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What Causes Neurological Impairment in HIV+
 
 
  Reported by Jules Levin
 
About 40% of individuals with HIV have mild cognitive impairment which persists, below are links to big HIV studies finding this: ALLRT (ACTG) and CHARTER. What causes neurological impairment or cognitive dysfunction in HIV+ ........Here are several studies among numerous others finding these associations with cognitive impairment in HIV+ individuals:
 
- Liver Dysfunction/Inflammation
- Belly Fat, Diabetes, Insulin Resistance, hyperglycemia
 
from Jules: diet & exercise are important ways address this concern right now and to reduce risk, both of these improve metabolics, lipids, hypertension, blood pressure, stress and all these are associated with neurologic impairment.
 
In this study at ICAAC they found a 45% cognitive impairment rate in patients that persisted, but this is not unusual, the same rates were found in CHARTER & ALLRT Studies.
 
ICAAC: Similar Cognition Outcomes After 48 Weeks for Tenofovir (TDF)/Emtricitabine (FTC) + Atazanavir/Ritonavir (ATV/r)-Experienced HIV+ Patients or Those Simplifying to Abacavir (ABC)/Lamivudine (3TC) + ATV - (09/16/13)
 
Belly Fat Linked to Cognitive Deficits in HIV, new published study in Neurology from HIV CHARTER Study http://www.natap.org/2012/HIV/021512_01.htm
 
"NCI (global impairment rating 5) was diagnosed in 40% (52/130)............In a cross-sectional substudy of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort.....Self-reported diabetes was associated with NCI in the substudy and in those >55 in the entire CHARTER cohort......Multivariate logistic regression analyses demonstrated that central obesity (as measured by WC) increased the risk of NCI and that greater body mass may be protective if the deleterious effect of central obesity is accounted for......In a multivariate regression analysis, having had a diagnosis of AIDS was associated with increased risk of impairment, with an odds ratio of 49.57 and a 95% confidence interval from 2.26 to 1,089. The association was significant at P=0.013.......Those with impairment were significantly older (at P=0.02) -- 48.3 years versus 44.9.....Those with impairment had an average waist circumference of 99 centimeters, or 38.9 inches, compared with 34.6 inches for the others. The difference was significant at P=0.0005.......Neurocognitive impairment (NCI) was defined by performance on neuropsychological tests adjusting for age, education, gender, and race/ethnicity. Global ratings and global deficit scores were determined......Dementia in older HIV-infected patients has been associated with diabetes, hyperglycemia, and insulin resistance......Likely mechanisms for the effect of diabetes on risk of NCI are either direct damage to the brain from hyperglycemia or increased risk for cerebral atherosclerosis. The decades required for diabetes to cause atherosclerosis could explain the why diabetes increased risk only in older persons......Diabetes has been associated in some imaging studies with cerebral macrovascular and microvascular disease that damages the brain in a predominantly subcortical pattern similar to the pattern of HIV damage.30,-,32 Moreover, 2 recent studies have associated both risk factors for atherosclerosis (prior cardiovascular disease, hypercholesterolemia, and hypertension) or structural evidence for it (increased carotid artery intima-media thickness) with cognitive impairment in patients with HIV. Alternatively, insulin resistance in the brain may attenuate the intracerebral neuroprotective effects of insulin......This effect of diabetes on NCI is similar to, but larger than, that reported by other studies of both HIV-infected and HIV-uninfected adults.9,10,12,34,-,37 NCI has been correlated with abnormal glucose metabolism, including diabetes and less severe abnormalities, in HIV-infected individuals.....The majority of participants [in CHARTER] had experienced CART-induced immune reconstitution based on having ARV therapy at the time of their study visit (82%), high current CD4 counts (median = 501 cells/mm3) compared to either much lower nadir CD4 counts (median = 120 cells/mm3) or AIDS diagnoses (70%), and median plasma HIV concentrations below the limit of detection (1.7 log copies/mL). The average duration of known HIV infection was 13 years."
 
Liver-induced inflammation hurts the brain.......http://www.natap.org/2012/HCV/030212_03.htm
 
The immune system is activated following injury or infection. The local response can be accompanied by a systemic response, which includes the synthesis and release of different mediators by innate immune cells. The liver is not an exception and when exposed to an acute or chronic insult generates an inflammatory response that may affect other organs. Liver-induced inflammation is able to cause disturbances in the central nervous system (CNS) including metabolic (hyperthermia, somnolence, loss of body weight) and behavioural manifestations (lethargy, anhedonia, decreased social interaction). These manifestations are collectively termed "sickness behaviour" [1], and are attributed to dysfunction of the CNS......Continuous activation of peripheral inflammation can have long-lasting consequences on the brain, as it has been proposed for chronic hepatitis C [16]. The occurrence of infections does increase the risk of Alzheimer's disease or accelerate the progression of established dementia [17], probably because peripheral inflammation causes a continuous activation of microglia
 
HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy CHARTER Study: 40-83% Neuro Impaired/33% asymptomatic/low nadir cd4 predicts/comorbidities contribute http://www.natap.org/2010/HIV/120810_02.htm
 
Fifty-two percent of the total CHARTER cohort (814/1555) were neuropsychologically impaired. NP impairment rates in the comorbidity groups (SEE TABLE BELOW LISTING COMORBIDITIES) were as follows: 40% of incidental; 59% of contributing; 83% of confounded
 
A majority of the CHARTER participants (54.2%; n=843) was classified as having only incidental comorbidities, and 30.4% (n=473) had contributing conditions; 15.4% (n=239) had confounding comorbidities that precluded a HAND diagnosis (see table 2 for details concerning rates of major co-morbidities found in these three groups)
 
Results
Prevalent neurocognitive impairment

 
A total of 458 subjects out of 1160 (39%) were classified as having mild neurocognitive impairment at the first neurological assessment (Table 1). Using a more stringent cut-off to define impairment, 304 (26%) of the 1160 subjects had mild to moderate impairment at their first visit. Of the original 1160 subjects, 991 had at least one follow-up Neuroscreen, and of these, 217 (22%) had sustained mild impairment. Of the 458 subjects classified as having mild impairment at baseline, 389 subjects had at least one follow-up visit, indicating that 217 out of 389 subjects (56%) impaired at baseline sustained impairment at follow-up, or from another view, 44% improved with treatment.
 
"CHARTER findings also indicate that a history of more severe immunosuppression confers an increased risk for HAND, even after CART-related immune recovery; over 70% of our participants receiving CART had a nadir CD4 <200. This raises the question of whether better neurobehavioral outcomes could be achieved by initiating CART earlier and preventing more advanced immunosuppression, rather than using declines in CD4 levels to trigger treatment. In fact, among CHARTER participants who did not have significant comorbid risks for CNS dysfunction, much lower rates of HAND were seen in those who achieved successful HIV suppression on CART and had nadir CD4 counts above 200"
 
"It is possible that advanced immunosuppression reflected by low nadir CD4 is a "legacy" event whose neurologic consequences may persist"
 
Here is a graphic showing neurocognitive impairment increasing from those with no other factor (incidental) to confounding. If you look only at Incidental on the left four points, this is about 40% averaged together and also consistent with the 39% that was found in the ALLRT study. http://www.natap.org/2007/HIV/083007_06.htm
 

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Probabilities of impairment, and 95% confidence intervals, for subjects on combination antiretroviral therapy, classified by comorbidity group (incidental, contributing, and confounding), plasma HIV-1 viral load (UD undetectable, Detdetectable), and nadir CD4 (<200 vs >200 cells/L) Follow-up of HIV-Associated Neurocognitive Disorders in the cART Era: the Neuradapt Study, CROI 2013 http://www.natap.org/2013/CROI/croi_169.htm During a 2 year follow-up period, the proportion of patients with a diagnosis of HAND dramatically increased, most of them displaying mild cognitive disorders, whether symptomatic or not. The main novel domains of impairment concerned executive functions, learning and working memory.

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