REVIEW ARTICLE
Cardiac Sequelae of Human Immunodeficiency Virus Disease Ashraf Alqaqa, MD, Addi Suleiman, MD, Stefani Birnhak, MD, Saad Tariq, MD, Raymund Sison, MD, Aiman Hamdan, MD, Vincent A. DeBari, PhD and Fayez Shamoon, MD
Abstract: Presently, patients with human immunodeficiency virus infection are living longer and are frequently encountered in medical practice. HIV infection is a systemic disease, which affects a wide spectrum of organs. Cardiac involvement is frequent, and the consequent clinical manifestations are a common reason to seek medical advice. In this review, we discuss the different cardiac sequelae of HIV infection. Key Indexing Terms: Cardiac manifestations; HIV; AIDS. [Am J Med Sci 2014;348(1):82–86.]
T
he burden of the worldwide epidemic of HIV infection continues to increase, especially in the developing world. However, with the advent of potent antiretroviral therapies, more patients are surviving longer, which is allowing clinicians to witness new clinical manifestations of chronic HIV infection.1 Pulmonary hypertension, coronary artery disease (CAD), myocardial diseases, endocardial disease, pericardial disease, arrhythmias and cardiac tumors are pathologies that may be encountered in HIV-infected patients. In this review, our goal is to update the reader on more recent reports of the abovementioned cardiovascular outcomes.
PULMONARY ARTERIAL HYPERTENSION HIV-associated pulmonary arterial hypertension (HIVPaHT) is a very rare complication with an estimated prevalence of 1 in 200 (0.5%) HIV-infected individual (Table 1); this has not changed in the post–highly active antiretroviral therapy (HAART) era.2 The pathogenesis of HIV-PaHTN is complex and is still poorly understood; however, both viral infection and patient factors are thought to play roles.3 It has been hypothesized that the HIV stimulates host cells to release cytokines and growth factors, including the potent vasoconstrictors, endothelin-1, interleukin 6, tumor necrosis factor a and platelet-derived growth factor a.4 These complex interactive changes will result in endothelial damage, laminar intimal fibrosis, smooth muscle and fibroblast proliferation and plexiform lesion formation, quite similar to those found in PaHTN from other causes.5 More recent evidence suggests that the patient’s immunologic response, virus HIV-negative factor (Nef), HIV transactivator of transcription (Tat) accessory proteins and human herpes virus-8 coinfection may play an important role in the cascade of events.6,7 The prognosis is poor and the reported mortality rate is high. PaHTN in HIV population is an independent predictor of mortality with 1-year survival rate reported to be 51% to From the Departments of Cardiology (AA, AS, AH, FS), Internal Medicine (SB, ST, VAD), and Infectious Disease (RS), St Michaels Medical Center, Newark, New Jersey; and Seton Hall University, South Orange, New Jersey (AA, AS, SB, ST, RS, AH, VAD, FS). Submitted October 2, 2013; accepted in revised form December 3, 2013. The authors have no financial or other conflicts of interest to disclose. Correspondence: Ashraf Alqaqa, MD, Department of Cardiology, St. Michael’s Medical Center, 111 Central Avenue, Newark, NJ 07201 (E-mail: [email protected]).
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88%.5,8 The severity of HIV infection and CD4 cell count has no apparent correlation with this complication. The effect of highly active antiretroviral therapy regimens on the clinical course is still not well defined and is presently being investigated; however, it has been suggested that long-duration treatment with HAART might reduce mortality.8 At present, the treatment of HIV-PaHTN is similar to that of patients with idiopathic pulmonary arterial hypertension. There have been reports of the use of diuretics, anticoagulation, phosphodiesterase V inhibitors and calcium channel blockers to treat HIV-PaHTN. However, HAART, prostacyclin analogs (eg, epoprostenol) and endothilin receptor inhibitors (eg, bosentan) were found to be effective in reducing the pulmonary arterial pressure in this population in several small studies. Heart-lung transplantation is the last treatment option in this subgroup of patients.9,10
CORONARY ARTERY DISEASE As the longevity of individuals with HIV has been increasing because of HAART, the clinicians would be expected to see more HIV-infected patients with CAD. HIV infection increases the risk of atherosclerosis and the development of CAD at earlier ages in comparison with noninfected subjects.11–15 Recently, it has been shown that cardiovascular mortality accounted for 6.5% of total deaths among HIVinfected patients from Europe and North America and for 8% among HIV-infected people in France. HIV patients have higher rates of CAD when compared with the general population; the standardized mortality ratio was 1.5 in a French database and a risk ratio of 1.7 in North American cohort. Moreover, the HIV patients were reported to have their first myocardial infarction in their late 40s, far earlier than that reported in the general population.16,17 During the pre-HAART era, the risk of ischemic heart disease was slightly, but not significantly, higher in HIV-infected patients than in control subjects (adjusted relative risk, 1.39; 95% confidence interval, 0.82–2.36) (Table 1). However, during the post-HAART period, there was a substantial increase in the risk of ischemic heart disease in the HIV population (adjusted relative risk, 2.12; 95% confidence interval, 1.62–2.76).11 The 3-year risk for myocardial infarction was found to increase from 0.30% in patients who are not on HAART to 1.07% in patients receiving antiretroviral agents.16 The viruses itself as well as HAART are potential causes of CAD. In addition to the conventional cardiovascular risk factors, which are found to be at higher, rates in this population.16–18 HAART, protease inhibitors (PIs) in particular and some nucleoside reverse transcriptase inhibitors might potentially increase the risk of CAD. The metabolic changes that are produced by PIs, including increased glucose levels and lipodystrophy as a result of decreased insulin sensitivity, can lead to acceleration in the process of atherosclerosis.19–21 Although all PIs may lead to these derangements to different degrees, the D:A:D study suggested that cumulative exposure to indinavir and the lopinavir-ritonavir combination in particular
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TABLE 1. Clinical presentations of the various HIV-related cardiac involvements Epidemiology HIV-related cardiac involvement Pulmonary arterial hypertension
2
Coronary artery disease16,17 Dilated cardiomyopathy28,a
Endocarditis34
Pericardial disease27,28,a
Arrhythmias41,44,45 Cardiac tumors27,39
Clinical presentation
Pre-HAART
Nonspecific symptoms. Exertional dyspnea, pedal edema and fatigue are common symptoms; causes right ventricular dysfunction, cor pulmonale and death; poor prognosis Silent ischemia, stable angina or acute coronary syndrome; patients usually young (,50 yr) Frequently asymptomatic but can present with decompensation (NYHA class III or IV); changes in echocardiogram: LV dilatation, global hypokinesis and reduced systolic function; poor prognosis Infective endocarditis: fever and sepsis; affects intravenous drug users; involves right-sided valves; Staphelcoccus aureus are most frequent pathogens Marantic endocarditis: seen in HIV wasting syndrome; affects left-sided valves Commonly asymptomatic, but can present with fever and chest pain of pleuritic nature (pericarditis); pericardial effusion is common and poor prognostic sign QTc interval prolongation, torsades de pointes, heart blocks and sudden cardiac death Kaposi’s sarcoma: pericardial effusion, and in some cases, tamponade. Non-Hodgkin’s lymphoma: infiltrative cardiac disease causing heart failure, intracavitary masses, arrhythmia, superior vena cava obstruction
Post-HAART
Prevalence 5 0.5%
Same
Adjusted relative risk 5 1.39
Adjusted relative risk 5 2.12; increased risk of MI by 13% per year Prevalence decreased by about 33%
Prevalence 30%–40%; annual incidence of 15.9/1000
20.5 per 1000 person-years 6.6 per 1000 person-years
Prevalence 3%–5%
Not available
Prevalence 5 11% in asymptomatic AIDS
Prevalence decreased by 35%
Prevalence (QTc prolongation) 69%
Prevalence (QTc prolongation) 10%–20%
Prevalence 5 12%–28%
Decreased by 50%.
Not available
Not available
a No clinical studies have quantified the reduction rates. HAART, highly active antiretroviral therapy; NYHA, New York Heart Association functional classification; MI, myocardial infarction.
was associated with increased risk of myocardial infarction by 12% and 13% per year, respectively.18 The data regarding nucleoside reverse transcriptase inhibitors as a risk for CAD are less clear. These agents cause mitochondrial toxicity, insulin resistance and lipid disturbances.19 In the D:A:D study, abacavir and didanosine were associated with increased risk of myocardial infarction.18 Choi et al20 also found that the exposure to abacavir within 6 months is independently associated with higher rates of cardiovascular events, myocardial infarction in particular. However, other studies could not confirm this relationship, especially after controlling for chronic kidney disease and the other traditional cardiovascular risk factors.17,21,22 Non-nucleoside reverse transcriptase inhibitors and integrase inhibitors have not been suspected of causing CAD.23,24 Interestingly, there is growing evidence suggesting that the HIV itself can independently increase the risk of accelerated CAD.21–24 Monocyte-macrophage activation induced by the virus is one possible mechanism in the multifactorial vascular inflammation process. Moreover, alteration of the immunologic response in this population, in addition to the exposure to various xenoantigens from HIV itself and other Ó 2014 Lippincott Williams & Wilkins
viral and bacterial infections have been claimed to induce an inflammatory condition that may speed up atherogenesis.24 Endothelial dysfunction, a marker of early stages of atherosclerosis, has also been reported in HIV infection and has been associated with increased viral load.21,22 The HIV has the ability to directly change the normal function of the endothelium.22,23 The latter interaction results in elevated levels of the various prothrombotic plasma markers, such as von Willebrand factor, b2 microglobulin and thrombomodulin.21,25 Also, researchers found increased levels of the circulating inflammatory molecules, such as interleukin 6 and D-dimer, in patients with elevated viral loads.25 Prevention of CAD is the mainstay of the management. Interruption of HAART therapy in chronically treated HIV patients should be avoided. It has been demonstrated by the SMART study that the rates of death and cardiovascular events increased significantly in patients who were assigned to a CD4guided drug conservation arm in comparison with continuous therapy arm.25 Controlling and modifying the risk factors and comorbidities are of paramount importance. The fasting serum concentrations of lipids should be evaluated before starting HAART, at
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3 to 6 months after the initiation of therapy and then at every year in the absence of dyslipidemia.26 The National Cholesterol Education Program III guidelines should be followed in managing those diagnosed with dyslipidemia. Lifestyle counseling on diet and exercise and addressing the other modifiable cardiovascular risk factors such as smoking, hypertension and diabetes mellitus should be the initial steps in management.26–30 If medications are necessary to treat dyslipidemia, elevated levels of low-density lipoprotein should be treated with statins. However, the dose and which statin to use should be selected with caution because of the risk of drug interaction and rhabdomyolysis. PI, ritonavir and some antimicrobial agents inhibit specific cytochrome P450 enzymes that are important in metabolizing several statins, and this could increase the toxicity of those drugs. Pravastatin (20–40 mg), rosuvastatin (5–10 mg) and low-dose atorvastatin (10 mg) seem to be safe to use with PIs. Ezetimibe can be used in combination with statins to achieve lower levels of low-density lipoprotein. However, switching to non–PI-based HIV therapy is a valid option to avoid using statins. Fibrates should be used to manage the triglyceride when the concentration is above 500 mg/dL.16,29,30
MYOCARDIAL DISEASES Myocarditis is an important cause of cardiomyopathy in HIV-infected patients and has been reported in up to 52% of autopsies of patients with AIDS during the pre-HAART era (Table 1). Dilated cardiomyopathy has been reported in about one third of HIV-infected patients.27,28 Before the introduction of HAART, the annual incidence of cardiomyopathy was estimated at 15.9/1000 in HIV-infected subjects with a prevalence rate of 30% to 40%. Because of reduced rates of myocarditis in the post-HAART era, however, the prevalence of cardiomyopathy has decreased by about one third.28 The prevalence of diastolic dysfunction (DD) in general population at age ,50 years is less than 6%. However, there are several reports suggesting that HIV-infected patients have higher incidence of diastolic left ventricular dysfunction than the general population. A recent meta-analysis reported the incidence of systolic and DD to be 8.33% and 43.38%, respectively.31 Moreover, Nayak et al32 have found the prevalence of mild-to-moderate DD in asymptomatic HIV patients to be 37%. Most of the patients in this cohort were on HAART and did not have the traditional risk factors associated with DD. In comparison with noninfected population, HIVinfected individuals with cardiomyopathy have a poor prognosis.33,34 Several mechanisms have been postulated to explain myocardial changes associated with HIV. A common hypothesis suggests that the virus induces inflammatory response by its direct effect on the cardiac myocytes; however, the exact mechanism is still not clear. Because the myocardial cells are CD4 negative, it is thought that dendritic cells may have an important role in the interaction between the virus and the myocardial cells.30,33,34 Other factors that may lead to cardiomyopathy in this population include the various opportunistic infections that may worsen the deleterious effect of HIV on the heart, the harmful effect of some HAART on the mitochondrial structures, selenium deficiency and the toxic effect of alcohol and illicit drugs.28,31,32
However, patients with AIDS with advanced disease are at higher risk of Salmonella bacteremia, which may infect the cardiac valves.27,33,35,36 The incidence of infective endocaritis has decreased from 20.5 to 6.6 per 1000 person-years in the preHAART and post-HAART era, respectively (Table 1).34 Nonbacterial thrombotic endocarditis (marantic endocarditis) has been reported in HIV patients, particularly in those with wasting syndrome. The prevalence of marantic endocarditis is estimated to be 3% to 5% of patients with AIDS in the period before HAART. Left heart valves are frequently affected and usually silent.27,28 These lesions usually are identified in the autopsies of HIV-infected individuals.28 As in general population, HIV individuals are more likely to have metastatic and secondary cardiac tumors rather than primary heart tumors.28,37,38 Kaposi’s sarcoma and nonHodgkin’s lymphoma are the common tumors, which frequently involve the heart in patients with AIDS.27,38,39
PERICARDIAL DISEASE The pericardium is commonly affected in patients with HIV/AIDS.27,33 Pericarditis and pericardial effusions are frequent cardiac findings in this population. The prevalence of pericardial effusion in patients with AIDS who are asymptomatic is estimated to be 11% before the introduction of HAART. Moreover, in some echocardiographic series, the pericardial effusion was found in more than 40% of the study population. However, the prevalence has decreased by 35% after the introduction of HAART (Table 1).27,28 The exact pathogenesis of this complication is not clearly understood.27,33 Decreased CD4 cell count, opportunistic infections and neoplasms seen in advances stages of HIV have been associated with pericardial involvement.28
ARRHYTHMIAS Toxicity due to medication and myocardial disease associated with HIV may contribute to dysrhythmias observed in this population.40–43 Charbit et al44 reported that 22% of HIV patients had at least 1 electrocardiogram abnormality and 12.5% had conduction defects. Several medications used by HIV patients can cause QTc interval prolongation and torsades de pointes. Pentamidine/ pyrimethamine and trimethoprim-sulfamethoxazole are agents used in the treatment of Pneumocystis jirovecii pneumonia and toxoplasmosis, respectively, and can lead to QTc changes.43–45 Ganciclovir can cause ventricular tachycardia, whereas, interferon alpha puts the patient at risk of developing heart blocks and sudden cardiac death.27,28 Moreover, fatal cardiac arrhythmia including torsades de pointes has been reported in patients who are not on medications.43 QTc prolongation has been found to be a frequent finding in HIV population. The prevalence of QTc prolongation has been reported up to 65% in HIV patients with autonomic neuropathy in the pre-HAART era, but most studies of the recent cohorts in the post-HAART era report the prevalence to be in the range of 10% to 20% (Table 1).41,44,45 It has been suggested that low CD4 cell count and high viral load are potential risk factors for QTc prolongation, however, no antiretroviral agent was linked to QTc prolongation after correction for potential confounders.41,44
ENDOCARDIAL DISEASE AND TUMORS
HIV-RELATED CARDIAC DISEASE IN SUB-SAHARAN AFRICA
Infective endocarditis occurs in both HIV-infected and noninfected individuals with the same risk factors at comparable rates.33–36 Additionally, the organisms responsible for endocarditis and the precise valve infected do not differ in HIV.35
The majority of HIV-infected people, estimated at 22 million, live in sub-Saharan Africa. South Africa is considered one of the worst-affected countries in the world. The access to HAART is limited in Africa, with less than 20% of patients able
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to be treated with HAART. In addition, tuberculosis is endemic. These factors have a major influence on the epidemiology and nature of cardiac disease in this population.46,47 The most commonly reported cardiac manifestations of HIV/AIDS in sub-Saharan Africa are cardiomyopathy, pulmonary hypertension and pericardial disease. The latter is related to Mycobacterium tuberculosis, in contrast to industrialized countries where the majority is idiopathic. In contrary to industrialized countries where the access to HAART is more common, CAD is an infrequent complication. The Heart of Soweto Study, the largest study of de novo cases of heart disease in sub-Saharan Africa, demonstrated that the prevalence of HIVrelated cardiomyopathy is 38% in the HIV-infected population. Primary and secondary diagnosis of pericardial effusion/pericarditis was diagnosed in 13% and 12% cases, respectively.47 The rate of HIV-PaHTN in cohorts from Africa was reported up to 8.1%, the rate of CAD was 2.4% and the rate of infective endocarditis was 1.2%, which is much lower than other part of the world where the use of intravenous drugs is high.46,47
CONCLUSIONS The effect of HIV infection on the heart is clinically important and can result in several sequelae. Pericardial effusion and cardiomyopathy are among the most common manifestations. HIV-PaHTN is a rare complication but carries a high mortality rate. Patients with HIV have higher rates of CAD when compared with the general population, and the risk has increased after the introduction of HAART. HIV-infected patients are not at increased risk of infective endocarditis, and intravenous drug use remains the main risk factor for infective endocarditis. Physicians treating HIV patients should be aware of increased risk of QTc prolongation in HIV population, and this can result in life-threatening conditions. Cardiac tumors in HIV individuals are a rare finding and are usually secondary to Kaposi’s sarcoma. The epidemiology of HIV-related cardiac disease in sub-Saharan Africa is not well studied but seems to be different from the industrialized population. REFERENCES 1. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008;372: 293–9. 2. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIVrelated pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008;177:108–13. 3. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–537. 4. Pellicelli AM, Barbaro G, Palmieri F, et al. Primary pulmonary hypertension in HIV disease: a systematic review. Angiology 2001; 52:31–41. 5. Almodovar S, Hsue PY, Morelli J, et al; Lung HIV Study. Pathogenesis of HIV-associated pulmonary hypertension: potential role of HIV-1Nef. Proc Am Thorac Soc 2011;8:308–12. 6. Cool CD, Rai PR, Yeager ME, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003;349:1113–22. 7. Degano B, Guillaume M, Savale L, et al. HIV-associated pulmonary arterial hypertension: survival and prognostic factors in the modern therapeutic era. AIDS 2010;24:67–75.
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8. Zuber JP, Calmy A, Evison JM, et al; Swiss HIV Cohort Study Group. Pulmonary arterial hypertension related to HIV infection: improved hemodynamics and survival associated with antiretroviral therapy. Clin Infect Dis 2004;38:1178–85. 9. Janda S, Quon BS, Swiston J. HIV and pulmonary arterial hypertension: a systematic review. HIV Med 2010;11:620–34. 10. Barnett CF, Hsue PY. Human immunodeficiency virus-associated pulmonary arterial hypertension. Clin Chest Med 2013;34:283–92. 11. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis 2007;44:1625–31. 12. Currier JS, Lundgren JD, Carr A, et al. Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation 2008;118:e29–35. 13. lass TR, Ungsedhapand C, Wolbers M, et al. Prevalence of risk factors for cardiovascular disease in HIV-infected patients over time: the Swiss HIV Cohort study. HIV Med 2006;7:404–10. 14. Qaqa AY, Debari VA, Elkersh K, et al. Epidemiologic aspects of abnormal ankle brachial index in the HIV infected population. Int Angiol 2012;31:227–33. 15. Qaqa AY, DeBari VA, Isbitan A, et al. The role of postexercise measurements in the diagnosis of peripheral arterial disease in HIVinfected patients. Angiology 2011;62:10–14. 16. Boccara F, Lang S, Meuleman C, et al. HIV and coronary heart disease: time for a better understanding. J Am Coll Cardiol 2013;61:511–23. 17. Lang S, Mary-Krause M, Cotte L, et al; Clinical Epidemiology Group of the French Hospital Database on HIV. Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus–infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4. Arch Intern Med 2010;170:1228–38. 18. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis 2010;201:318–30. 19. Hammond E, Nolan D, James I, et al. Reduction of mitochondrial DNA content and respiratory chain activity occurs in adipocytes within 6-12 months of commencing nucleoside reverse transcriptase inhibitor therapy. AIDS 2004;18:815–17. 20. Choi AI, Vittinghoff E, Deeks SG, et al. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS 2011;25:1289–98. 21. Ribaudo HJ, Benson CA, Zheng Y, et al. No risk of myocardial infarction associated with initial antiretroviral treatment containing abacavir: short- and long-term results from ACTG A5001/ALLRT. Clin Infect Dis 2011;52:929–40. 22. Bedimo RJ, Westfall AO, Drechsler H, et al. Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era. Clin Infect Dis 2011;53:84–91. 23. Fichtenbaum CJ. Does antiretroviral therapy increase or decrease the risk of cardiovascular disease? Curr HIV/AIDS Rep 2010;7:92–8. 24. Malvestutto CD, Aberg JA. Coronary heart disease in people infected with HIV. Cleve Clin J Med 2010;77:547–56. 25. El-Sadr WM, Lundgren J, Neaton JD, et al; Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283–96. 26. Rasmussen LD, Kronborg G, Larsen CS, et al. Statin therapy and mortality in HIV-infected individuals; a Danish nationwide populationbased cohort study. PLoS One 2013;8: e52828. [Published online ahead of print March 4, 2013]. doi:0.1371/journal.pone.0052828.
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27. Barbaro G. Cardiovascular manifestations of HIV infection. Circulation 2002;106:1420–5. 28. Barbaro G, Barbarini G. Human immunodeficiency virus & cardiovascular risk. Indian J Med Res 2011;134:898–903. 29. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769–818. 30. Grinspoon SK, Grunfeld C, Kotler DP, et al. State of the science conference: initiative to decrease cardiovascular risk and increase quality of care for patients living with HIV/AIDS: executive summary. Circulation 2008;118:198–210.
37. Fisher SD, Kanda BS, Miller TL, et al. Cardiovascular disease andtherapeutic drug-related cardiovascular consequences in HIV-infected patients. Am J Cardiovasc Drugs 2011;11:383–94. 38. Iwahashi N, Nakatani S, Kakuchi H, et al. Cardiac tumor as an initial manifestation of acquired immunodeficiency syndrome. Circ J 2005;69: 243–5. 39. Lee GY, Kim WS, Ko YH, et al. Primary cardiac lymphoma mimickinginfiltrative cardiomyopathy. Eur J Heart Fail 2013;15:589–91. 40. Chinello P, Lisena FP, Angeletti C, et al. Role of antiretroviral treatment in prolonging QTc interval in HIV-positive patients. J Infect 2007; 54:597–602.
31. Cerrato E, D’Ascenzo F, Biondi-Zoccai G, et al. Cardiac dysfunction in pauci symptomatic human immunodeficiency virus patients: a meta-analysis in the highly active antiretroviral therapy era. Eur Heart J 2013;34:1432–6.
41. Qaqa AY, Shaaban H, DeBari VA, et al. Viral load and CD4+ cell count as risk factors for prolonged QT interval in HIV-infected subjects: a cohort-nested case-control study in an outpatient population. Cardiology 2010;117:105–11.
32. Nayak G, Ferguson M, Tribble DR, et al. Cardiac diastolic dysfunction is prevalent in HIV-infected patients. AIDS Patient Care STDS 2009;23:231–8.
42. Kocheril AG, Bokhari SA, Batsford WP, et al. Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997;20:2810–6.
33. Olusegun-Joseph DA, Ajuluchukwu JN, Okany CC, et al. Echocardiographic patterns in treatment-naïve HIV-positive patients in Lagos, south-west Nigeria. Cardiovasc J Afr 2012;23:e1–6.
43. Patel N, Veve M, Kwon S, et al. Frequency of electrocardiogram testing among HIV-infected patients at risk for medication-induced QTc prolongation. HIV Med 2013;14:463–71.
34. Gebo KA, Burkey MD, Lucas GM, et al. Incidence of, risk factors for, clinical presentation, and 1-year outcomes of infective endocarditis in an urban HIV cohort. J Acquir Immune Defic Syndr 2006;43:426–32.
44. Charbit B, Rosier A, Bollens D, et al. Relationship between HIV protease inhibitors and QTc interval duration in HIV-infected patients: a cross-sectional study. Br J Clin Pharmacol 2009;67:76–82.
35. Preziosi MJ, Kandel SM, Guiney DG, et al. Microbiological analysis of nontyphoidal Salmonella strains causing distinct syndromes of bacteremia or enteritis in HIV/AIDS patients in San Diego, California. J Clin Microbiol 2012;50:3598–603.
45. Khan NU, Ahmed S, Wagner P, et al. Cardiac involvement in nonHodgkin’s lymphoma: with and without HIV infection. Int J Cardiovasc Imaging 2004;20:477–81.
36. Losa JE, Miro JM, Del Rio A, et al; Hospital Clinic Endocarditis Study Group. Infective endocarditis not related to intravenous drug abuse in HIV-1-infectedpatients, 2003 Infective endocarditis not related to intravenous drug abuse in HIV-1-infectedpatients: report of eight cases and review of the literature. Clin Microbiol Infect 2003;9:45–54.
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46. Ntsekhe M, Hakim J. Impact of human immunodeficiency virus infection on cardiovascular disease in Africa. Circulation 2005;112:3602–7. 47. Sliwa K, Carrington MJ, Becker A, et al. Contribution of the human immunodeficiency virus/acquired immunodeficiency syndrome epidemic to de novo presentations of heart disease in the Heart of Soweto Study cohort. Eur Heart J 2012;33:866–74.
Volume 348, Number 1, July 2014
Cardiac Sequelae of Human Immunodeficiency Virus Disease Ashraf Alqaqa, MD, Addi Suleiman, MD, Stefani Birnhak, MD, Saad Tariq, MD, Raymund Sison, MD, Aiman Hamdan, MD, Vincent A. DeBari, PhD and Fayez Shamoon, MD
Abstract: Presently, patients with human immunodeficiency virus infection are living longer and are frequently encountered in medical practice. HIV infection is a systemic disease, which affects a wide spectrum of organs. Cardiac involvement is frequent, and the consequent clinical manifestations are a common reason to seek medical advice. In this review, we discuss the different cardiac sequelae of HIV infection. Key Indexing Terms: Cardiac manifestations; HIV; AIDS. [Am J Med Sci 2014;348(1):82–86.]
T
he burden of the worldwide epidemic of HIV infection continues to increase, especially in the developing world. However, with the advent of potent antiretroviral therapies, more patients are surviving longer, which is allowing clinicians to witness new clinical manifestations of chronic HIV infection.1 Pulmonary hypertension, coronary artery disease (CAD), myocardial diseases, endocardial disease, pericardial disease, arrhythmias and cardiac tumors are pathologies that may be encountered in HIV-infected patients. In this review, our goal is to update the reader on more recent reports of the abovementioned cardiovascular outcomes.
PULMONARY ARTERIAL HYPERTENSION HIV-associated pulmonary arterial hypertension (HIVPaHT) is a very rare complication with an estimated prevalence of 1 in 200 (0.5%) HIV-infected individual (Table 1); this has not changed in the post–highly active antiretroviral therapy (HAART) era.2 The pathogenesis of HIV-PaHTN is complex and is still poorly understood; however, both viral infection and patient factors are thought to play roles.3 It has been hypothesized that the HIV stimulates host cells to release cytokines and growth factors, including the potent vasoconstrictors, endothelin-1, interleukin 6, tumor necrosis factor a and platelet-derived growth factor a.4 These complex interactive changes will result in endothelial damage, laminar intimal fibrosis, smooth muscle and fibroblast proliferation and plexiform lesion formation, quite similar to those found in PaHTN from other causes.5 More recent evidence suggests that the patient’s immunologic response, virus HIV-negative factor (Nef), HIV transactivator of transcription (Tat) accessory proteins and human herpes virus-8 coinfection may play an important role in the cascade of events.6,7 The prognosis is poor and the reported mortality rate is high. PaHTN in HIV population is an independent predictor of mortality with 1-year survival rate reported to be 51% to From the Departments of Cardiology (AA, AS, AH, FS), Internal Medicine (SB, ST, VAD), and Infectious Disease (RS), St Michaels Medical Center, Newark, New Jersey; and Seton Hall University, South Orange, New Jersey (AA, AS, SB, ST, RS, AH, VAD, FS). Submitted October 2, 2013; accepted in revised form December 3, 2013. The authors have no financial or other conflicts of interest to disclose. Correspondence: Ashraf Alqaqa, MD, Department of Cardiology, St. Michael’s Medical Center, 111 Central Avenue, Newark, NJ 07201 (E-mail: [email protected]).
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88%.5,8 The severity of HIV infection and CD4 cell count has no apparent correlation with this complication. The effect of highly active antiretroviral therapy regimens on the clinical course is still not well defined and is presently being investigated; however, it has been suggested that long-duration treatment with HAART might reduce mortality.8 At present, the treatment of HIV-PaHTN is similar to that of patients with idiopathic pulmonary arterial hypertension. There have been reports of the use of diuretics, anticoagulation, phosphodiesterase V inhibitors and calcium channel blockers to treat HIV-PaHTN. However, HAART, prostacyclin analogs (eg, epoprostenol) and endothilin receptor inhibitors (eg, bosentan) were found to be effective in reducing the pulmonary arterial pressure in this population in several small studies. Heart-lung transplantation is the last treatment option in this subgroup of patients.9,10
CORONARY ARTERY DISEASE As the longevity of individuals with HIV has been increasing because of HAART, the clinicians would be expected to see more HIV-infected patients with CAD. HIV infection increases the risk of atherosclerosis and the development of CAD at earlier ages in comparison with noninfected subjects.11–15 Recently, it has been shown that cardiovascular mortality accounted for 6.5% of total deaths among HIVinfected patients from Europe and North America and for 8% among HIV-infected people in France. HIV patients have higher rates of CAD when compared with the general population; the standardized mortality ratio was 1.5 in a French database and a risk ratio of 1.7 in North American cohort. Moreover, the HIV patients were reported to have their first myocardial infarction in their late 40s, far earlier than that reported in the general population.16,17 During the pre-HAART era, the risk of ischemic heart disease was slightly, but not significantly, higher in HIV-infected patients than in control subjects (adjusted relative risk, 1.39; 95% confidence interval, 0.82–2.36) (Table 1). However, during the post-HAART period, there was a substantial increase in the risk of ischemic heart disease in the HIV population (adjusted relative risk, 2.12; 95% confidence interval, 1.62–2.76).11 The 3-year risk for myocardial infarction was found to increase from 0.30% in patients who are not on HAART to 1.07% in patients receiving antiretroviral agents.16 The viruses itself as well as HAART are potential causes of CAD. In addition to the conventional cardiovascular risk factors, which are found to be at higher, rates in this population.16–18 HAART, protease inhibitors (PIs) in particular and some nucleoside reverse transcriptase inhibitors might potentially increase the risk of CAD. The metabolic changes that are produced by PIs, including increased glucose levels and lipodystrophy as a result of decreased insulin sensitivity, can lead to acceleration in the process of atherosclerosis.19–21 Although all PIs may lead to these derangements to different degrees, the D:A:D study suggested that cumulative exposure to indinavir and the lopinavir-ritonavir combination in particular
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TABLE 1. Clinical presentations of the various HIV-related cardiac involvements Epidemiology HIV-related cardiac involvement Pulmonary arterial hypertension
2
Coronary artery disease16,17 Dilated cardiomyopathy28,a
Endocarditis34
Pericardial disease27,28,a
Arrhythmias41,44,45 Cardiac tumors27,39
Clinical presentation
Pre-HAART
Nonspecific symptoms. Exertional dyspnea, pedal edema and fatigue are common symptoms; causes right ventricular dysfunction, cor pulmonale and death; poor prognosis Silent ischemia, stable angina or acute coronary syndrome; patients usually young (,50 yr) Frequently asymptomatic but can present with decompensation (NYHA class III or IV); changes in echocardiogram: LV dilatation, global hypokinesis and reduced systolic function; poor prognosis Infective endocarditis: fever and sepsis; affects intravenous drug users; involves right-sided valves; Staphelcoccus aureus are most frequent pathogens Marantic endocarditis: seen in HIV wasting syndrome; affects left-sided valves Commonly asymptomatic, but can present with fever and chest pain of pleuritic nature (pericarditis); pericardial effusion is common and poor prognostic sign QTc interval prolongation, torsades de pointes, heart blocks and sudden cardiac death Kaposi’s sarcoma: pericardial effusion, and in some cases, tamponade. Non-Hodgkin’s lymphoma: infiltrative cardiac disease causing heart failure, intracavitary masses, arrhythmia, superior vena cava obstruction
Post-HAART
Prevalence 5 0.5%
Same
Adjusted relative risk 5 1.39
Adjusted relative risk 5 2.12; increased risk of MI by 13% per year Prevalence decreased by about 33%
Prevalence 30%–40%; annual incidence of 15.9/1000
20.5 per 1000 person-years 6.6 per 1000 person-years
Prevalence 3%–5%
Not available
Prevalence 5 11% in asymptomatic AIDS
Prevalence decreased by 35%
Prevalence (QTc prolongation) 69%
Prevalence (QTc prolongation) 10%–20%
Prevalence 5 12%–28%
Decreased by 50%.
Not available
Not available
a No clinical studies have quantified the reduction rates. HAART, highly active antiretroviral therapy; NYHA, New York Heart Association functional classification; MI, myocardial infarction.
was associated with increased risk of myocardial infarction by 12% and 13% per year, respectively.18 The data regarding nucleoside reverse transcriptase inhibitors as a risk for CAD are less clear. These agents cause mitochondrial toxicity, insulin resistance and lipid disturbances.19 In the D:A:D study, abacavir and didanosine were associated with increased risk of myocardial infarction.18 Choi et al20 also found that the exposure to abacavir within 6 months is independently associated with higher rates of cardiovascular events, myocardial infarction in particular. However, other studies could not confirm this relationship, especially after controlling for chronic kidney disease and the other traditional cardiovascular risk factors.17,21,22 Non-nucleoside reverse transcriptase inhibitors and integrase inhibitors have not been suspected of causing CAD.23,24 Interestingly, there is growing evidence suggesting that the HIV itself can independently increase the risk of accelerated CAD.21–24 Monocyte-macrophage activation induced by the virus is one possible mechanism in the multifactorial vascular inflammation process. Moreover, alteration of the immunologic response in this population, in addition to the exposure to various xenoantigens from HIV itself and other Ó 2014 Lippincott Williams & Wilkins
viral and bacterial infections have been claimed to induce an inflammatory condition that may speed up atherogenesis.24 Endothelial dysfunction, a marker of early stages of atherosclerosis, has also been reported in HIV infection and has been associated with increased viral load.21,22 The HIV has the ability to directly change the normal function of the endothelium.22,23 The latter interaction results in elevated levels of the various prothrombotic plasma markers, such as von Willebrand factor, b2 microglobulin and thrombomodulin.21,25 Also, researchers found increased levels of the circulating inflammatory molecules, such as interleukin 6 and D-dimer, in patients with elevated viral loads.25 Prevention of CAD is the mainstay of the management. Interruption of HAART therapy in chronically treated HIV patients should be avoided. It has been demonstrated by the SMART study that the rates of death and cardiovascular events increased significantly in patients who were assigned to a CD4guided drug conservation arm in comparison with continuous therapy arm.25 Controlling and modifying the risk factors and comorbidities are of paramount importance. The fasting serum concentrations of lipids should be evaluated before starting HAART, at
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3 to 6 months after the initiation of therapy and then at every year in the absence of dyslipidemia.26 The National Cholesterol Education Program III guidelines should be followed in managing those diagnosed with dyslipidemia. Lifestyle counseling on diet and exercise and addressing the other modifiable cardiovascular risk factors such as smoking, hypertension and diabetes mellitus should be the initial steps in management.26–30 If medications are necessary to treat dyslipidemia, elevated levels of low-density lipoprotein should be treated with statins. However, the dose and which statin to use should be selected with caution because of the risk of drug interaction and rhabdomyolysis. PI, ritonavir and some antimicrobial agents inhibit specific cytochrome P450 enzymes that are important in metabolizing several statins, and this could increase the toxicity of those drugs. Pravastatin (20–40 mg), rosuvastatin (5–10 mg) and low-dose atorvastatin (10 mg) seem to be safe to use with PIs. Ezetimibe can be used in combination with statins to achieve lower levels of low-density lipoprotein. However, switching to non–PI-based HIV therapy is a valid option to avoid using statins. Fibrates should be used to manage the triglyceride when the concentration is above 500 mg/dL.16,29,30
MYOCARDIAL DISEASES Myocarditis is an important cause of cardiomyopathy in HIV-infected patients and has been reported in up to 52% of autopsies of patients with AIDS during the pre-HAART era (Table 1). Dilated cardiomyopathy has been reported in about one third of HIV-infected patients.27,28 Before the introduction of HAART, the annual incidence of cardiomyopathy was estimated at 15.9/1000 in HIV-infected subjects with a prevalence rate of 30% to 40%. Because of reduced rates of myocarditis in the post-HAART era, however, the prevalence of cardiomyopathy has decreased by about one third.28 The prevalence of diastolic dysfunction (DD) in general population at age ,50 years is less than 6%. However, there are several reports suggesting that HIV-infected patients have higher incidence of diastolic left ventricular dysfunction than the general population. A recent meta-analysis reported the incidence of systolic and DD to be 8.33% and 43.38%, respectively.31 Moreover, Nayak et al32 have found the prevalence of mild-to-moderate DD in asymptomatic HIV patients to be 37%. Most of the patients in this cohort were on HAART and did not have the traditional risk factors associated with DD. In comparison with noninfected population, HIVinfected individuals with cardiomyopathy have a poor prognosis.33,34 Several mechanisms have been postulated to explain myocardial changes associated with HIV. A common hypothesis suggests that the virus induces inflammatory response by its direct effect on the cardiac myocytes; however, the exact mechanism is still not clear. Because the myocardial cells are CD4 negative, it is thought that dendritic cells may have an important role in the interaction between the virus and the myocardial cells.30,33,34 Other factors that may lead to cardiomyopathy in this population include the various opportunistic infections that may worsen the deleterious effect of HIV on the heart, the harmful effect of some HAART on the mitochondrial structures, selenium deficiency and the toxic effect of alcohol and illicit drugs.28,31,32
However, patients with AIDS with advanced disease are at higher risk of Salmonella bacteremia, which may infect the cardiac valves.27,33,35,36 The incidence of infective endocaritis has decreased from 20.5 to 6.6 per 1000 person-years in the preHAART and post-HAART era, respectively (Table 1).34 Nonbacterial thrombotic endocarditis (marantic endocarditis) has been reported in HIV patients, particularly in those with wasting syndrome. The prevalence of marantic endocarditis is estimated to be 3% to 5% of patients with AIDS in the period before HAART. Left heart valves are frequently affected and usually silent.27,28 These lesions usually are identified in the autopsies of HIV-infected individuals.28 As in general population, HIV individuals are more likely to have metastatic and secondary cardiac tumors rather than primary heart tumors.28,37,38 Kaposi’s sarcoma and nonHodgkin’s lymphoma are the common tumors, which frequently involve the heart in patients with AIDS.27,38,39
PERICARDIAL DISEASE The pericardium is commonly affected in patients with HIV/AIDS.27,33 Pericarditis and pericardial effusions are frequent cardiac findings in this population. The prevalence of pericardial effusion in patients with AIDS who are asymptomatic is estimated to be 11% before the introduction of HAART. Moreover, in some echocardiographic series, the pericardial effusion was found in more than 40% of the study population. However, the prevalence has decreased by 35% after the introduction of HAART (Table 1).27,28 The exact pathogenesis of this complication is not clearly understood.27,33 Decreased CD4 cell count, opportunistic infections and neoplasms seen in advances stages of HIV have been associated with pericardial involvement.28
ARRHYTHMIAS Toxicity due to medication and myocardial disease associated with HIV may contribute to dysrhythmias observed in this population.40–43 Charbit et al44 reported that 22% of HIV patients had at least 1 electrocardiogram abnormality and 12.5% had conduction defects. Several medications used by HIV patients can cause QTc interval prolongation and torsades de pointes. Pentamidine/ pyrimethamine and trimethoprim-sulfamethoxazole are agents used in the treatment of Pneumocystis jirovecii pneumonia and toxoplasmosis, respectively, and can lead to QTc changes.43–45 Ganciclovir can cause ventricular tachycardia, whereas, interferon alpha puts the patient at risk of developing heart blocks and sudden cardiac death.27,28 Moreover, fatal cardiac arrhythmia including torsades de pointes has been reported in patients who are not on medications.43 QTc prolongation has been found to be a frequent finding in HIV population. The prevalence of QTc prolongation has been reported up to 65% in HIV patients with autonomic neuropathy in the pre-HAART era, but most studies of the recent cohorts in the post-HAART era report the prevalence to be in the range of 10% to 20% (Table 1).41,44,45 It has been suggested that low CD4 cell count and high viral load are potential risk factors for QTc prolongation, however, no antiretroviral agent was linked to QTc prolongation after correction for potential confounders.41,44
ENDOCARDIAL DISEASE AND TUMORS
HIV-RELATED CARDIAC DISEASE IN SUB-SAHARAN AFRICA
Infective endocarditis occurs in both HIV-infected and noninfected individuals with the same risk factors at comparable rates.33–36 Additionally, the organisms responsible for endocarditis and the precise valve infected do not differ in HIV.35
The majority of HIV-infected people, estimated at 22 million, live in sub-Saharan Africa. South Africa is considered one of the worst-affected countries in the world. The access to HAART is limited in Africa, with less than 20% of patients able
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to be treated with HAART. In addition, tuberculosis is endemic. These factors have a major influence on the epidemiology and nature of cardiac disease in this population.46,47 The most commonly reported cardiac manifestations of HIV/AIDS in sub-Saharan Africa are cardiomyopathy, pulmonary hypertension and pericardial disease. The latter is related to Mycobacterium tuberculosis, in contrast to industrialized countries where the majority is idiopathic. In contrary to industrialized countries where the access to HAART is more common, CAD is an infrequent complication. The Heart of Soweto Study, the largest study of de novo cases of heart disease in sub-Saharan Africa, demonstrated that the prevalence of HIVrelated cardiomyopathy is 38% in the HIV-infected population. Primary and secondary diagnosis of pericardial effusion/pericarditis was diagnosed in 13% and 12% cases, respectively.47 The rate of HIV-PaHTN in cohorts from Africa was reported up to 8.1%, the rate of CAD was 2.4% and the rate of infective endocarditis was 1.2%, which is much lower than other part of the world where the use of intravenous drugs is high.46,47
CONCLUSIONS The effect of HIV infection on the heart is clinically important and can result in several sequelae. Pericardial effusion and cardiomyopathy are among the most common manifestations. HIV-PaHTN is a rare complication but carries a high mortality rate. Patients with HIV have higher rates of CAD when compared with the general population, and the risk has increased after the introduction of HAART. HIV-infected patients are not at increased risk of infective endocarditis, and intravenous drug use remains the main risk factor for infective endocarditis. Physicians treating HIV patients should be aware of increased risk of QTc prolongation in HIV population, and this can result in life-threatening conditions. Cardiac tumors in HIV individuals are a rare finding and are usually secondary to Kaposi’s sarcoma. The epidemiology of HIV-related cardiac disease in sub-Saharan Africa is not well studied but seems to be different from the industrialized population. REFERENCES 1. Antiretroviral Therapy Cohort Collaboration. Life expectancy of individuals on combination antiretroviral therapy in high-income countries: a collaborative analysis of 14 cohort studies. Lancet 2008;372: 293–9. 2. Sitbon O, Lascoux-Combe C, Delfraissy JF, et al. Prevalence of HIVrelated pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008;177:108–13. 3. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009;30:2493–537. 4. Pellicelli AM, Barbaro G, Palmieri F, et al. Primary pulmonary hypertension in HIV disease: a systematic review. Angiology 2001; 52:31–41. 5. Almodovar S, Hsue PY, Morelli J, et al; Lung HIV Study. Pathogenesis of HIV-associated pulmonary hypertension: potential role of HIV-1Nef. Proc Am Thorac Soc 2011;8:308–12. 6. Cool CD, Rai PR, Yeager ME, et al. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med 2003;349:1113–22. 7. Degano B, Guillaume M, Savale L, et al. HIV-associated pulmonary arterial hypertension: survival and prognostic factors in the modern therapeutic era. AIDS 2010;24:67–75.
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8. Zuber JP, Calmy A, Evison JM, et al; Swiss HIV Cohort Study Group. Pulmonary arterial hypertension related to HIV infection: improved hemodynamics and survival associated with antiretroviral therapy. Clin Infect Dis 2004;38:1178–85. 9. Janda S, Quon BS, Swiston J. HIV and pulmonary arterial hypertension: a systematic review. HIV Med 2010;11:620–34. 10. Barnett CF, Hsue PY. Human immunodeficiency virus-associated pulmonary arterial hypertension. Clin Chest Med 2013;34:283–92. 11. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis 2007;44:1625–31. 12. Currier JS, Lundgren JD, Carr A, et al. Epidemiological evidence for cardiovascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation 2008;118:e29–35. 13. lass TR, Ungsedhapand C, Wolbers M, et al. Prevalence of risk factors for cardiovascular disease in HIV-infected patients over time: the Swiss HIV Cohort study. HIV Med 2006;7:404–10. 14. Qaqa AY, Debari VA, Elkersh K, et al. Epidemiologic aspects of abnormal ankle brachial index in the HIV infected population. Int Angiol 2012;31:227–33. 15. Qaqa AY, DeBari VA, Isbitan A, et al. The role of postexercise measurements in the diagnosis of peripheral arterial disease in HIVinfected patients. Angiology 2011;62:10–14. 16. Boccara F, Lang S, Meuleman C, et al. HIV and coronary heart disease: time for a better understanding. J Am Coll Cardiol 2013;61:511–23. 17. Lang S, Mary-Krause M, Cotte L, et al; Clinical Epidemiology Group of the French Hospital Database on HIV. Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus–infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4. Arch Intern Med 2010;170:1228–38. 18. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis 2010;201:318–30. 19. Hammond E, Nolan D, James I, et al. Reduction of mitochondrial DNA content and respiratory chain activity occurs in adipocytes within 6-12 months of commencing nucleoside reverse transcriptase inhibitor therapy. AIDS 2004;18:815–17. 20. Choi AI, Vittinghoff E, Deeks SG, et al. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS 2011;25:1289–98. 21. Ribaudo HJ, Benson CA, Zheng Y, et al. No risk of myocardial infarction associated with initial antiretroviral treatment containing abacavir: short- and long-term results from ACTG A5001/ALLRT. Clin Infect Dis 2011;52:929–40. 22. Bedimo RJ, Westfall AO, Drechsler H, et al. Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era. Clin Infect Dis 2011;53:84–91. 23. Fichtenbaum CJ. Does antiretroviral therapy increase or decrease the risk of cardiovascular disease? Curr HIV/AIDS Rep 2010;7:92–8. 24. Malvestutto CD, Aberg JA. Coronary heart disease in people infected with HIV. Cleve Clin J Med 2010;77:547–56. 25. El-Sadr WM, Lundgren J, Neaton JD, et al; Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283–96. 26. Rasmussen LD, Kronborg G, Larsen CS, et al. Statin therapy and mortality in HIV-infected individuals; a Danish nationwide populationbased cohort study. PLoS One 2013;8: e52828. [Published online ahead of print March 4, 2013]. doi:0.1371/journal.pone.0052828.
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37. Fisher SD, Kanda BS, Miller TL, et al. Cardiovascular disease andtherapeutic drug-related cardiovascular consequences in HIV-infected patients. Am J Cardiovasc Drugs 2011;11:383–94. 38. Iwahashi N, Nakatani S, Kakuchi H, et al. Cardiac tumor as an initial manifestation of acquired immunodeficiency syndrome. Circ J 2005;69: 243–5. 39. Lee GY, Kim WS, Ko YH, et al. Primary cardiac lymphoma mimickinginfiltrative cardiomyopathy. Eur J Heart Fail 2013;15:589–91. 40. Chinello P, Lisena FP, Angeletti C, et al. Role of antiretroviral treatment in prolonging QTc interval in HIV-positive patients. J Infect 2007; 54:597–602.
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32. Nayak G, Ferguson M, Tribble DR, et al. Cardiac diastolic dysfunction is prevalent in HIV-infected patients. AIDS Patient Care STDS 2009;23:231–8.
42. Kocheril AG, Bokhari SA, Batsford WP, et al. Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997;20:2810–6.
33. Olusegun-Joseph DA, Ajuluchukwu JN, Okany CC, et al. Echocardiographic patterns in treatment-naïve HIV-positive patients in Lagos, south-west Nigeria. Cardiovasc J Afr 2012;23:e1–6.
43. Patel N, Veve M, Kwon S, et al. Frequency of electrocardiogram testing among HIV-infected patients at risk for medication-induced QTc prolongation. HIV Med 2013;14:463–71.
34. Gebo KA, Burkey MD, Lucas GM, et al. Incidence of, risk factors for, clinical presentation, and 1-year outcomes of infective endocarditis in an urban HIV cohort. J Acquir Immune Defic Syndr 2006;43:426–32.
44. Charbit B, Rosier A, Bollens D, et al. Relationship between HIV protease inhibitors and QTc interval duration in HIV-infected patients: a cross-sectional study. Br J Clin Pharmacol 2009;67:76–82.
35. Preziosi MJ, Kandel SM, Guiney DG, et al. Microbiological analysis of nontyphoidal Salmonella strains causing distinct syndromes of bacteremia or enteritis in HIV/AIDS patients in San Diego, California. J Clin Microbiol 2012;50:3598–603.
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