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HIV & Aging Clinical Recommendations
HIV-associated neurocognitive disorder (HAND) remains a frequent problem despite effective antiretroviral therapy. Although the prevalence of HAND varies from study to study, a meta-analysis revealed that 44.9% of PLWH will exhibit HAND upon cognitive testing (Wei et al. 2020). Yet, only about a quarter of these patients will endorse everyday symptoms and very few (2.1%) meet the criteria for HIV-associated dementia (HAD)(Wei et al. 2020), a stark contrast of 15% with HAD back in the 1990s (McArthur et al. 1993). One large longitudinal study of PLWH showed that over an average of 35 months, 22.7% of participants’ neurocognitive status declined, 60.8% remained stable, and 16.5% improved (Heaton et al. 2015); this epitomizes the fact that the cognitive profile of adults with HIV is highly heterogenous. In fact, in the Women’s Interagency HIV Study, nine patterns of cognitive functioning were observed in virally suppressed women with impaired profiles being observed in various cognitive domains such as speed, learning + memory, and so forth (Fitzgerald et al. 2020). Risk factors for cognitive impairment include previous CNS disease, low nadir CD4 cell count, detectable plasma viral load, and low current CD4 cell count (Waldrop et al. 2021). Co-existing morbidities also contribute to poor neuropsychological (NP) performance, including diabetes, hypertension, HCV co-infection, medication toxicities, inflammation, psychoactive substance use disorders, and psychiatric disorders (Heaton et al. 2015; Vance et al. 2016). There is evidence for aging as a risk factor for HAND (Vance et al. 2016). This association of aging with HAND appears to be dependent upon the level of severity of HAND – greatest with HAD, less prominent with Mild Neurocognitive Disorder (MND — formerly minor cognitive-motor disorder) and least consistent with overall cognitive impairment (Cody and Vance 2016; Waldrop et al. 2021). There is mixed evidence on whether HIV accelerates normal aging, or whether it accentuates aging via additional risk factors (Cole et al. 2017; Pathai et al. 2014; Sheppard et al. 2017) . Yet a recent study found that independent of aging, HIV was associated with an almost 5-fold risk for developing incident cognitive impairment over a 1-year period (Sheppard, Iudicello, et al. 2015; Sheppard, Woods, et al. 2015; Sheppard et al. 2017). Among older PLWH, one must also consider concurrent neurodegenerative disorders, principally Alzheimer’s disease, mild cognitive impairment (MCI) (Sheppard, Iudicello, et al. 2015; Sheppard, Woods, et al. 2015; Sheppard et al. 2017), and the cognitive impact of cerebrovascular disease (McIntosh et al. 2020).
The current most widely used nosology for HAND in research studies is the Frascati criteria (Antinori et al. 2007; Blackstone et al. 2012). A diagnosis of HAD requires: (a) acquired moderate-to-severe NP impairment, documented by a score at least 2 Standard Deviations (SD) below demographically corrected normative means in at least 2 cognitive domains, (b) moderate-to-severe difficulty in functional status in activities of daily living due specifically to this impairment, (c) a duration of at least one month, (d) absence of delirium, and (e) absence of confounding conditions capable of otherwise explaining the impairment. Mild Neurocognitive Disorder (MND) is defined by: (a) an acquired mild level of NP impairment documented by a score of at least 1 SD below demographically-corrected norms on tests in at least 2 cognitive domains, (b) the impairment interferes at a mild level with functional status, and (c) through (e) – as above for HAD. Asymptomatic Neurocognitive Impairment (ANI) requires the same level of cognitive impairment as MND, but without any functional deficit. The differential diagnosis of these diagnostic entities cannot be determined by screening instruments but requires more in-depth NP and functional assessment. However, brief clinical screening techniques can and should be employed before more formal and comprehensive NP testing is sought (Vance, Lee, et al. 2019; Waldrop et al. 2021).
Note that while the Frascati criteria are considered the gold standard, other criteria have emerged (e.g., DSM-5), yet there is little literature on their application. While some criteria have been proposed to address criticism that the Frascati criteria (and DSM-5 criteria) are too sensitive and thus overestimate HAND (Gisslen, Price, and Nilsson 2011), there is longitudinal evidence that even ANI poses a significant risk for earlier development of symptomatic HAND (Grant et al. 2014). Thus, identifying those with such subtle impairment may have prognostic value in clinical settings and provide an opportunity to intervene and delay the progression of HAND. Symptoms of HAND often include deficits in attention, executive function (such as planning, organization, multi-tasking), and slowing.
Given the high frequency of HAND and its association with important functional outcomes such as adherence to antiretroviral medications, cognitive screening is clinically important. A two-tiered approach assessing symptoms with follow-up testing is a reasonable paradigm to follow for busy practices, although screening of all patients is recommended whenever possible (Waldrop et al. 2021). If cognitive impairment is detected on a comprehensive NP battery, a cognitive therapeutic plan should be developed, such as developing an individualized cognitive prescription designed to support brain health and cognitive reserve (Vance et al. 2017).
The demonstrated heterogeneity of the disease and the relatively high frequency of asymptomatic cognitive impairment must inform sensitive screening approaches in order to be effective. The selection of optimal screening instruments remains an issue in the field, as diagnostic criteria to determine cognitive impairment in PLWH may overestimate cognitive impairment (Underwood et al. 2018). This is concerning as a diagnosis of HAND can evoke feelings of fear, confusion, and anxiety as has been observed in a sample of 135 middle-aged and older PLWH who were notified of their HAND diagnosis (Vance, Jensen, et al. 2019).
Screening instruments exist for the most severe form of HAND (i.e., HAD), Alzheimer’s disease (AD), and vascular cognitive impairment. However, the overlap in content of these tests is limited given the differing presentations, particularly for AD (primarily cortical impairment) versus HAND (primarily sub-cortical impairment). Thus, optimal screening strategies for older PLWH need to cover broader areas than individual screens allow. Such screeners are good at quickly detecting global cognitive impairments, but they are not sensitive at identifying more nuanced cognitive impairments in various cognitive domains. Thus, referral for the administration of a fuller NP battery is encouraged, especially one that also tests for the impact of cognition on everyday functioning (Moore et al. 2017).
The Montreal Cognitive Assessment (MoCA) Test may be the best suited screening instrument for older PLWH, as it taps areas of cognitive performance involving executive functioning and other higher cognitive abilities thought to be most vulnerable in milder HAND, while remaining broad enough to detect diseases such as AD. The MoCA has also demonstrated associations with self-reported and clinician-rated everyday functioning (Fazeli, Casaletto, et al. 2017) (i.e., Karnofsky scores) in older PLWH. However, validation studies in younger and older samples of PLWH suggest this test does have sizable limitations, including lack of information processing speed and motor skills components and poor specificity resulting in a high false-positive rate (particularly among educationally disadvantaged patients) (Musso et al. 2018). Thus, clinicians should avoid using such cognitive screening tools as stand-alone diagnostic tools, but instead for determining which patients should be referred for comprehensive NP evaluation to clinically diagnose HAND.
The HIV Dementia Scale (HDS) is a well-established test from the pre-ART era; recent evidence suggest that it is superior over the International HIV Dementia Scale (IHDS) in screening for HAND in Spanish-speaking adults (Lopez et al. 2017). Similarly, the Mini Mental State Examination does not tap domains that are most impaired in HAND (i.e., executive) and has been shown less effective than MoCA, and thus is not recommended for screening in this setting. In fact, the sensitivity and specificity of many of these screeners to detect cognitive impairment and HAND varies depending on cultural background of the PLWH and country where administered (Milanini et al. 2016; Hakkers et al. 2018).
Consensus recommendations on the treatment and prevention of HAND focus primarily on the use of a stable, effective ART regimen (Waldrop et al. 2021). For example, measures of white matter in PLWH who were on stable treatment with evidence of antiretroviral CNS penetration were similar to those without HIV (Cysique et al. 2017). Beyond ART, there remains a wide range of approaches emerging in the literature to support cognitive reserve in order to decrease the prevalence and severity of HAND (Vance, Fazeli, et al. 2019b; Vance et al. 2021). These approaches need to be considered in the context of medication side-effects, antiretroviral adherence, and the risk of exposure to new medications that could alter resistance profiles and long-term HIV outcomes.
Cognitive impairment in patients with HIV is often multifactorial, thus work-up for non-HIV-associated treatable causes of neurocognitive disorder, such as thyroid disease, syphilis, B12 deficiency, psychiatric comorbidities, substance use disorders, as well as conditions specific to HIV infection, is important. Patients with presentations suggestive of CNS opportunistic infection or tumor, such as focal neurological findings, or even change in smell (i.e., olfactory ability require careful evaluation, as do cases with more rapid neurological progression (Cody and Vance 2016; Vance, Cody, et al. 2019b; Vance, Cody, et al. 2019a; Waldrop et al. 2021). Use of medications with higher CNS penetration effectiveness have demonstrated utility in these focused situations, particularly in rare cases of CNS escape where virus is identified in CSF despite suppression in plasma (Bogoch, Davis, and Venna 2011). Other therapies that have shown promise in research studies include anti-inflammatory agents, neurotrophic factors, nutritional supplements, and antioxidants. Studies using both minocycline as a novel antioxidant and lithium did not demonstrate efficacy on HAND (Decloedt et al. 2016). One pilot study by Morrison et al. (2020) found the use of a ketogenic diet in older PLWH improved cognitive functioning. Given the prevalence of microbial translocation “leaky gut” observed in HIV, which can disrupt the delicate gut-microbiota-brain axis that supports brain health and cognition, prebiotics and probiotics have been suggested as a way to support brain health and cognitive in PLWH (Wilson et al. 2016). More research on effective therapies is needed.
Based on general recommendations applied to HIV-negative populations, exercise (both physical and mental), remaining socially engaged (Fazeli et al. 2014), cognitive training (Vance, Fazeli, et al. 2019b), increasing resilience (Fazeli, Moore, and Vance 2018), reducing allostatic load (Fazeli et al. 2020), non-invasive brain stimulation (Ownby and Acevedo 2016; Fazeli, Woods, et al. 2017), monitoring for depression, and monitoring for cerebrovascular risk factors are relatively safe and possibly effective adjunctive strategies, some of which are beginning to be examined in PLWH (Cody and Vance 2016; Waldrop et al. 2021). While cognitive and behavioral interventions targeting lifestyle factors are needed, such approaches to preventing and improving HAND may be beneficial above pharmacologic approaches in a population already burdened by polypharmacy. While the prevalence of HAND is high, there nonetheless continues to be a subset of PLWH who are free from such cognitive and functional impairments (Fazeli, Woods, and Vance 2020) leading to a new focus in research on successful cognitive aging in this population and factors that might contribute to such a phenotype, thus informing treatment and prevention approaches for HAND.
As people continue to age with HIV, it is important to understand how to promote successful aging, specifically successful cognitive aging. It has been suggested that successful cognitive aging is the most important component of successful aging in general; having command of one’s cognitive abilities is essential in maintaining one’s physical and social health as well as quality of life (Vance, Blake, et al. 2019). But is it important to consider that successful aging is occurring within two social backgrounds, wide spread social disparities that also exert cognitive effects (Vance 2017) and life after COVID, which also has implications for successful cognitive aging (Vance in press).
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