Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability
Antimicrob Agents Chemother. 2024 Feb 21:e0137323. doi: 10.1128/aac.01373-23. Online ahead of print.ABSTRACTProtease inhibitors (PIs) remain an important component of antiretroviral therapy for the treatment of HIV-1 infection due to their high genetic barrier to resistance development. Nevertheless, the two most commonly prescribed HIV PIs, atazanavir and darunavir, still require co-administration with a pharmacokinetic boosting agent to maintain sufficient drug plasma levels which can lead to undesirable drug-drug interactions. Herein, we describe GS-9770, a novel investigational non-peptidomimetic HIV PI with unboosted ...
Source: Antimicrobial Agents and Chemotherapy - February 21, 2024 Category: Microbiology Authors: Andrew Mulato Eric Lansdon Ron Aoyama Johannes Voigt Michael Lee Albert Liclican Gary Lee Eric Singer Brian Stafford Ruoyu Gong Bernard Murray Julie Chan Johnny Lee Yili Xu Shekeba Ahmadyar Ana Gonzalez Aesop Cho George J Stepan Uli Schmitz Brian Schultz Source Type: research
Rational design, synthesis and biological evaluation of novel HIV-1 protease inhibitors containing 2-phenylacetamide derivatives as P2 ligands with potent activity against DRV-Resistant HIV-1 variants
Bioorg Med Chem Lett. 2024 Feb 9:129651. doi: 10.1016/j.bmcl.2024.129651. Online ahead of print.ABSTRACTA novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of...
Source: Bioorganic and Medicinal Chemistry Letters - February 11, 2024 Category: Chemistry Authors: Sihan Meng Yu Gao Guowei Qiang Zhiwei Hu Qi Shan Juxian Wang Yucheng Wang Jie Mou Source Type: research
Viruses, Vol. 16, Pages 182: Dynamics of Low-Level Viremia and Immune Activation after Switching to a Darunavir-Based Regimen
ki Tesselaar
Matthijs van Luin
Monique Nijhuis
Annemarie M. J. Wensing
LOWERIT Study Team
There is an ongoing debate regarding whether low-level viremia (LLV), in particular persistent LLV, during HIV treatment with optimal adherence originates from low-level viral replication, viral production, or both. We performed an observational study in 30 individuals with LLV who switched to a boosted darunavir (DRV)-based therapy. In-depth virological analyses were used to characterize the viral population and the (activity) of the viral reservoir. Immune activation was examined using cell-bound and soluble markers. Th...
Source: Viruses - January 25, 2024 Category: Virology Authors: Arjen J. Stam Nin ée V. E. J. Buchholtz Wouter F. W. Bierman Reinout van Crevel Andy I. M. Hoepelman Mark A. A. Claassen Heidi S. M. Ammerlaan Berend J. van Welzen Marjo E. E. van Kasteren Steven F. L. van Lelyveld Dorien de Jong Kiki Tesselaar Matthijs Tags: Article Source Type: research
A detailed characterization of drug resistance during darunavir/ritonavir monotherapy highlights a high barrier to the emergence of resistance mutations in protease but identifies alternative pathways of resistance
ConclusionsThe study highlights the high resistance barrier of ritonavir-boosted darunavir while identifying alternative pathways of resistance through Gag substitutions. During virological suppression, resistance patterns in HIV-1 DNA reflect treatment history, but due to technical and biological considerations, cautious interpretation is warranted. (Source: Journal of Antimicrobial Chemotherapy)
Source: Journal of Antimicrobial Chemotherapy - December 28, 2023 Category: Microbiology Source Type: research
Simultaneous pharmacokinetic modeling of unbound and total darunavir with ritonavir in adolescents: a substudy of the SMILE trial
Antimicrob Agents Chemother. 2023 Dec 11:e0100423. doi: 10.1128/aac.01004-23. Online ahead of print.ABSTRACTDarunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir/ritonavir in children and...
Source: Antimicrobial Agents and Chemotherapy - December 13, 2023 Category: Microbiology Authors: Seef Abdalla Alexandra Compagnucci Yoann Riault Man K Chan Alasdair Bamford Aoife Nolan Jos é T Ramos Valentin Constant Thao-Nguyen Nguyen Yi Zheng Jean-Marc Tr éluyer L éo Froelicher-Bournaud Nathalie Neveux Yacine Saidi Tim R Cressey D éborah Hirt S Source Type: research
Simultaneous pharmacokinetic modeling of unbound and total darunavir with ritonavir in adolescents: a substudy of the SMILE trial
Antimicrob Agents Chemother. 2023 Dec 11:e0100423. doi: 10.1128/aac.01004-23. Online ahead of print.ABSTRACTDarunavir (DRV) is an HIV protease inhibitor commonly used as part of antiretroviral treatment regimens globally for children and adolescents. It requires a pharmacological booster, such as ritonavir (RTV) or cobicistat. To better understand the pharmacokinetics (PK) of DRV in this younger population and the importance of the RTV boosting effect, a population PK substudy was conducted within SMILE trial, where the maintenance of HIV suppression with once daily integrate inhibitor + darunavir/ritonavir in children and...
Source: Antimicrobial Agents and Chemotherapy - December 13, 2023 Category: Microbiology Authors: Seef Abdalla Alexandra Compagnucci Yoann Riault Man K Chan Alasdair Bamford Aoife Nolan Jos é T Ramos Valentin Constant Thao-Nguyen Nguyen Yi Zheng Jean-Marc Tr éluyer L éo Froelicher-Bournaud Nathalie Neveux Yacine Saidi Tim R Cressey D éborah Hirt S Source Type: research
Development and validation of equilibrium dialysis UHPLC-MS/MS measurement procedures for total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. Application to patients with HIV
CONCLUSIONS: The UHPLC-MS/MS procedures developed could be used for research purposes and therapeutic drug monitoring of antiretrovirals in routine clinical practice.PMID:38042460 | DOI:10.1016/j.cca.2023.117678 (Source: International Journal of Clinical Chemistry)
Source: International Journal of Clinical Chemistry - December 2, 2023 Category: Chemistry Authors: Ra úl Rigo-Bonnin Laura Garc ía-Tejada Virg ínia Mas-Bosch Arkaitz Imaz Juan Manuel Tiraboschi Sof ía Scévola Jordi Niub ó Antonio Navarro-Alcaraz Daniel Podzamczer Source Type: research
Development and validation of equilibrium dialysis UHPLC-MS/MS measurement procedures for total and unbound concentrations of bictegravir, dolutegravir, darunavir and doravirine in human plasma. Application to patients with HIV
CONCLUSIONS: The UHPLC-MS/MS procedures developed could be used for research purposes and therapeutic drug monitoring of antiretrovirals in routine clinical practice.PMID:38042460 | DOI:10.1016/j.cca.2023.117678 (Source: International Journal of Clinical Chemistry)
Source: International Journal of Clinical Chemistry - December 2, 2023 Category: Chemistry Authors: Ra úl Rigo-Bonnin Laura Garc ía-Tejada Virg ínia Mas-Bosch Arkaitz Imaz Juan Manuel Tiraboschi Sof ía Scévola Jordi Niub ó Antonio Navarro-Alcaraz Daniel Podzamczer Source Type: research
Changes in Cerebrospinal Fluid, Liver and Intima-media-thickness Biomarkers in Patients with HIV-associated Neurocognitive Disorders Randomized to a Less Neurotoxic Treatment Regimen
AbstractThe prevalence of neurocognitive impairment in people living with HIV is estimated between 30 and 50%. The pathogenesis of HIV-associated neurocognitive disorders is complex and multifactorial. Aim of the study was to measure the change in CSF biomarkers, Fibroscan and IMT measurements in PLWH with HAND randomized to a less neurotoxic regimen, or continuing their treatment. Adult patients with HAND were screened and enrolled if presenting no major resistance associated mutations, no HIV viral replication, not on efavirenz or darunavir, with R5-tropic HIV and without major confounding conditions. Lumbar puncture, ...
Source: Journal of NeuroImmune Pharmacology - October 31, 2023 Category: Drugs & Pharmacology Source Type: research
Lopinavir-ritonavir versus darunavir-norvir for hospitalized COVID-19 patients
Conclusion: LPV/r, but not DRV/n demonstrated survival benefits in patients hospitalized for COVID-19 in this observational study. (Source: European Respiratory Journal)
Source: European Respiratory Journal - October 27, 2023 Category: Respiratory Medicine Authors: Paroczai, D., Bikov, A., Blidaru, A., Bobu, E., Cerbu, B., Marincu, I., Mihaicuta, S., Frent, S. Tags: Respiratory infections and bronchiectasis Source Type: research
HIV-1-specific T-cell responses and exhaustion profiles in people with HIV after switching to dual therapy vs. maintaining triple therapy based on integrase inhibitors
CONCLUSIONS: Our results suggest that simplification to DT does not negatively influence the HIV-1-specific T-cell response or the exhaustion phenotype after 96 weeks of follow-up.PMID:37871555 | DOI:10.1016/j.biopha.2023.115750 (Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie)
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - October 23, 2023 Category: Drugs & Pharmacology Authors: Esperanza Mu ñoz-Muela Mar ía Trujillo-Rodríguez Ana Serna-Gallego Abraham Saborido-Alconchel Ezequiel Ruiz-Mateos Luis F L ópez-Cortés Alicia Guti érrez-Valencia Source Type: research
HIV-1-specific T-cell responses and exhaustion profiles in people with HIV after switching to dual therapy vs. maintaining triple therapy based on integrase inhibitors
CONCLUSIONS: Our results suggest that simplification to DT does not negatively influence the HIV-1-specific T-cell response or the exhaustion phenotype after 96 weeks of follow-up.PMID:37871555 | DOI:10.1016/j.biopha.2023.115750 (Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie)
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - October 23, 2023 Category: Drugs & Pharmacology Authors: Esperanza Mu ñoz-Muela Mar ía Trujillo-Rodríguez Ana Serna-Gallego Abraham Saborido-Alconchel Ezequiel Ruiz-Mateos Luis F L ópez-Cortés Alicia Guti érrez-Valencia Source Type: research
Genetic variations of CYP3A4 on the metabolism of itraconazole in vitro
In this study, we aimed to completely evaluate the impacts of Cytochrome P450 3A4 (CYP3A4) variant proteins and drug interactions on the metabolism of itraconazole in recombinant insect microsomes, and to characterize the potential mechanism of substrate selectivity. Incubations with itraconazole (0.2-15 μM) in the presence/absence of lopinavir or darunavir were assessed by CYP3A4 variants, and the metabolite hydroxyitraconazole concentrations were measured by UPLC-MS/MS. Our data showed that when compared with CYP3A4.1, 4 variants (CYP3A4.9, 0.10, 0.28 and 0.34) displayed no significant differences, and 3 variants (CYP3A...
Source: Food and Chemical Toxicology - October 20, 2023 Category: Food Science Authors: Sai-Li Xie Xiayan Zhu Nanyong Gao Qianmeng Lin Chaojie Chen Yun-Jun Yang Jian-Ping Cai Guo-Xin Hu Ren-Ai Xu Source Type: research
A four-drug combination oral tablet of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide for the treatment of HIV-1 infection in adults
Expert Rev Anti Infect Ther. 2023 Oct 6. doi: 10.1080/14787210.2023.2268281. Online ahead of print.ABSTRACTINTRODUCTION: Darunavir (DRV)/cobicistat (COBI)/emtricitabine (FTC)/tenofovir alafenamide (TAF) is the only protease inhibitor-based single tablet regimen approved for the treatment of HIV infection of adults and pediatric patients weighing at least 40 kg. DRV/COBI/FTC/TAF has demonstrated to be an effective regimen, to have a high genetic barrier to resistance and to be well tolerated.AREAS COVERED: The authors summarize the chemistry and pharmacology of DRV, COBI, FTC and TAF and discuss trials conducted on antiretr...
Source: Expert Review of Anti-Infective Therapy - October 6, 2023 Category: Infectious Diseases Authors: Camilla Muccini Antonella Castagna Source Type: research
