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International Journal of Nanomedicine 2021Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV),...
INTRODUCTION
Human immunodeficiency virus (HIV) remains a persistent global challenge, impacting 38 million people worldwide. Antiretrovirals (ARVs) including tenofovir (TFV), raltegravir (RAL), and dapivirine (DAP) have been developed to prevent and treat HIV-1 via different mechanisms of action. In parallel, a promising biological candidate, griffithsin (GRFT), has demonstrated outstanding preclinical safety and potency against HIV-1. While ARV co-administration has been shown to enhance virus inhibition, synergistic interactions between ARVs and the oxidation-resistant variant of GRFT (Q-GRFT) have not yet been explored. Here, we co-administered Q-GRFT with TFV, RAL, and DAP, in free and encapsulated forms, to identify unique protein-drug synergies.
METHODS
Nanoparticles (NPs) were synthesized using a single or double-emulsion technique and release from each formulation was assessed in simulated vaginal fluid. Next, each ARV, in free and encapsulated forms, was co-administered with Q-GRFT or Q-GRFT NPs to evaluate the impact of co-administration in HIV-1 pseudovirus assays, and the combination indices were calculated to identify synergistic interactions. Using the most synergistic formulations, we investigated the effect of agent incorporation in NP-fiber composites on release properties. Finally, NP safety was assessed in vitro using MTT assay.
RESULTS
All active agents were encapsulated in NPs with desirable encapsulation efficiency (15-100%), providing ~20% release over 2 weeks. The co-administration of free Q-GRFT with each free ARV resulted in strong synergistic interactions, relative to each agent alone. Similarly, Q-GRFT NP and ARV NP co-administration resulted in synergy across all formulations, with the most potent interactions between encapsulated Q-GRFT and DAP. Furthermore, the incorporation of Q-GRFT and DAP in NP-fiber composites resulted in burst release of DAP and Q-GRFT with a second phase of Q-GRFT release. Finally, all NP formulations exhibited safety in vitro.
CONCLUSIONS
This work suggests that Q-GRFT and ARV co-administration in free or encapsulated forms may improve efficacy in achieving prophylaxis.
Topics: Anti-HIV Agents; Anti-Retroviral Agents; Cell Death; Cell Line; Drug Compounding; Drug Liberation; Drug Synergism; Female; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Lectins; Nanoparticles; Particle Size; Plant Lectins; Polylactic Acid-Polyglycolic Acid Copolymer; Pyrimidines; Raltegravir Potassium; Recombinant Proteins; Tenofovir
PubMed: 33623382
DOI: 10.2147/IJN.S287310 -
Clinical Pharmacokinetics Jun 2021Little is understood about neonatal pharmacokinetics immediately after delivery and during the first days of life following intrauterine exposure to maternal...
BACKGROUND AND OBJECTIVE
Little is understood about neonatal pharmacokinetics immediately after delivery and during the first days of life following intrauterine exposure to maternal medications. Our objective was to develop and evaluate a novel, physiologically based pharmacokinetic modeling workflow for predicting perinatal and postnatal disposition of commonly used antiretroviral drugs administered prenatally to pregnant women living with human immunodeficiency virus.
METHODS
Using previously published, maternal-fetal, physiologically based pharmacokinetic models for emtricitabine, dolutegravir, and raltegravir built with PK-Sim/MoBi, placental drug transfer was predicted in late pregnancy. The total drug amount in fetal compartments at term delivery was estimated and subsequently integrated as initial conditions in different tissues of a whole-body, neonatal, physiologically based pharmacokinetic model to predict drug concentrations in the neonatal elimination phase after birth. Neonatal elimination processes were parameterized according to published data. Model performance was assessed by clinical data.
RESULTS
Neonatal physiologically based pharmacokinetic models generally captured the initial plasma concentrations after delivery but underestimated concentrations in the terminal phase. The mean percentage error for predicted plasma concentrations was - 71.5%, - 33.8%, and 76.7% for emtricitabine, dolutegravir, and raltegravir, respectively. A sensitivity analysis suggested that the activity of organic cation transporter 2 and uridine diphosphate glucuronosyltransferase 1A1 during the first postnatal days in term newborns is ~11% and ~30% of that in adults, respectively.
CONCLUSIONS
These findings demonstrate the general feasibility of applying physiologically based pharmacokinetic models to predict washout concentrations of transplacentally acquired drugs in newborns. These models can increase the understanding of pharmacokinetics during the first postnatal days and allow the prediction of drug exposure in this vulnerable population.
Topics: Adult; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; Humans; Infant, Newborn; Models, Biological; Oxazines; Piperazines; Placenta; Pregnancy; Pyridones; Raltegravir Potassium
PubMed: 33527213
DOI: 10.1007/s40262-020-00977-w -
Journal of Acquired Immune Deficiency... Apr 2021Integrase strand transfer inhibitors (INSTIs) are first-line regimens for HIV treatment. We aimed to examine their impact on cognitive performance and depressive...
BACKGROUND
Integrase strand transfer inhibitors (INSTIs) are first-line regimens for HIV treatment. We aimed to examine their impact on cognitive performance and depressive symptoms in women with HIV (WWH).
SETTING
Women's Interagency HIV Study, a multisite, prospective, cohort study.
METHODS
WWH who started or switched to INSTI-based antiretroviral therapy (ART) and completed neuropsychological testing and the Center for Epidemiological Studies-Depression (CES-D) scale before and after INSTI start/switch were included in the analyses. Primary outcomes were demographically corrected cognitive domain T-scores. Linear mixed-effects models adjusted for relevant covariates were used to examine effects of start/switch of any INSTI and individual INSTI drugs on cognition and CES-D scores.
RESULTS
Six hundred thirty-nine WWH, median age 49 (interquartile range 12) years, 66% Black non-Hispanic, had neuropsychological and CES-D scale data before and after INSTI start/switch. Although 14% started INSTI-based ART, the remainder switched to INSTI-based ART from another regimen. Overall, any INSTI use was associated with poorer learning post-INSTI. Specifically, use of dolutegravir and elvitegravir, but not raltegravir, was associated with poorer learning. In analyses restricted to INSTI switch, any INSTI use, and dolutegravir use, was associated with poorer learning. Among those switching from a PI-based regimen, INSTIs overall and dolutegravir remained associated with poorer learning; switching from a nonnucleoside reverse transcriptase inhibitor to dolutegravir was also associated with poorer learning. INSTI start/switch was not related to depressive symptom changes.
CONCLUSIONS
INSTI use was associated with poorer learning among WWH. These changes were mainly observed in elvitegravir and dolutegravir users, indicating that the impact of INSTI on cognition in WWH may not be a class effect.
Topics: Adult; Female; HIV Infections; HIV Integrase; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Integrases; Middle Aged; Oxazines; Piperazines; Prospective Studies; Pyridones; Quinolones; Raltegravir Potassium; Reverse Transcriptase Inhibitors; United States
PubMed: 33394812
DOI: 10.1097/QAI.0000000000002608 -
CPT: Pharmacometrics & Systems... Feb 2021Once-daily two 600 mg tablets (1200 mg q.d.) raltegravir offers an easier treatment option compared to the twice-daily regimen of one 400 mg tablet. No... (Comparative Study)
Comparative Study
Once-daily two 600 mg tablets (1200 mg q.d.) raltegravir offers an easier treatment option compared to the twice-daily regimen of one 400 mg tablet. No pharmacokinetic, efficacy, or safety data of the 1200 mg q.d. regimen have been reported in pregnant women to date as it is challenging to collect these clinical data. This study aimed to develop a population pharmacokinetic (PopPK) model to predict the pharmacokinetic profile of raltegravir 1200 mg q.d. in pregnant women and to discuss the expected pharmacodynamic properties of raltegravir 1200 mg q.d. during pregnancy based on previously reported concentration-effect relationships. Data from 11 pharmacokinetic studies were pooled (n = 221). A two-compartment model with first-order elimination and absorption through three sequential transit compartments best described the data. We assessed that the bio-availability of the 600 mg tablets was 21% higher as the 400 mg tablets, and the bio-availability in pregnant women was 49% lower. Monte-Carlo simulations were performed to predict the pharmacokinetic profile of 1200 mg q.d. in pregnant and nonpregnant women. The primary criteria for efficacy were that the lower bound of the 90% confidence interval (CI) of the concentration before next dose administration (C ) geometric mean ratio (GMR) of simulated pregnant/nonpregnant women had to be greater than 0.75. The simulated raltegravir C GMR (90% CI) was 0.51 (0.41-0.63), hence not meeting the primary target for efficacy. Clinical data from two pregnant women using 1200 mg q.d. raltegravir showed a similar C ratio pregnant/nonpregnant. Our pharmacokinetic results support the current recommendation of not using the raltegravir 1200 mg q.d. regimen during pregnancy until more data on the exposure-response relationship becomes available.
Topics: Adult; Aged; Anti-HIV Agents; Biological Availability; Computer Simulation; Drug Compounding; Female; HIV Infections; HIV-1; Humans; Infectious Disease Transmission, Vertical; Middle Aged; Models, Biological; Predictive Value of Tests; Pregnancy; Pregnant Women; Raltegravir Potassium; Safety; Treatment Outcome
PubMed: 33369217
DOI: 10.1002/psp4.12586 -
Revista Espanola de Quimioterapia :... Feb 2021There are generic fixed-dose combinations (FDCs) of ritonavir-boosted darunavir (DRV/r) available in Argentina. Experiences with these FDCs in dual therapy remain...
OBJECTIVE
There are generic fixed-dose combinations (FDCs) of ritonavir-boosted darunavir (DRV/r) available in Argentina. Experiences with these FDCs in dual therapy remain limited in clinical practice. We aimed to describe clinical and virologic outcomes in patients exposed to FDC DRV/r + raltegravir (RAL) 400 mg every 12 h in a real-life setting.
METHODS
Retrospective analysis of electronic medical records of HIV-infected patients under FDC DRV/r + RAL in an HIV clinic in Argentina (2014-2018). Individuals were classified as "switch group" (SG, undetectable viral load [VL] with any toxicity/comorbidity) and "virologic group· (VG, detectable viremia and infection by multidrug-resistant HIV).
RESULTS
Of 7,380 patients on ART, 116 (1.5%) received FDC DRV/r + RAL, being 58% in SG. Sixty percent received DRV/r 800/100 mg dose (rest, 600/100 mg). The median (IQR) age and CD4+ T-cell count were: 52 (42-58) years, and 373 cell/µL (202-642). Ninety-eight percent were ART-experienced with a median of 3 (IQR 2-5) prior treatments. Main reasons for switch (SG) were renal (57%), cardiovascular (54%) and bone (14%) comorbidities. Median exposure to DRV/r + RAL was 18 months. Among patients in SG, 98% and 96% had undetectable VL at 6 and 12 months; in the VG, 89% and 87% had undetectable VL at 6 and 12 months. No patient required suspension due to toxicity/ intolerance.
CONCLUSIONS
In this cohort of mostly experienced HIV-infected patients, FDC DRV/r + RAL was effective and safe. Such therapy may be considered an option for patients with comorbid conditions and/or with multidrug-resistant HIV.
Topics: Anti-HIV Agents; Argentina; Darunavir; HIV Infections; HIV Protease Inhibitors; Humans; Raltegravir Potassium; Retrospective Studies; Ritonavir; Viral Load
PubMed: 33267555
DOI: 10.37201/req/090.2020 -
Journal of Infection and Public Health Dec 2020Outbreak of COVID-19 has been recognized as a global health concern since it causes high rates of morbidity and mortality. No specific antiviral drugs are available for...
Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine against main protease and RNA-dependent RNA polymerase of SARS-CoV-2: A molecular docking and drug repurposing approach.
BACKGROUND
Outbreak of COVID-19 has been recognized as a global health concern since it causes high rates of morbidity and mortality. No specific antiviral drugs are available for the treatment of COVID-19 till date. Drug repurposing strategy helps to find out the drugs for COVID-19 treatment from existing FDA approved antiviral drugs. In this study, FDA approved small molecule antiviral drugs were repurposed against the major viral proteins of SARS-CoV-2.
METHODS
The 3D structures of FDA approved small molecule antiviral drugs were retrieved from PubChem. Virtual screening was performed to find out the lead antiviral drug molecules against main protease (Mpro) and RNA-dependent RNA polymerase (RdRp) using COVID-19 Docking Server. Furthermore, lead molecules were individually docked against protein targets using AutoDock 4.0.1 software and their drug-likeness and ADMET properties were evaluated.
RESULTS
Out of 65 FDA approved small molecule antiviral drugs screened, Raltegravir showed highest interaction energy value of -9 kcal/mol against Mpro of SARS-CoV-2 and Indinavir, Tipranavir, and Pibrentasvir exhibited a binding energy value of ≥-8 kcal/mol. Similarly Indinavir showed the highest binding energy of -11.5 kcal/mol against the target protein RdRp and Dolutegravir, Elbasvir, Tipranavir, Taltegravir, Grazoprevir, Daclatasvir, Glecaprevir, Ledipasvir, Pibrentasvir and Velpatasvir showed a binding energy value in range from -8 to -11.2 kcal/mol. The antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine also exhibited good bioavailability and drug-likeness properties.
CONCLUSION
This study suggests that the screened small molecule antiviral drugs Raltegravir, Indinavir, Tipranavir, Dolutegravir, and Etravirine could serve as potential drugs for the treatment of COVID-19 with further validation studies.
Topics: Antiviral Agents; Coronavirus Protease Inhibitors; Drug Repositioning; Heterocyclic Compounds, 3-Ring; Humans; Indinavir; Molecular Docking Simulation; Nitriles; Oxazines; Piperazines; Pyridines; Pyridones; Pyrimidines; Pyrones; RNA-Dependent RNA Polymerase; Raltegravir Potassium; SARS-CoV-2; Sulfonamides; COVID-19 Drug Treatment
PubMed: 33168456
DOI: 10.1016/j.jiph.2020.10.015 -
European Journal of Pharmacology Jan 2021COVID-19 has intensified into a global pandemic with over a million deaths worldwide. Experimental research analyses have been implemented and executed with the sole...
COVID-19 has intensified into a global pandemic with over a million deaths worldwide. Experimental research analyses have been implemented and executed with the sole rationale to counteract SARS-CoV-2, which has initiated potent therapeutic strategy development in coherence with computational biology validation focusing on the characterized viral drug targets signified by proteomic and genomic data. Spike glycoprotein is one of such potential drug target that promotes viral attachment to the host cellular membrane by binding to its receptor ACE-2 via its Receptor-Binding Domain (RBD). Multiple Sequence alignment and relative phylogenetic analysis revealed significant sequential disparities of SARS-CoV-2 as compared to previously encountered SARS-CoV and MERS-CoV strains. We implemented a drug re-purposing approach wherein the inhibitory efficacy of a cluster of thirty known drug candidates comprising of antivirals, antibiotics and phytochemicals (selection contingent on their present developmental status in underway clinical trials) was elucidated by subjecting them to molecular docking analyses against the spike protein RBD model (developed using homology modelling and validated using SAVES server 5.0) and the composite trimeric structures of spike glycoprotein of SARS-CoV-2. Our results indicated that Camostat, Favipiravir, Tenofovir, Raltegravir and Stavudine showed significant interactions with spike RBD of SARS-CoV-2. Proficient bioavailability coupled with no predicted in silico toxicity rendered them as prospective alternatives for designing and development of novel combinatorial therapy formulations for improving existing treatment regimes to combat COVID-19.
Topics: Amides; Anti-Bacterial Agents; Antiviral Agents; Binding Sites; Drug Repositioning; Esters; Gabexate; Guanidines; Molecular Docking Simulation; Phytochemicals; Protein Binding; Pyrazines; Raltegravir Potassium; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Stavudine; Tenofovir; COVID-19 Drug Treatment
PubMed: 33160938
DOI: 10.1016/j.ejphar.2020.173720 -
Blood Jan 2021Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy that arises in a proportion of individuals who are long-term carriers of human...
Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive T-cell malignancy that arises in a proportion of individuals who are long-term carriers of human T-lymphotropic virus type 1. The median survival of aggressive subtypes is 8 to 10 months; with chemotherapy-based approaches, overall survival has remained largely unchanged in the ∼35 years since ATL was first described. Through the use of 4 representative case studies, we highlight advances in the biological understanding of ATL and the use of novel therapies such as mogamulizumab, as well as how they are best applied to different subtypes of ATL. We discuss the implementation of molecular methods that may guide diagnosis or treatment, although we accept that these are not universally available. In particular, we acknowledge discrepancies in treatment between different countries, reflecting current drug licensing and the difficulties in making treatment decisions in a rare disease, with limited high-quality clinical trial data.
Topics: Aged; Allografts; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Dexamethasone; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Human T-lymphotropic virus 1; Humans; Interferon-alpha; Leukemia-Lymphoma, Adult T-Cell; Male; Methotrexate; Middle Aged; Practice Patterns, Physicians'; Prednisone; Raltegravir Potassium; Recurrence; Remission Induction; Therapies, Investigational; Vincristine; Virus Activation; Zidovudine
PubMed: 33075812
DOI: 10.1182/blood.2019004045 -
HIV Medicine Feb 2021
Topics: Anti-HIV Agents; Emtricitabine; HIV Infections; Humans; Post-Exposure Prophylaxis; Pre-Exposure Prophylaxis; Raltegravir Potassium; Tenofovir
PubMed: 33063431
DOI: 10.1111/hiv.12938 -
AIDS Research and Human Retroviruses Jan 2021International guidelines recommend the use of integrase strand transfer inhibitor (INI)-based regimens as first-line antiretroviral (ARV) in both naive and experienced...
International guidelines recommend the use of integrase strand transfer inhibitor (INI)-based regimens as first-line antiretroviral (ARV) in both naive and experienced HIV-infected patients. We analyzed a multicenter cohort of HIV-infected patients, both naive and experienced, starting an ARV, including an INI. Chi-square test and nonparametric tests were used to assess differences in categorical and continuous variables, respectively. Kaplan-Meier survival analysis was performed to estimate the probability of maintaining the study drug and Cox-regression analysis to evaluate predictors of discontinuation. We enrolled 4,343 patients: 3,143 (72.4%) were males, with a median age of 49 years (interquartile range 41-55). Naive patients were 733 (16.9%), of whom 168 (22.9%) were AIDS presenters. Overall, 2,282 patients (52.5%) started dolutegravir (DTG), 1,426 (32.8%) raltegravir (RAL), and 635 (14.7%) elvitegravir (EVG). During 10,032 patient years of follow-up (PYFU), we observed 1,278 discontinuations (13 per 100 PYFU); 448 of them (35%) due to simplification and 355 (28%) to toxicities (98 for central nervous system toxicity). Reasons of discontinuation were different between INIs. Estimated probability of maintaining DTG at 3 and 4 years were 81.5% [95% confidence interval (CI): 80.5-82.5] and 76.3% (95% CI: 73.9-78.7), respectively; RAL 61.6% (95% CI: 60.2-63.0) and 54.1% (95% CI: 52.7-55.5); EVG 71.6% (95% CI: 69.2-74.0) and 68.3% (95% CI: 65.3-71.3) ( < .001). At a multivariable analysis, being on a RAL-based ARV [vs. DTG, adjusted hazard ratio (aHR) 2.9, 95% CI: 2.3-3.6, < .001], a EVG-based ARV (vs. DTG, aHR 1.3 95% CI: 1.1-1.7, = .049), and a peak HIV-RNA >500k cp/mL (aHR 1.3, 95% CI: 1.1-1.6, = .006) predicted INI discontinuation. Our data confirm the good tolerability of INIs in clinical practice. Differences emerge between the three drugs in reasons for discontinuation.
Topics: HIV Infections; HIV Integrase Inhibitors; Heterocyclic Compounds, 3-Ring; Humans; Italy; Male; Middle Aged; Oxazines; Piperazines; Raltegravir Potassium
PubMed: 32998526
DOI: 10.1089/AID.2020.0078