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Annelies Smeets, Robin Koekoekx, Christian Clasen, Guy Van den Mooter
The interest in using electrospraying as a manufacturing method for amorphous solid dispersions has grown remarkably. However, the impact of formulation and process parameters needs further clarification. In this study, amorphous solid dispersions of darunavir and hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC AS) and polyvinylpyrrolidone K-30 (PVP) were prepared with electrospraying and spray drying, in order to compare both solvent based manufacturing techniques...
June 18, 2018: European Journal of Pharmaceutics and Biopharmaceutics
Eric S Daar, Edwin DeJesus, Peter Ruane, Gordon Crofoot, Godson Oguchi, Catherine Creticos, Jürgen K Rockstroh, Jean-Michel Molina, Ellen Koenig, Ya-Pei Liu, Joseph Custodio, Kristen Andreatta, Hiba Graham, Andrew Cheng, Hal Martin, Erin Quirk
BACKGROUND: Switching from therapy based on a boosted protease inhibitor to bictegravir, emtricitabine, and tenofovir alafenamide could avoid drug interactions and unwanted side-effects in virologically suppressed adults with HIV-1 infection, while maintaining a high barrier to resistance and providing a simplified once-daily, single-tablet regimen. Here, we report 48 week results of a phase 3 study investigating this switch. METHODS: In this multicentre, randomised, open-label, active-controlled, non-inferiority, phase 3 trial, adults with HIV-1 infection were enrolled at 121 outpatient centres in ten countries...
June 15, 2018: Lancet HIV
Emma D Deeks
Darunavir/cobicistat/emtricitabine/tenofovir AF (Symtuza® ) is the first protease inhibitor (PI)-based single-tablet regimen (STR) available for the treatment of adults and adolescents (aged ≥ 12 years) with HIV-1 infection. It combines the PI darunavir (which has a high genetic barrier to resistance) with the pharmacokinetic booster cobicistat and the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (tenofovir AF), the latter being associated with less off-target tenofovir exposure than its predecessor tenofovir disoproxil fumarate (tenofovir DF)...
June 18, 2018: Drugs
Vincenzo Spagnuolo, Antonella Castagna, Adriano Lazzarin
Darunavir (DRV) was the last approved protease inhibitor (PI) and has been extensively used for the treatment of HIV in both naïve and experienced subjects due to its high genetic barrier and efficacy. The introduction in clinical practice of integrase strand transfer inhibitors limited its role in the management of naïve subjects and in antiretroviral treatment simplification strategies. However, recent data from trials that have investigated the new DRV/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) combination showed an excellent efficacy and tolerability of this coformulation both in naïve patients and in those with viral suppression, making D/C/F/TAF a new option for the treatment of HIV infection...
June 18, 2018: Expert Opinion on Pharmacotherapy
Virawudh Soontornniyomkij, Anya Umlauf, Benchawanna Soontornniyomkij, Ben Gouaux, Ronald J Ellis, Andrew J Levine, David J Moore, Scott L Letendre
OBJECTIVE: Antiretroviral therapy (ART) is currently recommended for all persons living with HIV (PLWH), regardless of their CD4+ T-cell count, and should be continued throughout life. Nonetheless, vigilance of the safety of ART, including its neurotoxicity, must continue. We hypothesized that use of certain ART drugs might be associated with aging-related cerebral degenerative changes among PLWH. DESIGN: Clinicopathological study of PLWH who were using ART drugs at the last clinical assessment...
June 14, 2018: AIDS
S A Hart, S Vardhanabhuti, S A Strobino, L J Harrison
IntroductionThe Stanford HIV-1 genotypic resistance interpretation algorithm has changed substantially over its lifetime. In many studies the algorithm version used is not specified. It is easy to assume results across versions are comparable, but the effects of version changes on resistance calls are unknown. We evaluate these effects for 20 antiretroviral drugs.MethodsWe calculated resistance interpretations for the same 5,993 HIV-1 sequences, from participants in AIDS Clinical Trials Group studies, under 14 versions of the Stanford algorithm from 2002 to 2017...
June 14, 2018: Journal of Acquired Immune Deficiency Syndromes: JAIDS
Minh P Lê, Marie-Laure Chaix, Sylvie Chevret, Julie Bertrand, François Raffi, Sébastien Gallien, El Mountacer Billah El Abbassi, Christine Katlama, Pierre Delobel, Yazdan Yazdanpanah, Juliette Saillard, Jean-Michel Molina, Gilles Peytavin
Background: In the ANRS 165 DARULIGHT study (NCT02384967) carried out in HIV-infected patients, the use of a darunavir/ritonavir-containing regimen with a switch to a reduced dose of darunavir maintained virological efficacy (≤50 copies/mL) for 48 weeks with a good safety profile. Objectives: To assess the total and unbound blood plasma pharmacokinetics of darunavir and associated antiretrovirals, and their penetration into semen before and after dose reduction...
June 13, 2018: Journal of Antimicrobial Chemotherapy
Nimish Patel, Peter Borg, Richard Haubrich, Ian McNicholl
PURPOSE: Results of a study of contraindicated concomitant medication use among recipients of preferred antiretroviral therapy (ART) regimens are reported. METHODS: A retrospective study was conducted to evaluate concomitant medication use in a cohort of previously treatment-naive, human immunodeficiency virus (HIV)-infected U.S. patients prescribed preferred ART regimens during the period April 2014-March 2015. Data were obtained from a proprietary longitudinal prescription database; elements retrieved included age, sex, and prescription data...
June 14, 2018: American Journal of Health-system Pharmacy: AJHP
Riethorst Danny, Brouwers Joachim, Motmans Jens, Augustijns Patrick
Intestinal permeability assessment is an important aspect of drug development, which strongly depends on the solvent system used in the intestinal donor compartment. For this purpose, human intestinal fluids (HIF) can be considered as the golden standard. A recent study demonstrated a reduced apparent permeation across rat intestinal tissue from fed versus fasted state HIF for 9 out of 16 compounds tested. Commercially available fed and fasted state simulated fluids (FeSSIF and FaSSIF) reproduced this food effect for only 3 out of 16 compounds...
June 11, 2018: European Journal of Pharmaceutical Sciences
Maria Nevot, Ana Jordan-Paiz, Glòria Martrus, Cristina Andrés, Damir García-Cehic, Josep Gregori, Sandra Franco, Josep Quer, Miguel Angel Martinez
One unexplored aspect of HIV-1 genetic architecture is how codon choice influences population diversity and evolvability. Here we compared the development of HIV-1 resistance to protease inhibitors (PIs) between wild-type (WT) virus and a synthetic virus (MAX) carrying a codon-pair re-engineered protease sequence including 38 (13%) synonymous mutations. WT and MAX viruses showed indistinguishable replication in MT-4 cells or PBMCs. Both viruses were subjected to serial passages in MT-4 cells with selective pressure from the PIs atazanavir (ATV) and darunavir (DRV)...
June 6, 2018: Journal of Virology
Haichen Nie, Huaping Mo, Stephen R Byrn
Understanding physicochemical stability of darunavir ethanolate is expected to be of critical importance for the development and manufacturing of high-quality darunavir-related pharmaceutical products. However, there are no enabling monographs for darunavir to illustrate its solid-state chemistry, impurity profile, and assay methods. In addition, the US Pharmacopeia reference standard of darunavir is still not commercially available. It has been also challenging to find reliable vendors to obtain highly purified darunavir ethanolate crystals to conduct the physicochemical stability testing...
June 4, 2018: AAPS PharmSciTech
Eugènia Negredo, Klaus Langohr, Anna Bonjoch, Núria Pérez-Alvárez, Carla Estany, Jordi Puig, Joaquim Rosales, Patricia Echeverría, Bonaventura Clotet, Guadalupe Gómez
Background: Osteoporotic fractures still remain very infrequent and physicians rarely evaluate bone health. We wanted to assess the magnitude of this problem in the near future by determining the risk and likelihood of progression to osteoporosis. Methods: We estimated the risk of progression to osteopenia/osteoporosis among HIV-infected patients with at least 2 DXA scans (3726 scans from 875 patients). Time-non-homogeneous bidirectional multistate models based on three states (normal bone mineral density, osteopenia and osteoporosis) were used to model the progression of bone mineral density as a function of age and to study the association between the risk of bone loss and antiretroviral use...
June 1, 2018: Journal of Antimicrobial Chemotherapy
Jean-Michel Molina, Sebastien Gallien, Marie-Laure Chaix, El Mountacer El Abbassi, Isabelle Madelaine, Christine Katlama, Nadia Valin, Pierre Delobel, Kristell Desseaux, Gilles Peytavin, Juliette Saillard, François Raffi, Sylvie Chevret
Objectives: To assess whether low-dose ritonavir-boosted darunavir (darunavir/r) in combination with two NRTIs could maintain virological suppression in patients on a standard regimen of darunavir/r + two NRTIs. Design: A multicentre, Phase II, non-comparative, single-arm, open-label study. Setting: Tertiary care hospitals in France. Subjects: One hundred HIV-1-infected adults with no darunavir or NRTI resistance-associated mutations (RAMs) and a plasma HIV RNA level ≤50 copies/mL for ≥12 months on once-daily darunavir/r (800/100 mg) + two NRTIs for ≥6 months were switched to darunavir/r 400/100 mg with the same NRTIs...
June 1, 2018: Journal of Antimicrobial Chemotherapy
Koushi Hidaka, Tooru Kimura, Rajesh Sankaranarayanan, Jun Wang, Keith F McDaniel, Dale J Kempf, Masanori Kameoka, Motoyasu Adachi, Ryota Kuroki, Jeffrey-Tri Nguyen, Yoshio Hayashi, Yoshiaki Kiso
The emergence of drug-resistant HIV from a wide-spread anti-viral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P3, P2 and P2´ moieties. The derivatives with P2 tetrahydrofuranylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains...
May 31, 2018: Journal of Medicinal Chemistry
Soo-Yon Rhee, Dana Clutter, W Jeffrey Fessel, Daniel Klein, Sally Slome, Benjamin A Pinsky, Julia L Marcus, Leo Hurley, Michael J Silverberg, Sergei L Kosakovsky Pond, Robert W Shafer
Background: There are few large studies of transmitted drug resistance (TDR) prevalence and the drug resistance mutations (DRMs) responsible for TDR in the U.S. Methods: HIV-1 RT and protease sequences were obtained from 4,253 antiretroviral therapy (ART)-naïve individuals in a California clinic population from 2003-2016. Phylogenetic analyses were performed to study linkages between TDR strains and selection pressure on TDR-associated DRMs. Results: From 2003-2016, there was a significant increase in overall (odds ratio [OR]=1...
May 26, 2018: Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America
Marie-Alice Colombier, Jean-Michel Molina
PURPOSE OF REVIEW: The current review addresses the role of doravirine (DOR), a novel once-daily nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line therapy at a time in which multiple options are available, and issues of antiviral efficacy, safety, simplicity and cost are critical to make informed decisions. RECENT FINDINGS: DOR combination regimens have been tested in two large randomized double-blinded clinical trials in treatment-naïve patients, showing noninferiority to ritonavir-boosted darunavir-based and efavirenz (EFV)-based regimens...
July 2018: Current Opinion in HIV and AIDS
Eugènia Negredo, Bonaventura Clotet
HIV eradication is not feasible and lifelong treatment is warranted to manage HIV infection. In this scenario, the advent of single-tablet, once-daily, fixed-dose co-formulations is important for reducing pill burden and maximize long-term drug adherence. Cobicistat-boosted darunavir along with emtricitabine and tenofovir alafenamide co-formulation (DRV/c/FTC/TAF or the trade name Symtuza®) is the first marketed protease inhibitor-based fixed-dose combination regimen for the treatment of HIV infection. It was approved in late 2017 by the European Medical Agency both for naïve patients and treatment-experienced patients with viral suppression...
May 16, 2018: Expert Opinion on Pharmacotherapy
A González-Cordón, M Doménech, M Camafort, M Martínez-Rebollar, B Torres, M Laguno, J Rojas, M Loncà, J L Blanco, J Mallolas, J M Gatell, E de Lazzari, E Martínez
OBJECTIVES: The aim of the study was to assess changes in and factors associated with anatomical [carotid artery intima-media thickness (CIMT)] and functional (arterial stiffness) markers of subclinical cardiovascular disease progression in antiretroviral-naïve patients starting triple combination antiretroviral therapy containing contemporary protease inhibitors. METHODS: This was a planned substudy of the ATADAR (Metabolic Effects of Atazanavir/Ritonavir Versus Darunavir/Ritonavir in Combination With Tenofovir/Emtricitabine in naïve HIV-1 Infected Patients) clinical trial (ClinicalTrials...
May 10, 2018: HIV Medicine
Lene Ryom, Jens D Lundgren, Wafaa El-Sadr, Peter Reiss, Ole Kirk, Matthew Law, Andrew Phillips, Rainer Weber, Eric Fontas, Antonella d' Arminio Monforte, Stéphane De Wit, Francois Dabis, Camilla I Hatleberg, Caroline Sabin, Amanda Mocroft
BACKGROUND: Although earlier protease inhibitors have been associated with increased risk of cardiovascular disease, whether this increased risk also applies to more contemporary protease inhibitors is unknown. We aimed to assess whether cumulative use of ritonavir-boosted atazanavir and ritonavir-boosted darunavir were associated with increased incidence of cardiovascular disease in people living with HIV. METHODS: The prospective Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study consists of people living with HIV-1 from 11 cohorts in Australia, Europe, and the USA...
May 3, 2018: Lancet HIV
Robin Augustine, Dana Levin Ashkenazi, Roni Sverdlov Arzi, Vita Zlobin, Rona Shofti, Alejandro Sosnik
Nanonizationhas been extensively investigated to increase theoral bioavailability of hydrophobicdrugsin general andantiretrovirals(ARVs)used inthe therapy of the human immunodeficiency virus (HIV) infection in particular. Weanticipatedthatin the caseofprotease inhibitors, a family of pH-dependent ARVsthatdisplay high aqueous solubility undertheacidconditionsof thestomach andextremely low solubilityunder the neutral ones ofthe small intestine, this strategy will failowing to an uncontrolled dissolution-re-precipitation process that will take place along the gastrointestinal tract...
April 30, 2018: Acta Biomaterialia
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