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HIV & Aging Clinical Recommendations
HIV-associated neurocognitive disorder (HAND) remains a frequent problem despite effective antiretroviral therapy. Up to 50% of HIV patients will exhibit HAND upon neuropsychological (NP) testing; however, only about a quarter of these patients will endorse everyday symptoms and less than half of those are estimated to have HIV-associated dementia (HAD) (Heaton 2010). 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 2015). Risk factors for neuropsychologic impairment include previous CNS disease, low nadir CD4 cell count, detectable plasma viral load, and low current CD4 cell count (Heaton 2010; Cysique 2010). Co-existing morbidities also contribute to poor neuropsychological performance, including diabetes, hypertension, HCV co-infection, medication toxicities, inflammation, psychoactive substance use disorders, and psychiatric disorders (Heaton 2015; Nasi 2017; Goodkin 2009). There is evidence for aging as a risk factor for HAND (Janssen 1992; McArthur 1993; Chiesi 1996; Valcour 2004a; Valcour 2004). This association of aging with HAND appears to be dependent upon the level of severity of HAND – greatest with HIV-associated dementia (HAD), less prominent with Mild Neurocognitive Disorder (MND — formerly minor cognitive-motor disorder) (Goodkin 2001; Larussa 2006; Wilkie 2003; Cherner 2004) and least consistent with overall cognitive impairment (Wilkie 2003; Cherner 2004; Hardy 1999; Hinkin 2001). There is mixed evidence on whether HIV accelerates normal aging, or whether it accentuates aging via additional risk factors (Cole 2017; Pathai 2014). Yet a recent study found that independent of aging, HIV was associated with an almost 5-fold risk for developing incident cognitive impairment (Sheppard 2015; Sheppard 2015a). Among older PLWH, one must also consider concurrent neurodegenerative disorders, principally Alzheimer’s disease, mild cognitive impairment (MCI) (Sheppard 2015; Sheppard 2015a), and the cognitive impact of cerebrovascular disease (Valcour 2004a; Valcour 2004).
The current most widely used nosology for HAND in research studies is the Frascati criteria (Antinori 2007). A diagnosis of HAD requires: (a) acquired moderate-to-severe neuropsychological (NP) impairment, documented by a score at least 2 SDs 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 require 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.
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 2011), there is longitudinal evidence that even ANI poses a significant risk for earlier development of symptomatic HAND (Grant 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.
The demonstrated disease heterogeneity and the relatively high frequency of asymptomatic cognitive impairment must inform sensitive screening approaches in order to be effective, and the selection of optimal screening instruments remains an issue in the field to date (Goodkin 2009).
Currently, simple 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 necessarily limited given the differing presentations, particularly for AD (primarily cortical impairment) versus HAND (primarily sub-cortical impairment). Thus, optimal screening strategies for older HIV infected adults need to cover broader areas than individual screens allow. Unfortunately, the tests designed to identify HAD (such as HIV Dementis Scale or HDS) perform considerably less well for milder conditions (MND and ANI) and cannot be recommended for screening and may need to be supplemented by other tests (such as the Trail Making Test) for this purpose (Goodkin 2009; Chalermchai 2013).
The Montreal Cognitive Assessment (MoCA) Test may be the best suited screening instrument for an older HIV-infected population, 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 2017) (i.e., Karnofsky scores) in older HIV-positive infected adults. 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 disadvanategd patients) (Musso 2016). 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; however most studies in the current era demonstrate that it fails to identify all but the more severe forms of impairment. The International HIV Dementia Scale (IHDS) is useful within the USA for patients from other cultures, of which Hispanics would be the most common, but maintains similar limitations as does the HDS (Sacktor 2005; Bottiggi 2007; Richardson 2005; Smith 2003; Morgan 2008; Davis 2002). 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.
Currently, consensus recommendations on the treatment of HAND are concordant in a focus on the use of a stable, effective ART regimen. Beyond this, the American Psychiatric Association Practice Guidelines for HIV/AIDS (Forstein 2006; DHHS 2011; McDaniel 2000) and the Guide for HIV/AIDS Clinical Care (DHHS 2011) recommend the use of CNS-penetrating antiretroviral therapy regimens and psychostimulants. However, it should be noted that there is considerable variability in how this approach is applied since there are no large-scale intervention trials that have consistently demonstrated efficacy for these recommendations. Furthermore, mixed findings exist on whether CNS-penetrating therapies have a beneficial effect on neurocognitive outcomes and some studies suggest these regimens may be neurotoxic (Marra 2009). A recent pilot study found that a maraviroc (a CCR5 chemokine co-receptor) enhanced ART regimen improved cognitive functioning in patients with HAND (Gates 2016).
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. More research is needed. Cognitive impairment in patients with HIV is often multifactorial, thus an exclusionary work-up for non-HIV-associated treatable causes of neurocognitive disorder, such as thyroid disease, syphilis, and B12 deficiency, psychiatric comorbidites and 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, require careful evaluation, as do cases with more rapid neurological progression. Use of medications with higher CNS penetration effectiveness have clearly demonstrated utility in these focused situations, particularly in rare cases of CNS escape where virus is identified in CSF despite suppression in plasma. In addition, psychostimulants have some evidence for efficacy in smaller studies (Hinkin 2001; Fernandez 1988; van Dyck 1997). Other therapies that have shown promise in research studies include the use of anti-inflammatory agents, neurotrophic factors, nutritional supplements, and antioxidants, although recent studies using both minocycline as a novel antioxidant and lithium (Decloedt 2016) did not demonstrate efficacy on HAND. More research is clearly needed.
Based on general recommendations applied to HIV-negative populations, exercise (both physical and mental), remaining socially engaged (Fazeli 2014), cognitive remediation therapy (Vance 2017), non-invasive brain stimulation (Ownby 2016), 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. 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 (Moore 2014), leading to a new focus in research on successful cognitive aging in this population and factors that might contribute to such a phenotype and thus inform treatment and prevention approaches for HAND.
Forstein M, al. e. GUIDELINE WATCH: Practice Guidelines for the Treatment of Patients with HIV/AIDS. American Psychiatric Association Available at: https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/... 2006
OARAC. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. DHHS Panel Working Group of the Office of AIDS Research, 2011 2011.