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Neurological/Cognitive Impairment on HAART: 50% on HAART have cognitive impairment
  HIV-Associated Neurocognitive Disease Continues in the Antiretoviral Era
patients who have common neurologic. complications, such as HIV-associated. neurocognitive disorders (HAND), pro-. Dr Letendre is Associate Professor in the
"we need to support efforts to decide if brain penetration is a crucial component in the design of therapy"
"As HIV practitioners, we must be aware of possible ongoing disruption of neurocognitive function in our patients who otherwise appear to be doing well and to the potential for HIV-related neurologic damage in the HIV-infected population as a whole. Optimization of HIV therapy in this regard may include starting antiretroviral treatment early enough to avoid neuronal loss and using viral control in the CNS as an efficacy measure. Good CNS penetration does not appear to have been a goal of recent antiretroviral drug development, and we need to support efforts to decide if brain penetration is a crucial component in the design of therapy. We should also encourage further research to develop effective means to protect the brain from alternate pathways of damage. New therapies for amyloid toxicity are being developed, and these may eventually play a role in the treatment of HIV-associated dementia."
"New therapies for amyloid toxicity are being developed, and these may eventually play a role in the treatment of HIV-associated dementia. A current AIDS Clinical Trials Group (ACTG) study (A5235) is assessing the effects of minocycline (a tetracycline-class antibiotic) in patients with HIV-related cognitive impairment. This drug has been shown to protect against encephalitis in the simian immunodeficiency virus model in association with dramatically reduced MCP-1 levels; potential beneficial effects include an anti-inflammatory and neuroprotective effect via suppression of p38 mitogen-activated protein kinase, antioxidant and antiapoptotic effects, inhibition of matrix metalloproteinases that may damage the blood-brain barrier, as well as a possible antiviral effect."
"patients on antiretroviral treatment with suppression of HIV RNA levels in the CSF to 400 copies/mL or below can still develop HIV cognitive impairment suggesting that ongoing damage resulting from immune activation driven by chronic low-level infection may account for continued neurologic complications in the potent antiretroviral era."
"Systematic evaluation of more than 1000 clinic patients in the CNS HIV Antiretroviral Effects Research (CHARTER) cohort shows thatneurologic impairment is present in 50% or more, a rate comparable to that in the pre-antiretroviral era (Figure 2). Many factors likely contribute to ongoing neurologic complications despite the ability of current drugs to profoundly suppress viral replication. These factors include ongoing viral replication and immune activation in the CNS, comorbid factors like the use of both nonprescription and prescription drugs, perhaps including antiretroviral drugs, coinfections like with hepatitis B and C, and genetic influences of both the virus and the host."
"study of CHARTER cohort patients with plasma HIV RNA levels of less than 50 copies/mL was performed using an ultrasensitive assay capable of detecting virus in CSF to the level of 2.5 copies/mL. Patients with CSF viral loads below the assay detection limit were receiving antiretroviral therapy with a CPE score of 2.0 (eg, 2 drugs from Table 3 with scores of 1), whereas patients with HIV RNA levels of 2.5 to 50 copies/mL were receiving treatment with a CPE score of 1.25 (P = .005) (Letendre, CROI, 2007). Thus, low-level viral replication is likely to be occurring in many patients with apparent suppression on antiretroviral therapy and may account for ongoing neurologic damage."
"increasing age has consistently been a risk factor for development of HIV-associated cognitive impairment.....possible relationship between HIV-associated dementia and dementia of Alzheimer type (DAT). Recent investigations have shown that β-amyloid deposition, which accounts for DAT senile plaques, can be identified in approximately half of HIV-seropositive patients' brains, both in plaques and in intraneuronal locations. A chronic inflammatory state may create an environment conducive to augmented amyloid-associated toxicity. Antiretroviral treatment may predispose the patient to amyloid deposition, both by facilitating aging and by causing metabolic toxicity and ubiquitin-proteosome dysfunction. Tat protein toxicity may also be associated with amyloid deposition....the condition present in the HIV-associated disorder is not the same as DAT but nevertheless appears to involve amyloid metabolism."
"Although current antiretroviral drugs can inhibit viral replication to low levels, low-level replication may still cause dysfunction of nerve cells via ongoing inflammatory response and astrocytic gliosis, mediated, for example, by tumor necrosis factor α and monocyte chemotactic protein 1 (MCP-1). This protein is potent in attracting inflammatory cells into infected organs and has high levels of expression in the brain"
"Findings like these support a scenario in which neurologic dysfunction before initiating or in the absence of antiretroviral treatment is predominantly associated with neuronal loss caused by direct viral mechanisms, whereas such dysfunction in patients on antiretroviral therapy is associated with chronic cellular activation and consequent dysfunction of nerve cells (Figure 3)." "Recent studies indicate that the Tat protein in clade C virus may be less directly toxic to neural cells than that in clade B virus and is associated with reduced production of MCP-1 from astrocytes"
"Some evidence also suggests that human genetic variation is associated with a predisposition to neurologic complications. 1 study showed that patients with a specific MCP-1 genotype had a 4.5-fold increase in risk of HIV-associated dementia"
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