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integrase inhibitor

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 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 (Mn++ ), and also provided important insight into a potential inhibitor binding mode...
July 30, 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
Fabien 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...
July 29, 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
Xue Zhi Zhao, Mathieu Métifiot, Evgeny Kiselev, Jacques J Kessl, Kasthuraiah Maddali, Christophe Marchand, Mamuka Kvaratskhelia, Yves Pommier, Terrence R Burke
HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity to these inhibitors underlies efforts to derive agents that antagonize IN function by alternate mechanisms. Integrase along with the 96-residue multifunctional accessory protein, viral protein R (Vpr), are both components of the HIV-1 pre-integration complex (PIC)...
July 26, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Matthew R Pennington, Ian E H Voorhees, Heather M Callaway, Shannon D Dehghanpir, Joel D Baines, Colin R Parrish, Gerlinde R Van de Walle
Alphaherpesvirus-associated ocular infections in humans, caused by human alphaherpesvirus 1 (HHV-1), remain challenging to treat due to the frequency of drug application required and the potential for the selection of drug resistant viruses. Repurposing on-the-market drugs is a viable strategy to accelerate the pace of drug development. It has been reported that the human immunodeficiency virus (HIV) integrase inhibitor raltegravir inhibits HHV-1 replication by targeting the DNA polymerase accessory factor and limits terminase-mediated genome cleavage of the human betaherpesvirus 5 (HHV-5)...
July 25, 2018: Journal of Virology
Michael S Saag, Constance A Benson, Rajesh T Gandhi, Jennifer F Hoy, Raphael J Landovitz, Michael J Mugavero, Paul E Sax, Davey M Smith, Melanie A Thompson, Susan P Buchbinder, Carlos Del Rio, Joseph J Eron, Gerd Fätkenheuer, Huldrych F Günthard, Jean-Michel Molina, Donna M Jacobsen, Paul A Volberding
Importance: Antiretroviral therapy (ART) is the cornerstone of prevention and management of HIV infection. Objective: To evaluate new data and treatments and incorporate this information into updated recommendations for initiating therapy, monitoring individuals starting therapy, changing regimens, and preventing HIV infection for individuals at risk. Evidence Review: New evidence collected since the International Antiviral Society-USA 2016 recommendations via monthly PubMed and EMBASE literature searches up to April 2018; data presented at peer-reviewed scientific conferences...
July 24, 2018: JAMA: the Journal of the American Medical Association
Purvi Shah, Dharav Naik, Nisha Jariwala, Deepali Bhadane, Sanjay Kumar, Smita Kulkarni, Kamlesh Kumar Bhutani, Inder Pal Singh
A plenty of natural products and synthetic derivatives containing quinoline moiety have been reported to possess various pharmacological activities. Quinolines such as 2-styrylquinolines and 8-hydroxyquinolines are extensively studied for their anti-HIV-1 activity and found to act mainly through HIV-1 integrase enzyme inhibition. In continuation of our efforts to search for newer anti-HIV-1 molecules, thirty-one quinoline derivatives with different linkers to ancillary phenyl ring were synthesized and evaluated for in vitro anti-HIV-1 activity using TZM-bl assays...
July 17, 2018: Bioorganic Chemistry
Lei Wang, Jing Tang, Andrew D Huber, Mary C Casey, Karen A Kirby, Daniel J Wilson, Jayakanth Kankanala, Michael A Parniak, Stefan G Sarafianos, Zhengqiang Wang
Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays, analogues of this new subtype potently inhibited RT RNase H in low nanomolar range without inhibiting RT polymerase (pol) or integrase strand transfer (INST) at the highest concentrations tested...
July 17, 2018: European Journal of Medicinal Chemistry
Lei Wang, Jing Tang, Andrew D Huber, Mary C Casey, Karen A Kirby, Daniel J Wilson, Jayakanth Kankanala, Jiashu Xie, Michael A Parniak, Stefan G Sarafianos, Zhengqiang Wang
Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not targeted by current drugs. Although a few chemotypes have been reported to inhibit HIV RNase H in biochemical assays, their general lack of significant antiviral activity in cell culture necessitates continued efforts in identifying highly potent RNase H inhibitors to confer antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-arylthio subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype...
July 17, 2018: European Journal of Medicinal Chemistry
Jeffrey Laurence, Sonia Elhadad, Jasimuddin Ahamed
HIV infection is a risk factor for cardiovascular disease (CVD). This risk is accentuated by certain combination antiretroviral therapies (cARTs), independent of their effects on lipid metabolism and insulin sensitivity. We sought to define potential mechanisms for this association through systematic review of clinical and preclinical studies of CVD in the setting of HIV/cART from the English language literature from 1989 to March 2018. We used PubMed, Web of Knowledge and Google Scholar, and conference abstracts for the years 2015-March 2018...
2018: Open Heart
Robert A Smith, Vincent H Wu, Christopher G Zavala, Dana N Raugi, Selly Ba, Moussa Seydi, Geoffrey S Gottlieb
We examined the antiviral activity of the integrase inhibitor (INI) cabotegravir against HIV-2 isolates from INI-naïve individuals. HIV-2 was sensitive to cabotegravir in both single-cycle and spreading infection assays, with EC50 values in the low to sub-nanomolar range; comparable results were obtained for HIV-1 in both assay formats. Our findings suggest that cabotegravir should be evaluated in clinical trials as a potential option for ART and PrEP in HIV-2-prevalent settings.
July 16, 2018: Antimicrobial Agents and Chemotherapy
Wendy W Zhang, Peter K Cheung, Natalia Oliviera, Marjorie A Robbins, P Richard Harrigan, Aniqa Shahid
Bictegravir (BIC) and cabotegravir (CAB) are the latest available HIV integrase inhibitors in clinical trials. The combination of major integrase inhibitor substitutions G140S/Q148H has been shown to confer high-level resistance to the approved integrase inhibitors raltegravir (RAL) and elvitegravir (EVG) but not necessarily dolutegravir (DTG). We assayed recombinant viruses made from patient-derived RNA extracts for resistance phenotype for a panel of viruses containing G140S/Q148H with additional accessory substitutions...
July 16, 2018: Journal of Infectious Diseases
Nicola Gianotti, Laura Galli, Nadia Galizzi, Marco Ripa, Andrea Andolina, Silvia Nozza, Vincenzo Spagnuolo, Andrea Poli, Adriano Lazzarin, Antonella Castagna
PURPOSE: To investigate if starting antiretroviral therapy (ART) with diverse regimens, differently affects the time spent with residual viremia (RV) after achieving <50 HIV-RNA copies/mL. METHODS: Retrospective cohort study on prospectively followed HIV-infected patients who started ART with a boosted protease inhibitors (PIs/r)-, a non-nucleoside reverse transcriptase inhibitor (NNRTIs)-, an integrase inhibitor (InSTI)-based triple regimens or with >3 drugs...
July 13, 2018: International Journal of Antimicrobial Agents
Elżbieta Jabłonowska, Piotr Pulik, Anna Kalinowska, Jacek Gąsiorowski, Miłosz Parczewski, Monika Bociąga-Jasik, Elżbieta Mularska, Łukasz Pulik, Ewa Siwak, Kamila Wójcik
Introduction: The aim of the study was to present the experience of Polish centers regarding dual therapy based on the integrase inhibitor raltegravir (RAL) and ritonavir-boosted protease inhibitors (PI/r) for treating treatment-naïve and -experienced HIV-infected patients. Material and methods: The paper concerns a retrospective multicenter study. The medical databases of six main Polish HIV centers from January 2009 to December 2014 were analyzed for the use of combined antiretroviral treatment consisting of RAL + PI/r...
June 2018: Archives of Medical Science: AMS
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