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Oxidative Medicine and Cellular... 2021Highly active antiretroviral therapy (HAART) is used in HIV-infected patients. Alongside the prolongation of patients' life, adverse side effects associated with...
Highly active antiretroviral therapy (HAART) is used in HIV-infected patients. Alongside the prolongation of patients' life, adverse side effects associated with long-term therapy are becoming an increasing problem. Therefore, optimizing of HAART is extremely important. The study is aimed at evaluating the toxicity of abacavir and etravirine in monotherapy on the reproductive system, liver, kidneys, and bones in young, sexually mature, male rats. Thirty-six 8-week-old male Wistar rats randomized into three 12-animal groups received either normal saline (control), abacavir 60 mg/kg (AB group), or etravirine 40 mg/kg (ET group) once daily for 16 weeks. Semen morphology, oxide-redox state parameters (MDA, SOD, catalase, GPx, glutathione, GSH/GSSG ratio) in tissue homogenates (testes, liver, kidneys), and serum samples were studied. In bones, microcomputed tomography and a four-point bending test were performed. Total sperm count, sperm concentration, motility, and sperm morphology did not differ significantly in AB or ET groups compared to the control. In the flow cytometry of semen, an increased percentage of cells with denatured DNA was noticed for both tested drugs. However, no significant changes of oxide-redox state in testicular homogenates were found, except of increased SOD activity in the AB-receiving group. Additionally, ET significantly altered catalase and GPx in the liver and SOD activity in kidneys. Abacavir decreased catalase in the liver and GSH levels in kidneys. AB caused significant changes to bone microarchitecture (bone volume fraction, trabecular number, connectivity density, total porosity) and increased Young's modulus. Etravirine had a greater impact on macrometric parameters of bones (tibial index, mid-tibial diameter, femur length). After 4 weeks in the ET group, a lower 1,25-dihydroxyvitamin D serum concentration was found. The results showed that abacavir and etravirine disturb oxidative stress. An increase in the percentage of sperms with chromatin damage suggests decreased fertility in rats receiving the studied drugs. Both drugs affected bone formation in growing rats. Additionally, etravirine disturbed vitamin D metabolism.
Topics: Animals; Anti-HIV Agents; Bone Density; Bone and Bones; Catalase; Dideoxynucleosides; Glutathione; Glutathione Peroxidase; Kidney; Liver; Male; Malondialdehyde; Nitriles; Oxidative Stress; Pyrimidines; Rats; Rats, Wistar; Semen; Superoxide Dismutase; Testis
PubMed: 34373766
DOI: 10.1155/2021/5596090 -
Pharmacogenomics Aug 2012Immunologically mediated drug reactions have been traditionally classified as unpredictable based on the fact that they cannot be predicted strictly on the... (Review)
Review
Immunologically mediated drug reactions have been traditionally classified as unpredictable based on the fact that they cannot be predicted strictly on the pharmacological action of the drug. Such adverse drug reactions are associated with considerable morbidity and include severe cutaneous adverse reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis and the drug hypersensitivity syndromes (drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome). Over the last decade there have been many associations between these syndromes and Class I and II HLA alleles of the MHC, which have enriched and driven our knowledge of their immunopathogenesis. Significant translation has also occurred in the case of HLA-B*5701 screening being used to exclude at risk patients from abacavir and prevent abacavir hypersensitivity. The ultimate translation of the knowledge of how drugs interact with HLA would be applicable to preclinical drug screening programs to improve the safety and cost-effectiveness of drug design and development.
Topics: Alleles; Biomarkers, Pharmacological; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; HLA Antigens; Humans; Pharmacogenetics; Stevens-Johnson Syndrome
PubMed: 22920398
DOI: 10.2217/pgs.12.108 -
PloS One 2022Indices of cardiovascular disease (CVD) risk, vascular endothelial dilation, arterial stiffness and endothelial repair were examined in persons with HIV (PWH) on an...
OBJECTIVE
Indices of cardiovascular disease (CVD) risk, vascular endothelial dilation, arterial stiffness and endothelial repair were examined in persons with HIV (PWH) on an antiretroviral therapy (ART) that included abacavir (ABC+) in comparison with PWH on ART without abacavir (ABC-), and with HIV seronegative (HIV-) individuals.
APPROACH
The 115 participants (63% men), aged 30-50 years, did not have CVD, metabolic, endocrine, or chronic renal conditions. PWH were on stable ART for six-months or more. Vascular assessments included flow-mediated dilation (FMD), aortic, radial and femoral arterial stiffness (cAIx, crPWV, cfPWV), and thigh and calf arterial compliance (Vmax50). Endothelial repair was indexed by endothelial progenitor cell colony forming units (EPC-CFU). Traditional CVD risk measures included blood pressure, central adiposity, lipids, insulin resistance (HOMA-IR), CRP and ASCVD score. Analyses controlled for demographics (age, sex, education), medications (antihypertensive, statin/fibrate, antipsychotic), and substance abuse (ASSIST).
RESULTS
No group differences were observed in central adiposity, HOMA-IR, CRP, or ASCVD risk score. However, the ABC- group displayed greater dyslipidemia. The ABC+ group displayed no difference on FMD, cAIx, cfPWV or calf Vmax50 compared with other groups. When CD4 count and viral load were controlled, no additional differences between the ABC+ and ABC- groups emerged. Analyses of crPWV and thigh Vmax50 suggested supported by a trend toward lower EPC-CFU in the HIV+ groups than the HIV- group.
CONCLUSIONS
Findings indicate that ABC treatment of 30-50 year-old PWH on stable ART is not likely to contribute in a robust way to higher CVD risk.
Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Dideoxynucleosides; Female; HIV Infections; Humans; Male; Middle Aged; Vascular Diseases
PubMed: 35271614
DOI: 10.1371/journal.pone.0264445 -
Antimicrobial Agents and Chemotherapy Sep 2017Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy...
Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters and assess its importance for pharmacokinetics Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; Biological Transport; Caco-2 Cells; Cell Line; Cell Line, Tumor; Dideoxynucleosides; Dogs; Drug Interactions; Humans; Intestinal Absorption; Lamivudine; Madin Darby Canine Kidney Cells; Male; Membrane Transport Proteins; Rats; Rats, Wistar; Reverse Transcriptase Inhibitors; Rilpivirine
PubMed: 28696229
DOI: 10.1128/AAC.00837-17 -
Drugs Nov 2018Bictegravir is a new integrase strand transfer inhibitor (INSTI) with a high genetic barrier to the development of HIV-1 resistance. The drug is co-formulated with the... (Review)
Review
Bictegravir is a new integrase strand transfer inhibitor (INSTI) with a high genetic barrier to the development of HIV-1 resistance. The drug is co-formulated with the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (AF) in a single-tablet regimen (STR) for the once-daily treatment of HIV-1 infection in adults (bictegravir/emtricitabine/tenofovir AF; Biktarvy). In phase 3 trials, bictegravir/emtricitabine/tenofovir AF was noninferior to dolutegravir-based therapy (dolutegravir/abacavir/lamivudine or dolutegravir plus emtricitabine/tenofovir AF) in establishing virological suppression in treatment-naïve adults through 96 weeks' treatment and, similarly, was noninferior to ongoing dolutegravir/abacavir/lamivudine or boosted elvitegravir- or protease inhibitor (PI)-based therapy in preventing virological rebound over 48 weeks in treatment-experienced patients. No resistance emerged to any of the antiretrovirals in the STR. Bictegravir/emtricitabine/tenofovir AF is generally well tolerated, requires no prior HLA-B*5701 testing (making it more suitable for 'rapid start' treatment), fulfils the antiretroviral regimen requirement for patients with hepatitis B virus (HBV) co-infection (i.e. contains tenofovir AF and emtricitabine, both of which are active against HBV) and can be used in renally impaired patients with creatinine clearance (CR) ≥ 30 mL/min. Thus, although cost-effectiveness analyses would be beneficial, current data indicate that bictegravir/emtricitabine/tenofovir AF is a convenient initial and subsequent treatment option for adults with HIV-1 infection, including those co-infected with HBV, and provides the first non-pharmacologically boosted, INSTI-based, triple-combination STR suitable for patients with CR 30-50 mL/min.
Topics: Adenine; Adult; Alanine; Amides; Anti-HIV Agents; Dideoxynucleosides; Dose-Response Relationship, Drug; Drug Combinations; Emtricitabine; HIV Infections; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, 4 or More Rings; Humans; Lamivudine; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Tenofovir; Treatment Outcome
PubMed: 30460547
DOI: 10.1007/s40265-018-1010-7 -
Microbiology and Immunology Mar 2020Susceptibility to abacavir hypersensitivity (ABH) in HIV-1-positive patients is strongly linked to the carriage of HLA-B*57:01 and the potential mechanism includes...
Susceptibility to abacavir hypersensitivity (ABH) in HIV-1-positive patients is strongly linked to the carriage of HLA-B*57:01 and the potential mechanism includes drug-specific activation of cytokine producing CD8 T cells exclusively in individuals carrying HLA-B*57:01. Here, we report a detailed characterization of abacavir-induced functional response of CD8 T cells in HLA-B*57:01 individuals. Peripheral blood mononuclear cells (PBMNCs) from HLA-B*57:01 ABH and HLA-B*57:01 ABH individuals were stimulated with abacavir. Multicolor flow cytometry was performed to assess the cytokine (IFNγ) production and degranulation (CD107a expression) after 6-18 hr culture and to enumerate proliferating CD4/CD8 T cells by culturing carboxyfluorescein diacetate succinimidyl ester-loaded PBMNCs for 7 days. CD8 T cells from HLA-B*57:01 ABH individuals were multifunctional: proliferating, IFNγ producing, degranulating (CD107a ), and both degranulating and IFNγ producing (CD107a IFNγ ). Degranulating CD8 T cells in general and both degranulating and IFNγ producing CD8 T cells in particular dominated abacavir-specific immune response. All functional responses were partially blocked by addition of HLA-B*57:01-reactive Bw4 mAb, but not by non-HLA-B*57:01-reactive Bw6 mAb. In conclusion, the study demonstrates that abacavir-specific CD8 T-cell-restricted immune response in HLA-B*57:01 ABH HIV-1 patients has multiple effector and proliferating functions, where the primary effector response appears to be the release of cytolytic granules. The findings have implications for immunotherapy of HLA-related drug hypersensitivities.
Topics: Anti-HIV Agents; CD8-Positive T-Lymphocytes; Cytokines; Dideoxynucleosides; Drug Hypersensitivity; HIV Infections; HIV-1; HLA-B Antigens; Humans; Interferon-gamma; Leukocytes, Mononuclear
PubMed: 31876322
DOI: 10.1111/1348-0421.12769 -
PloS One 2013Recent studies suggest certain antiretroviral therapy (ART) drugs are associated with increases in cardiovascular disease. (Review)
Review
BACKGROUND
Recent studies suggest certain antiretroviral therapy (ART) drugs are associated with increases in cardiovascular disease.
PURPOSE
We performed a systematic review and meta-analysis to summarize the available evidence, with the goal of elucidating whether specific ART drugs are associated with an increased risk of myocardial infarction (MI).
DATA SOURCES
We searched Medline, Web of Science, the Cochrane Library, and abstract archives from the Conference on Retroviruses and Opportunistic Infections and International AIDS Society up to June 2011 to identify published articles and abstracts.
STUDY SELECTION
Eligible studies were comparative and included MI, strokes, or other cardiovascular events as outcomes.
DATA EXTRACTION
Eligibility screening, data extraction, and quality assessment were performed independently by two investigators.
DATA SYNTHESIS
Random effects methods and Fisher's combined probability test were used to summarize evidence.
FINDINGS
Twenty-seven studies met inclusion criteria, with 8 contributing to a formal meta-analysis. Findings based on two observational studies indicated an increase in risk of MI for patients recently exposed (usually defined as within last 6 months) to abacavir (RR 1.92, 95% CI 1.51-2.42) and protease inhibitors (PI) (RR 2.13, 95% CI 1.06-4.28). Our analysis also suggested an increased risk associated with each additional year of exposure to indinavir (RR 1.11, 95% CI 1.05-1.17) and lopinavir (RR 1.22, 95% CI 1.01-1.47). Our findings of increased cardiovascular risk from abacavir and PIs were in contrast to four published meta-analyses based on secondary analyses of randomized controlled trials, which found no increased risk from cardiovascular disease.
CONCLUSION
Although observational studies implicated specific drugs, the evidence is mixed. Further, meta-analyses of randomized trials did not find increased risk from abacavir and PIs. Our findings that implicate specific ARTs in the observational setting provide sufficient evidence to warrant further investigation of this relationship in studies designed for that purpose.
Topics: Anti-HIV Agents; Cardiovascular Diseases; Humans; Protease Inhibitors; Reverse Transcriptase Inhibitors; Risk
PubMed: 23555704
DOI: 10.1371/journal.pone.0059551 -
Biomedicine & Pharmacotherapy =... Sep 2023Anti-human immunodeficiency virus (HIV) drug abacavir (ABC) binds to the specific allele of human leukocyte antigen (HLA-B*57:01) and activates CD8 T cells by presenting...
Anti-human immunodeficiency virus (HIV) drug abacavir (ABC) binds to the specific allele of human leukocyte antigen (HLA-B*57:01) and activates CD8 T cells by presenting altered abnormal peptides. Here, we examined the effect of ABC-induced altered self-presentation by HLA-B*57:01 on immunogenicity of cancer cells and CD8 T-cell-dependent anti-tumor immunity. We established human-mouse chimeric HLA-B*57:01-expressing tumor cell lines (B16F10 and 3LL) and tested the anti-tumor effect of ABC in vivo. ABC treatment inhibited the growth of HLA-B*57:01-expressing tumors by a CD8 T-cell-dependent mechanism. ABC treatment induced CXCR3-dependent infiltration of CD8 T cells into HLA-B*57:01-expressing tumors, and activated those tumor-infiltrating CD8 T cells to proliferate and secrete IFN-γ. The activation of CD8 T cells using drug-induced altered self-presentation may be a new strategy to increase tumor immunogenicity and improve the efficacy of immunotherapy.
Topics: Mice; Animals; CD8-Positive T-Lymphocytes; Antigens, Neoplasm; Cell Line, Tumor; Immunotherapy
PubMed: 37523987
DOI: 10.1016/j.biopha.2023.115241 -
British Journal of Pharmacology Jun 2023Abacavir, an antiretroviral drug used in HIV therapy associated with myocardial infarction, promotes thrombosis through P2X7 receptors. The role of platelets as...
BACKGROUND AND PURPOSE
Abacavir, an antiretroviral drug used in HIV therapy associated with myocardial infarction, promotes thrombosis through P2X7 receptors. The role of platelets as pro-thrombotic cells is acknowledged whereas that of neutrophils-due to their secretory capacity-is gaining recognition. This study analyses the role of neutrophils-specifically the secretome of abacavir-treated neutrophils (SN )-in platelet activation that precedes thrombosis.
EXPERIMENTAL APPROACH
Effects of abacavir or SN on platelet activation and platelet-leukocyte interactions and expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were analysed by flow cytometry. The secretome was analysed by proteomics. The role of leukocytes in the actions of abacavir was evaluated in a mouse model of thrombosis.
KEY RESULTS
Abacavir induced platelet-leukocyte interactions, not directly via effects of abacavir on platelets, but via activation of neutrophils, which triggered interactions between platelet P-selectin and neutrophil P-selectin glycoprotein ligand-1 (PSGL-1). SN stimulated platelet activation and platelet-leukocyte interactions through a process that was dependent on LOX-1, neutrophil P2X7 and platelet P2Y1, P2Y12 and P2X1 receptors. Abacavir induced the expression of LOX-1 on neutrophils and of the soluble form of LOX-1 (sLOX-1) in SN . Neutrophils, LOX-1, P2X7, P2Y1, P2Y12 and P2X1 receptors were required for the pro-thrombotic actions of abacavir in vivo.
CONCLUSION AND IMPLICATIONS
Neutrophils are target cells in abacavir-induced thrombosis. Abacavir released sLOX-1 from neutrophils via activation of their P2X7 receptors, which in turn activated platelets. Hence, sLOX-1 could be the missing link in the cardiovascular risk associated with abacavir.
Topics: Animals; Mice; Neutrophils; Receptors, Purinergic P2X7; Scavenger Receptors, Class E; Blood Platelets; Thrombosis; P-Selectin
PubMed: 36541109
DOI: 10.1111/bph.16016 -
HIV Medicine Apr 2022Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). The aim of the study was to evaluate changes in BMD in women who switched from... (Randomized Controlled Trial)
Randomized Controlled Trial
Bone mineral density, kidney function and participant-reported outcome measures in women who switch from tenofovir disoproxil emtricitabine and a nonnucleoside reverse transcriptase inhibitor to abacavir, lamivudine and dolutegravir.
OBJECTIVES
Tenofovir disoproxil fumarate (TDF) is associated with reduced bone mineral density (BMD). The aim of the study was to evaluate changes in BMD in women who switched from TDF, emtricitabine and a nonnucleoside reverse transcriptase inhibitor (TDF/FTC/NNRTI) to abacavir, lamivudine and dolutegravir (ABC/3TC/DTG).
METHODS
We conducted a randomized controlled trial in which women aged ≥ 40 years were randomized 1:2 to continue TDF/FTC/NNRTI or switch to ABC/3TC/DTG. We analysed changes in BMD at the hip and lumbar spine from baseline to week 96 using linear regression, and markers of bone turnover and kidney function using repeated measures mixed effects models with multiple imputation for missing data. We conducted exploratory analyses of weight, mental health, sleep and symptoms attributed to HIV infection and antiretroviral therapy.
RESULTS
Ninety-one women [mean (standard deviation) age 50.4 (6.6) years] were randomized. Women who switched to ABC/3TC/DTG maintained viral suppression and experienced improvements in BMD at the lumbar spine (but not the neck of the femur or the total hip), bone resorption markers and proteinuria (total protein, albumin and retinol-binding protein) and modest weight gain without changes in body mass index. Although mean anxiety, depression and sleep scores did not differ between the two study arms, anxiety, depression and sleep disturbance at baseline predicted ABC/3TC/DTG discontinuation for neuropsychiatric side effects [odds ratios (95% confidence intervals) 11.9 (2.0-71.6), 16.0 (2.6-97.9) and 10.0 (1.8-56.0), respectively].
CONCLUSIONS
Switching from TDF/FTC/NNRTI to ABC/3TC/DTG improved the BMD of the lumbar spine and kidney function. These benefits need to be balanced against modest weight gain and the need for antiretroviral therapy substitutions in a proportion of participants.
Topics: Adult; Anti-HIV Agents; Bone Density; Dideoxynucleosides; Drug Combinations; Emtricitabine; Female; HIV Infections; Heterocyclic Compounds, 3-Ring; Humans; Kidney; Lamivudine; Middle Aged; Oxazines; Patient Reported Outcome Measures; Piperazines; Pyridones; Reverse Transcriptase Inhibitors; Tenofovir
PubMed: 34866304
DOI: 10.1111/hiv.13215