bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hemodialysis Catheter Locking Solutions and the Prevention of Catheter Dysfunction: A Meta-Analysis
Authors: Chapla Kevin , Oza-Gajera Bharvi P. , Yevzlin Alexander S. , Shin Jung-Im , Astor Brad C. , Chan Micah R. 
Published: November 2014

Purpose Tunneled dialysis catheters (TDCs) continue to be utilized at an alarming rate despite having a higher rate of complications when compared to fistulas and grafts. One of the primary complications of TDCs involves catheter dysfunction resulting in reduced blood flow and poor dialysis adequacy, often requiring catheter removal in addition to thrombolytic therapy. Our objective was to compare the use of locking solutions containing heparin versus all other locking solutions for primary prevention of TDC dysfunction. Methods We searched Medline for English language literature from 1980 through December 2013, along with national conference proceedings and reference lists of all included publications to identify relevant studies. Inclusion criteria were a measure of incidence of catheter dysfunction, catheter exchange or use of thrombolytic therapy. Studies were excluded if they were not in English or if they included pediatric patients. Random effects models were used to derive the pooled risk ratios. Results Thirteen studies with a total of 1,883 subjects met the inclusion criteria. There was no significant difference in catheter patency in those receiving heparin versus those treated with other lock solutions (incidence rate ratio [IRR] 0.99; 95% confidence interval [CI] 0.66-1.48, p = 0.96). Catheter patency did not differ between treatments in experimental studies ( n = 10; IRR = 0.89; 95% CI: 0.56-1.39, p = 0.60) or observational design (n = 3; IRR = 1.64; 95% CI 0.40-6.85, p = 0.50). Significant heterogeneity was detected across studies (I2 = 84.4%, p<0.001). Conclusions Our results suggest that there is no substantial difference between heparin lock solutions versus all other types of catheter lock solutions for catheter dysfunction. Whether there are significant benefits of citrate or other novel lock solutions requires further robust studies. These findings have significant implications for future design of clinical trials in TDCs and the delivery of dialysis-related services.
Central Venous access Devices in Pediatric Malignancies: A Position Paper of Italian Association of Pediatric Hematology and Oncology
Authors: Crocoli Alessandro , Tornesello Assunta , Pittiruti Mauro , Barone Angelica , Muggeo Paola , Inserra Alessandro , Molinari Angelo Claudio , Grillenzoni Valeria , Durante Viviana , Cicalese Maria Pia , Zanazzo Giulio Andrea , Cesaro Simone 
Published: November 2014

Introduction Treatment of pediatric malignancies is becoming progressively more complex, implying the adoption of multimodal therapies. A reliable, long-lasting venous access represents one of the critical requirements for the success of those treatments. Recent technical innovations—such as minimally invasive procedures for placement, new devices and novel materials—have rapidly spread for clinical use in adult patients, but are still not consistently used in the pediatric population. Methods The Supportive Therapy Working Group of Italian Association of Hematology and Oncology (AIEOP) reviewed medical literature focusing on new aspects of central venous access devices (VADs) in pediatric patients affected by oncohematological diseases. Results Appropriate recommendations for clinical use in these patients have been discussed and formulated. Conclusions The importance of the correct choice, management and use of VADs in pediatric oncohematological patients is a necessary prerequisite for an adequate standard of care, also considering the increased chances of cure and the longer life expectancy of those patients with modern therapies.
Het Hof van Justitie in Kamino-Datema: horen in bezwaar onder voorwaarden gesanctioneerd
Authors: Buijze Anoeska 
Published: November 2014

Het Hof van Justitie in Kamino-Datema: horen in bezwaar onder voorwaarden gesanctioneerd
Met zijn uitspraak van 3 juli 2014 verduidelijkt het Hof van Justitie de betekenis van de rechten van de verdediging voor het Nederlandse bestuursrecht, meer in het bijzonder voor het douanerecht. Voor de douane lijkt de uitkomst positief: het horen van belanghebbenden tijdens de bezwaarprocedure is onder voorwaarden voldoende om aan de rechten van de verdediging tegemoet te komen. Afdeling 4.1.2 van de Awb blijft nog even in het beklaagdenbankje: de ruime uitzondering op de hoorplicht uit artikel 4:12 Awb lijkt niet altijd houdbaar en het Hof van Justitie wijst de rechtvaardiging van de Nederlandse regering expliciet af.HvJ EU 3 juli 2014, gevoegde zaken C-129/13, Kamino en C-130/13, Datema, ECLI:EU:C:2014:2041
Hof van Justitie sauveert nationale steunregeling inzake duurzame elektriciteit
Authors: Brinkman Iman , Huurnink Pauline 
Published: November 2014

Hof van Justitie sauveert nationale steunregeling inzake duurzame elektriciteit
Op 1 juli 2014 heeft het Hof van Justitie naar aanleiding van prejudiciële vragen van Förvaltningsrätt i Linköping over een Zweedse steunregeling voor de productie van duurzame elektriciteit een belangrijk arrest gewezen over de aanvaardbaarheid van territoriale beperkingen in een dergelijke regeling. Het Hof van Justitie oordeelt dat een nationale steunregeling die uitsluitend openstaat voor partijen die in de betrokken lidstaat duurzame elektriciteit produceren in beginsel geen ongeoorloofde inbreuk maakt op het vrij verkeer van goederen en dus is toegestaan.HvJ EU 1 juli 2014, zaak C-573/12, Ålands Vindkraft AB/Energimyndigheten, ECLI:EU:C:2014:2037
Does pregnancy increase the risk of ART‐induced hepatotoxicity among HIV‐positive women?
Authors: Huntington Susie , Thorne Claire , Anderson Jane , Newell Marie‐Louise , Taylor Graham , Pillay Deenan , Hill Teresa , Tookey Pat , Sabin Caroline 
Published: November 2014

IntroductionHigh rates of hepatotoxicity have been observed among HIV‐positive pregnant women using antiretroviral therapy (ART). However, the extent to which pregnancy affects the risk of ART‐induced hepatotoxicity is unclear since studies in this area have generated conflicting results.Material and MethodsCombined data from the UK Collaborative HIV Cohort (UK CHIC) study and the UK and Ireland National Study of HIV in Pregnancy and Childhood (NSHPC) were used. Alanine aminotransferase (ALT) data were assessed according to the Division of AIDS toxicity guidelines to identify factors associated with liver enzyme elevation (LEE) (grade 1–4). Women starting ART in 2000–11 aged 16–49 years were included irrespective of pregnancy status at ART start. Cox proportional hazards were used to assess the associations between fixed (ethnicity, exposure group, HBV/HCV co‐infection, prior ART use, and age, year, pregnancy status, viral load and CD4 count at ART start) and time‐dependent covariates (pregnancy status, age, year, CD4 count, viral load, duration on ART) and the risk of LEE.ResultsOf the 3426 women included, one‐quarter (25.0%, n=857) were pregnant during follow‐up and 14.4% (n=492) started ART during pregnancy. The rate of LEE was 15/100 person‐years (PY) during pregnancy and 6.1/100 PY outside pregnancy. The risk of LEE was increased during pregnancy (adjusted hazard ratio (aHR) 1.61 [1.26–2.06], p<0.001), including in secondary analysis excluding 493 women pregnant when starting ART. Other factors independently associated with LEE were lower CD4 count (<250 cells/mm3 vs. 251–350 cells/mm3 aHR 1.25 [1.02–1.54], p=0.03), HBV/HCV co‐infection (aHR 1.94 [1.58–2.39], p<0.001), HIV acquired via injecting drug use (aHR 1.61 [1.15–2.24], p=0.01 vs. heterosexually) and calendar year (aHR 1.05 [1.02–1.08], p<0.001 per one year increase). Three ART drugs were associated with increased risk of LEE (efavirenz aHR 1.27 [1.06–1.50], p‐value 0.008; maraviroc 4.19 [1.34–13.1], p=0.01; and nevirapine 1.59 [1.30–1.95], p‐value <0.001). Use of zidovudine was associated with decreased risk of LEE (aHR 0.74 [0.63–0.87], p<0.001) as was increasing time on an NNRTI‐based regimen (aHR 0.91 [0.86–0.96], p<0.001 per additional year).ConclusionsPregnant women were at increased risk of LEE, highlighting the importance of close monitoring of toxicity biomarkers during pregnancy.
More virological failure with lamivudine than emtricitabine in efavirenz and nevirapine regimens in the Dutch nationwide HIV Cohort
Authors: Rokx Casper , Fibriani Azzania , van de Vijver David , Verbon Annelies , Schutten Martin , Gras Luuk , Rijnders Bart JA 
Published: November 2014

IntroductionLamivudine (3TC) and emtricitabine (FTC) are considered interchangeable by HIV‐1 guidelines in first‐line tenofovir/efavirenz (TDF/EFV) and TDF/nevirapine (NVP) combination antiretroviral therapy (cART). Data from trials on equivalence of 3TC and FTC are inconsistent. We examined the effectiveness of 3TC and FTC in the national HIV cohort in the Netherlands.Material and MethodsObservational cohort study on cART naïve HIV‐1 patients. Therapy was initiated as 3TC or FTC with TDF/EFV or TDF/NVP between 2002 and 2012. Patients with baseline resistance or prior cART experience were excluded. Main outcomes were Week 48 virological failure (VF) by on treatment analysis, time to HIV‐RNA <400 copies/mL within 48 weeks and VF within 240 weeks after at least one HIV‐RNA <400 copies/mL. Acquired resistance to reverse transcriptase was evaluated. Analyses were done by logistic regression and Cox proportional hazard models. Propensity score adjusted models and intention to treat evaluations were included as sensitivity analysis.ResultsA total of 4836 patients initiated 3TC/TDF/EFV (n=546), FTC/TDF/EFV (n=3391), 3TC/TDF/NVP (n=207) or FTC/TDF/NVP (n=692). Ninety‐six patients were excluded for baseline resistance or prior cART experience. By Week 48, VF proportions were higher for 3TC/TDF/EFV (10.8%) compared to FTC/TDF/EFV (3.6%) and for 3TC/TDF/NVP (27.0%) compared to FTC/TDF/NVP (11.0%). The multivariable adjusted odds ratio (OR) on VF was 1.78 (95% CI 1.11–2.84; p=0.016) with 3TC/TDF/EFV compared to FTC/TDF/EFV and 2.09 (95% CI 1.25–3.52; p=0.005) with 3TC/TDF/NVP compared to FTC/TDF/NVP. Propensity score adjusted models and intention to treat analyses showed comparable results. The time to virological suppression within 48 weeks was not influenced by using 3TC or FTC in cART. If HIV‐RNA <400 copies/mL was achieved on initial cART first, no differences in VF within 240 weeks were observed between 3TC and FTC with TDF/EFV (p=0.090) or TDF/NVP (P=0.255). Patients failing 3TC‐containing cART had higher median HIV‐RNA at VF compared to FTC containing cART (p<0.001) and 89.8% had acquired resistance on 3TC compared to 81.2% on FTC.ConclusionsIncluding FTC in cART is associated with better virological responses compared to 3TC. As cost constraints may call for the use of generic 3TC, a well‐powered randomized trial to confirm the presumed equivalence of 3TC and FTC is needed.
Cardiovascular risk evaluation of HIV‐positive patients in a case‐control study: comparison of the D:A:D and Framingham equations
Authors: Markowicz Samuel , Delforge Marc , Necsoi Coca , De Wit Stéphane 
Published: November 2014

IntroductionPatients with HIV infection are at increased risk of developing cardiovascular disease (CVD) due to complex interactions between traditional CVD risk factors, antiretroviral therapy (ART) and HIV infection itself [1]. Prevention of CVD is essential as it remains the most common serious non‐AIDS event and contributes significantly to all‐cause mortality. A cardiovascular risk‐assessment model tailored to HIV population is thus essential.Materials and MethodsWe conducted a retrospective case‐control study within the HIV cohort of the Saint‐Pierre Hospital, Brussels. Cases (n=73) presented a first CVD (ischemic heart disease or stroke) between January 2002 and December 2012. Controls (n=142) were patients without any CVD and were matched for age, race, sex and follow‐up duration. We used Wilcoxon test to identify predictors of cardiovascular risk among the data collected. We compared Framingham [2] and DAD (Data Collection on Adverse Events of anti‐HIV drugs) [3] equations calculated in all patients at time of event, two, four and six years before. We then simulated the impact on the DAD scores if different therapeutic interventions had been introduced when patient cardiovascular risk at ten years exceeded 20%.ResultsComparison of cases and controls showed that C‐reactive protein (CRP) >3 mg/L (p=0.008) and HIV viral load >50 copies/ml (p=0.007) at time of event, as well as slower increase in CD4 cell count (p=0.035), were significantly more frequent in cases. DAD and Framingham median scores in cases and controls are shown in Figure 1 and Table 1. Smoking cessation lowered the DAD score of cases at time of event from 21.6% to 18.3%, modification of ART (discontinuation of indinavir, lopinavir and abacavir) lowered it from 21.6% to 17%, while both interventions with control of blood pressure and cholesterol lowered it from 21.6% to 12.4%.ConclusionsIncreased CRP levels, uncontrolled HIV viral load at time of event and slower immunologic response were found to be associated with increased CVD risk. DAD score in cases increased more and faster over time than the Framingham score and seems therefore to be more accurate in identifying HIV‐positive patients at high risk of CVD. Different therapeutic interventions could have led to a significant reduction of the DAD score in these patients and should remain a priority in patient management.
The R263K mutation in HIV integrase that is selected by dolutegravir may actually prevent clinically relevant resistance to this compound
Authors: Wainberg Mark , Anstett Kaitlin , Mesplede Thibault , Quashie Peter , Han Yingshan , Oliveira Maureen 
Published: November 2014

IntroductionDrug resistance against dolutegravir (DTG) or the nucleosides with which it has been co‐administered has never been observed in patients receiving this drug in first‐line therapy. In contrast, a R263K mutation that confers low‐level resistance (3–4 fold) to DTG has been selected by DTG in culture. Our group has ascribed the absence of resistance to DTG to the high fitness cost exacted by the R263K mutation and an inability of HIV to generate compensatory mutations.Materials and MethodsWe generated recombinant integrase enzymes and viruses containing various combinations of mutations and studied these enzymatically and in culture. We also selected for resistance against raltegravir (RAL) using viruses containing the R263K mutation.ResultsThe R263K mutation alone conferred an approximate 3‐fold level of resistance to DTG and a 40% loss in viral replicative capacity and recombinant integrase activity. Secondary mutations selected at positions H51Y or E138K did not individually affect either enzyme activity or DTG resistance, but the combination of R263K together with H51Y or E138K increased DTG resistance to about 7‐fold accompanied by a ≈75% loss in each of viral replication capacity, and both in vitro and in vivo integrase activity. Conversely, combinations of R263K together with multiple resistance mutations for RAL and/or EVG at positions 92,143, 148 and 155 resulted in even further diminished enzymatic activity that may be incompatible with viral survival. Modelling of the 3‐dimensional structure of integrase suggests that R263K is located in a region that may not permit further mutagenesis if secondary mutations at H51Y or E138K are also present. Moreover, integrase that contains R263K together with substitutions at positions 92, 143, 148 and 155 may be enzymatically inactive. The use of the R263K‐containing virus to select for resistance to RAL led to the appearance of RAL‐containing mutations but the loss of R263K.ConclusionsSecondary mutations to R263K following selection with DTG have all led to diminished viral and enzymatic fitness, helping to explain why resistance to DTG in previously drug‐naïve subjects has never been observed. The use of DTG in first‐line therapy may prevent the facile development of drug resistance and help to forestall ongoing HIV transmission.
Genotypic tropism testing in proviral DNA to guide maraviroc initiation in aviremic subjects: 48‐week analysis of the PROTEST study
Authors: Garcia Federico , Poveda Eva , Jesús Pérez‐Elías Maria , Hernández Quero José , Àngels Ribas Maria , Martínez‐Madrid Onofre J , Flores Juan , Crespo Manel , Gutiérrez Félix , García‐Deltoro Miguel , Imaz Arkaitz , Ocampo Antonio , Artero Arturo , Blanco Francisco , Bernal Enrique , Pasquau Juan , Mínguez‐Gallego Carlos , Pérez Núria , Aiestarán Aintzane , Paredes Roger 
Published: November 2014

IntroductionIn a previous interim 24‐week virological safety analysis of the PROTEST study [1], initiation of Maraviroc (MVC) plus 2 nucleoside reverse‐transcriptase inhibitors (NRTIs) in aviremic subjects based on genotypic tropism testing of proviral HIV‐1 DNA was associated with low rates of virological failure. Here we present the final 48‐week analysis of the study.MethodsPROTEST was a phase 4, prospective, single‐arm clinical trial (ID: NCT01378910) carried on in 24 HIV care centres in Spain. Maraviroc‐naïve HIV‐1‐positive adults with HIV‐1 RNA (VL) <50 c/mL on stable ART during the previous 6 months, requiring an ART change due to toxicity, with no antiretroviral resistance to the ART started, and R5 HIV by proviral DNA genotypic tropism testing (defined as a G2P FPR >10% in a singleton), initiated MVC with 2 NRTIs and were followed for 48 weeks. Virological failure was defined as two consecutive VL>50 c/mL. Recent adherence was calculated as: (# pills taken/# pills prescribed during the previous week)*100.ResultsTropism results were available from 141/175 (80.6%) subjects screened: 87/141 (60%) were R5 and 74/87 (85%) were finally included in the study. Their median age was 48 years, 16% were women, 31% were MSM, 36% had CDC category C at study entry, 62% were HCV+ and 10% were HBV+. Median CD4+ counts were 616 cells/mm3 at screening, and median nadir CD4+ counts were 143 cells/mm3. Previous ART included PIs in 46 (62%) subjects, NNRTIs in 27 (36%) and integrase inhibitors (INIs) in 1 (2%). The main reasons for treatment change were dyslipidemia (42%), gastrointestinal symptoms (22%), and liver toxicity (15%). MVC was given alongside TDF/FTC in 40 (54%) subjects, ABC/3TC in 30 (40%), AZT/3TC in 2 (3%) and ABC/TDF in 2 (3%). Sixty‐two (84%) subjects maintained VL<50 c/mL through week 48, whereas 12 (16%) discontinued treatment: two (3%) withdrew informed consent, one (1%) had a R5→X4 shift in HIV tropism between the screening and baseline visits, one (1%) was lost to follow‐up, one (1%) developed an ART‐related adverse event (rash), two (3%) died due to non‐study‐related causes (1 myocardial infarction at week 0 and 1 lung cancer at week 36), and five (7%) developed protocol‐defined virological failure, although two of them regained VL<50 c/mL with the same MVC regimen (Table 1).ConclusionsInitiation of MVC plus 2 NRTIs in aviremic subjects based on genotypic tropism testing of proviral HIV‐1 DNA is associated with low rates of virological failure up to one year.
The PROTEA trial: darunavir/ritonavir with or without nucleoside analogues, for patients with HIV‐1 RNA below 50 copies/mL
Authors: Antinori Andrea , Arribas Jose , Fehr Jan , Girard Pierre‐Marie , Horban Andrzej , Hill Andrew , van Delft Yvon , Moecklinghoff Christiane , Hill Andrew 
Published: November 2014

IntroductionIn previous studies, protease inhibitor (PI) monotherapy has shown trends for higher low‐level elevations in HIV‐1 RNA compared to triple therapy, but no increase in the risk of drug resistance.MethodsA total of 273 patients with HIV‐1 RNA <50 copies/mL for over 24 weeks on current antiretrovirals switched to DRV/r (darunavir/ritonavir) 800/100 mg once‐daily, either as monotherapy (n=137) or with 2NRTIs (nucleoside reverse‐transcriptase inhibitors) (n=136), after a 4 week run‐in phase with DRV/r + 2NRTI. Treatment failure was defined as HIV‐1 RNA levels above 50 copies/mL (FDA Snapshot method) by Week 48, or switches off study treatment. Patients with elevations in HIV‐1 RNA on DRV/r monotherapy could be re‐intensified with NRTIs. The trial had 80% power to show non‐inferiority for the monotherapy arm (delta = − 12%).ResultsPatients were 83% male and 87% Caucasian, with mean age 42 years; 10% were HCV antibody positive. In the DRV/r monotherapy arm, there were more patients with nadir CD4 count below 200 cells/µL (30% versus 22%). In the primary efficacy analysis, HIV‐1 RNA <50 copies/mL by Week 48 (intent‐to‐treat (ITT)) was 118/137 (86.1%) in the DRV/r monotherapy arm versus 129/136 (94.9%) in the triple therapy arm; DRV/r monotherapy did not show non‐inferiority versus triple therapy in the primary analysis (difference=− 8.7%, 95% CI −15.5 to −1.8%). In the multivariate analysis, the main predictor of treatment failure was nadir CD4 count. For patients with nadir CD4 counts <200 cells/µL, HIV‐1 RNA suppression rates at Week 48 were 27/41 (66%) in the DRV/r monotherapy arm and 29/30 (97%) in the triple therapy arm; for patients with CD4 nadir at least 200 cells/µL, HIV‐1 RNA suppression rates were 91/96 (95%) in the DRV/r monotherapy arm and 100/106 (94%) in the triple therapy arm. In the overall population, by a switch included analysis, efficacy was 92.0% versus 96.3%, showing non‐inferiority (difference=− 4.3%, 95% CI=−9.7 to +1.2%). No treatment‐emergent primary PI mutations were detected in three patients with sustained elevations in HIV‐1 RNA at least 400 copies/mL (two on PI monotherapy, one on triple therapy). CD4 counts remained stable during the trial in both arms.ConclusionsIn this study for patients with HIV‐1 RNA < 50 copies/mL at baseline, switching to DRV/r monotherapy showed lower efficacy versus triple antiretroviral therapy at Week 48 in the primary switch equals failure analysis (86% versus 95%). However, this lower efficacy was seen mainly in patients with CD4 nadir levels below 200 cells/µL. There was no development of PI resistance.