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ART / Neurotoxicity
  HAART & The Brain: "CNS Toxicity of Antiretroviral Drugs", "Can antiretroviral therapy prevent HIV-associated cognitive disorders?" - (01/13/14)
"the earlier initiation of cART may be associated with the development of neuronal toxicities......Summary: This review article highlights the recent literature and arguments for and against the earlier initiation of cART with regards to cognitive function.".......http://www.natap.org/2013/HIV/011314_02.htm
Numerous pathogenic mechanisms have been implicated with the development of cognitive impairment in the cART era. These include on-going neuroinflammation despite effective cART, antiretroviral factors and general patient factors such as other comorbidities, coinfections and lifestyle factors Table 1.
An individual's CD4+ lymphocyte count nadir is a marker of historical HIV-disease progression and a well described risk factor for the presence of cognitive impairment in many cohorts [4,10,15,25]. On the converse, for individuals on effective antiretroviral therapy, current CD4+ lymphocyte count has not been reported to be a strong risk factor for the presence of cognitive impairment. This may be due to HIV-disease progression, whereby as HIV-disease progresses, increased peripheral and CNS immune activation occurs. It is possible this process may persist despite effective cART and be a potential explanation for the strong clinical correlation observed between nadir CD4+ lymphocyte count and cognitive function, in which individuals with lower nadir CD4+ lymphocyte counts are more likely to display poorer cognitive function, despite higher CD4+ lymphocyte counts after effective cART.
On the converse, cerebral toxicities may ensue after the initiation of cART, which may cause cognitive decline. Laboratory studies suggest that many of the antiretroviral agents in current clinical use may have neuronal toxicities, even at the concentrations one would expect to observe in the CNS during general clinical usage [39]. In this study, cultured rat cortical neurones were challenged with several antiretroviral agents in current clinical use such as abacavir, efavirenz, etravirine, nevirapine and atazanavir within the range of concentrations one would expect to observe in plasma and CSF with standard clinical dosing. The study described a considerable loss of neurones caused by alterations of the neuronal calcium homeostasis and mitochondrial membrane potentials suggesting one possible mechanism for neuronal injury may be due to antiretroviral therapy itself.
CNS Toxicity of Antiretroviral Drugs
17th CROI Feb 16-20 2010 SF
J. Liner, R.B. Meeker, and K. Robertson*
Department of Neurology and Neurobiology Curriculum, University of North
Carolina, Chapel Hill
Could antiretroviral neurotoxicity play a role in the pathogenesis of cognitive impairment in treated HIV disease? - (01/23/15)
"This area is likely to become of increasing interest over the coming years, given that the cohort of PLWH is ageing, leading to an increase in comorbidity and drug-drug interactions with the added complication of age-related changes in the metabolism of antiretroviral drugs (mediated by changes in body mass, renal excretion, p-glycoprotein expression and the presence of polypharmacy amongst others). In conclusion, although there have been many studies assessing cognitive function in PLWH, few have looked specifically at the potentially toxic effects of cART. The evidence so far for antiretroviral CNS neurotoxicity is predominantly from preclinical work and further study is needed to assess the clinical significance of these findings and their impact on the modern manifestations of HIV-associated neurocognitive dysfunction."
In summary, there is compelling evidence that antiretroviral drugs are potentially toxic to neuronal cells because of disruption to the mitochondrial function, either by mutagenic effects on mtDNA or by disturbance of oxidative phosphorylation, leading to changes in cellular bioenergetics with increased production of ROS. This oxidative stress causes induction of multiple inflammatory pathways resulting in cellular dysfunction [32]. This potentially starts a vicious cycle with ROS and pro-inflammatory cytokines causing additional mitochondrial dysfunction though mtDNA damage and impairment of the electron transport chain. ROS from mitochondrial dysfunction has also been shown to produce amyloid beta which itself causes mitochondrial dysfunction and ROS exacerbating the vicious cycle further [33,34]. In addition, this pro-inflammatory milieu activates microglia and astrocytes, which in turn release pro-inflammatory cytokines, further contributing to this vicious cycle and setting up the conditions for chronic inflammation common to many neurodegenerative diseases, including HIV-associated cognitive dysfunction.
More recently, a more subtle form of neurotoxicity secondary to long-term efavirenz use has been associated with poorer cognitive function in cross-sectional studies [47,48].
Some specific symptoms have been associated with particular antiretroviral agents such as depression with raltegravir use, principally in those taking concomitant medications that would theoretically increase raltegravir plasma concentration
Evidence of depletion of mitochondrial DNA (mtDNA) in the frontal cortex, with a corresponding increase in oxidative DNA damage, has been reported in HIV-infected individuals compared to HIV-uninfected controls from a small autopsy series [13].
Interestingly, the authors of this series of experiments demonstrated that neuronal cells, from both human cell lines and primary rat culture, are more vulnerable to efavirenz-induced mitochondrial dysfunction than the glial cells.
Using an in-vitro primary neuronal cell culture model, the same authors reported neuronal death and damage after exposure to saquinavir and ritonavir, but not to stavudine or zidovudine.
Other models of potential toxicity have been reported. In a neuronal cell culture experiment, zidovudine, lamivudine, indinavir and abacavir were associated with increased neuronal beta-amyloid production, as well as a marked decrease in the ability of microglial cells to phagocytose beta-amyloid [26].

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