Cardiovascular complications in patients with HIV infection

As advances in early diagnosis and aggressive therapy, as well as better supportive care, become available to a larger number of patients with HIV infection, survival is being prolonged, and more patients are experiencing cardiac abnormalities. The most common cardiac manifestations of HIV disease are dilated cardiomyopathy, myocarditis, pericardial effusion, endocarditis, pulmonary hypertension, HIV-associated malignant neoplasms, and drug-related cardiotoxicity. The introduction of highly active antiretroviral therapy (HAART) regimens has substantially modified the course of HIV disease by lengthening survival and improving quality of life of HIV-infected patients. However, early data have raised concerns about HAART being associated with an increase in peripheral and coronary arterial disease. This review discusses the principal HIV-associated cardiovascular manifestations and emphasizes new knowledge about their prevalence, pathogenesis, and treatment.     

Cardiomyopathy and Heart Failure in Patients With HIV Infection

With the advent and widespread use of antiretroviral therapy (ART), the epidemiology of cardiomyopathy and heart failure (HF) associated with HIV infection is changing. Near-normal life expectancy in contemporary HIV-infected populations has been associated with prolonged exposure to increased cardiometabolic burden and chronic immune activation and systemic inflammation. Therefore, the pre-ART phenotype of HIV-associated cardiomyopathy with overt left ventricular systolic dysfunction and poor prognosis has been replaced over time by cardiomyopathy with a more insidious course, more frequent ischemic background, and highly prevalent left ventricular diastolic dysfunction. Patients with HIV are more prone to development of coronary artery disease and development of HF after myocardial infarction. The role of ongoing immune activation and systemic inflammation, despite highly active ART (HAART), appears to be central in this process. The role of HAART toxicity is controversial, as HAART itself appears to be protective for the development of HF, but recent data suggest that protease inhibitors might adversely affect the course of HIV-associated HF. Because of these unique features, the optimal therapeutic approach for HIV-associated cardiomyopathy remains unknown. The current therapeutic approaches are an extrapolation from noninfected populations. Importantly, the significance of the highly prevalent diastolic abnormalities among HIV-infected patients is not known. Therefore, further research is needed to identify its prognostic implications. Considering the prevalence of structural and functional cardiac abnormalities in HIV-infected persons and the lack of evidence on how to best screen and treat these patients, systematic research on this topic is a public health priority.     

Human papillomavirus infection and disease in HIV-infected individuals

The possibility of increases in both oral and anogenital pathologic conditions due to human papillomavirus (HPV) in patients infected with the human immunodeficiency virus (HIV) is of concern and is the focus of numerous current research studies. HIV-infected women are at higher risk for cervical HPV detection, for infection with high-oncogenic-risk types of HPV, for persistent HPV infection, for cervical cytologic abnormalities, and for cervical intraepithelial neoplasms. HIV-infected men are at increased risk for anal HPV infection, for anal infection with high oncogenic-risk types of HPV, for persistent anal HPV infection, and for anal intraepithelial defects. Recent studies have shown an increased risk of oral warts in HIV-infected individuals despite treatment with highly active antiretroviral therapy (HAART). Oral HPV infection rates have not declined since the initiation of HAART, and evidence suggests that the rates may have actually increased in white HIV-infected males.     

Cytokines in HIV-associated cardiomyopathy

Among the multiple cardiac manifestations occurring in HIV-infected patients, cardiomyopathy is one of the most challenging. Its incidence has only slightly decreased since the introduction of highly active antiretroviral therapy (HAART). Also, its pathogenesis remains relatively unclear. Although several studies demonstrated the presence of HIV genome in the heart of patients, more recent developments found that viral infection plays an indirect role only, as well as they recognized the contribution of proinflammatory cytokines in the progression of the disease. Experimental studies on animals and cultured myocytes have established the signalling pathway triggered by proinflammatory cytokines in heart failure and cardiomyopathy. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 promote expression of inducible nitric oxide synthase (iNOS) in cardiomyocytes through activation of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappaB (NFkappaB). TNF-alpha and high concentrations of NO also induce cardiomyocyte apoptosis by TNF type 1 receptor activation. This biological framework, which is also involved in progression of cardiomyopathy in humans, is more pronounced in HIV-infected patients, in whom proinflammatory cytokines TNF-alpha, IL-1 and IL-6 are increased, resulting in an enhanced expression of cardiac iNOS, especially in patients with a low CD4 T cell count. This may account for the worse outcome of heart failure in HIV-infected patients. However, there are only few data today to support future therapeutic implications of cytokines antagonism in treatment of HIV-infected patients with cardiomyopathy. Whether modulation of TNF production or selective inhibition of p38 MAPK pathway could be useful approaches remains uncertain.     

Sex and the course of HIV infection in the pre- and highly active antiretroviral therapy eras

We reviewed the available literature on the potential effects of sex on the course of HIV infection and found that there is little evidence for sex differences in the rate of disease progression in the pre-highly active antiretroviral therapy (HAART) and HAART era. Compared to men, women appeared to have lower HIV RNA levels and higher CD4 cell counts shortly after infection with HIV, but studies were inconclusive regarding whether these differences diminish over time. Differences in viral load or CD4+ cell count might cause women to delay initiation of HAART. Nonetheless, we found no substantial sex difference in the benefit of antiretroviral therapy. The studies we reviewed failed to find any harmful effect of pregnancy on HIV disease progression. With the availability of effective antiretroviral agents, HIV-infected women have increasingly decided to have children. Conflicting results exist on the effect of HAART on regression of cervical intra-epithelial neoplasia (CIN). Unlike CIN, invasive cervical cancer has not been found to be much higher in HIV-infected women than in HIV-uninfected women. Although publication bias cannot be ruled out, published studies suggest higher rates of adverse events among HIV-infected women on therapy as compared to men. As more pharmacological agents are developed, it is especially important that potential sex differences in pharmacodynamics are assessed. The relationship between metabolic abnormalities, changes in body habitus, and endocrine perturbations has not been extensively studied. Whether sex differences are due to unalterable genetic factors or social and environmental conditions, it is imperative that all HIV-infected individuals have equal access to interventions that can slow disease progression.     

抗艾滋病病毒药物的肝损伤

高效抗逆转录病毒治疗（HAART）已经明显地降低了艾滋病相关的发病率和死亡率。但是，接受HAART治疗的患者通常在遭受药物副作用的困扰。因此，HIV感染治疗已经成为持续HIV病毒抑制与药物毒性危险性之间复杂的平衡行为。HAART的毒性作用之一是肝毒性，其可造成HIV患者的治疗中断、亚临床肝炎，甚至出现致死性肝衰竭。目前，HAART导致肝毒性的机理尚不清楚。本文就HAART导致肝毒性的发病机制、发生率、临床影响、危险因素以及临床处理作一综述。     

Cardiovascular outcomes of pediatric seroreverters perinatally exposed to HAART

Seroreverters (uninfected children of HIV-infected mothers) have exhibited left ventricular (LV) dysfunction. Mitochondrial toxicity associated with in utero or postnatal exposure to highly active antiretroviral therapy (HAART) is a possible mechanism. Adult and animal models have demonstrated associations between LV abnormalities, cardiomyopathy, and components of HAART. Yet, outcomes in children are poorly understood. In this study, we explore HAART-associated LV abnormalities in seroreverters exposed to HAART (n = 144) or never exposed (n = 252). Subjects are drawn from the Women and Infants Transmission Study and the Pediatric Pulmonary and Cardiovascular Complications of HIV Study, respectively. Data include (1) echocardiographic studies of LV structure and function and (2) serologic cardiac biomarkers (cardiac troponin, probrain natriuretic peptide, high-sensitivity C reactive protein), both collected during the first month of life, and again at 6, 12, 24, 36, and 48 months postnatally. Planned analyses include several regression models. At this time, we have access to data for all 252 unexposed children, and 53 exposed subjects are enrolled. The cohorts are similar in terms of gender and race and the recruited subjects are representative of all eligible subjects in terms of exposure to HAART. Recruitment will continue into 2006.     

Endocrine complications of human immunodeficiency virus infection: hypogonadism, bone disease and tenofovir-related toxicity

Treatment with highly active antiretroviral therapy (HAART) has revolutionized care of patients with HIV infection. The cost of increased survival has been antiretroviral toxicity and increasing age-related co-morbidities that include significant metabolic issues. Hypogonadism was first described in the setting of advanced AIDS and can be primary or secondary. Data regarding treatment largely concern patients with wasting. Varied syndromes involving bone have been described in patients with HIV including osteonecrosis, low bone mineral density (BMD) and osteoporosis, and rarely osteomalacia. Low BMD leading to osteoporosis is the most common bone pathology and may be as a result of HIV infection, drug toxicity or co-morbidities. However, increasingly fragility fractures are reported in HIV-infected patients, suggesting bone demineralization in this population is of clinical relevance. Further research is required to understand its pathogenesis and determine effective management; however, initiation of antiretroviral therapy seems to accelerate (in the short-term) bone demineralization. One particular antiretroviral agent, tenofovir is widely used and is potentially implicated as having a greater role in long-term bone and renal dysfunction. As this population ages, screening for low BMD will become increasingly more important.     

Heart and HAART: Two sides of the coin for HIV-associated cardiology issues

The introduction of highly active antiretroviral therapy (HAART) has generated a contrast in the cardiac manifestations of acquired immunodeficiency syndrome. In developed countries, we have observed an approximately 30% reduction in the prevalence of human immunodeficiency virus (HIV)-associated cardiomyopathy, possibly related to a reduction of opportunistic infections and myocarditis. In developing countries, however, where the availablity of HAART is limited and the pathogenic impact of nutritional factors is significant, we have observed an approximately 32% increase in the prevalence of HIV-associated cardiomyopathy and a related high mortality rate from congestive heart failure. Also, some HAART regimens in developed countries, especially those including protease inhibitors, have been shown to cause, in a high proportion of HIV-infected patients, an iatrogenic metabolic syndrome (HIV-lipodystrophy syndrome) that is associated with an increased risk of cardiovascular events related to a process of accelerated atherosclerosis, even in young HIV-infected people. Careful cardiac screening is warranted for patients who are being evaluated for, or who are receiving, HAART regimens, particularly for those with known underlying cardiovascular risk factors. A close collaboration between cardiologists and infectious disease specialists is needed for decisions regarding the use of antiretrovirals, for a careful stratification of cardiovascular risk factors, and for cardiovascular monitoring of HIV-infected patients receiving HAART, according the most recent clinical guidelines.     

Atypical echocardiographic findings of endocarditis in an immunocompromised patient

Cardiovascular manifestations in patients infected with human immunodeficiency virus (HIV) have been altered by the introduction of highly active antiretroviral therapy regimens that allow more effective prophylactic treatment and an increased time of survival. Because of this, noninfectious cardiac conditions associated with HIV disease are being recognized with increasing frequency in these patients. Cardiac involvement in HIV-infected patients varies from clinically silent to overtly symptomatic disease. By some estimates a direct cardiac cause of mortality is between 1% and 6% of all cases. Pericardial effusion, pericarditis, myocarditis, cardiomyopathy, endocarditis, and pulmonary hypertension are well-recognized cardiac illnesses associated with HIV infection. Echocardiography has been crucial in evaluating HIV-infected patients to assess the extent of cardiac involvement. This case report illustrates atypical echocardiographic manifestations of endocarditis and paravalvular abscess in an immunocompromised patient.     

Left ventricular dysfunction in human immunodeficiency virus infection

The relationship between human immunodeficiency virus (HIV) infection and cardiovascular disease is still under debate, but it appears that the risk of myocardial infarction in those with HIV infection who are receiving highly active antiretroviral therapy (HAART) is increased. There has been less focus, however, on the effect of HIV and HAART on left ventricular function. Evidence from the past 20 years in both Westernized and developing countries has indicated that subclinical left ventricular dysfunction in HIV-infected individuals with and without well-controlled HIV infection is prevalent and may represent emerging cardiac disease. The specific roles of HIV infection and HAART are unclear, but they may exert independent direct and indirect effects on the myocardium. These effects may include chronic inflammation, metabolic complications (ie, insulin resistance, lipotoxicity, dyslipidemia), and mitochondrial toxicity. The objective of this article is to review the evidence for HIV- and HAART-related left ventricular dysfunction in persons infected with HIV.     

Pathogenesis of HIV-associated cardiovascular complications

Reviews and studies published before the introduction of highly active antiretroviral therapy (HAART) have tracked the incidence and course of HIV infection in relation to cardiac illness in both children and adults. The introduction of HAART regimens has significantly modified the course of HIV disease, with longer survival rates and improvement of life quality in HIV-infected people expected. However, early data raised concerns about HAART being associated with an increase in both peripheral and coronary arterial diseases. In this review we discuss HIV-associated cardiovascular complications focusing on pathogenetic mechanisms that could have a role in diagnosis, management, and therapy of these complications in the HAART era.     

Vorzeitige Arteriosklerose bei HIV-infizierten Patienten?

Complex lipodystrophic body changes in association with metabolic abnormalities such as dyslipidemia and insulin resistance have become a common feature in HIV patients on highly active antiretroviral therapy (HAART). If these metabolic changes will lead to an epidemic of cardiovascular events within the next decades, however, remains to be seen. The incidence of myocardial infarctions in HIV-infected patients continues to be low. Current data on changes of the incidence in the HAART era remains somewhat conflicting, probably due to methodological issues. In this review the key studies concerning the incidence of premature arteriosclerosis in HIV-infected patients are discussed.     

HIV infection, highly active antiretroviral therapy and the cardiovascular system

Cardiovascular complications in the course of human immunodeficiency virus (HIV) infection are multifactorial and may be caused by the virus itself or by the related opportunistic infections and neoplasms. Highly active antiretroviral therapy (HAART) has prolonged many patients' lives, but many cardiac sequelae of HIV are not affected by HAART and continue to develop even with treatment. In addition, HAART itself causes in a high proportion of patients a metabolic syndrome, characterized by lipodystrophy/lipoatrophy, dyslipidemia and insulin resistance that may be associated with an increase in peripheral artery and coronary artery diseases. Careful cardiovascular evaluation in the course of HIV disease can identify cardiac complications early enough to treat. All HIV-infected patients candidate to antiretroviral therapy and patients already under treatment should undergo an assessment that includes the evaluation of the cardiovascular risk with the available guidelines.     

Pulmonary infections in the HIV-infected patient in the era of highly active antiretroviral therapy: An update

The highly active antiretroviral therapy (HAART) era began in 1996 when the combination of multiple antiretroviral agents was found to improve outcomes in HIV-infected patients. HAART has made a tremendous impact on the progression of HIV and on the morbidity and mortality associated with its opportunistic infections. HIV-positive patients who respond to HAART have a decreased incidence of opportunistic infections. Studies have documented close to a 50% decline in the incidence of pneumocystis pneumonia and bacterial pneumonia with the use of antiretroviral therapy. Primary and secondary prophylaxis for pneumocystis pneumonia can be discontinued in patients who show a sustained response to antiretroviral therapy. Unique to the HAART era, immune reconstitution syndrome is characterized by a paradoxical deterioration of a preexisting infection that is temporally related to the recovery of the immune system. Recently, more and more patients are being admitted for non-AIDS related illnesses in the HAART era.     

Incidence of the involvement of the cardiovascular system in HIV infection

The epidemiology of cardiac complications related to HIV, including cardiomyopathy, increased left ventricular mass, myocarditis, pericardial effusion, endocarditis, and malignancy, are discussed. An increased number of HIV-infected individuals may present with cardiac complications in the next decade as chronic viral infection, co-infections, drug therapy, and immunosuppression affect the heart. Understanding the nature and course of cardiac illness related to HIV infection may allow appropriate monitoring, early intervention and therapy, and will provide a baseline to evaluate the effects of new therapeutic regimens such as highly active antiretroviral therapy on the cardiovascular system.     

Direkte und indirekte atherogene Effekte der HIV-Infektion und antiretroviralen Therapie

Highly active antiretroviral therapy (HAART) has led to a significant decrease in HIV-associated morbidity and mortality. Clinical data, however, suggest that both HIV infection and HAART may be associated with an increased cardiovascular risk. A variety of excellent review articles have been published on clinical evidence regarding cardiovascular events in HIV-positive and HAART-treated patients. The underlying mechanisms of the cellular and metabolic alterations in HIV-infected patients remain unclear. This article outlines the general pathogenesis of atherosclerosis and describes the potential role of HIV infection and antiretroviral therapy on direct and indirect effects in atherogenesis.     

Antiretroviral therapy in HIV-infected children: the metabolic cost of improved survival

Although highly active antiretroviral therapy (HAART) has positively altered the morality rates in HIV-infected children, these drugs have the potential to cause significant morbidity. These drugs cause changes in fat distribution, lipid profiles, glucose, homeostasis, and bone turnover. The direct relationship between duration of drug exposure and increased risk of cardiovascular disease is particularly concerning for HIV-infected infants and children, who likely will have longer cumulative exposure to HAART. It is unclear whether the metabolic effects of decades of exposure would be reversible with cessation of therapy. The benefits of HAART in HIV infection are indisputable, but the impetus to find a cure or design more tolerable therapy is clear. Infarction may replace infection as the major cause of morbidity and mortality from HIV.