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https://www.readbyqxmd.com/read/29121950/the-hiv-1-integrase-ledgf-allosteric-inhibitor-mut-a-resistance-profile-impairment-of-virus-maturation-and-infectivity-but-without-influence-on-rna-packaging-or-virus-immunoreactivity
#1
Céline Amadori, Yme Ubeles van der Velden, Damien Bonnard, Igor Orlov, Nikki van Bel, Erwann Le Rouzic, Laia Miralles, Julie Brias, Francis Chevreuil, Daniele Spehner, Sophie Chasset, Benoit Ledoussal, Luzia Mayr, François Moreau, Felipe García, José Gatell, Alessia Zamborlini, Stéphane Emiliani, Marc Ruff, Bruno P Klaholz, Christiane Moog, Ben Berkhout, Montserrat Plana, Richard Benarous
BACKGROUND: HIV-1 Integrase (IN) interacts with the cellular co-factor LEDGF/p75 and tethers the HIV preintegration complex to the host genome enabling integration. Recently a new class of IN inhibitors was described, the IN-LEDGF allosteric inhibitors (INLAIs). Designed to interfere with the IN-LEDGF interaction during integration, the major impact of these inhibitors was surprisingly found on virus maturation, causing a reverse transcription defect in target cells. RESULTS: Here we describe the MUT-A compound as a genuine INLAI with an original chemical structure based on a new type of scaffold, a thiophene ring...
November 9, 2017: Retrovirology
https://www.readbyqxmd.com/read/29066507/pqr309-is-a-novel-dual-pi3k-mtor-inhibitor-with-pre-clinical-antitumor-activity-in-lymphomas-as-a-single-agent-and-in-combination-therapy
#2
Chiara Tarantelli, Eugenio Gaudio, Alberto Jesus Arribas, Ivo Kwee, Petra Hillmann, Andrea Rinaldi, Luciano Cascione, Filippo Spriano, Elena Bernasconi, Francesca Guidetti, Laura Carrassa, Roberta Bordone Pittau, Florent Beaufils, Reto Ritschard, Denise Rageot, Alexander Sele, Barbara Dossena, Francesca M Rossi, Antonella Zucchetto, Monica Taborelli, Valter Gattei, Davide Rossi, Anastasios Stathis, Georg Stussi, Massimo Broggini, Matthias P Wymann, Andreas Wicki, Emanuele Zucca, Vladimir Cmiljanovic, Doriano Fabbro, Francesco Bertoni
PURPOSE: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types and pharmacological inhibition of the PI3K/mTOR pathway has shown activity in lymphoma patients. Here, we extensively characterized the in vitro and in vivo activity and the mechanism of action of PQR309 (bimiralisib), a novel oral selective dual PI3K/mTOR inhibitor under clinical evaluation, in preclinical lymphoma models. EXPERIMENTAL DESIGN: This study included preclinical in vitro activity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivo models and primary cells, proteomics and gene expression profiling and comparison with other signaling inhibitors...
October 24, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29045339/blood-pressure-response-to-renal-denervation-is-correlated-with-baseline-blood-pressure-variability-a-patient-level-meta-analysis
#3
Alexandre Persu, Daniel Gordin, Lotte Jacobs, Lutgarde Thijs, Michiel L Bots, Wilko Spiering, Atena Miroslawska, Jonas Spaak, Ján Rosa, Mark R de Jong, Elena Berra, Fadl Elmula M Fadl Elmula, Grégoire Wuerzner, Alison H M Taylor, Agnieszka Olszanecka, Danuta Czarnecka, Patrick B Mark, Michel Burnier, Jean Renkin, Sverre E Kjeldsen, Jiří Widimský, Arif Elvan, Thomas Kahan, Terje K Steigen, Peter J Blankestijn, Ilkka Tikkanen, Jan A Staessen
BACKGROUND: Sympathetic tone is one of the main determinants of blood pressure (BP) variability and treatment-resistant hypertension. The aim of our study was to assess changes in BP variability after renal denervation (RDN). In addition, on an exploratory basis, we investigated whether baseline BP variability predicted the BP changes after RDN. METHODS: We analyzed 24-h BP recordings obtained at baseline and 6 months after RDN in 167 treatment-resistant hypertension patients (40% women; age, 56...
October 16, 2017: Journal of Hypertension
https://www.readbyqxmd.com/read/29040633/prevalence-of-pre-antiretroviral-treatment-drug-resistance-by-gender-age-and-other-factors-in-hiv-infected-individuals-initiating-therapy-in-kenya-2013-2014
#4
Rachel A Silverman, Ingrid A Beck, Catherine Kiptinness, Molly Levine, Ross Milne, Christine J McGrath, Steve Bii, Barbra A Richardson, Grace John-Stewart, Bhavna Chohan, Samah R Sakr, James N Kiarie, Lisa M Frenkel, Michael H Chung
Background: Pre-antiretroviral-treatment drug resistance (PDR) is a predictor of HIV treatment failure. We determined PDR-prevalence and correlates in a Kenyan cohort. Methods: We conducted a cross-sectional analysis of antiretroviral (ARV) treatment-eligible HIV-infected participants in 2013-2014 at three clinics. PDR was defined as ≥2% mutant-frequency in a participant's HIV-quasispecies at pol codons K103N, Y181C, G190A, M184 V, or K65R by oligonucleotide ligation assay...
October 10, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/29035759/the-beliefs-about-voices-questionnaire-revised-a-factor-structure-from-450-participants
#5
Clara Strauss, Kenneth Hugdahl, Flavie Waters, Mark Hayward, Josef J Bless, Liv E Falkenberg, Bodil Kråkvik, Arve Egil Asbjørnsen, Erik Johnsen, Igne Sinkeviciute, Rune A Kroken, Else-Marie Løberg, Neil Thomas
Hallucinated voices are common across psychiatric and non-clinical groups. The predominant cognitive theory about the impact of voices posits that beliefs about voice power ('Omnipotence') and voice intent ('Malevolence'/'Benevolence') play a key role in determining emotional and behavioral reactions. The revised Beliefs about Voices Questionnaire (BAVQ-R) was designed to assess these constructs, together with two styles of responding (Engagement and Resistance). The BAVQ-R is widely used in clinical and research settings, yet it has not received validation of its constructs and factor structure...
October 5, 2017: Psychiatry Research
https://www.readbyqxmd.com/read/28983848/prevalence-of-hiv-1-pre-treatment-drug-resistance-in-a-southern-province-of-iran-2016-2017
#6
Arash Memarnejadian, Hamed Gouklani, Samira Mohammadi, Masoomeh Moosazadeh, Joshua Choi
HIV-1 transmitted drug resistance (TDR) occurs when primary viruses bear drug resistance mutations (DRMs). TDR causes first-line antiretroviral (ARV) therapy (ART) failure and is becoming more pronounced due to the widespread use of ART. With the absence of routine individual-level drug resistance testing, the World Health Organization (WHO) recommends the tracking of TDR mutations and optimizing the first-line ART following pre-treatment drug resistance (PDR) surveys. Here, we report the PDR frequency for the first time in Hormozgan, a southern province of Iran...
October 5, 2017: Archives of Virology
https://www.readbyqxmd.com/read/28970358/xenobiotic-nuclear-receptors-pxr-and-car-regulate-antiretroviral-drug-efflux-transporters-at-the-blood-testis-barrier
#7
Sana-Kay Whyte-Allman, Md Tozammel Hoque, Mohammad-Ali Jenabian, Jean-Pierre Routy, Reina Bendayan
Poor antiretroviral drug (ARV) penetration in the testes could, in part, be due to the presence of ATP-binding cassette membrane-associated drug efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins (MRPs) expressed at the blood-testis barrier (BTB). The functional expression of these transporters is known to be regulated by ligand-activated nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR), in various tissues...
September 28, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28968669/human-immunodeficiency-virus-type-1-drug-resistance-mutations-update
#8
Robert W Shafer
As treatment options coalesce around a smaller number of antiretroviral drugs (ARVs), data are emerging on the drug resistance mutations (DRMs) selected by the most widely used ARVs and on the impact of these DRMs on ARV susceptibility and virological response to first- and later-line treatment regimens. Recent studies have described the DRMs that emerge in patients receiving tenofovir prodrugs, the nonnucleoside reverse transcriptase inhibitors efavirenz and rilpivirine, ritonavir-boosted lopinavir, and the integrase inhibitors raltegravir and elvitegravir...
September 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28856560/ensemble-classifiers-for-predicting-hiv-1-resistance-from-three-rule-based-genotypic-resistance-interpretation-systems
#9
Letícia M Raposo, Flavio F Nobre
Resistance to antiretrovirals (ARVs) is a major problem faced by HIV-infected individuals. Different rule-based algorithms were developed to infer HIV-1 susceptibility to antiretrovirals from genotypic data. However, there is discordance between them, resulting in difficulties for clinical decisions about which treatment to use. Here, we developed ensemble classifiers integrating three interpretation algorithms: Agence Nationale de Recherche sur le SIDA (ANRS), Rega, and the genotypic resistance interpretation system from Stanford HIV Drug Resistance Database (HIVdb)...
August 30, 2017: Journal of Medical Systems
https://www.readbyqxmd.com/read/28810826/improving-fold-resistance-prediction-of-hiv-1-against-protease-and-reverse-transcriptase-inhibitors-using-artificial-neural-networks
#10
Olivier Sheik Amamuddy, Nigel T Bishop, Özlem Tastan Bishop
BACKGROUND: Drug resistance in HIV treatment is still a worldwide problem. Predicting resistance to antiretrovirals (ARVs) before starting any treatment is important. Prediction accuracy is essential, as low-accuracy predictions increase the risk of prescribing sub-optimal drug regimens leading to patients developing resistance sooner. Artificial Neural Networks (ANNs) are a powerful tool that would be able to assist in drug resistance prediction. In this study, we constrained the dataset to subtype B, sacrificing generalizability for a higher predictive performance, and demonstrated that the predictive quality of the ANN regression models have definite improvement for most ARVs...
August 15, 2017: BMC Bioinformatics
https://www.readbyqxmd.com/read/28791972/hcv-co-infection-is-associated-with-metabolic-abnormalities-among-haart-naive-hiv-infected-persons
#11
M A Kuti, J O Akinyemi, B O Ogunbosi, K M Kuti, O A Adesina, O A Awolude, O S Michael, I F Adewole
OBJECTIVES: To determine the metabolic abnormalities among Hepatitis C Virus (HCV) co infected HAART naïve HIV infected persons within the adult ARV clinic of the University College Hospital/University of Ibadan, Ibadan, Nigeria Methods: This was a retrospective study involving the review of clinical records of newly recruited HIV-infected persons in the adult antiretroviral (ARV) clinic over a 12 month period (January - December 2006). Baseline results for fasting plasma glucose (FPG) and fasting lipid profile were retrieved...
July 2017: Nigerian Journal of Clinical Practice
https://www.readbyqxmd.com/read/28753637/collaborative-update-of-a-rule-based-expert-system-for-hiv-1-genotypic-resistance-test-interpretation
#12
Roger Paredes, Philip L Tzou, Gert van Zyl, Geoff Barrow, Ricardo Camacho, Sergio Carmona, Philip M Grant, Ravindra K Gupta, Raph L Hamers, P Richard Harrigan, Michael R Jordan, Rami Kantor, David A Katzenstein, Daniel R Kuritzkes, Frank Maldarelli, Dan Otelea, Carole L Wallis, Jonathan M Schapiro, Robert W Shafer
INTRODUCTION: HIV-1 genotypic resistance test (GRT) interpretation systems (IS) require updates as new studies on HIV-1 drug resistance are published and as treatment guidelines evolve. METHODS: An expert panel was created to provide recommendations for the update of the Stanford HIV Drug Resistance Database (HIVDB) GRT-IS. The panel was polled on the ARVs to be included in a GRT report, and the drug-resistance interpretations associated with 160 drug-resistance mutation (DRM) pattern-ARV combinations...
2017: PloS One
https://www.readbyqxmd.com/read/28741965/cost-effectiveness-of-dolutegravir-abacavir-lamivudine-in-hiv-1-treatment-naive-tn-patients-in-france
#13
Gilles Pialoux, Anne-Geneviève Marcelin, Hélène Cawston, Caroline Guilmet, Laurent Finkielsztejn, Audrey Laurisse, Céline Aubin
BACKGROUND: To evaluate the cost-effectiveness of an integrase inhibitor (INI), dolutegravir (DTG), in combination with abacavir (ABC)/lamivudine (3TC) in France, in treatment-naive (TN) HIV adult patients. METHODS: The ARAMIS microsimulation Markov model, evaluates costs and effects of DTG vs. first-line ARVs options including INIs (raltegravir, elvitegravir/c), protease inhibitors (PIs) (darunavir/r, atazanavir/r, lopinavir/r), non-nucleoside reverse transcriptase inhibitors (efavirenz and rilpivirine)...
July 31, 2017: Expert Review of Pharmacoeconomics & Outcomes Research
https://www.readbyqxmd.com/read/28737291/nucleoside-reverse-transcriptase-inhibitor-reducing-strategies-in-hiv-treatment-assessing-the-evidence
#14
REVIEW
C Orkin, J M Llibre, S Gallien, A Antinori, Gmn Behrens, A Carr
Antiretroviral (ARV) therapy, comprising a backbone of two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) plus another ARV, is the recognized standard of care (SOC), which has helped extend life expectancy in people living with HIV. In a quest to reduce lifelong drug exposure and minimize or avoid the toxicity of NRTIs, "NRTI-reducing" regimens have been investigated. This descriptive review assessing the results of NRTI-reducing strategies from the largest randomized trials focuses on virological efficacy, resistance, regimen safety (in terms of bone mineral density, renal function, lipids and central nervous system function) and simplicity...
July 24, 2017: HIV Medicine
https://www.readbyqxmd.com/read/28710808/the-application-of-physiologically-based-pharmacokinetic-modelling-to-assess-the-impact-of-antiretroviral-mediated-drug-drug-interactions-on-piperaquine-antimalarial-therapy-during-pregnancy
#15
Olusola Olafuyi, Michael Coleman, Raj K S Badhan
Antimalarial therapy during pregnancy poses important safety concerns due to potential teratogenicity and maternal physiological and biochemical changes during gestation. Piperaquine (PQ) has gained interest for use in pregnancy in response to increasing resistance towards sulfadoxine-pyrimethamine in sub-Saharan Africa. Coinfection with HIV is common in many developing countries, however, little is known about the impact of antiretroviral (ARV) mediated drug-drug interaction (DDI) on piperaquine pharmacokinetics during pregnancy...
July 14, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28663582/bet-protein-proteolysis-targeting-chimera-protac-exerts-potent-lethal-activity-against-mantle-cell-lymphoma-cells
#16
B Sun, W Fiskus, Y Qian, K Rajapakshe, K Raina, K G Coleman, A P Crew, A Shen, D T Saenz, C P Mill, A J Nowak, N Jain, L Zhang, M Wang, J D Khoury, C Coarfa, C M Crews, K N Bhalla
Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins and NFkB target genes, which undermines the growth and survival of MCL cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in MCL cells. Unlike BETi, BET-PROTACs (proteolysis-targeting chimera) ARV-825 and ARV-771 (Arvinas, Inc.) recruit and utilize an E3-ubiquitin ligase to effectively degrade BETPs in MCL cells...
June 30, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28649306/decreasing-prevalence-of-transmitted-drug-resistance-among-art-naive-hiv-1-infected-patients-in-iceland-1996-2012
#17
Malik Sallam, Gülşen Özkaya Şahin, Hlynur Indriðason, Joakim Esbjörnsson, Arthur Löve, Anders Widell, Magnus Gottfreðsson, Patrik Medstrand
Introduction: Resistance to antiretroviral drugs can complicate the management of HIV-1 infection and impair control of its spread. The aim of the current study was to investigate the prevalence and transmission of HIV-1 drug resistance among 106 antiretroviral therapy (ART)-naïve patients diagnosed in Iceland (1996-2012). Methods: HIV-1 polymerase sequences were analysed using the Calibrated Population Resistance tool. Domestic spread of transmitted drug resistance (TDR) was investigated through maximum likelihood and Bayesian approaches...
2017: Infection Ecology & Epidemiology
https://www.readbyqxmd.com/read/28627427/efficacy-and-safety-of-a-once-daily-single-tablet-regimen-of-tenofovir-lamivudine-and-efavirenz-assessed-at-144-weeks-among-antiretroviral-na%C3%A3-ve-and-experienced-hiv-1-infected-thai-adults
#18
Anchalee Avihingsanon, Wirach Maek-A-Nantawat, Sivaporn Gatechompol, Vorapot Sapsirisavat, Wanida Thiansanguankul, Jiratchaya Sophonphan, Narujakorn Thammajaruk, Sasiwimol Ubolyam, David M Burger, Kiat Ruxrungtham
OBJECTIVE: To assess the efficacy and safety of a new single-tablet regimen (STR) of tenofovir disoproxil fumarate (TDF) 300mg, lamivudine (3TC) 300mg, and efavirenz (EFV) 600mg in HIV-infected Thai patients. METHODS: This was a prospective study performed for 144 weeks among 51 treatment-naïve patients and 49 experienced patients on separate tablets of TDF, 3TC, and EFV with HIV RNA<50 copies/ml. CD4, HIV RNA, liver and renal function, and lipid profiles were assessed at baseline, weeks 12, 24, and 48, and then every 24 weeks...
June 13, 2017: International Journal of Infectious Diseases: IJID
https://www.readbyqxmd.com/read/28600675/a-novel-capillary-nano-immunoassay-for-assessing-androgen-receptor-splice-variant-7-in-plasma-correlation-with-cd133-antigen-expression-in-circulating-tumor-cells-a-pilot-study-in-prostate-cancer-patients
#19
J L García, R Lozano, I Misiewicz-Krzeminska, J Fernández-Mateos, P Krzeminski, S Alfonso, R A Marcos, R García, F Gómez-Veiga, Á Virseda, M Herrero, D Olmos, J J Cruz-Hernández
PURPOSE: Androgen receptor (AR) splice variant 7 (AR-V7) has been related with both a higher risk of prostate cancer (PC) progression and differential responsiveness to hormonal agents versus chemotherapy. The objective of this study was to investigate the feasibility of a novel capillary nano-immunoassay in assessing AR-V7 in plasma from PC patients. METHODS: Patients with either localized or advanced PC were included in the study. Assessment of AR-V7 in plasma was performed through a capillary nano-immunoassay platform...
November 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/28585361/prevalence-of-hiv-1-transmitted-drug-resistance-in-the-incarcerated-population
#20
J Sapozhnikov, J D Young, M Patel, T D Chiampas, P Vaughn, M E Badowski
OBJECTIVES: The aim of the study was to determine the prevalence of transmitted drug resistance (TDR)-associated mutations among treatment-naïve, incarcerated individuals with HIV-1 infection in the USA as well as the class TDR and antiretroviral (ARV) mutations present at baseline. METHODS: Patients over the age of 18 years were included in the study if they had been diagnosed with HIV infection, if their HIV infection was managed through telemedicine and if they were incarcerated in the State of Illinois Department of Corrections between 10 July 2010 and 29 April 2016...
June 6, 2017: HIV Medicine
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