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IAS 2011: Cognitive Impairment is Common, but ART Reduces Risk

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Cognitive impairment remains common among people with HIV and is linked to more severe immune deficiency and absence of treatment, researchers reported at the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2011) this week in Rome. But drugs that penetrate the central nervous system do not appear to improve overall outcomes.

[Produced in collaboration with Aidsmap.com]

Prevalence and Risk Factors

Valerio Tozzi with the Italian National Institute of Infectious Disease and colleagues looked at the prevalence of and risk factors for HIV-associated neurocognitive disorders -- or HAND -- from the advent of combination antiretroviral therapy (ART) in 1996 through 2010. They also assessed severity and qualitative changes in cognitive function.

This observational study included 1375 HIV positive patients on ART at a single site in Italy. About 75% were men, the median age was 42 years, and they had a median 13 years of education. People with psychiatric or neurological conditions that could also cause neurocognitive problems were excluded, as were active drug users.

Participants had been infected with HIV for a median of 6 years and about one-third had an AIDS diagnosis. The current median CD4 T-cell count was near 400 cells/mm3, but the median nadir or lowest-ever count was 165 cells/mm3.

Participants underwent a series of about a dozen neuropsychological tests to measure cognitive function in 5 domains. The tests measured abilities such as verbal learning and drawing a complex figure from memory. Performance was compared to normal values for the HIV negative general population matched for sex and age.

The researchers used statistical methods to determine factors associated with higher or lower risk of HAND, looking at three clinical categories of cognitive impairment: HIV-associated dementia, mild neurocognitive disorder, and asymptomatic neurocognitive impairment.

Results

  • Overall, HAND prevalence decreased slightly over the course of the study:
    • 1996-1998: 46%;
    • 1999-2001: 44%;
    • 2002-2004: 40%;
    • 2005-2007: 39%;
    • 2008-2010: 38%.
  • Severity also shifted over time:
    • 30% of participants during 1996-1998 had dementia or mild symptomatic neurocognitive impairment;
    • The proportion was symptomatic impairment fell steadily, reaching 18% by 2008-2010;
    • The proportion of people with asymptomatic impairment rose.
  • In an unadjusted analysis, people with HAND differed from those without on the following characteristics:
    • Older average age (45 vs 41 years);
    • Older when they received their first HIV test (37 vs 35 years),
    • Infected with HIV for a longer time (8 vs 7 years);
    • Lower education (10 vs 13 years);
    • More likely to be coinfected with hepatitis C virus (HCV) (51% vs 31%);
    • More likely to have been diagnosed with AIDS (CDC stage C)(49% vs 24%);
    • Lower current CD4 cell count (349 vs 478 cells/mm3);
    • Lower nadir CD4 count (158 vs 231 cells/mm3);
    • More history of injection drug use (34% vs 18%);
    • Plasma HIV viral load, however, was not a significant predictor.
  • In a multivariate analysis, 5 factors remained "strongly and significantly" associated with HAND:
    • Older age (odds ratio [OR] 1.0 per 10 year increase);
    • Higher education level (OR 0.92 per 1 additional year);
    • AIDS diagnosis (OR 2.39);
    • Higher current CD4 cell count (OR 0.92 per 100 cell increase).
    • Longer duration of ART (OR 0.87 per additional year).
  • In this analysis, nadir CD4 count and HCV status were no longer significant predictors.
  • Looking at 569 people with dementia or mild symptomatic impairment, age, education, AIDS diagnosis, and current CD4 count were again significant predictors.
  • In the symptomatic analysis, cardiovascular risk factors were also associated with a greater likelihood of HAND.
  • Impairment in specific domains was variable, but overall indicated "very limited evidence" for a changes in HAND neurocognitive profiles over time.

The finding that nadir CD4 count and HCV coinfection were no longer significant predictors of HAND conflicts with some other studies. Tozzi explained that the strong association with AIDS diagnosis indicated that history of immune deficiency had an influence, but suggested that persistent rather that past immunodeficiency is most relevant. He suggested that the link with cardiovascular risk in the symptomatic analysis might be related to chronic inflammation.

CNS Penetration

If HIV infection is associated with neurocognitive impairment, it makes sense to ask whether antiretroviral drugs that are able to enter the central nervous system (CNS) and inhibit viral replication in the brain might lead to improvement.

Sean Rourke's team from Canada hypothesized that people using antiretroviral regimens with a higher CNS penetration effectiveness (CPE) score would do better in overall neurocognitive function and in specific domains.

CPE is a measure developed by Scott Letendre and colleagues to rank how well drugs enter the brain, based on chemical properties, levels in cerebrospinal fluid (CSF) and other factors. The index was first published in 2006 and revised in 2010 to include newer antiretrovirals.

This analysis included 529 participants at two hospital clinics in Ontario. Again, most were men, two-thirds were white, the mean age was about 48 years, and the average education level was about 14 years. Patients were categorized according to whether they were taking suppressive ART, suboptimal ART, or no treatment. About half had a current CD4 count below 500 cells/mm3, but two-thirds had a CD4 nadir below 200 cells/mm3.

Using 2006 CPE scores, just under half of participants were taking regimens with high CNS penetration. Using 2010 scores, the proportion rose to 60%.

The researchers again lookedat global neuropsychological impairment and a number of domain-specific cognitive measures.

Results

  • More than 50% of participants showed some degree of neuropsychological impairment.
  • Overall, there was no significant relationship between CPE score and neurocognitive outcomes using either the 2006 or 2010 criteria.
  • This remained the case after adjusting for demographics and disease-related factors.
  • Most individual tests and domains showed no difference, however:
    • 1 test (spatial span) showed significant improvement with higher CPE scores;
    • 1 test (digit-symbol test) showed significant worsening when using 2006 CPE scores.

Taken together, these studies indicate that cognitive impairment is a common problem among people with HIV. While ART is associated with improved functioning overall, specific drugs that enter the brain do not appear to make much difference. This finding adds support for the concept that the detrimental effects of HIV infection in the brain are related to inflammatory processes that can be triggered by even a small amount of virus.

7/20/11

References

Balestra P et al. Prevalence and risk factors for HIV associated neurocognitive disorders (HAND), 1996 to 2010: results from an observational cohort. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, MOAB0103, Rome, 2011.

Rourke S et al. Examining the impact of CNS penetration effectiveness of combination antiretroviral treatment (cART) on neuropsychological outcomes in persons living with HIV: findings from the Ontario HIV Treatment Network (OHTN) cohort study. Sixth International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, MOAB0104, Rome, 2011.