Selected metabolic and morphologic complications associated with highly active antiretroviral therapy

Metabolic and morphologic changes have been described in patients with human immunodeficiency virus (HIV) infection. In the short term, these disorders can be debilitating and may require medical intervention, including alterations in antiretroviral therapy regimens. The long-term consequences have not been fully realized, but are important, particularly in the era of durable HIV disease management with highly active antiretroviral therapy. This review focuses on 3 of the important morphologic or metabolic changes, namely alterations in body fat distribution, dyslipidemia, and lactic acidosis. The prevalence of each of these disorders remains unknown due to varied definitions and difficulty in recognition of the conditions for both the patient and the clinician. Treatment regimens directed at these abnormalities are being developed, but clinical trials are needed to fully ascertain the efficacy and safety of such interventions.     

Management of the metabolic effects of HIV and HIV drugs

Morphologic and metabolic abnormalities, including subcutaneous adipose tissue wasting, central adipose tissue accumulation, dyslipidemia and disorders of glucose metabolism are common among HIV-infected patients receiving highly active antiretroviral therapy (HAART) and contribute to the risk of cardiovascular disease in this population. The pathogenesis of these disorders is due to complicated interactions between effects of chronic HIV infection, HAART medications and patient factors, including genetic susceptibility. HAART has transformed HIV into a chronic condition for many patients and as a result the majority of HIV-infected patients in many areas of the developed world will soon be aged ≥50 years. Given that metabolic and cardiovascular diseases increase with aging, knowledge of the optimal management of these conditions is essential for practitioners caring for HIV-infected patients, including endocrine subspecialists. This Review highlights the clinical management of these disorders, focusing on the latest evidence regarding the efficacy of treatment strategies, newly available medications and potential interactions between HAART medications and medications used to treat metabolic disorders.     

Approach to the human immunodeficiency virus-infected patient with lipodystrophy

Subcutaneous atrophy and central fat accumulation are common among HIV-infected patients receiving highly active antiretroviral therapy, and may be accompanied by dyslipidemia and insulin resistance. These fat changes, although commonly referred to together as lipodystrophy, are best considered as separate disorders, with distinct pathogeneses and treatment approaches. These morphological and metabolic abnormalities first appeared after introduction of protease inhibitors more than 10 yr ago, but research has demonstrated that their pathogenesis is multifactorial, with contributions from other antiretroviral medications, patient-related factors, and HIV itself. Switching to a less toxic highly active antiretroviral therapy regimen has shown partial effectiveness for the management of fat atrophy and lipid abnormalities. Lifestyle modification or surgical approaches are the treatment of choice for lipohypertrophy, although novel therapies targeting the GH axis show promise. HIV-related dyslipidemia may be difficult to treat, and can be complicated by drug-drug interactions between some lipid-lowering medications and antiretroviral medications. Treatment of diabetes in HIV-infected patients should generally follow established guidelines, but thiazolidinediones, rather than metformin, may be considered first-line treatment in a patient with lipoatrophy, given their potential to increase sc fat. The contribution of body fat changes and metabolic abnormalities to cardiovascular risk and the changing risk profiles of newer antiretroviral regimens are under intense investigation.     

Dysregulation of glucose metabolism in HIV patients: epidemiology, mechanisms, and management

HIV-infected patients on highly active antiretroviral therapy (HAART) have increased prevalence of a number of chronic metabolic disorders of multifactorial but unclear etiology. These include disorders of lipid metabolism with or without lipodystrophy, insulin resistance, and an increased prevalence of impaired glucose tolerance, diabetes mellitus, and cardiometabolic syndrome. While much attention has been focused on the lipid and cardiovascular disorders, few investigations have attempted to characterize the prevalence, incidence, etiology, mechanisms, and management of glycemic disorders in HIV patients. In this review, we have focused specifically on a comprehensive assessment of dysglycemia in the context of HIV infection and HAART.     

Atherosclerotic vascular disorders in HIV infected patients

Individuals infected with human immunodeficiency virus (HIV) frequently demonstrate a metabolic syndrome associated with atherosclerosis and cardiovascular disease. Extensive functional and structural arterial wall changes have been observed in these individuals. It is documented that these vascular changes are closely related to highly active antiretroviral therapy (HAART) -induced disorders of metabolic parameters such as serum glucose, cholesterol, triglycerides and arterial blood pressure. In addition, characteristics of the HIV infection itself such as immunodeficiency, viral load, duration of the disease, appear to influence the pathogenesis of these vascular changes. Intensive treatment of vascular dysfunction might be helpful in preventing or retarding the atherosclerotic process in HIV patients.     

Metabolic complications associated with use of protease inhibitors

The potency of highly active antiretroviral therapy, including protease inhibitors have led to declining morbidity and mortality in patients with HIV infection. However the use of protease inhibitors is associated with onset of morphologic and metabolic disorders. A syndrome of lipodystrophy has been described. It is characterized by fast wasting of the face and limbs, and a central adiposity, breast hypertrophy and buffalo neck. The prevalence of lipodystrophy in patients treated with protease inhibition is about 60%. The principal metabolic disorders are lipid abnormalities, principally hypertriglyceridemia. New onset of diabetes mellitus is less frequent. The pathogenesis of these abnormalities unknown. Insulin resistance seems to be a common feature of protease inhibitor associated metabolic an morphologic side-effects.     

Clinical impact of HIV-related lipodystrophy and metabolic abnormalities on cardiovascular disease

Metabolic complications and altered fat distribution associated with HIV infection and antiretroviral therapy may lead to accelerated coronary artery disease (CAD). The high prevalence of multiple cardiovascular risk factors in a significant number of HIV patients is a cause for concern in both patients and physicians. Non-invasive strategies to measure subclinical CAD have been inconclusive. Long-term studies are underway to determine cardiac event rates, intervention strategies and consequences for the clinical management of HIV disease. In the present paper, we summarize the most prevalent risk factors in individuals with HIV infection receiving highly active antiretroviral therapy by focusing on the clinical implications of metabolic abnormalities and HIV-related lipodystrophy on CAD.     

Metabolic abnormalities associated with HIV infection and antiretroviral therapy

Although noted early in the HIV epidemic, metabolic abnormalities came to prominence when potent combination antiretroviral therapy was introduced. Complications associated with HIV infection and antiretroviral therapy include cardiovascular disease, lipid disorders, glucose metabolism disorders, adipose tissue disorders, bone metabolism disorders, and lactic acidosis. Metabolic complications have driven the discovery of new agents and classes of antiretrovirals, and have shaped guidelines for the management of HIV infection. However, significant uncertainty remains about pathogenesis and management. Substantial complexity exists in the treatment of these disorders, illustrated by the complex drugdrug interactions between lipid-lowering agents and antiretroviral regimens. Several important new developments include the association of a higher risk of cardiovascular events with the discontinuation of antiretroviral therapy or use of specific drugs like abacavir and didanosine. This article reviews the current understanding of metabolic abnormalities associated with HIV and its treatment.     

Outcome of HIV-infected patients with invasive squamous-cell carcinoma of the anal canal in the era of highly active antiretroviral therapy

PURPOSE: Before the development of highly active antiretroviral therapy for the treatment of HIV infection, HIV patients diagnosed with invasive squamous-cell carcinoma of the anal canal carried a very poor prognosis. This study was designed to determine the outcome in a similar group of patients in the era of highly active antiretroviral therapy.METHODS: HIV-positive patients treated for invasive squamous-cell carcinoma of the anal canal at the University of Texas Medical Center affiliated hospitals from 1980 to 2001 were identified from operative data and cancer registries. We reviewed these records and collected data regarding age, CD4 count, highly active antiretroviral therapy, cancer treatment, complications, and survival. The patients were divided into two groups based on the presence or absence of highly active antiretroviral therapy and compared using a Kaplan-Meier approach.RESULTS: Fourteen patients with HIV and invasive squamous-cell carcinoma of the anal canal were identified. Six were in the prehighly active antiretroviral therapy group and eight in the highly active antiretroviral therapy group. All were considered for treatment with chemotherapy and radiation. In the prehighly active antiretroviral therapy group, one patient refused therapy and three were unable to complete the squamous-cell carcinoma therapy as planned because of complications. Four of eight highly active antiretroviral therapy patients were unable to complete the squamous-cell carcinoma therapy as planned. The prehighly active antiretroviral therapy patients had a mean age of 40 years and a mean CD4 count of 190 at the time of diagnosis. The highly active antiretroviral therapy patients had a mean age of 44 years and a mean CD4 count of 255 at the time of diagnosis. The 24-month survival was 17 percent in the prehighly active antiretroviral therapy group and 67 percent in the highly active antiretroviral therapy group (P = 0.0524). All six patients in the prehighly active antiretroviral therapy group died with active squamous-cell carcinoma vs. two in the highly active antiretroviral therapy group. Four of the remaining six patients had no evidence of active squamous-cell carcinoma at the last follow-up visit.CONCLUSIONS: A review of patients with HIV and invasive squamous-cell carcinoma of the anal canal suggests a trend toward a higher CD4 count at the time of diagnosis and improved survival in patients receiving highly active antiretroviral therapy. In this new era, HIV-positive patients should be on highly active antiretroviral therapy. If not, highly active antiretroviral therapy should be initiated, and standard multimodality therapies for invasive squamous-cell carcinoma of the anal canal are recommended.Read at the meeting of The American Society of Colon and Rectal Surgeons, New Orleans, Louisiana, June 21 to 26, 2003.     

Metabolic disorders induced by highly active antiretroviral therapy and their relationship with vascular remodeling of the brachial artery in a population of HIV-infected patients

Antiretroviral therapy has positively modified the natural history of HIV infection; but this treatment can induce metabolic abnormalities, including dyslipidemia, fat redistribution, high blood pressure, and insulin resistance. The metabolic syndrome, a clustering of the metabolic disorders, is frequently detected among HIV patients, especially those on antiretroviral treatment. All the arteries can modify their diameter in response to a chronic injury. This process, defined vascular remodeling, was demonstrated for the brachial artery. It is well known that the diameter of the brachial artery was correlated with the number of the elements of the metabolic syndrome and was associated with the severity of coronary artery disease. On this basis, we postulate that brachial arterial enlargement may be a process potentially correlated with the metabolic disorders induced by antiretroviral therapy. We tested this hypothesis in a large population of HIV-infected patients in which we measured brachial artery diameter, as an indicator of artery remodeling, by noninvasive, ultrasonographic technique. Our population consisted of 570 patients, with a mean age of 46.3 ± 7.1 years. All the patients were chronically treated with highly active antiretroviral therapy. Brachial artery diameter was correlated with insulin resistance, evaluated by the homeostasis model assessment of insulin resistance index (r = 0.18, P < .0001). There was a significant linear increase in brachial artery diameter as the number of components of the metabolic syndrome increased: brachial artery diameter for those with 0, 1, 2, 3, or + characteristics was 39.3 ± 7.2, 41.0 ± 6.8, 42.0 ± 7.3, and 43.8 ± 7.9 mm, respectively (P < .001 for trend). In multivariable logistic regression analysis, brachial artery diameter was independently correlated with the presence of metabolic syndrome. Our results are in line with the hypothesis that, among HIV-infected patients chronically treated with antiretroviral therapy, those with a larger brachial artery diameter are at high risk for metabolic disorders, including a more severe insulin resistance and the presence of metabolic syndrome.     

Therapy insight: the changing spectrum of rheumatic disease in HIV infection

HIV infection and AIDS have protean and multisystem manifestations throughout the various stages of infection. Progression from HIV infection to AIDS is associated with a gradual loss of immunocompetence and the occurrence of opportunistic infections and malignancies; it is also associated with immune dysregulation and persistent, prolonged immune activation that leads to autoimmune phenomena such as vasculitis and serological abnormalities. In people who are infected with HIV, the recognition of autoinflammatory disorders, their differentiation from infections or lymphoproliferative malignancies and their treatment using potentially immunosuppressive drugs is a challenging clinical scenario. The spectrum of rheumatologic diseases reported in HIV-infected individuals has changed dramatically since the introduction of highly active antiretroviral therapy in 1995. Complications such as metabolic abnormalities, osteoporosis, and immune restoration inflammatory syndrome have emerged.     

A literature review on cardiovascular risk in human immunodeficiency virus-infected patients: implications for clinical management

IntroductionIn recent years, there has been growing concern about an increasing rate of cardiovascular diseases in human immunodeficiency virus-infected patients, which could be associated with side effects of highly active antiretroviral therapy. It is likely that the metabolic disorders related to anti-human immunodeficiency virus treatment will eventually translate into a increased cardiovascular risk in patients submitted to such regimens.ObjectiveTo evaluate if human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy are at higher risk of cardiovascular diseases than human immunodeficiency virus infected patients not receiving highly active antiretroviral therapy, or the general population.Research design and methodsWe conducted a computer-based search in representative databases, and also performed manual tracking of citations in selected articles.ResultThe available evidence suggests an excess risk of cardiovascular events in human immunodeficiency virus-infected persons compared to non-human immunodeficiency virus infected individuals. The use of highly active antiretroviral therapy is associated with increased levels of total cholesterol, triglycerides, low-density lipoprotein and morphological signs of cardiovascular diseases. Some evidence suggested that human immunodeficiency virus-infected individuals on highly active antiretroviral therapy regimens are at increased risk of dyslipidemia, ischemic heart disease, and myocardial infarction, particularly if the highly active antiretroviral therapy regimen contains a protease inhibitor.ConclusionPhysicians must weigh the cardiovascular risk against potential benefits when prescribing highly active antiretroviral therapy. Careful cardiac screening is warranted for patients who are being evaluated for, or who are receiving highly active antiretroviral therapy regimens, particularly for those with known underlying cardiovascular risk factors. A better understanding of the molecular mechanisms responsible for increased risk of cardiovascular diseases in human immunodeficiency virus-infected patients will lead to the discovery of new drugs that will reduce cardiovascular risk in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy.     

Haemopoiesis defects in HIV/AIDS-anaemia

Under physiological conditions haemopoiesis is continuous and maintains a stable number of blood elements. A defect at any stage presents as anaemia, neutropenia, thrombocytopenia or their combinations. The cause of haematological abnormalities with an HIV infection is multifactorial. HIV/AIDS patients may present identical haematological disorders as patients free of an HIV infection. Additionally, HIV-positive subjects tend to present disorders specific of an HIV infection. Anaemia may also be the first manifestation of an as yet undetected HIV infection. Moreover, many drugs used in the treatment of HIV/AIDS significantly affect haemopoiesis. Whatever the cause of anaemia, it is essential to initiate simultaneously with its treatment an appropriate highly active antiretroviral therapy. An antiretroviral therapy along the lines of state-of-the-art pharmacotherapy of HIV/AIDS significantly improves the efficacy of the actual haematological treatment. Key words: HIV infection-haemopoiesis-anaemia-antiretroviral therapy.     

AIDS-related malignancies: changing epidemiology and the impact of highly active antiretroviral therapy

PURPOSE OF REVIEW: Three cancers in people with HIV denote an AIDS diagnosis: Kaposi's sarcoma, high-grade B-cell non-Hodgkin's lymphoma and invasive cervical cancer. In addition a number of other cancers occur at increased frequency in this population group but are not AIDS-defining illnesses. This review discusses the impact of highly active antiretroviral therapy on the epidemiology and outcome of AIDS-defining cancers. RECENT FINDINGS: The incidence of both Kaposi's sarcoma and non-Hodgkin's lymphoma has declined in the era of highly active antiretroviral therapy and the outcome of both tumours has improved. Moreover, highly active antiretroviral therapy alone produces a response in a majority of antiretroviral-na?ve patients with Kaposi's sarcoma. In contrast, highly active antiretroviral therapy has had little impact on the incidence of human papilloma virus-associated tumours (cervical and anal cancer) in people with HIV, although it may improve survival by reducing opportunistic infection deaths. As people with HIV live longer with highly active antiretroviral therapy, an increased incidence of other non AIDS-defining cancers that have no known association with oncogenic infections is becoming apparent. SUMMARY: For those with access to highly active antiretroviral therapy, the good news from the AIDS-defining cancers - particularly Kaposi's sarcoma and non-Hodgkin's lymphoma - may be balanced by the increasing numbers of non AIDS-defining cancers.     

Does antiretroviral therapy prevent HIV transmission to sexual partners?

The majority of HIV-1 infections are acquired sexually, and interventions to prevent sexual transmission are urgently needed to curb the growth of the HIV pandemic. The potential role of antiretroviral therapy in preventing sexual transmission of HIV is still emerging. Highly active antiretroviral therapy has been shown to decrease HIV RNA shedding in the genital tract, and its use among serodiscordant couples has been associated with reduced seroconversions in partners who are HIV negative. However, other studies have associated the use of antiretroviral therapy with increased HIV transmission risk behaviors. In this review, we explore the rationale for using highly active antiretroviral therapy to prevent sexual transmission of HIV including its role in prevention strategies at the population level, as well as the cost-effectiveness and potential limitations of this approach.     

Multiple opportunistic AIDS-associated disorders strictly related to immunodeficiency levels, in a girl with congenital HIV infection

A 16-year-old girl with vertical HIV disease treated since birth suffered from six different AIDS-defining disorders until now. Even during the highly active antiretroviral therapy, multiple AIDS-related opportunistic infections may complicate the course of long-term congenital HIV disease, showing a strict relationship with immunological deterioration, which occurs shortly after virologic failure, due to an extensive genotypic resistance to all available antiretroviral compounds.     

Cardiovascular disease in HIV infection

The survival of patients with HIV infection who have access to highly active antiretroviral therapy has dramatically increased. In HIV-infected persons, cardiovascular disease can be associated with HIV infection, opportunistic infections or neoplasias, use of antiretroviral drugs or treatment of opportunistic complications, mode of HIV acquisition (such as intravenous drug use), or with the classic non-HIV-related cardiovascular risk factors (such as smoking or age). Diseases of the heart associated with HIV infection or its opportunistic complications include pericarditis and myocarditis. Pericarditis may lead to pericardial effusion rarely causing tamponade. Cardiomyopathy is often clinically silent with asymptomatic left ventricular systolic dysfunction. Endocarditis is mainly the consequence of intravenous drug abuse, possibly leading to life-threatening valvular insufficiency with the need for cardiac surgery. A further serious condition associated with HIV infection is pulmonary hypertension potentially leading to right heart failure. The cardiovascular complications of HIV infection such as cardiomyopathy and pericarditis have been reduced by highly active antiretroviral therapy, but premature coronary atherosclerosis is now a growing problem because antiretroviral drugs can lead to serious metabolic disturbances resembling those in the metabolic syndrome. Lipodystrophy, a clinical syndrome of peripheral fat wasting, central adiposity, dyslipidemia, and insulin resistance, is most prevalent among patients treated with protease inhibitors. These patients should thus be screened for hyperlipidemia, hyperglycemia, and hypertension, and they may be candidates for lipid-lowering therapies. When initiating lipid-lowering therapy, interactions between statins and HIV protease inhibitors affecting cytochrome P450 function must be considered. Restenosis rate after percutaneous coronary intervention may be unexpectedly high.     

HAART attack: metabolic disorders during long-term antiretroviral therapy

HIV infection has long been associated with changes in body metabolism, most notably in the form of AIDS wasting and in fat distribution changes. Abnormalities in blood lipid levels are associated with antiviral treatment, and the introduction of highly active antiretroviral therapy (HAART) has caused more cases of high triglycerides and unhealthy cholesterol levels. The frequency and extent of HAART-related metabolic changes is a controversial issue, and the AIDS Clinical Trials Group is drawing on most of its ongoing trials to enroll 3,000 people in a five-year study to track participants experiences with antiretroviral therapy. Several studies investigating the adverse effects associated with antiretroviral therapy are discussed.     

Diabetes, insulin resistance, and HIV

The transformation of HIV infection into a chronically managed illness through the widespread use of highly active antiretroviral therapy has brought with it comorbid conditions such as increased risk of cardiovascular disease. Diabetes and insulin resistance have emerged as important comorbidities associated with HIV infection and the use of antiretroviral therapy. Significant inroads have been made towards understanding the etiology of insulin resistance and diabetes in association with HIV and highly active antiretroviral therapy, and there are also emerging data on the prevalence and incidence of this problem. The recognition and management of diabetes mellitus, insulin resistance, and related complications will be an important part of long-term health maintenance for HIV-infected patients.     

The management of lymphoma in the immunosuppressed patient

Two forms of acquired immunodeficiency have dominated the last quarter of the twentieth century and are responsible for the majority of lymphomas in the immunosuppressed: post-transplantation lymphoproliferative disorders (PTLD) and AIDS-related lymphomas (ARL). The central role of Epstein-Barr virus in PTLD has led to novel treatment strategies designed to enhance immunity to this virus both as prevention and therapy. This is achieved by reducing iatrogenic immunosuppression and adoptive immunotherapy with allogeneic cytotoxic T-lymphocytes. Improved immune function in HIV seropositive patients treated with highly active antiretroviral therapy appears to be reducing the relative risk of AIDS-related lymphoma. However, ARL will remain a frequent diagnosis with the rapidly rising incidence of HIV throughout the world. The clinical management requires expertise in both the lymphoma chemotherapy and the treatment of HIV, including antiretroviral therapy and opportunistic infection management. Modest improvements in survival have been achieved recently for ARL.