HIV / AIDS: THE HEART OF THE MATTER

David Jankelow

Sir William Osler Professor, McGill University,

Professor of Medicine, Johns Hopkins University, Baltimore, Regius Professor of Medicine, Oxford University

“to know syphilis is to know all of medicine, because of the multisystem involvement and variable manifestations of the disease”

• HIV - protean disease of the era

• diverse manifestations & susceptibility to infection

2010: +34 million living with HIV worldwide; up 17% from 2001

Sub-Saharan Africa (12% global population); most affected region; with 68% of all living with HIV Pandemic severe in RSA; 5.6 million affected! “Represents the heart of darkness for any physician”, given the overwhelming implications in terms of mortality, morbidity & resources

• more effective Rx’s - longer survival, new complications of late-stage infection; HIV-heart disease

• growing group with acquired HD –

tremendous global impact

• % develop clinically apparent disease relatively small; burden substantial in view of exceptionally high prevalence of HIV in Africa

• require cardiac Dx & Rx resources; screening to detect cardiac abnormalities early & base Rx on these findings

PresenterPresentation Notespercentage of people living with HIV who develop clinically apparent cardiomyopathy is relatively small, the disease burden could be substantial in the face of the exceptionally high prevalence of HIV infection in sub-Saharan Africa.2

As more effective therapies have produced longer survival times for human immunodeficiency virus (HIV)-infected patients, new complications of late-stage infection have emerged and this includes HIV-related heart disease

Such patients represent one of the fastest growing groups with acquired heart disease and this will have a tremendous global impact

It ha been estimate that 60 to 70 million adults will be infected by the year 2000

Screening will detect early cardiac abnormalities, and treatment based on these findings may be helpful

The heart is now key for the prognosis of HIV/AIDS pt’s in developed countries, where cardiovascular disease is the most common cause of death, toppling even AIDS itself.

• mechanisms: direct

myocardial & coronary HIV infection, autoimmune responses; adverse risk factor profile

• cardiac disease usually overshadowed by manifestations in other organs systems

• involvement at autopsy exceeds number with significant heart disease during life

PresenterPresentation Noteseveral factors and mechanisms have been shown and suggested�to be involved, including direct myocardial and coronary HIV infec-�tion, autoimmune responses, and an adverse risk factor profile�(Figure 1).5 Moreover, the very same drugs which are used to As more effective therapies have produced longer survival times for human immunodeficiency virus (HIV)-infected patients, new complications of late-stage HIV infection including HIV-related heart disease have emerged. Almost any agent that can cause disseminated infection in patients with acquired immunodeficiency syndrome (AIDS) may involve myocardium, but clinical evidence of cardiac disease is usually overshadowed by manifestations in other organs, primarily the brain and lungs. Cardiac abnormalities are found at autopsy in two-thirds of patients with AIDS, and more than 150 reports of cardiac complications have been published. Cardiac involvement in HIV disease includes pericardial effusion, myocarditis, dilated cardiomyopathy, and/or endocardial involvement at any stage of the disease. This review deals with all the cardiac manifestations of AIDS and serves to highlight two problems and one indication. First of all, there are very few clinical studies. Current knowledge is based almost exclusively on echocardiography and autopsy studies. Observational or clinical trials would be useful. Second, there exists very poor information on the impact of treatment; and epidemiologic and clinicopathologic studies are mandatory for obtaining detailed data concerning the mechanisms of myocardial damage in AIDS. Almost any agent that can cause disseminated infection in patients with acquired immunodeficiency syndrome (AIDS) may involve myocardium, but clinical evidence of cardiac disease is usually overshadowed by manifestations in other organs, primarily the brain and lungs

As a consequence, the nuimber of patients with AIDS with cardiac involvement at autopsy, greatly exceedsthe number with significant heart disease during life

• premature CAD with HIV/AIDS evoked concern in high-income countries (post-ART Rx era)

• most common cardiac manifestations Sub-Saharan

Africa: cardiomyopathy

pericardial disease (often TB) pulmonary hypertension endocarditis & valve abnormalities • subclinical echocardiographic abnormalities

independently predict adverse outcome & identify high-risk pt’s who can be targeted for early intervention & Rx

PresenterPresentation NotesAlthough premature coronary artery disease (CAD) in patients with HV/AIDS has evoked concern in high-income coun- tries in the post-antiretroviral therapy era,2 – 4 the most commonly reported cardiac manifestations of HIV/AIDS in Sub-Saharan Africa are cardiomyopathy, pericardial disease (often related to tubercu- losis), and pulmonary hypertension.5

• cardiac complications occur late in the disease course

• clinical apparent in a small %

• very few clinical studies - based on autopsy & echocardiography

• poor information on the impact of Rx

PresenterPresentation NotesWhen reviewing the literature with respect to this, there are two problems that need to be specifically highlited

First of all, there are very few clinical studies

Current knowledge is based almost exclusively on echocardiography and autopsy studies. Observational or clinical trials would be useful.

Secondly, there exists very poor information on the impact of treatment; and epidemiologic and clinicopathologic studies are mandatory for obtaining detailed data concerning the mechanisms of myocardial damage in AIDS.

• CHF; dyspnea often incorrectly attributed to lung disease – LV dysfunction

• echocardiography useful to identify the cause

• pericardial effusion

• RV dilation

• arrhythmias

• endocarditis

PresenterPresentation NotesWhen there are clinical manifestations, CHF is the most common finiding and is due to LV dysfunction.

Because of the frequency of opportunistic pulmonary infections, dyspneoa may be attributed incorrectly to lung disease rather than HF.

Echocardiography may be useful identifying cardiomyopathy as the cause of the symptoms

Other common clinical and echocardiographic abnormalities that may result in symptoms include pericardial effusion (usually but not invariably without tamponade), arrhythmias and right ventricular dilatation and hypertrphy.

“Most of the cardiac problems are clinically unrecognized because they can easily be attributed to infectious disease complications or lung disease or things like that. All the signs and symptoms that you would associate with heart failure can sometimes be attributed to other causes. So what we've always pushed is that if you don't look, you don't know”

Steven Lipshultz 2000

• study to assess incidence of

unsuspected cardiac abnormalities in ambulatory VS hospitalized pt’s with HIV

• 60 hospitalized pt’s

• 40 (asymptomatic / early-stage

disease) out-pt’s

• WHO: normal activity – minor LOW/

mucocutanoeous manifestations/ zoster/ URTI’s

PneumoniaBronchiectasisPleural effusionTBPCP pneumoniaPyrexial illnessHepatitisGNPsychosisDiarrheaMalariaCahexiaOral thrush

316853811131713

HOSPITAL OPD CD4 (/ul) 254 475

p

Assessment of LV Function fractional shortening =

EDD-ESD/EDD Normal > 27%

Echocardiographic Data

27 of 60 hospital pt’s had unsuspected cardiac abnormalities on echocardiography : * pericardial effusion : 16 (17%) * dilated RV : 16 (17%) * LV dysfunction : 5 (5%)

Echocardiographic abnormalities & CD4

Significantly lower CD4 in pt’s with cardiac lesions: u 166 u 402 u p

Pericardial Effusion : 16 pt’s (16%)

• extremely low CD4 counts • 11 small 20mm • 1 tamponade - pericardioscentesis – TB • TB proven on pericadioscentesis / resolved with anti -TB Rx • advanced immune deficiency

Cardiac tamponade due to a large pericardial effusion

resolution of a pericardial effusion after anti-TB Rx & oral steroids

Pericardial Effusion • pre-HAART: common in

advanced HIV-disease with prevalence rates up to 45%

• most are asymptomatic

• effusions small

• independent predictor of

mortality & poor prognosis

PresenterPresentation NotesPericardial effusion commonly occurred in the the pre-HAART in people with advanced HIV disease, with rates up to 45%. Although most patients are asymptomatic and effusions are generally small; the presence of an effusion appears to be an independent predictor of mortality and poor prognosis.

Heidenreich; Circulation 95: Prospective Evaluation of Cardiac Involvement in AIDS

• 231 pt’s; 5yr study

• pericardial effusion 12%/y

• 80% small

• shortened survival

• 36% (PE) vs 93% (6m)

asymptomatic pericardial effusion may signal end-stage HIV disease

PresenterPresentation NotesA prospective evaluation followed 231 patients for 5 years. The annual rate of pericardial effusions was 12%. Once again the majority were small but was associated with significantly shortened survival; only 36% with effusions were alive at 6-months as opposed to 93% without.

• idiopathic in the majority of HIV-infected pt’s (industrialized countries)

• in Africa, the majority of pericardial disease in HIV-

infected people is caused by treatable microorganisms

• M tuberculosis: cause of large effusions in 86-100% of HIV-infected pt’s (Africa)

• non-HIV infected pt’s have other etiologies in 30–50% • atypical Mycobacteria / pyogenic / lymphoma & Kaposi

/ Cryptococcus / Nocardia / viral infections

PresenterPresentation NotesThe cause of pericardial effusion in the majority of HIV-infected patients living in industrialized countries is idiopathic. By contrast, in Africa, the majority associated with HIV-infected people is caused by treatable microorganism, with Tuberculosis the cause of larger effusions in over 80% of cases. By contrast, non-HIV infected subjects have other aetiologies for the pericardial effusion in 30–50% of cases Important alternative causes include pyogenic infection, lymphoma, and Kaposi sarcoma.

• HIV modifies the clinical presentation of TB pericarditis - high incidence of co-existing CMO

• histological pattern affected by the immune status with fewer granulomas with severely depleted CD4 counts

• lower incidence of effusive-

constrictive disease

• less likely to present with ascites & more likely to have an effusion on echo

PresenterPresentation NotesEarly observational work suggests that HIV modifies the clinical presentation of tuberculous pericarditis with a high incidence of coexisting cardiomyopathy or myopericarditis The histological pattern is also affected by the poor immune status with fewer granulomas, which may explain why these patients have a lower incidence of effusive constrictive disease in HIV associated TB pericarditis. Constriction with occurs when fibrosis & tightening of the pericardium limits the ventricles from filling. The HIV patients are therefore less likely to present with abdominal swelling and ascites and more likely to have an effusion on echocardiography. .

• small effusions: exhaustive search for the cause is unnecessary - not progressive

• usually no definitive etiology

• larger effusions - aggressive evaluation and Rx

PresenterPresentation NotesIn those with small effusions, an exhaustive search for the cause is unnecessary as they are generally not progressively. The larger effusions should ideally be drained with pericardioscentesis. The fluid should be sent for culture, cytology and biochemistry. There is no conclusive randomized evidence of an optimal duration for treatment of extra pulmonary tuberculosis in HIV-infected patients. Despite this, the mainstay of treatment of tuberculous pericarditis in Africa is the 6-month course of antimicrobial therapy.

TB pericarditis:

• no conclusive evidence for an optimal duration of Rx of extra-pulmonary TB in HIV-pt’s; 6-month’s Rx (WHO)

• access to HAART – timing & introduction of ART’s controversial

• potential problems: drug interactions & immune reconstitution

• advanced HIV / markedly CD4 (

pericardial effusions in HIV-infected pt’s are less frequent in the era of antiretroviral treatment

• HIV-HEART study: prospective & multicenter cohort • small effusions in only 2 of 802 HIV+ve out-pt’s

(2004-2006); 85.2% on HAART • effective blockade of viral replication; reduced

opportunistic infections, might explain the low effusion rate

Lind et al: Pericardial effusion of HIV-infected patients - results of a prospective multicenter cohort study in the era of antiretroviral therapy; European Journal of Medical Research 2011, 16:480

PresenterPresentation NotesThe HIV-HEART (HIV-infection and HEART disease) study is a cardiology driven, prospective and multicenter cohort study. Outpatients with a known HIV-infection were recruited during a 20 month period in a consecutive manner from September 2004 to May 2006.

It is probable seems that the effective blockade of virus replication and a reduced rate of opportunistic infections might have major effects on the low pericardial effusion rate.

Left Ventricular Dysfunction

•dilated LV : 6 pt’s EDD>5.7cm •mean EDD: 6.23+0.51cm •LV dysfunction (FS

Dilated Cardiomyopathy:

• common manifestation of late stage HIV infection – significantly survival

• trigger for HAART

independent of CD4

• pre-HAART era: 15.9/1000pt’s (PM & echo)

• Africa: 9-57% (echo) • LV dysfunction may occur in

acutely ill pt’s (even outside setting of HIV) – distorted the figures

PresenterPresentation NotesDilated Cmo is the most common manifestation of late stage HIV disease, is associated with a poor outcome and is considered to be a trigger for ART independent of the CD4 count.

In the developed world before HAART, the annual incidence of HIV-associated cardiomyopathy was 15.9 per 1000 patients.

In Africa, cross-sectional echocardiographic studies of both in and outpatients, report the prevalence between 9% to 57%.

The fact that left ventricular dysfunction is common in acutely ill patients even outside the setting of HIV may also have distorted these figure.

39There has been a significant reduction of HIV-associated cardiomyopathy in the HAART era.41 One Italian study reported the prevalence at 1.8%, an almost 7-fold reduction from the pre-HAART ear

There is no conclusive evidence that HAART reverses cardiomyopathy, but it does appear that by preventing profound immunosuppression and the development of AIDS, heart muscle remains healthier.

http://www.annalsnyas.org/content/vol946/issue1/images/large/4ff1.jpeg

• CMO less frequent in developed countries, since introduction of HAART

• 8.1% - 1.8% : 7X pre-HAART (Pugliese et al: J infection 2000:40:282)

• no conclusive evidence that HAART reverses

CMO

• myocardium remains healthier - preventing profound immunosuppression

• developing countries; availability of HAART

scanty & role of other factors NB

PresenterPresentation NotesThere has been a significant reduction of HIV-associated cardiomyopathy following the introduction of HAART. One Italian study reported the prevalence 7-fold reduction in incidence.

• pathogenesis largely unknown- likely

multifactorial

• direct infection of myocardial cells by HIV-virons (CD4-independent infection GP 120 & Tat),

• immune activation / co-infection with other viruses

(coxsackievirus B3, CMV)

• as well as nutritional deficiencies, autoimmune factors (increased anti-α myosin ab’s), drug toxicity (AZT)

• pathology: myocarditis in > half of pt’s

PresenterPresentation NotesThe aetiology of HIV related cardiomyopathy is likely multifactorial, and may be due to direct infection of myocardial cells by HIV-1 virions, immune activation, or co-infection with other viruses such as coxsackievirus B3 and CMV, as well as nutritional deficiencies, autoimmune factors (increased anti-α myosin antibodies), and HAART toxicity (zidovudine).w91 One myocardial biopsy series demonstrated that pathology is consistent with myocarditis in more than half of patients.w9

• median survival: 101 (CMO) vs 472 days

• CMO (CD4 <

100)

HIV-CMO associated more advanced immunosuppression, CD4 counts: independently associated with death

Currie et al: BMJ 94

PresenterPresentation NotesHIV-associated cardiomyopathy has been shown to be associated with more advanced immunosuppression and lower CD4 lymphocyte counts and is independently associated with death. In a study from Scotland, their median survival was 101 days as opposed to 472 days in matched controls. Cariomyopathy was strongly associated with CD4 counts of less than 100.

The treatment of HIV related cardiomyopathy is unclear, and usual treatment for heart failure with afterload reduction appears reasonable. What remains unknown is the role of inflammation and immune response in the disease. One study in children with HIV and left ventricular dilation showed improvement in left ventricular contractility in those with higher endogenous IgG values or after treatment with intravenous immunoglobulin, suggesting that myocardial impairment may be immunologically mediated.w93 The prognosis of HIV related cardiomyopathy appears to be worse than other non-ischaemic cardiomyopathies, and one study in children with vertical HIV transmission demonstrated that even mild left ventricular dysfunction was associated with increased overall mortality.w94 Further data will emerge from the ongoing HIV-Heart study, which is examining the prevalence and natural history of myocardial dysfunction in HIV infected adults.

However, Currie et al has reported the largest prosective study specifically desiged to assesss the natural course of heart muscle disease in 296 pt's with HIV.

Cardiac dysfunction was identified in 13 pt's & was strongly associated with profound immune supression ( CD4 counts of less than 100)

The outlook for these pt's is poor even after adjustment for the significantly reduced CD4 counts.

Dilated CMo is therefore an independent prognosticator in pt's with HIV

There is currently the bleief that it is inapprprite to rely solely on the CD4 counts when assessing the need for antiretroviral therapy

A decline in CD4 correlates well with diseae progression but a wide intraindavidual variation can exist, reducing the predictive power of this value for individual pt's. Decisions on treatment should take into account the trend of serological results as well as clinical factors, including the presence of heart muscle disease.

Median survival was 101 days as compared with 472 days for those with normal hearts.

beta-blockers and angiotensin-converting enzyme inhibitors represent the cornerstone of treatment of other types of left ventricular dysfunction, should be formally tested in this setting to appraise correctly their impact on survival, symptoms and ventricular remodelling.

• Rx HIV-CMO is unclear • afterload , BB’s, aldosterone I’s: cornerstone of

Rx of other types LV dysfunction

• remains unknown: role of inflammation & immune response

• children with HIV & LVEDD: LVEF after Rx with

IVI IG’s; suggests that myocardial impairment is immunologically mediated

– Lipshultz SE et al. Immunoglobulins and left ventricular structure and function in pediatric HIV infection. Circulation 1995;92:222

PresenterPresentation NotesThe usual treatment for heart failure with afterload reduction, BB’s and aldosterone inhibitors are appropriate and remain the cornerstone of Rx for other forms of LV dysfunction.

What remains unknown is the role of inflammation and immune response in the disease.

10 million children with HIV! • prognosis of HIV-CMO worse than other non-ischaemic types

• prospective P2C2 HIV Multicenter Study: Am Heart J 2005;150:439–47

• children with vertical transmission of HIV

• even mild LV dysfunction associated with overall high mortality

• HIV-Heart study

PresenterPresentation NotesPrognosis of HIV related cardiomyopathy appears to be worse than other non-ischaemic types. In children with vertical HIV transmission demonstrated that even mild left ventricular dysfunction was associated with increased overall mortality.

Further data will emerge from the ongoing HIV-Heart study, which is examining the prevalence and natural history of myocardial dysfunction in HIV infected adults.

pulmonary hypertension & RV dilatation:

*16 (16%) pt’s *RVEDD :3.39 ±1.37cm

*PAP : 46 ± 7.2 mmHg

• did not occur in the absence of respiratory disease / LV dysfunction

• PHT - pneumonia / hypoxia / PCWP

• successful Rx - RV afterload - normal RV dimension

• prevalence - 1/200 vs. 1/200000 (general pop); constant since the advent of HAART

• high mortality & progressive

course; median survival 1.3 vs 2.6 years in HIV-ve matched controls

• association independent of 2o

causes • asymptomatic PASP is

frequent; 35.2% of HIV pt’s PASP >30 mm Hg vs. 7.7% of non-infected controls

HIV associated pulmonary arterial hypertension (PAH):

PresenterPresentation NotesThe prevalence of pulmonary arterial hypertension (PAH) in HIV infected patients is several thousand times that of the general population and has remained constant since the advent of the HAART era.

it has however been shown that the prevalence of asymptomatic elevations in pulmonary arterial systolic pressures (PASP) as assessed by echocardiography may in fact be much higher, with a PASP >30 mm Hg in 35.2% of HIV patients, compared with 7.7% of non-infected controls.w81 This association between HIV and PAH is largely independent of secondary causes of PAH, with HIV being the sole risk factor for PAH in 82% of HIV infected patients. These patients have higher mortality rates and a more rapidly progressive disease course when compared with those without HIV,

It will be important to document the African experience and epidemiology more systematically, because long-term survival is significantly lower in patients with median survival of 1.3 versus 2.6 years

pathogenesis not defined: pulmonary vessel endothelial proliferation & vasoconstriction triggered by pleomorphic cytokines (eg, endothelin-1, IL-6, TNF) released by HIV-infected pulmonary macrophages - not potential targets for Rx

PresenterPresentation NotesPulmonary vessel endothelial cell proliferation and vasoconstriction triggered by pleomorphic cytokines (eg, endothelin-1, interleukin-6, and tumor necrosis factor-[alpha]) released by HIV-infected pulmonary macrophages and dendritic cells are central to the pathogenesis of HIV-associated pulmonary hypertension. None of these cells or cytokines is a potential target for antiretroviral therapy.,

The pathogenesis of HIV associated PAH has not been clearly defined. Certain HIV proteins have been shown to activate endothelial cells indirectly, such as the envelope glycoprotein-120, which has been linked to higher endothelin-1 values.w27 w84 Endothelin-1 in turn is a potent vasoconstrictor and may play a central role in the pathogenesis of PAH. Increased markers of inflammation such as vascular endothelial growth factor A, platelet derived growth factor, and interleukin 1 and 6 have also been demonstrated in HIV associated PAH.w85 In addition, autoimmunity may play a role,w86 and a genetic predisposition has also been suggested.w87 Co-infection with human herpesvirus 8, on the other hand, did not appear to be associated with elevated PASP.

• Rx HIV-PAH & role of HAART unclear

• few studies of the role of pulmonary vasodilators:

Bosentan & prostacyclin analogues

• Swiss cohort study: HAART prolongs survival & reverses underlying physiology - RVSP-RAP PG 3.2 mm Hg in ART pt’s; 19.0 mm Hg in controls

• specific drugs: use of a ritonavir-boosted PI &

Abacavir independently associated PAH

PresenterPresentation Notes

The treatment of HIV associated PAH including the role of HAART remains unclear.

Few studies have examined the role of pulmonary vasodilators: one uncontrolled study showed improvement in clinical measures of heart failure and haemodynamics with bosentan, suggesting that endothelin may play a role in the pathogenesis.w88 The role of prostacyclin analogues in HIV associated PAH is limited to several small prospective studies demonstrating hemodynamic improvement

When analyzing the use of specific drugs, the use of a ritonavir-boosted PI and abacavir were independently associated with pulmonary hypertension and LV hypertrophy, respectively. In the large Data Collection on Adverse Events of Anti-HIV Drugs Study, subjects taking abacavir had a nearly doubled relative risk of myocardial infarction over 5 years of follow-up [45]. This risk was restricted to recent or current use of abacavir and waned with its discontinuation. Importantly, the absolute risk of myocardial infarction remained quite low (1.6% over a 5-year period). Analyses from another large HIV cohort, the SMART study, found abacavir to be associated with increases in inflammatory biomarkers (interleukin 6 and C-reactive protein) among participants [43]. Whether these inflammatory and vascular effects of abacavir may affect cardiac remodeling requires additional investigation.

• HIV not associated with ↑ risk IE

• SA (prospective study of risk factors for IE),

– only 1/92 pt’s HIV +ve – main factors: RVD in 76%, congenital

HD, prosthetic valves, hx of IE

• high prevalence of both HIV & RHD (Africa); more cases of IE that are coincidentally HIV+ve

• IVI drug abusers – right-sided IE

• S Aureus (75% of cases); incidence of Gram-ve organisms & fungi – worse prognosis

• nonbacterial thrombotic endocarditis; in 3-5% of Western series (pre-HAART); predilection for pt’s with the wasting syndrome; not described in Africa

INFECTIVE ENDOCARDITIS

PresenterPresentation NotesEndocardial/ valvular disease in patients with HIV/AIDS can be secondary to bacterial or non-bacterial (marantic) endocarditis [4]. Bacterial endocarditis is usually secondary to intravenous drug abuse in this patient population [25], making Staphylococcus aureus and Streptococcus viridans the most common organisms and the tricuspid valve, the

HIV infection is not associated with an increased risk of infective endocarditis. In a South African prospective observational study that examined the risk factors for infective endocarditis, only 1 of their cohort of 92 patients was HIV seropositive.23 The main risk factors included rheumatic valve disease in 76%, congenital heart disease, the presence of prosthetic valves, and a history of infective endocarditis.23 Of 83 consecutive HIV-infected patients with cardiac disease in the DRC, only 1.2% had infective endocarditis.24 Given the high prevalence of both HIV and rheumatic valvular heart disease in Africa, future prevalence studies may find that a significant proportion of patients with infective endocarditis and underlying rheumatic valvular disease are coincidentally HIV infected. In regions of the world where the use of intravenous drugs is high (unlike Africa), the prevalence of infective endocarditis has been reported to be as high as 34% in HIV-seropositive cohorts.6 Right-sided valves are most commonly involved, and the predominant organism is Staphylococcus aureus (75% of cases). There may also be a higher incidence of Gram-negative organisms and fungi.49 The prognosis is similar to that in HIV-uninfected patients unless there is involvement of the left-sided valves, the CD4 count is

• overall incidence of unsuspected cardiac abnormalities (HIV infected pt’s) - 27%

• associated with late-stage infection

• depends on the stage of HIV disease

• degree of immunosuppression correlates with the presence of cardiac disease

• significantly lower CD4 counts (166 vs 402/ul)

PresenterPresentation NotesOur data is in keeping with previous work with an overall incidence of unsuspected cardiac abnormalities of 27%, The prevalence depends on the stage of the illness, with the sickest patients having the most lesions.

The degree of immunosupression correlates with the presence of cardiac abnormalities.

• prospective, clinical registry: data from all de novo cases of HD presenting @ CH Baragwanath 2006–08

• largest study of the spectrum of cardiac manifestations of HIV /AIDS relative to de novo advanced HD in sub-Saharan Africa

• 518 of 5328 de novo cases of HD identified as HIV+ve (9.7%); 54% on HAART

PresenterPresentation NotesThis Is professor Karin Sliwa who has directed the “Heart of Soweto Study”, a prospective, clinical registry examining the data from all new cases cases of heart disease, presenting to Cardiology at Baragwanath Hospital.

This is the largest study to examine the spectrum of cardiac manifestations of HIV /AIDS relative to overall pattern of de novo advanced HD in sub-Saharan Africa

518 of 5328 de novo cases were identified as being HIV-+ve (9.7%); Just over half of these patients were on HAART.

• CMO: most common primary dx attributable to HIV/AIDS:

128 (12.5%) cases pericarditis / effusion

42 cases PHT

14 cases CAD – AMI; IVUS - fresh thrombus & minimal underlying atherosclerotic disease; mean age 41y’s

196 cases HIV-CMO • viral load (110 000 vs.19 000;

P = 0.018) • CD4 (180 vs. 211; P = 0.019) • introduction of

HAART • more likely to be on

HAART (64%) – cautious interpretation

• immune reconstitution

syndrome

• higher than usual cardiac involvement - paradoxical inflammatory reaction

in agreement with other reports suggesting CAD in HIV/AIDS has a different pathophysiology than non-infected IHD pt’s

PresenterPresentation NotesCardiomyopathy was the most common diagnosis attributable to HIV; there were 196 patients & they had the highest viral loads and lowest CD4 counts. As I mentioned before, the incidence of LV dysfunction has significantly declined following the introduction of HAART in developed countries. More of this cardiomyopathy group were on HAART at the time of diagnosis; this should be interpreted with caution. The immune reconstitution inflammatory syndrome has been described in most organ systems including the heart and, potentially, there was a higher than usual cardiac involvement in a paradoxical immune reaction in this group. Alternatively, the data may reflect increased detection of the condition in those who are HIV-positive. None of anti-retroviral agents recommended for use in South Africa have been shown to cause cardiomyopathy in large studies

An additional 128 cases (25%) were diagnosed with pericarditis/pericardial effusion with a range of other concurrent diagnoses evident, including 42 cases (8.1%) of HIV-related pulmonary arterial hypertension. Only 14 of all 581 cases of coronary artery disease (CAD) (2.4%, mean age 41 ± 13 years) were confirmed HIV-positive more likely to be prescribed HAART than the rest (127/196 vs. 147/322; OR 2.85, 95% CI 1.81 – 3.88). When viral load was significantly higher in HIV-related cardiomy- opathy cases [median 110 000 (IQR 26 000 – 510 000) vs. 19 000 (IQR 3200 – 87 000); P 1⁄4 0.018] and their CD4 count was lower

• individuals with HIV infection are at risk for IHD events

• clinical presentations distinct

• ACS: more than a decade younger

• males; smokers; low HDL

• tend to have 1-vessel disease rather than MVD

• PCI: restenosis & stent related complications

accelerated atherosclerosis in young HIV+ individuals without traditional coronary risk factors

PresenterPresentation NotesPatients with HIV infection are at greater risk for CVS events

There clinical presentations is distinct.

Those who present with ACS are more than a decade younger;

They are more often males smokers and tend to have single vessel rather than multivsessel disease.

Those who undergo PCI have more restenosis & stent related complications.

The first case reports of acute myocardial infarction (MI) in HIV infected patients on HAART were described in 1998.w3 w4 Since then, it has become increasingly clear that individuals with HIV infection are at high risk for cardiovascular events. The relative contributions of HIV infection versus potential adverse effects of HAART to CHD risk, however, remain unclear. Although the data from numerous studies on coronary events in HIV disease are conflicting (table 1), the majority of studies suggest that antiretroviral therapy increases CHD risk in HIV patients. observational studies suggest a 1.5–2 fold increased risk of CHD in HIV infected individuals when compared with uninfected controls, with absolute rates remaining low.5 The discrepancy in findings among observational studies with regard to the impact of PI use is likely due to inherent biases specific to observational studies, such as differences in study design, short follow-up times, lack of non-infected control groups, and unclear duration and specifics of HAART.w1What appears to indicate an increased risk with long term PI use in observational studies is in contrast to findings from the SMART study. A total of 5472 HIV infected patients were randomised to a strategy of viral suppression (continuous HAART) versus drug conservation (intermittent HAART) and followed for an average of 16 months. Although not powered to examine cardiovascular events as a primary end point, patients assigned to continuous HAART had a decreased risk of fatal or non-fatal cardiovascular disease when compared with those on intermittent HAART (hazard ratio (HR) 1.6

Furthermore, the initiation of HAART in treatment naïve patients results in dramatic improvement in endothelial dysfunction,7 suggesting that in the short term, treatment of HIV infection may actually decrease cardiovascular risk. These studies suggest that, although long term treatment with HAART may lead to detrimental cardiovascular effects, there may be beneficial effects of HAART in the short term, providing additional evidence that HIV itself is mechanistically associated with increased CHD risk

Clinical characteristics of CHD in HIV infected individualsClinical presentations of CHD in HIV infection tend to be distinct from CHD due to traditional risk factors. Demographically, HIV patients who develop acute coronary syndrome are more than a decade younger, with a mean age of 50 years, compared with non-infected controls. They are also more likely to be male, to be current smokers and to have low HDL (high density lipoprotein) cholesterol. As might be expected from these clinical features, HIV patients tend to have low TIMI risk scores, and tend to have single vessel rather than multiple vessel coronary artery disease.8 In general, HIV patients hospitalised with acute coronary syndrome have excellent immediate outcomes,w19–21 with successful percutaneous coronary intervention procedures.w20 However, when compared with non-infected controls, HIV patients tend to develop higher rates of future stent related complications. Prior studies comparing outcomes of percutaneous coronary interventions in HIV patients with non-infected controls have demonstrated a higher incidence of restenosis before the era of drug eluting stents (52% vs 14%, p = 0.006),8 and stent related complications requiring target vessel revascularisation (43% vs 11%, p = 0.02).w18 Preliminary data demonstrate that HIV patients treated with drug eluting stents had a 30% rate of major adverse cardiovascular events (Ren et al. Percutaneous coronary intervention in human immunodeficiency virus. Abstract presented at American Heart Association Scientific Sessions 2008, New Orleans, Louisiana, USA).Pathogenesis of CHD in HIV infectionAtherosclerosis in HIV patients appears to be pathologically distinct from atherosclerosis in the general population. One autopsy study demonstrated accelerated atherosclerosis in young HIV-1 infected patients, with intermediate features between lesions in common CHD and transplant vasculopathy.w24 In another study, HIV associated atherosclerosis was characterised by diffuse and circumferential vessel involvement with unusual proliferation of smooth muscle cells mixed with abundant elastic fibres, forming endoluminal protrusions.w19 Interestingly, in an autopsy study of young to middle aged patients who died of advanced AIDS, HIV patients had three times greater odds of having a significant stenosis in the coronary arteries, even after adjustment for age and gender.

The underlying mechanism of early atherosclerosis in HIV disease is not well understood, but similarly may be closely linked to increased vascular inflammation. This may be due to direct viral effects, the use of HAART and associated metabolic changes, or host immune responses.

Other risk factorsIn addition to the above metabolic changes, other traditional cardiovascular risk factors also appear quite prevalent in the HIV infected population. Smoking is quite common among HIV patients

Lipodystrophy in HIV patients is commonly associated with a constellation of findings characteristic of the metabolic syndrome, including insulin resistance, impaired fasting glucose tolerance, elevated triglycerides, low HDL cholesterol, and hypertension.11 Metabolic syndrome appears to be highly prevalent among HIV patients. In a recent cross-sectional study of 710 HIV patients, 17% had metabolic syndrome, a finding which was independently associated with the use of stavudine and lopinavir/ritonavir.w45 Progression to metabolic syndrome is substantial in the first 3 years after initiation of HAART, and incident metabolic syndrome was associated with increased risk of CHD in a study of 88 HAART naïve patients who started on treatment (

The potential role of HIV disease in the pathogenesis of early atherosclerosis is supported by the consistent observation that both CD4+ count and viral load influence cardiovascular disease. The CD4+ count nadir predicts subclinical carotid atherosclerosis in our group,9 and a low CD4+ count on HAART has been associated with increased risk of cardiovascular disease.w28–30 A recent study showed that low CD4+ count was independently associated with increased prevalence of carotid lesions.w30 Prior studies have also shown that higher viral loads correlate with endothelial dysfunction as measured by brachial artery flow mediated vasodilation

HIV AND CARDIOVASCULAR RISK FACTORSIn addition to a direct viral effect, HIV infection and treatment with HAART may increase cardiovascular risk by influencing other traditional cardiovascular risk factors. A recent study demonstrated increased prevalence of traditional risk factors in HIV infected men without known CHD, leading to higher calculated 10 year Framingham risk scores when compared with non-infected controls (17% vs 11% 10 year risk of ≥25%).

Lipid abnormalitiesChanges in lipid profile with HIV infection appear to be twofold: in the early stages of HIV infection before treatment, the predominant changes appear to be hypertriglyceridaemia, low HDL and low LDL (low density lipoprotein) values with predominant small, dense LDL particles when compared with controls.10 w38 After initiation of HAART, however, LDL and total cholesterol concentrations appear to increase, with little change in HDL cholesterol, findings that are particularly associated with the use of PIs.w

n the Swiss HIV Cohort study, hypercholesterolaemia and hypertriglyceridaemia were 1.7–2.3 times more common among patients on HAART containing PIs when compared with those without PIs.w40 The overall effect of HIV infection is thus toward an atherogenic lipid profile with significant reduction in HDL, and increase in triglycerides, oxidised LDL and small dense LDL.5 The prevalence of hyperlipidaemia in HIV patients is between 28–80% in different studies, with the majority of cases being hypertriglyceridaemia (40–80%).w

Current recommendations for the treatment of hyperlipidaemia in HIV patients include lifestyle modifications, and dietary and exercise interventions have been shown to decrease total cholesterol values by 11–25% in the HIV population. When lipid lowering therapy is indicated, pravastatin or atorvastatin are first line therapies for the treatment of elevated LDL cholesterol in patients taking any PI or delarvidine (fig 1). The recommended starting doses are pravastatin 20–40 mg daily and atorvastatin 10 mg daily.

Specific effects of HAART are important to consider. In general, most forms of HAART may increase LDL concentrations. With regard to hypertriglyceridaemia, the PI ritonavir has been associated with the most significant increases in triglycerides, in some cases causing extreme hypertriglyceridaemia exceeding 1000 mg/dl (11.3 mmol/l), although full doses of ritonavir are rarely used today.w42 Increased triglyceride concentrations are also seen with the use of ritonavir–saquinavir or ritonavir–lopinavir combinations. The PI with perhaps the least effect on triglyceride values is the relatively newly developed PI atazanavir.w43The pathogenesis of lipid abnormalities associated with HIV infection and HAART are not well understood. Proposed mechanisms include increased hepatic lipogenesis, impaired clearance of lipids from the bloodstream, and potential effects of immunologic status

Lipodystrophy and metabolic syndromeHIV associated lipodystrophy is characterised by uniform subcutaneous and peripheral fat loss, with relative preservation or increase in visceral fat, resulting in relative central adiposity, as well as fat accumulation in the neck and dorsocervical region.10 In prospective studies, these abnormalities are clinically evident in 20–35% of patients 12–24 months after starting HAART. Certain combinations of HAART are strongly associated with the development of lipoatrophy, in particular the use of PIs as well as the concomitant use of the two NRTIs, stavudine and didanosine.10 newer PI atazanavir for 48 weeks was not associated with abnormal fat redistribution or metabolic disturbances commonly seen in HIV associated lipodystrophy.w

prevalence of diabetes mellitus and hypertension also appear quite elevated when compared with the general population.

REATMENTCurrently, the treatment of CHD in HIV infected individuals should largely be guided by existing recommendations in uninfected patients, as clinical studies in HIV patients with CHD are limited. However, there are two aspects particular to HIV infected patients that deserve mention: the potential role of HAART with regard to cardiovascular disease, and the treatment of hyperlipidaemia in HIV disease, for which separate recommendations have been devised.

AARTRecent evidence suggests that the risk of non-AIDS related mortality may exceed the risk of AIDS related mortality in individuals with CD4 counts >200 cells/μl.w71 Of particular concern are increased rates of coronary events and mortality compared with non-infected controls.3 9 w9 Despite existing evidence that long term HAART may have adverse effects, it is becoming clearer that uncontrolled HIV replication leads not only to increased cardiovascular risk but also other non-AIDS complications, as was shown in the SMART study.6 w29 w71 Current recommendations by the International AIDS Society USA Panel guidelines thus support HAART initiation for asymptomatic individuals at CD4 count 100 000 copies/ml, rapidly declining CD4 count >100/μl per year, active hepatitis B or C infections, or the presence of HIV associated nephropathy).14The initial choice of HAART regimen is primarily targeted at viral suppression, although metabolic profiles of drugs should be considered in patients at high cardiovascular risk. While traditional HAART may be constrained by HIV resistance and medication tolerability, novel antiretroviral agents such as integrase inhibitors and viral entry inhibitors may in the future provide better options with regard to cardiovascular side effect profiles.15

Currently there is no evidence to treat hyperlipidaemia in HIV patients to goals that are different from those for HIV uninfected patients. However, it is important to consider specific drug–drug interactions when initiating lipid lowering therapy in this patient population. Both PIs and NNRTIs can affect cytochrome P450 isoforms. In general, all PIs inhibit CYP3A4, with the highest level of inhibition with ritonavir, followed by indinavir, nelfinavir, amprenavir, and saquinavir. Delavirdine, an NNRTI, is also an inhibitor of CYP3A4, whereas nevirapine and efavirenz result in induction of the enzyme. Both simvastatin and lovastatin concentrations increase dramatically in the setting of PI use and have led to rhabdomyolysis,w73 thus are contraindicated in this setting. Atorvastatin concentrations appear to be increased to a lesser degree, and atorvastatin may be used at lower doses in HIV patients. Since pravastatin is not metabolised by CYP3A4, it is a first line agent for lowering LDL in HIV patients. Similarly, fluvastatin is metabolised by CYP2C9, and can be used as a second line agent.w73 Rosuvastatin has minimal P450 metabolism, although concentrations appear to be increased when used in combination with atazanavir/ritonavir and lopinavir/ritonavir, limiting doses to 10 mg in that setting.

he treatment of hypertriglyceridaemia is mainly achieved with fibrates (gemfibrozil 600 mg twice a day or micronised fenofibrate 54–160 mg daily) for triglyceride values exceeding 500 mg/dl (5.6 mmol/l).

Niacin can cause insulin resistance, and is therefore not recommended as first line therapy with concurrent PI use or the presence of lipodystrophy. In general, bile sequestering resins are not recommended for use in HIV patients.13 Ezetemibe appears safe and effective when added to maximally tolerated doses of lipid lowering therapy,w76 and has modest lipid lowering activity when used alone in HIV patients.

mechanism of early atherosclerosis in HIV not well understood: vascular inflammation; viral effects; HAART; metabolic changes are important

PresenterPresentation NotesThe underlying mechanism of early atherosclerosis in HIV disease is not well understood, but similarly may be closely linked to increased vascular inflammation. This may be due to direct viral effects, the use of HAART and associated metabolic changes, or host immune responses

overall effect of HIV infection is toward an atherogenic lipid profile: • metabolic changes with HIV infection; 2-fold:

• early HIV stages, Tg’s predominantly, HDL & small, dense LDL’s

• after initiation ART & particularly associated with PI’s: LDL , with little change in HDL

• Swiss HIV Cohort: LDL & TG’s 1.7–2.3X in pt’s on

HAART

PresenterPresentation NotesHIV infection and treatment with HAART may increase cardiovascular risk by influencing other traditional cardiovascular risk factors. A recent study demonstrated increased prevalence of traditional risk factors in HIV infected men without known CHD, leading to higher calculated 10 year Framingham risk scores when compared with non-infected controls (17% vs 11% 10 year risk of ≥25%Lipodystrophy in HIV patients is commonly associated with a constellation of findings characteristic of the metabolic syndrome, including insulin resistance, impaired fasting glucose tolerance, elevated triglycerides, low HDL cholesterol, and hypertension.11 Metabolic syndrome appears to be highly prevalent among HIV patients. In a recent cross-sectional study of 710 HIV patients, 17% had metabolic syndrome, a finding which was independently associated with the use of stavudine and lopinavir/ritonavir.w45 Progression to metabolic syndrome is substantial in the first 3 years after initiation of HAART, and incident metabolic syndrome was associated with increased risk of CHD in a study of 88 HAART naïve patients who started on treatment (The potential role of HIV disease in the pathogenesis of early atherosclerosis is supported by the consistent observation that both CD4+ count and viral load influence cardiovascular disease. The CD4+ count nadir predicts subclinical carotid atherosclerosis in our group,9 and a low CD4+ count on HAART has been associated with increased risk of cardiovascular disease.w28–30 A recent study showed that low CD4+ count was independently associated with increased prevalence of carotid lesions.w30 Prior studies have also shown that higher viral loads correlate with endothelial dysfunction as measured by brachial artery flow mediated vasodilationMetabolic syndrome appears to be highly prevalent among HIV patients. In a recent cross-sectional study of 710 HIV patients, 17% had metabolic syndrome, a finding which was independently associated with the use of stavudine and lopinavir/ritonavir.w45 Progression to metabolic syndrome is substantial in the first 3 years after initiation of HAART, and incident metabolic syndrome was associated with increased risk of CHD in a study of 88 HAART naïve patients who started on treatment (

constellation of characteristics of metabolic syndrome: insulin resistance, IFG; Tg’s HDL, HT

recent cross-sectional study: α17% of 710 HIV-pt’s; α Stavudin / Lopinavir-Ritonavir

progression to metabolic syndrome is substantial in the first 3y’s after initiation of HAART,

associated with increased risk of CHD

• uniform subcutaneous &

peripheral fat loss, relative visceral fat - central adiposity, fat accumulation in the neck & dorsocervical region

• 20–35% within 12–24m’s after

starting HAART

• combinations of HAART – lipoatrophy: PI’s & concomitant use of NRTIs, Stavudine & Didanosine

• prevalence DM & HT increased

Lipodystrophy:

The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-2296.

relative contribution of HIV vs. potential adverse effects of HAART to CHD risk, unclear SMART study: randomized 5472 HIV+ve pt’s to strategy of viral suppression (continuous HAART) vs. drug conservation (intermittent Rx) episodic Rx risk of opportunistic disease / all cause death continuous HAART: risk of fatal / non-fatal CAD (HR 1.6)

uncontrolled HIV replication - CV risk & other non-AIDS complications

PresenterPresentation NotesFigure 2. Cumulative Probability of the Primary End Point (Panel A); Death from Any Cause (Panel B); Major Cardiovascular, Renal, or Hepatic Disease (Panel C); and Grade 4 Adverse Events (Panel D). Grade 4 adverse events were determined on the basis of toxicity grades developed by the Division of AIDS of the NIAID. End-point definitions are listed in the Supplementary Appendix.

TREATMENT OF CAD: existing recommendations in uninfected pt’s • 2 particular aspects in HIV-pt’s:

– potential role of HAART w.r.t CVD – Rx of hyperlipidaemia in HIV - goals same as for

HIV-ve pt’s • guidelines: HAART (asymptomatic pt’s) CD4 350 • earlier HAART: high CV risk & other features (viral

loads >100000/ml, CD4 >100/ul/yr, hepatitis B/C or nephropathy)

• earlier initiation of Rx (higher CD4’s) improves CV risk ?

PresenterPresentation NotesTREATMENT OF CAD: is guided by existing recommendations in uninfected pt’s

There are 2 particular aspects:

The potential role of HAART w.r.t coronary riskThe treatment of hyperlipidaemia in HIV, the goals of which are the same as for HIV-ve pt’s

Guidelines recommend that ARV’s be prescribed in asymptomatic pt’s with CD4 counts of less than 350; and individualized Rx above this level

This could be considered in those at risk & with high viral loads and markedly depressed CD4 counts.

It is not definitively known whether earlier Rx improves CV risk ?

Treatment of hyperlipidaemia in HIV infected individuals consider specific drug–drug interaction

PIs inhibit CYP3A4; NB Ritonavir Simvastatin (contraindicated) as concentrations dramatically with PI – rhabdomyolysis Atorvastatin lesser degree – lower doses Pravastatin not metabolized by CYP3A4 - 1st line Rx Rosuvastatin Atazanavir/Ritonavir & Lopinavir/Ritonavir; limit to 10mg Rx of TG – fibrates

address traditional modifiable CVD risk factors (e.g. smoking); diet, exercise

PresenterPresentation NotesTreatment of hyperlipidaemia in HIV infected individuals. HAART, highly active antiretroviral therapy; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; TG, triglyceride.

CONCLUSION

• importance of cardiac involvement in HIV / AIDS,

should not be overlooked

• shortness of breath; common; consideration of CMO / pericardial disease / PAH - echocardiography

• HIV will constitute an important cause of heart

disease

• prevalence of older HIV individuals; by 2015 (CDC), over ½ of all HIV-pt’s will be >50 y’s

• chronic diseases, atherosclerosis, heart failure

•Importance of cardiac involvement should not be overlooked •HIV will constitute an important cause of heart disease

•!!!

• co-ordination between ID & cardiology – improve quality of care to

develop an individualized Rx plan

• eimportant barometer of current & future impact of HIV/AIDS on the heart health of urban Africa

• HIV- CMO (3.7% entire cohort) & pericardial disease (2.4%): only minor contributors to overall burden of HD in the overall Heart of Soweto cohort (5328 de novo cases)

• PHT: 0.8% HIV-CAD: 0.3%

• data is encouraging; 5.5m infected & 500 000 HIV-related deaths / yr;

• previous reports suggesting high levels of myocardial &/ pericardial disease

• expected ‘tsunami’ of cardiac disease α HIV-pandemic, has yet to arrive.

• HAART’s potential impact on premature CAD - still potential to truncate at least one of the many devastating consequences of this disease

PresenterPresentation NotesGiven an estimated 5.5 million people infected, 500 000 HIV-related deaths annually, and previous reports suggesting high levels (up to 1 in 2 affected cases) of myocardial and/or pericardial disease5 in South Africa, these data are encouraging. The expected ‘tsunami’ of cardiac cases from the HIV pandemic, for the moment, has yet to arrive. With the introduction of HAART and pre-warning of its potential impact on premature forms of CAD, there is still potential to truncate at least one of the many devastating consequences of this disease.

Pericardial Disease

•

• pericardial effusions are rather common, occurring in up to to 46% of AIDS patients

• common cause of clinical cardiovascular symptoms and signs

• most idiopathic. • wide array of pathogens,

often in conjunction with disseminated infection

• infections, neoplasias, myocarditis, endocarditis or myocardial infarct are possible etiologies.

http://heart.bmjjournals.com/content/vol86/issue4/images/large/001110.f3.jpeg

• HIV associated pulmonary arterial hypertension:

• Unexplained HIV-pulmonary HT has a prevalence of 1/200 compared with 1/200 000 in the general population.unexplained primary pulmonary hypertension (PPH)

• similar presentation to the non-HIV form

PresenterPresentation NotesHIV associated pulmonary arterial hypertensionThe prevalence of pulmonary arterial hypertension (PAH) in HIV infected patients is several thousand times that of the general population. Older studies had shown an incidence of 0.5%, which appears to have remained constant since the advent of the HAART era.w79 w80 However, recently we have shown that the prevalence of asymptomatic elevations in pulmonary arterial systolic pressures (PASP) as assessed by echocardiography may in fact be much higher, with a PASP >30 mm Hg in 35.2% of HIV patients, compared with 7.7% of non-infected controls.w81 This association between HIV and PAH is largely independent of secondary causes of PAH, with HIV being the sole risk factor for PAH in 82% of HIV infected patients.w82 It has also been shown that HIV infected patients with PAH have higher mortality rates and a more rapidly progressive disease course when compared with those without HIV, with a median survival rate of 6 months.

Data from the developed world suggest that HIV-associated pulmonary hypertension has a prevalence of 1/200 compared with 1/200 000 in the general population.6 The few available prevalence studies from Burkina Faso and Zimbabwe suggest rates of 0.6% to 5%.21,29 Pulmonary hypertension was much more common in hospitalized as opposed to ambulant patients.21,29 Pulmonary vessel endothelial cell proliferation and vasoconstriction triggered by pleomorphic cytokines (eg, endothelin-1, interleukin-6, and tumor necrosis factor-[alpha]) released by HIV-infected pulmonary macrophages and dendritic cells are central to the pathogenesis of HIV-associated pulmonary hypertension.2 None of these cells or cytokines is a potential target for antiretroviral therapy. Despite this, there are studies, such as the Swiss cohort study, that suggest that the use of HAART prolongs survival and reverses the underlying pathophysiology.51 It will be important to document the African experience and epidemiology more systematically, because long-term survival is significantly lower in patients with HIV-associated pulmonary hypertension than in HIV-negative controls, with a median survival of 1.3 versus 2.6 years

• HIV not associated with ↑ risk IE

• SA (prospective study of risk factors for IE),

– only 1/92 pt’s HIV +ve – main factors: RVD in 76%, congenital

HD, prosthetic valves, hx of IE

• high prevalence of both HIV & RHD (Africa); significant % with IE that are coincidentally HIV+ve

• IVI drug abusers – right-sided IE

• S Aureus (75% of cases); incidence of Gram-ve organisms & fungi – worse prognosis

• nonbacterial thrombotic endocarditis; in 3-5% of Western series (pre-HAART); predilection for pt’s with the wasting syndrome; not described in Africa

INFECTIVE ENDOCARDITIS

PresenterPresentation NotesEndocardial/ valvular disease in patients with HIV/AIDS can be secondary to bacterial or non-bacterial (marantic) endocarditis [4]. Bacterial endocarditis is usually secondary to intravenous drug abuse in this patient population [25], making Staphylococcus aureus and Streptococcus viridans the most common organisms and the tricuspid valve, the

HIV infection is not associated with an increased risk of infective endocarditis. In a South African prospective observational study that examined the risk factors for infective endocarditis, only 1 of their cohort of 92 patients was HIV seropositive.23 The main risk factors included rheumatic valve disease in 76%, congenital heart disease, the presence of prosthetic valves, and a history of infective endocarditis.23 Of 83 consecutive HIV-infected patients with cardiac disease in the DRC, only 1.2% had infective endocarditis.24 Given the high prevalence of both HIV and rheumatic valvular heart disease in Africa, future prevalence studies may find that a significant proportion of patients with infective endocarditis and underlying rheumatic valvular disease are coincidentally HIV infected. In regions of the world where the use of intravenous drugs is high (unlike Africa), the prevalence of infective endocarditis has been reported to be as high as 34% in HIV-seropositive cohorts.6 Right-sided valves are most commonly involved, and the predominant organism is Staphylococcus aureus (75% of cases). There may also be a higher incidence of Gram-negative organisms and fungi.49 The prognosis is similar to that in HIV-uninfected patients unless there is involvement of the left-sided valves, the CD4 count is

Kaposi's Sarcoma • most common AIDS-related

neoplasm • at autopsy, heart

involvement is observed in 5-8% of pt’s with a widely disseminated form

• the epicardium and pericardium are most frequently involved

•AIDS-related large cell B immunoblastic lymphoma involving the atrial septum •Malignant lymphoma presenting as a primary cardiac tumor is rare; however, its incidence is apparently increasing in HIV+ patients

http://www.annalsnyas.org/content/vol946/issue1/images/large/4ff9.jpeghttp://www.annalsnyas.org/content/vol946/issue1/images/large/4ff9.jpeg

Accelerated atherosclerosis has been observed in young

HIV+ individuals without traditional coronary risk

factors

• Despite the clinical benefits of protease inhibitors, complications such as lipodystrophy, insulin resistance, high levels of LDL cholesterol and TG develop in up to 60% of pt’s

• Angiographically proven advanced symptomatic coronary artery disease has been reported in men < 40 y’s, Rx with protease inhibitors

• anecdotal information suggesting that the risk of angina and myocardial infarction is increased with HAART

AIDS drugs and heart attacks

• “New research raises the possibility that lifesaving AIDS drugs may also increase the risk of heart trouble, though experts say the medicines' benefits still far outweigh any hazard” CNN 10/03/02

• CDC study - the overall risk is low, nevertheless, those on the drugs have about 5X the usual risk of MI’s

• followed the health of 5,676 HIV+ people (1993 to 2001) – 13 MI’s (PI) vs 2 (no PI’s)

• UCSCD : questioned whether patients have actually had more heart problems since the introduction of the drug combinations with protease inhibitors.

• examined records of 36,766 HIV-infected pt’s - 1,800 hospital admissions for heart disease and strokes.

• Concluded – a slight decline in heart disease & strokes following the introduction of PI’s

http://www.cnn.com/

cardiac lesions are common in acutely ill patients

• overall incidence of unsuspected cardiac abnormalities - 27%

• depends on the stage of HIV disease • degree of immunosupression

correlates with the presence of cardiac lesions

• CMO is associated with late-stage infection & CD4

• dilated RV & pericardial effusion - 26.7%

• dilated CMO - 8.3%

• limitation of this study - not prospective

• Currie et al (BMJ 1994) ; Heidenreich et al (Circulation 1995) : pericardial effusion / LV dysfunction is associated with shortened survival independent of CD4

Dilated Cardiomyopathy • 8.3% of hospitalized pt’s had

significant and unexpected severe LV dysfunction

• many studies documented an association between AIDS & CMO

• rare in control’s with haematological malignancy and in drug users without HIV infection

• probably a direct effect of HIV rather than cahexia

PresenterPresentation Notes8.3% of our hospitalized group were unexpectedly found to have significant LV dysfunction.

There are many studies documenting an association between AIDS and dilated cardiomyopathy, which is rare in control s with haematological malignancy and in drug abusers without HIV infection.

It is therefore probably due to a direct effect of HIV rather than a direct consequence of cahexia.

• 296 pt’s • CMO in 13 (CD4 <

100) • median survival 101

d’s (CMO) as compared with 472 d’s (normal hearts)

• independent adverse prognostic factor

Currie et al : BMJ 94

PresenterPresentation NotesThis paper unfortunately did not address the prognosis of these pt's

However, Currie et al has reported the largest prosective study specifically desiged to assesss the natural course of heart muscle disease in 296 pt's with HIV.

Cardiac dysfunction was identified in 13 pt's & was strongly associated with profound immune supression ( CD4 counts of less than 100)

The outlook for these pt's is poor even after adjustment for the significantly reduced CD4 counts.

Dilated CMo is therefore an independent prognosticator in pt's with HIV

There is currently the bleief that it is inapprprite to rely solely on the CD4 counts when assessing the need for antiretroviral therapy

A decline in CD4 correlates well with diseae progression but a wide intraindavidual variation can exist, reducing the predictive power of this value for individual pt's. Decisions on treatment should take into account the trend of serological results as well as clinical factors, including the presence of heart muscle disease.

Median survival was 101 days as compared with 472 days for those with normal hearts.

What about children (10 million) with HIV??????

• echocardiographic data

- Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection study:

• mortality higher in children with LVFS

• regular echo’s for HIV+ infants - help to single out those risk of dying, even when immune and neurological markers show no cause for alarm

• Circulation 2000

LV dysfunction common - prevalence of 5.7% ; 2-year cumulative incidence was 15.3%

"The benefits of

zidovudine during pregnancy in reducing vertical transmission of HIV outweigh the reported cardiac risks - a conclusion similar to that of other studies. Any decision not to initiate zidovudine therapy, or to stop it, should be made with great caution."

Infants born to women with HIV infection who were exposed to zidovudine (AZT) in the perinatal period appear to have no increased risk of cardiac abnormalities over those without such exposure

No cardiac toxicity found among infants exposed to zidovudine - N Engl J Med 2000

Prevalence of congenital cardiovascular malformations in children of human

immunodeficiency virus-infected women :

The prospective P2C2 HIV multicenter study

No statistically significant difference in congenital cardiovascular malformation prevalence in HIV-infected versus HIV-uninfected children born to HIV-infected women

CONCLUSION • observational study • prospective published studies have

tracked the incidence & course of HIV infection in relation to cardiac illness

• subclinical echocardiographic abnormalities independently predict adverse outcomes and identify high-risk groups who can then be targeted for early intervention and therapy

•Importance of cardiac involvement should not be overlooked •HIV will constitute an important cause of heart disease •Global estimates - 36 million people living with HIV infection & may rise to 120 million worldwide in next decade •If there is a 8-10% incidence of symptomatic CHF over 5 years, then there will be about 3 to 12 million expected cases during this period!!!!!!!!!

"The bottom line is, the people who are dying from AIDS don't matter in this world." “When the philosopher Thucydides was asked when justice would come to Rome, he famously replied that it would come when those who are not injured are as indignant as those who are. So let us all feel indignant about the worsening HIV pandemic as if "we all have AIDS“ and let us make sure that the global AIDS fund turns this anger into action” Gavin Yamey, deputy editor William W Rankin, president BMJ 2002;324:181-182 ( 26 January ) AIDS and global justice:

METHODS

• clinical examination • ECG • chest X-ray • 2-D, M-mode, Doppler, colour

Doppler echocardiography • hemoglobin • CD4+ T-lymphocyte count

DEMOGRAPHICS

• mean age 32 years (range 21-48 years)

• 57 males • no alcohol / drug abuse • no cardiotoxic medications • no prior HT, diabetes, valve or IHD

HEMOGLOBIN

HOSPITAL OPD Hb (g/dl) 11.6 ± 2.7 13.2 ± 2.3

ECG’s of 60 hospital pt’s

• 24 pt’s (40%) - abnormal ECG *18 minor ST/T *2 RVH *4 RV strain *2 R axis *2 RBBB *1 L axis *1 sinus bradycardia *1 bigeminy

Hospitalized patients PneumoniaBronchiectasisPleural effusionTBPCP pneumoniaPyrexial illnessHepatitisGNPsychosisDiarrheaMalariaCahexiaOral thrush

316853811131713

AN OBSERVATIONAL STUDY D Jankelow, Dept Internal Medicine,

University Witwatersrand • incidence of unsuspected

cardiac abnormalities in ambulatory and hospitalized patients with HIV

• University of Witwatersrand, Ethics Committee

AIDS — Past and Future: “Living with AIDS is the politically correct euphemism. Dying with a potentially manageable HIV infection is the horrible reality. Can there be a more shameful medical emergency than 30 million patients' urgently requiring life-prolonging therapy and not getting it? Not only should existing antiretroviral drugs be provided, but massive efforts to explore all other potential therapeutic options should begin immediately”

NEJM 2002: 346; 710

'Aloof' Mbeki has a lot to learn – J Carter 11/03/02

• Barbaro et al, NEJM 98: 952 pt’s over 60 months follow-up

• 76 - CMO (8%) • incidence if CD4 < 400 / AZT • myocarditis - 63 • HIV nucleic acid sequences - 58 • active myocarditis in 36 • Coxsackie B 17% ; CMV 6% ; EBV 3% • CMO - direct action of HIV on myocardial

tissue / autoimmune process induced in association with other viruses.

PresenterPresentation NotesBarbaro an co workers has performed the largest study of 952 asyptomatic pt's with HIV , published in the NEJM of last year, to evaluate the incidence and to furhter analyze the variables associated with the development of CMO

76 pt's were diagnosed with CMO over a mean follow-up of 60 months - that translates to a prevalence of 8%.

The incidence was higher in those with a CD4 count of less than 400 & in those who received AZT.

These pt's underment endomyocardial biopsy & 63 had histological evidece of myocarditis

HIV nucleic acid sequences were detected in 58 of which 36 had active myocarditis and were coinfected with Coxcackie B in 17%, CMV in 6% and EBV in 3%.

The authors concluded that dialted CMO may be related to a direct myocardial effect of the HIV itself or an autoimmune process induced by HIV in association with other cardiotropic viruses

Radiological features of the 60 hospitalized pt’s

• 35 pt’s (58%) abnormal CXR’s

* lobar consolidation 12 * infiltrates 5 *bronhiectasis 4 *pleural effusion 8 * cardiomegaly 10

No evidence of any heart disease in the out-patient’s

• normal : cardiac examination

ECG CXR ECHO

Pericardial Disease

•

• pericardial effusions are rather common, occurring in up to to 46% of AIDS patients

• common cause of clinical cardiovascular symptoms and signs

• most idiopathic. • wide array of pathogens,

often in conjunction with disseminated infection

• infections, neoplasias, myocarditis, endocarditis or myocardial infarct are possible etiologies.

http://heart.bmjjournals.com/content/vol86/issue4/images/large/001110.f3.jpeg

• overall incidence of unsuspected cardiac abnormalities - 27%

• depends on the stage of HIV disease • degree of immunosupression

correlates with the presence of cardiac lesions

• associated with late-stage infection & CD4

pulmonary hypertension & RV dilatation:

*16 (26.7%) pt’s *RVEDD :3.39 ±1.37cm

*PAP : 46 ± 7.2 mmHg

• did not occur in the absence of respiratory disease / LV dysfunction

• PHT - pneumonia / hypoxia

• successful Rx - RV afterload - normal RV dimension

• unexplained primary pulmonary hypertension (PPH)

• similar presentation to the non-HIV form

• mechanism is uncertain

• not simply a phenomenon of immunodeficiency

Accelerated atherosclerosis has been observed in young

HIV+ individuals without traditional coronary risk

factors

• Despite the clinical benefits of protease inhibitors, complications such as lipodystrophy, insulin resistance, high levels of LDL cholesterol and TG develop in up to 60% of pt’s

• Angiographically proven advanced symptomatic coronary artery disease has been reported in men < 40 y’s, Rx with protease inhibitors

• anecdotal information suggesting that the risk of angina and myocardial infarction is increased with HAART

initiating lipid lowering Rx: specific drug–drug interaction • PIs inhibit CYP3A4; NB Ritonavir • Simvastatin (contraindicated) as concentrations rise dramatically with PI

use – rhabdomyolysis

• Atorvastatin lesser degree – lower doses in HIV-pt’s

• Pravastatin not metabolised by CYP3A4 - 1st line Rx

• Rosuvastatin concentrations Atazanavir/Ritonavir & Lopinavir/Ritonavir, limiting doses to 10mg

• Rx hypertriglyceridaemia – fibrates for Tg>5.6 mmol/l

CD4 Pericardial effusion 119 ± 41

Dilated RV 184 ± 119

LV dysfunction 173 ± 113

• unexplained primary pulmonary hypertension (PPH)

• similar presentation to the non-HIV form

• mechanism is uncertain

• not simply a phenomenon of immunodeficiency

CD4 COUNTS

HOSPITAL OPD CD4 (/ul) 254 ± 202 475

± 175 p

• prevalence of older HIV individuals; by 2015 (CDC), over ½ of all HIV-pt’s will be >50 y’s

• chronic diseases & atherosclerosis • ultimately, HIV-specific adjuvant Rx in addition to ART that

target key inflammatory & coagulation pathways, should be developed to mitigate premature HIV-associated CVD

• co-ordination between ID & cardiology – improve quality of care to develop an individualized Rx plan

PresenterPresentation NotesHIV appears to increase the risk of coronary heart disease (CHD) by 1.5–2 fold in HIV infected individuals when compared with uninfected controls.Although long term treatment with highly active antiretroviral therapy (HAART) may lead to detrimental cardiovascular effects, there may be beneficial effects of HAART in the short term, providing evidence that HIV itself is mechanistically associated with increased CHD risk. The identification and treatment of cardiovascular risk factors, particularly smoking and hyperlipidaemia, should be considered in all patients with HIV infection.

HIV / AIDS: �THE HEART OF THE MATTERSir William Osler�Professor, McGill University, �Professor of Medicine, Johns Hopkins University, Baltimore,� Regius Professor of Medicine, Oxford UniversitySlide Number 32010: +34 million living with HIV worldwide; up 17% from 2001Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11hospital patientsAssessment of LV Function�fractional shortening = �EDD-ESD/EDD�Normal > 27%Echocardiographic DataEchocardiographic abnormalities & CD4Pericardial Effusion : 16 pt’s (16%)Cardiac tamponade due to a large pericardial effusionresolution of a pericardial effusion after anti-TB Rx & oral steroidsPericardial Effusion Heidenreich; Circulation 95: Prospective Evaluation of Cardiac Involvement in AIDSSlide Number 21Slide Number 22Slide Number 23Slide Number 24pericardial effusions in HIV-infected pt’s are less frequent in the era of antiretroviral treatment�Left Ventricular Dysfunction���Dilated Cardiomyopathy:���Slide Number 28Slide Number 29HIV-CMO associated more advanced immunosuppression, CD4 counts: independently associated with death Slide Number 3110 million children with HIV!pulmonary hypertension�& RV dilatation:Slide Number 34�pathogenesis not defined: pulmonary vessel endothelial proliferation & vasoconstriction triggered by pleomorphic cytokines (eg, endothelin-1, IL-6, TNF) released by HIV-infected pulmonary macrophages - not potential targets for Rx�Slide Number 36Slide Number 37Slide Number 38Slide Number 39Slide Number 40Slide Number 41Slide Number 42Slide Number 43Slide Number 44Slide Number 45Slide Number 46Slide Number 47CONCLUSIONSlide Number 49Slide Number 50Slide Number 51Pericardial DiseaseSlide Number 53Slide Number 54Slide Number 55Accelerated atherosclerosis has been observed in young HIV+ individuals without traditional coronary risk factors�Slide Number 57AIDS drugs and heart attacks�cardiac lesions are common in acutely ill patientsSlide Number 60Slide Number 61Dilated CardiomyopathyCurrie et al : BMJ 94What about children (10 million) with HIV?????? Prevalence of congenital cardiovascular malformations in children of human immunodeficiency virus-infected women : �The prospective P2C2 HIV multicenter study �CONCLUSIONSlide Number 68Slide Number 69METHODSDEMOGRAPHICS HEMOGLOBINECG’s of 60 hospital pt’sHospitalized patientsAN OBSERVATIONAL STUDY �D Jankelow, Dept Internal Medicine, University WitwatersrandSlide Number 76Slide Number 77Radiological features of the 60 hospitalized pt’sNo evidence of any heart disease in the out-patient’sPericardial DiseaseSlide Number 81pulmonary hypertension�& RV dilatation:Slide Number 83�Accelerated atherosclerosis has been observed in young HIV+ individuals without traditional coronary risk factors�Slide Number 85Slide Number 86Slide Number 87CD4 COUNTSSlide Number 89Slide Number 90