raltegravir-potassium and AIDS-Dementia-Complex

The neuro-pathogenic mechanism(s) underlying HIV-associated neurocognitive disorders are mostly unknown. HIV-infected macrophages and microglial cells play a crucial role and the metabolic fate of l-arginine may be highly relevant to microglia activation. In this context, arginase (ARG), which uses l-arginine as substrate, can be on the same time a target and source of oxidative stress and inflammation. In this study, we investigated whether integrase strand transfer inhibitors share with the other antiretroviral drugs the ability to inhibit ARG activity. We used the previously validated cell model, namely the human microglia cell line, as well as the computational chemistry approach. Furthermore, here we characterized the activity of purified human ARG in a cell-free in vitro system, and investigated the effects of integrase strand transfer inhibitors in this newly validated model. Overall evidence shows that Dolutegravir, Raltegravir and Elvitegravir inhibit ARG activity.

Topics: AIDS Dementia Complex; Arginase; Cell-Free System; Cells, Cultured; Heterocyclic Compounds, 3-Ring; HIV Integrase Inhibitors; Humans; Microglia; Molecular Docking Simulation; Oxazines; Piperazines; Pyridones; Quinolones; Raltegravir Potassium

The application of combination antiretroviral therapy has greatly reduced the death rate from AIDS. However, up to 50% of patients on combination antiretroviral therapy develop HIV-associated neurocognitive disorders (HAND), which is associated with residual neuroinflammation and oxidative injury in the brain. Neural stem cells (NSCs) and progenitors play a vital role in repairing neuronal injuries. Therefore, we hypothesize that combination antiretroviral therapy may adversely affect NSCs/progenitors, contributing to the increasing prevalence of HAND. Here, we show that combined medication of three antiretroviral drugs tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and raltegravir (RAL) affects NSC homeostasis and progenitor proliferation in the mouse dentate gyrus (DG). Our results also show that TDF/FTC/RAL treatment prohibits proliferation and induces apoptosis of cultured mouse neural progenitor cells (NPCs), resulting in a reduction in the viability of NPCs. Moreover, we find that TDF, among the three drugs used in this combination antiretroviral treatment, accounts for most of the effects on neural progenitors. Together, our results offer a mechanistic explanation for the prevalence of HAND in AIDS patients treated with combination antiretroviral therapy.

Topics: AIDS Dementia Complex; Animals; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Cell Proliferation; Emtricitabine; Mice; Mice, Inbred C57BL; Neural Stem Cells; Raltegravir Potassium; Tenofovir

We report a case of a new diagnosis of HIV with an extremely high viral load presenting with HIV encephalopathy, in a 54-year-old woman who had been treated with 2 years of extended high-dose immunosuppressant therapy for a recalcitrant pruritic rash before diagnosis.

Topics: AIDS Dementia Complex; Anti-HIV Agents; Black People; CD4 Lymphocyte Count; Darunavir; Delayed Diagnosis; Dermatitis, Atopic; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Female; HIV-1; Humans; Immunosuppressive Agents; Middle Aged; Predictive Value of Tests; Prednisolone; Raltegravir Potassium; Ritonavir; Treatment Outcome; Viral Load

A 57-year-old man presented with subacute progression of cognitive impairment (MMSE 22/30). He had been diagnosed as AIDS two years before and taking atazanavir, abacavir, and lamivudine. HIV RNA of plasma had been negative. On admission, HIV RNA was 4,700 copy/ml and 5,200 copy/ml in plasma and in cerebrospinal fluid respectively, suggesting treatment failure of cART. The brain magnetic resonance imaging showed high intensity areas in the white matter of the both frontal lobes and brain stem. The drug-resistance test revealed the resistance of lamivudine and abacavir. We introduced the CNS penetration effectiveness (CPE) score to evaluate the drug penetration of HIV drugs. As the former regimen had low points (7 points), we optimized the regimen to raltegravir, zidovudine, and darunavir/ritonavir (scoring 10 points). His cognitive function improved as normal (MMSE 30/30) in 2 weeks and HIV-RNA became undetectable both in plasma and CSF in a month. In spite of the cognitive improvement, the white matter hyperintensity expanded. To rule out malignant lymphoma or glioblastoma, the brain biopsy was performed from the right frontal lobe. It revealed microglial hyperplasia and diffuse perivascular infiltration by CD8+/CD4-lymphocytes. No malignant cells were found and the polymerase chain reaction analyses excluded other viruses. Considering the drug penetration to the central nervous system is important for treating HIV encephalopathy.

Topics: AIDS Dementia Complex; Anti-Retroviral Agents; Central Nervous System; Cognition Disorders; Darunavir; Disease Progression; Drug Resistance, Viral; Drug Substitution; HIV; HIV Infections; Humans; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Ritonavir; RNA, Viral; Sulfonamides; Time Factors; Viremia; Zidovudine

We report the first published case of integrase inhibitor resistance in the central nervous system compartment in the absence of evidence of integrase inhibitor resistance in the plasma of a patient without human immunodeficiency virus (HIV)-encephalitis in the context of other HIV-associated central nervous system infections.

Topics: AIDS Dementia Complex; Anti-HIV Agents; Brain; Cerebrospinal Fluid; Drug Resistance, Viral; HIV; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Plasma; Pyrrolidinones; Radiography; Raltegravir Potassium

Topics: Adult; AIDS Dementia Complex; CD4 Lymphocyte Count; Chromatography, Liquid; HIV Infections; HIV-1; Humans; Male; Pyrrolidinones; Raltegravir Potassium; RNA, Viral; Spinal Puncture; Young Adult