bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel Functional Variants Locus in PLCE1 and Susceptibility to Digestive Tract Cancer in the Chinese Population: A Meta-Analysis
Authors: Duan Fujiao , Song Chunhua , Dai Liping , Cui Shuli , Zhang Xiaoqin , Zhao Xia
Published: November 2014

Three large-scale genome-wide association studies (GWAS) have identified a shared susceptibility variation phospholipase C epsilon 1 ( PLCE1) rs2274223 for esophageal squamous cell carcinoma (ESCC) and/or gastric cardia adenocarcinomas (GCA) in the Chinese population. However, the association between PLCE1 rs2274223 A>G and the risk of digestive tract cancer (DTC) has been inconsistent. We therefore carried out a meta-analysis of published case-control studies to derive a more precise estimation of the association between PLCE1 rs2274223 A>G and DTC risk. A comprehensive search was conducted to identify all eligible studies of PLCE1 rs2274223 polymorphism and DTC risk. Crude odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to estimate the strength of associations in fixed or random effect models. Heterogeneity and publication bias were also assessed. A total of 15 case-control studies were identified, including 29,805 cases and 32,225 controls. Overall, we found a statistically significant association between the PLCE1 rs2274223 polymorphism and DTC risk (G vs A: OR=1.29, 95% CI: 1.17-1.43; GA vs AA: OR=1.33, 95% CI: 1.18-1.51; GG vs AA: OR=1.71, 95% CI: 1.26-2.32; GG/GA vs AA: OR=1.33, 95% CI: 1.17-1.51), but the recessive model did not reach statistical significance (GG vs GA/AA: OR=0.94, 95% CI: 0.63-1.42). In the subgroup analysis by cancer types, we observed a significant risk for DTC in the ESCC and GCA subgroups. When stratified for source of controls, the results of the population-based subgroup analysis showed that the variant G allele might generally induce a significantly increased risk of DTC, except in hospital-based subgroups. In conclusion, PLCE1 rs2274223 polymorphism may be used as a potential biomarker for DTC susceptibility particularly for ESCC and GCA in the Chinese population.
Circulating Endothelial Cells as a Biomarker in Non-Small Cell Lung Cancer Patients: Correlation with Clinical Outcome
Authors: Najjar Fadi , Alammar Moosheer , Bachour Marroan , Al-Massarani Ghassan
Published: November 2014

Background

Circulating endothelial cells (CECs) have been proposed as a biomarker for the assessment of patients with solid tumors. However, few data are available in non-small cell lung cancer (NSCLC). We therefore analyzed the clinical significance of CECs in newly diagnosed NSCLC patients. In addition, we tried to determine the prognostic value of CECs in NSCLC.

Methods

In this prospective study, 151 newly diagnosed NSCLC patients and 25 healthy volunteers were included. Furthermore, 25 patients with a partial response (n=15) or stable disease (n=10) after treatment were evaluated at recurrence with a mean follow-up of 117 days (range: 47-364 days). CECs were counted using magnetic beads coupled to a specific antibody against CD146.

Results

The pre-treatment CEC count was significantly higher in patients with all histological subtypes of NSCLC than in healthy volunteers (p<0.0001). High baseline CEC counts were significantly correlated with advanced clinical stages (p=0.026), weight loss (p=0.03), and poorly differentiated NSCLC (p=0.02). The amount of CECs increased significantly at recurrence compared with their amount after treatment in 20/21 assessable patients (p=0.0001). Nevertheless, there was no significant correlation between baseline CEC count and median duration of progression-free survival (p=0.402).

Conclusions

Increased CEC counts were present in patients with newly diagnosed NSCLC compared with healthy subjects. Elevated levels of baseline CECs correlated with high-risk factors in NSCLC. In addition, increased CEC count during follow-up seems to be correlated with recurrence in NSCLC patients.
Methylation in the Promoters of HS3ST2 and CCNA1 Genes is Associated with Cervical Cancer in Uygur Women in Xinjiang
Authors: Zuo Qiangqiang , Zheng Weinan , Zhang Jinli , Pan Zemin , Liu Yinyin , Long Haichen , Fan Peiwen , Guo Caili , Li Feng , Shao Renfu
Published: November 2014

We assessed the suitability of HS3ST2 and CCNA1 genes as biomarkers for the early detection of cervical cancer in Uygur women in Xinjiang, China. Methylation-specific PCR (MSP) and HPV (HPV16 and HPV18)–specific PCR were performed on 110 cervical samples: 40 normal cervices, 10 cervical intraepithelial neoplasia 1 (CIN1), 10 CIN2, 10 CIN3 and 40 cervical cancer tissues. The expression of the 2 genes was measured by reverse transcription PCR (RT-PCR) in 10 methylation-positive and 10 methylation-negative cervical tissues. We found that both HS3ST2 and CCNA1 genes were methylated in 38 of the 40 cervical cancer tissues, 9 of the 10 CIN3, and 6 of the 10 CIN2. In contrast, methylation of these 2 genes was found in only 1 of the 40 normal tissues and none of 10 CIN1. Furthermore, hypermethylated HS3ST2 and CCNA1 genes were correlated with infection with HPV16 and HPV18 in high-grade squamous intraepithelial lesions (HSILs) and cervical cancer (both p<0.05). The expression of HS3ST2 and CCNA1 genes was lower in the methylation-positive cervical tissues than in the methylation-negative cervical tissues. Our results indicate that HS3ST2 and CCNA1 genes may play important roles in HPV-induced cervical cancer and that patients with specific hypermethylated genes may have a greater risk of progressing to invasive cervical cancer.
Vascular access in the Obese: Superficialisation of Native Radio-Cephalic and Brachio-Cephalic Fistulae
Authors: Evans Richard P.T. , Meecham Lewis , Buxton Pauline , Jafferbhoy Sadaf , Legge Jocelyn , Papp Laszlo , Ehsan Omer , Pherwani Arun D.
Published: November 2014

Purpose

The Department of Health estimates that currently in the UK, 61.3% of the population are overweight or obese (BMI >25 kg/m2). Fistulae in the obese often fail to mature or prove inadequate to needle due to excessive depth (>6 mm). This study is a summary of our experience with brachio and radio-cephalic vein superficialisation in the obese.

Methods

From May 2008 to October 2012, 22 patients underwent superficialisation of the cephalic vein following radio-cephalic or brachio-cephalic Arterio-venous fistula (AVF) creation. Data were obtained from a prospective database (Cyberen®) and retrospectively analysed.

Results

The study included 23 AVFs in 22 patients (seven males, 15 females), of which 13 were brachio-cephalic and 10 radio-cephalic. The mean age of the patients was 56 years (median 60, range 19-78 years). The mean BMI was 36.7 kg/m2 (median 32, 25-58 kg/m2). Six-week post procedure duplex ultrasonography recorded the mean fistula depth to be 7.7 mm (median 8 mm, 5-15 mm) and mean flow rates were 961 ml/min (median 800 ml/min, 320-1968 ml/min). Of the 23, 21 fistulae matured successfully. There were no procedure-related complications. During follow-up, two patients underwent transplantation prior to fistula use and three patients died of unrelated causes. The remaining 16 fistulae remain in use and under access surveillance.

Conclusions

Superficialisation of brachio/radio-cephalic fistulae is an excellent option to optimise the cephalic vein for needling, assisting primary patency. Superficialisation of the cephalic vein helps maintain long-term functional access in overweight and obese patients.
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.
SISTEMA DE METAS DE INFLAÇÃO NO BRASIL: UMA ANÁLISE DA ESTRUTURA
Authors: Piccoli Medeiros Braga Bernardo , Ribas Pereira Joaquim Israel
Published: November 2014

Há quatorze anos, em junho de 1999, o Brasil adotou o Sistema de Metas para Inflação (SMI) como regime monetário. A essência desse regime monetário é a aceitação, por parte dos agentes econômicos, do comprometimento e eficácia do Banco Central em perseguir um nível estipulado de variação dos preços. Neste período, a autoridade monetária enfrentou um ambiente externo difícil (1999 – 2002), benigno (2003 – 2008) e novamente adverso mais recentemente. Certamente o Sistema de Metas de Inflação não conquistou a unanimidade, mas os fatos são incontroversos em apontar que o país conquistou e tem mantido um ambiente econômico de inflação moderada (conseqüência das metas) com equilíbrio externo (devido ao câmbio flutuante). O presente artigo pretende estudar o SMI brasileiro com objetivo de analisar as características fundamentais do sistema, no que diz respeito a sua adequação com o provimento de um guia eficiente para as expectativas dos agentes
As manifestações e a questão da reforma urbana: é possível retomar a capacidade de planejamento e intervenção?
Authors: Castro Demian , Carneiro Leão Igor Zanoni Contant , Welters Angela
Published: November 2014

O artigo discute, a propósito das manifestações de junho de 2013, a necessidade de incluir e articular analiticamente três eixos de problemas que obstruem a capacidade de planejamento dos governos municipais, pois tendem a produzir uma privatização perversa do habitat urbano, afetando o modo de vida das pessoas e, também, à sua mobilidade. Estes eixos, quais sejam, a industria automobilística, o capital imobiliário e a (in) segurança urbana, por sua vez, suscitam outras questões que são tratadas na forma de réplica.
Lei de Inovação do Estado do Paraná: uma visão sistêmica focada em negócio.
Authors: Felix Júlio César
Published: November 2014

Resumo: O presente artigo trata da legislação que ampara a atividade econômica nos estados e municípios, em especial àquelas existentes no Estado do Paraná. O artigo apresenta um breve panorama das leis existentes, buscando sistematizar a legislação e apresentar o status desse movimento no País. Em seguida detêm-se sobre o Lei do Estado do Paraná apresentando seus principais aspectos. Por fim faz uma síntese dos desafios e próximos passos da regulamentação dessa importante base legal para a atividade empreendedora.
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
The Unit Makes All the Difference
Authors: Rollick Mary Beth
Published: November 2014

An advertisement in a local store prompted the author to create activities for the classroom that focus on sense-making and the unit being used.
Piecing It Together
Authors: Wickstrom Megan H.
Published: November 2014

Use quilting as a context to relate area to perimeter as well as an opportunity to examine second graders' conceptions and misconceptions about measurement.
PARTICIPATION BASED MODEL OF SHIP CREW MANAGEMENT
Authors: Bielić Toni , Ivanišević Dalibor , Gundić Ana
Published: November 2014

This paper analyse the participation - based model on board the ship as possibly optimal leadership model existing in the shipping industry with accent on decision - making process. In the paper authors have tried to define master’s behaviour model and management style identifying drawbacks and disadvantages of vertical, pyramidal organization with master on the top. Paper describes efficiency of decision making within team organization and optimization of a ship’s organisation by introducing teamwork on board the ship. Three examples of the ship’s accidents are studied and evaluated through “Leader - participation” model. The model of participation based management as a model of the teamwork has been applied in studying the cause - and - effect of accidents with the critical review of the communication and managing the human resources on a ship. The results have showed that the cause of all three accidents is the autocratic behaviour of the leaders and lack of communication within teams.
Orphans of the HIV epidemic: the challenges from toddlerhood to adolescence and beyond
Authors: Lala Mamatha M
Published: November 2014

This presentation focuses on the challenges and practical issues faced each day by orphans of the HIV epidemic and the holistic care that can be provided, as they continue to grow from toddlerhood to adolescence and beyond. An HIV Research Trust Scholarship enabled me to spend quality time in a sub‐Saharan African province worst hit by the HIV epidemic and to interact with local experts and learn from mutual clinical experience. It was an immensely useful exercise as the clinical spectra of the diseases are very similar to ours and they have ongoing active research programs very relevant to our setting. India is arguably home to the largest number of orphans of the HIV epidemic. The responsibility of caring for orphaned children overwhelms and pushes many extended families beyond their ability to cope. Many countries are experiencing large increases in the number of families headed by women and grandparents, or even young children. These households are often unable to meet basic needs, and so the number of children living on the streets is rising. Orphaned children are disadvantaged in many devastating ways. In addition to the trauma of witnessing the sickness and death of one or both parents and perhaps siblings, they lack the necessary parental guidance through crucial life‐stages of identity formation and transition into adulthood. They are more likely to suffer damage to their cognitive and emotional development and be subjected to; exploitation in terms of labour, social exclusion, extreme economic uncertainty, physical and sexual abuse, illiteracy, malnutrition and illness. Education remains a distant dream. With stigma and discrimination, they lack legal protection, lose inheritance rights, access to essential services available to other community members and professional help from doctors, teachers and lawyers. The implications for these unfortunate children are extraordinarily grave but governments, international agencies, non‐governmental organizations, schools, other community groups and individuals can still alter the course of the crisis. The Committed Communities Development Trust (CCDT) is a voluntary secular Trust, reaching out to 300,000 people annually, focusing intensively on children affected and infected by HIV/AIDS, mainly orphans, child headed families, children living in street situations, brothels, institutions and children at risk of drug addiction, abuse and exploitation in Mumbai. We run several comprehensive HIV/AIDS programmes addressing issues of prevention, care, support, education, awareness, empowerment, training and research through strongly structured home‐based care programs, community based programs and temporary residential shelters. The CCDT recognizes and understands the daunting challenges these children face and helps them overcome these as a team by providing comprehensive care and support, giving them an opportunity in life and enabling them to become productive citizens of tomorrow.
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

Introduction

High 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 Methods

Combined 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.

Results

Of 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).

Conclusions

Pregnant women were at increased risk of LEE, highlighting the importance of close monitoring of toxicity biomarkers during pregnancy.
Managing first‐line failure
Authors: Cooper David A
Published: November 2014

WHO standard of care for failure of a first regimen, usually 2N(t)RTI's and an NNRTI, consists of a ritonavir‐boosted protease inhibitor with a change in N(t)RTI's. Until recently, there was no evidence to support these recommendations which were based on expert opinion. Two large randomized clinical trials, SECOND LINE and EARNEST both showed excellent response rates (>80%) for the WHO standard of care and indicated that a novel regimen of a boosted protease inhibitor with an integrase inhibitor had equal efficacy with no difference in toxicity. In EARNEST, a third arm consisting of induction with the combined protease and integrase inhibitor followed by protease inhibitor monotherapy maintenance was inferior and led to substantial (20%) protease inhibitor resistance. These studies confirm the validity of the current recommendations of WHO and point to a novel public health approach of using two new classes for second line when standard first‐line therapy has failed, which avoids resistance genotyping. Notwithstanding, adherence must be stressed in those failing first‐line treatments. Protease inhibitor monotherapy is not suitable for a public health approach in low‐ and middle‐income countries.
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

Introduction

Lamivudine (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 Methods

Observational 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.

Results

A 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.

Conclusions

Including 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.
Integrated care pathways and task shifting
Authors: Panton Linda
Published: November 2014

Delivery of HIV care has evolved over the last 10 years, and nurse specialists are a driving force in developing new pathways to enhance patient care. Despite the continued rise in numbers of people living with HIV, the financial constraints on the NHS have unfortunately resulted in a reduction in service provision. Experienced nurses are integral to patient care management. They not only provide standardized care for stable patients, therefore increasing consultant capacity for the more complex medical patient, but have a degree of flexibility that allows newly diagnosed patients quick access to care and support. With a strong emphasis being placed on an integrated and collaborative multidisciplinary team approach, to ensure patients receive the same standard of care, Scotland's HIV centres follow an integrated care pathway. The nurse oversees the completion of this document and co‐ordinates the pathway of care depending on the clinical need. Nurses develop and maintain necessary partnerships between primary care, specialist care, psychological services, social care and third sector support services. The nurse case load continues to expand and diversify. Stable patients may be maintained on therapy but are living with a stigmatized long‐term chronic condition and rely on the nurse as a point of contact to access advice and support readily. The more chaotic and vulnerable clients with complex care needs require the nurse to co‐ordinate their care, ensuring the appropriate agencies remain involved. Overseeing the transition of care to other units and tracing patients who are lost to follow up is also a necessity, as retention in care is paramount for the continued improvement in clinical outcomes. The contribution that specialist nurses make to the provision of HIV care is valuable and will continue to play a large role in the delivery of such care.
Drug use, HIV, HCV and TB: major interlinked challenges in Eastern Europe and Central Asia
Authors: Kazatchkine Michel
Published: November 2014

Eastern Europe and Central Asia have the largest drug epidemic globally and the fastest and still expanding HIV epidemic. The Russian Federation and Ukraine together account for over 90% of the reported AIDS cases in the region. If small in absolute numbers, the epidemics are however significant in prevalence rate in most countries of Central Asia. Most heroin and many of the new synthetic or home‐made drugs are injected, which has led to high prevalence levels (up to 90%) of HCV infection in people who inject drugs (PWID). The two epidemics of HIV and HCV are in turn interlinked with TB and MDR‐TB that are highly prevalent among marginalized populations in the region. Despite progress in the last two years, access to antiretroviral treatment remains far below global levels and increases more slowly than new reported cases of HIV. Access to prevention is limited with low coverage of needle exchange programs and very low or inexistent access to opioid substitutive therapy. There are few exceptions to this situation, including Ukraine where harm reduction programs are being scaled up together with significant peer outreach programs for PWIDs. This is likely to be the reason why the epidemic curves in the Russian Federation and Ukraine are now diverging. The region faces many structural, cultural, societal and political obstacles in responding to these quadruple epidemics. Without a significantly expanded and strengthened response, these epidemics will remain major causes of illness and premature deaths in the region.
HIV epidemic in Russia and neighbouring countries
Authors: Pokrovskiy Vadim
Published: November 2014

Reports of HIV/AIDS cases attributed to sexual transmission from foreigners were published in the USSR in the mid of 80s. In the initial decade of the epidemic, the subtype B was found in men who have sex with men (MSM) population and several non‐B subtypes were identified in heterosexual persons. The first case of HIV infection in intravenous drug users (IVDU) was reported in 1993 and since then a specific subtype A and its recombinants invaded the intravenous drug users (IVDU) populations of the region with the highest rate in Estonia, Russia and Ukraine. The concentrated HIV epidemic in IVDUs is still the main problem in the Eastern Europe; however, the rate of heterosexual transmission is increasing and many evidences of HIV prevalence rise in MSM are published. UNAIDS estimations for the number of HIV‐positive persons living in the region range from 980,000 to 1,300,000 but distribution of HIV‐cases is uneven and the prevalence rate of HIV infection in separate regions is over 1%. Mass seasonal labour migration from Central Asia and Caucasian republics to Russia transmits HIV to these countries. Prevention programs in the region are limited, and ART coverage is not more than 20% of the total HIV‐positive population. The lack of concern about the epidemic, absence of effective national strategies and limited allocated resources are the main barriers to prevention and care in many countries. Local conflicts, rising religiosity and discrimination are adverse factors. The near‐term forecast for the epidemic in the region is pessimistic and further international advocacy is needed to improve the situation.
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

Introduction

Patients 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 Methods

We 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%.

Results

Comparison 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%.

Conclusions

Increased 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

Introduction

Drug 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 Methods

We 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.

Results

The 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.

Conclusions

Secondary 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

Introduction

In 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.

Methods

PROTEST 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.

Results

Tropism 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).

Conclusions

Initiation 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.
Treatment as Prevention: unanswered questions and progress to date
Authors: Vella Stefano
Published: November 2014

Prevention of HIV infection has recently acquired new effective tools, based on the provision of antiretrovirals, to both decrease the “source” of HIV infection and/or to decrease host susceptibility to HIV infection. The milestone concept of using antiretrovirals for prevention has been tested already in the 1990s, to interrupt maternal–child. The suggestion of using antiretrovirals to decrease inter‐human HIV transmission was born already in 2006, and definitely proven by a randomized controlled study on HIV‐discordant couples demonstrating an astonishing 96% efficacy, and with numerous studies proving the efficacy of pre‐exposure prophylaxis. It now appears clear that antiretroviral therapy not only provides clinical benefit to the individual (although the exact starting time remains controversial, in terms of risk‐benefit ratio and public health policy) but has the potential of decreasing the incidence of new infections at a population level. The concept of Treatment as Prevention is now gaining momentum, as a way to progressively end the AIDS epidemic by expanding the access to antiretrovirals, with “test and treat” being the ultimate possibility, although not already tested in the field and with huge implementation barriers. The presentation will deal with successes, failures, and foreseen barriers of using antiretrovirals for prevention, at the individual and population level, also including the social issues, the need to target key‐affected populations, and, finally, the perspectives of new technologies under development.
A community perspective on pre‐exposure prophylaxis
Authors: Collins Simon
Published: November 2014

The history of pre‐exposure prophylaxis (PrEP) is notable for being a community rather than industry‐driven development. This talk will review this history, covering factors that include community demand, study results, regulatory challenges, commercial interests and practical issues of public health. It will also look at some of the controversies that appear to limit broader access, and important changes since US approval for PrEP in 2012. If PrEP had been discovered in the 1980s, the demand for access is likely to have been very different and it would now be universally available. Yet in many health settings, the willingness to include the option of PrEP appears to be inversely correlated with the increasingly impressive data showing its effectiveness. The limitations of condoms are shown in continued rates of new HIV infections in high‐risk populations. These rates have remained persistently high for the last decade, even with the dramatic impact of treatment as prevention (TasP) on reducing further transmission. Within the last year, the polarized debate about PrEP appears to be shifting to a middle ground focused on individual choice. Together with TasP, this has started a new dialogue on the potential benefits on quality of life. This has brought a new focus on the cumulative and largely unmeasured impact for HIV negative gay men who live for decades focused on a fear of HIV. Looking forwards, the rate‐limiting steps of cost and adherence have the potential to be overcome with lower priced generic tenofovir in 2017 and the development of long‐acting formulations.
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

Introduction

In 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.

Methods

A 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%).

Results

Patients 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.

Conclusions

In 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.