients with widespread Kaposi sarcoma had cardiac

involvement60. Kaposi sarcoma has not been found invading the coronaries

but is often an endothelial cell neoplasm with predilection for subpericardial fat

around the coronaries. Pericardial fluid found in patients with Kaposi sarcoma

is typically serosanguinous without malignant cells or infection.60

Primary cardiac malignancy associated with HIV infection is generally

due to cardiac lymphoma. Non-Hodgkin lymphomas are 25 to 60 times more

common in HIV infected individuals. They are the first manifestation of AIDS

in up to 4 percent of cases.61 Patients with primary cardiac lymphoma can

present with dyspnoea, right heart failure, biventricular failure, chest pain or

arrhythmias.61 Cardiac lymphoma is associated with rapid progression to

cardiac tamponade, symptoms of congestive heart failure, myocardial

infarction, tachyarrhythmias, conduction abnormalities or superior vena cava

syndrome. Pericardial fluid typically reveals malignant cells.

Leiomyosarcoma associated with Epstein-Barr virus, is a rare

malignant tumour of smooth muscle origin. Protease inhibitor use has

significantly decreased the incidence of Kaposi sarcoma.60

.

.

EFFECT OF LIPIDS BY HIV AND ANTIRETROVIRAL DRUGS

In a recent review of the effect of HAART associated dyslipidemia on

cardiovascular risk and life expectancy, a HAART regimen associated with a

24% increase in total cholesterol (28% increase in LDL cholesterol) compared

with one with only a 4% increase in total cholesterol (1% increase in LDL

cholesterol) was associated with a 50% increase in cardiovascular risk over

10 years70. Absence of dyslipidemia was estimated to preserve life

expectancy by 0.15- 1.53 additional years, with the greatest effect of

dyslipidemia on life expectancy seen among younger patients and those at

high or very high risk62.

HIV has been associated with dyslipidemia independent of

antiretroviral therapy. Grunfeld et al found that HIV infection was associated

with elevated triglyceride levels that worsened with progression of HIV-related

disease63. Antiretroviral therapy can also contribute to dyslipidemia.

Dyslipidemia has been described as being more common and more severe in

HIV patients receiving antiretroviral therapy than in patients not on therapy64.

The severity of the dyslipidemia and the typical pattern of the lipid profile differ

among and within the classes of antiretroviral agents55. Also, dyslipidemia

does not develop in everyone who takes these medications, suggesting that

host factors play a major role in its development64

Reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors have been associated

with elevated levels of high-density lipoprotein cholesterol (HDL-C).

Nucleoside reverse transcriptase inhibitors, on the other hand, are

heterogeneous in their lipid effects, which may depend somewhat on

interactions with other antiretroviral drugs in the regimen. For example,

stavudine is often associated with elevated total cholesterol, low-density

lipoprotein cholesterol (LDL-C), and triglyceride levels.

Protease inhibitors

Protease inhibitors are generally associated with elevated levels of

total cholesterol and triglycerides. Triglyceride levels of greater than 1,000

mg/dL have been reported in association with protease inhibitors. Carr et al

reported elevated total cholesterol levels, defined as greater than 5.5 mmol/L,

in 58% of patients receiving protease inhibitors vs 11% of those not receiving

them; elevated triglycerides, defined as greater than 2.0 mmol/L, were seen in

50% of patients receiving these drugs vs 22% of those not receiving them55.

Segerer et al, in another study, reported a 15% increase in total cholesterol

and a 25% increase in triglycerides after 3 to 6 months of protease inhibitor

therapy64. Protease inhibitor therapy increased lipoprotein (a) by 48 percent in

patients with elevated pretreatment values(>20mg/dl).57 All protease inhibitors

are not the same in regard to dyslipidemia, however, and lipid abnormalities

may vary. Ritonavir has been most associated with triglyceride elevations,

whereas indinavir is more associated with elevations of LDL-C.

Although HIV and its treatment have been associated with dyslipidemia

in some studies, no one has definitively established that this association

translates to an increased risk of cardiovascular events. Recent reports of

myocardial infarction in young patients receiving protease inhibitors have

focused interest on the association between HIV infection, antiretroviral

therapy, and coronary artery disease. For example, in a small French study,

patients treated with protease inhibitors had an almost threefold increase in

risk of myocardial infarction compared with untreated controls, suggesting that

rapidly forming drug induced plaques are unstable and prone to rupture. The

most compelling evidence that dyslipidemia in HIV patients may increase the

risk of myocardial infarction comes from the Data Collection of Adverse

Events of Anti-HIV Drugs study65. In this prospective, observational study, the

relative risk of myocardial infarction attributed to antiretroviral therapy

increased by 26% per year.

Measurement of lipid values58.

Evaluation of serum lipid levels should be performed after fasting for a

minimum of 8 h, and preferably for 12 h, and the levels should be determined

before initiation of antiretroviral therapy (B-III). The standard screening lipid

profile should include measurement of total cholesterol, HDL-C, and

triglyceride levels . Using these measured values, LDL-C and non–HDL-C

levels are calculated. This should be repeated within 3–6 months after the

initiation of HAART, then yearly, unless abnormalities are detected or

therapeutic interventions are initiated. For individuals with an elevated

triglyceride level (1200 mg/dL) at baseline, it may be preferable to repeat a

lipid profile sooner (e.g., within 1–2 months after initiating HAART)

Lipodystrophy in patients on HAART.

Fat redistribution was first described with PIs but has also been

described in patients not on PI therapies66. Characteristic clinical findings

include dorsocervical fat pad (“buffalo hump”), increased abdominal girth and

breast size, lipoatrophy of subcutaneous fat of the face, buttocks, and limbs,

and prominence of veins on the limbs (“pseudovenomegaly”). Despite the

intensive investigations, a case definition for its general term “lipodystrophy”

still does not exist, and well-controlled studies and long-term followup data are

lacking. An increased incidence of abdominal fat accumulation in HIV-positive

women suggests that gender differences may be affecting the presentation of

this syndrome55. The mechanisms for this phenomenon are not well defined;

however, several intriguing findings have suggested decreased lipolytic

activity (4), stoichiometric similarity between the binding site of PIs with

retinoic-acid binding protein type 1 (RBAP-1), and LDL-receptor-related

protein (LRP) causing impaired adipocyte differentiation and apoptosis as well

as chylomicron uptake and triglyceride clearance67

Unfortunately for the sufferers of these side effects, there are no

consistent data showing reversal of fat redistribution after removal of the

suspected offending antiretroviral((s) from the treatment regimen; however,

lipid profiles tend to improve68. Expanded study of the effects of HIV infection

and its treatment on cardiovascular disease and metabolic abnormalities is

warranted for several reasons. Additionally studies specifically designed to

assess the relative risk of metabolic and cardiovascular diseases in HIV-

infected women are lacking, From the perspective of basic science, the

causes of many syndromes do not appear to be manifesting as single entities

but rather a complex interaction among HIV-, drug-, and immune-related

factors, especially in the study of metabolic complications of HIV66.

TREATMENT

Targeting LDL cholesterol

Recommendations for managing dyslipidemia in HIV patients are

based on the NCEP’s third Adult Treatment Panel guidelines for the general

population69. The first step is to assess the patient’s cardiovascular risk, which

affects the decision whether to start treatment and the goals of treatment. The

main factor is the LDL-C concentration, but the assessment also takes into

account other risk factors such as confirmed cardiovascular disease, age

older than 45 years in men and 55 in women, cigarette smoking,

hypertension, low HDL-C (< 40 mg/dL), and diabetes. The level of

cardiovascular risk is traditionally classified as low, intermediate, or high, and

each category entails a different LDL-C treatment goal: Lowest risk means no

risk factors or one risk factor; the goal LDL-C concentration is less than 160

mg/dL. Intermediate risk means one or two risk factors; the goal LDL-C is less

than 130 mg/dL.

High risk means confirmed coronary heart disease or coronary heart

disease equivalents, or two or more cardiovascular risk factors and a

Framingham 10-year risk score of 20%; the goal LDL-C is less than 100

mg/dL. In view of several recent studies, 22–26 the NCEP recently modified

these guidelines to include an LDL-C goal of less than 70 mg/dL as an option

in patients at very high risk, ie, those with established cardiovascular disease

and multiple major risk factors (especially diabetes), severe and poorly

controlled risk factors, multiple risk factors of the metabolic syndrome, and

acute coronary syndromes68-69.

Although lower LDL-C levels are the primary goal of lipid-lowering

therapy, the triglyceride level and the “non-HDL” cholesterol level (ie, total

cholesterol minus HDL-C) are often significant factors in patients with

antiretroviral therapy-related dyslipidemia, who commonly have triglyceride

elevations. When triglyceride levels are borderline high (150–199 mg/dL),

dietary and exercise interventions are emphasized. When triglyceride levels

are high (200–499 mg/dL), non-HDL cholesterol becomes a secondary target

of therapy. When triglyceride levels are 500 mg/dL or higher, triglycerides are

the primary target of therapy68. The NCEP guidelines recommend non-HDL

cholesterol as a secondary target of therapy in people with high triglyceride

levels (200 mg/dL). The goals for non- HDL cholesterol are defined as 30

mg/dL higher than those for LDL-C.69

Preliminary guidelines for the evaluation and management of

dyslipidaemia in HIV positive patients receiving HAART have recently been

published. Statins which are independent of the cytochrome P450 system (for

example, pravastatin, atorvastatin) are recommended to avoid interaction with

protease inhibitors, and use of fibrates and gemfibrozil has been described in

patients with isolated hypertriglyceridaemia.

OBSERVATIONS

TABLE 1: SEX DISTRIBUTION

N = 96

During the study total of 96 clinically stable patients attending JJ ART

Center OPD were randomly selected and enrolled into the study. 73% of total

patients were male (70) and 27% of patients were female (26) [Table 1, Fig 1].

TABLE 2 : AGE SEX DISTRIBUTION .

N=96

AGE GROUP MALE FEMALE TOTAL Percentage %

20- 29 8 8 16 17

30- 39 35 11 46 43

40- 49 19 6 25 27

50- 60 5 2 7 7

The youngest patient in our study was 18 years and oldest was 60

years. The age sex distribution is shown in above Table ( Fig 2). The mean

age of the patients is 36.5 ± 8 years and majority (43%) belonged to 3rd – 4th

decade age group.

SEX NO. OF PATIENTS PERCENT %

MALE 70 73

FEMALE 26 27

TABLE 3: DURATION OF ILLNESS

N=96

Duration of illness in years

Total No Patients Percentage %

< 1 24 25

1 – 5 59 62

> 5 12 13

The average duration of known HIV illness is 3 years with 25% of

patients belonging to < 1 year duration of illness and majority, 62% belonging

to 1 – 5 years group and 13% to >5 years age group. (Table 3) (Fig 3). The

shortest duration of known HIV illness recorded was 1 month and the longest

was 14 years.

TABLE 4: CARDIAC SYMPTOMS

N= 96

Cardiac symptoms Total No Percentage %

Angina 22 34

Dyspneoa 27 41

Palpitations 11 17

Giddiness, Syncope 5 8

Out of 96 patients examined 36 (37%) patients had some cardiac

complaints and rest of 60 (63%) patients had no cardiac symptoms. Among

the reported symptoms dyspnoea was the commonest (41%), followed by

angina (34%), palpitations (17%) and least common reported was giddiness

or presyncope (8%) and none complained of frank syncope. All the symptoms

were of minor nature, NYHA class I to II except 2 patients, one with

depressed LV function and other had severe mitral stenosis due to rheumatic

heart disease.

TABLE 5: CARDIAC RISK FACTORS

N=96

Cardiac Risk Factors No Patients Percentage of Total Patients %

Hypertension 2 2

Diabetes Mellitus 0 0

Smoking 12 12.5

Family H/O IHD 1 1.04

In the study 84.3% of patients had no cardiac risk factors, and 15

patients had some cardiac risk factors, smoking being the commonest among

them (12 patients) and 2 patients had history of hypertension and 1 patient

had family history of IHD.

TABLE 7: Clinical staging and HAART

N=96

HAART regime Clinical Stage

A

Clinical stage

B

Clinical Stage

C

Total No in Various HAART regimes

SLN 3 6 21 30 (32%)

SLE 0 0 5 5 (5%)

ALN 0 3 17 20 (21%)

ALE 1 0 1 2 (2%)

none 5 7 26 38 (40 %)

Total no in Clinical Stages

9 (9%) 16 (17%) 71 (74%) 96 (100%)

According to CDC Atlanta criteria patients were assessed and clinically

classified into 3 groups A, B & C. 74% of patients belonged to group C, while

17% belonged to group B and 9 % to group A. This is depicted in chart (Fig.

5). 58(60%) patients were on some HAART regime. 38 (40%) patients were

from pre ART group not taking any anti retroviral drug. Maximum patients

were receiving SLN regime around 30 patients, 20 patients were on ALN, 6

patients were on SLE regime and 2 patients were on ALE drugs.

TABLE 8: HIV patients in different Categories based on CD4 count

N = 95

CD4 COUNT Total No of

Patients

Percentage %

Category 1 (CD4>500) 25 26

Category 2

(CD4 = 499- 200)

42 45

Category 3 (CD4<200) 28 29

25 (26%) our patients belonged to category 1 with CD4 count >500, 42

(45%) belonged to category 2 with CD4 count between 499 – 200 and 28

(29%) patients had CD4 counts less than 200. The mean CD4 count of the

patients was 384

In specific general examination findings, clubbing was the commonest

finding observed in total of 11 patients followed by minor degree of pallor but

all the patients had Hb > 12 gm. 12 patients had minor auscultable physical

findings and majority were normal clinically.

.

TABLE 9:

DISTRIBUTION OF PATIENTS IN DIFFERENT BMI GROUPS:

N=96

BMI No of Patients Percentage %

<18 24 25

18 -25 67 70

25 - 30 3 3

>30 2 2

Most of patients (70%) were in normal BMI range group between 18-25, 24%

were underweight i.e. BMI < 18, 3% belonged to overweight and 2% obese

group.

TABLE 10: ABNORMAL X RAY FINDINGS

N=96

X RAY ABNORMALITY NO. OF PATIENTS PERCENTAGE

NORMAL X RAY 78 82

CARDIOMEGALY 4 4

OTHER CARDIAC FINDINGS

3 4

PULMONARY PATHOLOGY 9 9

BOTH CARDIO- PULMONARY

PATHOLGY

2 2

64 (66%) patients had normal ECG findings and rest had minor ECG

changes. 8 patients had right axis deviation and non specific T inversions, 2

had VPC`S, 4 had bundle branch blocks and 5 had early repolarisation

abnormalities. 82% had normal x-ray findings and 4 patients had

cardiomegaly out of which 2 patients were found to have dilated

cardiomyopathy ( Table 10:, Figure: 7)

ECHOCARDIOGRAPHY

TABLE 11: ECHOCARDIOGRAPHY FINDINGS OF HIV PATIENTS AND

INFLUENCE OF HAART

N=45

CARDIAC DISEASE TOTAL patients

No patients on HAART

p value

DILATED CARDIOMYPATHY

4 (6%) 2 0.634

PERICARDIAL DISEASE 14 (21%) 8 0.748

LV SYSTOLIC DYSFUNCTION

15 (23%) 9 0.66

LV DIASTOLIC DYSFUNCTION

16 (24%) 10 0.9252

PULMONARY HYPERTENSION

9 (14%) 4 0.303

RV DYSFUNCTION 8 (12%) 5 0.747

Out of 96 patients examined 45 (46.8%) patients had positive ECHO

findings. The commonest echocardiography finding in our study was diastolic

dysfunction, which was present in 16 (24%) patients. Next common

abnormality was LV systolic dysfunction not associated with much dilatation or

regional wall motion abnormality. Some of them had increased myocardial

thickness with poor contractility. Only one patient had very poor left ventricular

function (20%) and others had mild to moderate impaired LV function

Pericardial effusion was detected in 14 (21%) patients. 3 patients had

moderate effusion and rest had mild pericardial effusion. Frank dilated

cardiomyopathy occurred in only 4 (6%) patients, which was less common

than idiopathic pulmonary hypertension 9 (14%) patients, or isolated RV

dysfunction 8 (12%) patients. The pulmonary hypertension and RV

dysfunction could not be attributed to pulmonary or left heart abnormality. One

patient had severe mitral stenosis due rheumatic heart disease. 57% of

patients with positive ECHO findings were on HAART regimes and others

were not. There was no statistical difference between those patients on

HAART and those who were not with respect to any of the echocardiography

findings.

Table 12: Influence of Duration of HIV illness and ECHO findings

N=96

CARDIAC DISEASE < 1 year n = 24

1-5 years n =59

> 5 y ears n=12

Total P value

DILATED CARDIOMYPATHY 2 1 1 4 0.35

PERICARDIAL DISEASE 3 8 3 14 0.727

LV SYSTOLIC DYSFUNCTION 7 6 3 16 0.102

LV DIASTOLIC DYSFUNCTION 6 8 2 16 0.484

PULMONARY HYPERTENSION 6 4 0 9 0.02

RV DYSFUNCTION 4 4 0 8 0.18

Patients were categorised into 3 groups depending upon known HIV

illness duration. The incidence of abnormal cardiac findings were more

frequently detected in those with symptom duration < 1 year (n=30) than when

compared to other groups, second group with symptom duration between 1 –

5 years (n=53) and last one with illness duration >5 years (n=13). However

the numbers did not achieve statistical significance. Only PAH was

significantly association with duration of illness (p = 0.02) occurs more

commonly in those with lesser duration of illness.

TABLE 13: RELATIONSHIP OFECHOCARDIOGRAPHY FINDINGS AND

CD4 COUNTS

N=45

CARDIAC DISEASE Category 1 CD4

Category N= 42

Category 3

N =28

Total P value

DILATED

CARDIOMYPATHY

0 0 4 4 0.006

PERICARDIAL DISEASE 4 5 5 14 0.8

LV SYSTOLIC

DYSFUNCTION

1 10 5 16 0.08

LV DIASTOLIC

DYSFUNCTION

2 9 5 16 0.31

PULMONARY

HYPERTENSION

1 4 4 9 0.424

RV DYSFUNCTION 1 2 5 8 0.09

RHD MS 1

On subgroup analysis of various echocardiography findings with CD4

count, only dilated cardiomyopathy was associated with low CD4 count

(p = 0.006) whereas other ECHO findings did not achieve statistical

significance.

TABLE 14: STRESS TEST RESULTS

N=96

STRESS TEST RESULT No of Pateints Percentage %

Negative 68 71

Not done 14 15

Positive 8 8

Terminated early 6 6

Eight patients had positive stress test among, 15 patients not done and 6

patients terminated early because of poor effort tolerance. 67 patients had

negative test. The positive yield of the stress test was approximately 10%.

Average METS achieved by HIV patients was 10.13 (SD 2.32). Average work

duration of exercise of HIV patients was 10.57(SD 2.23) minutes. The

average heart rate of the subjects was 153 bpm. 92 % of patients achieved

target heart rate. Average BP recorded of the subjects during stress test was

140/88 mm Hg. Out of 8 patients 3 had history of angina and 5 patients had

no symptoms of angina. There were no significant differences between stress

test positive and those with negative groups, with respect to age group, BMI,

duration of illness, CD4 count or lipid profile status.

TABLE 15: LIPID LEVELS IN HIV PATIENTS

N=85

Type of cholestrol Mean value of

patients on

HAART

Mean value of not

on HAART

p value

Total cholestrol 170 184 0.146

Total triglycerides 147 142 0.824

LDL cholestrol 102 120 0.018

HDL cholestrol 40 39 0.958

VLDL cholestrol 27 25 0.61

85 HIV patients had complete lipid profile. 52 patients were found to have

dyslipidemia i.e. 61% of our HIV patients were found to be dyslipidemic. 57%

of the dyslipidemic patients were receiving HAART, whereas rest were not on

any antiretroviral drugs. None pf the patients were found to have

lipodystrophy. The mean values of various lipids in two groups, those who

were on ART drugs and those who were not, are similar except LDL

cholesterol which was lower in HAART group (mean 102 vs 120; p = 0.018)

TABLE 16: INCIDENCE OF DYSLIPIDEMIA IN HIV PATIENTS

N=85

Cholesterol Levels Total no of

patients

No on

HAART

p value

Hypercholestremia 6 (8%) 2 0.13

Low HDL 45 (62%) 27 0.419

High LDL 7 (10%) 2 .06

Hypertriglyceridemia 9 (12%) 6 .417

High VLDL 6 (8%) 4 0.7

. The commonest lipid abnormality found was low HDL (62%) followed by

hypertriglceridemia (12%), high LDL cholesterol (10%), high VLDL cholesterol

(8%) and hypercholestremia (8%). There were no statistically significant

differences in numbers between those who were on HAART and those who

were not on antiretroviral drugs.

DISCUSSION

The heart is an organ frequently affected in patients with AIDS.

Researchers have demonstrated cardiac involvement in as many as 28%–

73% of patients infected with HIV3,8,9,11 Cardiac involvement generally occurs

in the latter stages of the disease but can occur at any point. Although it can

be clinically silent or masked by other comorbid diseases and demonstrated

only by echocardiography or at autopsy, cardiac involvement can result in

significant cardiac morbidity and mortality. In 1996, the estimated

prevalence’s of a significant cardiac morbidity or cardiac mortality among HIV-

positive patients were 6%–7% and 1%–5%, respectively34.

During the period of one year total of 96 clinically stable patients

attending JJ ART Centre OPD were randomly selected and enrolled into the

study. The total no of male patients were 70 (73%) and females were 26

(27%). Patients belonged to age group between 18 years to 60 years with

average age of being 36.5 years. The mean duration of illness is 2 years and

majority belonged to Category 2 with CD4 count in range of 200- 499. 60% of

patients were on HAART and the commonest regime is SLN.

47% of our study patients had positive ECHO findings. Himelman33

and colleagues showed echocardiographic abnormality in 64% of admitted

HIV patients. De Casto8 et al in 1992 studied 72 AIDS patients and found that

47 (65.2%) presented with cardiac involvement. However some studies

showed a lower prevalence of heart disease. Steffen43 and colleagues

reported 21% prevalence of heart disease in HIV infected patients. Among

those patients with positive ECHO findings, many of them had non specific

complaints of minor degree and even ECG, Chest X-ray were not suggestive

of significant cardiac disease in these cases

Electrocardiographic changes were of little clinical relevance. In one

multicenter trial, 57 percent of asymptomatic HIV infected individuals had

baseline abnormalities on ECG including supraventricular and ventricular

ectopic beats. The chest radiogram has low sensitivity and specificity for

congestive heart failure72. Our study showed 44% of patients had minor ECG

changes and 6 percent had cardiac findings on chest X-ray. So we conclude

that Echocardiography was very useful in detecting cardiac abnormalities in

HIV patients even when clinical pointers for cardiac disease are not very

significant

STUDY

PE

SYSTOLIC DSFUNCTION

ECHO

DD

DCM

PAH

RVD

DE Casto8 18% 5.5% 12% 1%

Himelman33 10% 11%

Cuire36 et al 7% 15% 4%

Barbaro73 et al 16% 8%

Cardoso75 JS 16.4% 64% 2%

Present study 21% 23% 24% 6% 9% 8%

The incidence of pericardial effusion in patients with asymptomatic

AIDS (defined as patients with CD4 count <200 cells/µL) was 11% per year

before the introduction of effective ART37. In a review of 15 autopsy and

echocardiography studies involving 1139 patients with HIV disease, incidence

of pericardial disease was 21%39. Some studies showed lower incidence of

pericardial involvement. Himelman33 et al reported 10% prevalence of

pericardial involvement, whereas Corallo and Multinelli9 reported 38%

incidence of pericardial involvement but the study included only patients in

advanced stage of the disease i.e. AIDS. Our study findings are in

accordance general prevalence of pericardial effusion in HIV patients39 i.e.

21%.

Himelman46 and colleagues showed that 11% of HIV patients in their

study had dilated cardiomyopathy and systolic LV dysfunction. Currie36 et al

showed 7% incidence of borderline LV systolic dysfunction, 4.3% dilated

cardiomyopathy and 4% RV dysfunction. Our study shows mild to moderate

degree of impaired LV dysfunction without LV dilatation and regional wall

motion abnormality, as one of the commonest echocardiography finding

(23%), more than that of pericardial effusion (21%).

Our study showed that diastolic dysfunction to be the commonest

finding during echocardiography (24%). These findings are similar to Indian

studies carried out which have demonstrated the presence of diastolic

dysfunction as commonest finding on echocardiography in HIV infected

adults70. Diastolic dysfunction was the commonest (63%) cardiac finding in a

prospective study by Cordoso J.S74 et al. and also studies by Paula Moyer75

et al which showed that 50% of HIV positive patients have diastolic

dysfunction.

The other findings in were 9 patients (14%) had PAH, and 8 patients

(12%) had RVD and one patient had incidental RHD with severe mitral

stenosis and no patient was found to have infective endocarditis unlike

previous studies6,8,11.

Prospective echocardiography studies reported increase frequency of

cardiac diseases as duration of HIV illness increases7,8,9,11. But our study after

categorising patients into 3 groups based on duration of HIV illness failed to

establish statistical significance between illness duration and cardiac

abnormality, except for pulmonary hypertension which seemed to occur

commonly in those with duration of illness less than 1 year (p = 0.02)

(Table: 12 ).

Currie36 et al reported high incidence of dilated cardiomyopathy in HIV

patients with low CD4 counts. In their study DCM was strongly associated

with CD4 count less than 100/µ. In our study DCM is strongly associated with

low CD4 count < 200 (p =0.006) but other cardiac abnormalities had no

relation to CD4 count (Table: 13)

After introduction of HAART both the mortality and morbidity of AIDS

patients is reduced and also the incidence of severe cardiac

complications35,44,46. In our study there were no statistical difference between

those who are on HAART and those not on any antiretroviral drugs, probably

due to relatively small sample size analysed. (Table: 15)

Numerous studies have shown that a silent ischemic

electrocardiography response to an exercise test is a powerful predictor of

major coronary events, including sudden cardiac death, in clinically healthy

populations14. In asymptomatic men in their fourth and fifth decades,

prevalence’s of SMI of 5% have already been documented58. However, SMI is

more frequent in populations at high risk for coronary disease, such as

patients with diabetes, in whom the prevalence of SMI ranges from 10% to

15%, and in patients with familial hypercholesterolemia14,58. In our study, a

higher than normal expected prevalence of positive stress test (10%) for the

age group indicating HIV patients constitute a high risk group for coronary

ischaemia

Duong et a in their study on Silent Myocardial Iscahemia in HIV

patients found that central fat accumulation, age and cholestrol levels were

the factors most strongly associated with a positive exercise test result,

whereas duration of HIV illness, duration of HAART therapy or use of

protease inhibitors did not influence positive stress test result14. In present

study patients with positive stress test had no association with HAART intake

(Table: 15), which could be explained on basis that none of our patients were

on protease inhibitors, the main drugs implicated in drug induced metabolic

syndrome, and also HIV infection itself constituted higher prevalence of

ischaemia irrespective of HAART intake.

The increased prevalence of accelerated atherosclerosis in HIV

patients could be, at least in part, related to an improvement in the overall

survival of HIV-positive patients and inclusion in HAART of protease

inhibitors, which have been reported to produce lipodystrophy, hyperlipidemia,

and hyperglycemia52,55. In our study there were 13 (14%) HIV patients having

> 5 year duration of illness, but none of our patients were on protease

inhibitors. Therefore these patients are likely to have abnormal cardiovascular

risk status. Results from D:A:D Study indicate that incidence of MI increases

26% per year of exposure to HAART10 but none of our patients had history,

ECG or ECHO evidence of myocardial infarction.

Out of 85 patients who had complete lipid profile and 61% had

dyslipedemia which is similar to several other several studies55-59 indicating

that incidence of dyslipidemia is very common in HIV patients (44%-66%).

The commonest lipid abnormality observed was low HDL cholesterol (62%)

followed by hypertriglceridemia (12%).

Carr et al reported elevated total cholesterol levels, defined as greater

than 5.5 mmol/L, in 58% of patients receiving protease inhibitors vs 11% of

those not receiving them; elevated triglycerides, defined as greater than 2.0

mmol/L, were seen in 50% of patients receiving these drugs vs 22% of those

not receiving them55. Segerer et al, in another study, reported a 15% increase

in total cholesterol and a 25% increase in triglycerides after 3 to 6 months of

protease inhibitor therapy64 . Our study showed (Table 15; Fig 11) that mean

total cholesterol level is lower in HAART group than non drug group (170 vs

184). Mean triglycerides and LDL cholesterol were also low in HAART group

whereas mean HDL and VLDL levels are higher. Only LDL cholesterol was

significantly lower in HAART group than non drug group (p = 0.018)

Dyslipidemia has been seen in patients with HIV infection, even prior to

use of protease inhibitors and has been linked both to HIV infection and to

ART. In untreated HIV infected patients, lower CD4 counts are associated

with lower total blood cholesterol, lower HDL cholesterol, and higher

triglyceride levels67. Total and LDL cholesterol decreased after the onset of

HIV disease, but rose to preinfection levels or higher with ART, while HDL

cholesterol levels decreased markedly after the onset of HIV and did not

recover. Furthermore, an early placebo-controlled study of zidovudine

monotherapy reported declines in both IFN-α and triglycerides in patients

taking zidovudine56. This may be the likely reason why no significant elevation

of lipids is seen in HAART group. Dyslipidemia is an important risk factor for

atherosclerotic coronary heart disease and the high prevalence of

dyslipidemia (61% in our study) and improved survival of AIDS patients,

indicates these patients must be investigated more often and treated early to

prevent adverse cardiovascular events in future.

LIMITATIONS

This is an observational study and there are no matched controls of normal

population to compare.

There is no follow up to determine the long term effects on mortality and

morbidity in HIV patients of the cardiac abnormalities detected.

Sample size is relatively small especially for the individual cardiac

abnormalities detected.

ART regimes used in JJ Hospital do not contain protease inhibitors and

therefore

SUMMARY

Total of 96 clinically stable HIV patients not known to have any prior

cardiac illness were studied, which included 70 male patients and 26 female

patients. The average age of patients was 36.7±8 years.

37 % of patients had insignificant cardiac complaints often nonspecific

involving other systems also.

60 % of patients were on some HAART regime, the commonest being

SLN regime.

Routine 12 lead ECG and chest X ray were not very sensitive in

detecting cardiac abnormalities in HIV patients.

47% had some cardiac abnormality detected echocardiographically,

commonest being diastolic dysfunction followed by impaired LV function,

pericardial effusion, PAH, isolated RV dysfunction and least dilated

cardiomyopathy.

The positive echocardiographic findings were not significantly

influenced by duration of illness or CD4 counts except for dilated

cardiomyopathy, which was strongly associated with CD4, count < 200.

HAART regimes used in JJ hospital had no influence on any of the

echocardiographic abnormalities detected.

Exercise testing was positive in 10 % of HIV patients tested, which is

higher than general population prevalence constituting high risk group for

coronary artery disease.

Dyslipidemia is widely prevalent in HIV patients (61%) even when

patients are not on any protease inhibitors.

The commonest lipid abnormality detected was low HDL cholesterol

(62%) followed by hypertrigliceredemia (12%).

HAART regimes used in JJ Hospital did not significantly influence the

lipid levels in except for LDL cholesterol.

CONCLUSIONS

Cardiovascular complications are very common in HIV patients,

especially after introduction of HAART. ECHO, exercise testing and lipid

profiles are useful to detect cardiac complications early and should be

performed routinely when indicated.

FIGURE 1:

FEMALE27%

8

35

8

0

5

10

15

20

25

30

35

40

20- 29 30

NO

OF

PA

TIE

NT

S

MALE73%

SEX RATIO

35

19

5

11

6

2

30- 39 40- 49 50- 60

AGE GROUPS

AGE SEX DISTRIBUTION

MALE

FEMALE

MALE

FEMALE

FIGURE 2:

FIGURE 3:

0

< 1

1 – 5

> 5

24

18

in y

ears

20 40 60

24

53

No of patients

DURATION OF HIV ILLNESS

Total No Patients

FIGURE 4:

FIGURE 5:

Dyspneoa

Palpitations17%

Giddiness, Sync

CARDIAC SYMPTOMS REPORTED BY PATIENTS

Angina34%

Dyspneoa41%

Giddiness, Syncope8%

CARDIAC SYMPTOMS REPORTED BY PATIENTSCARDIAC SYMPTOMS REPORTED BY PATIENTS

FIGURE 6:

0

5

10

15

20

25

30

SLN

3

No of patients

DISTRIBUTION OF HIV PATIENTS IN VARIOUS HAART

Category 2 (CD4 = 499

Category 3 (CD4<200)

30%

DISTRIBUTION OF PATIENTS BASED ON CD4 COUNT

SLN SLE ALN ALE none

01

56

0

3

7

21

5

17

1

26

HAART Category

DISTRIBUTION OF HIV PATIENTS IN VARIOUS HAART REGIMES

Category 1 (CD4>500)

26%

Category 2 (CD4 = 499- 200)

44%



Category 2 (CD4 = 499


DISTRIBUTION OF HIV PATIENTS IN VARIOUS HAART

Clinical Stage A

Clinical stage B

Clinical Stage C



Category 2 (CD4 = 499- 200)


FIGURE 7:

4%3%

10%

81%

10% 2%0%

X RAY FINDINGS IN HIV PATIENTSX RAY FINDINGS IN HIV PATIENTS

NORMAL X RAY

CARDIOMEGALY

OTHER CARDIAC FINDINGS

PULMONARY PATHOLOGY

BOTH CARDIAC AND PULMONARY

FIGURE 8:

6%

21%23%

24%

14%12%

0%

5%

10%

15%

20%

25%

30%

FREQUENCY OF ECHOCARDIOGRAPHY FINDINGS

ECHO observation

FIGURE 9:

NO OF PATIENTS

INCIDENCE OF CARDIAC DISEASE AND DURATION OF HIV

< 1 year

1-5 years

> 5 y ears n=13

0

1

2

3

4

5

6

7

8

DIL

AT

ED

CA

RD

IOM

YP

AT

HY

PE

RIC

AR

DIA

L D

ISE

AS

E

LV

SY

ST

OLIC

DY

SF

UN

CT

ION

LV

DIA

ST

OLIC

DY

SF

UN

CT

ION

PU

LM

ON

AR

Y

HY

PE

RT

EN

SIO

N

2

3

7

6 6

1

8

6

8

4

1

33

2

0

NO OF PATIENTS

CARDIAC DISEASE

INCIDENCE OF CARDIAC DISEASE AND DURATION OF HIV ILLNESS

RV

DY

SF

UN

CT

ION

4 4

0

0

INCIDENCE OF CARDIAC DISEASE AND DURATION OF HIV

FIGURE 10:

FIGURE 11:

0

1

2

3

4

5

6

7

8

9

10

No fo patients

INCIDENCE OF CARDIAC DISEASES BASED ON CD4 COUNT

0

20

40

60

80

100

120

140

160

180

200

Total cholestrol triglycerides

170

184

MEAN LIPID LEVELS IN HIV PATIENTS

DIL

AT

ED

C

AR

DIO

MY

PA

TH

Y

PE

RIC

AR

DIA

L

DIS

EA

SE

LV

SY

ST

OLIC

D

YS

FU

NC

TIO

N

LV

DIA

ST

OLIC

D

YS

FU

NC

TIO

N

PU

LM

ON

AR

Y

HY

PE

RT

EN

SIO

N

0

4

1

2

1

0

5

10

9

44

5 5 5

4

Cardiac disease


Total triglycerides

LDL cholestrol

HDL cholestrol

VLDL cholestrol

147

102

4027

142

120

39


RV

DY

SF

UN

CT

ION

1

2

5


CD4 COUNT >500

CD4 COUNT 500-200

CD4 COUNT <200

VLDL cholestrol

27 25


FIGURE 12:

0

Hypercholestremia

Low HDL

High LDL

Hypertriglyceredemia

High VLDL

2

2

10 20 30 40 50

6

45

7

9

6

27

6

4

No of patients

DYSLIPEDEMIA IN HIV PATIENTS

50

No on HAART

Total no of patients

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