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.     

Osteoarticular complications related to HIV infection and highly active antiretroviral therapy.

With the significant increase in life expectancy for HIV-infected patients in the era of high potency antiretroviral therapy, major metabolic changes have been observed due to the prolonged period of the viral infection and the treatment itself. Osteoarticular changes resulting from these processes are mainly reported in long term HIV-infected patients receiving high potency antiretroviral therapy and include osteopenia/osteoporosis, osteonecrosis, carpal tunnel syndrome and adhesive capsulitis of the shoulder.     

Metabolic syndrome associated with HIV and highly active antiretroviral therapy

The introduction of highly active antiretroviral therapy (HAART) has significantly improved the clinical outcome of HIV disease with increased survival rates. However, some HAART regimens, especially those including protease inhibitors, have been shown to cause in a high proportion of HIV-infected patients metabolic (dyslipidemia, insulin resistance) and somatic (lipodystrophy/lipoatrophy) changes that are associated with an increased risk of cardiovascular disease (coronary artery disease and stroke). The pathogenesis of HAART-associated metabolic syndrome and of its atherogenic profile is complex, and several factors are involved, including direct effects of HAART on lipid metabolism, endothelial and adipocyte cell function, activation of proinflammatory cytokines, and mitochondrial dysfunction. A better understanding of the molecular mechanisms responsible for this syndrome will lead to the discovery of new drugs that will reduce the incidence of lipodystrophy and related metabolic complications in HIV-infected patients facing long-term HAART.     

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.     

Effect of highly active antiretroviral therapy and thymic transplantation on immunoreconstitution in HIV infection

The purpose of this study was to determine whether thymic transplantation in addition to highly active antiretroviral therapy (HAART) will restore T cell function in HIV infection. Eight treatment-naive HIV-infected patients with CD4+ T cell counts of 200-500/mm3 were randomized into thymic transplantation and control arms. All patients received HAART (zidovudine, lamivudine, and ritonavir) for 6 weeks prior to transplantation. Thymic transplantation was done without immunosuppression, using postnatal HLA-unmatched cultured allogeneic thymus tissue. Patients were immunized every 6 months with the neoantigen keyhole limpet hemocyanin (KLH) and the recall antigen tetanus toxoid (TT). T cell phenotype and function and T cell receptor rearrangement excision circles (TRECs) were assessed. Thymic allografts were biopsied at 2 months. Six HIV-infected patients completed the study. Four patients received cultured allogeneic postnatal thymic grafts, two others were controls. CD4+ T cell counts increased and T cell-proliferative responses to Candida antigen and TT normalized in all patients. Proliferative responses to KLH developed in three of four transplant recipients and one of two controls. Patients responding to KLH after secondary immunization had greater TREC increases compared with the patients who did not respond. All thymic allografts were rejected within 2 months. In summary, four of six patients developed T cell-proliferative responses to the neoantigen KLH over the first 2 years of HAART. The transplanted thymus tissue, however, was rejected. There was no clear difference in restoration of T cell function in the transplant recipients compared with the controls. Increases in TRECs after initiation of HAART may correlate with improved immune function.     

Timing of highly active antiretroviral therapy and chemotherapy for Kaposi's sarcoma in patients with HIV infection

Highly active antiretroviral therapy (HAART) is an important part of the treatment of Kaposi's sarcoma (KS) in HIV-infected patients. We describe two cases of KS, which worsened on HAART.     

Metabolic and anthropometric consequences of interruption of highly active antiretroviral therapy

BACKGROUND: HAART has been associated with metabolic abnormalities (hyperlipidemia, insulin resistance, alterations in cortisol metabolism) and fat redistribution. SETTING: A prospective study of 26 Caucasian men (median age 43.5 years) with HIV-1 viral loads < 500 copies/ml for 12 months while on highly active antiretroviral therapy (HAART) who interrupted treatment for a median of 7.0 weeks (range 4.9-10.3 weeks). Seventeen (65.4%) patients reported at least one fat redistribution symptom at baseline. METHOD: Serum lipids, glucose and insulin levels during an oral glucose tolerance test, 24-h urinary free cortisol and 17-hydroxycorticosteroids, and anthropometric parameters were measured before HAART cessation and prior to its reinstitution. RESULTS: When baseline values were compared with those obtained after HAART interruption (means +/- SD), there was a significant decrease in total cholesterol (194+/-47.3 versus 159+/-29.3 mg/dl; P < 0.0001), low density lipoprotein (LDL) cholesterol (114+/-32.6 versus 96+/-24.7 mg/dl; P = 0.0013), triglycerides (261+/-244.3 versus 185+/-165.4 mg/dl; P = 0.008), and 24-hour urinary 17-hydroxycorticosteroids (15+/-7.9 versus 5+/-2.5 mg/24 h, P < 0.0001) and a significant increase in 24-hour urinary free cortisol (45+/-34.1 versus 62+/-32.2 microg/24 h; P = 0.016). There were no significant changes in glucose or insulin levels or in anthropometric measurements. CONCLUSIONS: A relatively brief interruption of HAART resulted in significant improvements in total cholesterol, LDL cholesterol, and triglyceride levels. No changes were observed in insulin resistance profiles or anthropometric measurements, perhaps because of the brief duration of HAART interruption. These results suggest that hyperlipidemia and alterations in corticosteroid metabolism in the setting of HAART are a direct drug effect that reverses with drug withdrawal. However, glucose metabolism and fat redistribution do not change over the short term.     

Metabolic complications of antiretroviral therapy

HIV-infected patients receiving long-term antiretroviral treatment experience a number of metabolic abnormalities, including lipid abnormalities, dysregulation of glucose metabolism, body-fat redistribution, mitochondrial abnormalities, and bone abnormalities, as well as the sequelae of these disorders. These complications can be severe and life threatening, disrupt adherence to antiretroviral therapy, limit options in therapy, and profoundly affect quality of life. Risk for such complications should be considered in selection of antiretroviral therapy, and patients should be monitored for the occurrence of abnormalities and changes in risk factors. This article summarizes a presentation by Donna E. Sweet, MD, on the metabolic complications of long-term antiretroviral therapy at the IAS-USA course in New York in March 2005.     

Pulmonary manifestations of HIV infection in the era of highly active antiretroviral therapy.

STUDY OBJECTIVES: To determine whether the spectrum of HIV-related pulmonary disease seen by a university medical center Pulmonary and Critical Care Medicine Service has changed since the introduction of highly active antiretroviral therapy (HAART). DESIGN: Retrospective chart review. SETTING: A tertiary care university hospital. PATIENTS: All HIV-infected patients referred to the Pulmonary and Critical Care Medicine Service from January 1, 1993, through December 31, 1995 (era 1) and from July 1, 1997, through June 30, 2000 (era 2). INTERVENTIONS: Inpatient and outpatient charts were reviewed for data regarding patient demographics, CD4 cell counts, viral load levels, duration of HIV seropositivity, history of opportunistic infections, and final diagnosis. RESULTS: Pneumocystis carinii pneumonia (PCP) was less common in the HAART era than in the pre-HAART era, whereas bacterial pneumonia and non-Hodgkin's lymphoma (NHL) were more common in the HAART era than in the pre-HAART era. HAART was protective against PCP (odds ratio [OR], 0.37; confidence interval [CI], 0.16 to 0.89) in a manner dependent on the CD4 cell count. Patients receiving HAART were at increased risk for the development of bacterial pneumonia (OR, 2.41; CI, 1.12 to 5.17) and NHL (OR, 15.11; CI, 3.14 to 28.32). A history of PCP indicated a risk factor for bacterial pneumonia (OR, 2.14; CI, 1.13 to 4.04). A history of cytomegalovirus infection indicated a risk factor for NHL (OR, 6.0; CI, 1.27 to 28.32). CONCLUSIONS: There have been significant changes in the spectrum of HIV-related pulmonary complications seen by our Pulmonary and Critical Care Medicine Service in the HAART era.     

Therapy insight: Body-shape changes and metabolic complications associated with HIV and highly active antiretroviral therapy

Increasingly effective therapies for HIV infection are now available. These treatments, referred to collectively as highly active antiretroviral therapy, comprise various combinations of anti-HIV drugs from different drug classes. Recently, a range of metabolic complications have emerged as important toxicities in treated patients. Complications present as abnormalities of body-fat mass distribution in association with an often significant dyslipidemia and glucose homeostasis dysregulation. The body-shape changes, manifesting as peripheral lipoatrophy or central lipohypertrophy, can have a negative impact on quality of life and consequently on adherence to treatment. The combination of central lipohypertrophy, dyslipidemia and insulin resistance is associated with accelerated rates of atherosclerosis and other potentially significant long-term effects. The pathogenesis of these effects is complex and is still being actively investigated. Possible contributing factors relate to host characteristics, HIV viral parameters and specific effects of anti-HIV drugs on adipose-tissue biology and on intermediary metabolism. Management of these complications involves manipulation of the anti-HIV drugs using an understanding of their particular effects on lipid and glucose metabolism, in association with standard therapeutic interventions. Individualized approaches, taking into consideration quality-of-life issues, and assessment of potential cardiovascular risks, are now an important component of effective care of HIV-infected patients.     

Metabolic complications associated with the use of highly active antiretroviral therapy in HIV-1-infected adults

The availability of highly active antiretroviral therapy (HAART) has resulted in dramatic declines in morbidity and mortality in patients infected with human immunodeficiency virus-1 (HIV-1). However, the success of HAART has been tempered by the recognition of adverse metabolic effects clearly associated with its use. These "metabolic complications" include dyslipidemia, changes in body fat distribution, insulin resistance and glucose intolerance, metabolic bone disease, and lactic acidosis. Guidelines to assist clinicians in the management of these complications have been put forth by various organizations, including the International AIDS Society, the HIV Medicine Association of the Infectious Disease Society of America, and the Adult AIDS Clinical Trials Group.     

HIV infection in the era of highly active antiretroviral therapy: the Malaga Study

We analyse the characteristics of patients diagnosed with HIV infection in the highly active antiretroviral therapy era in the southeast of Spain. Data were collected on 470 HIV patients diagnosed between January 1997 and December 2002. The number of cases fell over recent years and HIV transmission was sexual in 70.5%. The mean CD4 lymphocyte count was 302.1 x 10(6)/L and the mean viral load 4.70 log(10). Diagnosis of HIV coincided with an AIDS-defining opportunistic illness in 30.6% of patients and a late diagnosis (CD4 < 200 x 10(6)/L) was made in 48.3% of patients. A late diagnosis was related to male gender (OR 2.50; 95% CI 1.20-5.12; P < 0.001) and AIDS case (OR 18.80; 95% CI 10.50-33.80; P < 0.00001). These results suggest that there has been a progressive reduction in new cases of HIV-infected patients, with the main route of transmission being sexual and that the diagnosis was late in almost half the patients.     

Pegylated liposomal doxorubicin plus highly active antiretroviral therapy versus highly active antiretroviral therapy alone in HIV patients with Kaposi's sarcoma

Twenty-eight HIV patients either naive or failing highly active antiretroviral therapy (HAART)with moderate-advanced Kaposi's sarcoma (KS)were randomly chosen to initiate a new HAART regimen plus pegylated liposomal doxorubicin(PLD) or the new HAART regimen alone. After 48 weeks, better response rates were observed in the HAART plus PLD group (76% versus 20%).In HIV-infected patients with moderate-advanced KS, HAART alone may not be enough for KS response.     

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.     

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.     

Both long-term HIV infection and highly active antiretroviral therapy are independent risk factors for early carotid atherosclerosis

ObjectiveThere is controversy over whether or not chronic HIV infection contributes to atherosclerosis. We investigated the relationship between HIV infection, antiretroviral medication and ultrasound evidence of early atherosclerosis in the context of vascular risk factors.DesignA case–control design with 292 HIV-positive subjects and 1168 age- and sex-matched controls.MethodsWe assessed vascular risk factors, blood pressure, serum lipids and carotid intima media thickness (IMT) in cases and controls. With multivariate regression models, we investigated the effects of HIV status and antiretroviral medication on IMT.ResultsThe common carotid artery (CCA) IMT value was 5.70% (95% confidence interval [3.08–8.38%], p < 0.0001) or 0.044 mm [0.021–0.066 mm] (p = 0.0001) higher in HIV-positives, adjusted for multiple risk factors. In the carotid bifurcation (BIF), the IMT values were 24.4% [19.5–29.4%] or 0.250 mm [0.198–0.303 mm] higher in HIV patients (p < 0.0001). An investigation of antiretroviral substances revealed higher CCA- and BIF-IMT values in patients receiving combination antiretroviral therapy (HAART).ConclusionsHIV infection and HAART are independent risk factors for early carotid atherosclerosis. Assuming a risk ratio similar to that in large population-based cohorts, the observed IMT elevation suggests that vascular risk is 4–14% greater and the “vascular age” 4–5 years higher in HIV-positive subjects. The underlying mechanisms remain to be clarified.