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AGING AND INFECTIOUS DISEASES CID 2006:42 (15 May) 1449

A G I N G A N D I N F E C T I O U S D I S E A S E SI N V I T E D A R T I C L E

Kevin P. High, Section Editor

HIV Infection and Dementia in Older Adults

Victor Valcour1 and Robert Paul2

1Hawaii AIDS Clinical Research Program and the Department of Geriatric Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu;

and 2Department of Psychiatry and Human Behavior, Brown Medical School, Providence, Rhode Island

Human immunodeficiency virus (HIV) infection in older patients is becoming increasingly common as seropositive individuals

live longer because of long-term antiretroviral treatment. Simultaneously, the development and expression of dementia among

HIV-infected patients is evolving in the era of highly active antiretroviral therapy (HAART) and immune reconstitution. How

long-term HAART interacts with chronic HIV infection and advanced age with regard to cognition is not fully understood.

This article provides an overview of HIV cognitive impairment as it relates to aging and presents some emerging issues in

the field. Particular emphasis is placed on describing the changing landscape of HIV-related cognitive impairment and

discussing possible concerns regarding the long-term effects of antiretroviral treatment. A brief discussion of potential

adjunctive therapies to reduce cognitive symptoms associated with HIV infection in older individuals is provided.

Historically, persons aged 150 years with HIV infection were

referred to as older, a classification supported by the relatively

bell-shaped demographic distribution of US HIV/AIDS cases

designated by the Centers for Disease Control and Prevention

(figure 1). Around 10% of HIV-infected individuals fall in this

older age group, which is a percentage that is roughly equivalent

to the percentage of the general population in their retirement

ages. Widespread use of antiretroviral therapy (ART) is begin-

ning to alter this somewhat arbitrary distinction. Because of

long-term survival of HIV-infected persons, the upper tail of

the epidemic is beginning to extend into the older age groups.

Currently, 160,000 HIV-infected individuals are 150 years old.

The number of HIV-infected individuals 165 years of age in-

creased from 1000 to 110,000 in the past decade [2]. The US

Senate Special Committee on Aging predicts that 50% of na-

tionally prevalent AIDS cases will fall into this older age group

by the year 2015 [3].

Older HIV-infected patients are either aging with HIV in-

fection or becoming newly infected at older ages. These dis-

tinctions may have clinical and prognostic implications. Cur-

rently, older HIV-infected individuals belong primarily to thefirst group, having been infected in their 30s or 40s and living

Received 7 October 2005; accepted 27 January 2006; electronically published 13 April

2006.

Reprints or correspondence: Dr. Victor Valcour, Office of Neurology and Aging Research,

Sinclair 202, Leahi Hospital, 3675 Kilauea Ave., Honolulu, Hawaii 96816 (Vvalcour

@hawaii.edu).

Clinical Infectious Diseases 2006;42:144954

2006 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2006/4210-0017$15.00

with chronic HIV infection and prolonged ART. In the Hawaii

Aging with HIV Cohort, the mean self-reported duration since

the first HIV test result among individuals50 years old (mean

age, 54.6 years) is 11.8 years, compared with 7.2 years for

individuals !40 years old, which is roughly equivalent to the

mean duration reported by other groups [4]. Although the

Hawaii Aging with HIV Cohort is enrolled entirely in Hawaii,

it appears to be reasonably representative of the US HIV-in-

fected population, because the demographic constitution issimilar to that of the Multicenter AIDS Cohort Study and be-

cause most of the individuals were born and raised in the

continental United States. Exposure to ART is increased among

older individuals in the Hawaii Aging with HIV Cohort as well.

A mean of 5.1 years compared with a mean of 2.6 years of

nucleoside reverse-transcriptase inhibitor exposure was self-

reported by older participants, compared with younger partic-

ipants, respectively ( ). The long-term consequences ofP! .001

chronic infection and extended exposure to ART with respect

to the brain are not known.

Although it is currently less common, patients who develop

HIV infection in their older years represent a special issue forhealth care providers, because it continues to be an invisible

problem. Diagnosis is often delayed, and risk behaviors may

be increasing in the absence of needed factors to support safer

sexual practices [5, 6]. Although most cases of HIV infection

among the older population occur in men, women account for

more new cases of infection in this group, and nearly 70% of

cases in older female persons occur among minority popula-

tions [7]. The magnitude of the problem may be understated,

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1450 CID 2006:42 (15 May) AGING AND INFECTIOUS DISEASES

Figure 1. Estimated percent of persons living with HIV/AIDS in the

United States in 2003, by age group, based on Centers for Disease Control

and Prevention data [1].

because seniors are less likely to be tested for HIV. Newly

infected older individuals represent a group that is potentially

vulnerable to presenting with dementia as a sentinel HIV

event [8].

DEMENTIA IN HIV-INFECTED PATIENTS

Existing definitional criteria for dementia and the epidemi-

ology of dementia associated with HIV. The American Acad-

emy of Neurology designates 2 main categories of HIV-related

cognitive impairment, including HIV-associated dementia

(HAD) and minor cognitive motor disorder (MCMD). In gen-

eral, a diagnosis of HAD necessitates an acquired abnormality

in at least 2 cognitive domains, with an additional abnormalityin either motor function or motivation and/or emotional con-

trol. Representing milder impairment, MCMD requires at least

2 cognitive and/or behavioral symptoms and an objective find-

ing of 1 acquired cognitive or motor abnormality. Both require

that cognitive difficulties reduce the ability to complete daily

activities or work. Determining functional decline due to cog-

nition can be problematic among older patients who are often

retired or have decreased their work load for medical reasons

and may not have reasonable insight into expected levels of

performance. Confidentiality issues and confounding of func-

tional capabilities due to other illnesses can produce further

barriers to functional assessment. Consequently, some centers

advocate objective assessments of function.

Before the widespread use of HAART, up to 30% of indi-

viduals with AIDS developed either HAD or MCMD [9]. Be-

cause advanced immune compromise is a major HAD risk

factor, a decrease in incidence was seen after the use of HAART

became widespread. However, HAD prevalence has not

changed, and an increased incidence of MCMD relative to HAD

has been noted. An increased proportion of individuals diag-

nosed with dementia now have a CD4 cell count 1200 cells/

mm3 [10]. Incomplete neuropsychological improvement fol-

lowing HAART has been described [10, 11], and the rate of

HIV encephalitis at autopsy may be increasing [12]. Taken

together, there is evidence to suggest that the brain remains

vulnerable in the era of HAART, and significant cognitive dif-

ficulties may persist within the limits of current treatment

approaches.Both epidemiological data and focused research initiatives

identify an increased rate of HAD among older patients [8, 13,

14]. The Multicenter AIDS Cohort Study identified a relative

hazard ratio for dementia of 1.60 per decade of life at AIDS

onset [15]. Similarly, after controlling for duration of infection,

use of HAART, and CD4 T lymphocyte count, older patients

are 3 times more likely to meet structured HAD criteria in a

research setting [13]. Whether there is an additive or synergistic

relationship between aging and HIV on neuropsychological

testing performance is not fully known, because discrepant re-

ports exist [4, 1618].

Identifying the specific mechanisms related to increased risk

for HAD is not straightforward. The presence of coexisting

diseases, particularly neurodegenerative disorders, among older

patients limits our ability to identify HIV-specific etiologies

[19]. It is not known whether HIV infection, per se, increases

the risk for other age-related neurodegenerative disorders, per-

haps decreasing the age of onset. Such a relationship would

not be surprising, considering that other conditions, when co-

existing (e.g., cerebral infarction and Alzheimers disease),

lower the threshold for clinical expression of dementia [20].

The term dementia in HIV may be more appropriate for

older patients, given existing challenges in confidently excludecontributing factors.

Characteristics of dementia among HIV-infected patients:

past and present. Dementia due to HIV infection is consid-

ered to be a subcortical dementia, because the cognitive

symptoms are predominately characterized by difficulties in

cognitive functions purportedly subserved by white matter

pathways and specific gray matter nuclei that lie deep in the

subcortical regions of the brain. Patients with HAD often ex-

hibit slowed response times, marked slowness in psychomotor

speed, poor cognitive flexibility, and emotional lability or ap-

athy. The impact on cortical brain regions may be more com-

mon in the era of HAART, altering the clinical expression ofcognitive impairment. Such changes have been identified in

neuropsychological testing profiles and in neuroimaging by

positron emission tomography [21, 22]. Milder cognitive ab-

normalities are more frequent, and HAD subtypes have been

introduced, reflecting chronic progressive, active, and nonpro-

gressive disease courses [23]. Markers of immune activation in

the CSF (e.g., b-2-microglobulin) that were classically described

with HAD may now have less specificity for active disease [24],

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and current CD4 T lymphocyte count is less useful [10]. Mean-

while, markers that were classically associated with Alzheimers

disease may be emerging. Because disease severity is generally

milder, some discussion has ensued advocating greater reliance

on neuropsychological testing results to categorize asymptom-

atic, mild, moderate, and severe impairment rather than using

diagnostic categorization. This contention is supported by the

knowledge that milder degrees of impairment remain risks forHIV disease progression, poor medication adherence (partic-

ularly among older adults), and encephalitis [2527].

In contrast to most other types of dementia, temporal fluc-

tuation in cognitive deficits have been seen in contemporary

cohorts of HIV-infected patients [23]. This fluctuation may

represent a relapsing and/or remitting pattern of cognitive im-

pairment and would not be surprising, because cognitive find-

ings are believed to reflect inflammatory processes that may

fluctuate over time and because vacillation occurs in a number

of secondary factors, such as degree of viral suppression, med-

ication adherence, treatment regimens, and drug toxicities. One

study demonstrated a relationship between CSF oxidative stressand a progressive disease course [28], and another suggested

that undetectable CSF b-2-microglobulin and undetectableCSF

HIV RNA do not preclude active disease [24]. From a clinical

perspective, it is important to note that cognitive abnormalities

remain prevalent and, though less severe, remain risk factors

for meaningful outcomes in the era of HAART.

EMERGING ISSUES AND CONTROVERSIES

RELATING TO HIV INFECTION AND DEMENTIA

IN OLDER PATIENTS

Immune reconstitution. Having a low CD4 lymphocytecountincreased the risk for HAD in the pre-HAART era, likely

through indirect means. After the advent of HAART, the mean

CD4 cell count in patients diagnosed with HAD increased sub-

stantially [10, 22], rendering CD4 cell counts less clinically

useful. Nadir CD4 cell count, the lowest CD4 cell count ever

achieved, may have diagnositc utility in the short-term. Nadir

CD4 cell count correlates to prevalent distal symmetric poly-

neuropathy among older (but not younger) individuals [29]

and to neurocognitive impairment [30]. This marker may be

particularly relevant to individuals who were infected before

HAART was readily available or who sustain low CD4 cell

counts before diagnosis of HIV infection2 situations that aremore common among older patients.

There is some speculation that age-related changes in im-

mune function may negatively influence HIV disease outcome

among older individuals. Age-related changes in immune func-

tion include decreased ability to respond to novel pathogens

and decreased proliferation of T lymphocytes [31, 32]. Several

investigators have posited that immunosenesence will result in

accelerated HIV disease progression in older patients [31, 33].

On the other hand, the overall impact of these changes may

be partly mitigated by enhanced adherence to ART [34].

Control of HIV viremia. HIV is thought to enter the CNS

early in infection [35]. Mild cognitive abnormalities have been

identified early in infection using sensitive neuropsychological

measures (reviewed in [36]) and functional neuroimaging [37].

Nevertheless, great variability in the timing of clinically signif-

icant cognitive difficulties is seen. It is likely that the indirecteffects of HIV, particularly inflammatory responses, are vitally

important (reviewed in [38]). Controlling plasma viremia is

the standard of care for individuals with low CD4 cell counts.

One might surmise that this would control cognitive sequelae

among successfully treated individuals. There are several im-

portant caveats, however, resulting in markedly dampened op-

timism, and clinical experience mandates continued vigilance.

First, there is evidence to suggest that CNS compartmen-

talization of the virus occurs. Phylogenetic analyses and HIV

resistance profiles from the brains of dementia patients support

this concept [39, 40]. Plasma HIV RNA levels are not necessarily

reflective of brain parenchymal exposure and vulnerability. Be-

cause of proximity, CSF may serve as a better marker of brain

vulnerability, although it is not necessarily reflective of degree

of parenchymal infection. Some studies indicate that CSF vi-

remia may reflect risk for cognitive impairment [41, 42].

The clinical implications are immediately evident. Although

it is not possible to measure the degree of brain parenchymal

infection, measurement of CSF HIV RNA can be done and

may provide some clinical utility, particularly among patients

who deteriorate during successful peripheral control of virus

[43]. This may suggest treatment approaches, because some

antiretrovirals are thought to have better activity in the CNS,whereas others are actively transported out [44]. It is not yet

known whether ART regimens with profiles that suggest high

levels of CNS penetration should be broadly recommended,

because limited data exist. There is sufficient evidence from

cross-sectional studies and case reports to suggest individual-

ized decisions regarding ART choice and CSF HIV RNA mon-

itoring among selected cases [43, 45, 46].

Eradicating HIV from PBMCs may be important as well. A

leading hypothesis for HIV entry into the brain relates to traf-

ficking of monocytes from the periphery into the CNS (i.e.,

the Trojan horse effect). Intracellular levels of HIV DNA in

PBMCs relate to both HIV disease progression [47] and prev-alent HAD [48], with the relationship to HAD remaining sig-

nificant among individuals with undetectable plasma HIV RNA.

HAART neurotoxicity. The neurotoxicities of some anti-

retrovirals have been demonstrated [49, 50]. Newer antiret-

rovirals appear to have improved toxicity profiles; however,

older patients have often survived extensive past exposure to

more toxic antiretrovirals, and others continue the regimen

because of resistance profiles. Although speculative, long-term

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treatment in a more vulnerable host (e.g., older individuals)

may expose cognitive consequences.

Particular concern can be raised for the metabolic changes

related to HAART. Lipid abnormalities, glucose intolerance, and

a condition akin to the metabolic syndrome are associated with

HAART [51] and relate to cardiovascular sequelae [52]. Among

the seronegative population, these risk factors relate to cere-

brovascular disease and cognitive impairment. To date, thisrelationship has not been uniformly demonstrated in HIV-in-

fected patients [53, 54]; however, cerebrovascular endothelial

changes have been identified in patients with lipodystrophy

[55], and diabetes has been linked to HAD [56]. These findings

suggest continued vigilance is required.

Aging and contributing causes to dementia. Historically,

there was little need to consider age-related neurodegenerative

diseases as contributing causes to cognitive impairment in HIV

infection, because infection existed almost exclusively among

younger individuals. This supposition no longer exists, raising

new issues regarding the diagnosis and treatment of HAD. Cur-

rently, there is little formal basis on which a clinician can con-fidently determine the etiology of cognitive impairment in an

older HIV-infected patient. Relying on signs, symptoms, and

neuropsychological profiles may be problematic in the face of

newly identified changes in the presentation and course of

HAD. If HIV infection lowers the threshold for the clinical

presentation of other neurodegenerative disease (cerebral re-

serve hypothesis), then these challenges may even impact mid-

dle-aged patients.

Existing data suggest that an overlap in neuropathology is

reasonable to consider. The pathology typically attributed to

Alzheimer disease has now been reported in HIV-infected pa-

tients, including increased brain b-amyloid deposition [57],

increased extracellular amyloid plaques [58], and decreased CSF

b-amyloid levels [22]. Neprolysin, an enzyme responsible for

amyloid degradation in the extracellular environment, is in-

hibited by Tat [59]. Similar to Alzheimer disease, the existence

of an apolipoprotein e4 allele correlates to HAD [60], possibly

in an age-dependent fashion [61]. Parkinson disease may be

another particularly vulnerable disease for older HIV-infected

patients, given the importance of the basal ganglia and dopa-

minergic pathways in both diseases [62, 63].

TREATMENT OPTIONS: PAST, PRESENT,

AND FUTURE

Currently, the mainstay of HAD treatment is the initiation of

HAART and maintenance of undetectable plasma viremia.

There is little basis on which to make recommendations for

individuals who experience cognitive deterioration while on

HAART with adequate plasma and CSF viral control [43].Some

controversy remains as to whether this does occur; however,

there are limited data supporting the contention that progres-

sion can occur within the context of current treatment param-

eters [24, 64]. The existence of confounding factors and a pau-

city of molecular markers are notable research disadvantages

for identifying treatment options for HAD. The hypothesis that

actively progressive HIV dementia [28, p. 176] is associated

with ongoing oxidative stress has received some attention. Two

studies evaluating the efficacy of selegiline (enrollment com-

plete) and minocycline (in development) are underway.Selegiline is a dopamine agonist used in the treatment of

Parkinson disease. The drug exhibits supportive trophic effects

on damaged neurons as well as antioxidant qualities. In pre-

liminary studies, HIV-seropositive individuals receiving sele-

giline for 10 weeks experienced improvement in memory and

fine motor speed [65]; although early reports from the larger

placebo-controlled study have been disappointing [66]. Min-

ocycline is an antibiotic with antiinflammatory effects and

good brain penetration at tolerable doses. In a pigtail macaque

model of simian immunodeficiency virus encephalitis with rap-

idly progressive disease, minocycline was associated with de-

creased inflammatory markers, intermediates of neuronal ap-

optosis, and simian immunodeficiency virus concentrations in

brain aggregates [67]. These effects were observed at doses that

would be considered tolerable in humans, suggesting that min-

ocycline may be a useful adjunctive therapy.

Several other agents have been considered. A studyevaluating

the efficacy of memantine, a low-to-moderate affinity N-

methyl-d-aspartate receptor antagonist, has been completed

based on in vitro evidence that memantine blocks neuronal

injury resulting from gp120 and Tat [68] and improves hip-

pocampal function in a mouse model of HIV encephalitis [69].

Results of the clinical trial are not yet published. Use of theCNS stimulant modafanil resulted in improved performance

in neuropsychological testing profiles in an open-label, 4-week

evaluation [70]. A placebo-controlled study is under consid-

eration. Additional adjunctive targets have been proposed [71],

including neurotropic factors (e.g., brain-derived neurotropic

factor, nerve growth factor, and insulin growth factor) and anti-

inflammatory agents (e.g., IL-4, IL-10, and erythropoietin). A

particularly interesting approach focuses on GSK-3b, an en-

zyme that is expressed in the brain and may play a role in

cellular signaling. To our knowledge, evaluation of these the-

oretical targets remains preclinical.

Providing treatment approaches that are specific to olderHIV-infected patients is problematic, given a paucity of research

addressing this issue. An algorithmic approach for all ages has

been proposed and has broad applicability to older patients

[43]. It may be warranted to broaden the differential of alter-

native etiologies for impairment among older patients. It is

reasonable to speculate that medications known to abate Alz-

heimer disease symptoms may have some efficacy in older pa-

tients when a combination of neurodegenerative etiologies may

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underlie the clinical syndrome. However, there are no clinical

trials on which to base such recommendations. It is important

to have a high level of suspicion for HIV infection in older

individuals newly identified to have dementia and thought to

be HIV-seronegative. This concern would be most warranted

if the dementia has predominantly subcortical features, if con-

comitant constitutional symptoms exist, or if the patient is

relatively young (perhaps in their 60s) for the typical age ofonset of common neurodegenerative disorders.

SUMMARY

There is little question that the natural history of HIV infection

is changing in the contemporary era, and advanced age will

likely be an important moderator of clinical outcome associated

with the disease. The observation that HIV, advanced age, and

concomitant neurodegenerative disorders may interact in ad-

ditive or synergistic ways raises many questions regarding best

practice among this population. To date, no consensus has been

established regarding optimal approaches, and no clinical trialshave specifically addressed older HIV-infected patients. It is

likely that HIV will represent the most common infectious

etiology of dementia until a cure for HIV infection is identified.

Clinicians are encouraged to consider HIV infection a primary

contributor to cognitive impairment in older individuals

thought to be HIV-seronegative and to integrate the possibility

that age-related cognitive disorders may contribute to clinical

findings in older HIV-infected patients.

Acknowledgments

Financial support. National Institute of Neurological Disorders and

Stroke (grant 1U54NS43049 to V.V.); the National Institute of Allergy andInfectious Diseases (grant 5U01A134853 to V.V.), and the NationalInstitute

of Mental Health (grant K23MH065857 to R.P.).

Potential conflicts of interest. V.V. and R.P.: no conflicts.

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