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The purpose of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study is to research how central and peripheral nervous system HIV-related complications are affected by ART.1 The study has been running since 2002 with several sites in the United States comprising about 1,600 patients. The CHARTER group presented numerous studies at CROI 2012.2 Those studies that appear to have the most direct impact on diagnosing, predicting or preventing neurocognitive decline are discussed here.
Blackstone and colleagues assessed 578 participants with a comprehensive neuropsychological battery, self-report questionnaires of cognitive complaints and everyday functioning, as well as performance-based tasks measuring employment capacity and medication management. Of these 375 patients were classified as normal and 175 met criteria for ANI. A further 40 met criteria for symptomatic HIV associated neurocognitive disorder (HAND) of whom 14 had HIV-associated dementia.
The symptomatic HAND group reported significantly more symptoms of depression and had lower current CD4 counts. After controlling for current CD4 and depression symptoms, the ANI participants had worse employment capacity than the normal participants, but were comparable to the HAND group (p <0.001 for both comparisons). There were no between-group differences on the test of medication management. The researchers concluded their study suggests ANI is a less benign condition than is widely perceived. They indicate that their findings are consistent with research showing that mild neuropsychological impairment is associated with worse functional outcomes. They further suggest that performance-based tests of everyday functioning should be incorporated into the diagnosis of HAND.3
Heaton and colleagues followed neurocognitive function in HIV-positive patients measured by comprehensive laboratory, neuromedical, and neurobehavioral assessments every 6 months, over 18 to 42 months.4
The study reported that 99 (22.7%) participants experienced neurocognitive decline, 266 (61%) remained stable, and 72 (16.5%) improved over 18 to 42 months. However, the only predictors in the multivariate Co regression analysis were having a confounding co-morbidity (RR 2.4; 95%CI 1.4, 4.0; p=0.0015), being off ART (RR 1.6; 95%CI 1.1, 2.5; p=0.025) and low CD4 count (RR 1.1: 95%CI 1.02, 1.21; p=0.017.
In another study by Heaton on what appears to be the same cohort, patients with ANI (n=84) and mild neurocognitive disorders (MND) (n=57) were more likely to experience statistically meaningful decline than neurocognitively normal patients (n=246) (23%, 30% vs. 13%; p=0.004). Also ANI patients were less likely to improve than the neurocognitively normal group (7% vs. 21%; p=0.008). These results were used to validate the ANI and MND as clinically important factors associated with reduced cognitive function over time and is consistent with Blackwell's findings.5
CHARTER researchers have been looking for biomarkers that predict cognitive decline. Cerebrospinal fluid (CSF) was collected from nearly 350 study participants, of whom 85% were on ART. Follow-up samples were collected within approximately a year for 70% of subjects. There were no associations at baseline between biomarkers and neurocognitive impairment. However interesting associations were found after follow-up. A lower baseline ratio of sphingomyelin to ceramide predicted a decline in neurocognitive performance (p=0.047). Sphingomyelin is a lipid that mainly occurs in nerve tissue. Ceramide is a lipid that occurs in large concentrations in cells and is one of the components of sphingomyelin. The authors note that the predictive potential of this ratio appeared to be driven by increases of certain species of ceramide over time. Lower levels of some multiple cholesterol esters were also associated with neurocognitive decline (p ranged from 0.046 to 0.007, depending on the species).
On the other hand, high levels of two triglycerides at baseline predicted neurocognitive improvement (p=0.005 and p=0.006 for the two species). At follow-up these were lower, suggesting they normalised over time.6
Another study by CHARTER researchers tested a panel of biomarkers to predict cognitive impairment. Just under 100 people with HIV were categorised into four groups: stably normal, stably impaired, reliably worsening and reliably improving. All underwent neurocognitive testing, phlebotomy, and lumbar puncture at two time points separated by a median of just over 6 months (IQR 5.6 to 70). The researchers measured CCL2, CXCL10, CX3CL1, CXCL12, IL-6, TNF-alpha, soluble TNF receptors (sTNFR, p75) and sCD14. 74% of patients were on ART at the first time point (median current CD4 of 394 cells/mm3 and median nadir of 110 cells/mm3), of whom 54% had undetectable viral loads in plasma and CSF. A combination of sCD14, CCL2, CXCL10, sTNFR, TNF-alpha predicted neurocognitive status in 92% of patients. Allowing a higher misclassification rate, 20%, meant that TNF-alpha could be removed from the panel.
For patients with normal performance at the first time point, a combination of sCD14, IL-6, CXCL12, CCL2 and sTNFR correctly classified the cognitive status of 94% at the second time point. Allowing for a 20% error rate, sCD14, CXCL12 and IL-6, correctly classified 82%, including all subjects in the stably normal group. For subjects with impaired performance at the first time point, CCL2, TNF-alpha, sCD14 and CX3CL1 classified 96% correctly. CCL2 and TNF-alpha correctly classified 81%, including all people in the stably impaired group.
The two most frequently identified biomarkers were sCD14 and CCL2. These are indicators of monocyte or macrophage activation. All cases of neurocognitive stability were correctly classified.7
Another biomarker study compared neurocognitive status in 34 HIV-positive patients virally suppressed on ART to 34 age-matched HIV-negative controls. Each patient had two visits. Differences between the two cohorts are not reported but one interesting finding was that of 13 subjects who were impaired at the first visit, 10 remained impaired at the second visit, and all but one of the 21 neuropsychologically normal subjects remained normal. Subjects who remained impaired showed little change in their baseline adjusted sCD163 level, while those who remained normal showed a drop in baseline adjusted sCD163 (least squares means: -1.1 versus -280; p=0.056).8
Another CHARTER sub-study presented by Allen McCutchan and colleagues looked at the relationship between diabetes, obesity and cognitive decline in 130 HIV positive patients.9
Neurocognitive impairments was diagnosed in 40% of participants. Age and longer duration of infection predicted impairment. So did waist circumference but this was only measured in 55 participants. There was no assoiciation with BMI, HOMA score (a predictor of insulin resistance) and leptin levels. Self-reported diabetes was associated with impairment in patients in this sub-study. This contrasts with an analysis of the whole CHARTER cohort which found an association in patients older than 55 only but not patients younger than 55.
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