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integrase inhibitor

Omobolanle J Jesumoroti, Faridoon, Dumisani Mnkandhla, Michelle Isaacs, Heinrich C Hoppe, Rosalyn Klein
In an attempt to identify potential new agents that are active against HIV-1 IN, a series of novel coumarin-3-carbohydrazide derivatives were designed and synthesised. The toxicity profiles of these compounds showed that they were non-toxic to human cells and they exhibited promising anti-HIV-1 IN activities with IC50 values in nM range. Also, an accompanying molecular modeling study showed that the compounds bind to the active pocket of the enzyme.
January 1, 2019: MedChemComm
Emily A Blumberg, Christin C Rogers
These updated guidelines from the Infectious Diseases Community of Practice of the American Society of Transplantation review the management of transplantation in HIV infected individuals. Transplantation has become the standard of care for patients with HIV and end stage kidney or liver disease. Although less data exist for thoracic organ and pancreas transplantation, it is likely that transplantation is also safe and effective for these recipients as well. Despite what is typically a transient decline in CD4+ T lymphocytes, HIV remains well-controlled and infection risks are similar to those of HIV uninfected transplant recipients...
February 17, 2019: Clinical Transplantation
Douglas D Richman, Karissa Huang, Steven M Lada, Xiaoying Sun, Sonia Jain, Marta Massanella, Bryson Menke
Latently infected CD4 lymphocytes preclude cure of HIV infection, even with the most effective antiretroviral therapy. The replication competent latent HIV reservoir has been quantified with the terminal dilution quantitative viral outgrowth assay, which induces virus propagation in CD4+ T cell culture supernatants following cellular activation. Efforts to improve the sensitivity of this inefficient assay have introduced more sensitive p24 ELISA and RNA PCR based endpoints, but these more sensitive endpoints have raised the question whether they are measuring induced replication competent or defective virions...
February 15, 2019: Retrovirology
Lambert Assoumou, Laurence Bocket, Coralie Pallier, Maxime Grude, Rachid Ait-Namane, Jacques Izopet, Stéphanie Raymond, Charlotte Charpentier, Benoit Visseaux, Marc Wirden, Mary-Anne Trabaud, Hélène Le Guillou-Guillemette, Chakib Allaoui, Cécile Henquell, Anne Krivine, Georges Dos Santos, Catherine Delamare, Magali Bouvier-Alias, Brigitte Montes, Virginie Ferre, Anne De Monte, Anne Signori-Schmuck, Anne Maillard, Laurence Morand-Joubert, Camille Tumiotto, Samira Fafi-Kremer, Corinne Amiel, Francis Barin, Stéphanie Marque-Juillet, Laurence Courdavault, Sophie Vallet, Agnès Beby-Defaux, Alexis de Rougemont, Honorine Fenaux, Véronique Avettand-Fenoel, Annick Allardet-Servent, Jean-Christophe Plantier, Gilles Peytavin, Vincent Calvez, Marie-Laure Chaix, Diane Descamps
Objectives: We estimated the prevalence of transmitted-drug-resistance-associated mutations (TDRAMs) in antiretroviral-naive chronically HIV-1-infected patients. Patients and methods: TDRAMs were sought in samples from 660 diagnosed HIV-1-infected individuals in 2015/2016 in 33 HIV clinical centres. Weighted analyses, considering the number of patients followed in each centre, were used to derive representative estimates of the percentage of individuals with TDRAMs...
February 11, 2019: Journal of Antimicrobial Chemotherapy
S Requena, A B Lozano, E Caballero, F García, M C Nieto, R Téllez, J M Fernández, M Trigo, I Rodríguez-Avial, L Martín-Carbonero, P Miralles, V Soriano, C de Mendoza
Background: HIV-2 is a neglected virus despite estimates of 1-2 million people being infected worldwide. The virus is naturally resistant to some antiretrovirals used to treat HIV-1 and therapeutic options are limited for patients with HIV-2. Methods: In this retrospective observational study, we analysed all HIV-2-infected individuals treated with integrase strand transfer inhibitors (INSTIs) recorded in the Spanish HIV-2 cohort. Demographics, treatment modalities, laboratory values, quantitative HIV-2 RNA and CD4 counts as well as drug resistance were analysed...
February 11, 2019: Journal of Antimicrobial Chemotherapy
Hanh Thi Pham, Said Hassounah, Brandon F Keele, Koen K A Van Rompay, Thibault Mesplède
No abstract text is available yet for this article.
February 12, 2019: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Inmaculada Jarrin, Ines Suarez-Garcia, Cristina Moreno, Maria Tasias, Jorge Del Romero, Rosario Palacios, Joaquim Peraire, Miguel Gorgolas, Santiago Moreno
BACKGROUND: We compared time to treatment change (TC), viral suppression (VS) and change in CD4+ T-cell counts of first-line antiretroviral regimens (ART). METHODS: We analyzed HIV treatment-naïve adults from the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) initiating the most commonly used ART regimens from September 2014 to November 2015. We used proportional hazards models on the sub-distribution hazard to estimate sub-distribution hazard ratios (sHR) for time to TC, logistic regression to estimate odds ratios (ORs) for VS (viral load<50 copies/ml), and linear regression to assess mean differences in CD4 changes from ART initiation...
February 12, 2019: Antiviral Therapy
Nisha Chhokar, Sourav Kalra, Monika Chauhan, Anjana Munshi, Raj Kumar
The failure of the Integrase Strand Transfer Inhibitors (INSTIs) due to the mutations occurring at catalytic site of HIV integrase (IN) has led to the design of allosteric integrase inhibitors (ALLINIs). Lens epithelium derived growth factor (LEDGF/p75) is the host cellular cofactor helps chaining IN to the chromatin. The protein-protein interactions (PPIs) were observed at allosteric site (LEDGF/p75 binding domain) between LEDGF/p75 of host cell and IN of virus. In the recent years, many small molecules such as CX04328, CHIBA-3053 and CHI-104 are reported as LEDGF/p75-IN interaction inhibitors (LEDGINs)...
February 8, 2019: Current Topics in Medicinal Chemistry
Myosotys Rodriguez, Jessica Lapierre, Chet Raj Ojha, Shashank Pawitwar, Mohan Kumar Muthu Karuppan, Fatah Kashanchi, Nazira El-Hage
Accelerated neurological disorders are increasingly prominent among the HIV-infected population and are likely driven by the toxicity from long-term use of antiretroviral drugs. We explored potential side effects of antiretroviral drugs in HIV-infected primary human astrocytes and whether opioid co-exposure exacerbates the response. HIV-infected human astrocytes were exposed to the reverse transcriptase inhibitor, emtricitabine, alone or in combination with two protease inhibitors ritonavir and atazanavir (ERA) with and without morphine co-exposure...
February 11, 2019: Journal of Neurovirology
Patcharapong Thangsunan, Sakunna Wongsaipun, Sila Kittiwachana, Nuttee Suree
Development of a highly accurate prediction model for protein-ligand inhibition has been a major challenge in drug discovery. Herein we describe a novel predictive model for the inhibition of HIV-1 integrase (IN)-LEDGF/p75 protein-protein interaction. The model was constructed using energy parameters approximated from molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. Chemometric analysis using partial least squares (PLS) regression revealed that solvent accessible surface area energy (ΔGSASA ) is the major determinant parameter contributing greatly to the prediction accuracy...
February 12, 2019: Journal of Biomolecular Structure & Dynamics
Jing Tang, Ha T Do, Andrew D Huber, Mary C Casey, Karen A Kirby, Daniel J Wilson, Jayakanth Kankanala, Michael A Parniak, Stefan G Sarafianos, Zhengqiang Wang
The pharmacophore of active site inhibitors of human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated RNase H typically entails a flexible linker connecting the chelating core and the hydrophobic aromatics. We report herein that novel 3-hydroxypyrimidine-2,4-dione (HPD) subtypes with a nonflexible C-6 carbonyl linkage exhibited potent and selective biochemical inhibitory profiles with strong RNase H inhibition at low nM, weak to moderate integrase strand transfer (INST) inhibition at low μM, and no to marginal RT polymerase (pol) inhibition up to 10 μM...
February 2, 2019: European Journal of Medicinal Chemistry
Binh Nguyen, Michelle M Foisy, Christine A Hughes
OBJECTIVE: To synthesize data on the pharmacokinetics and safety of dolutegravir and elvitegravir in pregnant women living with HIV. DATA SOURCES: A PubMed, EMBASE, Web of Science, and Google Scholar literature search (January 2010 to December 2018) was performed using the search terms dolutegravir, elvitegravir, women, pregnant*, and HIV. Additional reports were identified from conference abstracts and review of reference lists. STUDY SELECTION AND DATA EXTRACTION: English-language studies reporting pharmacokinetic and/or safety data in pregnant women receiving dolutegravir or elvitegravir/cobicistat were included...
February 10, 2019: Annals of Pharmacotherapy
R Karahoda, M Ceckova, F Staud
In spite of remarkable reduction in the number of children born with HIV due to antiretroviral therapy, concerns remain on the short- and long-term effects of antiretroviral drugs at the feto-placental unit. Cardio- and skeletal myopathies have been reported in children exposed to antiretroviral drugs prenatally. These conditions have also been described in perturbed placental transfer of l-carnitine, an essential co-factor in fatty acid oxidation. Due to limited fetal and placental synthesis, carnitine supply is maintained through the placental carnitine uptake from maternal blood by the organic cation/carnitine transporters OCTN1 and OCTN2 (SLC22A4 and SLC22A5, respectively)...
February 5, 2019: Toxicology and Applied Pharmacology
Jordi Navarro, José Ramón Santos, Ana Silva, Joaquin Burgos, Vicenç Falcó, Esteban Ribera, Arkaitz Imaz, Adrian Curran
STUDY OBJECTIVE: Dual therapy with once-daily dolutegravir (DTG) plus boosted darunavir (DRV/b) may be a suitable and effective strategy with a high genetic barrier to resistance in human immunodeficiency virus (HIV)-infected patients. Our aim was to evaluate the effectiveness of DTG plus DRV/b (DTG+DRV/b) as a switch strategy in HIV-infected patients, irrespective of their history of virologic failure (VF). DESIGN: Multicenter, retrospective cohort study. SETTING: HIV outpatient treatment clinics at three university hospitals in Spain...
February 5, 2019: Pharmacotherapy
Antonella d'Arminio Monforte, Alessandro Cozzi-Lepri, Antonio Di Biagio, Giulia Marchetti, Sergio Lo Caputo, Stefano Rusconi, Nicola Gianotti, Valentina Mazzotta, Giovanni Mazzarello, Andrea Costantini, Antonella Castagna, Andrea Antinori
Objectives: To evaluate the durability of three integrase strand transfer inhibitors (INSTIs) and two NRTIs in ART-naive individuals. Methods: The study design was observational. Patients were HIV-positive, ART-naive subjects starting raltegravir, elvitegravir/cobicistat or dolutegravir with two NRTIs. The primary endpoint was time to treatment failure, i.e. occurrence of virological failure (first of two consecutive plasma HIV RNAs  ≥200 copies/mL after 24 weeks) or INSTI discontinuation for any reason apart from simplification...
January 29, 2019: Journal of Antimicrobial Chemotherapy
Hanh Thi Pham, Thibault Mesplède
Current antiretroviral therapy is more effective and simpler than in previous times due to the development of new drugs with improved pharmacokinetic and pharmacodynamic profiles and the advent of single pill regimens with low toxicity that facilitate long-term adherence. The recent approval of the novel potent integrase strand-transfer inhibitor bictegravir (BIC) co-formulated with emtricitabine (FTC) and tenofovir alafenamide (TAF) in a fixed daily dose pill, B/F/TAF, adds to the list of single-tablet regimens available to treat HIV infection...
January 30, 2019: Expert Opinion on Pharmacotherapy
J M Llibre, A Montoliu, J M Miró, P Domingo, M Riera, J Tiraboschi, A Curran, F Homar, J Ambrosioni, N Abdulghani, L Force, J Peraire, J Casabona
OBJECTIVES: The aim of the study was to assess the rates of discontinuation of integrase inhibitor regimens because of any neuropsychiatric adverse event (NPAE) and the factors associated with discontinuation. METHODS: A population-based, prospective, multicentre cohort study was carried out. Treatment-naïve subjects starting therapy with a regimen containing integrase inhibitors, or those switching to such a regimen, with plasma HIV-1 RNA < 50 HIV-1 RNA copies/mL in 14 hospitals in Catalonia or the Balearic Islands (Spain) were included in the study...
March 2019: HIV Medicine
Liwen Sun, Lei Jia, Yongjian Liu, Jingwan Han, Jingyun Li, Hanping Li, Lin Li
There has been a rapid increasing of HIV cases in the men who have sex with men (MSM) population in China. This study enrolled 223 HIV-1 sero-positive drug-na?ve patients from Shijingshan district in Beijing MSM population. The full-length gag, pol, and partial env gene sequences were amplified. Subsequently, genetic characterization and transmission of drug-resistance of HIV-1 were examined. Many stains, including CRF01_AE (48.25%), CRF07_BC (31.47%), subtype B (4.9%), 0107 (6.29%), 01B (1.40%), 01BC (2.10%), 55_01B (1...
January 25, 2019: AIDS Research and Human Retroviruses
Paula Debroy, Myung Sim, Kristine M Erlandson, Julian Falutz, Carla M Prado, Todd T Brown, Giovanni Guaraldi, Jordan E Lake
Objectives: Although weight gain on ART is common, the long-term trajectory of and factors affecting increases in fat mass in people living with HIV are not well described. Methods: Men and women living with HIV in the Modena HIV Metabolic Clinic underwent DXA scans every 6-12 months for up to 10 years (median 4.6 years). Regression modelling in both combined and sex-stratified models determined changes in and clinical factors significantly associated with trunk and leg fat mass over the study period...
January 18, 2019: Journal of Antimicrobial Chemotherapy
Maninder Kaur, Ravindra K Rawal, Goutam Rath, Amit K Goyal
HIV-1 integrase, a member of a polynucleotidyl transferases superfamily, catalyze the insertion of the viral DNA into the genome of host cells. It has emerged as a potential target for developing anti-HIV agents. In last two decades, number of integrase inhibitors has been developed as potential anti-HIV therapeutics. Several integrase inhibitors have reached later stages of clinical trials including S-1360, L870,810, L870,812 and BMS-707035. Into the bargain, Raltegravir, Elvitegravir and Dolutegravir have been approved by FDA as anti-HIV agents...
January 19, 2019: Current Topics in Medicinal Chemistry
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