CHARTER Study Finds Neurocognitive Impairment Still Common in ART Era, Linked to Lowest CD4 Cell Count

		SUMMARY: Neurocognitive impairment ranging from subtle to severe remains common among people with HIV despite widespread use of effective combination antiretroviral therapy (ART), according to findings from the large CHARTER study presented at the XVIII International AIDS Conference (AIDS 2010) last month in Vienna. Impairment was associated with nadir or lowest-ever CD4 cell count, even among individuals whose immune function has since recovered on ART.

By Liz Highleyman

Neurocognitive impairment is a well-establish HIV-related condition. While several studies indicate that the occurrence of frank AIDS-related dementia has decreased since the advent of ART, milder impairment -- which may be so subtle that it can only be detected using specialized tests -- may actually be more common as HIV positive people live longer.

CHARTER (CNS HIV Antiretroviral Therapy Effects Research) is an ongoing cohort study with more than 1000 participants looking at central nervous system (CNS) and neurocognitive manifestations in people with HIV.

Prevalence

As described in a poster by Robert Heaton and colleagues (abstract THPDB106), the CHARTER team assessed the prevalence of neurocognitive impairment before and after the advent of combination ART among people at various stages of HIV infection.

This analysis included nearly 1800 participants who received comprehensive neurological and neuropsychological evaluations; individuals with co-existing conditions known to cause CNS problems were excluded.

	857 from the pre-ART era (1990-1995):
	179 HIV negative; 516 HIV positive but not progressed to AIDS; 162 with AIDS.
	936 from the ART era (2000-2007):
	94 HIV negative; 336 HIV positive but not AIDS; 506 with AIDS.

Reflecting the aging of the HIV positive population, the average age was just over 30 years in the pre-ART era compared with just over 40 in the ART era (although the ART-era HIV negative control participants were younger).

Results

	Overall, 40% of HIV positive individuals were found to have neurocognitive impairment in the ART era compared with 33% during the pre-ART era, a statistically significant difference (P = 0.004).
	Breaking this down by disease severity, only people with less advanced HIV disease in the past had a significantly higher rate of neurocognitive impairment since the advent of ART, while those with more severe stages, as well as HIV negative control participants, did not see significant increases:
	CDC stage A (asymptomatic; median current CD4 count 466 cells/mm3): 36% ART era vs 29% pre-ART (P = 0.001); CDC stage B (symptomatic; current CD4 count 437 cells/mm3): 40% vs 42%, respectively; CDC stage C (AIDS-defining conditions; current CD4 count 346 cells/mm3): 45% vs 52%, respectively; HIV negative: 16% vs 19%, respectively.
	Despite these relative changes over time, neurocognitive impairment remained most common among people with a history of more severe HIV disease.
	Not surprisingly, participants were much more likely to be on treatment during the combination ART era compared with the pre-ART era (70% vs 47%) and more likely to have undetectable plasma viral load (65% vs 5%).
	Due to prolonged survival, the estimated duration of HIV infection was significantly longer in the combination ART era than in the pre-ART era (9.9 vs 2.8 years).
	However, the effect of duration of infection on likelihood of neurocognitive impairment was only significant during the pre-ART era (3.4 years for those with impairment vs 2.5 years for non-impaired; P = 0.0005).

"Neurocognitive impairment remains prevalent despite combination ART," the investigators concluded. "Of interest, more post-combination ART non-AIDS cases have neurocognitive impairment than pre-combination ART."

This suggests, they continued, that there are "negative CNS effects of longer survival in a pre-AIDS state during which the brain remains exposed to repeated fluxes in HIV and/or chronic immune stimulation."

Risk Factors

In a second cross-sectional analysis, presented in a late-breakers session by Igor Grant (abstract THLBB109), CHARTER investigators looked at factors associated with HIV-related neurocognitive problems among 1525 participants evaluated at 6 U.S. university medical centers.

Again, participants underwent comprehensive neuropsychological assessments covering 7 cognitive domains, or functional areas. Researchers also collected data on co-existing conditions and HIV-related measures including present and past CD4 cell counts, obtained through medical records or self-report.

About three-quarters of the participants were men, about 40% were white, and the average age was 43 years. About 45% had co-existing conditions considered contributing causes of cognitive problems. About 70% were currently on ART and 60% had undetectable plasma viral load. The median current CD4 count was relatively high, at 420 cells/mm3, but the median CD4 nadir was much lower, at about 170 cells/mm3; about 2 years, on average, had elapsed since the nadir level was reached.

Results

	52% of the participants were found to have some degree of neurocognitive impairment.
	Participants with impairment had a lowest-ever CD4 count of 155 cells/mm3, significantly lower than that of non-impaired participants at 187 cells/mm3 (P = 0.002).
	There was a consistent relationship between CD4 nadir and presence of neurocognitive impairment:
	50 cells/mm3 or lower: approximately 60% prevalence; Never below 350 cells/mm3: approximately 50% prevalence; Never below 800 cell/mm3: approximately 45% prevalence.
	Lower CD4 cell nadir was strongly associated with neurocognitive impairment after adjusting for relevant demographic and clinical factors.
	Current CD4 cell count, however, was not a significant predictor (409 for impaired vs 428 for non-impaired; P = 0.40).
	In this analysis, duration of HIV infection was the same for impaired and non-impaired participants (120 vs 121 months), and time since nadir was also similar (2.2 vs 2.3 years).
	Participants with cognitive impairment were significantly more likely to have contributing or confounding co-existing conditions.
	Looking at a subset of 589 participants who were on ART with undetectable viral load, lowest CD4 cell count was still a significant predictor of neurocognitive problems.
	Use of antiretroviral drugs able to penetrate the blood-brain barrier had only a modest effect.

Based on these findings, the CHARTER investigators concluded, "HIV-associated neurocognitive disorders persist in many patients despite good immune recovery on ART as indexed by current CD4 [count]".

However, they added, "HIV+ individuals experiencing low CD4 nadir counts are at greater risk of neurocognitive impairment than those whose CD4 [count] has never been allowed to decline to lower levels."

"CD4 nadir may represent a 'legacy event' that contributes substantially to HIV-related brain injury and neurocognitive impairment," and may not be fully reversible, they continued. "Prevention of severe immunosuppression by earlier ART may lead to more favorable neurocognitive outcomes in HIV+ individuals."

Investigator Affiliations:

THPDB106: University of California, San Diego, CA; Washington University, St. Louis, MO; Mount Sinai School of Medicine, New York, NY; Fordham University, New York, NY; University of Washington, Seattle, WA; University of Texas Medical Branch, Galveston, TX; Johns Hopkins University, Baltimore, MD.

THLBB109: University of California, San Diego, CA; Washington University, St. Louis, MO; University of Washington, Seattle, WA; University of Texas Medical Branch, Galveston, TX; Johns Hopkins University, Baltimore, MD; Mt. Sinai School of Medicine, New York, NY.

8/6/10

References

R Heaton, D Franklin, R Ellis, I Grant, and others (CHARTER and HNRC Groups). Increased prevalence of HIV neurocognitive impairment (NCI) among non-AIDS cases in the post-CART versus pre-CART era. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract THPDB106.

R Ellis, J Badiee, S Letendre, I Grant, and others (CHARTER Group). Nadir CD4 is a predictor of HIV neurocognitive impairment (NCI) in the era of combination antiretroviral therapy (cART): results from the CHARTER study. XVIII International AIDS Conference (AIDS 2010). Vienna, July 18-23, 2010. Abstract THLBB109.