ABSTRACT

BACKGROUND

HAART increases the longevity of the patients infected with HIV so mortality due to

Opportunistic infections is reducing and late complications like cardiovascular

manifestations are on its rise. Cardiac involvement can be over looked in HIV positive

patients because symptoms of breathlessness, fatigue and poor exercise tolerance are

ascribed to other conditions associated with HIV patients.

OBJECTIVES:

Primary :To evaluate cardiac manifestations and determine type of cardiac involvement

in both HAART naïve patients and patients on HAART and correlate with CD4+ counts.

Secondary :To evaluate cardiac manifestations in patients having opportunistic infections

METHODS

200 HIV infected patients presenting in OPD and inpatients are included. Information is

collected and detailed history is taken using pre-formed proforma. At the time of

admission or follow up, steps are taken to send for all the investigations and detailed

clinical examination of the patient done, focusing more on cardiovascular system.

RESULTS:

41% of the patients with normal cardiac function were NOT ON HAART and 62.7% of

the patients with cardiac dysfunction were HIV naïve and it was found to be statistically

XVI
significant(p value 0.003). Tricuspid regurgitation(42.1% vs 57.9%, p value 0.035) and

IHD(0% vs 100% p value 0.049) found to have significant association in patients who

were ON HAART. Systolic dysfunction (p value 0.048) and IHD(p value 0.019) were

both significantly associated with the low CD4+ counts in patients NOT ON HAART.

CONCLUSION

There was significant association of HAART on the occurance of cardiac dysfunction.

Cardiac dysfunction is noted with low CD4+Counts, it is therefore important to undergo

2DECHO at diagnosis and at regular intervals in all HIV infected patients and to initiate

early treatment for the same.

KEYWORDS

HIV positive, Oppurtunistic infections, CD4+counts,NOT ON HAART, ON HAART,

Tricupid Regurgitation, Systolic dysfunction, IHD, WHO Staging, 2DECHO

XVII
INTRODUCTION

1
 INTRODUCTION

HIV infection is a major health problem in the entire world including India and

globally 36.7 million [34.0 million–39.8 million] people were living with HIV at the

end of 20151.

As per the NACO, India HIV Estimation 2015 report, National adult (15-49) years

HIV prevalence in India is estimated at 0.26% in 2015 with 0.30% among males and

0.22% among females.

The total number of people living with HIV in India is estimated at 21.17 lakhs (17.11

lakhs-26.49 lakhs) in 20152.

The prevalence of cardiac involvement in AIDS patients have been reported to range

between 28% and 73%3.

Cardiac involvement in AIDS/HIV infected persons may be attributed to virus itself,

the effects of anti-retroviral medications; or altered immune mechanisms associated

with the infection4.

From the beginning of AIDS epidemic, cardiac involvement was recognized at

autopsy and later by non-invasive techniques such as electrocardiogram.

Patients with HIV infection can have variety of cardiovascular manifestations.

The most common are pericarditis, pericardial effusion, pulmonary vascular diseases,

myocarditis, cardiomyopathy and increased incidence of coronary artery disease,

malignant neoplasm, coronary artery disease and drug related cardio toxicity5. The

prevelance of heart muscle disease is around 15% and has 3 forms global left

2
ventricular dysfunction, isolated right ventricular dilatation and borderline left

ventricular dysfunction.

Dilated cardiomayopathy is an independent adverse prognostic factor. It is strongly

associated with very low CD4 cell count.

Present study is undertaken to determine type of cardiac involvement in both

HAART naïve patients and patients on HAART and correlate pattern of cardiac

involvement with CD4+ counts

3
OBJECTIVES

4
OBJECTIVES

Primary objective :

To evaluate cardiac manifestations and determine type of cardiac involvement in

both HAART naïve patients and patients on HAART and correlate pattern of cardiac

involvement with CD4+ counts

Secondary objective :

To evaluate cardiac manifestations in patients having opportunistic infections

5
REVIEW OF

LITERATURE

6
 REVIEW OF LITERATURE

HUMAN IMMUNODEFICIENCY VIRUS DISEASE

HISTORY

In 1908 Ellerman and Bank discovered the viral etiology of fowl leukemia. This

triggered a search for oncogenic viruses in cancers in human beings and animals6.

In 1970 Temin and Beltimore discovered reverse transcriptase enzyme7.

In 1970s Feline leukaemia virus was discovered to be the causative agent of ―fading

kitten syndromes‖ characterized by immunodeficiency and associated with leukaemia.

In 1981 HTLV I (Human T cell leukaemia virus)was discovered and shown to be the

causative agent of T cell leukaemia in human beings.

In 1981 pneumocystis carinii pneumonia (PCP)was reported in 5 young homosexual

men. PCP was a rare disease till then. This was followed by reports PCP and other

unusual infections in homosexual men and Haiti immigrants to US. The disease was

termed Gay related immunodeficiency disorders8(GRID).

In 1982 the disease was reported in Hemophiliacs and in female sexual contracts of

infected men suggesting transmission through blood and sexual transmission.

In September 1982 the term Gay related Acquired Immunodeficiency

Syndrome(AIDS) replaced immunodeficiency syndrome.

In May 20th 1983, Luc Montagnier and his colleagues (Pasteur Institute – Paris)

isolated a retrovirus from AIDS patient with generalized lymphadenopathy and called

it lymphadenopathy associated virus (LAV), which was similar but distinct from

HTLV 1 and HTLV 2.

7
May 4th 1984, Robert C Gallo and colleagues (National Institute of Health, Bethseda)

isolated a retrovirus from AIDS patient , similar to HTLV and called it HTLV III7.

Cloning and molecular characterization of genetic material proved that the viruses

were same and consistent isolation from patients of different origin, high degree of

trophism for CD4 lymphocytes and isolation of similar simian virus causing AIDS in

Macaques proved that HTLV III/LAV was the causative of AIDS.

In 1984 screening test for HIV in blood donors in industrialized countries was started

(Earlier they were screened only for Hepatitis B and syphilis).

In 1986 Centres for disease control provided working definition of AIDS.

In 1986 HTLV III/LAV was renamed as human immunodeficiency virus (HIV) by

international committee for taxonomy of viruses9.

In 1987 Zidovudine was approved for use.

In late eighties progress was made in area of prophylaxis against opportunistic

infections.

In early nineties didanosine and zalcitabine were approved for use.

In 1995 dual combination of nucleosides were shown to be superior to monotherapy.

In 1996 protease inhibitors in triple regimens showed marked reduction in progression

to AIDS and death over the short to median term.

In 1997 non nucleoside reverse transcriptase inhibitors were introduced8,9.

Newer antiretroviral drugs like entry inhibitors, integrase inhibitors, chemokines co

receptor(CCR) antagonists are recently approved by FDA.

8
Fig 1: Structure of HIV(Adopted from API 9th edition, chapter 16.2, Virology,

Immunology and Diagnosis, page no. 1014)

TAXONOMY

Human immunodeficiency virus (HIV) belongs to

Family : Retroviridae

Sub family : Lentiviridae

Genus : Lentivirus

Subtype C of M group of HIV-1 is the most common form prevalent worldwide and

in India5.

9
MORPHOLOGY

Like other retroviruses HIV has an icosahedral structure with multiple external spikes.

The envelope is bilipid layer within which host proteins like major histocompatibility

complex antigens are incorporated and spikes are formed by glycoprotein 120 (gp

120), which is linked non covalently to transmembrane glycoprotein 41 (gp 41) .

Within the envelope is a cone shaped capsid made of P24 viral protein , which

contains 2 single stranded RNA. Each strand has a copy of 9 genes of the virus.

Table-1 HIV genes and its functions

HIV Gene Function

Gene Product

Gag p17 Matrix protein

p24 Capsid protein

p7 Nucleocapsid promotes RNA dimerization and

encapsidation

10
 Gene Product Function

HIVGene

p6 Regulates viral budding by interacting with

TSG101 and ALIX1

Env gp160 Precursor of gp 120 and gp 41

gp 120 Surface envelope for binding to CD4 molecule

gp 41 Transmembrane glycoprotein results in membrane

fusion of virus envelope with CD4 lymphocyte

Pol Protease Cleaves gag and pol gag products

Reverse Catalyze reverse transcription of HIV RNA to

transcriptase double stranded DNA

Integrase Integrase viral DNA into host cell chromosome

Tat Tat Enhances transcription of viral RNA

Rev Rev Cytoplasmic transport of unspliced RNA

Vpu Vpu Promotes selective degradation of CD4 also

facilitates virion release from host cell

Vif Vif Stabilizes the virion upon entry into host cell

Vpr Vpr Induces arrest of host cell in G2 phase

Nef Nef Down regulates CD4 and major histocompatibility

complex expression

11
LIFE CYCLE

FIGURE 2: Various steps in replication of HIV(Adopted from API 9th edition, chapter

16.2, Virology, Immunology and Diagnosis, page no.1015)

HIV binds to CD4 molecule of T helper lymphocytes through gp120. Binding to

either CXCR4 or CCR5 coreceptor is also essential. This induces a conformational

change in gp41 and results in fusion of viral envelope with host cell membrane

releasing the genomic RNA to target cell. Viral reverse transcriptase catalyze

transcription of viral RNA to double stranded DNA. Integrase integrates viral DNA

into host chromosome. Tat enhances transcription of viral RNA. Rev mediates

transport of unspliced and spliced RNA to the cytoplasm. Spliced RNA is translated

into viral proteins. The viral particle is formed from unspliced viral RNA and viral

proteins. Budding occurs and external lipid bilayer envelope is acquired from host cell

membrane. Viral protease then cleaves gag pol precursor protein to form the mature

virion10,11.

12
 TRANSMISSION

Sexual transmission is most common mode of spread of infection worldwide and

also in india. The presence of sexually transmitted disease, unprotected receptive anal

intercourse(URAI) increases the chances of transmission. Although data are limited,

the per-act risk for HIV transmission via URAI has been estimated to be ~1.4%. Male

to female transmission is more common than vice versa.

Transmission through blood is seen in intravenous drug abusers who share

syringe needle etc., the per-act risk of transmission from injection drug use with a

contaminated needle has

been estimated to be approximately 0.6%.

Transmission via whole blood , packed red cells, platelets and plasma is reduced

now following adoption of screening the donors for HIV. It is estimated that >90% of

individuals

exposed to HIV-contaminated blood products become infected

Occupational transmission of healthcare workers and laboratory workers through

contaminated needle/ other sharp instruments, exposure of abraded skin/mucosa to

blood or other infectious fluid. The risk of HIV transmission following skin puncture

from a needle or a sharp object that was contaminated with blood from a person with

documented HIV infection is ~0.3% and after a mucous membrane exposure it is

0.09%

Mother to fetus/infant transmission in perinatal period. In the absence of

prophylactic antiretroviral therapy to the mother during pregnancy, labor, and

delivery, and to the fetus following birth, the probability of transmission of HIV from

13
mother to infant/fetus ranges from 15% to 25% in industrialized countries and from

25% to 35% in developing countries.

EPIDEMIOLOGY

From 5 cases reported in homosexual men in 1981 the disease has grown into a

global pandemic with an estimated 36.7 million people infected throughout the world,

two thirds of them in Sub Saharan Africa, one fifth in Asia.

Total no. of people living with HIV in India is estimated at 21.17 lakhs in 2015

National prevelance rate was 0.26% and 0.29% in antenatal women. Prevelance rate

in Karnataka is 0.45%12.

HIV disease: Pathogenesis

HIV disease is characterized by chronicity of infection and by dysfunction and

depletion of CD4+ T lymphocytes.

Primary HIV infection

Mucosal exposure results in infection of langerhans cell which passes the

infection to CD4+ T lymphocytes in the local draining lymphnode. In the local

lymphnode the virus replicates to a critical level followed by viremia. This initial

viremia disseminates the virus to other lymphoid tissues. This is followed by

persistent active viral replication and progressive CD4+ T cell depletion- latent stage.

The lymph nodes have hyperplasia of germinal centres with copius amount of virion

trapped in the processes of follicular dendritic cells. These trapped virions are

constant source of infection to CD4+ T lymphocytes in the parafollicular area. The

trapped virion serves as a persistent source of cellular activation, which results in

secretion of IL-1B, TNF,IL-6 which upregulate viral replication and expression in

14
infected cells. As the disease progresses the architecture of lymph node, the thymus

and other lymphoid organs is lost.

CHRONICITY OF INFECTION

HIV has an extraordinary ability to mutate especially V region of gp 120

hence escapes from immune defences like neutralizing antibodies. Extensive analyses

of sequential HIV isolates and host responses have demonstrated that viral escape

from B cell and CD8+ T cell epitopes occurs early after infection and allows the virus

to stay one step ahead of effective immune responses. Cytolytic CD8+ T

lymphocytes require CD4+ lymphocytes help in induction and maintenance of

cytolytic CD8+T cell responses. With depletion of CD4+ T cells the functions of

CD8+ T cells are reduced. There is also deletion and loss of CD8+ T lymphocytes due

overwhelming exposure to viral antigen. A large pool of latently infected cells is

present in HIV infected. These cells are quiescent and on activation they express the

HIV virus.

ROLE OF CHRONIC CELLULAR ACTIVATION

Persistent infection leads to hyperactivation of B-lymphocytes resulting in

hypergammaglobulinemia. The initially strong response becomes qualitatively

dysfunctional owing to the overwhelming immune activation resulting from persistent

viral replication. Activation of monocytes, CD4+ T lymphocytes and CD8+T

lymphocytes results in increase in proinflammatory cytokines. Proinflammatory

cytokines increase the expression of HIV in infected cells. Activation also induces

viral expression and multiplication in latently infected CD4+ T lymphocytes. Several

studies have indicated that exhaustion of HIV-specific CD8+ T cells during prolonged

15
immune activation is associated with expression of inhibitory receptors, such as

programmed death (PD) 1 molecule (of the B7-CD28 family of molecules), as well as

loss of polyreactivity and proliferative capacity.

EFFECT OF CO-INFECTION WITH OTHER MICROBES

Coinfection with other microbes like Herpes simplex virus, cytomegalovirus,

Ebsteinbar virus, Hepatitis B virus, HTLV, mycoplasma, mycobacterium tuberculosis

upregulate HIV expression and active tuberculosis accelerates the course of disease.

Immunization with common antigens like tetanus toxoid, influenza, pneumococcal

polysaccharide causes activation of immune system and transient rise in plasma

viremia.

ROLE OF CYTOKINES IN HIV PATHOGENESIS

Proinflammatory cytokines like tumor necrosis factor α (TNF α ) , interleukin-1β,

Interluekin 6(IL-6) are potent inducers of HIV expression. TNF α activates

transcriptional activators of HIV expression (NF κβ).

Interferon α and Interferon β suppress HIV replicaton. Interleukin 10 inhibits

replication of HIV in acutely infected monocytes by blocking secretion of TNF α and

IL6.

Chemokines-RANTES, Macrophage inflammatory protein(MIP)-1α and MIP-1β

inhibit infection by and spread of macrophage tropic/R5 HIV strains. They block the

CCR5 coreceptor. They are secreted by natural killer cells. Stromal cell derived factor

(SDF)-1 inhibits infection and spread of T cell tropic/X4 HIV strains. They block the

CXCR4 coreceptor on the target cells.

16
 T helper -1 type of response which upregulates cellular immunity is reduced in

HIV infected. Interleukin-2 (IL-2) and Interleukin 12 (IL-12) stimulate proliferation

and lytic activity of cytotoxic T lymphocytes and natural killer cells. HIV infected

individuals have loss of IL-2 receptors and reduced ability to produce IL-2 and IL-12.

DYSFUNCTION AND DEPLETION OF CD4+ T LYMPHOCYTES

CD4+ T cell dysfunction is the hallmark of HIV disease. Both qualitative and

quantitative defects are seen. Early abnormalities noted are a loss of response to

remote recall antigens like tetanus toxoid,influenza etc. This is followed by loss of

proliferative response of T cells to alloantigens and later to mitogenic stimulation.

MECHANISM OF CD4+ T CELL DEPLETION AND DYSFUNCTION

A) DIRECT MECHANISM

 Single cell killing due to direct infection with HIV is unlikely to be a

major contributor for immune dysfunction, at least in early HIV

infection. The proportion of HIV infected CD4+ T cells in peripheral

blood varies from 1 to 10000 in early infection to 1 in 100 cells in

advanced stages13.

 Accumulation of unintegrated viral DNA

 High intracellular levels of viral RNA, intereferes with processing of

cellular RNA and disrupts cellular protein synthesis

 Intracellular gp10-CD4 fusion intereferes with signal transduction and

induces energy.

 Plasma membrane integrity is lost due to viral budding.

 HIV infected cells may be killed by virus specific immune responses.

17
B) INDIRECT MECHANISMS

 Syncytium formation from fusion of cell membranes of infected and

uninfected CD4+ T cell has been observed in vitro.

 Molecular mimicry between gp120 and Class II MHC results in

autoantibodies to self MHC determinants and elimination of those cells.

 Elimination of uninfected CD4+ T cells coated with HIV gp120 by HIV

specific immune response –―Innocent bystander killing‖.

 Apoptosis: gp120 and CD4+ interaction causes a state of altered cell

activation wherein a second activation signal like antigen binding of T

cell receptor triggers apoptosis. Viral tat protein also upregulates CD95

ligand (Fas) which can lead to apoptotic cell death.

 Infection of CD34+ bone marrow progenitor cells and of thymocytes

leads to depletion of T cell precursors. Thymic microenvoirnment is

disrupted13.

CD8+ T LYMPHOCYTES

Initially a robust cytotoxic response is mounted but this gradually wanes

in later stages. In advanced HIV disease the cells lose functional capability of

cytolytic activity and develop abnormal phenotype. CD4+ helper lymphocytes

are necessary for inducing and maintaining cytotoxic lymphocyte response.

B LYMPHOCYTES

HIV or its products like gp41 can induce polyclonal B cell activation

resulting in hypergammaglogulinemia. B cells are also functionally defective

18
and respond poorly to immunization. These defects are partly responsible for

increased susceptibility to certain bacterial infections5.

MONOCYTES/ MACROPHAGES

Though HIV can replicate in monocyte lineage cells it has little cytopathic

effect on them. Decreased secretion of cytokines and defects in antigen

presentation are functional deficits seen in monocytes/macrophages.

NATURAL KILLER CELLS

They are normal in function and number and serve as important source of

HIV inhibitory chemokines.

CLINICAL MANIFESTATIONS

ACUTE HIV SYNDROME

Synonyms: Primary HIV illness, acute primary illness, acute HIV

seroconversion illness, acute retroviral syndrome.

Acute HIV syndrome occurs 3-6 weeks after infection in 50-70% of

infected individuals and can vary in severity from individual to individual. It

presents as an acute mononucleosis like illness, with fever, pharyngitis,

lymphadenopathy(70%), headache, retroorbital pain, arthralgia, lethargy,

anorexia, nausea, vomiting diarrhea, weight loss, meningitis, encephalitis,

myelopathy, peripheral neuropathy, mucocutaneous ulceration, rash. Symptoms

last one to several weeks. About 10% of patients manifest a fulminant course of

19
deterioration5. Differential diagnosis includes infectious mononucleosis,

secondary syphilis, and acute viral hepatitis, parvovirus infection, influenza but

detection of these does not exclude HIV infection.

ASYMTOMATIC STAGE/PERIOD OF CLINICAL LATENCY

The time to development of clinical disease vary greatly and approximate

median time is 10 years. Patients are usually asymptomatic during this period or

may continue to have persistent generalized lymphadenopathy commonly

axillary,cervical and inguinal chain(atleast two non-contagious sites must be

involved). Patient may develop seborrheic dermatitis, new onset or worsening

of psoriasis. Idiopathic thrombocytopenia, polymyositis, Guillian Barre

Syndrome which is related to immune activation, may occur at this stage.

SYMPTOMATIC/ INTERMEDIATE STAGE

Usual complication at this stage include dermatological, oral and

constitutional manifestations. Though not a serious nature these complications

are bothersome to the patient. Dermatological complications include herpes

zoster, bacterial folliculitis, molluscum contagiosum, seborrhic dermatitis,

dermatophyte infections, psoriasis and anogenital warts. Oral complications

include oral candidiasis, oral hairy leukoplakia, aphthous ulcers, necrotizing

ulcerative periodontitis. Constitutional manifestions include fever, weight loss,

fatigue, myalgia, arthalgia, and headache. Patient may develop recurrent

20
diarrhea, recurrent bacterial sinusitis and pulmonary tuberculosis. HIV

associated nephropathy can manifest at this stage.

LATE STAGE

The CD 4+ lymphocyte count is less than 200/microlitre in these

patients. The opportunistic infections, neoplasms and neurological disorders

seen at this stage constitute the AIDS defining conditions and include:

 Candiadisis of Oesophagus, bronchi, trachea or lungs diagnosed by

endoscopy/ histology.

 Invasive cervical cancer diagnosed by histology.

 Extrapulmonary coccidiomycosis diagnosed by histology, culture or

detection of antigen in tissues.

 Extrapulmonary cryptococcosis detected by histology or detection of

antigen in fluid/tissue.

 Cryptosporidiasis of more than one month duration diagnosed by

histology or detection of antigen.

 Cytomegalovirus retinitis, diagnosed by detection of antigen/histology

or presumptively diagnosed by ophthalmic evaluation.

 Cytomegalovirus disease (other than liver, spleen, or nodes), onset at

age >1 month

 HIV related encephalopathy characterized by progressive disabling

cognitive/ motor dysfunction in absence of concurrent illness(excluded

by CSF examination and CT/MRI imaging).

21
 Herpes simplex, causing ulcers (>1 month), bronchitis, pneumonia or

esophagitis, diagnosed by histology, cytology or culture.

 Extrapulmonary or disseminated histoplasmosis, diagnosed by

histology/cytology/culture or detection of antigen.

 Chronic intestinal isosporiasis(>1 month), diagnosed by histology/

cytology/culture of detection of antigen in tissue.

 Kaposi sarcoma, presumptive diagnosis by characteristic appearance,

confirmed by histology and cytology.

 Non Hodgkins lymphoma, diagnosed histologically.

 Mycobacterium tuberculosis, diagnosed by compatible illness and

isolation of mycobacterium tuberculosis from clinical specimen.

 Other mycobacterial diseases-diagnosed by culture from normally sterile

site.

 Pneumocytosis carinii- presumptive diagnosis based on history of non-

productive cough and dyspnoea (<3month) with compatible radiologic

picture and confirmed by cytologic evidence.

 Recurrent bacterial pneumonia – diagnosed on occurrence of culture and

radiologically proven pneumonia of more than two episodes in a year.

 Progressive multifocal leukoencephalopathy, diagnosed by

histology/cytology.

 Recurrent salmonella septicemia proved by culture.

 Toxoplasmosis onset of age >1 month, mass lesion on CT/MRI imaging

and by presence of toxoplasma antibody.

 Wasting syndrome characterized by involuntary weight loss of more

than 10% of body weight with chronic diarrhoea >30days. Chronic

22
 weakness and fever >30days. Chronic weakness and fever >30days, in

absence of other causative conditions5,14.

WHO STAGING SYSTEM FOR HIV INFECTION AND DISEASE IN ADULTS

AND ADOLESCENTS

CLINICAL STAGE 1

1. Asymptomatic

2. Persistant Generalized lymphadenopathy

CLINICAL STAGE II

1. Moderate unexplained weight loss <10% of body weight.

2. Minor mucocutaneous manifestations (seborrhoeic dermatitis, prurigo, fungal

nail infections, recurrent oral ulcerations, angular cheilitis)

3. Herpes zoster within the last five years

4. Recurrent upper respiratory tract infections(i.e, bacterial sinusitis)

CLINICAL STAGE III

1. Severe weight loss > 10% of body weight

2. Unexplained chronic diarrhea >1 month

3. Unexplained prolonged fever (intermittent or constant)>1month

23
 4. Oral candidiasis (thrush)

5. Oral hairy leukoplakia

6. Pulmonary tuberculosis

7. Severe presumed bacterial infections (i.e, pneumonia, pneumonitis,empyema

meningitis bacteremia)

8. Acute necrotizing ulcerative stomatitis,gingivitis or periodontitis

9. Unexplained anemia(<8g/dl) and or neutropenia

thrombocytopenia(<50,000/mm3) for more than a month

CLINICAL STAGE IV

1. HIV wasting syndrome

2. Pneumocystitis carinii pneumonia

3. Toxoplasmosis of the brain

4. Cryptosporidosis with diarrhea >1month

5. Cryptococosis, extrapulmonary

6. Cytomegalovirus(CMV) diseases of an organ other than liver, spleen or

lymph node(e.g. retinitis)

7. Herpes simplex virus infection, mucocutaneous (>1 month) or visceral

8. Progressive multifocal leucoencephalopathy

9. Any disseminatd endemic mycosis

10. Candidiasis of oesophagus, trachea, bronchi

11. Atypical mycobacteriosis, disseminated or pulmonary

12. Non typhoid salmonella septicemia

13. Extrapulmonary tuberculosis

24
 14. Lymphoma(cerebral or B cell non Hodgkin)

15. Kaposi’s sarcoma

16. HIV encephalopathy

17. Invasive cervical carcinoma

18. Visceral leishmaniasis15.

Diagnosis of HIV infection

NACO recommends the use of ELISA kits with a sensitivity of ≥99.5 percent

and the specificity of ≥98 percent and rapid kits with a sensitivity of ≥99.5 percent

and the specificity of ≥98 percent.

Western blot is a confirmatory test and detects antibodies to HIV proteins.

Other diagnostic modalities include DNA PCR, RNA PCR, b DNA assay and P

24 antigen capture assay.

Guidelines for detection of HIV infection in India (NACO)

Strategy 1

This strategy is used for ensuring donation safety (e.g., blood, blood products,

organs, tissues, sperms etc.). A single ELISA test is done, if negative the serum is

considered to be free of HIV. If positive the donor is not informed.

Figure 3: Strategy 1, for transfusion and transplant safety

25
Strategy 2A

This is used for sentinel surveillance and also for diagnosis in presence of AIDS

defining illness. Sample is considered negative, if first ELISA test is negative. If first

test is positive, second ELISA test is done and the sample is reported positive when

both the tests are positive.

Figure 4: Strategy 2A, for survelliance(Adopted from National guidelines for HIV

testing; NACO: July 2015, page no. 39)

Strategy 2 B

This strategy is used to determine the HIV status of a clinically symptomatic

suspected AIDS cases. The specimen is considered negative if the test gives a non-

reactive result. In case the test result is reactive the specimen is tested with another

test kit, If the result is also reactive with the second test kit, the specimen is

considered to be positive for HIV in a symptomatic AIDS case. In case a specimen is

reactive with the first test kit and non reactive with the second test kit, the specimen is

subjected to a third tiebreaker test. If the third test is reactive, the specimen is reported

26
as indeterminate and follow up testing is undertaken after 2 to 4 weeks. In case the

third tiebreaker test is non-reactive, the specimen is reported negative

Figure 5: Strategy 2B, Diagnosis of an individual with AIDS indicator disease

symptoms(Adopted from National guidelines for HIV testing; NACO: July 2015 page

no.40 )

Strategy 3

This is used for diagnosis of HIV in asymptomatic individuals. In strategy 3 the HIV

testing done is similar to strategy 2, with the added testing of a third test for a positive

result. Positive confirmation of a third reactive test is required for a specimen to be

reported HIV positive. If the specimen gives a reactive result with two and non-

27
reactive result with the third assay, it is reported as ―indeterminate‖ and the patient is

called again for repeat testing after 2-4 weeks.

This strategy is used for the diagnosis of HIV infection in asymptomatic individuals at

ICTCs and PPTCT centres16.

Figure 6: Strategy 3, To detect HIV infection in asymptomatic individuals(ICTC’s,

PPTCT’s) (Adopted from National guidelines for HIV testing; NACO: July 2015

page no. 41)

28
Markers for HIV disease progression

The likelihood and timing of clinical AIDS varies among individuals and cannot

be readily predicted, but monitoring certain measurable traits help in disease staging

and in predicting susceptibility to opportunistic infections.

β2 Microglobulin (β2M)

β2 M is a low molecular weight polypeptide, It is a sensitive but nonspecific

marker of immune activation. High β2M levels (3.5 mg/liter) in HIV infected group

are associated with progression to AIDS13,17-19.

High levels of' β2M are also found in patients with various viral infections and in

patients with lymphoproliferative disorders like lymphoma.

Neopterin

Neoptrin/6-D-erythro—trihydroxypropylpterin is derived from macrophages and B-

lymphocytes activated by Interferon gamma and is a product of Guanine- Tri-

Phosphate catabolism. Neopterin is estimated using liquid chromatography and radio

immunoassay. Elevated serum neopterin is a very early marker of HIV infection. High

neopterin levels are found in progressors compared to non- progressors17. CD4 and

neopterin are strong predictors in late-stage disease.

Elevated neopterin levels are also found in infections and inflammatory disorders,

collagen vascular disease and certain malignancies. Neopterin is not specific to HIV

or AIDS19.

Soluble Interleukin 2 receptor (sIL-ZR)

SIL—2R is composed of two peptides IL2Rα and IL2Rβ. High sIL 2R are found in

patients with AIDS and correlate negatively, with CD4 T cell counts. Apart from HIV

29
infection, elevated IL2Rα is found in acute and chronic lymphocytic leukemia,

rheumatoid arthiritis, systemic lupus erythematosis and sarcoidosis19.

Soluble CD8

Released by activated CD8 cells is an early marker to HIV infection and precedes

appearance of anti HIV specific markers and levels correlate with number of

circulating CD8 lymphocytes.

Anti P24 antibody

A decline in anti P24 core antibodies correlates with poor prognosis in HIV infected

individuals.

Anti gp120 antibody

Absence of anti gp120 antibodies is associated with progression to clinical AIDS.

P24 antigen

They are one of the first virally encoded molecules to be detectable in blood of HIV

infected. P24 antigen is transiently present during acute stages of infection and

reappears again in later progressed state of disease. Presence of p24 antigenemia with

low CD4 + T cell count is a very strong predictor of disease progression — Sabin20 et

al (2001). A positive P 24 antigen result, in chronic HIV infected individual is

associated with declining CD4 cell counts - Hughes et al. P24 antigen detection is

hindered by P24 antigen — antibody complex.

Syncytium inducing Phenotype (SI)

Certain HIV isolates have syncytium inducing capacity. Such variants are usually

detected during later course of disease, often prior to AIDS diagnosis.

CD38 positive CD8 + T cells

30
CD8 + CD38 + T lymphocytes are cytotoxic and increased percentage of CD38 +

CD8 + T lymphocytes in peripheral blood reflects a higher viral load and disease

progression13,22.

Anergy

In advanced HIV disease diminished delayed hypersensitivity response to recall

antigens (mumps, candida, tetanus and trichophyton) is seen. Anergy was earlier used

as a criterium in Walter reed staging system13,23.

All the above markers do reflect disease activity but they are no longer used in

monitoring the HIV disease progression. HIV disease progression is now monitored

using CD4+ T lymphocyte count and HIV RNA estimation.

HIV RNA Determination

It is a predictor of progression to AIDS independent of CD4 + T lymphocyte count.

Measuring CD4 + T cell count reflects degree of immunodeficiency and short term

risk of opportunistic diseases whereas HIV RNA levels predict what is likely to

happen to immune system23. Plasma RNA is measured by RT-PCR (reverse

transcription-polymerase chain reaction), branched DNA (b-DNA) assay or nucleic

acid sequence based amplification (NASBA). Each of these assays can detect viral

levels as low as 20-50 molecules of HIV RNA per m1 of plasma.

Plasma viral load can be used to predict the progress of the disease24. Plasma

viral load of > 30,000 copies/ml by bDNA assay and > 55000 copies/ml by RT PCR

method is an indication for starting antiretroviral therapy. Effective response to

treatment is reflected by sustained low viral load25,26. Plasma viral load should be

monitored every 3-4 months after starting antiretroviral therapy.

CD4 + Lymphocyte count as marker for HIV disease progression

31
CD4 + lymphocytes play a central role in both humoral and cell mediated immune

defense. Progressive depletion of CD4 + lymphocytes is the hallmark of HIV disease.

CD4 + lymphocytes are progressively lost during the course of HIV disease and lower

levels of CD4 + lymphocyte count are indicative of more serious immunodeficiency

and more advanced disease (Phillips27 et al, 1991).

CD4 + T cell enumeration

The currently available techniques for CD4 + T cell counting can be classified into

automated and manual methods. Automated methods include flowcytometry and

dedicated cytometers. Flowcytometry is the gold standard technology for CD4 + T

cell counting.

32
CARDIAC MANIFESTATIONS OF ACQUIRED IMMUNODEFICIENCY

SYNDROME

Cardiac involvement in AIDS patients was first described in 1983 by Autrain et

al, who reported myocardial Kaposi sarcoma at autopsy. The prevalence of cardiac

involvement in AIDS patients has been reported to range between 28% to 73%.

Because of the longer survival in HIV patients, the more manifestations of late—stage

HIV infection will be seen, including HIV—related cardiac diseases. These cardiac

diseases include pericardial efflusion, myocarditis, dilated cardiomyopathy,

endocarditis, pulmonary hypertension, malignant neoplasms, coronary artery disease

and drug-related cardiotoxicity.

PERICARDIAL EFFUSION

Pericardial effusion is one of the most common forms of cardiovascular

involvement in HIV infection. There are varieties of clinical manifestations, which

include asymptomatic pericardial effusion, percarditis, cardiac tamponade, and

constrictive pericarditis. Approximately one fifth of AIDS patients have pericardial

effusion. The pericardial effusion is often small and without hemodynamic

consequence; however, large effusion can occur and may cause cardiac tamponade.

The clinical manifestations of pericarditis are similar between patients with and

without HIV infection. The etiology of pericardial effusion in HIV is often difficult to

identify, but may be related to opportunistic infection, metabolic abnormality or

malignancy, and it could be a part of the ―capillary leak syndrome‖ which is related to

enhanced cytokine production in the later stages of HIV disease

Moreno28 et a1 reviewed echocardiographic studies in 141 HIV-infected patients,

and 55 (39.0%) of them had pericardial effusion. Most (34 of 55) were small. The

clinical presentation of pericarditis was compared between patients with small

33
pericardial effusion and those with moderate to large pericardial effusion. They found

that the presence of pericardial friction rub and electrocardiographic repolarization

abnormalities consistent with pericarditis were more often seen in patients with

moderate to large pericardial effusions. The reason for these findings is unclear.

Specific identifiable causes of pericardial effusion in AIDS patients are not always

possible.

Flum29 et a1 performed pericardial fluid cultures and pericardial biopsies in 29

AIDS patients with pericardial effusion who underwent a pericardial window

procedure. The causes were identified in 7 (24%) of the 29 patients. The causes

included Staphylococcus aureus (1 patient), Mycobacterium tuberculosis (1 patient),

and lymphoma (3 patients). Staphylococcus auerus pericarditis is a serious condition,

and cardiac tamponade may develop rapidly30.

Karve31 et al reported penumococcal pericarditis in 2 HIV patients, and both of

them developed cardiac tamponade.

Sunderam32 et a1, studied a select group of 29 AIDS patients who had M

tuberculosis. Of these 29 patients, 21 (72%) had extrapulmonary tuberculosis.

Tuberculous pericarditis was found in 1 (5%) of these 21 patients with

extrapulmonary tuberculosis.

Zuer33 et al reported that l (4%) of 26 AIDS patients with cryptococcal infection

had pericarditis.

Eisenberg34 et a1 could identify the cause of pericardial effusion in 4 (29%) of 14

AIDS patients with pericardial effusion. The causes included lymphoma (1 patient),

myocardial infarction (1 patient) and endocarditis (2 patients). Kaposi sarcoma has

been reported to cause pericardial effusion and cardiac tamponade. Numerous case

34
reports have shown multiple unusual organisms associated with pericardial effusion in

HIV patients.

Heidenreich35 et al studied the incidence of pericardial effusion and its relation

to mortality in HIV patients. Two hundred thirty-one patients were recruited during a

5 year period, and 74 had AIDS. Fifteen patients with HIV infection had pericardial

effusion, and 12 (80%) of these pericardial effusions were small. Only 2 patients (1

with a moderate and l with a large pericardial effusion) developed symptoms and

signs of cardiac tamponade, which required drainage. Patients with AIDS who have

pericardial effusion have a 9% annual incidence of cardiac tamponade and 1% of all

AIDS patients developed cardiac tamponade annually. The size of pericardial effusion

did not correlate with the shortened survival, but the presence of pericardial effusion

did. The mean ±SD 6 month survival was 36% ± 11% compared with 93% ± 3% in

AIDS patients without effusion. The CD4 (T helper lymphocyte) cell count was lower

in AIDS patients with effusion than in those without effusion (0.059 vs 0.146 x

109/L). Pericardial effusion in HIV patients may be a marker of end-stage HIV

infection because it is associated with low CD4 cell count and is often caused by

opportunistic infections and malignant neoplasms seen in the advanced stage of

AIDS.

Ayaskantha singh36 et al did an echocardiographic study in patients with HIV

showed Pericardial effusion in 17.4% of cases. The pericardial effusion detected was

often small in amount and without any hemodynamic significance. Pericardial

effusion in HIV patients may be marker of end stage HIV infection because it is

associated with low CD4 count.

Lind37 et al did a cohort study on pericardial effusion in HIV in the ART era,

the rate of the subjects who actually developed a pericardial effusion was rather small,

35
only in two of the 802 (0.25 %) HIV-infected patients pericardial effusion could be

seen by echocardiography. Although antiretroviral drugs might diminish the incidence

of pericardial effusion due to opportunistic infections, other causes for the

development of this cardiac disorder might have become more frequent. In particular,

the improvement of the immune defence by the use of antiretroviral drugs could

induce pericardial effusions in the context of an immune reconstitution inflammatory

syndromes The reason, why the rate of pericardial effusion is significantly reduced in

the era of antiretroviral therapy is yet unknown. Nevertheless, it seems to be obvious,

that the effective blockade of virus replication and a reduced rate of opportunistic

infections might have major effects on the low pericardial effusion rate

Pugliese38 et al showed a dramatic and significant decrease of cardiac

involvement in his study, especially in pericarditis 3.4% (n=17) when they were

treated with HAART (P\0.0001).

MYOCARDITIS

Myocarditis is the most common cardiac abnormality found on biopsy tissue,

present in some degree, in more than 50% of HIV patients39 [Howes et al., 2010]. The

prevalence of myocarditis in HIV infected patients has been difficult to establish with

estimates ranging from 6%40 [Barbaro et al., 1998b] to 52%41 [Levy et al., 1989]. In

other studies about 10 percent of people with HIV develop myocarditis, either

because HIV directly invades the heart muscle or because the patient’s weakened

immune system makes the heart muscle more susceptible to attack by other infectious

agents, especially toxoplasmosis42,43 [Grange et al., 1990, Matturi et al., 1990].

Probable etiologies include myocardial invasion with HIV itself, opportunistic

infections, viral infections, and autoimmune response to viral infection, drug-related

cardiac toxicity, nutritional deficiencies, endothelial dysfunction, autonomic

36
dysfunction, and prolonged immunosuppression. Zidovudine (AZT), an antiretroviral

drug used in treatment of HIV, has also been associated with myocarditis44

[Herskowitz et al., 1992a].

Anderson45 et al suggested that myocarditis in HIV patients may play a role in the

development of ventricular dysfunction. The autopsy incidence of myocarditis was

approximately one third of all AIDS patients.

A specific cause was found in less than 20% of these patients. Common

pathogens in AIDS myocarditis include Toxoplasma gondii, M tuberculosis, and

Cryptococcus neoformans. Other infectious organisms have been reported to include

Myocobacterium avium—intracellulare complex, Aspergillus fumigatus, Candida

albacians, Histoplasma capsulatum, Coccidiodes immitis, cytomegalovirus, and

herpes simplex. Recent data suggested that HIV alone can cause myocarditis. Either

HIV or its proteins (p17, p24 and gp120/160) have been found in the heart specimens

of patients with AIDS with or without cardiac diseases by culture, by in situ

deoxyribonucleic acid hybridization and Southern blot-tests40.46,47.

Superantigen plays an important role in the pathogenesis of many diseases by

forming a trimolecular complex with major histocompatibility complex class II

molecules on the antigen-presenting cells and the VB-specific region on the T

lymphocyte receptor. The binding results in a massive stimulation of the T

lymphocyte. The role of superantigen in the pathogenesis of AIDS has been

described. After the binding of HIV regulatory protein (Net) with major

histocompatability complex class II on antigen—presenting cells, the T lymphocytes

become activated. The activation of T lymphocytes stimulates the proliferation and

release of cytokines such as interferon γ and interleukin 2. Therefore, the viral load in

the heart will increase from creating a cellular reservoir for HIV, Apoptosis, anergy or

37
both may cause T-lymphocyte depletion. Proliferation of the B cell may result in

hypergammaglobulinemia. Autoimmune response may occur as a result of B—cell

differentiation into immunoglobulin secreting cells and activation of T-lymphocyte48.

Lymphocytic myocarditis was found in 37 (52%) of 71 patients who died of AIDS,

There were 3 types of histological features: lymphocytic infiltrate with necrosis of the

myocardial fibers, lymphocytic infiltrate without necrosis of the myocardial fibers,

and local and mild myocarditis with a mono-nuclear infiltrate. Reily et al studied the

relation between clinical and histopathological cardiac findings in patients with AIDS,

Interestingly, myocarditis was found in all patients with congestive heart failure, left

ventricle dysfunction, and ventricular tachycardia. Baroldi et al evaluated the relation

between cardiac dysfunction and myocarditis. Of 26 patients with AIDS, 8 underwent

premortem echocardiography. Of these 8 patients, 6 had abnormal cardiac function

(abnormal fractional shortening, globular shape, hypokinesis, or mild ventricular

dilation). All patients with abnormal echocardiographic findings had lymphocytic

myocarditis with or without myocardial necrosis postmortem.

High rates of myocarditis are associated with CD4 counts of less than 400

cells/mm3 and up to two-thirds of untreated AIDS patients having histological

evidence of myocarditis on autopsy 49,50

By preventing opportunistic infections and reducing the incidence of Myocarditis

in HIV Positive Patients 163 myocarditis, HAART regimens have reduced the

prevalence of HIV-associated myocarditis to about 30%51 [Barbaro 2005]. One Italian

study reported an almost 7-fold reduction of the prevalence of HIV-associated

myocarditis from the pre-HAART era38[Pugliese et al., 2000]. In that study there is no

conclusive evidence that HAART reverses cardiomyopathy, but it does appear that by

38
preventing profound immunosuppression and the development of AIDS, heart muscle

remains healthier38[Pugliese et al., 2000]

DILATED CARDIOMYOPATHY

In 1986, Cohen46 et al described the first case of rapidly fatal, dilated

cardiomyopahty in a patient with AIDS. The prevalence of dilated cardiomyopathy

ranges from 10% to 30% by echocardiographic and autopsy studies.

The incidence of dilated cardiomyopathy (DCM) in HIV infected individuals

has been shown to be 15.9% per year before introduction of HAART, and an autopsy

series showed a prevalence of about 25%52. However, the prevalence has been

reduced by about 30% in developed countries in the HAART era due to highly potent

treatment and management of associated opportunistic infections53

Herskowitz54 et al found that patients with severe symptomatic heart failure

had a low CD4 cell count, myocarditis, and a persistent elevation of antiheart

antibodies. The postmortem gross findings of dilated cardiomyopathy in patients with

AIDS have included increased heart weight, with either biventricular or 4-chamber

dilation, and a pale appearing myocardium55. Echocardiographic findings, included 4-

chamber enlargement, diffuse left ventricular hypokinesis, and decreased fractional

shortening. Coudray and colleagues56 demonstrated that left ventricular diastolic

impairment could occur in the early stage of HIV infection. Dilated cardiomyopathy

occurs late in the course of HIV infection and is usually associated with a significant

reduced CD4 cell count57,58, however, there was no association between the

progression of left ventricular dysfunction and the rate of CD4 cell count decline.59

The pathogenesis of cardiomyopathy remains unclear. Several studies60,61 have

supported the direct role for HIV l-mediated cardiac injury, but the mechanism

39
remains unclear. One hypothesis focuses on the role of an alteration of T-helper cell

function inducing myocardial inflammation by uncontrolled

hypergammaglobulinemia. The HIV gene may provoke cell surface cardiac muscle

protein, resulting in the induction of circulated cardiac autoantibodies, which can

trigger a progressively destructive autoimmune reaction62.

Selenium deficiency and its association with cardiomyopathy have been

described. Case reports of pediatric63,64 AIDS patients have shown an improvement of

cardiac function after selenium supplementation. Barbaro52 et al performed a

prospective, longterm clinical and echocardiographic follow up study of 952

asymptomatic HIV positive patients. An echocardiographic diagnosis of dilated

cardiomyopathy was made in 76 patients (80%) with a mean annual incidence of, 15.9

per 1000 patients during a mean ±SD follow up period of 60.0 ± 5.3 months. All

patients with an echocardiographic diagnosis of dilated cardiomyopathy underwent

endomyocardial biopsy within 1 month They found myocarditis in 63 (83%) of the

patients with dilated cardiomyopathy on histological examination, and 36 (57%) of

the patients with myocarditis had a positive hybridization signal for HIV nucleic acid

sequences. Among these 36 patients who had myocarditis and a positive hybridization

signal for HIV nucleic acid sequences, 6 (17%) were infected with Coxsackievirus

group B, 2 (6%) were infected with cytomegalovirus, and l (3%) was infected with

Epstein-Barr virus.

Drugs such as zidovudine, doxorubicin and foscarnet sodium have direct

cardiotoxicity. Zidovudine destroys cardiac mitochondrial ultrastructure and inhibits

mitochondrial DNA replication65

DCM is strongly associated with a poor prognosis in HIV infected individuals.

Currie et al57 demonstrated a median survival of 101 days in patients with CD4

40
count<100, as compared with 472 days in patients with normal hearts at comparable

stage of the disease.

Although the association between use of antiretroviral therapy with AZT and the

development of cardiomyopathy has been described, the state of immunodeficiency

played a major role in the development of cardiomyopathy52

Nowadays severe, symptomatic dilated cardiomyopathy, as previously seen in

end-stage AIDS, is declining as the predominant clinical manifestation of HIV

associated cardiomyopathy. Subclinical, diastolic dysfunction and abnormal

ventricular strain patterns are being seen more frequently in HIV-infected individuals

with adequate HIV viral control66

ENDOCARDITIS

Marantic endocarditis or nonbacterial thrombotic endocarditis is ~

characterized by friable, fibrinous clumps of platelet and red blood cells adherent to

the cardiac valves without an inflammatory reaction. It is estimated that this condition

occurs in 3% to 5% of AIDS patients67. It usually occurs in patients older than 50

years. Marantic endocarditis is known to be associated with malignant neoplasms,

hypercoagulable states and chronic wasting disease. Mitral and aortic valves are

commonly involved in HIV negative patients68, but the tricuspid valve is usually

involved in AIDS patients. Systemic emoblism can occur in up to 42% of patients, but

most of these events are clinically silent Embolisation can involve the brain, lung,

spleen, kidney, and coronary arteries. Systemic emoblization from marantic

endocarditis is a rare cause of death in AIDS patients. Before the advent of HAART,

marantic endocarditis was highly prevalent among HIV infected individuals with a

prevalence of 4-10% of autopsy cases of HIV patients; however this is less commonly

encountered in the post HAART era69.

41
 Infective endocarditis in patients with AIDS usually occurs in parenteral drug

users. Human immunodeficiency virus infection may increase the risk of infective

endocarditis among intravenous drug user. The incidence of Infective Endocarditis

(IE) among HIV infected intravenous drug users (IDU) varies from 6.3% to 34%

independent of HAART regimens and it is rare among non-IDU HIV infected

patient70.Nahass et al studied the causes of infective endocarditis in 34 HIV patients,

and they found that Saureus (75%) and Streptococcus viridans (20%) were the major

responsible organisms. Other unusual organisms described as case reports were

Salmonella, A fumigatus, and Pseudallescheria boydii. The triscuspid valve is the

most commonly affected valve. The affected patients usually present with fever,

sweats, weight loss, and coexisting pneumonia and/or meningitis. The presentation

and survival of infective endocarditis in patients with and without HIV infection are

generally different; however, in the late stage of HIV-infected patients, significant

increased mortality from infective endocarditis has been reported compared with

asymptomatic HIV patients. The approach to diagnosis and management of IE is

similar in both HIV and HIV-uninfected individuals.

Pugliese38 et al showed that HAART did not significantly modify the incidence

of mycobacterial pericarditis and staphylococcal endocarditis.

PULMONARY HYPERTENSION

Kim and Factor first described human immunodeficiency virus associated

pulmonary hypertension in 1987. By 1998, 88 patients with HIV infection were

described with this entity. On a global scale, the prevalence of PH in HIV-infected

individuals varies between 0.5 and 5.0% with HIV being recognized as an

independent risk factor for the development of PH71.

42
 HIV-associated pulmonary artery hypertension (HIVPAH) is a distinct clinical

condition, with no overt cause for PAH, other than being infected with HIV. HIV-

PAH is classified, along with idiopathic PAH, under group 1 of the World Health

Organization’s classification72 .

It is more common in male and young patients (mean age, 32 years). The

common risk factors are intravenous drug use, homosexual contacts, and hemophilia.

The major symptom of this condition is dyspnea. There was no correlation between

either a history of opportunistic infections or CD4 cell count and the development of

pulmonary artery systolic pressure was 68 mm Hg. The major causes of death were

right—sided heart failure and respiratory failure. Half of the patients died in 1 year.

Petitpretz73 et a1 performed a prospective study of 20 patients with HIV infection and

pulmonary hypertension who were HIV negative. They found that patients with HIV

infection were younger and had a lesser degree of disabilities. Interestingly, mortality

between these 2 groups was not different. Plexogenic pulmonary arteriopathy was the

most frequent pathologic finding.

The pathogensis of pulmonary hypertension associated with HIV infection is

unclear. Mette et al were unable to demonstrate the presence of HIV in pulmonary

endothelial cells by electron microscopy, immunochemistry, DNA insitu

hybridization, and the polymerase chain reaction technique. This finding supports an

indirect mechanism for HIV associated pulmonary hypertension. Ehrenreich et al

demonstrated that HIV-1 envelope glycoprotein (GP-12) stimulated the production of

the secretion of endothelin 1 (a potent vasoconstrictor) and tumor necrosis factor from

macrophage. Platelet derived growth factor can stimulate smooth muscle cell and

fibroblast proliferation and migration. Humber et al showed that platelet-derived

growth factor expression was increased in patients with HIV-associated pulmonary

43
hypertension. Morse et al found that the incidence of HLA—DR6 and HLA-DR52

was increased in 10 HIV patients with primary pulmonary hypertension compared

with matched control subjects. Human immunodeficiency virus-associated pulmonary

hypertension is a diagnosis of exclusion.

Pulmonary hypertension, associated with HIV/AIDS, differs from idiopathic/

primary pulmonary hypertension in terms of rapidity of progression, is unrelated to

CD4 count and is associated with a worse prognosis compared to non- AIDS

patients74.

Studies have shown no change in incidence of HIV-PH since the advent of

cART. Combination antiretroviral therapy alone without specific treatment for PH

does not result in an improved cardiac function71.

CARDIAC NEOPLASM AND HIV

Two types of malignant neoplasms affecting the heart have been described in

patients with HIV infection: Kaposi sarcoma and malignant lymphoma.

Kaposi Sarcoma

In 1983, Autran et al first described Kaposi sarcoma of the heart in an HIV

patient. The incidence of Kaposi sarcoma involving the heart ranged from 12% to

28% in retrospective autopsy findings. Most (90%) of the autopsies were performed

on homosexual or bisexual patients. Cardiac involvement with Kaposi sarcoma in an

HIV infected patient usually occurs as a part of disseminated Kaposi sarcoma.

Acquired immunodeficiency syndrome related metastatic Kaposi sarcoma involves

either the visceral layer of serous pericardium or the subepicardial fat. There is a

predilection of Kaposi sarcoma to involve the subepicardial adipose tissue adjacent to

a major coronary artery with or without involvement of the adventitia of the

ascending aorta or pulmonary trunk. Pericardial and myocardial involvement has also

44
been reported. Chyu75 et al demonstrated premortem detection of cardiac Kaposi

sarcoma by transthoracic echocardiography, which revealed pericardial tamponade

and a mobile multilobular mass at the apex protruding into the pericardial space.

Clinical cardiac findings are obscure; most of the cases are found at autopsy. Fatal

cardiac tamponade and pericardial constriction have been reported. Vijay et al

reported 5 cases of Kaposi sarcoma of the visceral layer of serous pericardium or

pericardium causing fatal tamponade in the patients with AIDS. Pericardicentesis was

performed, resulting in a transient improvement in Vital signs but with subsequent

deterioration and death within a variable period ranging from 5 hours to a few days.

The diagnosis of pericardial Kaposi sarcoma was delayed until autopsy. All were

noted to have a tense pericardial sac with dark bloody fluid, presumably as a result of

the pericardiocentesis needle penetrating the Kaposi sarcoma lesions.

Pericardiocentesis not only has no diagnostic role but it is also a high risk procedure

in this group of patients. In patients with AIDS in whom the clinician has a high index

of suspicion of Kaposi sarcoma pericardial effusion, a pericardial window should be

the procedure of choice for providing decompression and establishing the pathologic

diagnosis.

Malignant

Lymphoma

In 1985, the Centers for Disease Control and Prevention recognized the linkage

between intermediate and high-grade lymphoma and HIV seropositivity and

included this in the diagnostic criteria for AIDS. Lymphoma is the second most

common tumor that involved the heart. Cardiac involvement with non- Hodgkin

lymphoma; usually derived from B cells, is typically high grade and is often

disseminated early in patients with AIDS. Disseminated cardiac lymphoma is more

45
 common than primary cardiac lymphoma. It has been reported to account for 15% of

all cardiac and peri-cardial metastases in non-AIDS series76. Primary cardiac

lymphoma is extremely rare. Patients may present with intractable congestive heart

failure, pericardial effusion, cardiac arrhythmia, or cardiac tamponade. Patients

usually have non-specific symptoms, but rapid progression of cardiac dysfunction

can occur after these symptoms. The most common gross appearance is nodular or

polypoid masses predominantly involving the pericardium, with variable myocardial

infiltration. Histologically, these are diffuse, aggressive lymphomas, usually of small

noncleaved or immunoblastic types. Patients with mechanical obstruction may

benefit from surgical resection.

The overall prognosis is poor, but HAART therapy has reduced the incidence of

Kaposi sarcoma and HIV-related non-Hodgkin lymphoma.

CORONARY ARTERY DISEASE

Coronary artery disease has been reported in a patient with HIV infection at

autopsy. HIV infection has been associated with an approximately 1 to 2 fold increase

in risk to develop coronary artery disease (CAD) compared to the general

population77. Eccentric atherosclerosis or fibrosis of the tunica media of the coronary

artery was found at autopsy. Sclerohyalinosis of the smaller arteries and myocardial

interstitial fibrotic lesions were also found.

The cause of these lesions is uncertain. Coronary artery disease in HIV-positive

patients may be due to artherogenesis as a result of virus-infected monocytes-

macrophages, possibly through altered adhesion or due to angitis. Recent studies

showed that HIV-infected patients presented with large thrombus burdens than

atherosclerotic plaques suggesting thrombophilia as a possible cause of CAD events78

46
 In a retrospective study of HIV patients with MI, HIV patients who had

undergone coronary angioplasty had a significantly higher rate of restenosis than

HIV-uninfected controls. Mary-Krause et al demonstrated a 3-fold increase in the risk

of MI in HIV-infected individuals compared to HIV-uninfected individuals. They

showed a duration-related effect relationship between use of PI and MI, with a higher

MI incidence rate among men exposed to PI for 18 months or more79

Atherosclerosis and atherothrombosis from dyslipoproteinemia caused by highly

active antiretroviral therapy, especially protease inhibitors, have been reported. The

relationship between anti-retroviral therapy and coronary artery disease is a topic of

much debate and uncertainty. Suffice, to say, the current literature suggests that

HAART therapy decreases cardiovascular risk in the short term, but prolonged use of

HAART therapy, especially protease inhibitors has been shown to be associated with

increased risk of CAD/ MI80.

DRUG-INDUCED CARDIOTOXICITY

Patients with HIV are exposed to many medications to treat conditions related to

HIV diseases, such as cancer and opportunistic infections. Some of these medications

may have cardiovascular toxicities. Dilated cadiomyopathy has been reported in a

young male patient treated with amphotericin B. In this patient, cardiac function

returned to normal after the medication had been discontinued for 6 months.

Bradycardia was described in children treated with amphotericin B. The incidence

was 6.7% in the patients who received amphotericin B and usually occurred between

day 3 and day 7 after the start of therapy. Doxorubicin cardiomyopathy has been well

described and occurred with a total dose of 400 mg/m2 or more. The prevalence of

hypertension associated with erythropoietin therapy is 47%, and the mechanism of

47
this adverse effect may be related to an increase in hematocrit and blood` viscosity.

Reversible cardiomyopathy has been described in HIV patients treated with foscarnet

sodium for cytomegalvorius esophagitis.

Cohen et al described 2 patients who developed ventricular tachycardia during an

intravenous infusion of ganciclovir.

Sonnenblick and Rosin81 reviewed 44 cases of interferon – induced cardiotoxicity.

Arrhythmia was the most common manifestation of cardiotoxicity (25 patients). Other

cardiotoxicities included myocardial infarction or ischemia (9 patients),

cardiomyopathy (5 patients), sudden death (2 patients), AV block (2 patients) and

congestive heart failure (I patient). Cardiac adverse effects from interferon were not

associated with the dosage or the duration of treatment. Cardiac dysfunction has been

found in adults or children treated with zidovudine. Zidovudine inhibits retroviral

replication and interferes with the action of reverse transciptase of HIV. Diffuse

destruction of cardiac mitochondrial ultrastructures and inhibition of mitochondrial

DNA replication may be responsible for zidovudine-induced cardiomyopathy.

Many drugs used during the treatment of HIV and associated opportunistic

infections can also prolong QTc (Atazanavir, IV Pentamidine, Trimethoprim-

Sulfamethoxazole, antifungals like Ketoconazole are a few). Hence, it is prudent to

closely monitor patients with HIV infection for QTc prolongation and development of

related life threatening arrhythmias like Torsades de Pointes82.

Other Cardic Manifestations

ANEURYSMAL DISEASE

Patients with HIV/AIDS are more predisposed to aneurysmal disease, especially

that of the aortic and cerebral blood vessels; at a higher incidence than the general

population. It is characterized by occlusion of the vasa vasorum by an inflammatory

48
cell infiltrate, leading to weakening of the vessel wall and aneurysm formation.
79
Aneurysms can be due to vasculitis, either by the HIV virus itself or secondary

infections with CMV or tuberculosis . The aneurysms are usually atypical and

multiple when caused by the HIV virus itself.

SUDDEN CARDIAC DEATH.

Even though most HIV infected patients die from AIDS-related disease, sudden

cardiac death (SCD) is a significant contributor to HIV-related mortality . During a

median follow-up of 3.7 years in a single center, 13% of all deaths in 2,860 HIV-

infected patients met criteria for SCD, which is 4-fold higher than expected for the

general population . Importantly, no relationship between CD4 cell count or viral load

levels and SCD were found, suggesting that the entire HIV population is at increased

risk of SCD, regardless of cART or immune status83 .

ATRIAL FIBRILLATION.

In a registry of 30,533 HIV-infected patients, 780 (2.6%) developed atrial

fibrillation (AF) over a 15-year period84 . A lower CD4 cell count and higher viral

load were independently associated with the risk of incident AF. The pathogenesis of

AF in HIV-positive patients may be related to inflammation.

Cardiovascular monitoring in HIV-positive patients

Routine physical examination is not as reliable way of diagnosing

cardiovascular problems in HIV-infected patients as in uninfected patients.

Breathlessness, effort intolerance, fluid retention, hepatomegaly, and poor survival

can be clinical characteristics of heart failure in HIV-associated complications.

Evidence supports the usefulness of a number of different monitoring modalities in

HIV-positive patients. Some modalities (such as echocardiographic monitoring) may

be appropriate for all HIV-positive patients, whereas others (such as

49
electrocardiography) are probably useful only for a selected group. Screening and

monitoring are essential for detecting early disease and for targeting patients who

require early intervention and aggressive early antiretroviral therapy.

Echocardiographic monitoring

Serial echocardiography is useful for following HIV- infected patients over

time. It can clearly identify three conditions that are common among HIVinfected

adults and that are associated with poor outcomes: pericardial effusions, valvular heart

disease, and often endocarditis. Transesophageal echocardiography is more sensitive

for detecting endocarditis than is conventional transthoracic echocardiography.

Echocardiography can also provide clear images of thrombi and masses within

the myocardium, including sarcoma and lymphoma both of which have been

identified in the hearts of HIV-infected patients. Clinicians can then initiate

preventive strategies against pulmonary emboli or stroke or treatments for

malignancy.

Echocardiography can provide information about pulmonary hypertension,

which can focus attention on pulmonary interstitial disease or chronic upper airway

obstruction, both of which are more common in this population than in healthy

people. Early treatment can reduce the chance of developing cor pulmonale. Regional

wall motion abnormalities may be helpful in identifying dyskinetic segments

secondary to ischemia or infarction. Echocardiography has been especially helpful at

identifying left ventricular systolic dysfunction and inappropriately increased left

ventricular hypertrophy.

In previous multivariable analyses, Steven E. Lipshultz85 reported that the

development of either of these abnormalities in-an HIV-infected infant or child is an

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independent predictor of all-cause mortality, even when wasting, encephalopathy,

CD4 cell count, HIV viral load, and other risk factors are taken into account. Steven

E. Lipshultz found that both of these abnormalities when identified on

echocardiography predict patients at higher risk of mortality –more than 1 year before

it occurs, which should allow ample time for preventive or therapeutic strategies to be

initiated. Some studies have defined left ventricular systolic dysfunction as a left

ventricular ejection fraction below 40%. This can be symptomatic or asymptomatic.

Diastolic heart failure is difficult to diagnose but usually includes clinical heart failure

in the setting of normal or mildly abnormal left ventricular systolic function and

evidence of abnormal left ventricular relaxation, filling, diastolic distensibility, or

diastolic stiffness.

Steven E. Lipshultz found that left ventricular diastolic dysfunction is

common in HIV-infected children. The clinical significance of this dysfunction in

these patients is not entirely clear, but in other patient groups diastolic dysfunction is

a primary or contributing cause of 30-60% of cases of congestive heart failure. The

mechanisms regulating myocyte active relaxation, passive elasticity and stiffness, and

early and late diastolic ventricular filling (e.g., increased left ventricular wall

thickness and fibrosis or myocardial ischemia) in HIV- infected patients have not

been well studied. However, abnormalities of these basic mechanisms relate to the

clinical diastolic dysfunction syndrome. The most common causes are hypertension

and coronary heart disease (CHD); cardiomyopathies and pericardial disease may also

cause diastolic dysfunction and diastolic heart failure. The diagnosis of left ventricular

diastolic dysfunction is made when cardiac catheterization or echo-Doppler data

indicate an abnormality in the diastolic properties of the ventricle; the ejection

fraction may be normal or abnormal and the patient may or may not have symptoms.

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Thus, diastolic dysfunction may be present in asymptomatic patients with

hypertensive heart disease .as well as in symptomatic patients with heart failure and a

low ejection fraction. By contrast, the term diastolic heart failure, refers to patients

who have congestive heart failure or pulmonary edema in the presence of a normal

ejection fraction; diastolic dysfunction is virtually always present in such patients.

Recommendations for use of echocardiography

Steven.E. Lipshultz recommends serial echocardiography in HIV-infected

patients who do not have evidence of cardiac involvement. Cardiac abnormalities are

common and, without echocardiography, health-care providers often cannot

differentiate cardiac from non-cardiac causes of symptoms. Echocardiography can

identify patients at high risk for all-cause mortality, and these patients can be targeted

for a more aggressive evaluation and preventive treatments.

Recommended schedule for echocardiography

On the basis of data from the pre-highly active antiretroviral therapy

(HAART) era, Steven E. Lipshultz recommends a baseline echocardiographic

evaluation at the time of diagnosis of HIV. Asymptomatic patients should then have a

follow-up echocardiogram every 1-2 years. Patients with symptomatic HIV infection

without cardiovascular abnormalities should have annual echocardiographic follow-

up. When echocardiography identifies cardiovascular abnormalities, a cardiologist

should guide the follow-'up

Electrocardiography and Holter monitoring

Conditions detectable by electrocardiography are common among

HIVinfected patients, and such studies may be helpful in high-risk patients.

Abnormalities of intraventricular conduction and rhythm appear to be more common

in HIV-infected individuals than in the general population. Autonomic dysfunction is

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also very common in this population. Sinus tachycardia is frequently found in HIV-

infected patients, and some studies suggest that the degree of abnormality affects the

patient's outcome. In addition, many medications given to HIV-infected patients may

result in QT prolongation, and electro-cardiography algorithms addressing the

baseline QTc interval and change in the QTc interval with medications have been

proposed to reduce the risk of developing pentamidine-associated torsades de pointes.

Routine electrocardiography or Holter monitoring of HIV-infected patients may not

be indicated. However, it may be useful for HIV-infected patients with palpitations,

syncope, near-syncope, unexplained stroke, or known autonomic dysfunction, and for

those who are starting or receiving medications known to be arrhythmogenic or to

affect repolarization.

Stress testing

Cardiopulmonary exercise testing may be helpful for HIV-infected patients.

Stress testing may be helpful to screen for ischemia on exertion. Non-invasive stress

testing with dobutamine challenge can also be performed to detect focal ischemia,

myocyte viability and residual ischemia

Ultrafast electron beam computerized tomography

Ultrafast electron beam computerized tomography (EBCT) scans 3-mm

Sections of the coronary arteries to detect calcium accumulation, which correlates

strongly with the severity of coronary atherosclerosis. This non-invasive test is used

to calculate a coronary calcium score; these scores have about 90% Sensitivity for

detecting. Early CHD and nearly 100% sensitivity for advanced disease.

Other tests of subclinical atherosclerosis

Early atherosclerosis involves the endothelium of many arteries, and Information

about peripheral arterial anatomy and function might be pertinent to the coronary

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circulation. Such information can be derived from vascular imaging studies such as

studies of brachial artery reactivity and carotid intima medial thickness, or from the

ankle-brachial blood pressure index. Recent reviews of works in adults without HIV

infection have concluded that flow-mediated dilation is abnormal in atherosclerotic

vessels, and that abnormal dilation is associated with cardiovascular risk factors and

may be a marker of preclinical disease. Treating atherosclerotic risk factors improves

flow mediated dilation, and some data suggest that vascular responsiveness is related

to outcome. In these non-HIV-infected patients, carotid intima medial thickness is

associated with cardiovascular risk factors, and increased levels can predict

myocardial infarction and stroke. Aggressive risk factor management can decrease

intima medial thickness. The reviews concluded that brachial artery reactivity and

carotid intima medial thickness are functional and structural markers of the

atherosclerotic process.

Intravascular ultrasound can provide detailed images of the artery and assess the

volume, content, and vulnerability of coronary plaques. Intravascular ultrasound has

demonstrated that coronary atherosclerosis begins at a young age and that lesions are

present in one of six teenagers. Thus, this technique offers the sensitivity to detect

coronary changes in young HIV-infected patients. However, the relationship between

plaque volume and cardiovascular events has not yet been established, and invasive

studies for coronary artery disease are risky- in HIV-infected patients.

Nuclear cardiology

Indium-111-antimyosin antibody scanning may be useful for detecting

myocarditis in HIV-infected patients and for distinguishing acute coronary syndromes

from myocardities in patients with clinical symptoms. Perfusion studies at rest or with

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exercise may help diagnose coronary artery disease in HIV infected patients on

HAART.

Catheterization and biopsy

For HIV-infected patients with congestive heart failure of unclear etiology

that has not responded to 2 weeks of anticongestive therapy, cardiac catheterization

with endomyocardial biopsy may be indicated.

Pericardiocentesis

Pericardiocentesis in an HIV-infected patient with a pericardial effusion leads

to a diagnosis in about 50% of cases and may be useful diagnostically as well as

therapeutically. Patients with pericardial effusion without tamponade should be

evaluated for treatable opportunistic infections such as tuberculosis and malignancy.

HAART should be initiated if it has not yet been. Repeat echocardiography is

recommended after I month, or sooner if clinical symptoms of tamponade develop in

the interim.

Tests for treatable nutritional and biochemical causes of heart failure

Deficiencies of micronutrients including selenium and carnitine are reversible

causes of cardiomyopathy and should be considered in HlV-infected patients with left

ventricular dysfunction.

Serum and plasma markers of myocadial injury and left ventricular dysfunction

Serum cardiac troponin T

For a patient with left ventricular dysfunction, serum cardiac troponin T (cTnT),

a biomarker of active myocardial injury, may help identify myocarditis, unstable

angina, or acute myocardial infarction. This may lead to additional testing such as

endomyocardial biopsy for histology and viral polymerase chain reaction panel

studies for suspected myocarditis, and stress, viability, and angiographic studies for

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suspected acute coronary syndromes. In some series, myocarditis was found in the

majority of HIV-infected adults. Persistently elevated cTnT levels, a marker of

ongoing myocycte damage and degeneration, in dilated cardiomyopathy predict poor

outcome, just as elevated cTnT levels are associated with higher risk in patients with

chest pain or acute coronary syndromes. These cTnT elevations may be useful in

monitoring response to therapy. Troponin T is a reliable measure in heart failure but

reproducibility data are lacking

Plasma brain natriuretic peptides

The natriuretic peptides are a family of three related forms: atrial natriuretic

peptide is a 28-amino-acid peptide found in the atrium; the B- type natriuretic peptide

is a 32-amino-acid peptide found mainly in the ventricles of the heart; and the C-type

natriuertic peptides are 53-amino-acid and 22-amino-acid peptides found in the

endothelium. A BNP cut-off of 480 pg/ml identified one –third of the patients who

had a heart failure-related death and 53% of those who developed atleast one of the

heart failure outcomes. This cut-off point had an accuracy of 85.5% and a of 91.4%

in predicting a heart failure outcome using BNP levels in patients presenting with

symptoms of heart failure should proved to be cost- effective. A missed diagnosis of

heart failure in the setting of an increased BNP predisposed patients to a 15-fold

increase in adverse outcomes. BNP complements echocardiography but may

eventually replace it as the test of choice in the differential diagnosis of dyspnea.

However, the role of natriuretic peptide measurements in the evaluation of patients

with or at risk for heart failure is unclear but promising. Although BNP

measurements are rapid and less expensive than other diagnostic modalities, it still

remains unclear whether BNP determination offers differential or incremental benefit

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over simple diagnostic methods or physical examination. Plasma BNP after

myocardial infarction is useful in predicting left ventricular dilation 6 months later.

General inflammatory markers

These include general inflammatory markers that are potential biochemical

surrogates, such as hsCRP, serum amyloid A, and fibrinogen. C reactive protein is an

acute phase protein produced by the liver in response to inflammation is considered to

be an etiologic factor in cardiovascular events such as myocardial infarction and

stroke.

Cytokines

Cytokines released from macrophages are considered probable promoters of

inflamation because increases are associated with a general inflammatory response.

Cytokies including tissue necrosis factor (TNF a) TNF a receptor, and IL-6 have also

been studied as potential inflammatory biochemical surrogates.

Lipid profiles for preventive cardiology

Long-term therapies with protease inhibitors and HAART, although effective

in prolonging life and disease-free survival, have deleterious effects on cardiovascular

health. The mechanism of HAART-associated premature atherosclerosis is unclear, as

is its incidence and severity. Lipid prpfiles and other blood tests for preventive

cardiology should be routine before and during HAART therapy. A number of

biochemical surrogates have been targeted. Before HAART is started, lipid profiles

should be measured after an 8-12 h fast to establish a baseline, and the measurements

should be repeated routinely during the HAART therapy. Serum glucose and

hemoglobin AIC measurements are especially indicated for patients on HAART.

Fasting lipids and glucose should be measured before the initiation of protease

inhibitors and at regular 3-6 month intervals thereafter. For patients with elevated

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triglyceride levels at baseline, lipid measurements should be repeated within 1-2

months of stating HAART. If fasting triglyceride levels are above 400 mg/dl, then the

calculated LDL cholesterol level will be unreliable.

LDL cholesterol is currently the primary therapeutic target for cardiovascular disease,

but other lipoproteins [HDL, apolipoprotein B, and lipoprotein (a)] may also be useful

for stratifying non-HIV-infected patients by risk for cardiovascular disease. Other

potential biochemical lipid surrogates include triglycerides, HDL subfractions

(HDL2C/HDL3C), LDL fractions (small, dense/pattern B), remnant particles,

apolipoprotein Al, lipoprotein Al particles, apolipoprotein CIII, and lipoprotein CIII:

Non-B (HDL apohpoprotein CIII). Nuclear magnetic resonance spectroscopy can

identify small, dense LDL particles that are important predictors of the risk of

ischemic heart disease. Other potential biochemical surrogates of CHD, as already

discussed, include lipid/apolipoprotein, procoagulant/fibrinolytic substances,

inflammatory molecules, adhesion molecules, and lesion lytic enzymes. Elevated

plasma homocysteine levels are caused by genetic variants, malnutrition, drugs or

renal failure, among other causes, and are risk factors for atherosclerosis, especially

when above 10 mol/L, and can be treated with dietary supplementation of folic acid,

vitamin B6, and vitamin Bl2.

Traditional cardiovascular risk profiling

As with any patient, long-term cardiovascular risk factors must be addressed.

Clinicians should identify risk factors such as a history of tobacco use, a family

history of premature atherosclerosis, poor diet, high alcohol intake, lack of physical

exercise, older age, diabetes, dyslipidemia, hypertriglyceridemia, hypertension,

menopausal status, cocaine use, and heroin use. Other important risk factors are a

family or patient history of hypothyroidism, renal disease, liver disease, or

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hypogonadism. A strong, angry temperament, rather than anger in reaction to unfair

treatment, places middle-aged persons at risk for CHD events with a risk similar to

hypertension.

The global risk profile for coronary artery disease is based on seven factors

identified from the Framingham study: age, sex, systolic or diastolic blood pressure,

HDL cholesterol, total cholesterol, cigarette smoking, and diabetes. Commercially

available, evidence-based programs are available to calculate risk for coronary artery

disease, type II diabetes and stroke from the patient's clinical signs and symptoms,

results of laboratory tests, and family history. Although these products use only

conventional risk factors, they may still be of use for HIV-positive patients.

Screening for Hypertention

Routine assessment of blood pressure in HIV-infected patients is important

because these patients seem to be at higher risk of developing hypertension, and of

developing it at a young age than the general population. Predisposing conditions

include such, for example, vasculitis, acquired glucocorticoid resistance, acute and

chronic renal failure, atherosclerosis, and drug interactions (e.g. the interaction

between indinavir and stavudine-phenylproanolamine). The true prevalence of

hypertension in HIV-infected patients is unknown. Echocardiography is useful in

assessing for increased left ventricular mass in patients with systemic hypertension or

to assess right ventricular pressure in a patient with suspected pulmonary

hypertension.

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METHODOLOGY

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