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integrase inhibitor

Ronit Dalmat, Negar Makhsous, Gregory Pepper, Amalia Magaret, Keith R Jerome, Anna Wald, Alexander L Greninger
HIV drug resistance genotyping is a critical tool in the clinical management of HIV infections. Although resistance genotyping has traditionally been conducted using Sanger sequencing, next-generation sequencing (NGS) is emerging as a powerful tool due to its ability to detect lower frequency alleles. However, the clinical value added from NGS approaches to antiviral resistance testing remains to be demonstrated. We compared the variant detection capacity of NGS versus Sanger sequencing methods for resistance genotyping in 144 drug resistance tests (105 protease-reverse transcriptase tests and 39 integrase tests) submitted to our clinical virology laboratory over a four-month period in 2016 for Sanger-based HIV drug resistance testing...
October 10, 2018: Journal of Clinical Microbiology
Theodoros Karantanos, Lisa Rooper, Youme Kang, Cheng Ting Lin, Pawla Wenga, Sarah Sagorsky, Josh Lauring, Hyunseok Kang
Integrase interactor 1 (INI-1)-deficient carcinoma is a rare cancer characterized by the loss of the SWItch/Sucrose Non-Fermentable-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 gene ( SMARCB1 ) and tends to follow an aggressive clinical course. There is no currently available standard therapy option, although a few promising treatment strategies, including enhancer of zeste homolog 2 (EZH2) inhibition, are under active investigation. This report describes a 30-year-old woman with INI-1-deficient carcinoma who progressed on combination chemotherapy and an EZH2 inhibitor...
October 8, 2018: Oncologist
Parul Patel, Susan L Ford, Yu Lou, Kalpana Bakshi, Allan R Tenorio, Zhiping Zhang, Rennan Pan, William Spreen
Cabotegravir is an integrase inhibitor in clinical development for the treatment and prevention of HIV infection using oral tablets for short-term, lead-in use before subsequent administration of a long-acting injectable formulation. This phase 1, single-center, randomized, 2 × 2 crossover study evaluated the effect of a high-fat meal on the pharmacokinetics (PK) of oral cabotegravir. Healthy adults received oral cabotegravir 30 mg as a single dose on 2 separate occasions, either after fasting or following a high-fat meal (∼53% fat, ∼870 kcal)...
September 19, 2018: Clinical Pharmacology in Drug Development
Wooyong Jeong, In Young Jung, Heun Choi, Jung Ho Kim, Hye Seong, Jin Young Ahn, Su Jin Jeong, Nam Su Ku, June Myung Kim, Jun Yong Choi
Updated guidelines for the treatment of antiretroviral therapy (ART)-negative patients with human immunodeficiency virus (HIV) recommend integrase strand transfer inhibitor (INSTI)-based regimens. HIV patients are tested for resistance to antiretrovirals, and the reported prevalence of transmitted INSTI resistance remains rare worldwide. However, no data related to INSTI resistance in Korean HIV patients have been reported. We aimed to determine the prevalence of INSTI resistance-related mutations in South Korea...
September 19, 2018: AIDS Research and Human Retroviruses
Kylie M Wagstaff, Stephen Headey, Sushama Telwatte, David Tyssen, Anna C Hearps, David R Thomas, Gilda Tachedjian, David A Jans
Human immunodeficiency virus (HIV) continues to be a major contributor to morbidity and mortality worldwide, particularly in developing nations where high cost and logistical issues severely limit the use of current HIV therapeutics. This, combined HIV's high propensity to develop resistance, means that new antiviral agents against novel targets are still urgently required. We previously identified novel anti-HIV agents directed against the nuclear import of the HIV integrase (IN) protein, which plays critical roles in the HIV lifecycle inside the cell nucleus, as well as in transporting the HIV preintegration complex (PIC) into the nucleus...
September 14, 2018: Cellular Microbiology
Sibes Bera, Krishan K Pandey, Hideki Aihara, Duane P Grandgenett
Retrovirus integrase (IN) catalyzes the concerted integration of linear viral DNA ends into chromosomes. The atomic structures of five different retrovirus IN-DNA complexes, termed intasomes, have revealed varying IN subunit compositions ranging from tetramers to octamers, dodecamers, and hexadecamers. Intasomes containing two IN-associated viral DNA ends capable of concerted integration are termed stable synaptic complexes (SSC), whereas those formed with a viral/target DNA substrate representing the product of strand-transfer reactions are strand-transfer complexes (STC)...
September 5, 2018: Journal of Biological Chemistry
Rita Melo, Agostinho Lemos, António J Preto, Beatriz Bueschell, Pedro Matos-Filipe, Carlos Barreto, José G Almeida, Rúben D M Silva, João D G Correia, Irina Moreira
Paediatric Acquired ImmunoDeficiency Syndrome (AIDS) is a life-threatening and infectious disease in which the Human Immunodeficiency Virus (HIV) is mainly transmitted through Mother-To-Child Transmission (MTCT) during pregnancy, labour and delivery, or breastfeeding. This review provides an overview of the distinct therapeutic alternatives to abolish the systemic viral replication in paediatric HIV-1 infection. Numerous classes of antiretroviral agents have emerged as therapeutic tools for downregulation of different steps in the HIV replication process...
September 4, 2018: Current Medicinal Chemistry
Hortensia Álvarez, Ana Mariño, Nieves Valcarce, Jesús García-González, Helena Díaz-Cambre, Josep M Llibre
INTRODUCTION: Data are lacking regarding overdose of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (E/C/F/TAF). MATERIAL AND METHODS: We present the first report of suicidal attempt with E/C/F/TAF in a Human Immunodeficiency Virus-infected subject. RESULTS: A reversible acute renal failure with no proximal tubulopathy and neuropsychiatric issues are discussed. E/C/F/TAF withdrawal resulted in favourable renal and neuropsychiatric outcomes...
August 25, 2018: Infection
Robin M Nance, J A Chris Delaney, Jane M Simoni, Ira B Wilson, Kenneth H Mayer, Bridget M Whitney, Frances M Aunon, Steven A Safren, Michael J Mugavero, W Christopher Mathews, Katerina A Christopoulos, Joseph J Eron, Sonia Napravnik, Richard D Moore, Benigno Rodriguez, Bryan Lau, Rob J Fredericksen, Michael S Saag, Mari M Kitahata, Heidi M Crane
Background: Because HIV viral suppression is essential for optimal outcomes and prevention efforts, understanding trends and predictors is imperative to inform public health policy. Objective: To evaluate viral suppression trends in people living with HIV (PLWH), including the relationship of associated factors, such as demographic characteristics and integrase strand transfer inhibitor (ISTI) use. Design: Longitudinal observational cohort study...
August 21, 2018: Annals of Internal Medicine
Wouter A van der Heijden, Reinout van Crevel, Ph G De Groot, Rolf T Urbanus, Hans J P M Koenen, Marjolein Bosch, Monique Keuter, Andre J van der Ven, Quirijn de Mast
OBJECTIVE: Platelet hyper-reactivity and increased platelet-monocyte aggregation (PMA) are associated with increased cardiovascular risk and inflammation. In a previous cross-sectional study, individuals using a raltegravir (RAL)-based regimen were found to have reduced platelet reactivity and PMA compared to other antiretroviral regimens. Our aim was to investigate whether switching from a non-integrase inhibitor regimen to a RAL-based regimen reduces platelet reactivity or PMA. DESIGN: An investigator initiated, single-centre, prospective randomised, open-label, blinded endpoint trial...
August 20, 2018: AIDS
Hung-Chin Tsai, I-Tzu Chen, Susan Shin-Jung Lee, Yao-Shen Chen
Purpose: Sparse data are available on the prevalence of resistance among HIV-1-infected patients with virological failure to a single-tablet regimen (STR). This study aimed to evaluate the prevalence of HIV genotypic drug resistance in HIV-1-infected patients with virological failure to STRs in southern Taiwan. Patients and methods: This retrospective study investigated drug resistance in patients with virological failure to STR from January 2016 to September 2017...
2018: Infection and Drug Resistance
Maureen Oliveira, Ruxandra-Ilinca Ibanescu, Kaitlin Anstett, Thibault Mésplède, Jean-Pierre Routy, Marjorie A Robbins, Bluma G Brenner
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are recommended for first-line HIV therapy based on their relatively high genetic barrier to resistance. Although raltegravir (RAL) and elvitegravir (EVG) resistance profiles are well-characterized, resistance patterns for dolutegravir (DTG), bictegravir (BIC), and cabotegravir (CAB) remain largely unknown. Here, in vitro drug selections compared the development of resistance to DTG, BIC, CAB, EVG and RAL using clinical isolates from treatment-naïve primary HIV infection (PHI) cohort participants (n = 12), and pNL4...
August 17, 2018: Retrovirology
Leonard Rogers, Adetayo E Obasa, Graeme B Jacobs, Stefan G Sarafianos, Anders Sönnerborg, Ujjwal Neogi, Kamalendra Singh
Human immunodeficiency virus type 1 (HIV-1) integrase (IN) integrates viral DNA into the host genome using its 3'-end processing and strand-transfer activities. Due to the importance of HIV-1 IN, it is targeted by the newest class of approved drugs known as integrase strand transfer inhibitors (INSTIs). INSTIs are efficient in maintaining low viral load; however, as with other approved antivirals, resistance mutations emerge in patients receiving INSTI-containing therapy. As INSTIs are becoming increasingly accessible worldwide, it is important to understand the mechanism(s) of INSTI susceptibility...
2018: Frontiers in Microbiology
Caroline H Shiboski, Tzy-Jyun Yao, Jonathan S Russell, Mark I Ryder, Russell B Van Dyke, George R Seage, Anna-Barbara Moscicki
OBJECTIVES: This study explores the association between combination antiretroviral therapy (cART) and oral health outcomes (dental and periodontal) among perinatally HIV-infected (PHIV) youth. METHODS: We conducted a cross-sectional study of oral health among PHIV youth participating in the Oral Health substudy of Pediatric HIV/AIDS Cohort Study (PHACS). Dentists at research sites were trained/calibrated on how to perform a standardized oral mucosal, dental, and periodontal examination...
August 8, 2018: AIDS
Michael H Cynamon, Ernest N Damianopoulos
To model the ART (antiretroviral therapeutic) drug interaction with the HIV-1 virus, a two-domain model is proposed that separates HIV-1 into a stable non-proliferating domain where the virus is integrated into the host resting memory CD4+ t cells; and, a second domain where the virus is in the blood in a rapidly reproductive state. ART inhibits blood HIV-1 reproduction levels sufficient to prevent progression to the AIDS end-stage, the principal goal of ART. There are 25 FDA approved antiretroviral drugs toward this goal grouped into 6 classes: NRTIs (nucleoside/nucleotide inhibitors), NNRTIs (non-nucleoside/nucleotide inhibitors), PIs (protease inhibitors), FIs (fusion inhibitors), CCR5s (chemokine cell receptor 5 antagonists), and INSTIs (integrase inhibitors)...
August 3, 2018: AIDS Research and Human Retroviruses
Lucia Taramasso, Paola Tatarelli, Elena Ricci, Giordano Madeddu, Barbara Menzaghi, Nicola Squillace, Giuseppe Vittorio De Socio, Canio Martinelli, Roberto Gulminetti, Paolo Maggi, Giancarlo Orofino, Francesca Vichi, Antonio Di Biagio, Paolo Bonfanti
BACKGROUND: Dyslipidemia represents a significant non-infectious comorbidity among people living with HIV. The aim of this study is to evaluate the impact on lipid profile of switches from an efavirenz (EFV) or protease inhibitor/ritonavir (PI/r)-based regimen to a rilpivirine (RPV) or a once-daily integrase inhibitor-based regimen. METHODS: We analyzed data from SCOLTA prospective database. All patients with HIV-RNA < 50 copies/ml in therapy with two NRTI + EFV or PI/r were included if they switched from EFV to dolutegravir (group EFV-DTG), elvitegravir (EFV-EVG), or RPV (EFV-RPV) and from PI/r to DTG (PI/r-DTG), PI/r to EVG (PI/r-EVG), or PI/r to RPV (PI/r-RPV)...
July 31, 2018: BMC Infectious Diseases
Jennifer T Miller, Haiyan Zhao, Takashi Masaoka, Brittany Varnado, Elena M Cornejo Castro, Vickie A Marshall, Kaivon Kouhestani, Anna Y Lynn, Keith E Aron, Anqi Xia, John A Beutler, Danielle R Hirsch, Liang Tang, Denise Whitby, Ryan P Murelli, Stuart F J Le Grice
Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma, belongs to the Herpesviridae family, whose members employ a multicomponent terminase to resolve nonparametric viral DNA into genome-length units prior to their packaging. Homology modeling of the ORF29 C-terminal nuclease domain (pORF29C) and bacteriophage Sf6 gp2 have suggested an active site clustered with four acidic residues, D476 , E550 , D661 , and D662 , that collectively sequester the catalytic divalent metal (Mn2+ ) and also provided important insight into a potential inhibitor binding mode...
October 2018: Antimicrobial Agents and Chemotherapy
D B Fofana, M d'Almeida, S Lambert-Niclot, G Peytavin, P M Girard, B Lafia, L Zohoun-Guidigbi, R K Keke, C Soulie, A G Marcelin, L Morand-Joubert
Background: In Africa a high percentage of HIV-infected children continue to experience HIV treatment failure despite enormous progress. In Benin (West Africa), there are currently no data on HIV drug resistance at failure in paediatric populations. Objectives: To assess the frequency and patterns of HIV drug resistance among children with virological ART failures. Methods: Dried blood spots from 62 HIV-infected children with virological failure were collected at the paediatric clinic of the National Hospital Center in Cotonou for genotyping and plasma drug concentration determination...
July 27, 2018: Journal of Antimicrobial Chemotherapy
F Fily, E Ayikobua, D Ssemwanga, S Nicholas, P Kaleebu, C Delaugerre, E Pasquier, I Amoros Quiles, S Balkan, B Schramm
OBJECTIVES: The number of patients on second-line antiretroviral therapy is growing, but data on HIV drug resistance patterns at failure in resource-constrained settings are scarce. We aimed to describe drug resistance and investigate the factors associated with extensive resistance to nucleoside/nucleotide reverse transcriptase inhibitors (NRTI), in patients failing second-line therapy in the HIV outpatient clinic at Arua Regional Referral Hospital, Uganda. METHODS: We included patients who failed on second-line therapy (two consecutive viral loads ≥1000 copies/mm3 by SAMBA-1 point-of-care test) and who had a drug resistance test performed between September 2014 and March 2017...
October 2018: Tropical Medicine & International Health: TM & IH
Huldrych F Günthard, Vincent Calvez, Roger Paredes, Deenan Pillay, Robert W Shafer, Annemarie M Wensing, Donna M Jacobsen, Douglas D Richman
Background: Contemporary antiretroviral therapies (ART) and management strategies have diminished both human immunodeficiency virus (HIV) treatment failure and the acquired resistance to drugs in resource-rich regions, but transmission of drug-resistant viruses has not similarly decreased. In low- and middle-income regions, ART roll-out has improved outcomes, but has resulted in increasing acquired and transmitted resistances. Our objective was to review resistance to ART drugs and methods to detect it, and to provide updated recommendations for testing and monitoring for drug resistance in HIV-infected individuals...
July 20, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
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