1. Introduction

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Worldwide, between 34 and 41 million people was living with HIV at the end of 2014. During the same period, nearly 1.2 million people died from AIDS-related causes including cardiovascular complications. Sub-Saharan Africa remains the region most severely affected by HIV infection accounting for 66% of the globa total of new HIV infections. In 2014 alone, there were 190,000 new HIV infections among children in sub-Saharan Africa [4].Unfortunately, the incidence of AIDS-related cardiac disease is also very high in Africa compared to that seen in the developed countries[2,3,5,6].

Cardiac complications of human immunode - ficiency virus (HIV) were appreciated early in the epidemic of acquired immunodeficiency syndrome (AIDS), even before the etiologic agent, the virus itself, was isolated and characterized [1].Globally, infection with HIV is a leading cause of acquired heart disease and specifically of symptomatic heart failure, accelerated atherosclerosis and pulmonary hypertension. Human immunodeficiency virus related cardiac abnormalities tend to occur late in the disease in those with AIDS or prolonged viral infection [2,3].

Longitudinal cardiovascular studies have shown that all components of the cardiovascular system are vulnerable during the course of the disease process. The possible causes of HIV associated cardiac disease include HIV directly affecting the heart, opportunistic infections, side effects of therapy, nutritional deficiencies, or yet unknown mechanisms[7].

There is paucity of published data addressing the cardiovascular complications of pediatric HIV infection from African setting. Hence, the goal of this clinical review is to describe the clinical spectrum of HIV-associated cardiovascular diseases in children with an emphasis on sub-Saharan Africa where it is home to the majority of the world’s HIV-infected population.

2. Materials And Methods

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Literature search for published evidence on cardiovascular complications of HIV-infection was conducted on MEDLINE, EMBRASE (inclusive from 1980-2015) and Cochrane collaboration and the Cochrane Register of Controlled Trials. The following search terms were used: human immunodeficiency virus, acquired immunodeficiency syndrome, cardiomyopathy, pericardial effusion, pulmonary hypertension, infective endocarditis, rhythm abnormalities, and accelerated atherosclerosis. Additional relevant articles were retrieved from bibliographies. Articles in both full text and abstract form were included.

As to eligibility criteria randomized clinical trials, observational cohort studies (retrospective and prospective), case control studies and case reports that had been published in English language were included. The selected outcome measures were potential cardiovascular compl - ications of HIV infection: cardiomyopa -thy, pericardial effusion, infective endocarditis, pulmonary hypertension, rhythm abnormalities and accelerated atherosclerosis.

The studies were assessed for use of an appropriate source population, measurement methods of exposure and outcome, methods to deal with design specific issues such as bias and lost to follow up. Data extraction and synthesis was done using a prepared data extraction sheet for the specific HIV-associated cardiovascular complications.

3. Results

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A total of ninety one studies were identified through electronic database searching. After adjusting for duplicates eighty four remained. Of these eight studies were discarded because after reviewing the abstracts it was found that these papers did not fulfil the inclusion criteria or full text of the study was not available in English language.

It appeared that fifteen studies did not meet the eligibility criteria as described in the flow diagram (Fig.1).The rest of the relevant papers met the inclusion criteria and were included in the systematic review.

Figure 1

4. Discussion

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Most of the published data about cardiovascular complications of HIV/AIDS have been in adults. However, HIV-related cardiac complications in children are very similar to the spectrum of disease described in adults with few exceptions [8].In developed countries, antiretroviral therapy has transformed HIV/AIDS in to a chronic and manageable condition in HIV- infected children. On the other hand, the spectrum of HIV related concerns has shifted from reduction of mortality towards long-term complications of HIV disease including various HIV- associated cardiovascular complications.

4.1. Myocardial Involvement
Human immunodeficiency virus- associated myocardial disease might be in the form of myocarditis or cardiomyopathy with systolic or diastolic dysfunction[3,8,9].One longitudinal study revealed that among HIV-infected children up to 10 years old in the pre-HAART era,25% died of chronic cardiac disease and 28% experienced serious cardiac events after an AIDS – defining illness[10].In low and middle income countries, HIV associated cardio - myopathy is a commonly encountered HIV-associated cardiac disease[5,11-13].

A multinational prospective registry of acute heart failure in sub-Saharan Africa showed that HIV-related cardiomyopathy is one of the causes of heart failure in the region [14].Few studies in Africa and the Indian sub-continent, also demonstrated that HIV-associated myocardial disease is a commonly encountered clinical problem in this patient population [6,15-17,18,20].A multicenter, observational, prospective cohort study among ART naïve patients showed that HIV-associated cardiomyo -pathy is a significant clinical problem in HIV-infected patients not receiving HAART. In the same study, it was reported that low socioeconomic status, CD4 count, HIV1-viral load, disease stage and low serum selenium level were significantly associated risk factors for HIV-associated myocardial disease[15]. Nzuobontane et al from Yaoude, Cameroon, also reported that dilated cardiomyopathy occurred in nearly a quarter of HIV-infected ART naïve patients and it was found to be associated with low CD4 count [18].

However, a study among HIV-infected Thai children failed to show the correlation between left ventricular dysfunction and HIV disease stage and nutritional status [19].Such inconsistent research work reports might be partly explained by the difference in the study population and the difference in the ART status. Because ART has significant effects on the risk factors of HIV- associated cardiovascular disease in children [21].

Several studies described that the factors that contribute to the development of myocardial dysfunction in HIV- infected individuals are multifactorial which include cytokine dysregulation, selenium deficiency, autoimmune reaction, and cardiotoxicity from therapeutic agents [22-24]. In one study, a significant selenium deficiency was demonstrated in AIDS patients [25].There is also evidence that cardiomyopathy was reversed by selenium supplementation in HIV-infected pediatric patient [23].Because nutritional deficiencies are quite common in HIV- infected children in sub-Saharan Africa, nutritional supplementation might be of help in mitigating malnutrition associated cardiomyopathy in this patient population.

Animal studies showed that cardiotoxicity from therapeutic agents such as pentamidine and possibly zidovudine produces cardiomyopathy in mice with pathologic changes in the mitochodraia[26]. A prospective, echocardiographic study with a review of clinical records and laboratory data was reported in 137 HIV-infected children receiving zidovudine, didanosine, both or no antiretroviraltherapy. In this study, the odds that dilated cardiomyopathy would develop was 8.4 times greater in children who had previously received zidovudine than those who had not [27].

An African follow up study from Kinshasa, Congo demonstrated that more than half of HIV- infected patients develop cardiac lesions. In a similar study, low socioeconomic status which is undoubtedly a common scenario in most African countries was reported to be one of the independent predictors of mortality [28].In children left ventricular fractional shortening was found to be a useful predictor of mortality, and left ventricular wall thickness a useful short-term predictor [10,29].A prospective cohort study also showed that over a 2 year period approximately 10% of HIV – infected children had congestive heart failure[30].

On the other hand, several studies showed that HAART decreased overall mortality associated with HIV infection and it has significant cardioprotective benefit by significantly decreasing the incidence of cadiomyopathy among HIV-infected children[31-33,35-37].In the largest study to date of pediatric patients, over 3000 children with HIV-infection were longitudinally followed for incident cardiomyopathy and assess the effect of HAART. In this study, the authors noted that the incidence of cardiomyopathy decreased dramatically in the post-HAART era from 25.6 cases per 1000 person-years to 3.9 cases per 100 person-years(34). However, patients remain at increased risk of cardiomyopathy if there is ongoing exposure to zidovudine [27,34].

Hence, universal access to HAART appears to be a good strategy to decrease HIV-related heart disease in developing countries particularly in sub-Saharan Africa.

4.2. Pericardial Disease
Several studies revealed that pericardial disease is commonly observed in patients with HIV infection[7,38-41].Before the HAART era, pericardial effusion occurred in up to 11% of patients with AIDS[42].According to one report the prevalence of pericardial effusion in pediatric patients with AIDS is quite high(68%) and is often associated with other HIV associated cardiac disease[38].However, a prospective and multicenter cohort study in a developed country setting showed that pericardial effusion in HIV infected patients is less frequent in the era of HAART compared to the pre-HAART period emphasizing the role of antiretroviral therapy in reducing the burden of HIV-associated pericardial disease[42].

On the other hand, in sub-Saharan Africa, the incidence of AIDS-related pericardial disease is very high compared to that seen in western developed countries [7]. Cegielski and colleagues from Tanzania reported that pericardial effusion is strongly associated with an early manifestation of HIV infection(43).

The clinical spectrum of disease etiology in HIV infected patients with pericardial effusions is associated with opportunistic infection or malignancy particularly lymphoma and Kaposi’s sarcoma. In a review of 74 reported cases of cardiac tamponade in HIV infected patients, the major causes were idiopathic(45%),mycobateria(20%),bacteria(19 %),lymphoma(7%),Kaposi’s sarcoma(5%),viruses(3%) and fungi(1%)[44].Hence, more than half of symptomatic patients with HIV- associated pericarditis have an identifiable ,and possibly treatable etiology.

In sub-Saharan Africa, where tuberculosis is endemic and access to ART is limited, pericardial disease is one of the most common forms of heart disease seen in HIV infected patients [2,5,44,46].Tuberculouspericarditis is the most common cause of pericarditis in Africa and studies from Malawi and other African country demonstrated that tuberculous pericardial effusion is strongly associated with HIV infection [43,45,46]. Although HIV-related pericardial effusion is in the majority of patients small and asymptomatic, it is a bad prognostic sign. However, the pericardial effusions rarely directly contribute to mortality but rather serve as a marker of advanced HIV infection [23,42].

4.3. Pulmonary Hypertension
Pulmonary arterial hypertension(PAH) is a progressive disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance(PVR) leading to right ventricular failure and premature death[32,47,51].Human immunodeficiency virus-related PAH is a rare entity with an estimated prevalence of 0.5% in HIV- infected patients. This rate is, however, 25-fold higher than the prevalence of PAH in the general population [47,48].

There is paucity of published data about the prevalence of HIV-related PAH in Sub-Saharan Africa. Few available studies based on echocardiography suggested that PAH were found in the range of 0.6-15% of HIV-infected individuals which is notably high compared with to those in developed countries [39,49,50].Although interstitial lung disease and vascular bed destruction by multiple pulmonary infections were thought to be involved in the pathogenesis, the exact mechanism by which idiopathic pulmonary hypertension might occur in HIV- infected patients is not well understood.One study suggested that HIV may cause endothelial damage and mediator-related vasoconstriction through stimulation by the envelope gp120,including direct release and effects of endothelin-1(vasoconstrictor),interleukin-6 and TNF-α in the pulmonary arteries.Unlike HIV-associated dilated cardiomyopathy, there was no relationship identified in the published data between CD4 cell count and HIV-related PAH[47].

Studies showed that the prevalence of HIV– related PAH has remained at 0.5% even in the modern era of HIV therapy, suggesting that HAART has not made a dramatic impact on its prevention and why HAART has not reduced the incidence or course of PAH is unknown .In view of its poor outcome once it occurs in HIV –infected patients, routine clinical and echocardiography evaluation is suggested for early detection and aggressive treatment in this patient population.

4.4. Endocardial Involvement
Most of the studies on infective endocarditis in HIV- infected individuals had been in adults. Although infective endocarditis had been reported in the literature as the first presentation of AIDS in an infant, it is rarely reported in pediatric patients [52].Common organisms reported to be associated with endocarditis in HIV include Staphylococcus aureus and Salmonella species . Nel SH et al reported no significant differences in the clinical presentation of infective endocarditis between HIV-infected and HIV-negative patients [54].

One retrospective study demonstrated that the incidence of infective endocarditis has declined with the introduction of HAART. In the same study, it was also shown that increased risk of infective endocarditis was associated with low CD4 count(< 50cells/microL) and high viral load (>100,000 copies/ml) and a history of intravenous drug abuse [55].The treatment approach to infective endocarditis in HIV-infected patients is similar to the approach to those who are HIV-seronegative.In 105 HIV- infected patients with infective endoc - arditis, severe immuno suppression and left side valvular involvement were associated with greater risk for mortality[53].

4.5. Rhythm Abnormalities
Various conduction system abnormalities have been described in patients with HIV infection. In a prospective series of 31 pediatric patients with AIDS, the occurrence of frequent rhythm abnormalities was reported[56].According to one autopsy study in six children who died of AIDS the identified histological abnormalities in the conduction system were vasculitis, myocard -itis and fragmentation with lobulation and fibrosis of the conduction system[57].

A cross-sectional study from Nigerria found that the QTc interval and resting heart rate were higher in ART naïve HIV infected patients suggesting that such patients are at a higher risk of sudden death [59].A research work from a developing country setting also demonstrated that sudden cardiac deaths account for most cardiac and non-AIDS natural deaths in HIV-infected patients .There is also a published data evidence that infection with HIV is independently associated with QTc prolongation which is almost doubled with hepatitis C co-infection and associated with a 4.5 fold higher than expected rate of sudden death[60].

4.6. Metabolic Complications And Accelerated Atherosclerosis
Patients with HIV infection are at increased risk of developing coronary heart disease at a younger age without traditional risk factors .Studies showed that endothelial dysfunction is the most plausible link between HIV infection and atherosclerosis. Increased expression of adhesion molecules, such as intercellular adhesion molecule (ICAM-1) and endothelial adhesion molecule (E-selectin), and inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL-6) occur in HIV-positive patients contributing the development of accelerated atherosclerosis [61].

The long-term benefits of ART are associated with metabolic complications including lipodystrophy, dyslipidemias, lactic acidosis, glucose intolerance, osteopenia and osteoporosis [63]. According to one study, the prevalence of lipodystrophy ranges from 1 to 57% among HIV infected children and from 2 to 84% among HIV- infected adults . In a large prospective study, it was also demonstrated the occurrences of fat redistribution being observed in 42% of children after more than 5 years of ART suggesting that such metabolic complication of ART remain a serious and on-going problem in perinatally HIV- infected children[62].

Protease inhibitors(PI) have consistently been associated with dyslipidemias(increased cholesterol and triglycerides) in children which may increase the risk of accelerated atherosclerosis in early adulthood[63].The cardio-metabolic effects of protease inhibitors was also described in animal studies showing increased LDL-cholesterol[64].On the other hand, a randomized trial among HIV- infected individuals on HAART,showed that low cholesterol diet reduces the incidence of dyslipidemia emphasizing the importance of dietary adjustments while being on antiretroviral therapy[65].

In view of the published evidences that chronic HIV therapy is associated with the development of several metabolic disturbances particularly dyslipidemia,it is recommended to obtain lipid profiles from all HIV-infected children prior to the initiation of ART with subsequent monitoring every 6 to 12 months once they are on HAART[63].

5. Conclusion And Recommendation

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Antiretroviral therapy made the long-term outcome of perinatally infected children with HIV-1 encouraging. However, with longer survival, its clinical sequelae are changing and HIV associated cardiovascular complications are one of the emerging and challenging issues in the continuum of HIV care and treatment articularly in adolescents[66-68].Higher prevalence of HIV –related cardiac complications tend to occur among children with most advanced clinical and immunologic category of HIV disease.Predictors of serious cardiac events include recurrent bacterial infection,wasting,encephalopathy,male gender,lower CD4 and IgG levels and earlier year of AIDS diagnosis[69].

There is evidence suggesting that in low and middle-income countries, chronic cardiovascular diseases are increasing in HIV-infected individuals [72].In sub-Saharan Africa little is known about the knowledge and practice of HIV-infected patients about the potential cardiovascular complications. A cross-sectional study from Kenya revealed that adult patients living with HIV lack the knowledge that they are at risk of cardiac complications [70].

As part of the continuum of pediatric HIV care and treatment, systematic cardiac evaluation including a comprehensive history and cardiac examination are essential for HIV- infected patients.It is prudent to be aware that cardiac symptoms, when present, are disguised by secondary effects of HIV-infection. However, the occurrence of cardiac symptoms warrants a formal cardiac assessment including baseline echocardiography, electrocardiography, and Holter monitoring preferably by a cardiologist. Studies in resource rich setting suggest that routine screening of HIV-infected individuals for associated cardiovascular diseases with involvement of cardiologists could be economically attractive [72-76].However; there is no evidence for the feasibility of routine HIV-related cardiac disease screening in sub-Saharan Africa which is the epicenter of the pandemic.

Based on the available evidence, strategic preventive interventions to mitigate the burden of HIV- associated cardiovascular complications include timely initiation of HAART as per local guidelines with appropriate monitoring, low cholesterol diet and exercise 65],71, 73].Considering the proven cardioprotective benefit of HAART, universal access to antiretroviral therapy is strongly recommended particularly in sub-Saharan Africa where the majority of HIV infected individuals reside.

6. Acknowledgment

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I would like to thank Children’s Heart Fund of Ethiopia (CHFE) for supporting the review research work.

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