RESUMEN
Boosted protease inhibitor (bPI) monotherapy has demonstrated high efficacy for maintaining viral suppression in the blood. bPI monotherapy has the theoretical advantage of avoiding the long-term toxicity associated with the use of nucleoside reverse transcriptase inhibitors. Concern about the efficacy of bPI monotherapy in preventing HIV replication in the CNS is one reason that has precluded the widespread use of this therapeutic strategy. In several studies, a low CNS penetration-effectiveness (CPE) score has been associated with a higher risk of virological failure in the CNS and with neurocognitive impairment. Since the CPE score is substantially lower for bPI monotherapy than for triple-drug highly active antiretroviral therapy (HAART), it has been postulated that bPI monotherapy might have a higher risk for CNS virological failure and neurocognitive impairment. However, the available evidence, although limited, does no support this notion. Lopinavir and darunavir achieve CSF drug levels that are sufficient to fully suppress HIV replication. In clinical trials, when compared with triple-drug HAART, patients receiving bPI monotherapy with lopinavir and darunavir who maintain full virological suppression in plasma do not appear to be at a higher risk of discordant HIV replication in the CSF or of neuropsychiatric adverse events. It should be noted that several studies have suggested that nucleoside reverse transcriptase inhibitors might have neurotoxic effects and, consequently, bPI monotherapy might be able to avoid the CNS toxicity induced by nucleosides. It is clear that more studies including detailed neurocognitive testing are needed to completely establish the risk/benefit ratio of bPI monotherapy or triple-drug HAART for preserving neurocognitive function in HIV-infected patients.
Asunto(s)
Complejo SIDA Demencia/prevención & control , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/efectos adversos , Inhibidores de la Proteasa del VIH/uso terapéutico , Síndromes de Neurotoxicidad/psicología , Terapia Antirretroviral Altamente Activa/efectos adversos , Quimioterapia Combinada , Infecciones por VIH/líquido cefalorraquídeo , Inhibidores de la Proteasa del VIH/líquido cefalorraquídeo , Humanos , Pruebas Neuropsicológicas , Medición de Riesgo , Replicación ViralRESUMEN
La neuroinflamación constituye un proceso clave en la neuropatogénesis del virus del sida como consecuencia de la activación aberrante de receptores de quimiocinas (CXCR4, CX3CR1 y CCR5), ya que la liberación de citocinas proinflamatorias por las células infectadas amplifica la neurotoxicidad microglial y genera lipoperóxidos y especies reactivas de oxígeno que, en última instancia, dañan la neurona. Por otro lado, la neurotoxina Tat induce alteraciones dendríticas por interacción con el receptor LRP (receptor de lipoproteínas de baja densidad) e induce una excesiva estimulación de los receptores de N-metil D-aspartato. Además, la interacción aberrante de la glucoproteína gp120 con el receptor CXCR4 induce apoptosis dependiente de caspasa 3 (también libera ceramida) y activa las proteínas apoptóticas p53 y retinoblastoma como mecanismos neurotóxicos asociados a la disfunción neural en el virus de la inmunodeficiencia humana 1 (VIH-1). Asimismo, la gliosis/activación microglial y la liberación de factores virales por los monocitos infectados, y el incremento de determinadas quimiocinas en el líquido cefalorraquídeo (MCP-1 y fractalcina, entre otras), contribuyen a la neuropatogénesis del VIH-1. Por otro lado, se han detectado depósitos de alfa-sinucleína y de beta-amiloide en cerebros post mortem de seropositivos de edad avanzada. Además, se han descrito varios marcadores sistémicos relacionados con los efectos degenerativos del virus y de sus neurotoxinas en el sistema nervioso central, tales como osteopontina, CD163 y fractalcina, entre otros. Por último, se han realizado ensayos clínicos basados en estrategias protectoras relacionadas con la inhibición de proteínas apoptóticas (inhibidores de GSK-3 beta), con inhibidores de la activación microglial (minociclina), antioxidantes (selegilina) o factores tróficos (IGF-1, hormona del crecimiento o eritropoyetina), que muestran efectos beneficiosos como tratamientos complementarios a la terapia antirretroviral (AU)
Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors (CXCR4, CX3CR1 and CR5) produces proinflammatory cytokine release by infected cells, increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species (ROS) that eventually damage the neuron. Moreover, the neurotoxin Tat produces dendritic loss by interacting with the low-density lipoprotein receptor (LRP) and also overstimulates N-methyl D-aspartate receptors (NMDA). Furthermore, the aberrant interaction of glycoprotein gp120 with the CXCR4 chemokine receptor causes caspase-3-dependent apoptosis (ceramide is also released) activating apoptotic proteins (p53 and retinoblastoma), which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS. Similarly, gliosis/microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid (MCP-1 and fractalkine, among others) contribute to the neuropathogenesis of HIV-1. Alpha-synuclein and beta amyloid deposits have also been detected in post mortem brains of seropositives patients. In addition, there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system; such as osteopontin, CD163 and fractalkine, among others. Lastly, clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins (GSK-3 beta), microglial activation inhibitors (minocycline), antioxidants (selegiline) or trophic factors (IGF-1, growth hormone or erythropoietin). These trials have shown that their treatments are beneficial and complementary to treat complications of HIV/AIDS (AU)