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  6th IAS Conference on HIV Pathogenesis
Treatment and Prevention
July 17-20, 2011, Rome
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Slow Drop in HIV Neurocognitive Disorder in Italian HIV Cohort: 'cognitive impairment persists in HIV-positive people.....'
  6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Mark Mascolini
Prevalence of HIV-associated neurocognitive disorder (HAND) declined slowly over the course of 15 years in a large Italian observational study [1]. Higher current CD4 count, long antiretroviral duration, and more education independently predicted a lower risk of HAND, while older age predicted a higher risk.
A recent 1800-person study in the United States found that lower nadir CD4 count predicted neurocognitive impairment in the years before combination antiretroviral therapy (cART, 1998-1995) and in the cART era (2000-2007) [2]. Among people with asymptomatic HIV infection (CDC stage A), neurocognitive impairment was significantly more common in the cART era than in the pre-cART era (36.2% versus 25.2%, P=0.001). Among people with more advanced HIV infection (CDC stage B or C), neurocognitive impairment was also more common in the cART era, but the difference from pre-cART prevalence lacked statistical significance. The Italian results run counter to those trends.
The new study involved 1375 HIV-positive people who completed a set of 11 neuropsychological tests in 5 domains, all administered by the same investigator. The researchers adjusted neuropsychological scores for age, gender, and years of education, then compared results to population-based norms. They defined cognitive impairment as a result 1 standard deviation (SD) below the normative mean on at least two tests or 2 SD below the normative mean on at least one test. The investigators calculated Z scores for each neuropsychological test and for each cognitive domain, and they calculated the global NPZ-8 deficit score. The study used 2007 criteria to rate HAND severity as asymptomatic neurocognitive impairment, mild neurocognitive disorder, or HIV-associated dementia.
Three quarters of the study group were men, median age stood at 42 years (interquartile range [IQR] 36 to 49), and median years of education at 13 (IQR 8 to 13). Median HIV duration was 6 years (IQR 1.6 to 12.2), and 34.5% had AIDS. Median current CD4 count measured 381 (IQR 198 to 599) and lowest-ever (nadir) CD4 count 165 (IQR 60 to 294). About one quarter of study participants (24.1%) had taken combination antiretrovirals (cART) for fewer than 2 weeks, 20% for 2 to 52 weeks, and 56.9% for more than 52 weeks. Current viral load averaged 4.16 log (about 15,000 copies). One quarter of participants had injection drug use experience, and 29.2% had HCV infection.
Overall, 806 people (58.6%) had unimpaired neuropsychological function, and 569 (41.4%) had HAND.
Over the 1996-2010 study period, the proportion of people with more than 52 weeks of cART experience rose from 23.2% to 73.2%. Over that same period, HAND prevalence waned slowly, from 45.6% in 1996-1998, to 44.4% in 1999-2001, 39.4% in 2002-2004 and 2005-2007, and 38.2% in 2008-2010. Multivariate analysis determined that each later year lowered the risk of HAND 3% (odds ratio 0.97, P = 0.016).
Multivariate analysis also identified five independent predictors of HAND at the following odds ratios (OR) (and 95% confidence intervals):
Raised the risk:
--Every 10 years of age: OR 1.51 (1.26 to 1.79), P < 0.001
--Clinical AIDS: OR 2.39 (1.76 to 3.25), P < 0.001
Lowered the risk:
--Every additional 1 year of education: OR 0.92 (0.86 to 0.99), P = 0.016
--Every 100-cell higher current CD4 count: OR 0.92 (0.87 to 0.97), P = 0.002
--Every additional year of cART: OR 0.87 (0.83 to 0.91), P < 0.001
The proportion of people with symptomatic HAND (HIV-associated dementia or mild neurocognitive disorder) also drifted downward over the study period, from 29.9% in 1996-1998, to 27.2% in 1999-2001, 29.2% in 2002-2004, 25.4% in 2005-2007, and 18.4% in 2008-2010. Five factors independently predicted dementia or mild neurocognitive disorder versus asymptomatic neurocognitive impairment at the following odds ratios (OR) (and 95% confidence intervals):
Raised the risk:
--Every 10 years of age: OR 1.03 (1.00 to 1.05), P = 0.028
--Clinical AIDS: OR 2.06 (1.31 to 3.23), P = 0.003
--Any cardiovascular risk factor: OR 1.71 (1.08 to 2.72), P = 0.023
Lowered the risk:
--Every 100-cell higher current CD4 count: OR 0.92 (0.85 to 0.99), P = 0.029
--Every additional year of education: OR 0.92 (0.87 to 0.97), P = 0.005
The researchers noted that they did not evaluate the role of possibly contributing conditions such as HCV infection or prior injection drug use. They also stressed that their findings rest solely on neuropsychological evaluation, not on other measures such as magnetic resonance imaging or HIV RNA in cerebrospinal fluid.
Given those limitations, they concluded that cognitive impairment persists in HIV-positive people, though they found a small but significant decline in HAND. Combination antiretroviral therapy protected against HAND in this analysis, while an AIDS diagnosis or current low CD4 count raised the risk. Nadir CD4 count did not up the odds of neurocognitive disorder in this cohort, as it has in the US CHARTER cohort [2,3].
The Italian team proposed that less education may result in "reduced cognitive reserve" and so heighten the risk of HAND. Similar factors affected the risk of symptomatic HAND (dementia and minor neurocognitive disorder). They suggested that chronic inflammation explains the link between cardiovascular risk factors and a higher risk of symptomatic HAND.

1. Balestra P, Tozzi V, Zaccarelli M, et al. Prevalence and risk factors for HIV associated neurocognitive disorders (HAND), 1996 to 2010: results from an observational cohort. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract MOAB0103.
2. Heaton RK, Franklin DR, Ellis RJ, et al; CHARTER Group; HNRC Group. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17:3-16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032197/?tool=pubmed.
3. Ellis RJ, Badiee J, Vaida F, et al, for the CHARTER Group. Nadir CD4 is a predictor of HIV neurocognitive impairment in the era of combination antiretroviral therapy. AIDS. July 6, 2011. Epub ahead of print.