Evidence of sexual dimorphism in relationships between estrogen receptor polymorphisms and bone mass: the Hertfordshire study

OBJECTIVE: To examine the relationship between estrogen receptor (ER) a and ss gene polymorphisms and bone mass. METHODS: Bone mineral density (BMD) was measured at the lumbar spine and proximal femur twice, 4 years apart, in a cohort of 147 men and 125 women aged 61-73 years. Genomic DNA was extracted from whole blood samples, and genotyping for the ER (PvuII, XbaI, and AluI) was undertaken. RESULTS: There were no significant associations between either the XbaI or PvuII polymorphisms and bone mass, or bone loss in the cohort as a whole. However, men homozygous for the aa beta receptor polymorphism had higher BMD at the lumbar spine (p = 0.05), femoral neck (p = 0.01), and total femur (p = 0.01). Women homozygous for aa had lower femoral neck and total femoral BMD than women of the AA or Aa genotypes (p = 0.01 and p = 0.02). Gender*ERbeta interaction terms were statistically significant (p = 0.02 for lumbar spine BMD, p = 0.0004 for femoral neck BMD, and p = 0.0003 for total femoral BMD, each test with 2 degrees of freedom unadjusted). Adjustment for sex hormone concentration and lifestyle factors made little difference to our results. CONCLUSION: We found relationships between the ERbeta gene and the determination of bone mass among men and women in their seventh decade.     

Impaired proinsulin secretion before and during oral glucose stimulation in HIV-infected patients who display fat redistribution

The beta-cell function of HIV-infected patients on highly active antiretroviral therapy who display lipodystrophy may be impaired. An early defect in beta-cell function may be characterized by an increase in secretion of 32-33 split proinsulin (SP) and intact proinsulin (IP). To address this issue, the secretion patterns of SP and IP of 16 HIV-infected men with lipodystrophy (LIPO) and 15 HIV-infected men without lipodystrophy (NONLIPO) were studied during an oral glucose tolerance test (OGTT). All patients received highly active antiretroviral therapy. Insulin secretion rates were determined by deconvolution of plasma C-peptide concentrations. More LIPO than NONLIPO patients displayed diabetes mellitus and impaired glucose tolerance than normal glucose tolerance (LIPO 2/8/6 vs NONLIPO 1/2/12, P = .05). LIPO patients had increased fasting levels of SP and IP, ratio of SP/IP, and area under the curve of SP and IP during the early phase (0, 10, and 20 minutes) and during the late phase (45, 75, and 105 minutes) of the OGTT compared with NONLIPO patients (Ps < .05). LIPO patients exhibited significantly increased fasting SP/IP ratio, fasting SP/insulin ratio, and total proinsulin to C-peptide ratio during the OGTT. LIPO patients displayed increased incremental secretion of IP during the first 10 minutes of the OGTT (P < .05), although the incremental insulin secretion during this period did not differ between LIPO and NONLIPO patients. These data suggest that HIV-infected patients with lipodystrophy display major perturbations of proinsulin secretion in the fasting state and during an OGTT, which is compatible with the notion of a beta-cell dysfunction of such patients.     

High-density lipoprotein cholesterol is low in HIV-infected patients with lipodystrophic fat expansions: implications for pathogenesis of fat redistribution

OBJECTIVE: To demonstrate relationships between plasma high-density lipoprotein (HDL) cholesterol and fat expansions in the fat redistribution syndrome. DESIGN: Patients who had significant buffalo humps or intra-abdominal fat (IAF) expansions were identified and their HDL levels were measured. Control patients were all those undergoing a single trial of antiretroviral treatment. Some patients answered a self-administered questionnaire concerning self-perceived fat expansions, and their responses were related to their HDL levels. In other patients, relationships were studied between IAF measured by cross-section computerized tomography scans and HDL levels. Finally, patients who had IAF > 70 cm(2), were administered niacin, 3000 mg/day for > or = 6 months, in order to test whether raising HDL induced a decrease in IAF. RESULTS: Twenty-three patients with buffalo humps had mean HDL of 30.4 mg/dl; 47 HIV-positive controls had mean HDL of 41.9 mg/dl (P = 0.001). In 27 patients, IAF area and HDL were negatively correlated (r, 0.40; P = 0.04). Among these 27, the 17 patients with IAF area > 100 cm(2) had mean HDL of 35.3 mg/dl; the 10 patients with IAF area < 100 cm(2) had mean HDL of 51 mg/dl (P < 0.05). The 24 patients who indicated in a questionnaire that they had self-perceived IAF expansion had a median HDL of 36.0 mg/dl; the 20 who indicated that they did not have IAF expansion had a median HDL of 44.5mg/dl (P = 0.06). IAF decreased by 26.9% in 13 (81%) of the 16 patients who took niacin for 1 year; and the decrease in IAF was associated with a significant (P = 0.002) increase in HDL.     

Intrathoracic fat in HIV-infected patients

BACKGROUND: The impact of HIV infection or antiretroviral therapy on the intrathoracic fat compartment is unknown. METHODS: Consecutive clinically stable HIV-infected adult patients, irrespective of exposure to antiretroviral therapy, and non-HIV-infected healthy volunteers, both without clinical evidence of body fat changes consistent with lipodystrophy and adjusted for age, gender and body mass index, were recruited for this study. Thoracic and abdominal fat was assessed by computed tomography and compared between patients and controls. RESULTS: There were nine women (33%) and 18 men (67%) in each group. Nineteen patients (70%) had been taking antiretrovirals for a median of 8 months (interquartile range: 6-11). Among the HIV-infected patients, intrathoracic fat (median; interquartile range) did not differ significantly between treated (6.7 cm(2); 4.5-8.3 cm(2)) and untreated (6.9 cm(2); 5.7-10.9 cm(2)) individuals (P=0.288). However, intrathoracic fat content (median; interquartile range) was higher in HIV-infected patients (6.8 cm(2); 5.6-10.5 cm(2)) than in controls (5.6 cm(2); 3.9-6.7 cm(2)) (P=0.025). Intrathoracic fat was positively correlated with intra-abdominal fat both in patients (rho=0.6, P=0.002) and in controls (rho=0.7, P=0.004). CONCLUSION: In HIV-infected adults without clinical evidence of lipodystrophy, intrathoracic fat content was higher than in healthy persons and positively correlated with intra-abdominal fat content.     

Effect of HAART on salivary composition and oxidative profile in HIV-infected patients

Although it has been widely suggested that oxidative stress contributes to the pathogenesis of HIV infection, salivary composition and its oxidative related aspects have never been studied in HIV patients, both HAART-treated and untreated. Human saliva and serum were collected and analyzed for various biochemical, redox related and immunological parameters from 43 consenting HIV-infected patients (20 untreated and 23 treated with HAART) and 20 healthy controls, age and gender matched. Saliva composition of HIV infected patients was completely altered but returned to normal following HAART. HIV patients had significantly-increased levels of oxidative stress damaging markers, compared to healthy controls. Carbonyl levels increased by 110% (p=0.005), and superoxide dismutase enzyme (SOD) and antioxidant capacity (ImAnOx) levels by 45% and 16% (0.035) respectively, but returned to normal levels in treated patients (p=0.005, p=0.03 and 0.02 respectively). Also, the significantly-altered salivary composition (pH and lactate dehydrogenase (LDH) enzyme) and concentration (calcium (Ca), magnesium (Mg), albumin, salivary total protein, secretory IgA) of HIV-infected patients reverted to normal following HAART treatment. Salivary analysis may be used for assessing patient status: treated vs untreated, based on the increase or decrease in the concentration of a given salivary parameter in the HIV-untreated group vs controls, and a return to normal following the HAART treatment. Salivary collection is simple, non-invasive and not associated with risk of infection spread. Antioxidants in HIV patients may be recommended, as well as local oral means aimed at resuming salivary functions compromised in HIV patients.     

Dietary fat intake and relationship to serum lipid levels in HIV-infected patients with metabolic abnormalities in the HAART era

OBJECTIVE: To evaluate dietary intake and its relationship to lipid parameters in HIV-infected patients with metabolic abnormalities. METHOD: We prospectively determined dietary intake (4-day food records or 24-h recall) in 356 HIV-infected patients and 162 community-derived HIV-negative controls evaluated for metabolic studies between 1998-2005. Differences in dietary intake between HIV-infected patients and non-HIV-infected controls, in relation to the established 2005 USDA (United States Department of Agriculture) Recommended Dietary Guidelines, were determined. The relationship between dietary fat intake and serum lipid levels among HIV-infected individuals was also evaluated. RESULTS: Assessment of dietary intake in this group of HIV-infected patients demonstrated increased intake of total dietary fat (P < 0.05), saturated fat (P = 0.006), and cholesterol (P = 0.006) as well as a greater percentage of calories from saturated fat (P = 0.002) and from trans fat (P = 0.02), despite similar caloric intake to the control individuals. A significantly higher percentage of HIV-infected patients were above the 2005 USDA Recommended Dietary Guidelines for saturated fat (> 10%/day) (76.0% HIV vs. 60.9% controls, P = 0.003), and cholesterol (> 300 mg/day) (49.7% HIV vs. 37.9% controls, P = 0.04). Saturated fat intake was strongly associated with triglyceride level [triglyceride level increased 8.7 mg/dl (parameter estimate) per gram of increased saturated fat intake, P = 0.005] whereas total fat was inversely associated with triglyceride level [triglyceride level decreased 3.0 mg/dl (parameter estimate) per gram of increased total fat intake, P = 0.02] among HIV-infected individuals. CONCLUSIONS: Increased intake of saturated fat is seen and contributes to hypertriglyceridemia among HIV-infected patients who have developed metabolic abnormalities. Increased saturated fat intake should be targeted for dietary modification in this population.     

Pneumocystis carinii pneumonia in HIV-infected patients in the HAART era

Since the advent of highly active antiretroviral therapy (HAART), the incidence of opportunistic infections (OI) in patients with HIV has markedly decreased. Despite this, there are still large numbers of Pneumocystis carinii pneumonia (PCP) cases at Cook County Hospital (CCH). To better understand this patient group, we performed a retrospective chart review of 120 pathologically proven cases of PCP from January 1998 to June 2001. One hundred four patients were included in the study. Sixty-nine percent of our patients were active substance abusers and 50% had previous knowledge of HIV disease. Of our patients, fewer than 5% were on HAART or PCP prophylaxis on study admission. The overall mortality rate was 14%. Of discharged patients, 65% were placed on HAART therapy and 59% of these achieved a viral load of less than 1000 copies per milliliter in the year postdischarge. Patients who failed to achieve a viral load less than 1000 copies per milliliter were more likely active substance abusers or had a viral load greater than 100,000 copies per milliliter prior to study admission. Our study shows that patients are still being admitted with PCP in the HAART era. Active substance abuse and failure to recognize HIV status contributed heavily to this late presentation of HIV disease. An aggressive approach toward HIV identification and substance abuse treatment may decrease admissions to the hospital for PCP and improve response to HAART therapy.     

Protease inhibitor-based HAART, HDL, and CHD-risk in HIV-infected patients

ObjectiveTo study the effects of HIV-infection and protease inhibitor (PI)-based highly active anti-retroviral therapy (HAART) on the lipid and high-density lipoprotein (HDL) subpopulation profile and to relate the changes to coronary heart disease (CHD)-risk.Methods and designThe lipid and HDL subpopulation profiles of HIV-positive subjects (n = 48) were studied prospectively by comparing pre- and post-PI-HAART data as well as cross-section by comparing the profiles to HIV-negative subjects with (n = 96) and without CHD (n = 96).ResultsHIV-infected HAART-naïve subjects had lower concentrations of low-density lipoprotein cholesterol (LDL-C) and HDL-C and higher concentration of triglycerides (TG) than healthy controls. After receiving PI-based HAART, LDL-C and TG concentrations increased, while HDL-C concentrations remained unchanged. The HDL subpopulation profiles of HAART-naïve HIV-positive patients were significantly different from those of healthy controls and were similar to those with CHD. Moreover, the HDL subpopulation profile changed unfavorably after PI-based HAART, marked with increased concentrations of the small, lipid-poor pre-β-1 HDL (32% or 3.9 mg/dl; p < 0.001), and decreased concentration of the large, cholesterol-rich α-1 HDL(9% or 1 mg/dl ns).ConclusionAn already unfavorable lipid and HDL subpopulation profile of HIV-positive HAART-naïve subjects further deteriorated after receiving PI-based treatment, which may cause increased CHD-risk in these subjects.     

Cytomegalovirus-specific cell-mediated immunity in HIV-infected children on HAART

The objectives of this study were to define the magnitude, time course, and virologic and immunologic correlates of HAART-associated reconstitution of cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) in pediatric HAART recipients. Thirty-five HIV-infected CMV-seropositive subjects < or = 22 years on or about to receive HAART had CMV-CMI measured by responder cell frequency (RCF) and interferon-gamma (IFN-gamma) secretion over 3 years. RCF was detected in 33, 52, 38, and 28% before HAART and at years 1, 2, and > or = 3, respectively. Corresponding percentages for IFN-gamma were 100, 85, 100, and 38%. Neither RCF nor IFN-gamma was significantly associated with CD4% before or after HAART initiation. Lower HIV replication was associated with a higher proportion of subjects with positive RCF, but not IFN-gamma. There were no clinical CMV manifestations during the study. HIV-infected children did not demonstrate a significant increase in CMV-CMI with longer HAART duration, which suggests that CMV immunereconstitution involves more complex immunologic and virologic interactions than previously anticipated.     

Neurocognitive impairment influences quality of life in HIV-infected patients receiving HAART

The objective of the study was to determine the association of neurocognitive impairment with health-related quality of life (HRQoL) in patients receiving highly active antiretroviral therapy (HAART). Seventy subjects were cross-sectionally analysed with a standardized neuropsychological test battery and a questionnaire including an Italian translation of the MOS-HIV Health Survey. The presence of neurocognitive impairment was significantly associated with lower HRQoL scores: pain (P = 0.03), physical functioning (P = 0.01), role functioning (P = 0.01), social functioning (P = 0.029), mental health (P = 0.001), energy (P = 0.036), health distress (P = 0.002), cognitive functioning (P = 0.05), current health perception (P <0.001), physical health summary score (PHS) (P = 0.005), mental health summary score (MHS) (P = 0.002). Years of education (odds ratio [OR] 0.79; 95% confidence interval [CI] 0.65-0.96), PHS (OR 0.71; 95% CI 0.54-0.95) and MHS (OR 0.67; 95% CI 0.51-0.88) were also associated with cognitive impairment. Neurocognitive impairment in patients receiving HAART was associated with reduced HRQoL. Identifying cognitive impairment may provide motivation for additional treatment to help patients to compensate for deficits in functioning.     

Mortality after myocardial infarction in HIV-infected patients who have initiated HAART

We identified all Danish HIV patients registered with myocardial infarction (MI) when on HAART (44 patients) and compared their mortality with that of matched patients with MI and no HIV and patients with HIV and no MI. Mortality in HIV-infected MI patients was not significantly different to that of MI only patients in the first 90 days post-MI and thereafter was not significantly different to that of HIV patients without MI.     

Successful treatment of Castleman's disease with HAART in two HIV-infected patients

Castleman's disease is a heterogeneous group of lymphoproliferative disorders of unknown aetiology. Recently, human herpesvirus type 8 (HHV-8) has been associated with various diseases in individuals with HIV infection, including Kaposi's sarcoma, B cell non Hodgkin's lymphomas, and Castleman's disease.In Castleman's disease it has been hypothesized that HHV-8, encoding a number of various virokines, can be responsible for clinical manifestations of the disease.Previously, two reports have described a clinical recovery from HIV-associated Castleman's disease: by administration of a monoclonal antibody neutralizing human IL-6 in one case, and in another case by treatment with highly antiretroviral therapy and anti-herpesvirus therapy, following splenectomy. We report two cases where HAART alone led to clinical recovery from Castleman's disease.In both the cases reported here, although follow-up biopsy was not performed, it is likely that the inhibition of HHV-8 replication and of virokine release, through the restoration of immunity by HAART, was the basis for the disappearance of the clinical symptoms.     

Graves' disease during immune reconstitution in HIV-infected patients treated with HAART

Autoimmune phenomena after immune recovery due to HAART are not frequently described. Recently we found 3 patients with Graves' disease after starting HAART, outnumbering the expected incidence; 13 patients have been reported in the literature up to the present time.A probable relation between immune restoration and development of Graves' disease might be suspected.     

Increased PAI-1 and tPA antigen levels are reduced with metformin therapy in HIV-infected patients with fat redistribution and insulin resistance

Cardiovascular disease (CVD) risk associated with fat redistribution seen among HIV-infected individuals remains unknown, but may be increased due to hyperlipidemia, hyperinsulinemia, increased visceral adiposity, and a prothrombotic state associated with these metabolic abnormalities. In this study we characterized plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) antigen levels, markers of fibrinolysis and increased CVD risk, in HIV lipodystrophic patients compared to controls. Furthermore, we investigated the effect of treatment with metformin on PAI-1 and tPA antigen levels in patients with HIV-associated fat redistribution. Eighty-six patients (age 43 +/- 1 yr, BMI 26.1 +/- 0.5 kg/m(2)) with HIV and fat redistribution were compared to 258 age- and BMI-matched subjects from the Framingham Offspring study. In addition, 25 HIV-infected patients with fat redistribution and fasting insulin >15 microU/mL [104 pmol/L] or impaired glucose tolerance, but without diabetes mellitus were enrolled in a placebo-controlled treatment study of metformin 500 mg twice daily. PAI-1 and tPA antigen levels were significantly increased in patients with HIV related fat redistribution compared to Framingham control subjects (46.1 +/- 4 vs 18.9 +/- 0.9 microg/L PAI-1, 16.6 +/- 0.8 vs. 8.0 +/- 0.3 microg/L tPA, P = 0.0001). Among patients with HIV infection, a multivariate regression analysis including age, sex, waist-to-hip ratio, BMI, smoking status, protease inhibitor use and insulin area under the curve (AUC), found gender and insulin AUC were significant predictors of tPA antigen. Twelve weeks of metformin treatment resulted in decreased tPA antigen levels (-1.9 +/- 1.4 vs +1.4 +/- 1.0 microg/L in the placebo-treated group P = 0.02). Similarly, metformin resulted in improvement in PAI-1 levels (-8.7 +/- 2.3 vs +1.7 +/- 2.9 microg/L, P = 0.03). Change in insulin AUC correlated significantly with change in tPA antigen (r = 0.43, P = 0.03). PAI-1 and tPA antigen, markers of impaired fibrinolysis and increased CVD risk, are increased in association with hyperinsulinemia in patients with HIV and fat redistribution. Metformin reduces PAI-1 and tPA antigen concentrations in these patients and may ultimately improve associated CVD risk.     

Positive outcomes of HAART at 24 months in HIV-infected patients in Cambodia

OBJECTIVES: African and Asian cohort studies have demonstrated the feasibility and efficacy of HAART in resource-poor settings. The long-term virological outcome and clinico-immunological criteria of success remain important questions. We report the outcomes at 24 months of antiretroviral therapy (ART) in patients treated in a Médecins Sans Frontières/Ministry of Health programme in Cambodia. METHODS: Adults who started HAART 24 +/- 2 months ago were included. Plasma HIV-RNA levels were assessed by real-time polymerase chain reaction. Factors associated with virological failure were analysed using logistic regression. RESULTS: Of 416 patients, 59.2% were men; the median age was 33.6 years. At baseline, 95.2% were ART naive, 48.9% were at WHO stage IV, and 41.6% had a body mass index less than 18 kg/m. The median CD4 cell count was 11 cells/microl. A stavudine-lamivudine-efavirenz-containing regimen was initiated predominantly (81.0%). At follow-up (median 23.8 months), 350 (84.1%) were still on HAART, 53 (12.7%) had died, six (1.4%) were transferred, and seven (1.7%) were lost to follow-up. Estimates of survival were 85.5% at 24 months. Of 346 tested patients, 259 (74.1%) had CD4 cell counts greater than 200 cells/microl and 306 (88.4%) had viral loads of less than 400 copies/ml. Factors associated with virological failure at 24 months were non-antiretroviral naive, an insufficient CD4 cell gain of less than 350 cells/microl or a low trough plasma ART concentration. In an intention-to-treat analysis, 73.6% of patients were successfully treated. CONCLUSION: Positive results after 2 years of advanced HIV further demonstrate the efficacy of HAART in the medium term in resource-limited settings.     

Lipodystrophy syndrome by HAART in HIV-infected patients: manifestation,mechanisms and management

Progressive changes in the distributions of body fat and severe alterations of lipid, glucose and lactate levels challenge the mid and long-term success of highly active antiretroviral therapy of HIV-infection. Both clinical diagnosis of the lipodystrophy syndrome and scientific elucidation of the underlying mechanisms may benefit from a working case definition. In this article, pathophysiological and therapeutic aspects are discussed with reference to physical and metaboloic changes. Checkpoints for a practical approach to the patient at risk are given. Specific care and management depend on th epredominant alteration, the stage of HIV disease and the medical and antiretroviral history of the individual patient. Received: February 26, 2002 · Revision accepted: May 14, 2002 M. Battegay (corresponding author)     

Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART

OBJECTIVES: The aim of our work is to evaluate the role of statins and fibrates in the management of hyperlipidaemia in HIV-infected patients receiving highly active antiretroviral therapy. DESIGN: Open-label, randomized, prospective study of the efficacy and safety of bezafibrate, gemfibrozil, fenofibrate, pravastatin and fluvastatin as pharmacologic treatment for protease inhibitor-related dyslipidaemia. METHODS: Plasma lipid levels of 656 HIV-infected patients who referred to our tertiary care centre and were on protease inhibitor-based antiretroviral therapy for at least 12 months have been evaluated. All patients had HIV viral load < 50 copies/ml and presented with hypertriglyceridaemia of at least 6 months duration that was unresponsive to a hypolipidaemic diet; all have been treated with bezafibrate, gemfibrozil, fenofibrate, pravastatin, or fluvastatin for 12 months. RESULTS: Of the 656 patients observed 113 (17.2%) received pharmacological therapy, while seven patients were excluded from evaluation due to early drop-out. Of the 106 evaluable subjects, bezafibrate was used in 25 cases, gemfibrozil in 22, fenofibrate in 22, pravastatin in 19, and fluvastatin in 18. At the close of 1-year follow-up, fibrates led to a reduction of 40.7% and 21.9% versus baseline triglyceridaemia and cholesterolaemia, respectively (P < 0.001), and statins led to a reduction of 34.8% and 25.2% versus baseline triglyceride and total cholesterol levels, respectively (P < 0.001), without significant differences according to each different administered hypolipidaemic drug. CONCLUSIONS: All administered statins and fibrates revealed a similar, significant efficacy in the treatment of diet-resistant hyperlipidaemia, and showed a favourable tolerability profile.     

Neurocognitive impairment and survival in a cohort of HIV-infected patients treated with HAART

Before the introduction of HAART, HIV-associated neurocognitive impairment (NCI) was recognized as an independent risk factor for death. Since 1996, we conducted a prospective study to assess whether NCI still represents a negative prognostic factor for mortality. Patients were administered measures of neurocognitive function (a battery of 17 neuropsychological tests), clinical and neurological evaluation, laboratory testing, and brain imaging studies. Among the 412 enrolled patients, 224 (54.4%) were neurocognitively impaired and 188 (45.6%) were neurocognitively unimpaired. A durable virological suppression under highly active antiretroviral therapy (HAART) was achieved by 63.3% of unimpaired patients and by 49.6% of impaired patients (p = 0.007). Overall, 47 deaths were recorded, 38 among impaired and 9 among unimpaired patients. At 84 months, the estimated survival proportions in impaired and unimpaired patients were 68.5% and 84.9%, respectively (p < 0.001). At univariate analysis the virological response to HAART was the variable most strongly associated with survival, since patients with virological failure had a nearly 10-fold increased risk of death than those with durable virological suppression (HR = 9.9, 95% CI: 3.9-25.0). After stratification for virological response to HAART, an increased risk of death for neurocognitively impaired patients was seen only among the 182 patients with virological failure (HR: 2.9, 95% CI: 1.2-7.1), while the survival probability of the 230 patients with durable virological suppression was not affected by neurocognitive impairment (p = 0.89). Our results highlight the clinical relevance of HIV-related central nervous system (CNS) involvement in the HAART era, and raise concerns regarding the clinical relevance of CNS involvement as potent antiretroviral therapies become less effective.