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  18th CROI
Conference on Retroviruses
and Opportunistic Infections
Boston, MA
February 27 - March 2, 2011
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Risk of Stage 1 AIDS Dementia 12% Over 2 Years in Asymptomatic People
  18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
Antiretroviral-treated people with no symptoms of neurologic disease have an estimated 35% risk of stage 0.5 or higher AIDS dementia complex (ADC) after 2 years of follow-up and an estimated 12% risk of at least stage 1 ADC after 2 years [1]. Those predictions emerged from a prospective analysis of brain markers in 167 people by the US HIV Neuroimaging Consortium.
The Consortium aims to map the course of functional and structural brain injury over time and the relationship of such injury to cognitive impairment in antiretroviral-treated people with chronic HIV infection. The group also hopes to identify host factors and HIV disease factors that contribute to brain injury and cognitive impairment in this population.
This analysis included HIV-positive people at seven centers who had a lowest recorded CD4 count below 200 and had taken antiretrovirals for at least 12 weeks. The investigators excluded people with confounding neurologic, psychiatric, and medical disorders (including diabetes and liver and kidney disease). Active illicit drug use was also an exclusion criterion. Study participants are evaluated every 6 months and undergo several types of scans, including magnetic resonance imaging, magnetic resonance spectroscopic imaging, and diffusion tensor imaging.
Median age at enrollment was 46 years, and 7% were older than 60. Median duration of HIV infection stood at 12 years, and 9% had HIV for 20 years or more. Median nadir CD4 count was 36, and 232 people had a nadir at or below 100. Median CD4 count at entry measured 290, and 88 people (30%) had an entry CD4 count below 200. While 168 people (56%) had no neurologic symptoms, 68 (23%) had evidence of subclinical neurologic impairment. More than 90% of these people were taking antiretrovirals; 90% had an undetectable viral load in plasma and 80% had undetectable HIV RNA in cerebrospinal fluid.
Cross-sectional data on 216 people on current antiretroviral regimens demonstrated atrophy of the corpus callosum, a bundle of nerve fibers beneath the cortex that connects the left and right cerebral hemispheres. Atrophy was worse in people with worsening neurocognitive impairment but could also be detected in asymptomatic people. Nadir CD4 count predicted corpus callosum atrophy.
Analysis to detect progression to neurocognitive impairment (ADC stage 0.5 or greater) involved 167 asymptomatic people studied over a 2-year period. Identification of factors that predict change in magnetic resonance spectroscopy and magnetic resonance imaging over 2 years involved 186 people with no neurologic symptoms and 40 with ADC. In the 167 previously asymptomatic people, imaging estimated progression risks to ADC stage 0.5 or worse of 13.6% after 1 year and 35% after 2 years. Predicted risk of progression to ADC stage 1.0 or worse was 3.9% after 1 year and 12.3% after 2 years. Six factors independently predicted risk of progression to ADC stage 0.5 or worse, at the following hazard ratios (HR) (and 95% confidence intervals):
-- Baseline CD4 count below 350: HR 2.07 (1.10 to 3.90), P = 0.025
-- Detectable HIV RNA in plasma: HR 2.48 (1.29 to 4.77), P = 0.006
-- Decreasing (glutamate/glutamine)/creatinine in frontal white matter: HR 1.47 (1.06 to 2.04), P = 0.020
-- Decreasing N-acetyl aspartate/creatinine in basal ganglia: HR 2.42 (1.55 to 3.24), P < 0.0001
-- Decreasing choline/creatinine in basal ganglia: HR 2.04 (1.53 to 3.04), P = 0.0005
-- Increasing myoinositol/creatinine in the midfrontal cortex: HR 1.53 (1.11 to 2.12), P = 0.010
Choline and myoinositol are inflammatory metabolites; N-acetyl aspartate is a neuronal metabolite.
The only factor that independently predicted risk of progression to ADC stage 1 or greater was a decrease in N-acetyl aspartate/creatinine in basal ganglia (P = 0.0006). Age, duration of HIV infection or antiretroviral therapy, and antiretroviral central nervous system penetration effectiveness score did not predict progression to ADC stage 0.5 or 1 in these analyses.
In 226 people with two to five evaluations during the 2-year study period, absolute concentrations of seven metabolites decreased significantly:
-- N-acetyl aspartate in frontal white matter: 2.8% per year, P < 0.0001
-- Choline in frontal white matter: 2.6% per year, P = 0.0002
-- Glutamate/glutamine in basal ganglia: 3.0% per year, P = 0.00062
-- N-acetyl aspartate in midfrontal cortex: 1.9% per year, P = 0.0006
-- Creatinine in midfrontal cortex: 1.6% per year, P = 0.0273
-- Choline in midfrontal cortex: 2.0% per year, P = 0.0231
-- Glutamate/glutamine in midfrontal cortex: 6.1% per year, P < 0.0001
Factors associated with these decreases included detectable HIV RNA in plasma (decreased N-acetyl aspartate in frontal white matter, P = 0.005), nadir CD4 count below 50 (glutamate/glutamine in frontal white matter, P = 0.014), longer duration of HIV infection (glutamate/glutamine in midfrontal cortex, P= 0.0034), high current CD4 count (choline in midfrontal cortex, P = 0.012), and longer antiretroviral duration (choline in midfrontal cortex, P = 0.0197).
HIV Neuroimaging Consortium researchers concluded that neuroasymptomatic people on antiretroviral therapy run a significant risk of progressing to subclinical or mild cognitive impairment. They proposed that N-acetyl aspartate in basal ganglia as measured by magnetic resonance spectroscopy may be useful in identifying people at risk of neurocognitive impairment and could serve as an endpoint in clinical trials.
The investigators stressed that nadir CD4 count before antiretroviral therapy begins is significantly associated with persistent injury and neurocognitive impairment. They argued that their findings underline the need for routine central nervous system monitoring in people with HIV and the need to begin antiretroviral therapy at earlier stages of HIV infection.

1. Navia B, Harezlak J, Schifitto G, et al. A longitudinal study of neurological injury in HIV-infected subjects on stable ART: the HIV Neuroimaging Consortium Cohort Study. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 56.