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Nicholas T Funderburg, Grace A McComsey, Manjusha Kulkarni, Tammy Bannerman, Jessica Mantini, Bernadette Thornton, Hui C Liu, Yafeng Zhang, Qinghua Song, Liang Fang, Jason Dinoso, Andrew Cheng, Scott McCallister, Marshall W Fordyce, Moupali Das
BACKGROUND: Initiation of antiretroviral therapy (ART) and subsequent virologic suppression reduces immune activation and systemic inflammation. METHODS: We examined longitudinal changes in biomarkers of monocyte activation (sCD14, sCD163), and systemic (IL-6, hsCRP, sTNFR-I and D-dimer) and vascular (Lp-PLA2) inflammation in a subgroup (N=100 per arm) of participants enrolled in a randomized, placebo-controlled trial comparing elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF; TAF) to E/C/F/tenofovir disoproxil fumarate (E/C/F/TDF; TDF) in treatment-naïve adults...
October 11, 2016: EBioMedicine
Eva Heger, Alexandra Theis, Klaus Remmel, Hauke Walter, Alejandro Pironti, Elena Knops, Veronica Di Cristanziano, Björn Jensen, Stefan Esser, Rolf Kaiser, Nadine Lübke
Phenotypic resistance analysis is an indispensable method for determination of HIV-1 resistance and cross-resistance to novel drug compounds. Since integrase inhibitors are essential components of recent antiretroviral combination therapies, phenotypic resistance data, in conjunction with the corresponding genotypes, are needed for improving rules-based and data-driven tools for resistance prediction, such as HIV-Grade and geno2pheno[integrase]. For generation of phenotypic resistance data to recent integrase inhibitors, a recombinant phenotypic integrase susceptibility assay was established...
October 10, 2016: Journal of Virological Methods
F Raffi, S Esser, G Nunnari, I Pérez-Valero, L Waters
In an era when most individuals with treated HIV infection can expect to live into old age, clinicians should proactively review their patients' current and future treatment needs and challenges. Clinical guidelines acknowledge that, in the setting of virological suppression, treatment switch may yield benefits in terms of tolerability, regimen simplification, adherence, convenience and long-term health considerations, particularly in the context of ageing. In this paper, we review evidence from six key clinical studies on switching virologically suppressed patients to regimens based on integrase strand transfer inhibitors (INSTIs), the antiretroviral class increasingly preferred as initial therapy in clinical guidelines...
October 2016: HIV Medicine
Jun Yong Choi, Somnuek Sungkanuparph, Thanomsak Anekthananon, Paul Sax, Edwin DeJesus, Howard Edelstein, Mark Nelson, Jennifer DeMorin, Hui C Liu, Raji Swamy, Joonwoo Bahn, Sunjin Hwang, Sang Youn Yang, Christopher Ng, David Piontkowsky
The efficacy and safety of a single tablet regimen (STR) of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) were analyzed in Phase 3 clinical trials in antiretroviral therapy (ART)-naïve and ART-experienced Asian subjects infected with human immunodeficiency virus (HIV)-1. Studies GS-US-236-102 and GS-US-236-103 were randomized, double-blind, placebo-controlled, 144-week studies conducted in ART-naïve subjects, comparing E/C/F/TDF versus efavirenz (EFV)/F/TDF or ritonavir-boosted atazanavir (ATV+RTV) plus emtricitabine/tenofovir DF (F/TDF), respectively...
September 2016: Infection & Chemotherapy
Janani Varadarajan, Mary Jane McWilliams, Bryan T Mott, Craig J Thomas, Steven J Smith, Stephen H Hughes
BACKGROUND: HIV-1 integrase is the target for three FDA-approved drugs, raltegravir, elvitegravir, and dolutegravir. All three drugs bind at the active site of integrase and block the strand transfer step of integration. We previously showed that sub-optimal doses of the anti-HIV drug raltegravir can cause aberrant HIV integrations that are accompanied by a variety of deletions, duplications, insertions and inversions of the adjacent host sequences. RESULTS: We show here that a second drug, elvitegravir, also causes similar aberrant integrations...
September 29, 2016: Retrovirology
Frank A Post, Pablo Tebas, Amanda Clarke, Laurent Cotte, William Short, Michael E Abram, Shuping Jiang, Andrew Cheng, Moupali Das, Marshall W Fordyce
Tenofovir disoproxil fumarate (TDF) is associated with renal and bone toxicity. In a single-arm, open-label study of 242 virologically suppressed, HIV-infected participants with creatinine clearance 30-69 mL/min who switched to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF), participants had stable creatinine clearance, significant and durable improvements in proteinuria, albuminuria, and tubular proteinuria (P < .001), and significant increases in hip and spine bone mineral density through 96 weeks (P < ...
September 23, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Manuel Tsiang, Gregg S Jones, Joshua Goldsmith, Andrew Mulato, Derek Hansen, Elaine Kan, Luong Tsai, Rujuta A Bam, George Stepan, Kirsten M Stray, Anita Niedziela-Majka, Stephen R Yant, Helen Yu, George Kukolj, Tomas Cihlar, Scott Lazerwith, Kirsten L White, Haolun Jin
Bictegravir (BIC; GS-9883), a novel potent, once-daily, unboosted inhibitor of HIV-1 integrase (IN) specifically targets IN strand transfer activity (IC50 = 7.5 ± 0.3 nM) and HIV-1 integration in cells. BIC exhibits potent and selective in vitro antiretroviral activity in both T-cell lines and primary human T-lymphocytes with EC50 values ranging from 1.5 to 2.4 nM and selectivity indices up to 8800 relative to cytotoxicity. BIC exhibits synergistic in vitro antiviral effects in pairwise combinations with tenofovir alafenamide, emtricitabine or darunavir and maintains potent antiviral activity against HIV-1 variants resistant to other classes of antiretrovirals...
September 19, 2016: Antimicrobial Agents and Chemotherapy
Zhang Dawei, He Hongqiu, Liu Mengmeng, Meng Zhixia, Guo Shunxing
HIV-1 integrase (IN) plays an essential role in viral replication and thus serves as an important target for chemotherapeutic intervention against HIV-1 infection. However, the current three clinical IN inhibitors, raltegravir, elvitegravir and dolutegravir share the same inhibitory mechanism, resulting in a common clinical resistance profile which have emerged in infected patients receiving treatment. Therefore, it is important to develop small molecule inhibitors that impair IN function with distinct mechanisms of action...
2016: Scientific Reports
J Ambrosioni, D Nicolás, C Manzardo, F Agüero, J L Blanco, M M Mosquera, J Peñafiel, J M Gatell, M A Marcos, J M Miró
OBJECTIVES: The most recent guidelines suggest using integrase strand-transfer inhibitors (InSTIs) as the preferred antiretroviral regimens for naive HIV-infected individuals. However, resistance to InSTIs is not monitored in many centres at baseline. This study aimed to evaluate the prevalence of InSTI resistance substitutions in newly diagnosed patients with acute/recent HIV infection. METHODS: Genotypic drug resistance tests were performed in all consecutive patients prospectively enrolled with a documented infection of <6 months, from 12 May 2015 to 12 May 2016...
September 13, 2016: Journal of Antimicrobial Chemotherapy
Junjun Jiang, Xi Xu, Wenqin Guo, Jinming Su, Jiegang Huang, Bingyu Liang, Hui Chen, Ning Zang, Yanyan Liao, Li Ye, Hao Liang
BACKGROUND: The first-generation integrase inhibitors (INIs) raltegravir (RAL) and elvitegravir (EVG) have shown efficacy against HIV infection, but they have the limitations of once-more daily dosing and extensive cross-resistance. Dolutegravir (DTG, S/GSK1349572), a second-generation drug that overcomes such shortcomings, is under spotlight. The purpose of this study is to review the evidence for DTG use in clinical settings, including its efficacy and safety. METHODS: PubMed, EMbase, Ovid, Web of Science, Science Direct, and related websites were screened from establishment until July 2013, and scientific meeting proceedings were manually searched...
2016: AIDS Research and Therapy
Dario Cattaneo, Sara Baldelli, Davide Minisci, Paola Meraviglia, Emilio Clementi, Massimo Galli, Cristina Gervasoni
Stribild should be administered under fed conditions to optimize drugs exposure. Here we assessed to what extent this advice is applied in the real life scenario by therapeutic drug monitoring in 75 HIV-infected patients given Stribild-based antiretroviral therapy. Fifty-three percent of our patients took Stribild at lunch/supper time, 23% in the morning with breakfast, and 24% middle in the morning or late in the evening. Twelve out of the 75 patients had unquantifiable elvitegravir concentrations, whereas in the remaining the levels were largely distributed...
October 15, 2016: International Journal of Pharmaceutics
M Biagi, M E Badowski, T Chiampas, J Young, M Patel, P Vaughn
We report the use of elvitegravir 150 mg/cobicistat 150 mg/tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (EVG/COBI/TDF/FTC) once daily, in addition to once-daily atazanavir (ATV) 300 mg, in treatment-experienced patients with human immunodeficiency virus (HIV). Due to limited data available on the co-administration of these agents, our objective was to evaluate and monitor safety and efficacy of this regimen in patients who developed resistance or intolerance to conventional antiretroviral therapy (ART)...
September 1, 2016: International Journal of STD & AIDS
Kathleen Squires, Cissy Kityo, Sally Hodder, Margaret Johnson, Evgeny Voronin, Debbie Hagins, Anchalee Avihingsanon, Ellen Koenig, Shuping Jiang, Kirsten White, Andrew Cheng, Javier Szwarcberg, Huyen Cao
BACKGROUND: Women are under-represented in HIV antiretroviral therapy (ART) studies. Guidelines for selection of ART as initial therapy in patients with HIV-1 infection do not contain sex-specific treatment. We aimed to assess the safety and efficacy of the single tablet integrase inhibitor regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate compared with a boosted protease inhibitor regimen of ritonavir-boosted atazanavir with emtricitabine and tenofovir disoproxil fumarate...
September 2016: Lancet HIV
Jordi Navarro, Adrian Curran, Joaquin Burgos, Ariadna Torrella, Inma Ocaña, Vicenç Falcó, Manuel Crespo, Esteban Ribera
An HIV-infected patient treated with tenofovir disoproxil fumarate /emtricitabine/elvitegravir/cobicistat developed severe acute ischemia of both legs during a migraine episode. After being interrogated he admitted taking an ergotamine containing preparation. Ergotism due to interaction between ergotics and cobicistat was diagnosed. We describe the first reported case of this interaction.
August 22, 2016: Antiviral Therapy
Jiangzhou You, Hongren Wang, Xiaojun Huang, Zhen Qin, Zhaomin Deng, Jun Luo, Baoning Wang, Mingyuan Li
BACKGROUND: Integrase strand transfer inhibitors (INSTIs) are a novel class of anti-HIV agents that show high activity in inhibiting HIV-1 replication. Currently, licensed INSTIs include raltegravir (RAL), elvitegravir (EVG) and dolutegravir (DTG); these drugs have played a critical role in AIDS therapy, serving as additional weapons in the arsenal for treating patients infected with HIV-1. To date, long-term data regarding clinical experience with INSTI use and the emergence of resistance remain scarce...
2016: PloS One
Sej Todd, C R Emerson
We report this case to highlight the possibility of a severe hypersensitivity reaction as an important potential consequence of couples, living with HIV, sharing anti-retroviral treatment. An HIV-1 positive and carrier of HLA-B*57:01 allele, treatment experienced man was commenced one pill Regimen Stribild (tenofovir, emtricitabine, elvitegravir and cobicistat) in July 2015. On running short of medication, he admitted to sharing his partner's treatment (Triumeq; abacavir, lamivudine and dolutegravir). On the second occasion, re-introduction resulted in whole body rash 4 h post dose and was associated with fever, respiratory symptoms, headache and vomiting...
August 16, 2016: International Journal of STD & AIDS
A Zoufaly, C Kraft, C Schmidbauer, E Puchhammer-Stoeckl
PURPOSE: Treatment guidelines often do not advocate testing for integrase inhibitor resistance associated mutations (IRAM) before initiation of first line ART given the extremely low prevalence of mutations found in older surveillance studies. We aimed to describe the prevalence of IRAM in Austrian patients recently diagnosed with HIV in the 5 years following introduction of integrase inhibitors and to analyse trends and factors associated with their detection. METHODS: Samples of antiretroviral treatment (ART) naïve patients recently diagnosed with HIV in Austria between 2008 and 2013 were analysed for the existence of IRAM and drug penalty scores were calculated to estimate response to drugs...
August 16, 2016: Infection
Pavan Kumar Prathipati, Subhra Mandal, Christopher J Destache
Combination antiretroviral (cARV) treatment is more common in human immunodeficiency virus (HIV) infection. In many instances, treatment regimen includes two or more combination of drugs from six different classes. Some of the antiretroviral combination medications are under study at preclinical and clinical stages. A precise method is required to quantify the drug concentration in biological matrices to study pharmacokinetic behavior and tissue distribution profile in animals and/or humans. We have developed and validated a sensitive and precise liquid chromatography-tandem mass spectrometry method for simultaneous quantification of selected antiretroviral drugs, tenofovir (TNF), emtricitabine (FTC), rilpivirine (RPV), dolutegravir (DTG) and elvitegravir (EVG) in mouse biological matrices...
September 10, 2016: Journal of Pharmaceutical and Biomedical Analysis
A Imaz, J Niubó, A D Kashuba, E Ferrer, C Sykes, N Rozas, L Acerete, A Vila, D Podzamczer
OBJECTIVES: The aim of the study was to quantify elvitegravir (EVG) concentrations in the semen of HIV-1-infected men receiving antiretroviral therapy (ART) consisting of an elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) single-tablet regimen. METHODS: A phase IV, cross-sectional study was carried out including HIV-1-infected male adults with suppressed plasma HIV-1 RNA who switched ART to EVG/COBI/FTC/TDF. Total EVG concentrations at the end of the dosing interval (C24 h ) and HIV-1 RNA were measured in paired seminal plasma (SP) and blood plasma (BP) samples 4 weeks after switching to EVG/COBI/FTC/TDF...
August 1, 2016: HIV Medicine
Amanda K Gibson, Bhavik M Shah, Puja H Nambiar, Jason J Schafer
OBJECTIVE: To review the pharmacology, efficacy, safety, and place in therapy for tenofovir alafenamide (TAF). DATA SOURCES: A search using PubMed was conducted (2004 to May 2016) using the following keywords: tenofovir alafenamide, TAF, and GS-7340 Articles were evaluated for content, and bibliographies were reviewed. Data available exclusively as abstracts from major infectious diseases and HIV conferences were also evaluated for inclusion. STUDY SELECTION AND DATA EXTRACTION: Studies included were in vitro investigations; phase I, II, and III clinical trials; and pharmacokinetic and pharmacodynamic evaluations...
July 26, 2016: Annals of Pharmacotherapy
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