abacavir and etravirine

Highly active antiretroviral treatment has led to unprecedented efficacy and tolerability in people living with HIV. This effect was also observed in the central nervous system with the nowadays uncommon observation of dementias; yet in more recent works milder forms are still reported in 20-30% of optimally treated individuals. The idea of a subclinical neuronal toxicity induced by antiretrovirals has been proposed and was somehow supported by the late-emerging effects associated with efavirenz use. In this manuscript we are reviewing all the potential mechanisms by which antiretroviral drugs have been associated with in vitro, ex vivo, or in vivo toxicity to cells pertaining to the central nervous system (neurons, astrocytes, oligodendrocytes, and endothelial cells). These include direct or indirect effects and pathological pathways such as amyloid deposition, damage to small cerebral vessels, and impairment in neurotransmission. The aim of this review is therefore to provide a detailed description of the available literature in order to guide further clinical research for improving patients' neurocognition and quality of life.

Topics: Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Astrocytes; Atazanavir Sulfate; Benzoxazines; Central Nervous System; Cognitive Dysfunction; Cyclopropanes; Dideoxynucleosides; Endothelial Cells; HIV Infections; Humans; Neurons; Nevirapine; Nitriles; Oligodendroglia; Pyrimidines

TMC125, a next generation, non-nucleoside reverse transcriptase inhibitor (NNRTI), demonstrated a remarkable decline of plasma HIV-1 RNA during a phase IIa study. We compared the initial rate of decline of plasma HIV-1 RNA achieved by TMC125 monotherapy with that of a triple class, five-drug regimen, containing drugs from all three currently licensed classes (zidovudine, lamivudine, abacavir, indinavir and nevirapine).. The decline in plasma HIV-1 RNA of 12 HIV-1 infected, antiretroviral (ART) naive patients treated for 1 week with TMC125 monotherapy was compared with that observed in the ERA study (n = 11). The plasma HIV-1 RNA elimination rate constant was calculated based on at least four plasma HIV-1 RNA measurements during the first week of treatment (first-order elimination) and compared using the Student's t test.. Median ages were 23 and 38 years for TMC125 and ERA patients, respectively (P = 0.001), median baseline plasma HIV-1 RNA levels were 4.2 and 4.8 log10 copies/ml (P = 0.001) and median baseline CD4 T-cell counts were 458 x 10(6) and 360 x 10(6) cells/l (P = 0.08). The median plasma HIV-1 RNA elimination rate constant was 0.68/day in TMC125 treated patients, and 0.56/day in ERA participants (P = 0.24). The median decline in plasma HIV-1 RNA after 7 days was 1.92 and 1.76 log10 copies (P = 0.77) and the median increase of CD4 T cells was 119 x 10(6) and 60 x 10(6) cells/l, respectively (P = 0.29).. Monotherapy with TMC125 in ART-naive, HIV-1-infected individuals resulted in a similar rate of decline of plasma HIV-1 RNA during 1 week of therapy as therapy with a five-drug regimen.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; Dideoxynucleosides; Double-Blind Method; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Lamivudine; Male; Nevirapine; Nitriles; Pyridazines; Pyrimidines; Reverse Transcriptase Inhibitors; RNA, Viral; Treatment Outcome; Zidovudine

Topics: Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Insulin; Lamivudine; Menopause; Nitriles; Oxazines; Piperazines; Pyridones; Pyrimidines; Raltegravir Potassium; Waist Circumference; Weight Gain

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

Topics: Animals; Anti-HIV Agents; Bone and Bones; Bone Density; Catalase; Dideoxynucleosides; Glutathione; Glutathione Peroxidase; Kidney; Liver; Male; Malondialdehyde; Nitriles; Oxidative Stress; Pyrimidines; Rats; Rats, Wistar; Semen; Superoxide Dismutase; Testis

Trends in resistance to antiretroviral drugs for HIV-1 may inform clinical support and drug development. We evaluated drug resistance mutation (DRM) trends for nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), and integrase strand transfer inhibitor (INSTI) in a large U.S. reference laboratory database. DRMs with a Stanford HIV Drug Resistance Database mutation score ≥10 from deidentified subtype B NRTI/NNRTI/PI specimens (2006-2017; >10,000/year) and INSTI specimens (2010-2017; >1,000/year) were evaluated. Sequences with NRTI, NNRTI, or PI single- or multiclass DRMs declined from 48.9% to 39.3%. High-level dual- and triple-class resistance declined from 43.3% (2006) to 17.1% (2017), while sequences with only single-class DRMs increased from 40.0% to 52.9%. The prevalence of DRMs associated with earlier treatment regimens declined, while prevalence of some DRMs associated with newer regimens increased. M184V/I decreased from 48.3% to 29.4%. K103N/S/T declined from 42.5% in 2012 to 36.4% in 2017. Rilpivirine and etravirine DRMs E138A/Q/R and E138K increased from 4.9% and 0.4% to 9.7% and 1.7%, respectively. Sequences with ≥1 darunavir DRM declined from 18.1% to 4.8% by 2017. INSTI DRM Q148H/K/R declined from 39.3% (2010) to 13.8% (2017). Prevalence of elvitegravir-associated DRMs T66A/I/K, E92Q, S147G, and the dolutegravir-associated DRM R263K increased. For a subset of patients with serial testing, 50% (2,646/5,290) of those who initially had no reportable DRM subsequently developed ≥1 DRM for NRTI/NNRTI/PI and 49.7% (159/320) for INSTI. These trends may inform the need for baseline genotypic resistance testing. The detection of treatment-emergent DRMs in serially tested patients confirms the value of genotypic testing following virologic failure.

Topics: Anti-HIV Agents; Darunavir; Dideoxynucleosides; Drug Resistance, Viral; Genotype; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; HIV Protease Inhibitors; HIV-1; Humans; Mutation; Nitriles; Oxazines; Piperazines; Pyridazines; Pyridones; Pyrimidines; Reverse Transcriptase Inhibitors; Rilpivirine

Recently increasing emphasis is placed on preventive health and management of chronic comorbidities avoiding long-term toxicities of antiretroviral therapy (ART). Drawing from this background we decided to use the Saos-2, osteosarcoma cell line, as a cellular model, to evaluate the effects of some antiretroviral drugs such as abacavir (ABC), tenofovir (TDF), efavirenz (EFV), etravirine (ETR), and darunavir (DRV), on bone differentiation related pathways. According to our observation, treatment with TDF and ABC affects the ability of the cells to produce calcium deposits with a reduced expression of type I collagen gene and p21 mRNA, also increasing the activity of Wnt3a related pathway. On the other hand treatment with EFV and DRV was not related to any significant reduction of calcium deposits but displayed a decrease in the expression of Wnt3a at day 14 and Type I Collagen at day 7 compared with untreated cells, even if this last down regulation was not confirmed at day 14. Instead ETR administration to Saos-2 cells increases the calcium deposits collagen type I production, as a result of Wnt3a mRNA overexpression, and of an upregulation of collagen type I expression, being also the only drug able to increase the expression of p21 cdk inhibitor as further marker of terminal differentiation. In summary these data suggest the potential negative interference of TDF and ABC on bone differentiation. DRV and EFV partially affect collagen type I production, instead ETR facilitates a positive bone balance as a result of an increased osteoblasts terminal differentiation.

Topics: Alkynes; Antiretroviral Therapy, Highly Active; Benzoxazines; Bone Development; Calcium; Cell Differentiation; Cell Line, Tumor; Collagen Type I; Cyclopropanes; Darunavir; Dideoxynucleosides; Gene Expression Regulation, Developmental; HIV-1; Humans; Nitriles; Osteosarcoma; p21-Activated Kinases; Pyridazines; Pyrimidines; RNA, Messenger; Tenofovir; Wnt3A Protein

Topics: Adult; Anti-HIV Agents; Brain Edema; Darunavir; Diagnosis, Differential; Dideoxynucleosides; Emergencies; Female; Hepatitis C, Chronic; HIV Infections; HIV-1; Humans; Hypertension, Malignant; Hypertensive Encephalopathy; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Nitriles; Posterior Leukoencephalopathy Syndrome; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Ritonavir; Sulfonamides; Tomography, X-Ray Computed; Toxoplasmosis, Cerebral

Topics: Anti-HIV Agents; Child; Controlled Clinical Trials as Topic; Dideoxynucleosides; Drug Approval; Drug Labeling; Female; Growth Hormone-Releasing Hormone; HIV Infections; HIV-Associated Lipodystrophy Syndrome; Humans; Infant; Infant, Newborn; Male; Nitriles; Pyridazines; Pyrimidines; Randomized Controlled Trials as Topic; Reverse Transcriptase Inhibitors; Stavudine; United States; United States Food and Drug Administration

Topics: Alkynes; Anti-HIV Agents; Benzoxazines; Body Fat Distribution; Cognition; Cyclopropanes; Diabetes Mellitus; Dideoxynucleosides; Ginkgo biloba; Growth Hormone-Releasing Hormone; Heart Diseases; Humans; Nitriles; Pyridazines; Pyrimidines

Topics: Acyclovir; Anti-HIV Agents; Circumcision, Male; Cyclohexanes; Dideoxynucleosides; Drug Interactions; Female; Hepatitis C; HIV Fusion Inhibitors; HIV Infections; Humans; Male; Maraviroc; Multicenter Studies as Topic; Nitriles; Organic Chemicals; Pyridazines; Pyrimidines; Pyrrolidinones; Raltegravir Potassium; Randomized Controlled Trials as Topic; Triazoles