Impact of Human Immunodeficiency Virus Infection on Cardiovascular Dis
http://www.100md.com
《循环学杂志》
The Cardiac Clinic (M.N.), Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa, and the Department of Medicine (J.H.), University of Zimbabwe, Harare, Zimbabwe.
Abstract
Background— Human immunodeficiency virus (HIV) infection is the single greatest health challenge facing Africa today. However, the impact of the HIV epidemic on the cardiovascular system in Africans has received scant attention in the world literature.
Methods and Results— We searched MEDLINE (January 1, 1980, to December 31, 2004) and reference lists of literature on HIV and the heart in Africa and contacted experts in the field. The search for this review yielded 22 articles involving HIV and the cardiovascular system from 8 countries in Africa.
Conclusions— The available information suggests that there are unique features in the etiology, presentation, and spectrum of HIV-associated cardiovascular disorders in people living in Africa. First, pericardial disease may be the initial manifestation of HIV infection in the early stages of the illness. Second, the etiology of cardiac disease tends to reflect the prevalent infectious diseases, such as tuberculosis. Third, unique cardiovascular disorders such as aneurysm of large vessels have been reported in association with HIV infection in several parts of Africa. Finally, the HIV/AIDS pandemic has put pressure on the meager healthcare resources and fragile infrastructure in many African countries, making the diagnosis and treatment of heart disease unrelated to HIV even more difficult.
Key Words: AIDS cardiomyopathy pericarditis pulmonary heart disease Africa
Introduction
Africa is home to the majority of the world’s HIV (human immunodeficiency virus)–infected population.1 Despite this, very few of the recent reviews on the cardiovascular manifestation of HIV have systematically examined the African experience.2–9 Much of the work described in the literature was conducted before highly active antiretroviral therapy (HAART) became available. Given that most HIV-infected patients in Africa do not have access to HAART,1 this body of work serves as a useful frame of reference to compare with the African experience of HIV-associated cardiac disease.
This report reviews the epidemiology and clinical spectrum of HIV-associated cardiovascular disease encountered in Africa, with emphasis on areas where the African experience has been different from that described elsewhere; the prognostic implication of HIV-related cardiovascular disease in Africans; and the extent to which HIV has had an impact on the management of non–HIV-related cardiac disease. We searched MEDLINE (January 1, 1980, to December 31, 2004) and reference lists of literature on HIV and the heart in Africa and contacted experts in the field. The search for this review yielded 22 articles involving HIV and the cardiovascular system from 8 countries in Africa (Figure 1). The majority of the articles examined aspects of pericardial disease in HIV-infected African patients.10–18 The remainder described the prevalence, clinical spectrum, and unusual features of cardiac disease in HIV-infected patients.19–32
We review and discuss the available African literature on pericardial disease, cardiomyopathy, and vascular disease. We also address other HIV-associated cardiovascular manifestations, such as endocarditis, pulmonary hypertension, and coronary disease. Finally, we highlight the impact of the HIV epidemic on health services in Africa.
Pericardial Disease
In the pre-HAART era, pericardial effusions were common in people with advanced HIV disease. The annual incidence of pericardial effusions in asymptomatic patients with AIDS was reported as 11%.33 The presence of pericardial effusion conferred a relative risk for mortality of 2.2 compared with CD4-matched controls.33 The cause of pericardial effusion in the majority of HIV-infected patients living in industrialized countries is idiopathic.33 By contrast, in Africa, the majority of pericardial disease in HIV-infected people is caused by treatable microorganisms.8 Mycobacterium tuberculosis (M tuberculosis) has been found to be the cause of pericardial disease in 86% to 100% of HIV-infected patients in Africa.11,13,16 These studies suggest that mycobacteria other than tuberculosis are rarely causative.11,13,16 Important alternative causes include pyogenic infection, lymphoma, and Kaposi sarcoma.34,35
To date, there is no conclusive randomized evidence to support claims of an optimal duration for treatment of extrapulmonary tuberculosis in HIV-infected patients.36 Despite this, the mainstay of treatment of tuberculous pericarditis in Africa is the 6-month course of antituberculosis drugs that is recommended by the World Health Organization.36 Where patients have access to HAART, the timing of the introduction of antiretroviral drugs is controversial. Potential problems related to drug interactions and the immune reconstitution syndrome are the main concerns. In those with clinically advanced HIV disease or markedly depressed CD4 count (<100x106/L), the mortality reduction associated with early introduction of HAART outweighs the cost of the increased drug toxicity and immune reactions.36,37 In those with early HIV infection, a good case can be made to delay introduction of HAART at least until after the intensive first 2 months of antituberculosis therapy.36,37 Adjunctive corticosteroids have not been shown to have a significant beneficial effect on mortality in HIV-positive patients with tuberculous pericarditis, and thus their use cannot be recommended on a routine basis.38
Early observational work from Africa suggested that HIV infection modifies the clinical presentation but not the outcome of patients with tuberculous pericarditis.14 An interesting finding was that there may be a high incidence of coexisting cardiomyopathy or myopericarditis in HIV-positive patients with tuberculous pericarditis.15 Niakara et al15 noted that the prevalence of cardiomyopathy in their retrospective analysis of patients hospitalized with pericarditis was 40%. In the pre-HIV era, antituberculosis chemotherapy was associated with a mortality of 8% to 17%, whereas a recent prospective study of patients with tuberculous pericarditis and HIV reported a mortality of 17% to 34%.12 The impact of HIV infection on the clinical course and outcome of tuberculous pericarditis is being explored in the Investigation of the Management of Pericarditis in Africa (IMPI Africa) Registry, which is expected to report its findings in the near future.18
Cardiomyopathy
In the developed world, postmortem and echocardiography studies suggest that the prevalence of HIV-associated cardiomyopathy in the pre-HAART era was 30% to 40%, and the annual incidence was 15.9 per 1000 patients.6 In Africa, cross-sectional echocardiographic studies of outpatient and inpatient HIV-infected patients suggest a prevalence of cardiomyopathy of 9% to 57%.21,29,30,32 Only 1 study followed ambulant patients prospectively,24 and it reported an incidence of 16.9% over 18 months.24 Varying study designs and populations and the lack of a common definition for HIV-associated cardiomyopathy may account in part for the wide range of observed prevalence rates. The fact that left ventricular dysfunction is common in acutely ill patients even outside the setting of HIV may also have distorted the prevalence rates.39
HIV-associated cardiomyopathy has been shown to be associated with more advanced immunosuppression and lower CD4 lymphocyte counts and is independently associated with death. A study from Scotland noted that the median survival to AIDS-related death is 101 days in patients with dilated cardiomyopathy as opposed to the 472 days in their CD4-matched controls.40 Cardiomyopathy was strongly associated with CD4 counts <100x106/L. A recent study from Cameroon demonstrated a similar relationship between the degree of immunosuppression and the likelihood of cardiomyopathy.30 Interestingly, a CD4 count of 100x106/L proved to be the important threshold in that study as well.30 The prognostic implication of the diagnosis of cardiomyopathy in HIV-infected Africans is not as clear and may be different. Among 133 Congolese patients with cardiomyopathy reviewed retrospectively over a 10-year period, the reported overall mortality was 15% to 20%.32 In a study on the determinants of survival in HIV-positive patients with cardiac involvement from the Democratic Republic of Congo (DRC), cardiomyopathy was associated with a slower progression to AIDS and death.25 The average CD4 count in that study was high (>700x106/L) at enrollment, which suggests that the apparent protection against progression to AIDS may have been an epiphenomenon and should be interpreted with caution. In the absence of a carefully conducted study with strict exclusion and inclusion criteria and that is free of any biases that may be present in some of the above studies, it is very difficult to link cardiomyopathy to HIV status or CD4 counts and separate it from comorbid conditions.
There are limited data on the pathogenesis of cardiomyopathy in HIV-infected individuals in Africa. Information on cardiac histology is available from 16 patients from the DRC.25 All 16 patients had histopathological evidence of myocarditis. The cause of the myocarditis was Toxoplasma gondii in 3 (18.75%) of 16, Cryptococcus neoformans in another 3 (18.75%), Mycobacterium avium intracellulare in 2 (12.5%), and direct HIV invasion in the remainder (50%). Although it is difficult to extrapolate these results to larger populations of patients with HIV cardiomyopathy, it is noteworthy that there was such a significant proportion of opportunistic infectious causes. By contrast, opportunistic infectious diseases were not a common cause of myocarditis in the pre-HAART era in the developed world, where cardiotropic viruses were implicated in the majority of cases.2,4
There 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 era.41 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.41
Vascular Disease
Estimates from outside Africa are that the incidence of HIV-associated vasculitis is less than 1%.42 HIV-associated vascular disease is classified into 4 groups, as outlined in the Table.42 Group IV large-vessel vasculopathy involving the aorta or its major branches is increasingly being recognized in young African patients (mean age 31 years) who have no evidence of atherosclerosis, syphilis, or another cause for vasculitis and occurs at a relatively early stage of HIV disease (median CD4 count 370x106/L; Figure 2). 26–28,31,43 Typical histological features are a lymphocytic and monocytic inflammatory infiltrate of the endothelium and vasa vasorum, which results in a fibro-occlusive pattern with luminal narrowing and dilatation.20 This pathological process has been described as either an idiopathic focal necrotizing vasculitis associated with aneurysm formation or a granulomatous vasculitis with fibroproliferative vascular occlusion.26
Classification of HIV-Associated Vascular Disease42
Clinically, the majority of patients present with growing masses that may or may not be painful. Occasionally, patients present due to symptoms related to compression of surrounding tissue with peripheral neuropathies, dysphagia, and abdominal pain.27 A few of the cases also involved the left ventricle.26 Management is conservative, with only the occasional patient requiring surgery.27,28,43
Other Cardiovascular Manifestations: Coronary Artery Disease, Infective Endocarditis, and Pulmonary Hypertension
There is a paucity of literature addressing coronary artery disease, infective endocarditis, and pulmonary hypertension in HIV-infected patients in Africa. However, in view of experience elsewhere in the world, the absence of systematic documentation of the scope of these problems in Africa should not diminish their potential impact or importance.
HIV can affect coronary arteries by several mechanisms. It can initiate an inflammatory response in the coronary vasculature, which may induce endothelial dysfunction and promote atherosclerosis.44 Using in situ hybridization, HIV-1 genomic sequences have been found in the coronary vessels of HIV-infected patients who died of coronary arteritis and acute myocardial infarction.45 Furthermore, there is an association between the use of protease inhibitor antiretroviral drugs and coronary artery events.46 The high background prevalence of conventional risk factors for coronary artery disease where the issue has been addressed has made it difficult to demonstrate a firm link.46 A large prospective, observational study concluded that combination antiretroviral drugs were independently associated with a small but significant increase in coronary events but that the bulk of the attributable risk was related to conventional risk factors.47 Coronary disease is relatively uncommon among black Africans at present, but with the ongoing rapid urbanization of many African societies, this may soon change.48 In light of the much publicized World Health Organization 3x5 initiative, in which by the end of 2005 it is hoped that 3 million people in lower- and middle-income countries will be provided with HAART,1 the issue of coronary disease in HIV-infected individuals receiving HAART may become more important in the near future.
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 200/μL, or Gram-negative organisms or fungi are involved.49,50 Finally, friable endocardial vegetations known as nonbacterial thrombotic endocarditis were noted in 3% to 5% of patients in Western series in the pre-HAART era.6 The disorder, which has a predilection for patients with the wasting syndrome, has not been described in Africa.
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-) 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.51
Impact of HIV on Health Care in Africa
Recent projections suggest that in the African countries with the highest seropositive prevalence rates, 60% of today’s 15-year-olds will not live to age 601 (Figure 3).52 The mortality rate for HIV-infected 14- to 49-year-olds is 40 times that of their HIV-seronegative age-matched compatriots. Compared with their HIV-positive age-matched counterparts in the developed world, death rates are up to 20 times higher in people living in Africa.1 Given what we know about HIV-associated cardiac disease, a small but significant proportion of the morbidity and mortality will be due to cardiovascular disease. For those interested in cardiology, this may represent a major opportunity to both help those in need and learn from well-conducted research of people with potentially unique problems.
The meager healthcare budgets in most African countries have not sufficient to cope with the added burden imposed by the HIV pandemic. In an environment where most people are dependent on government health care, the impact of AIDS has been crippling. In some countries, up to 16% of healthcare workers are HIV seropositive, and it is estimated that between 19% and 53% of all government health employee deaths are AIDS related.53 The result has been a continuous depletion from the healthcare sector of much needed skills and personnel.1 Despite this, between 1992 and 2002 in some of the areas most affected by HIV, clinic visits increased by as much as 88% and hospital admissions by 81%.53 Overall, the result has been that decades of progress in socioeconomic development, health care, and improvement in life expectancy are rapidly being reversed.1
There is good evidence that HAART significantly reduces the incidence of cardiovascular manifestations of HIV infection.41 However, only 5% of infected adults on the African continent who need HAART receive it.1 African countries are only able to spend 1000 times less on care per HIV-infected patient than the United States.1 There is a glimmer of hope that this vicious circle of severe poverty, high incidence of HIV, poor access to HAART, and high prevalence of HIV-related cardiac disorders will eventually be broken. Several large international funding initiatives have been launched to tackle the HIV/AIDS epidemic in Africa. These include The Global Fund to Fight AIDS, Tuberculosis and Malaria; The Bill and Melinda Gates Foundation; and the World Health Organization’s 3x5 program. These will provide the financing for the much-needed comprehensive treatment programs and other requirements necessary to reverse the impact of what Nelson Mandela has described as "a tragedy of unprecedented proportions unfolding in Africa."
Conclusions
The incidence of opportunistic infections of the heart has increased significantly since the beginning of the HIV epidemic in Africa. Cardiologists and physicians from across the continent are reporting more heart muscle disease, and vascular surgeons have been seeing a larger number of unusual diseases of the aorta and its branches. Unfortunately, to date, most African countries have been unable to deal adequately with the massive healthcare burden the pandemic has created, and despite signs that there is a brighter future ahead, the impact of HIV on this continent will likely be felt for generations to come.
Acknowledgments
The authors acknowledge MESAB (Medical Education for South African Blacks) for their funding through the Don Kennedy Research Grant and the following individuals for their critical comment: Gary Maartens, Patrick Commerford, Graeme Meintjes, and Azeem Latib. A special thanks to Charles Wiysonge and Lucien Bushidi for translating the French articles.
Disclosures
None.
References
Joint United Nations Programme on HIV/AIDS. UNAIDS 2004 report on the global AIDS epidemic. Available at: http://www.unaids.org/bangkok2004/report.html. Accessed January 12, 2004.
Barbaro G. Pathogenesis of HIV-associated heart disease. AIDS. 2003; 17: S12–S20.
Barbaro G, Klatt E. HIV infection and the cardiovascular system. AIDS Rev. 2002; 4: 93–103.
Barbaro G, Fisher SD, Lipshultz SE. Pathogenesis of HIV-associated cardiovascular complications. Lancet Infect Dis. 2001; 1: 115–124.
Barbaro G. Cardiovascular manifestations of HIV infection. Circulation. 2002; 106: 1420–1425.
Barbarini G, Barbaro G. Incidence of the involvement of the cardiovascular system in HIV infection. AIDS. 2003; 17: S46–S50.
Autran B, Gorin I, Leibowitch M, Laroche L, Escande JP, Hewitt J, Marche C. AIDS in a Haitian woman with cardiac Kaposi’s sarcoma and Whipple’s disease. Lancet. 1983; 1: 767–768.
Magula NP, Mayosi BM. Cardiac involvement in HIV infected people living in Africa: a review. Cardiovasc J S Afr. 2003; 14: 231–237.
Prendergast BD. HIV and cardiovascular medicine. Heart. 2003; 89: 793–800.
Cegielski JP, Ramiya K, Lallinger GJ, Mtulia IA, Mbaga IM. Pericardial disease and human immunodeficiency virus in Dar es Salaam, Tanzania. Lancet. 1990; 335: 209–212.
Cegielski JP, Lwakatare J, Dukes CS, Lema LE, Lallinger GJ, Kitinya J, Reller LB, Sheriff F. Tuberculous pericarditis in Tanzanian patients with and without HIV infection. Tuber Lung Dis. 1994; 75: 429–434.
Hakim JG, Ternouth I, Mushangi E, Siziya S, Robertson V, Malin A. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart. 2000; 84: 183–188.
Longo-Mbenza B, Tonduangu K, Seghers KV. HIV infection and pericardial disease invasion in Africa [in French]. Arch Mal Coeur Vaiss. 1997; 90: 1377–1384.
Maher D, Harries AD. Tuberculous pericardial effusion: a prospective clinical study in a low-resource setting: Blantyre, Malawi. Int J Tuberc Lung Dis. 1997; 1: 358–364.
Niakara A, Kambire Y, Drabo YJ. Pericarditis in HIV infected patients: retrospective study of 40 cases in Ouagadougou, Burkina Faso [in French]. Sante. 2001; 11: 167–172.
Taelman H, Kagame A, Batungwanayo J, Nyirabareja A, Abdel Aziz M, Blanche P, Bogaerts J, van de Perre P. Pericardial effusion and HIV infection. Lancet. 1990; 335: 924. Letter.
Pozniak AL, Weinberg J, Mahari M, Neill P, Houston S, Latif A. Tuberculous pericardial effusion associated with HIV infection: a sign of disseminated disease. Tuber Lung Dis. 1994; 75: 297–300.
Wiysonge CS, Ntsekhe M, Mayosi BM. Initial report of the initiative to investigate the optimal management of tuberculous pericarditis in Africa. J Am Coll Cardiol. 2005; 45: 141A. Abstract.
Amoah A, Kallen C. Aetiology of heart failure as seen from a National Cardiac Referral Centre in Africa. Cardiology. 2000; 93: 11–18.
Chetty R, Batitang S, Nair R. Large artery vasculopathy in HIV positive patients: another vasculitic enigma. Hum Path. 2000; 31: 374–379.
Hakim JG, Matenga JA, Siziya S. Myocardial dysfunction in human immunodeficiency virus: an echocardiographic study of 157 patients in hospital in Zimbabwe. Heart. 1996; 76: 161–165.
Hakim JG, Manyemba J. Cardiac disease distribution among patients referred for echocardiography in Harare, Zimbabwe. Cent Afr J Med. 1998; 44: 140–144.
Koegelenberg CFN, Doubell AF, Orth H, Reuter H. Infective endocarditis in the Western Cape Province of South Africa: a three year prospective study. QJM. 203; 96: 217–225.
Longo-Mbenza B, Tonduangu K, Muvova D, Phuati MB, Seghers KV, Kestelot H. A clinical study of cardiac manifestations related to acquired immunodeficiency syndrome (AIDS) in Kinshasa [in French]. Arch Mal Coeur Vaiss. 1995; 88: 1437–1443.
Longo-Mbenza B, Seghers KV, Phuati M, Bikangi FN, Mubagwa K. Heart involvement and HIV infection in African patients: determinants of survival. Int J Cardiol. 1998; 64: 63–73.
Marks C, Kuskov S. Pattern of arterial aneurysms in acquired immunodeficiency disease. World J Surg. 1995; 9: 127–132.
Nair R, Robbs JV, Naidoo NG, Woolgar J. Clinical profile of HIV-related aneurysms. Eur J Vasc Endovasc Surg. 2000; 20: 235–240.
Nair R, Abdool-Carrim A, Chetty R, Robbs J. Arterial aneurysms in patients infected with human immunodeficiency virus: a distinct clinico-pathology entity J Vasc Surg. 1999; 29: 600–607.
Niakara A, Drabo YJ, Kambire Y, Nebie LV, Kabore NJ, Simon F. Cardiovascular diseases and HIV infection: study of 79 cases at the National Hospital of Ouagadougou (Burkina Faso) [in French]. Bull Soc Pathol Exot. 2002; 95: 23–26.
Nzuobontane D, Blackett KN, Kuaban C. Cardiac involvement in HIV infected people in Yaounde, Cameroon. Postgrad Med J. 2002; 78: 678–681.
Sinzobahamvya N, Kalangu K, Hamel-Kalinowski W. Arterial aneurysms associated with human immunodeficiency virus (HIV) infection. Acta Chir Belg. 1989; 89: 185–158.
Bouramoue C, Ekoba J. The heart and AIDS [in French]. Med Trop (Mars). 1996; 56: 33–39.
Heidenreich PA, Eisenberg MJ, Kee LL, Somelofski CA, Hollander H, Schiller NB, Cheitlin MD. Pericardial effusion in AIDS: incidence and survival. Circulation. 1995; 92: 3229–3234.
Chen Y, Brennessel D, Walters J, Johnson M, Rosner F, Raza M. Human immunodeficiency virus-associated pericardial effusion: report of 40 cases and review of the literature. Am Heart J. 1999; 137: 516–521.
Reynolds MM, Hecht SR, Berger M, Kolokathis A, Horowitz SF. Large pericardial effusions in the acquired immunodeficiency syndrome. Chest. 1992; 102: 1746–1747.
Blanc L, Chaulet P, Espinal M, Graham S, Grzemska M, Harries AD, Luelmo F, Maher D, O’Brien R, Raviglione MC, Rieder H, Starke J, Uplekar M, Wells C. HIV infection and tuberculosis. In: Lee JW, ed. Treatment of Tuberculosis: Guidelines for National Programmes. 3rd ed. Geneva, Switzerland: World Health Organization; 2003: 75–85.
Dheda K, Lampe FC, Johnson MA, Lipman MC. Outcome of HIV associated tuberculosis in the era of highly active anti-retroviral therapy. J Infect Dis. 2004; 190: 1670–1676.
Ntsekhe M, Wiysonge C, Volmink JA, Commerford PJ, Mayosi BM. Adjuvant corticosteroids for tuberculous pericarditis: promising, but not proven. QJM. 2003; 96: 593–599.
Artucio H, Digenio A, Pereyra M. Left ventricular function during sepsis. Crit Care Med. 1989; 17: 323–327.
Currie PF, Jacob AJ, Foreman AR, Elton AR, Brettle RP, Boon NA. Heart muscle disease related to HIV infection: prognostic implications. BMJ. 1994; 309: 1605–1607.
Pugliese A, Isnardi D, Saini A, Scarabelli T, Raddino R, Torre D. Impact of highly active antiretroviral therapy in HIV-positive patients with cardiac involvement. J Infect. 2000; 40: 282–284.
Johnson RM, Barbarini G, Barboro G. Kawasaki-like syndromes and other vasculitic syndromes in HIV infected patients. AIDS. 2003; 17: S77–S82.
van Marle JTL, Weir G, Botes K. Vascular disease in HIV/AIDS patients. S Afr Med J. 2002; 92: 974–979.
de Gaetano Donati K, Rabagliati R, Iacoviello L, Cauda R. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. Lancet Infect Dis. 2004; 4: 213–222.
Barbaro G, Barbarini G, Pellicelli AM. HIV-associated coronary arteritis in a patient with fatal myocardial infarction. N Engl J Med. 2001; 344: 1799–1800.
Mooser M. Atherosclerosis and HIV in the highly active antiretroviral therapy era: towards an epidemic of cardiovascular disease AIDS. 2003; 17: S65–S69.
The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003; 349: 1993–2003.
Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases, part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation. 2001; 104: 2855–2864.
Cicalini S, Forcina G, De Rosa FG. Infective endocarditis in patients with human immunodeficiency virus infection. J Infect. 2001; 42: 267–271.
Miro JM, del Rio A, Mestres CA. Infective endocarditis and cardiac surgery in intravenous drug abusers and HIV-1 infected patients. Cardiol Clin. 2003; 21: 167–184.
Opravil M, Pechere M, Speich R, Joller-Jemelka HI, Jenni R, Russi EW, Hirschel B, Luthy R. HIV associated primary pulmonary hypertension: a case control study: Swiss HIV Cohort Study. Am J Respir Crit Care Med. 1997; 155: 990–995.
US Census Bureau, Population Division, International Programs Center. HIV/AIDS surveillance data base maps, September 2004. Available at: http://www.census.gov/ipc/www/hivmaps.html. Accessed November 7, 2005.
Benatar SR. Health care reform and the crisis of HIV and AIDS in South Africa. N Engl J Med. 2004; 351: 81–92.(Mpiko Ntsekhe, MD; James Hakim, FRCP)
Abstract
Background— Human immunodeficiency virus (HIV) infection is the single greatest health challenge facing Africa today. However, the impact of the HIV epidemic on the cardiovascular system in Africans has received scant attention in the world literature.
Methods and Results— We searched MEDLINE (January 1, 1980, to December 31, 2004) and reference lists of literature on HIV and the heart in Africa and contacted experts in the field. The search for this review yielded 22 articles involving HIV and the cardiovascular system from 8 countries in Africa.
Conclusions— The available information suggests that there are unique features in the etiology, presentation, and spectrum of HIV-associated cardiovascular disorders in people living in Africa. First, pericardial disease may be the initial manifestation of HIV infection in the early stages of the illness. Second, the etiology of cardiac disease tends to reflect the prevalent infectious diseases, such as tuberculosis. Third, unique cardiovascular disorders such as aneurysm of large vessels have been reported in association with HIV infection in several parts of Africa. Finally, the HIV/AIDS pandemic has put pressure on the meager healthcare resources and fragile infrastructure in many African countries, making the diagnosis and treatment of heart disease unrelated to HIV even more difficult.
Key Words: AIDS cardiomyopathy pericarditis pulmonary heart disease Africa
Introduction
Africa is home to the majority of the world’s HIV (human immunodeficiency virus)–infected population.1 Despite this, very few of the recent reviews on the cardiovascular manifestation of HIV have systematically examined the African experience.2–9 Much of the work described in the literature was conducted before highly active antiretroviral therapy (HAART) became available. Given that most HIV-infected patients in Africa do not have access to HAART,1 this body of work serves as a useful frame of reference to compare with the African experience of HIV-associated cardiac disease.
This report reviews the epidemiology and clinical spectrum of HIV-associated cardiovascular disease encountered in Africa, with emphasis on areas where the African experience has been different from that described elsewhere; the prognostic implication of HIV-related cardiovascular disease in Africans; and the extent to which HIV has had an impact on the management of non–HIV-related cardiac disease. We searched MEDLINE (January 1, 1980, to December 31, 2004) and reference lists of literature on HIV and the heart in Africa and contacted experts in the field. The search for this review yielded 22 articles involving HIV and the cardiovascular system from 8 countries in Africa (Figure 1). The majority of the articles examined aspects of pericardial disease in HIV-infected African patients.10–18 The remainder described the prevalence, clinical spectrum, and unusual features of cardiac disease in HIV-infected patients.19–32
We review and discuss the available African literature on pericardial disease, cardiomyopathy, and vascular disease. We also address other HIV-associated cardiovascular manifestations, such as endocarditis, pulmonary hypertension, and coronary disease. Finally, we highlight the impact of the HIV epidemic on health services in Africa.
Pericardial Disease
In the pre-HAART era, pericardial effusions were common in people with advanced HIV disease. The annual incidence of pericardial effusions in asymptomatic patients with AIDS was reported as 11%.33 The presence of pericardial effusion conferred a relative risk for mortality of 2.2 compared with CD4-matched controls.33 The cause of pericardial effusion in the majority of HIV-infected patients living in industrialized countries is idiopathic.33 By contrast, in Africa, the majority of pericardial disease in HIV-infected people is caused by treatable microorganisms.8 Mycobacterium tuberculosis (M tuberculosis) has been found to be the cause of pericardial disease in 86% to 100% of HIV-infected patients in Africa.11,13,16 These studies suggest that mycobacteria other than tuberculosis are rarely causative.11,13,16 Important alternative causes include pyogenic infection, lymphoma, and Kaposi sarcoma.34,35
To date, there is no conclusive randomized evidence to support claims of an optimal duration for treatment of extrapulmonary tuberculosis in HIV-infected patients.36 Despite this, the mainstay of treatment of tuberculous pericarditis in Africa is the 6-month course of antituberculosis drugs that is recommended by the World Health Organization.36 Where patients have access to HAART, the timing of the introduction of antiretroviral drugs is controversial. Potential problems related to drug interactions and the immune reconstitution syndrome are the main concerns. In those with clinically advanced HIV disease or markedly depressed CD4 count (<100x106/L), the mortality reduction associated with early introduction of HAART outweighs the cost of the increased drug toxicity and immune reactions.36,37 In those with early HIV infection, a good case can be made to delay introduction of HAART at least until after the intensive first 2 months of antituberculosis therapy.36,37 Adjunctive corticosteroids have not been shown to have a significant beneficial effect on mortality in HIV-positive patients with tuberculous pericarditis, and thus their use cannot be recommended on a routine basis.38
Early observational work from Africa suggested that HIV infection modifies the clinical presentation but not the outcome of patients with tuberculous pericarditis.14 An interesting finding was that there may be a high incidence of coexisting cardiomyopathy or myopericarditis in HIV-positive patients with tuberculous pericarditis.15 Niakara et al15 noted that the prevalence of cardiomyopathy in their retrospective analysis of patients hospitalized with pericarditis was 40%. In the pre-HIV era, antituberculosis chemotherapy was associated with a mortality of 8% to 17%, whereas a recent prospective study of patients with tuberculous pericarditis and HIV reported a mortality of 17% to 34%.12 The impact of HIV infection on the clinical course and outcome of tuberculous pericarditis is being explored in the Investigation of the Management of Pericarditis in Africa (IMPI Africa) Registry, which is expected to report its findings in the near future.18
Cardiomyopathy
In the developed world, postmortem and echocardiography studies suggest that the prevalence of HIV-associated cardiomyopathy in the pre-HAART era was 30% to 40%, and the annual incidence was 15.9 per 1000 patients.6 In Africa, cross-sectional echocardiographic studies of outpatient and inpatient HIV-infected patients suggest a prevalence of cardiomyopathy of 9% to 57%.21,29,30,32 Only 1 study followed ambulant patients prospectively,24 and it reported an incidence of 16.9% over 18 months.24 Varying study designs and populations and the lack of a common definition for HIV-associated cardiomyopathy may account in part for the wide range of observed prevalence rates. The fact that left ventricular dysfunction is common in acutely ill patients even outside the setting of HIV may also have distorted the prevalence rates.39
HIV-associated cardiomyopathy has been shown to be associated with more advanced immunosuppression and lower CD4 lymphocyte counts and is independently associated with death. A study from Scotland noted that the median survival to AIDS-related death is 101 days in patients with dilated cardiomyopathy as opposed to the 472 days in their CD4-matched controls.40 Cardiomyopathy was strongly associated with CD4 counts <100x106/L. A recent study from Cameroon demonstrated a similar relationship between the degree of immunosuppression and the likelihood of cardiomyopathy.30 Interestingly, a CD4 count of 100x106/L proved to be the important threshold in that study as well.30 The prognostic implication of the diagnosis of cardiomyopathy in HIV-infected Africans is not as clear and may be different. Among 133 Congolese patients with cardiomyopathy reviewed retrospectively over a 10-year period, the reported overall mortality was 15% to 20%.32 In a study on the determinants of survival in HIV-positive patients with cardiac involvement from the Democratic Republic of Congo (DRC), cardiomyopathy was associated with a slower progression to AIDS and death.25 The average CD4 count in that study was high (>700x106/L) at enrollment, which suggests that the apparent protection against progression to AIDS may have been an epiphenomenon and should be interpreted with caution. In the absence of a carefully conducted study with strict exclusion and inclusion criteria and that is free of any biases that may be present in some of the above studies, it is very difficult to link cardiomyopathy to HIV status or CD4 counts and separate it from comorbid conditions.
There are limited data on the pathogenesis of cardiomyopathy in HIV-infected individuals in Africa. Information on cardiac histology is available from 16 patients from the DRC.25 All 16 patients had histopathological evidence of myocarditis. The cause of the myocarditis was Toxoplasma gondii in 3 (18.75%) of 16, Cryptococcus neoformans in another 3 (18.75%), Mycobacterium avium intracellulare in 2 (12.5%), and direct HIV invasion in the remainder (50%). Although it is difficult to extrapolate these results to larger populations of patients with HIV cardiomyopathy, it is noteworthy that there was such a significant proportion of opportunistic infectious causes. By contrast, opportunistic infectious diseases were not a common cause of myocarditis in the pre-HAART era in the developed world, where cardiotropic viruses were implicated in the majority of cases.2,4
There 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 era.41 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.41
Vascular Disease
Estimates from outside Africa are that the incidence of HIV-associated vasculitis is less than 1%.42 HIV-associated vascular disease is classified into 4 groups, as outlined in the Table.42 Group IV large-vessel vasculopathy involving the aorta or its major branches is increasingly being recognized in young African patients (mean age 31 years) who have no evidence of atherosclerosis, syphilis, or another cause for vasculitis and occurs at a relatively early stage of HIV disease (median CD4 count 370x106/L; Figure 2). 26–28,31,43 Typical histological features are a lymphocytic and monocytic inflammatory infiltrate of the endothelium and vasa vasorum, which results in a fibro-occlusive pattern with luminal narrowing and dilatation.20 This pathological process has been described as either an idiopathic focal necrotizing vasculitis associated with aneurysm formation or a granulomatous vasculitis with fibroproliferative vascular occlusion.26
Classification of HIV-Associated Vascular Disease42
Clinically, the majority of patients present with growing masses that may or may not be painful. Occasionally, patients present due to symptoms related to compression of surrounding tissue with peripheral neuropathies, dysphagia, and abdominal pain.27 A few of the cases also involved the left ventricle.26 Management is conservative, with only the occasional patient requiring surgery.27,28,43
Other Cardiovascular Manifestations: Coronary Artery Disease, Infective Endocarditis, and Pulmonary Hypertension
There is a paucity of literature addressing coronary artery disease, infective endocarditis, and pulmonary hypertension in HIV-infected patients in Africa. However, in view of experience elsewhere in the world, the absence of systematic documentation of the scope of these problems in Africa should not diminish their potential impact or importance.
HIV can affect coronary arteries by several mechanisms. It can initiate an inflammatory response in the coronary vasculature, which may induce endothelial dysfunction and promote atherosclerosis.44 Using in situ hybridization, HIV-1 genomic sequences have been found in the coronary vessels of HIV-infected patients who died of coronary arteritis and acute myocardial infarction.45 Furthermore, there is an association between the use of protease inhibitor antiretroviral drugs and coronary artery events.46 The high background prevalence of conventional risk factors for coronary artery disease where the issue has been addressed has made it difficult to demonstrate a firm link.46 A large prospective, observational study concluded that combination antiretroviral drugs were independently associated with a small but significant increase in coronary events but that the bulk of the attributable risk was related to conventional risk factors.47 Coronary disease is relatively uncommon among black Africans at present, but with the ongoing rapid urbanization of many African societies, this may soon change.48 In light of the much publicized World Health Organization 3x5 initiative, in which by the end of 2005 it is hoped that 3 million people in lower- and middle-income countries will be provided with HAART,1 the issue of coronary disease in HIV-infected individuals receiving HAART may become more important in the near future.
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 200/μL, or Gram-negative organisms or fungi are involved.49,50 Finally, friable endocardial vegetations known as nonbacterial thrombotic endocarditis were noted in 3% to 5% of patients in Western series in the pre-HAART era.6 The disorder, which has a predilection for patients with the wasting syndrome, has not been described in Africa.
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-) 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.51
Impact of HIV on Health Care in Africa
Recent projections suggest that in the African countries with the highest seropositive prevalence rates, 60% of today’s 15-year-olds will not live to age 601 (Figure 3).52 The mortality rate for HIV-infected 14- to 49-year-olds is 40 times that of their HIV-seronegative age-matched compatriots. Compared with their HIV-positive age-matched counterparts in the developed world, death rates are up to 20 times higher in people living in Africa.1 Given what we know about HIV-associated cardiac disease, a small but significant proportion of the morbidity and mortality will be due to cardiovascular disease. For those interested in cardiology, this may represent a major opportunity to both help those in need and learn from well-conducted research of people with potentially unique problems.
The meager healthcare budgets in most African countries have not sufficient to cope with the added burden imposed by the HIV pandemic. In an environment where most people are dependent on government health care, the impact of AIDS has been crippling. In some countries, up to 16% of healthcare workers are HIV seropositive, and it is estimated that between 19% and 53% of all government health employee deaths are AIDS related.53 The result has been a continuous depletion from the healthcare sector of much needed skills and personnel.1 Despite this, between 1992 and 2002 in some of the areas most affected by HIV, clinic visits increased by as much as 88% and hospital admissions by 81%.53 Overall, the result has been that decades of progress in socioeconomic development, health care, and improvement in life expectancy are rapidly being reversed.1
There is good evidence that HAART significantly reduces the incidence of cardiovascular manifestations of HIV infection.41 However, only 5% of infected adults on the African continent who need HAART receive it.1 African countries are only able to spend 1000 times less on care per HIV-infected patient than the United States.1 There is a glimmer of hope that this vicious circle of severe poverty, high incidence of HIV, poor access to HAART, and high prevalence of HIV-related cardiac disorders will eventually be broken. Several large international funding initiatives have been launched to tackle the HIV/AIDS epidemic in Africa. These include The Global Fund to Fight AIDS, Tuberculosis and Malaria; The Bill and Melinda Gates Foundation; and the World Health Organization’s 3x5 program. These will provide the financing for the much-needed comprehensive treatment programs and other requirements necessary to reverse the impact of what Nelson Mandela has described as "a tragedy of unprecedented proportions unfolding in Africa."
Conclusions
The incidence of opportunistic infections of the heart has increased significantly since the beginning of the HIV epidemic in Africa. Cardiologists and physicians from across the continent are reporting more heart muscle disease, and vascular surgeons have been seeing a larger number of unusual diseases of the aorta and its branches. Unfortunately, to date, most African countries have been unable to deal adequately with the massive healthcare burden the pandemic has created, and despite signs that there is a brighter future ahead, the impact of HIV on this continent will likely be felt for generations to come.
Acknowledgments
The authors acknowledge MESAB (Medical Education for South African Blacks) for their funding through the Don Kennedy Research Grant and the following individuals for their critical comment: Gary Maartens, Patrick Commerford, Graeme Meintjes, and Azeem Latib. A special thanks to Charles Wiysonge and Lucien Bushidi for translating the French articles.
Disclosures
None.
References
Joint United Nations Programme on HIV/AIDS. UNAIDS 2004 report on the global AIDS epidemic. Available at: http://www.unaids.org/bangkok2004/report.html. Accessed January 12, 2004.
Barbaro G. Pathogenesis of HIV-associated heart disease. AIDS. 2003; 17: S12–S20.
Barbaro G, Klatt E. HIV infection and the cardiovascular system. AIDS Rev. 2002; 4: 93–103.
Barbaro G, Fisher SD, Lipshultz SE. Pathogenesis of HIV-associated cardiovascular complications. Lancet Infect Dis. 2001; 1: 115–124.
Barbaro G. Cardiovascular manifestations of HIV infection. Circulation. 2002; 106: 1420–1425.
Barbarini G, Barbaro G. Incidence of the involvement of the cardiovascular system in HIV infection. AIDS. 2003; 17: S46–S50.
Autran B, Gorin I, Leibowitch M, Laroche L, Escande JP, Hewitt J, Marche C. AIDS in a Haitian woman with cardiac Kaposi’s sarcoma and Whipple’s disease. Lancet. 1983; 1: 767–768.
Magula NP, Mayosi BM. Cardiac involvement in HIV infected people living in Africa: a review. Cardiovasc J S Afr. 2003; 14: 231–237.
Prendergast BD. HIV and cardiovascular medicine. Heart. 2003; 89: 793–800.
Cegielski JP, Ramiya K, Lallinger GJ, Mtulia IA, Mbaga IM. Pericardial disease and human immunodeficiency virus in Dar es Salaam, Tanzania. Lancet. 1990; 335: 209–212.
Cegielski JP, Lwakatare J, Dukes CS, Lema LE, Lallinger GJ, Kitinya J, Reller LB, Sheriff F. Tuberculous pericarditis in Tanzanian patients with and without HIV infection. Tuber Lung Dis. 1994; 75: 429–434.
Hakim JG, Ternouth I, Mushangi E, Siziya S, Robertson V, Malin A. Double blind randomised placebo controlled trial of adjunctive prednisolone in the treatment of effusive tuberculous pericarditis in HIV seropositive patients. Heart. 2000; 84: 183–188.
Longo-Mbenza B, Tonduangu K, Seghers KV. HIV infection and pericardial disease invasion in Africa [in French]. Arch Mal Coeur Vaiss. 1997; 90: 1377–1384.
Maher D, Harries AD. Tuberculous pericardial effusion: a prospective clinical study in a low-resource setting: Blantyre, Malawi. Int J Tuberc Lung Dis. 1997; 1: 358–364.
Niakara A, Kambire Y, Drabo YJ. Pericarditis in HIV infected patients: retrospective study of 40 cases in Ouagadougou, Burkina Faso [in French]. Sante. 2001; 11: 167–172.
Taelman H, Kagame A, Batungwanayo J, Nyirabareja A, Abdel Aziz M, Blanche P, Bogaerts J, van de Perre P. Pericardial effusion and HIV infection. Lancet. 1990; 335: 924. Letter.
Pozniak AL, Weinberg J, Mahari M, Neill P, Houston S, Latif A. Tuberculous pericardial effusion associated with HIV infection: a sign of disseminated disease. Tuber Lung Dis. 1994; 75: 297–300.
Wiysonge CS, Ntsekhe M, Mayosi BM. Initial report of the initiative to investigate the optimal management of tuberculous pericarditis in Africa. J Am Coll Cardiol. 2005; 45: 141A. Abstract.
Amoah A, Kallen C. Aetiology of heart failure as seen from a National Cardiac Referral Centre in Africa. Cardiology. 2000; 93: 11–18.
Chetty R, Batitang S, Nair R. Large artery vasculopathy in HIV positive patients: another vasculitic enigma. Hum Path. 2000; 31: 374–379.
Hakim JG, Matenga JA, Siziya S. Myocardial dysfunction in human immunodeficiency virus: an echocardiographic study of 157 patients in hospital in Zimbabwe. Heart. 1996; 76: 161–165.
Hakim JG, Manyemba J. Cardiac disease distribution among patients referred for echocardiography in Harare, Zimbabwe. Cent Afr J Med. 1998; 44: 140–144.
Koegelenberg CFN, Doubell AF, Orth H, Reuter H. Infective endocarditis in the Western Cape Province of South Africa: a three year prospective study. QJM. 203; 96: 217–225.
Longo-Mbenza B, Tonduangu K, Muvova D, Phuati MB, Seghers KV, Kestelot H. A clinical study of cardiac manifestations related to acquired immunodeficiency syndrome (AIDS) in Kinshasa [in French]. Arch Mal Coeur Vaiss. 1995; 88: 1437–1443.
Longo-Mbenza B, Seghers KV, Phuati M, Bikangi FN, Mubagwa K. Heart involvement and HIV infection in African patients: determinants of survival. Int J Cardiol. 1998; 64: 63–73.
Marks C, Kuskov S. Pattern of arterial aneurysms in acquired immunodeficiency disease. World J Surg. 1995; 9: 127–132.
Nair R, Robbs JV, Naidoo NG, Woolgar J. Clinical profile of HIV-related aneurysms. Eur J Vasc Endovasc Surg. 2000; 20: 235–240.
Nair R, Abdool-Carrim A, Chetty R, Robbs J. Arterial aneurysms in patients infected with human immunodeficiency virus: a distinct clinico-pathology entity J Vasc Surg. 1999; 29: 600–607.
Niakara A, Drabo YJ, Kambire Y, Nebie LV, Kabore NJ, Simon F. Cardiovascular diseases and HIV infection: study of 79 cases at the National Hospital of Ouagadougou (Burkina Faso) [in French]. Bull Soc Pathol Exot. 2002; 95: 23–26.
Nzuobontane D, Blackett KN, Kuaban C. Cardiac involvement in HIV infected people in Yaounde, Cameroon. Postgrad Med J. 2002; 78: 678–681.
Sinzobahamvya N, Kalangu K, Hamel-Kalinowski W. Arterial aneurysms associated with human immunodeficiency virus (HIV) infection. Acta Chir Belg. 1989; 89: 185–158.
Bouramoue C, Ekoba J. The heart and AIDS [in French]. Med Trop (Mars). 1996; 56: 33–39.
Heidenreich PA, Eisenberg MJ, Kee LL, Somelofski CA, Hollander H, Schiller NB, Cheitlin MD. Pericardial effusion in AIDS: incidence and survival. Circulation. 1995; 92: 3229–3234.
Chen Y, Brennessel D, Walters J, Johnson M, Rosner F, Raza M. Human immunodeficiency virus-associated pericardial effusion: report of 40 cases and review of the literature. Am Heart J. 1999; 137: 516–521.
Reynolds MM, Hecht SR, Berger M, Kolokathis A, Horowitz SF. Large pericardial effusions in the acquired immunodeficiency syndrome. Chest. 1992; 102: 1746–1747.
Blanc L, Chaulet P, Espinal M, Graham S, Grzemska M, Harries AD, Luelmo F, Maher D, O’Brien R, Raviglione MC, Rieder H, Starke J, Uplekar M, Wells C. HIV infection and tuberculosis. In: Lee JW, ed. Treatment of Tuberculosis: Guidelines for National Programmes. 3rd ed. Geneva, Switzerland: World Health Organization; 2003: 75–85.
Dheda K, Lampe FC, Johnson MA, Lipman MC. Outcome of HIV associated tuberculosis in the era of highly active anti-retroviral therapy. J Infect Dis. 2004; 190: 1670–1676.
Ntsekhe M, Wiysonge C, Volmink JA, Commerford PJ, Mayosi BM. Adjuvant corticosteroids for tuberculous pericarditis: promising, but not proven. QJM. 2003; 96: 593–599.
Artucio H, Digenio A, Pereyra M. Left ventricular function during sepsis. Crit Care Med. 1989; 17: 323–327.
Currie PF, Jacob AJ, Foreman AR, Elton AR, Brettle RP, Boon NA. Heart muscle disease related to HIV infection: prognostic implications. BMJ. 1994; 309: 1605–1607.
Pugliese A, Isnardi D, Saini A, Scarabelli T, Raddino R, Torre D. Impact of highly active antiretroviral therapy in HIV-positive patients with cardiac involvement. J Infect. 2000; 40: 282–284.
Johnson RM, Barbarini G, Barboro G. Kawasaki-like syndromes and other vasculitic syndromes in HIV infected patients. AIDS. 2003; 17: S77–S82.
van Marle JTL, Weir G, Botes K. Vascular disease in HIV/AIDS patients. S Afr Med J. 2002; 92: 974–979.
de Gaetano Donati K, Rabagliati R, Iacoviello L, Cauda R. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. Lancet Infect Dis. 2004; 4: 213–222.
Barbaro G, Barbarini G, Pellicelli AM. HIV-associated coronary arteritis in a patient with fatal myocardial infarction. N Engl J Med. 2001; 344: 1799–1800.
Mooser M. Atherosclerosis and HIV in the highly active antiretroviral therapy era: towards an epidemic of cardiovascular disease AIDS. 2003; 17: S65–S69.
The Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003; 349: 1993–2003.
Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases, part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation. 2001; 104: 2855–2864.
Cicalini S, Forcina G, De Rosa FG. Infective endocarditis in patients with human immunodeficiency virus infection. J Infect. 2001; 42: 267–271.
Miro JM, del Rio A, Mestres CA. Infective endocarditis and cardiac surgery in intravenous drug abusers and HIV-1 infected patients. Cardiol Clin. 2003; 21: 167–184.
Opravil M, Pechere M, Speich R, Joller-Jemelka HI, Jenni R, Russi EW, Hirschel B, Luthy R. HIV associated primary pulmonary hypertension: a case control study: Swiss HIV Cohort Study. Am J Respir Crit Care Med. 1997; 155: 990–995.
US Census Bureau, Population Division, International Programs Center. HIV/AIDS surveillance data base maps, September 2004. Available at: http://www.census.gov/ipc/www/hivmaps.html. Accessed November 7, 2005.
Benatar SR. Health care reform and the crisis of HIV and AIDS in South Africa. N Engl J Med. 2004; 351: 81–92.(Mpiko Ntsekhe, MD; James Hakim, FRCP)