HIV and the Brain: Longitudinal Results From CHARTER and Other Studies

Cytomegalovirus (CMV) Levels and Cognitive Decline

Letendre and colleagues studied 138 HIV-positive people to determine associations between CMV levels, neurocognitive characteristics, disease and demographics. CMV antibody concentrations were measured by enzyme-linked immunosorbent assay.

Higher CMV antibody levels were associated with older age (r=0.23; p=0.006), lower nadir CD4 cell counts (r=-0.34; p <0.0001), ART use (p=0.004), and worse global deficit score (r=0.17; p=0.04). For patients not taking ART higher CMV antibody levels were also associated with higher HIV RNA levels in CSF (r=0.29; p=0.05) but not in plasma. Multivariate analysis showed that worse global deficit score was associated with higher CMV antibody levels, more co-morbid conditions, and an interaction between CMV antibody level and plasma HIV RNA (p=0.02).

Analysis of the interaction identified that higher CMV antibody levels were only associated with worse global deficit scores among subjects who had undetectable HIV RNA in plasma.

The authors conclude that higher CMV antibody levels were associated with worse neurocognitive functioning. They suggest their findings have implications for earlier initiation of ART, for the aging of the HIV population, and for the effect of CMV on HIV in the central nervous system. They also say that their findings add to existing data that suggest that CMV prophylaxis may be beneficial.¹⁰

Another finding relevant to older age and cognitive functioning in people with HIV comes from a study of over 205 CHARTER patients. These patients provided 162 CSF and 230 plasma samples. Tenofovir CSF (n=44) concentrations increased more steeply with age than plasma (n=44). Efavirenz concentrations increased in CSF (n=66) in patients older than 55 with a less steep and steadier increase with age for plasma (n=77) concentrations. Plasma (n=109) atazanavir concentrations slightly declined with age while CSF (n=58) concentrations remained stable. Higher ARV concentrations were also associated with worse neurocognitive functioning, which the authors note may indicate drug neurotoxicity. They concluded that more data in older HIV-positive people was needed to validate their findings.¹¹

European AIDS Clinical Society (EACS) Guidelines for Diagnosing HAND Not Sensitive Enough

Ignacio Perez-Valero and colleagues compared the recently released EACS guidelines and the HIV Dementia Scale (HDS) for diagnosing symptomatic and non-symptomatic HAND.¹²

CHARTER's comprehensive neurobehavioral assessments that involve several hours of comprehensive testing were used as the gold standard.

While the authors stated that neither EACS nor HDS screens had sufficient sensitivity for detecting cases for referral, concluding that EACS sensitivity is especially poor if the full range of HAND is considered, they failed to consider that the EACS guidelines were established to provide increased awareness for a simple intervention, based not only on the limited time that most doctors have with patients, but also that for many doctors, assessing NCI is not currently a significant aspect of HIV management. These results do not mean that easy to use evaluations that within minutes can clarify, even roughly, the urgency for some referrals, or do not have a place in clinical care.

Comment

The effect of HIV on the brain remains an important aspect of care and these data help. While advanced HIV disease causes HAND and dementia, the biological mechanisms are poorly understood. Whether HIV or ARVs contribute to cognitive decline in asymptomatic patients, especially at higher CD4 counts and/or controlled viraemia, with or without ART is unclear.

The results from CHARTER may help predict diagnosis but evidence of sub-clinical changes, while worrying, do not suggest different management, other than perhaps more careful observation.

Higher rates of cognitive problems in HIV positive compared to negative people, even on stable ART, are subject to confounding and the difficulty of an appropriately matched control.

The biomarker studies from CHARTER are interesting, but given the large number of biomarkers that were considered, some of these may be chance associations and their findings still need to be validated.

The study reporting an association between central obesity, diabetes and NCI did not report on the possibility of reverse causality -- that NCI may have contributed to poor diet, but this is a US study so the diet may have been regionally normal -- or whether a common cause be responsible for NCI and diabetes.

While the authors suggested "avoiding ARV drugs that induce central obesity might protect patients from or reverse neurocognitive impairment" this is easy to say but more complicated to interpret with any degree of precision, given that central lipohypertrophy has been associated with all classes of ARVs and no single ARV has been shown to be clearly protective.

Three key questions remain unanswered: Does pre-AIDS HIV infection significantly affect cognitive functioning? What are the long-term effects of HIV on cognitive functioning? Can earlier ART improve cognitive outcomes in people with HIV?

Hopefully research from the START trial, which has a neurology substudy, will provide data at higher CD4 counts (>500 cells/mm³), together with any impact of earlier ART. The substudy will have 300 recruits in each arm.¹³

The higher prevalence of impairment in HIV positive people suggests that neurocognitive assessment should be addressed in guidelines and integrated into routine care.