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Alan Winston, Wolfgang Stöhr, Andrea Antinori, Helene Amieva, Philippe Perré, Stephane De Wit, Jacques Reynes, Mark Gompels, Antonella d'Arminio Monforte, Jose-Maria Gatell, Jesper Grarup, Anton Pozniak, Abdel Babiker, François Raffi, Laura Richert
BACKGROUND: Improvements in cognitive function are described after initiation of combination antiretroviral therapy (cART), with sparse data on differences between cART strategies. METHODS: We assessed changes in cognition, over 96 weeks, in therapy naïve HIV-positive adults randomised to darunavir/ritonavir (800/100mg once daily) with either raltegravir (400mg twice daily, Arm1) or tenofovir/emtricitabine (245/200mg once daily, Arm2). Seven cognitive tests were administered at baseline and week 96...
October 3, 2016: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Carmela E Corallo, Louise Grannell, Huyen Tran
A 62-year-old man was admitted to hospital for elective revision of a left total hip arthroplasty. His history was significant for human immunodeficiency virus (HIV) infection for which he was taking the following antiretroviral agents (ARVs): etravirine, ritonavir, darunavir, raltegravir and tenofovir/emtricitabine. Rivaroxaban 10 mg daily was commenced on the second postoperative day for venous thromboembolism (VTE) prophylaxis. Approximately 24 h later, the patient developed hypotension and anaemia, accompanied by thigh swelling due to bleeding at the surgical site...
December 2015: Drug Saf Case Rep
Motoko Ikuma, Dai Watanabe, Hiroki Yagura, Misa Ashida, Masaaki Takahashi, Masaaki Shibata, Tadafumi Asaoka, Munehiro Yoshino, Tomoko Uehira, Wataru Sugiura, Takuma Shirasaka
An elderly woman with human immunodeficiency virus-1 infection developed short bowel syndrome as a result of extensive intestinal resection. Considering the possibility of poor absorption of antiretroviral drugs (ARVs), therapeutic drug monitoring (TDM) was performed. A single-dose test of 6 ARVs (darunavir, ritonavir, lopinavir, etravirine, maraviroc, and raltegravir) did not provide information on the appropriate ARV, and repeated TDM under continuous antiretroviral therapy resulted in viral suppression below 50 copies/mL, which was considered to be treatment success...
2016: Internal Medicine
Nicholas T Funderburg, Dihua Xu, Martin P Playford, Aditya A Joshi, Adriana Andrade, Daniel R Kuritzkes, Michael M Lederman, Nehal N Mehta
BACKGROUND: Persons infected with HIV often have altered lipid profiles that may be affected by antiretroviral therapies (ART). Traditional lipid measurements may be insufficient to assess cardiovascular disease (CVD) risk in this population. METHODS: We report results from 39 ART-naïve participants in a substudy of A5248, a single-arm study of raltegravir (RAL), emtricitabine/tenofovir administration. Samples were collected at baseline, 12, 24, and 48 weeks after ART initiation...
October 14, 2016: Antiviral Therapy
Eva Heger, Alexandra Andrée 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 11, 2016: Journal of Virological Methods
Peter S Fong, Devon M Flynn, Christopher D Evans, P Todd Korthuis
Integrase strand transfer inhibitors (INSTIs) have become integral antiretroviral therapy (ART) agents for treating HIV infection. We report the case of a 44-year-old male with a history of hemophilia A who developed diabetes mellitus four months after switching from abacavir, lamivudine, and efavirenz to abacavir, lamivudine, and raltegravir. Hemoglobin A1C normalized without further need for exogenous insulin after raltegravir was switched back to efavirenz. In this case report, we will review a possible mechanism for INSTI-induced hyperglycemia and/or diabetes mellitus...
October 12, 2016: International Journal of STD & AIDS
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
Paul Randell, Akil Jackson, Ana Milinkovic, Marta Boffito, Graeme Moyle
BACKGROUND: We aimed to measure the effect of raltegravir (RAL) on insulin sensitivity and surrogates of CV risk in healthy HIV-seronegative volunteers compared to that of lopinavir/r (LPV/r), a positive control. METHODS: An open label, two phase crossover study in HIV-negative male subjects randomized 1:1 to receive either 2 weeks of LPV/r followed by a two week washout period and two weeks of RAL, or RAL initially followed by LPV/r. A hyperinsulinaemic euglycaemic clamp was performed prior to and following each 2-week dosing phase...
October 6, 2016: Antiviral Therapy
Rajesh Krishna, Lilly East, Patrick Larson, Tara Siringhaus, Lisa Herpok, Crystal Bethel-Brown, Helen Manthos, John Brejda, Michael Gartner
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV-1 infected treatment-naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP-glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, co-administration of UGT1A1 inducers may alter plasma levels of raltegravir...
October 5, 2016: Biopharmaceutics & Drug Disposition
Sahera Dirajlal-Fargo, Carlee Moser, Todd T Brown, Theodoros Kelesidis, Michael P Dube, James H Stein, Judith Currier, Grace A McComsey
Background.  Antiretroviral therapy (ART) can alter glucose metabolism, but little data exist on the association of raltegravir (RAL) with insulin resistance. Methods.  A5260s was a substudy of A5257, a prospective open-label randomized trial in which human immunodeficiency virus (HIV)-infected treatment-naive participants were randomized to tenofovir-emtricitabine (TDF/FTC) plus atazanavir-ritonavir (ATV/r), darunavir-ritonavir (DRV/r), or RAL over 96 weeks. Baseline and changes in insulin resistance as estimated by the homeostatic model assessment of insulin resistance (HOMA-IR) were assessed...
September 2016: Open Forum Infectious Diseases
Rajesh Krishna, Lilly East, Patrick Larson, Chandni Valiathan, Kathleen Deschamps, Julie Ann Luk, Crystal Bethel-Brown, Helen Manthos, John Brejda, Michael Gartner
Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice-daily (BID). Raltegravir 1200 mg once-daily (QD) [investigational QD formulation of 2 x 600 mg tablets; QD RAL] was found to be generally well tolerated and non-inferior to the marketed 400 mg BID dose at 48 weeks in a Phase 3 trial. Since raltegravir is eliminated mainly by metabolism via a uridine diphosphate glucuronosyltransferase (UGT) 1A1-mediated glucuronidation pathway, coadministration of UGT1A1 inhibitors may increase plasma levels of QD RAL...
September 30, 2016: Biopharmaceutics & Drug Disposition
Juan Carlos Domínguez-Hermosillo, José Antonio Mata-Marin, Norma Estela Herrera-González, Marcelino Chávez-García, Gloria Huerta-García, Nohemí Nuñez-Rodríguez, José Gerardo García-Gámez, Anai Jiménez-Romero, Jesús Enrique Gaytán-Martínez
INTRODUCTION: Although both tipranavir (TPV) and darunavir (DRV) represent important options for the management of patients with multi-protease inhibitor (PI)-resistant human immunodeficiency virus (HIV), currently there are no studies comparing the effectiveness and safety of these two drugs in the Mexican population. The aim of this study was to compare the effectiveness of TPV versus DRV as a salvage therapy in HIV-1 treatment-experienced patients. METHODOLOGY: This was a comparative, prospective, cohort study...
September 30, 2016: Journal of Infection in Developing Countries
Ildefonso Pulido, Miguel Genebat, Ana I Alvarez-Rios, Rebeca S De Pablo-Bernal, Mohammed Rafii-El-Idrissi Benhnia, Yolanda M Pacheco, Ezequiel Ruiz-Mateos, Manuel Leal
Toxicities related to the use of nucleoside analogues have increased the interest in developing nucleoside-sparing regimens, mainly combining protease inhibitors with raltegravir. However, data regarding the use of CCR5-antagonists in this setting and in the naive scenario are scarce. The main objective was to analyze the immunovirological efficacy and tolerability of a low-dose, once-daily, maraviroc (MVC)-containing, nucleoside reverse transcriptase inhibitor-sparing dual therapy compared with standard triple therapy after 48 weeks for naive HIV-infected patients in the routine clinical practice setting...
October 2016: Viral Immunology
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
Dominic Chow, Cecilia Shikuma, Corey Ritchings, Muxing Guo, Lisa Rosenblatt
INTRODUCTION: Patients with human immunodeficiency virus (HIV) infection have an increased risk of cardiovascular disease (CVD). While viral suppression with antiretroviral therapy decreases CVD risk overall, several studies have suggested that certain antiretrovirals, particularly certain protease inhibitors, may be associated with an increased relative risk of CVD. In AIDS Clinical Trials Group 5260 s, ritonavir-boosted atazanavir (ATV) was associated with slower atherosclerosis progression compared to ritonavir-boosted darunavir and raltegravir, potentially due to hyperbilirubinemia...
September 27, 2016: Infectious Diseases and Therapy
Rajesh Krishna, Lilly East, Patrick Larson, Chandni Valiathan, Kristin Butterfield, Yang Teng, Martha Hernandez-Illas
OBJECTIVES: Raltegravir is a human immunodeficiency virus (HIV)-1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once-daily regimen (QD) at a dose of 1200 mg is under development. The effect of calcium carbonate and magnesium/aluminium hydroxide antacids on the pharmacokinetics of a 1200 mg dose of raltegravir was assessed in this study. METHODS: An open-label, four-period, four-treatment, fixed-sequence study in 20 HIV-infected patients was performed...
September 27, 2016: Journal of Pharmacy and Pharmacology
Theodoros Kelesidis, Thuy Tien T Tran, Todd T Brown, Carlee Moser, Heather J Ribaudo, Michael P Dube, Otto O Yang, Grace A McComsey, James H Stein, Judith S Currier
BACKGROUND: The role of oxidized lipoproteins (high-density [HDLox] and low-density [LDLox]) and total lipoprotein particle (Lp) number and size in HIV-related cardiovascular disease (CVD) is unclear. The goal of this study was to evaluate changes of these biomarkers and their associations with rate of carotid intima media thickness progression over 3 years (ΔCIMT) in chronic HIV infection. METHODS: Prospective study of 234 HIV-infected antiretroviral treatment naïve participants without CVD who were randomized to receive tenofovir-emtricitabine plus atazanavir/ritonavir, darunavir/ ritonavir, or raltegravir (RAL) and achieved plasma HIV-1 RNA <50 copies/ml by week 24 and thereafter...
September 23, 2016: Antiviral Therapy
Angela Corona, Francesco Saverio di Leva, Giuseppe Rigogliuso, Luca Pescatori, Valentina Noemi Madia, Frederic Subra, Olivier Delelis, Francesca Esposito, Marta Cadeddu, Roberta Costi, Sandro Cosconati, Ettore Novellino, Roberto di Santo, Enzo Tramontano
HIV-1 integrase (IN) inhibitors are one of the most recent innovations in the treatment of HIV infection. The selection of drug resistance viral strains is however a still open issue requiring constant efforts to identify new anti-HIV-1 drugs. Pyrrolyl diketo acid (DKA) derivatives inhibit HIV-1 replication by interacting with the Mg(2+) cofactors within the HIV-1 IN active site or within the HIV-1 reverse-transcriptase associated ribonuclease H (RNase H) active site. While the interaction mode of pyrrolyl DKAs with the RNase H active site has been recently reported and substantiated by mutagenesis experiments, their interaction within the IN active site still lacks a detailed understanding...
October 2016: Antiviral Research
Steve Kanters, Marco Vitoria, Meg Doherty, Maria Eugenia Socias, Nathan Ford, Jamie I Forrest, Evan Popoff, Nick Bansback, Sabin Nsanzimana, Kristian Thorlund, Edward J Mills
BACKGROUND: New antiretroviral therapy (ART) regimens for HIV could improve clinical outcomes for patients. To inform global guidelines, we aimed to assess the comparative effectiveness of recommended ART regimens for HIV in ART-naive patients. METHODS: For this systematic review and network meta-analysis, we searched for randomised clinical trials published up to July 5, 2015, comparing recommended antiretroviral regimens in treatment-naive adults and adolescents (aged 12 years or older) with HIV...
September 6, 2016: Lancet HIV
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
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