bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy and safety of rilpivirine‐based regimens in treatment‐experienced HIV‐1 infected patients: a prospective cohort study
Authors: Gazaignes Sandrine , Resche‐Rigon Matthieu , Yang Chloe , Gatey Caroline , Munier Anne‐Lise , Desseaux Kristell , Rozenbaum Willy , Molina Jean‐Michel 
Published: November 2014

IntroductionRilpivirine (RPV) is a new once‐daily, non‐nucleoside, reverse transcriptase inhibitor (NNRTI). In treatment‐naïve patients, RPV has shown non‐inferior antiviral activity to efavirenz but data in treatment‐experienced patients are more limited. We assessed the efficacy and safety of RPV in treatment‐experienced patients switching to a RPV‐based regimen.MethodsBetween September 2012 and June 2013, all antiretroviral therapy (ART) experienced HIV‐1 infected patients with a plasma HIV‐RNA level <50 cp/mL, and switching to a RPV‐based regimen, were enrolled in this prospective monocentric cohort study. Clinical and laboratory data were collected every 3 months to assess safety and efficacy. The primary endpoint was the proportion of patients with virologic success (HIV‐RNA load <50 cp/mL) at 12 months using the FDA snapshot algorithm.ResultsA total of 281 patients (76% male, median age: 47 years, 56% MSM) were enrolled in this study. Median lymphocyte CD4 count at baseline was 640/mm3. Patients have received ART for a median of 7 years and viral replication was fully suppressed for a median of 3 years. Before the switch, 39% patients were treated with NNRTI, 52% with protease inhibitor and 7% with integrase inhibitor‐based regimens. Reasons for switch were simplification (176 cases), adverse events (AEs) (93 cases) and others (12 cases). At month 12 (database frozen on June 2014) in the snapshot analysis, 56% of patients met virologic success, 5% experienced virologic failure (n=14) and 39% had no data in the window period. In the LOCF analysis (using data from the previous available visit before month 12), 89% patients were suppressed, 5% had virologic failure and 6% had no data. Genotypic resistance analysis was performed in 7/14 patients at the time of virologic failure (3 of whom had previous NRTI/NNRTI resistance‐associated mutations (RAMs)), and new NNRTI and NRTI RAMs emerged in 4 patients. RPV‐based regimen was generally well tolerated and only 6% of patients discontinued treatment for AEs. Grade 2–4 treatment‐related AEs occurred in 39 patients: 6 had rashes, 13 neuropsychiatric symptoms, 10 GI symptoms, 10 biological abnormalities. At month 12, significant changes from baseline were seen for total and LDL cholesterol (−0.5 and −0.28 mmol/L, respectively, p<0.05 for both), and plasma creatinine (+5.8 µmol/L, p<10–4).ConclusionsIn patients fully suppressed on ART, switching to a RPV‐based regimen in clinical practice was well tolerated and associated with few virologic failures.
Renal safety profile of STB in virologically suppressed subjects from two randomized phase 3b switch trials
Authors: Reeves Iain , Fisher Martin , Kegg Stephen , Arribas Jose , Dau Lauren , Garner Will , Walker Ivan , Nguyen Thai 
Published: November 2014

IntroductionCobicistat, a component of stribild (STB), is known to inhibit renal creatinine secretion. A detailed analysis of the renal safety profile of STB in two Phase 3b switch studies of virologically‐suppressed individuals on stable therapy: STRATEGY(S)‐PI (STB vs a RTV‐boosted protease inhibitor [PI] with emtricitabine and tenofovir DF [FTC/TDF]); and STRATEGY(S)‐NNRTI (STB versus a non‐nucleoside reverse transcriptase inhibitor [NNRTI] with FTC/TDF) is herein described.Materials and MethodsBaseline eGFR ≥70 mL/min was an inclusion criterion. The renal safety profile of STB was examined by baseline eGFR through week 48 (i.e., changes in eGFR, renal tubular laboratory abnormalities, investigator‐reported renal adverse events leading to discontinuation and unreported subclinical proximal renal tubulopathy [PRT]). Subclinical PRT was defined as a confirmed serum‐creatinine increase ≥0.4 mg/dL and two or three markers of renal tubular dysfunction (hypophosphatemia, normoglycemic glycosuria, proteinuria) occurring at the same visit at least once and with no alternative etiologies.ResultsIn S‐PI, 433 subjects (STB 293; PI 140) and in S‐NNRTI, 434 subjects (STB 291; NNRTI 143) were randomized and treated. Most (>85%) STB subjects had a baseline eGFR ≥90 mL/min. STB subjects with baseline eGFR <90 mL/min had smaller declines in eGFR compared to those with baseline eGFR ≥90 mL/min and similar occurrences of renal tubular laboratory abnormalities (Table 1). Rate of renal adverse events leading to study drug discontinuation were similar for the STB group (one PRT in a subject with baseline tubular laboratory abnormalities consistent with underlying PRT and one isolated increase in serum creatinine) and PI group (one isolated decrease in eGFR); none in the NNRTI group. The case of PRT improved after study drug discontinuation. There were no cases of unreported subclinical PRT in any group.ConclusionsIn this virologically suppressed patient population, the renal safety of STB did not differ by baseline eGFR. The renal discontinuation rate was low in the STB group, similar to the RTV‐boosted PI group, and consistent with published historical rates.
Removing inactive NRTIs in a salvage regimen is safe, maintains virological suppression and reduces treatment costs: 96 weeks post VERITAS study
Authors: Trottier Benoit , Longpré Daniele , Dion Harold , Vezina Sylvie , Lavoie Stephane , Galanakis Chrissi , Machouf Nima , Thomas Réjean 
Published: November 2014

IntroductionIn HIV+ patients exhibiting multidrug resistance (MDR), NRTIs often have little activity, increased toxicity, drug interactions and add unnecessary treatment costs. The 48 week VERITAS study demonstrated that these patients can have a safe and effective simplification of salvage regimen by removing inactive NRTIs as determined by genotypic data. Virological, immunological, clinical and financial outcomes were evaluated at an additional 96 weeks of follow‐up.Materials and MethodsMDR patients with an undetectable viral load (VL) on a stable regimen containing at least four ARVs (including one inactive NRTI) were enrolled in an open‐label, prospective simplification trial, where one inactive NRTI was removed at baseline (BL). A second NRTI could be removed at week 24 if the regimen contained at least five ARVs at enrolment.Results31 male patients participated. The mean length of treatment was 14 years, with a median CD4 count of 525. The BL regimen consisted of 4 ARVs in 22 patients (71%) and 5 ARVs in 9 patients (29%). 3TC or FTC was removed in 29 patients (94%), and either AZT or TDF was interrupted in 2 others. Four patients had a second NRTI stopped. One patient was removed at W26 as an active NRTI was removed for creatinine elevation. 30 well‐controlled patients continued follow‐up after W48. At W144, six patients had additional changes in their ARV regimen. Half were due to toxicity (jaundice, neuropathy and nephrotoxicity) while the other half were the result of treatment simplification. None of the patients exhibited virologic failure at the time of treatment change and maintained undetectable VLs throughout the entire follow‐up. These six patients had a mean gain of 79 CD4 (p=0.17) compared to baseline. 22 of the 24 patients (92%) with no changes in ARV therapy after W48 had undetectable VLs. The other two had confirmed virologic failure, one with genotypic resistance. All 24 had elevated CD4 counts (mean +118 CD4, p<0.0001). No deaths or serious adverse events were observed. One or two ARV removals translated to a mean annual saving of $3319 CDN (11%) and $8630 (24%) respectively.ConclusionsFinal results indicate that removing one or two inactive NRTIs from a regimen in patients taking four or more ARVs with controlled VL appears to be safe, maintains virological suppression through 144 weeks and significantly reduces treatment costs.
Nuke‐sparing regimens as a main simplification strategy and high level of toxicity resolution after antiretroviral switch: the SWITCHART Study
Authors: Carrero‐Gras Ana , Antela Antonio , Muñoz‐Rodríguez Jessica , Díaz‐Menéndez Marta , Viciana Pompeyo , Torrella‐Domingo Adriadna , Sanz‐Moreno José , Jesús Téllez‐Molina María , Moreno Javier , Hernández‐Quero José , Pérez‐Hernández Isabel A , Domingo‐Pedrol Pere 
Published: November 2014

BackgroundThe advent of combined antiretroviral therapy (ART) in the past decade has led to HIV suppression in most cases. Virological failure was the main reason for ART switch a few years ago; however, toxicity and treatment simplification have now gained importance due to the availability of more effective and convenient drugs. This study assessed the reasons for ART switch in daily practice.Material and MethodsObservational retrospective study that included patients whose ART was switched between January 2011 and July 2012. Patients with any other switch during the follow‐up period (until September 2013) were excluded.ResultsA total of 246 patients were included. Main reasons for ART switch were simplification (33%) and toxicity (31%), followed by clinical trial inclusion (13%), virological failure (6%), drug interaction (4%), patient decision (3%), lack of adherence (2%), pregnancy (1%) and other (8%). Eighty patients switched to a simpler regimen (median age 48 [40–53], mean CD4 count 608±265 cells/cl, 89% <50 copies/ml, mean number of previous regimens 6±5, mean time on previous ART 3±2 years). In this case, previous ART mostly included 2NRTI+1PI/r (54%) (Figure 1). The simplification strategy mainly contained nuke‐sparing regimens (60%) based on PI (DRV/r 48%): monotherapy 46%, dual therapy 13% (PI/r+maraviroc 9%, PI/r+NNRTI 4%) and triple therapy 1% (PI/r+maraviroc+raltegravir). The second preferred simplification option was 2NRTI+1NNRTI (24%). Seventy‐seven patients switched due to toxicities (median age 47 [43–53], mean CD4 count 606±350 cells/μl, <50 copies/ml 82%, mean number of previous regimens 4±3, mean time on previous ART 3±3 years). Renal (25%) and CNS (18%) toxicities were the main reasons for ART switch, followed by diarrhoea (16%), liver enzyme elevation (ALT 10%; AST 9%; bilirubin 7%), lipid elevation (cholesterol 5%; triglycerides 8%), nausea (7%) and other (=5%) (Figure 2). All patients with renal toxicity were under TDF and in most cases this drug was removed from the new regimen (with 3TC/ABC or nuke‐sparing). Among patients with CNS toxicity, 79% were taking EFV; the main new treatment was a second‐generation NNRTI (ETR)+2NRTI. Toxicities were completely resolved in 66% of patients, partially resolved in 22% and not resolved in only 12%; the median time from ART switch to toxicity resolution was 4 (2–8) months.ConclusionsThe main reasons for ART switch in daily practice are simplification and toxicities, renal and CNS toxicities being the most prevalent. The preferred simplification strategies are nuke‐sparing regimens, mainly DRV/r‐based monotherapy and dual therapy. ART switch leads to a complete resolution of toxicities in most cases in the short term.
Switching from ritonavir to cobicistat in HIV patients with renal impairment who are virologically suppressed on a protease inhibitor
Authors: Fisher Martin , McDonald Cheryl , Moyle Graeme , Martorell Claudia , Ramgopal Moti , Laplante Francois , Curley Joanne , Graham Hiba , Tran‐Muchowski Cecilia , Liu Yapei , Rhee Martin , Szwarcberg Javier 
Published: November 2014

IntroductionCobicistat (COBI) is a pharmacoenhancer and one of the components of ECF/TDF (elvitegravir/cobicistat/emtricitabine/tenofovir DF), which is approved in treatment‐naïve HIV patients with creatinine clearance (CrCl) ≥70 mL/min. Study 118 assessed the renal safety of COBI‐containing regimens in HIV patients with mild to moderate renal impairment.Material and MethodsPhase 3, open label study in HIV‐1‐infected patients with CrCl 50–89 mL/min who are virologically suppressed on a stable regimen containing ritonavir (RTV)‐boosted atazanavir (ATV) or darunavir (DRV). Patients switched RTV to COBI, while keeping the rest of their regimen unchanged. We present the 96‐week (Wk) data.ResultsSeventy‐three patients were enrolled. Mean age was 54 years; male 82%; white 77%; hypertension 38%; diabetes 18%; baseline proteinuria (≥trace) 51%; median CrCl 71 mL/min (range: 42–98). At Wk 96, 89% maintained virologic suppression (95% CI 77.4–95.8%). No emergent resistance developed. Reductions in CrCl (median [IQR]) were observed as early as Wk 2, after which they were nonprogressive through Wk 96 (Wk 48: −3.8 [−9–0.8]; Wk 96: −5.0 [−13.0–0.1]). Changes in CrCl by baseline CrCl (<70 vs ≥70) at Wk 96 were: −3.1 [−5.1–0.5] vs −7.6 [−15.2 to −3.6], respectively. Cystatin C‐based eGFR remained stable through Wk 96 (median [IQR]: −2.8 [−7.4–8.9 mL/min/1.73 m2). Actual GFR assessment using CLiohexol (n=14) was unaffected over 24 Wks (median at baseline: 82.5, median changes from baseline at Wks 2, 4, and 24: 1.6, 7.0, −4.1 mL/min, respectively). Three renal discontinuations occurred (two worsening CrCl and one proteinuria/hematuria); none had proximal renal tubulopathy [PRT]. No patient had laboratory evidence of PRT (>1 confirmed renal laboratory abnormalities [increase in serum Cr≥0.4 mg/dL, ≥2‐grade increase in proteinuria,≥1‐grade increase in normoglycemic glycosuria or hypophosphatemia]).ConclusionsIn HIV‐infected patients with CrCl 50–89 mL/min, on ATV‐ or DRV‐based regimen switching to COBI from RTV, demonstrated that COBI was well tolerated with no cases of PRT through 96 Wks. The renal safety profile of COBI in patients with mild to moderate renal impairment was consistent with the long‐term data in patients without renal impairment (CrCl≥70 mL/min) from the phase 3 studies of COBI‐containing regimens.
Hypovitaminosis D in HIV‐infected patients in Lisbon: a link with antiretroviral treatment
Authors: Boura Márcia , Filipa Sutre Ana , Badura Robert , Zagalo Alexandra , Afonso Cláudia , Caldeira Luís , Valadas Emília 
Published: November 2014

IntroductionRecent data indicates that low vitamin D (25(OH)D) levels can lead to a worst prognosis in HIV‐infected individuals, even in those on successful antiretroviral therapy (ART) [1]. Portugal is the European country that has the largest average sun exposure time but prevalence of hypovitaminosis D is mostly unknown. Our aim was to determine the prevalence of hypovitaminosis D in HIV patients in Lisbon and the possible association with ART.MethodsFrom 2012 to January 2014, plasma samples from 518 HIV‐infected patients were collected to 25(OH)D levels determination. Data on demographic features (age, ethnicity, country of origin) and clinical/laboratory parameters were collected from clinical files (HIV subtype, CD4+ cell count, CD4+ nadir, viral load (VL), HBV/HCV co‐infection and ART). 25(OH)D status was defined as: deficiency <20 ng/mL, insufficiency 20–30 ng/mL, optimal >30 ng/mL.ResultsMedian age was 46 years old (±11); 62.0% (321/518) were male; 81.3% (421/518) were Caucasian and 78.6% (407/518) were Portuguese. Most patients (96.1%; 498/518), were HIV‐1 infected, 22.9% (114/498) and 4.0% (20/498) of them were HCV and/or HBV co‐infected, respectively. Mean CD4+ cell count was 648 cells/µL (±333) and nadir was 219 cells/µL (±179). On treated patients VL was <40 HIV RNA/mL in 86.7% (417/481). The median levels of 25(OH)D was 20.0 ng/mL (range 4.1–99.7) and we found differences between values observed during Winter (median 16.7 ng/mL) and Summer (median 24.9 ng/mL) (p<0.0001). Low 25(OH)D levels were not correlated to ethnicity (p=0.066). 25(OH)D level was <30 ng/mL in 80.1% (415/518) of the patients, from which 30.9% (160/518) and 49.2% (255/518) had insufficiency and deficiency levels, respectively. Most (92.9%; 481/518) were on ART: regimens containing PI (47.5%), NNRTI (40.3%; 41.3% on NVP and 58.7% on EFV), II (1.2%), PI+NNRTI (3.9%). Comparing the 25(OH)D level along the different ART regimens (PI vs NVP; PI vs EFV; PI vs no ART) there were differences between PI and EFV (p=0.044).ConclusionsIn this study, 80.1% of the HIV‐infected patients had hypovitaminosis D and ART regimens with EFV were more often associated with low 25(OH)D levels. Understanding the impact of the different antiretroviral drugs on 25(OH)D status could help to decide in clinical practice whether 25(OH)D supplementation or drug switch are the best options for each patient.
Recreational drugs and HIV in Europe: current use of recreational drugs and principal HIV guidelines related recommendations
Authors: Garin Escriva Noe , Velasco Muñoz Cesar , Thomas De Pourcq Jan , Lopez Garcia Belen , Maria Haro Abad Josep , Antonia Mangues Bafalluy Maria , Trilla Garcia Antoni 
Published: November 2014

IntroductionRecreational drug consumption has been associated with both higher rates of risk activities related to HIV transmission and also worse adherence and management of HIV patients under HAART treatment. Moreover, relevant interactions may be present in patients under HAART treatment. Our aim is to present the European trends of drug consumption per country and age groups and assess the way drug consumption is addressed in general HIV guidelines.Materials and MethodsLast 12‐month prevalence drug use was obtained from the European Monitoring Centre for Drugs and Drug Addiction for the four most consumed drugs (cannabis, cocaine, amphetamines, ecstasys). Consumption rates were collected and analyzed by country and age. Principal HIV guidelines were assessed to identify the degree of incorporation of drug use issues at three levels: transmission risk, adherence to the HAART and management of interactions. Guidelines: (a) WHO; (b) EACS; (c) BHIVA; (d) US DHHS; (e) IAS‐USA; (f) GESIDA; (g) French CPG; (h) Italian CPG.ResultsData on drugs of abuse consumption was obtained from 29 European countries, with results showing relevant drug utilization in Europe. Cannabis was the most frequent drug across all countries, with 10 countries over 5% of prevalence over the last year. Other drugs prevalence accounted for about 0.5–1%, reaching up to: 2.1% for cocaine in Spain, 1.4% for ecstasy in the Netherlands and 1.1% for amphetamines in Estonia. 15–24 and 25–34 years old subgroups had the highest prevalence, although notable use of cannabis and cocaine was also found in the 35–44 and 45–54 subgroups. From the eight guidelines assessed, six considered recreational drugs at any point. Recommendations for specific drugs were given in 50% of the guidelines. From those guidelines addressing drug consumption: three assessed risk habits which related to transmission risk, six appraised issues on adherence to HAART and five comprised data on interactions between recreational drugs and HAART. Additionally, five guidelines mentioned drugs in the context of other issues, such as sexual dysfunction or HIV‐associated neurocognitive impairment.ConclusionsUse of recreational drugs is frequent in Europe, not only in the younger population but also in other unexpected older subgroups. The scarce information found in the guidelines has a potential implication for patients and clinicians; therefore, there is a need to include specific recommendations about the clinical management of people living with HIV who use recreational drugs.
Isolation of Thymic Epithelial Cells and Analysis by Flow Cytometry
Authors: Jain Reema , Gray Daniel H.D. 
Published: November 2014

AbstractThe epithelial cells of the thymus govern the differentiation of hematopoietic precursors into T cells, which are critical for acquired immunity. Thymic epithelial cells (TEC) provide molecular cues that direct precursor recruitment, commitment to the T cell lineage, thymocyte proliferation, and the processes of positive and negative selection. Despite the importance of TEC to the immune system, fundamental questions regarding their differentiation, turnover, and function throughout life remain unanswered. This knowledge gap is largely due to technical difficulties in isolating, quantifying, and purifying this rare cell type. Here, we describe methods for the enzymatic digestion of the thymus to obtain single‐cell suspensions of TEC, their analysis by flow cytometry, enrichment using magnetic beads, and purification for a variety of downstream applications. © 2014 by John Wiley & Sons, Inc.
Isolation and Purification of Proteasomes from Primary Cells
Authors: Steers Nicholas J. , Peachman Kristina K. , Alving Carl R. , Rao Mangala 
Published: November 2014

AbstractProteasomes play an important role in cell homeostasis and in orchestrating the immune response by systematically degrading foreign proteins and misfolded or damaged host cell proteins. We describe a protocol to purify functionally active proteasomes from human CD4+ T cells and dendritic cells derived from peripheral blood mononuclear cells. The purification is a three‐step process involving ion‐exchange chromatography, ammonium sulfate precipitation, and sucrose density gradient ultracentrifugation. This method can be easily adapted to purify proteasomes from cell lines or from organs. Methods to characterize and visualize the purified proteasomes are also described. © 2014 by John Wiley & Sons, Inc.
Global estimate of submarine groundwater discharge based on an observationally constrained radium isotope model
Authors: Kwon Eun Young , Kim Guebuem , Primeau Francois , Moore Willard S. , Cho Hyung‐Mi , DeVries Timothy , Sarmiento Jorge L. , Charette Matthew A. , Cho Yang‐Ki 
Published: November 2014

AbstractAlong the continental margins, rivers and submarine groundwater supply nutrients, trace elements, and radionuclides to the coastal ocean, supporting coastal ecosystems and, increasingly, causing harmful algal blooms and eutrophication. While the global magnitude of gauged riverine water discharge is well known, the magnitude of submarine groundwater discharge (SGD) is poorly constrained. Using an inverse model combined with a global compilation of 228Ra observations, we show that the SGD integrated over the Atlantic and Indo‐Pacific Oceans between 60°S and 70°N is (12 ± 3) × 1013 m3 yr−1, which is 3 to 4 times greater than the freshwater fluxes into the oceans by rivers. Unlike the rivers, where more than half of the total flux is discharged into the Atlantic, about 70% of SGD flows into the Indo‐Pacific Oceans. We suggest that SGD is the dominant pathway for dissolved terrestrial materials to the global ocean, and this necessitates revisions for the budgets of chemical elements including carbon.
Generation of Mammalian Offspring by Haploid Embryonic Stem Cells Microinjection
Authors: Shuai Ling , Li Wei , Wan Haifeng , Zhao Xiao‐Yang , Wang Liu , Zhou Qi 
Published: November 2014

AbstractIn this unit we introduce the derivation and genetic modification of mouse haploid embryonic stem (ES) cells. We detail how to produce haploid embryos and the subsequent ES derivation and cell culture. We further introduce readers to the intracytoplasmic injection processes of two types of haploid ES cells [androgenetic haploid ES (ahES) and parthenogenetic ES (phES)], both of which possess potential to produce fertile progenies by microinjection. This unit will be interesting to researchers who focus on recessive screens and transgenic animal model production with haploid stem cells. © 2014 by John Wiley & Sons, Inc.
Visible‐Light‐Mediated Radical Aryldifluoroacetylation of N‐Arylacrylamides to give Difluoroacetylated Oxindoles
Authors: Fu Weijun , Zhu Mei , Zou Guanglong , Xu Chen , Wang Zhiqiang 
Published: November 2014

AbstractA simple and practical approach to oxindole derivatives via visible‐light‐photocatalyzed aryldifluoroacetylation of N‐arylacrylamides with BrCF2CO2Et has been developed. This method provides convenient access to a variety of difluoroester‐substituted oxindoles under mild conditions.