Cost impact of prospective HLA-B*5701-screening prior to abacavir/lamivudine fixed dose combination use in Germany.

OBJECTIVE: Avoiding abacavir in HIV-infected patients tested positive for HLA-B*5701 reduces the risk of abacavir hypersensitivity reaction (ABC-HSR). Our aim was to assess the costs of clinically suspected HSR and to estimate potential cost savings of implementing prospective HLA-B*5701-screening for HIV-infected patients initiating abacavir/lamivudine fixed-dose combination (ABC/3TC FDC) compared to initiating respective treatment without screening. METHODS: Employing a decision tree model the expected HSR-related costs of screening vs. no screening were estimated from the societal and healthcare payer perspective (reference year 2007). A retrospective standardized assessment of all clinically suspected ABC-HSR cases without screening at 5 German HIV-centres was performed to measure resource consumption. In- and outpatient care, discarded ABC/3TC FDC and concomitant medication were considered. Direct resource utilization was valued using German fees (EBM, G-DRGs). Indirect costs were measured with the human capital approach. Estimates for the HLA-B*5701-prevalence, HSR-incidence, and hospitalization rate were based on clinical trials and cohorts and it was assumed that screening reduces the incidence of clinically suspected ABC-HSR from 10% to 0.5%. RESULTS: Thirty-two ABC-HSR cases were identified from 1998 to 2007. Mean direct and total costs per clinically suspected HSR case were Euro 1,362 and Euro 2,235, respectively. Hospital costs contributed 63.3% to direct costs. Potential cost savings when implementing genetic screening were estimated at Euro 44 and Euro 127 per screened patient, from a healthcare payer or societal perspective. CONCLUSION: HLA-B*5701 screening prior to ABC/3TC FDC initiation prevents significant HSR-related costs per screened patient and is likely to lead to overall net savings.

Ceramide and raft signaling are linked with each other in UVA radiation-induced gene expression.

Solar ultraviolet A (UVA) (320-400 nm) radiation-induced gene expression in keratinocytes is initiated at the level of the cell membrane via generation of singlet oxygen and subsequent formation of ceramide from sphingomyelin. We now report that the UVA response also involves raft signaling and that ceramide and raft signaling are linked with each other. Upon UVA irradiation, the lipid composition of rafts decreased 40% in sphingomyelin and 60% in cholesterol (Chol). Also, decrease of Chol increased the susceptibility towards UVA-induced gene expression, whereas increase of Chol completely abolished their capacity to generate signaling ceramides and to mount the subsequent UVA response. This inhibition was not associated with UVA-induced Chol oxidation and was also seen after treatment of cells with plant sterols. The UVA responsiveness depended on the ratio of Chol versus ceramide in rafts. A ratio smaller than 1 permitted initiation and transduction of the signaling response, whereas a ratio greater than 1, for example, upon sterol pretreatment, abolished this response, indicating that UVA radiation-induced ceramide signaling is controlled by the lipid composition of rafts.

Concomitant use of gastric acid-reducing agents is frequent among HIV-1-infected patients receiving protease inhibitor-based highly active antiretroviral therapy.

OBJECTIVE: The aim of the study was to assess the frequency of the concurrent use of gastric acid-reducing agents among HIV-1-infected patients treated with highly active antiretroviral therapy (HAART) combinations. METHODS: An anonymous, semistructured, self-administered questionnaire was consecutively distributed among HIV-1-infected patients at routine visits to specialized HIV clinics. The questionnaire contained 17 items asking specifically for information on current antiretroviral treatments and the use of gastric acid-reducing agents as well as demographic data. RESULTS: A total of 424 patients in 12 centres participated in the study: 85% were male, 88% were of German nationality, 82% were >35 years of age and 201 (47.4%) were receiving a protease inhibitor (PI)-containing HAART regimen. Of these, 74 (37%) had received an acid-reducing drug within the previous 6 months and 43 (58%) were currently still on it. Two-thirds of patients (64.9%) were treated with proton-pump inhibitors (pantoprazole, omeprazole or esomeprazole) and 56% of patients on PI-containing regimens had been taking these drugs for longer than 2 months and up to a maximum of 3 years. The majority of patients (77%) had received the prescription for the acid-reducing drugs from their HIV specialist and the remaining patients had received over the counter (OTC) medication or prescriptions from other medical personnel. CONCLUSIONS: A substantial subset of patients treated with HAART combinations, including those on PI-containing regimens, were using concomitant acid-reducing drugs, most often proton-pump inhibitors. As negative drug-drug interactions between some of the (boosted) PIs and gastric acid-reducing agents have recently been reported, HIV physicians should take this into account when prescribing PI-containing HAART combinations in order to avoid an additional risk of treatment failure.

Thyroid hypoechogenicity in patients with chronic hepatitis receiving interferon-alpha therapy: evaluation by standardized grey scale ultrasonography.

BACKGROUND: Recombinant human interferon-a therapy of chronic hepatitis B and C is associated with the induction of thyroid dysfunction in up to 15%. Little is known about morphological changes of the thyroid gland, especially about its tissue echogenicity under this immunomodulative drug treatment. METHODS: 116 patients with chronic hepatitis B or C were consecutively investigated. 53 patients qualified for treatment with interferon-a alone or in combination with ribavirin. Patients with normal serum aminotransferase levels, advanced liver cirrhosis, hepatocellular carcinoma, active intravenous drug or alcohol abusus and with focal thyroid lesions (nodes, cysts, calcifications) were excluded. Thyroid function was determined by measurements of FT4, TSH and thyroidal autoantibodies. Ultrasonography was performed before, during and after interferon-a therapy including volumetry and standardized grey scale analysis. The data were compared with values of 100 euthyroid volunteers as control group. RESULTS: After six months of therapy patients differed from controls by significant TSH elevation (12.8 +/- 9.34 vs. 2.8 +/- 1.1 microU/ml, p<0.02). Six patients (11%) developed overt hypothyroidism with detectable thyroidal autoantibodies. Thyroid volume in patients was similar (13.0 +/- 4.1 ml) to that in the control group (12.6 +/- 4.7 ml). However, thyroid echogenicity of the patients was significantly lower after 6 months of therapy (21.9 +/- 2.5 grey scales) compared to the status before (25.6 +/- 2.3 grey scales) and compared to the values of controls (25.4 +/- 2.1 grey scales, p <0.002). CONCLUSION: Beside of functional disorders interferon-alpha leads to thyroid hypoechogenicity suggesting relevant morphological changes of the organ.

Improvement of HAART-associated insulin resistance and dyslipidemia after replacement of protease inhibitors with abacavir.

OBJECTIVE: To assess the effect of replacing protease inhibitors (PIs) with abacavir on insulin sensitivity and plasma lipids. - DESIGN: Pilot study including 31 patients with sustained virological control on their first PI-containing HAART regimen. 16 patients were switched from PIs to abacavir (ABC group), 15 patients continued on PIs (PI group). In all patients, nucleoside-analogue reverse transcriptase inhibitors were continued. METHODS: Insulin sensitivity (using an intravenous insulin tolerance test) and fasting total cholesterol and triglycerides were determined at baseline, month 3, 6, 9 and 12. RESULTS: In the ABC group, there was a significant increase in median insulin sensitivity from baseline within 6 months (+ 49 micromol/l/min), and a significant decrease in both triglycerides (-41mg/dl) and cholesterol (-40mg/dl) at month 3. These changes were sustained through month 12. In addition, a reversal of baseline insulin resistance, hypercholesterolemia and hypertriglyceridemia was observed in the majority of patients. In the PI group, no significant changes in insulin sensitivity, triglycerides and cholesterol were observed. There was a significant correlation between the changes in insulin sensitivity, triglycerides and cholesterol. INTERPRETATION: Switching from PIs to abacavir is associated with an improvement of insulin sensitivity and a decrease of cholesterol and triglycerides in the majority of patients with HAART-associated metabolic alterations and therefore might be an alternative for patients to PI-containing HAART regimens.

Th1/Th2 shift in HIV lymph nodes: no contribution of CD6o cells.

BACKGROUND: An expansion of CD8+60+ cells with Th2 type helper function has been observed in HIV-infected individuals. A Th1/Th2 shift in late HIV infection might be related to the functional activity of this subset. Our objective was to test the ability of lymph node (LN) lymphocytes to produce cytokines of the Th1 and Th2 type. PATIENTS AND METHODS: LN cells were stimulated with PMA in the presence of ionomycin and brefeldin A. After surface staining for CD4, CD8 and CD60 and intracellular staining for interferon gamma (IFNgamma), interleukin 2 (IL-2) or IL-4 and IL-10, the percentage of cytokine producing lymphocytes (CPL) was determined by flow cytometry. LN of nine individuals in the early stage of HIV infection were compared to late stage patients. RESULTS: CD4+ subset: in early stages of HIV infection the percentage of Th1 CPL was 1.9 times higher than that of Th2 CPL. In late stages of infection the Th1 responding cells were not found more frequently than Th2 ceLLs. CD8+ subset: no Th1/Th2 shift was detected during early or late stages of HIV infection. CD60+ subset: a maximum of 32.1 +/- 7.8% of double positive cells of the CD8+60+ type produced Th2 type cytokines. A small percentage (< 8%) of CD60+ cells also produced Th1 cytokines. No shift in the cytokine production was seen in early or late stages of infection. CONCLUSION: At single cell level a shift in cytokine production in LN cells can only be detected in the CD4+ subset. Thus, the CD60+ subset does not seem to contribute to the putative Th1/Th2 shift attributed to the immunopathogenesis of HIV-induced destruction of the immune system.

Alterations of apolipoprotein B metabolism in HIV-infected patients with antiretroviral combination therapy.

BACKGROUND: Dyslipidemia (predominantly hypertriglyceridemia) is frequently seen in patients receiving antiretroviral combination therapy (ART). However, the underlying mechanisms and long-term risks (e.g., cardiovascular events) are still unclear. OBJECTIVES/METHODS: In 5 patients with ART-associated dyslipidemia, stable isotope labeled amino acid tracer (d3-Leu) kinetic analysis over 12 days was used to investigate the metabolism of apolipoprotein B-containing lipoproteins (very low density lipoproteins [VLDL]1, VLDL2, intermediate density lipoproteins [IDL] and low density lipoproteins [LDL]). Data were compared with those in 6 healthy normolipidemic controls. RESULTS: The patients under ART showed significantly increased fasting triglycerides (359 vs. 77 mg/dl) and VLDL (54 vs. 15 mg/dl), compared with controls. They had significantly higher total cholesterol (213 vs. 157 mg/dl) and there was a nonsignificant trend toward higher LDL (136 vs. 93 mg/dl), and toward lower HDL (26 vs. 46 mg/dl). The ratio of large, buoyant LDL1 over small, dense LDL2 was markedly reduced in patients under ART (0.80 vs. 2.00). Total apo B synthesis was significantly increased (25.5 vs. 14.5 mg/kg/d) and shifted toward triglyceride rich VLDL1 (18.5 vs. 8.7 mg/kg/d) in patients receiving ART. There was also a significantly reduced rate of apo B lipoprotein transfer from VLDL1 to VLDL2 (3.7 vs. 20.7 pools/d). In addition, all patients revealed insulin resistance. CONCLUSIONS: These data indicate that increased triglycerides in HIV-infected patients with ART are primary due to reduced rates of VLDL transfer into denser lipoproteins implying a lower rate of lipoprotein lipase-mediated delipidation. In addition, total apo B synthesis was increased and shifted toward triglyceride-rich VLDL1. Overall, this lipoprotein profile in patients with ART-associated dyslipidemia implies an increased risk for cardiovascular events.

Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus.

Antiretroviral therapy (ART) is frequently associated with metabolic alterations, including insulin resistance and diabetes mellitus. In this pilot study, we evaluated the effect of the PPARgamma activator troglitazone on ART-associated insulin resistance in HIV-infected patients with ART-associated diabetes mellitus. Six patients with protease inhibitor (PI)-associated diabetes mellitus, lipodystrophy and dyslipidemia were treated with troglitazone 400 mg q.d. for 3 months. Previous oral antidiabetics were discontinued prior to the study. At baseline and after 3 months, insulin sensitivity (intravenous insulin tolerance test), body composition (multifrequence bioelectrical impedance analysis) and fat distribution (CT scan quantification) were assessed. Glycaemic control (fasting and postprandial blood glucose, fructosamine, glycosylated haemoglobin) and serum lipid status were determined monthly. In four of the six patients, there was a clear improvement in insulin sensitivity, resulting in a reversal of insulin resistance in two of these patients. Overall, there was an increase in lean body mass and a decrease in total body fat. The volume of visceral adipose tissue decreased whilst the volume of subcutaneous adipose tissue increased. Total cholesterol, LDL and HDL cholesterol increased, and total triglycerides and VLDL-cholesterol decreased. No adverse effects such as hepatotoxicity were observed. Treatment with troglitazone 400 mg q.d. can ameliorate and in some cases even reverse ART-associated insulin resistance. Therefore, further studies including non-diabetic patients with ART-associated insulin resistance may be helpful in evaluating the long-term effects of thiazolidinediones on ART-associated insulin resistance and other metabolic complications, such as adipose maldistribution and dyslipidaemia.

Hyperlipidemia under treatment with proteinase inhibitors.

To define the extent and time course of HIV-proteinase inhibitor (PI) effects on serum lipid levels 148 patients on triple combination therapy including PIs and 91 patients on therapy with two nucleosides as a control group were evaluated. In the PI group there was a significant increase in total cholesterol after 3, 6 and 12 months compared to the baseline level (198, 204 and 203 vs. 176 mg/dl). The increase in triglycerides was 25.5% from the baseline at month 3. Indinavir had a significantly higher impact on cholesterol levels than saquinavir. No changes in lipids were seen in the control group. It was concluded that hyperlipidemia is associated with PI use, becomes evident within 3 months of treatment and seems to be substance specific.

[Regression of cytomegalovirus retinitis in AIDS patients without systemic maintenance anti-cytomegalovirus therapy treated with highly active antiretroviral therapy]. / Regression der Zytomegalievirus-Retinitis bei AIDS-Patienten ohne systemische Anti-Zytomegalievirus-Erhaltungstherapie unter hochaktiver antiretroviraler Therapie (HAART).

BACKGROUND: The purpose of this study was to evaluate the course of CMV retinitis after initiation of highly active antiretroviral therapy (HAART) and discontinuation of systemic anti-CMV maintenance therapy. PATIENTS AND METHODS: Case reports are presented for two AIDS patients (2 eyes, ages 34, 43, male) with CMV retinitis. The CD4 count at the time of CMV retinitis was 20/microliter (patient 1) and 35/microliter (patient 2). Under HAART the CD4 count rose up to 202/microliter (patient 1) and 350/microliter (patient 2); the viral load was under detection limit in both patients. At that time systemic maintenance therapy was discontinued in both patients. RESULTS: There was no progression of retinitis during the observation period of 21 months (patient 1) and 24 months (patient 2). CONCLUSIONS: In selected patients with immune recovery under HAART it is possible to discontinue systemic anti-CMV maintenance therapy.

Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients.

BACKGROUND: The use of protease inhibitors in the treatment of HIV-1 infection is associated with the new onset of diabetes mellitus, hyperlipidaemia and lipodystrophy. It is unclear whether these findings are coincidental or whether they reflect a causative effect of protease inhibitors. OBJECTIVE: To evaluate the effect of treatment with protease inhibitors on insulin sensitivity, oral glucose tolerance and serum lipids in HIV-infected patients in order to determine whether treatment with protease inhibitors can cause peripheral insulin resistance. DESIGN: Cross-sectional controlled study in HIV-infected patients treated with protease inhibitors to assess insulin sensitivity, oral glucose tolerance and changes in serum lipids. METHODS: Sixty-seven patients treated with protease inhibitors, 13 therapy-naive patients and 18 HIV-negative control subjects were tested for insulin sensitivity (intravenous insulin tolerance test). In a subgroup of 24 treated patients, oral glucose tolerance was determined. Serum lipids prior to and under treatment with protease inhibitors were compared. RESULTS: Patients on protease inhibitors had a significantly decreased insulin sensitivity when compared with therapy-naive patients (median, 75 and 156 micromol/l/min, respectively; P < 0.001). All treated patients with impaired (n=4) or diabetic (n=9) oral glucose tolerance, and four out of 11 patients with normal glucose tolerance showed peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. Treatment with protease inhibitors led to a significant increase in total triglycerides and cholesterol in the 67 treated patients (median increase, 113 and 37 mg/ml, respectively). CONCLUSION: Treatment with protease inhibitors is associated with peripheral insulin resistance, leading to impaired or diabetic oral glucose tolerance in some of the patients, and with hyperlipidaemia. Overall, there is a large variation in the severity and clinical presentation of protease inhibitor-associated metabolic side-effects.

Longitudinal monthly body measurements from 1 to 12 months of age: a study by practitioners for practitioners. Zurich Association of Practicing Paediatricians.

UNLABELLED: A longitudinal growth study with monthly measurements during the 1st year of life was conducted by nine paediatricians working in private practice in Zurich. Of 92 children, none was lost to the study and only 32 of 1104 planned visits were missed; the quality of the measurements was comparable to that of a specialised university clinic. Compared to the Zurich Longitudinal Growth Studies, children of this study were considerably heavier and taller. In 92% of the subjects, growth velocity was at least once outside the reference range (3rd 97th percentile). For weight increments, the corresponding proportion was 87%. CONCLUSIONS: The data indicate that current standards for the 1st year of life for the Zurich area might no longer be appropriate and need to be updated. The currently used velocity percentiles based on 3-monthly measurements are not suitable to assess individual height and weight increments calculated from monthly measurements.

HIV-1-infected long-term slow progressors heterozygous for delta32-CCR5 show significantly lower plasma viral load than wild-type slow progressors.

OBJECTIVE: Patients heterozygous for delta32-CCR5 may have a delayed progression of HIV-1 disease. The aim of the present study was to investigate the influence of CCR5/delta32-CCR5 genotype in long-term slow progressors using plasma viral load as a marker of disease progression. DESIGN: We analyzed 70 long-term slow progressors (diagnosis > 8 years previously; CD4 count > 500/microl; asymptomatic, never received antiretroviral therapy) for CCR5 genotype, plasma viral load, and lymphocyte subsets. Distribution of CCR5 genotypes was compared with a cohort of 61 multiply exposed noninfected individuals and a group of 336 control subjects. All study participants were white. METHODS: CCR5 genotype was determined by polymerase chain reaction (PCR) amplification. Plasma viral load was quantified by branch DNA hybridization, lymphocyte subsets were determined by fluorescence-activated cell sorter (FACS) analysis. The Mann-Whitney-Wilcoxon test was used for statistical analyses. RESULTS: The frequency of the CCR5/delta32-CCR5 heterozygote genotype was higher in long-term slow progressors (37.1%) and multiply exposed noninfected individuals (26.2%), compared with the control group (15.8%). In addition, plasma viral load was found to be significantly lower in CCR5/delta32-CCR5 heterozygous long-term slow progressors (median < log10 2.70; 53.8% < log10 2.70; 0% > log10 4.0) relative to that seen in CCR5/CCR5 long-term slow progressors (median log10 3.64; 22.7% < log10 2.70; 22.7% > log10 4.0). CONCLUSIONS: These findings strengthen the hypothesis of a favorable influence of CCR5/delta32-CCR5 genotype on progression of HIV-1 infection. Therefore, evaluation of CCR5 genotype might influence antiretroviral therapy strategies in early stages of HIV-1 infection.

Identification and biochemical characterization of the human brain galanin receptor.

Human galanin (hGal) is an important neuro-modulator present in the brain, gastrointestinal system and the hypothalamo-pituitary axis. A specific receptor for hGal has been identified in various areas in human brain. A single class of high affinity binding sites was found on plasma membranes of the amygdala (Kd 0.23 nM, Bmax 44 fmol/mg), the hypothalamus (Kd 0.20 nM, Bmax 25 fmol/mg) and the cortex cerebri (Kd 0.11 nM, Bmax 8.2 fmol/mg). Other brain areas, i.e. cerebellum, thalamus or pons, expressed binding sites of identical high affinity in lower quantities (Bmax < 3 fmol/mg). Specific binding of 125I-labelled hGal was found to be reversible, time- and temperature-dependent and inhibited by Ca2+, Na+ and K+ ions at a concentration of 5 mM. Non-hydrolysable guanosine nucleotides potently reduced specific binding of 125-I-labelled hGal by more than 80%. Synthetic hGal analogues substituted in the N-terminal region exhibited strongly reduced binding affinity for the hGal receptor. Using 3-[(3-cholamidopropyl) dimethylammonio]-2-hydroxy-1-propanesulphonate, hGal receptors were successfully solubilized from human cortical membranes, exhibiting no significant loss of binding affinity. Affinity cross-linking to 125I-labelled hGal revealed a labelled band of approximately 60 kDa sensitive to unlabelled Gal. This putative hGal receptor is glycosylated since its molecular size was reduced after treatment with endoglycosidase F. Receptors bound to 125I-labelled hGal could be specifically adsorbed to wheat germ agglutinin and ricinus communis agglutinin, suggesting that receptor glycosylation involves N-acetyl glucosamine and galactose respectively.

Purification of the PACAP-1 receptor by ligand affinity chromatography.

Employing the Fmoc solid phase strategy, analogues of pituitary adenylate cyclase activating polypeptide (PACAP) were synthesized containing single cysteine residues. Monobiotinylation of these analogues was achieved via thioether formation between the sulfhydryl groups provided by the cysteine residues and the biotinylation reagent N-lodoacetyl-N'biotinyl-hexylenediamine. Almost all of the S-biotinylated analogues revealed full binding activity to the solubilized PACAP-1 receptor from pig brain membranes. To minimize sterical hindrance of ternary complex formation between the biotinylated analogues, the PACAP-1 receptor and streptavidin, an analogue was designed which contains seven consecutive alanine residues between position 28 and 34. This biotinylated analogue, S-biotinyl[Ala28-34,Cys35]PACAP(1-35), was highly capable of ternary complex formation and therefore used as high affinity ligand for affinity chromatography. By means of lectin adsorption chromatography and ligand affinity chromatography the PACAP-1 receptor was purified more than 6000-fold from porcine brain membranes solubilized with 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propane-sulfonate (CHAPSO).

[Weight, length and head circumference of the newborn infant and their relationship to maternal and infant factors. Standards for intrauterine growth]. / Gewicht, Länge und Kopfumfang neugeborener Kinder und ihre Abhängigkeit von mütterlichen und kindlichen Faktoren. Normwerte für das intrauterine Wachstum.

Means, standard deviations and smoothed percentiles of fetal weight, length and head circumference at birth, and weight of the placenta between 26 and 44 weeks of gestation are presented. The data are based on 5136 single and 208 twin, live-born newborn infants delivered at the cantonal Hospital Winterthur between 1969 and 1974. The percentile curves differ considerably from those of the widely used "Lubchenco-Curves". Fetal weight correction factors for maternal weight, parity and sex of the child are given. Among the various maternal and infantile variables influencing fetal growth, gestational age and maternal weight were found to be the most significant ones affecting weight and length of the newborn. Parity and sex of the child were of moderate, maternal height and nationality of minor importance.