Navin presentation for hiv disease

CARDIAC MANIFESTATIONS OF HIV DISEASE

DR.NAVIN AGRAWAL

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.

Acquired Immunodeficiency Syndrome (AIDS)

History 1950s: Blood samples from Africa have

HIV 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.

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.

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.

Mildly symptomatic Disease (CDC category B) Median interval from infection to development of

symptoms is 10 yearsHIV 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

AIDS (CDC category C) (CD4 < 200/cmm or one of the following) Esophageal or tracheobronchial candidiasis CMV retinitis CMV disease (other than liver, spleen or lymph nodes) Pulmonary or extrapulmonary TB, recurrent pneumonia Mycobacterium avium complex, M. kansasii, other

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

At the end of 2002, the Joint United Nations Programme on 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.

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-α-myosin Ab, cytokines

Cardiomyopathy and endothelial dysfunction

Nutritional deficiencies (carnitine, Se, thiamine)

Cardiomyopathy

Drug toxicity (HAART, antifungals, antivirals)

Cardiomyopathy, conduction disorders, glucose intolerance, CAD, CVA

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)

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

PCR test:Qualitative plasma HIV DNA PCR used when non antibody dependent test is necessory. Sensitivity 97-98 %, specificity 98%

Not useful for screening, 2-9% of false positives (viral loads <10000c/ml)

Rapid testsOraQuick Rapid HIV I test Reveal rapid Antibody testUniGold Recombigen HIV testresults available in 20- 30 minssensitivity and specificity >99%

Negative result considered definitive –ve unless tested in window period

+ve results should be confirmed with WB or IFA

Guidelines for monitoring cardiac dysfunction in patients with HIV Asymptomatic or symptomatic cardiovascular disease 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.

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.

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.

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

Inflammation, oxidant stress, & endothelial dysfunction are central to the pathogenesis of atherosclerosis/CVD Deakin S et al. Atheroscler Thromb Vasc Biol 2007; 27: 1390-5

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

SMARTEl-Sadr NEJM 2006

Emery S, et al. J Infect Dis. 2008;197:1133-1144.

Deferred ArmIntermittent ART

(n = 2720; 228 not receiving ART at trial start)

Immediate ArmContinuous ART

(n = 2752; 249 not receivingART at trial start)

Study halted prematurely;

mean follow-up:18 mos

HIV-infected patientswith CD4+ cell count

> 350 cells/mm3

(N = 5472)

In short term ARV prevents artherosclerosis

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

Plasma LPS in HIV Infected Patients (Hunt 2008)

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)

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

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)

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

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

Prevalence of Congenital Cardiovascular Malformations in Childrenof 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)

DRUGS

NRTIs – Zidovudine has been associated with mitochondrial 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.

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

DRUGS

Ganciclovir – VT, hypotension Foscarnet – reversible cardiac failure Pentamidine – QT prolongation, torsades, hyperglycemia

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.

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,

Atazanavir Fusion inhibitor - Enfuviritide

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.