HIV disease and its cardiovascular manifestations:-diagnosis

1. CARDIAC MANIFESTATIONS
OF HIV DISEASE
DR.NAVIN AGRAWAL

3. AIDS (Acquired Immunodeficiency Syndrome) was 1st
described in 1981
It is a chronic infection caused by HIV 1 & 2
It continuously replicates leading to progressive dysfunction
and gradual depletion of CD4 + lymphocytes. ( can also
infect macrophages and B lymphocytes)
The total no infected HIV/ AIDS globally as of Dec 2000, 58
million, of whom 21.8 million died since beginning of the
epidemic.

4. Acquired Immunodeficiency
Syndrome (AIDS)
History
 1950s: Blood samples from Africa have HIV
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antibodies.
1976: First known AIDS patient died.
1980: First human retrovirus isolated (HTLV-1).
1981: First reports of “Acquired Immuno-deficiency
Syndrome” in Los Angeles.
1983: Virus first isolated in France (LAV).
1984: Virus isolated in the U.S. (called HTLV-III and
AIDS-Related Virus, ARV).
1985: Development and implementation of antibody
test to screen blood donors.

5. Acquired Immunodeficiency
Syndrome (AIDS)
History (Continued)
 1986: Consensus name Human Immunodeficiency
Virus (HIV-1).
Related virus (HIV-2) identified.
 1992: AIDS becomes the leading cause of death
among adults ages 25-44 in the U.S.
 1997: Mortality rates of AIDS starts to decline due to
the introduction of new drug cocktails.
 2001: World Health Organization predicts up to 40
million infected individuals. More than 22 million
have already died.

7. Asymptomatic infection (CDC
Category A)
 Viral replication takes place in lymphoid tissue.
 Sustained viremia with steady decline in CD4
count (50-150 cells/year).
 Persistent generalized lymphadenopathy, but
the patient remains well.

8. Mildly symptomatic Disease
(CDC category B)
 Median interval from infection to development of symptoms is 10
years
HIV infection and one of the following:
 Bacillary angiomatosis
 Candidiasis, oropharyngeal, vulvovaginal; persistent or poorly
responsive to therapy
 Cervical dysplasia/CIN
 Fever>38.5 C, diarrhoea > 1m
 Oral hairy leukoplakia
 Herpes zoster involving more than one dermatome or 2 distinct
episodes
 ITP
 Listeriosis
 PID, particularly if complicated by tuboovarian abscess
 Peripheral neuropathy

9. AIDS (CDC category C) (CD4 <
200/cmm or one of the
 Esophageal or tracheobronchial candidiasis
following)
 CMV retinitis
 CMV disease (other than liver, spleen or lymph nodes)
 Pulmonary or extrapulmonary TB, recurrent pneumonia
 Mycobacterium avium complex, M. kansasii, other
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species, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, intestinal (>1m duration)
Toxoplasmosis of brain
Kaposi’s sarcoma
Burkitt’s lymphoma
Primary CNS lymphoma, HIV-associated encephalopathy
Wasting syndrome

10.  At the end of 2002, the Joint United Nations Programme on
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HIV/AIDS estimated that worldwide, more than 40 million adults and
children were living with HIV/AIDS.
In India, 2.4 million adults live with the virus. Overall prevalence –
0.3%.
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(40%)
In the late 1980s, cardiac abnormalities were detected more often
on ECHO (25%) than would be expected from clinical symptoms and
physical examination (<10%).
Prevalence of cardiac manifestations: 28-73%.
Death due to HIV related cardiac disease <2%.
In HIV – infected children <10 y of age, 25% die with chronic cardiac
disease and 28% experience serious cardiac events after an AIDS–
defining illness.

11. Potential mechanisms of cardiac
complications in AIDS
Mechanism
Effect
Direct infection of cardiac
myocytes
Cardiomyopathy/myocarditis
Toxicity of HIV
components
Impaired myocardial
contractility
Immune processes
involving MHC I, anti-αmyosin Ab, cytokines
Cardiomyopathy and
endothelial dysfunction
Nutritional deficiencies
(carnitine, Se, thiamine)
Cardiomyopathy
Drug toxicity (HAART,
antifungals, antivirals)
Cardiomyopathy, conduction
disorders, glucose intolerance,
CAD, CVA

19. Laboratory findings in HIV
ELISA – screening test, sensitivity >99.9%
Western blot – confirmatory test (P24 ++ gp120/160 or gp41 +gp120/160)
to avoid false positives, all repeatedly +ve EIA results must be confirmed
with WB
Specificity when combined with ELISA >99.99%
Indeterminate result – early HIV inf, HIV- 2, auto immune
disease, pregnancy, recent TT administration
False +ve tests – 0.0004 – 0.0007% due to technical errors, HIV vaccines
(Arch Intern Med 2003, 163, 1857)
False –ve tests –
high prevalence population (seroprevalence>30%)- 0.3% (JID 1993, 168; 327)
low prevalence populatiion 0.001% (NEJM;1991; 325;1;593)
during time between transmission and
seroconversion, agammaglobulinemia, antigenically distinct strain infection
(Subtype O / N HIV- I)

21. CBP: anemia, neutropenia, thrombocytopenia
Absolute CD4 count:
CD4 lymphocyte %: more reliable than counts
HIV viral loads: Best test available for diagnosis of acute
HIV inf, progression and response to ART. <500c/ml false
+ve

22. PCR test:
Qualitative plasma HIV DNA PCR used when non
antibody dependent test is necessory. Sensitivity 9798 %, specificity 98%
Not useful for screening, 2-9% of false positives (viral
loads <10000c/ml)
Rapid tests
OraQuick Rapid HIV I test
Reveal rapid Antibody test
UniGold Recombigen HIV test
results available in 20- 30 mins
sensitivity and specificity >99%
Negative result considered definitive –ve unless tested
in window period
+ve results should be confirmed with WB or IFA

30. Guidelines for monitoring cardiac
dysfunction in patients with HIV
 Asymptomatic or symptomatic cardiovascular disease
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with normal initial ECHO – repeat ECHO every 1-2 years
if asymptomatic.
Initial ECHO is abnormal – Rx of CCF if systolic
dysfunction, investigate and manage pericardial
effusion, consider HAART, specific management for mass
or vegetation.
LV systolic dysfunction in clinically stable patients –
repeat ECHO after 2 weeks.
If repeat ECHO at 2 weeks shows improvement and
patient continues to improve clinically – yearly ECHO.
Persistent or worsened systolic function – consider
endomyocardial biopsy, CAG, immunomodulatory
therapy.

31. ENDOCARDITIS
 Prevalence of 6.4% – 34%, independent of HAART
regimen.
 Overall incidence of IE is same as in HIV negative
patients with increased risk in IV drug abusers.
 May be less likely to sustain valvular damage due to
impaired immune response.
 S. aureus (>75%), Salmonella spp., Str.
pneumoniae, Hemophilus influenzae, Candida
albicans, Aspergillus fumigatus and Cryptococcus may be
responsible.

32.  Mobile mass, variable size localised on the
auricular surface of the auriculo-ventricular
valves or ventricular surfaces of semilunar
valves. Valve abscess and rupture are
common.
 Clinical features and management are as in
HIV negative patients.

33.  Potent antiretroviral therapy (ART)
dramatically improves morbidity & mortality
from HIV infection
 ART may increase cardiovascular disease
(CVD) risk
Friis-Moller N et al. NEJM 2003; 349: 1993-2003
DAD Study Group. NEJM 2007; 356: 1723-35
 Traditional Framingham prediction may
underestimate CVD risk in HIV infected
patients on ART
Law MG et al. HIV Med 2006; 7: 218-30
De Socio GV et al. J Infect 2008; 57: 33-40

34.  Inflammation, oxidant stress, & endothelial
dysfunction are central to the pathogenesis of
atherosclerosis/CVD
1390-5
Deakin S et al. Atheroscler Thromb Vasc Biol 2007; 27:
 HIV-infection &/or ART may influence these
factors
 hsCRP correlates with CVD outcomes in the
general population; limited data in HIV infection
Pearson TA et al. Circulation 2003; 107: 499-511
 A urinary marker (isoprostane) of oxidant stress
correlated with traditional CVD risk factors
Wang B et al. Atherosclerosis 2006; 184: 425-30
Basarici I et al. Coron Artery Dis 2007; 18: 615-20
 Vascular reactivity appears impaired in HIV
infection
Torriani F et al. 4th IAS Conference 2007. Abstr WEAB302
Solages A et al. Clin Infect Dis 2006; 42: 1325-32

53. SMART
El-Sadr NEJM 2006
HIV-infected patients
with CD4+ cell count
> 350 cells/mm3
(N = 5472)
Deferred Arm
Intermittent ART
(n = 2720; 228 not receiving
ART at trial start)
Immediate Arm
Continuous ART
(n = 2752; 249 not receiving
ART at trial start)
Study halted
prematurely;
mean follow-up:
18 mos
In short term ARV prevents
artherosclerosis
Emery S, et al. J Infect Dis. 2008;197:1133-1144.

57. Carotid IMT in HIV infected and
uninfected individuals (Hsue AIDS 2009)

58. Plasma LPS in HIV
Infected Patients
(Hunt 2008)

59. The Gut and Inflammation
 ART fails to completely restore normal health
in HIV infected patients
 Persistent immune activation may drive CVD
risk
 Microbial translocation and Th17 depletion
causing persistent immune activation
 Role of Th17 and Treg imbalance in
pathogenesis of arthrosclerosis
(Siliciano 2007,Cheng Clin Imm 2009,Xie Cytokine 2010)

60. Carotid IMT is Increased in HIV
Elite Controllers ( Hsue AIDS 2009)

61. Role of CRP and CVD Risk in HIV
(Hasson NEJM 2005)
 hsCRP elevated in HIV and associated
 Mortality
 RR of MI
 Elevated D-Dimer, not CRP is associated with
CV events in HIV patients
 Fibrinogen is independent predictor of
mortality in HIV infected individuals
 hsCRP,IL-6,D-Dimer and cystatin C are
elevated even after ART (Neuhaus JID 2010)

63. Effects of Individual ART on Lipids
(Hills HIV Clin Trials 2009)

70. Treatment of Hyperlipidemia in HIV Infected Patients
(Ho Circulation 2009)

78. Prevalence of Congenital Cardiovascular Malformations in Children
of Human Immunodeficiency Virus-Infected Women
 There was no statistically significant difference in
congenital cardiovascular alformation prevalence in
HIV infected versus HIV-uninfected children born to
HIV-infected women.
 With the use of early screening
echocardiography, rates of congenital cardiovascular
malformations in both the HIV-infected (8.9%) and
HIV-uninfected children (5.6%) were five- to ten-fold
higher than rates reported in population-based
epidemiologic studies but not higher than in normal
populations similarly screened.
 Potentially important subclinical congenital
cardiovascular malformations were detected.
(J Am Coll Cardiol 1998;32:1749 –55)

79. DRUGS
 NRTIs – Zidovudine has been associated with mitochondrial
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abnormalities and can lead to myocarditis, skeletal muscle myopathy,
lactic acidosis, hypotension.
NNRTIs – altered mitochondrial DNA replication. Delavirdine
increases toxicity of antiarrhythmics and CCBs.
Protease inhibitors – implicated in premature CAD, dyslipidemia,
insulin resistance, fat redistribution.
Ritonavir – most potent CYP3A activator and P-glycoprotein
inhibitor; most likely to interact.
Indinavir, amprenavir, nelfinavir – intermediate probability
Saquinavir – lowest probability to interact
Cautious use with other drugs metabolized through this pathway –
simvastatin, cisapride, antihistamines, sildenafil, antiarrhythmics like
amiodarone, lidocaine, quinidine.
Ritonavir and nelfinavir induce glucuronidation – lessen efficacy of
fibrates.

80. DRUGS
 Rifampin – reduces therapeutic effect of digoxin by
inducing intestinal P-glycoprotein, reduces protease
inhibitor concentration and effect.
 Erythromycin – torsades, orthostatic hypotension, VT
 Trimethoprim-sulfamethoxazole – increases warfarin
effects, QT prolongation, hypokalemia, torsades

81. DRUGS
 Ganciclovir – VT, hypotension
 Foscarnet – reversible cardiac failure
 Pentamidine – QT prolongation, torsades, hyperglycemia
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and hypoglycemia, hypomagnesemia and SCD.
Vincristine and doxorubicin – can decrease Digoxin
levels, associated with MI, autonomic neuropathy
Human IFN-α ACS, hypotension, hypertension, DCM, arrhythmias, AV
block
IL-2 – capillary
leak, hypotension, arrhythmias, MI, SCD, thyroid
alterations
Corticosteroids –
hyperglycemia, HTN, cardiomyopathy, increase gastric
ulceration in combination with salicylates.

82. HIV treatment
 Antiretroviral treatment is recommended for all patients with
symptomatic HIV disease and for asymptomatic patients with
<250 CD4 cells/µL, acute HIV syndrome and with >50,000
copies/ml of HIV RNA.
 HAART consists of 4 broad classes, nucleoside inhibitors
(NRTI), non-nucleoside inhibitors (NNRTI), protease
inhibitors (PI) and fusion inhibitors.
 NRTIs –
Ziduvudine, Lamivudine, Stavudine, DDI, DDC, Abacavir, Emtricitabine
 NNRTIs – Nevirapine, Delavirdine, Efavirenz
 PIs –
Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir, Lopinavir, Ataza
navir
 Fusion inhibitor - Enfuviritide

83. Postexposure prophylaxis
 Risk of HIV infection following percutaneous
exposure to HIV contaminated blood is 0.3%,
and after a mucous membrane exposure,
0.09%.
 Following universal precautions.
 Cleansing of wound and application of
antiseptic immediately.
 2 NRTIs for 4 weeks or 2 NRTIs plus a third
drug for 4 weeks are usually used.