Management of dyslipidaemia in HIV-infected patients receiving antiretroviral therapy

Dyslipidaemia associated with the treatment of HIV infection, particularly with the use of protease inhibitors (PIs), can raise cholesterol and triglyceride (TG) levels to the thresholds indicated for intervention. Recent evidence from epidemiological studies has shown that there are correlations between antiretroviral drug use and increased risks for, and incidences of, cardiovascular disease, including myocardial infarction and coronary heart disease. The primary goals of dyslipidaemia therapy for HIV patients are reductions of both low-density lipoprotein cholesterol (LDL-C) and markedly elevated TG levels. Dietary strategies and exercise programs may be tried, although these have shown inconsistent results. The two options for drug therapy are switching antiretroviral agents and using lipid-lowering drugs. Each approach is associated with advantages and limitations, and the need to maintain viral suppression must be balanced with the need to treat abnormal lipid levels. Most drug switches replace the PI component with drugs from another antiretroviral class. Selection of drug therapy for lipid lowering depends on the type of dyslipidaemia predominating and the potential for drug interactions. The use of the statins pravastatin and atorvastatin is recommended for the treatment of patients with elevated LDL-C levels and gemfibrozil or fenofibrate for patients with elevated TG concentrations. Development of new PIs with more favourable effects on the lipid profile should be of benefit.     

Influence of hepatitis C genotypes on lipid levels in HIV-positive patients during highly active antiretroviral therapy

BACKGROUND: The independent role of HCV genotype 3 (HCV-3) in dyslipidaemia following highly active antiretroviral therapy (HAART) is still unexplored. METHODS: Analysis of data from a cohort of 307 HIV/HCV-coinfected patients and 415 HIV-monoinfected controls was conducted. Patients with available lipid levels at baseline and minimum 3-month follow-up were ranked into three groups by HCV status (HCV-3, other HCV genotypes or HCV negative). Univariate and multivariate GEE models were performed to assess factors correlated with lipid serum levels as coefficient (Coef., defined as mean difference [mg/dl] across the follow-up). Univariate and multivariate logistic regression analyses were performed for prediction of relevant hypertriglyceridaemia (> or = 500 mg/dl) and relevant hypercholesterolaemia (> or = 240mg/dl) at 3 months of follow-up. RESULTS: HCV-3 correlated with lower triglyceridaemia (Coef.=-38.22; P=0.001), independently from the other considered variables, including age, gender and use of stavudine or lopinavir. Even though HCV infection per se appeared to be protective, HCV-3 in particular was also independently associated with lower cholesterolaemia (Coef.=-46.35; P<0.001). At logistic regression analyses, HCV-3, but not HCV-non-3, was associated with lower risk of relevant hypercholesterolaemia (odds ratio [OR] 0.06; P=0.01) and relevant hypertriglyceridaemia (OR 0.11; P=0.05), independently from other considered variables. CONCLUSIONS: Our data confirm that HCV coinfection per se is associated with lower risk of hypercholesterolaemia after HAART. This effect was particularly attributed to HCV-3, which was the only genotype associated with lower triglyceridaemia during HAART.     

Cardiovascular considerations in patients treated with HIV protease inhibitors.

Highly active antiretroviral therapy (HAART) has dramatically reduced mortality from HIV infection, transforming it in many cases to a chronic condition. However, protease inhibitors (PIs), which are integral components of most HAART regimens, are commonly associated with a host of metabolic disturbances that may increase the risk of cardiovascular disease in patients with HIV infection, potentially counteracting some of the positive health effects of PIs. Dyslipidemia is of particular concern. The Adult AIDS Clinical Trials Group has established preliminary guidelines to evaluate and treat PI-associated dyslipidemia. A number of strategies exist for the management of PI-based dyslipidemia in HAART recipients; their advantages and disadvantages should be considered when treating patients with HIV infection.     

Endothelial function in HIV-infected patients receiving protease inhibitor therapy: does immune competence affect cardiovascular risk?

BACKGROUND: The use of HIV protease inhibitors (PIs) as a component of combination antiretroviral therapy in HIV-infected patients has been associated with dyslipidaemia, but its significance as a risk factor for cardiovascular disease is unclear. Endothelial dysfunction is an early phase of atherogenesis that may be assessed non-invasively with ultrasonography in vivo. AIM: To evaluate vascular function and investigate potential determinants of endothelial dysfunction of the peripheral circulation in PI-treated, HIV-infected men with dyslipidaemia. DESIGN: Observational, case-control study. METHODS: We studied 24 HIV-infected, PI-treated men with dyslipidaemia and 24 normolipidaemic, healthy male controls matched for age and body mass index. Brachial artery endothelial function was studied using high-resolution ultrasound and computerized edge-detection software. This non-invasive technique measured post-ischaemic flow-mediated dilatation (FMD), and the endothelium-independent vasodilatory response to glyceryl trinitrate (GTN). RESULTS: Within the HIV patient group, FMD was significantly associated with percentage of 'na?ve' CD4 + 45RA + T cells (p = 0.03), while plasma lipid/lipoprotein and insulin levels, body mass, and smoking status did not correlate with endothelial function. FMD was not significantly different between the study group and the controls. CONCLUSIONS: The atherogenic potential of PI-associated dyslipidaemia may be attenuated in HIV-infected patients with decreased immune competence, reflecting a possible contribution of cell-mediated immune responses to the pathogenesis of atherosclerosis.     

Human immunodeficiency virus (HIV) related heart disease: A review

Summary Recent advances in the knowledge of human immunodeficiency virus (HIV) replication and transmission as well as the emergence of effective antiretroviral therapies are leading to longer survival times for HIV- infected individuals. As a result, organ-related manifestations of late-stage HIV infection, including HIV-related heart diseases have emerged. It is now clear that cardiac involvement in HIV seropositive patients is relatively common and is associated with increased morbidity and mortality. Cardiac involvement in HIV infection is multifactorial. The epidemiology has changed dramatically since the introduction of highly active antiretroviral therapy (HAART), but studies carried out before the introduction of HAART remain relevant because of limited access to this treatment in many areas of the world. A variety of cardiac lesions have been reported in HIV infection and AIDS, including pericardial disease with effusion and tamponade, nonspecific or infectious myocarditis, dilated cardiomyopathy with global left ventricular dysfunction, endocardial valvular disease due to marantic or infective endocarditis, arrhythmias, pulmonary hypertension and neoplastic invasion. In the post HAART-era, coronary artery disease and dyslipidaemia, drug-related cardiotoxicity and cardiac autonomic dysfunction are becoming increasingly prevalent. In this review, we highlight the importance of cardiac complications in HIV disease and discuss measures that can be taken to improve survival.     

Protease inhibitor-sparing simplified maintenance therapy: a need for perspective

Body fat changes and metabolic abnormalities such as hyperlipidaemia and diabetes have been increasingly reported following the successful introduction of highly active antiretroviral therapy (HAART). These side effects were attributed initially to the use of protease inhibitors (PIs). As a consequence, a series of trials were conducted where patients with well-controlled HIV viraemia either continued on PIs or were switched to a simplified maintenance therapy (SMT) without PIs. Evidence from these trials is still insufficient to show that switching from PIs to either abacavir, nevirapine or efavirenz is safe. However, patients with suboptimal pre-HAART treatment are at increased risk of virological failure if switched to an SMT. Patients switched from PI regimens tend to stay longer on an SMT and those switched to abacavir show a reduction in total cholesterol, but there is no evidence of any additional benefit from non-PI-based SMT. There is a clear need for a better understanding of HAART-related lipodystrophy and metabolic toxicity, and pharmacogenetic tests to identify those patients most at risk. The advent of simpler formulations for all drug classes, and new PIs with less metabolic toxicity, is likely to reshape completely the role of SMT.     

Antiretroviral therapy based on protease inhibitors as a protective factor against liver fibrosis progression in patients with chronic hepatitis C

Cohort studies have shown that highly active antiretroviral therapy (HAART) can improve liver-related mortality in HIV/hepatitis C virus (HCV)-coinfected patients. A reduction in the accelerated liver fibrosis progression observed in HIV infection induced by HAART could explain these findings. A few studies have assessed the impact of HAART on liver fibrosis, but with contradictory results. Therefore, we evaluated the associations between the use of different antiretroviral drug classes and HAART combinations, and liver fibrosis in HIV-infected patients with chronic hepatitis C. Six hundred and eighty-three HIV/HCV-coinfected patients, who underwent a liver biopsy and who had not received anti-HCV treatment were included. Age at HCV infection < 23years (adjusted odds ratio [AOR] = 0.7, 95% confidence interval [95% CI] = 0.3-0.9, P = 0.05) and protease inhibitor (PI)-based HAART versus no use of HAART (AOR = 0.5, 95% CI = 0.3-0.9, P = 0.01) were negatively associated with advanced fibrosis (> or = F3). PI-based HAART versus no use of HAART (AOR = 0.4, 95% CI = 0.2-0.7, P = 0.001) was negatively associated with fibrosis progression rate > or = 0.2 units/year and independently of age at HCV infection and CD4+ T-cell counts. Fifteen (17%) patients treated only with PIs and zidovudine plus lamivudine showed > or = F3, compared with 65 (37%) patients without HAART (P = 0.001). Forty (31%) patients on PI and stavudine plus lamivudine showed > or = F3 (P = 0.3, when compared with patients with no HAART). The use of PI-based HAART in HIV/HCV-coinfected patients is associated with less severe fibrosis and slower progression of fibrosis. The nucleoside analogue backbone in a HAART regimen may influence this association.     

The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling

Highly active antiretroviral therapy (HAART), which includes HIV protease inhibitors (PIs), has been associated with bone demineralization. To determine if this complication reflects accelerated resorptive activity, we studied the impact of two common HIV PIs, ritonavir and indinavir, on osteoclast formation and function. Surprisingly, we find that ritonavir, but not indinavir, inhibits osteoclast differentiation in a reversible manner and also abrogates bone resorption by disrupting the osteoclast cytoskeleton, without affecting cell number. Ritonavir given in vivo completely blunts parathyroid hormone-induced osteoclastogenesis in mice, which confirms that the drug is bone sparing. In keeping with its antiresorptive properties, ritonavir impairs receptor activator of nuclear factor kappaB ligand-induced (RANKL-induced) activation of NF-kappaB and Akt signaling pathways, both critical to osteoclast formation and function. In particular, ritonavir is found to inhibit RANKL-induced Akt signaling by disrupting the recruitment of TNF receptor-associated factor 6/c-Src complex to lipid rafts. Thus, ritonavir may represent a bone-sparing PI capable of preventing development of osteopenia in patients currently on HAART.     

Long-term treatment with lopinavir-ritonavir induces a reduction in peripheral adipose depots in mice

Highly active antiretroviral therapy (HAART) of human immunodeficiency virus-infected patients is associated with adverse effects, such as lipodystrophy and hyperlipidemia. The lipodystrophic syndrome is characterized by a peripheral lipoatrophy and/or fat accumulation in the abdomen and neck. In order to get insights into the physiopathological mechanisms underlying this syndrome, we treated mice with protease inhibitors (PIs) over a long period of time. Although atazanavir-treated mice presented the same circulating triglyceride concentration as control mice, lopinavir-ritonavir-treated mice rapidly became hypertriglyceridemic, with triglyceride levels of 200 mg/dl, whereas control and atazanavir-treated animals had triglyceride levels of 80 mg/dl. These results obtained with mice reproduce the metabolic disorder observed in humans. White adipose tissue (WAT) was analyzed after 8 weeks of treatment. Compared to the control or atazanavir treatment, lopinavir-ritonavir treatment induced a significant 25% weight reduction in the peripheral inguinal WAT depot. By contrast, the profound epididymal WAT depot was not affected. This effect was associated with a 5.5-fold increase in SREBP-1c gene expression only in the inguinal depot. Our results demonstrate that the long-term treatment of mice with PIs constitutes an interesting experimental model with which some aspects of the lipoatrophy induced by HAART in humans may be studied.     

Anti-IFN alpha immunization raises the IFN alpha-neutralizing capacity of serum--an adjuvant to antiretroviral tritherapy.

HAART (highly active antiretroviral therapy) suppresses but does not eradicate HIV-1 infection. However, since the antiretroviral agents used in HAART may also be toxic in the long-term, immunotherapies which correct HIV-1 immunosuppression or the cytokine dysregulation associated with it may be beneficial. In this respect, a double blind multicentric placebo-controlled phase II/III anti-IFN alpha vaccine trial has been carried out on 242 HIV-1 patients, the majority of whom were undergoing HAART treatment. In vaccinated patients (vaccinees) who responded to immunization by increased levels of IFN alpha Abs (whether under HAART or not) when compared to placebo or non-responder vaccinees, a strong correlation was found between an increased IFN alpha neutralizing capacity and the reduction of clinical manifestations.     

Highly active antiretroviral therapy-associated metabolic syndrome: pathogenesis and cardiovascular risk

The introduction of highly active antiretroviral therapy (HAART) has significantly modified the course of HIV disease, with longer survival and improved quality of life of HIV-infected subjects. However, HAART regimens, especially those including protease inhibitors (PIs) have been shown to cause in a high proportion of HIV-infected patients a metabolic syndrome that may be associated with an increased risk of cardiovascular disease (about 1.4 cardiac events per 1,000 years of therapy according to the Framingham score). Metabolic features associated with somatic changes (lipodystrophy/lipoatrophy) include dyslipidemia (about 70% of patients), insulin resistance (elevated C-peptide and insulin), type 2 diabetes mellitus (8%-10% of the patients), hypertension (up to 75% of patients), coagulation abnormalities (25% of patients), lactic acidemia, and elevated hepatic transaminases (nonalcoholic steatohepatitis). HAART-associated metabolic syndrome is an increasingly recognized clinical entity. A better understanding of the molecular mechanisms responsible for this syndrome will lead to the discovery of new drugs that will reduce the cardiovascular risk in patients under HAART. A careful stratification of the cardiovascular risk and cardiovascular monitoring of patients under HAART is needed according to the most recent clinical guidelines.     

The relationship between CD4 cell count nadirs and the toxicity profiles of antiretroviral regimens

BACKGROUND: It has been suggested that a lower pre-highly active antiretroviral therapy (HAART) CD4 count nadir may lead to a greater risk of experiencing HAART-related toxicity. We investigated the relationship between the pre-HAART CD4 count nadir, HAART and the occurrence of laboratory-defined toxicities. METHODS: Previously antiretroviral-naive individuals starting HAART at the Royal Free Hospital, London, UK, were included. Drug discontinuation, increases in total cholesterol (by > 1 mmol/l), alanine aspartate transferase/ alanine aminotransferase (AST/ALT) (by >2.5 times the upper limit of normal), bilirubin (by > 2.5 times the upper limit of normal), triglycerides (by > 1 mmol/l) and decreases in haemoglobin (by > 2 g/dl) were assessed. RESULTS: 377/847 (45%) individuals starting HAART stopped at least one antiretroviral within the first 48 weeks. Lower CD4 nadirs were not associated with a greater rate of discontinuing antiretrovirals (adjusted hazard ratio (HR)=1.04 per 100 cells/mm3 higher; 95% confidence intervals (CI) 0.99 - 1.10; P = 0.15). 70/297 (24%), 39/192 (20%) and 73/358 (20%) with a CD4 cell nadir of 0-100, 100-200 and 200+ cells/mm3, respectively, stopped for toxicity reasons; 11/297 (4%), 5/192 (3%) and 3/358 (11%) stopped for reasons of insufficient efficacy; 63/297 (21%), 33/192 (17%) and 80/358 (22%) stopped for other reasons (P = 0.1). Reasons for stopping were similar between CD4 nadir groups. Lower CD4 nadirs were not associated with an increased risk of hypercholesterolaemia, anaemia, hypertriglyceridaemia or increases in AST/ALT but were associated with increased incidence of hyperbilirubinaemia (HR=0.67 per 100 cells/mm3 higher; 95% CI 0.49-0.92; P = 0.01). DISCUSSION: Lower CD4 nadirs were not found to be associated either with discontinuing an antiretroviral or with a higher risk of toxicity, except for an increased risk of experiencing an increase in bilirubin levels.     

Effect of antiretroviral protease inhibitors alone,and in combination with paromomycin,on the excystation,invasion and in vitro development of Cryptosporidium parvum

With the spread of the human immunodeficiency virus in the early 1980s, cryptosporidiosis was regarded as an AIDS-defining disease. As an opportunistic pathogen, the intestinal parasite Cryptosporidium parvum became an important cause of chronic diarrhoea, leading to high morbidity and mortality in immunocompromised patients. To date, no effective chemotherapy is available. With the introduction of protease inhibitors (PIs) in highly active antiretroviral therapy (HAART), the incidence of cryptosporidiosis in AIDS patients has declined substantially in western countries. We have therefore tested the effect of five PIs used in HAART on the excystation, invasion and development of the parasite in a cell culture system. The human ileocaecal adenocarcinoma cell line HCT-8 served as a host cell. None of the substances had an effect on the excystation rate, and only nelfinavir moderately, but statistically significantly, inhibited the host cell invasion over a period of 2 h. There were more pronounced inhibitory effects when PIs were present over the total time of intracellular development (48 h). Indinavir, nelfinavir and ritonavir inhibited parasite development significantly. The inhibitory effect was increased when the aminoglycoside paromomycin was combined with the PIs indinavir, ritonavir, and to a lesser extent saquinavir, compared to the PIs alone.     

Gene therapy for lipoprotein disorders

Existing approaches to the treatment of refractory hypercholesterolaemia, severe hypertriglyceridaemia, low levels of high-density lipoprotein cholesterol and certain inherited disorders of intracellular lipid metabolism are ineffective in a substantial number of patients. Somatic gene therapy is considered to be a potential approach to the therapy of several of these lipid disorders. In many cases preclinical proof-of-principle studies have already been performed, and in one (homozygous familial hypercholesterolaemia) a clinical trial has been conducted. Other clinical gene therapy trials for dyslipidaemia are likely to be initiated within the next several years.     

Gene therapy for lipoprotein disorders

Existing approaches to the treatment of refractory hypercholesterolaemia, severe hypertriglyceridaemia, low levels of high-density lipoprotein cholesterol and certain inherited disorders of intracellular lipid metabolism are ineffective in a substantial number of patients. Somatic gene therapy is considered to be a potential approach to the therapy of several of these lipid disorders. In many cases preclinical proof-of-principle studies have already been performed, and in one (homozygous familial hypercholesterolaemia) a clinical trial has been conducted. Other clinical gene therapy trials for dyslipidaemia are likely to be initiated within the next several years.     

The effects of HAART on the expression of MUC1 and P65 in a cervical cancer cell line,HCS-2

Cervical cancer is the third most commonly diagnosed cancer globally and it is one of three AIDS defining malignancies. Highly active antiretroviral therapy (HAART) is a combination of three or more antiretroviral drugs and has been shown to play a significant role in reducing the incidence of some AIDS defining malignancies, although its effect on cervical cancer is still unclear. The aim of this study was to investigate the relationship between cervical cancer and HAART. This was achieved by studying the expression of two signalling molecules expressed in cervical cancer; MUC1 and P65. Following the 24-hour treatment of a cervical cancer cell line, HCS-2, with drugs, which are commonly used as part of HAART at their clinical plasma concentrations, real-time qPCR and immunofluorescence were used in order to study gene and protein expression. A one-way ANOVA followed by a Tukey-Kramer post-hoc test was conducted using JMP 11 software on both sets of data. The drug classified as a protease inhibitor (PI) (i.e. LPV/r) reduced MUC1 and P65 gene and protein expression more than the other drug tested. PIs are known to play a significant role in cell death; therefore, the cells were thought to be more susceptible to cell death following treatment with PIs. In conclusion, the drugs used, especially the PI showed some anticancer effects by facilitating cell death through decreased gene and protein expression of MUC1 and P65 and present promising agents for cancer treatment.