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Moving on From HAND: Why We Need New Criteria for Cognitive Impairment in Persons Living With HIV and a Proposed Way Forward
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the issues around cognitive impairment & the brain for PLWH but particularly for those aging & elderly PLWH are serious. Yet this problem gets too little discussion & attention. And too little research to gather current facts on elderly PLWH & how they are functioning - impaired or not - in normal daily living activities. In recent years several small studies found significant percents of older >50 had impaired functioning on normal daily activities. The "determinants of health" are many - including - food & diet related, cultural competency, health literacy, Mental health, stigma, brain function, cognitive function, physical impairment are all critical problem issues for aging & elderly PLWH. Not only quality of life but mortality are tied to these problems as well s our independence & living facilities. So far we have no pharmaceutical interventions for PLWH around brain function despite trials of such interventions. The concerns for elderly around will brain function decline for a subgroup or for some of the elderly PLWH remains an unanswered question; the risk for alzheimers & others diseases for elderly PLWH remains unanswered. One of the biggest fears elderly PLWH have is if they become unable to care for themselves how will they live, this too remains unanswered & not discussed at all. We are in unchartered waters with a significant number of PLWH aging past 65 years old, around 300,000 are I think over 60 now. Their future physical & mental function remains mostly a question. Despite that many are functioning past the age of 70, how many are not - we do not have numbers on this. Are we discussing & planning for their future, mostly NO.
This article discusses he may complexities around the brain & mental function for PLWH. The authors suggest a new approach to diagnosing & characterizing cognitive impairment in PLWH. FOR SURE, we need to discuss these issues much more, our the HIV research & neurology community & leadership at HHS, OAR, HRSA, & ONAP need to transparently discuss these concerns & how to characterize cognitive impairment and engage with the community. This as well as the aging/HIV problem in general must receive more attention, instead it seems like key agencies such as HHS, OR, ONAP & NIMH are paying less attention & have deprioritized these concerns.
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Clinical Infectious Diseases 27 April 2021
Sam Nightingale,1 Anna J. Dreyer,1 Deanna Saylor,2,3 Magnus Gisslén,4,5 Alan Winston,6,7 and John A. Joska1
1HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, Neuroscience Institute, Cape Town, South Africa, 2University Teaching Hospital, Lusaka, Zambia, 3Department
of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, 4Institute of Biomedicine, Department of Infectious Diseases, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden, 5Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden, 6Department of Infectious Disease, Imperial College London, London, United Kingdom, and 7HIV Clinical Trials, Winston Churchill Wing, St Mary's Hospital, London, United Kingdom
Abstract
Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) criteria are frequently used to describe cognitive impairment in persons living with HIV (PLWH) across diverse populations globally. These criteria typically find 20-60% of PLWH meet criteria for HAND, which does not tally with clinical observations in the modern era that cognitive disorders present relatively infrequently. Most with HAND have asymptomatic neurocognitive impairment; however, the significance of low cognitive test performance without symptoms is uncertain. Methods underlying HAND criteria carry a false-positive rate that can exceed 20%. Comorbidities, education, and complex socioeconomic factors can influence cognitive test performance, further increasing the potential for misclassification. We propose a new framework to characterize cognitive impairment in PLWH that requires a clinical history and acknowledges the multifactorial nature of low cognitive test performance. This framework is intended to be applicable across diverse populations globally, be more aligned with clinical observations, and more closely represent HIV brain pathology.
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The most frequently used criteria for cognitive impairment in persons living with human immunodeficiency virus (PLWH) are the human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) criteria, developed in 2007 by a working group formed by the US National Institute of Mental Health and National Institute of Neurological Diseases and Stroke (sometimes referred to as the Frascati criteria after the Italian town in which they were formulated) [1]. The HAND criteria were intended for use in research, but the terminology has become widely used to refer to clinical burden of disease [2-5]. Several authors have expressed that the HAND criteria may not be appropriate for the modern era [3, 6-13].
HAND criteria typically characterize 20-60% of PLWH with a cognitive disorder, with some studies describing rates as high as 70-90% [4, 5]. A recent meta-analysis of global studies showed a HAND prevalence of 43% (range, 11-92%) [5]. These figures do not tally with clinical observations that cognitive impairment presents rarely in PLWH in the modern era, usually in those with viral nonsuppression or significant comorbidities. A recent UK study showed a 3.2% prevalence of cognitive impairment when diagnosed clinically [14].
Prior to HAND were the 1991 American Academy of Neurology criteria [15], which defined HIV-associated dementia (HAD) and HIV-associated minor cognitive/motor disorder. These criteria stated that cognitive deficits causing mild impairment to activities of daily living should be verified by a reliable history, when possible from an informant, to ensure the timing and nature of impairment are consistent with HIV as a cause of the impairment [15]. The 2007 HAND criteria moved away from this by including an Asymptomatic Neurocognitive Impairment (ANI) category, whereby the minimum criteria for cognitive disorder were met by low performance on cognitive tests when compared with a control population matched for certain parameters (namely, age, sex, ethnicity, and years of education) [1]. In the modern era, most of those classified as HAND have ANI with no evidence of functional limitation [5]. The clinical relevance of the ANI category is unclear and most clinical guidelines have moved away from recommending screening for this [16].
By definition, HAND is due to the direct effect of HIV. However, performing poorly on cognitive tests without functional impairment (ie, ANI) does not always reflect the direct effect of HIV on the brain, particularly in populations with a high prevalence of socioeconomic stressors and inequalities, low educational attainment, and comorbid conditions. The statistical methods underlying ANI lead to a high false-positive rate; over 20% of cognitively normal HIV-negative control subjects can be defined as impaired based on the current approach [8, 12].
When HAND criteria were developed the frequency of cognitive disorders was such that an algorithm that was simple to apply and reduced the need for clinical assessments was appealing. Now that viral suppression is more common, antiretroviral therapy (ART) less toxic, and the relative contribution of comorbid/lifestyle factors has increased, a full clinical assessment has become essential. Here we review the current criteria as applied to diverse settings in the modern era and propose a new framework to describe cognitive impairment in PLWH.
DISCUSSION
Our assertion that the HAND criteria risk overestimating the extent of cognitive disorders in PLWH should not be mistaken for a view that we do not believe HIV brain pathology and cognitive impairment in PLWH to be important or widespread. It is clear that HIV has distinct neuropathological effects that may not always be apparent clinically and may have important implications for an aging population. ART coverage is not universal, and many remain at risk of uncontrolled disease. Compartmentalization of HIV in the CNS occurs, and the fulminant syndromes observed are likely to be the tip of the iceberg [9]. The fact that cognitive impairment in PLWH is multifactorial does not detract from its impact on the individual or the potential for functional effects on daily living, economic viability, and ART adherence, nor the importance of fully understanding this entity and developing interventions to reduce its impact. While some of those with asymptomatic low performance on cognitive tests may fall on the spectrum of normality, others may have subtle neuropathology or a lower cognitive reserve conferring a greater vulnerability to cognitive impairment. Identifying biomarkers or imaging signatures to differentiate these 2 groups will be essential. Furthermore, while our framework excludes this group from a label of cognitive impairment, it aims to improve their study by analyzing cognition as a continuous variable to provide greater statistical power. This is important as ANI forms the majority of HAND in most research studies.
Cognitive impairment is a much-feared complication and can be stigmatized. Persons living with HIV are an already marginalized population who risk additional discrimination if cognitive impairment is perceived to be common among this group. Our proposed framework is intended to more robustly define cognitive impairment to give more meaningful prevalence figures and avoid those with asymptomatic low performance on cognitive tests being labeled as having a cognitive disorder.
There are limitations to an approach that focuses on symptomatology for diagnosis. People with cognitive impairment can lack insight into their symptoms, and depressed people are more likely to report symptoms regardless of objective function. Our recommendation of an observer account is aimed at addressing this. However, this may pose additional challenges as PLWH do not always disclose their status to those close to them and some visit the clinic alone. In many low-resource settings, standardized cognitive measures are applied by local-language-speaking research assistants without the medical or neuropsychology training to obtain a detailed history [4]. As such, there is a need for objective measures of acquired symptoms for use in research settings.
Accurate identification of HIV brain pathology may be difficult as no biomarker has yet been validated for this purpose. This is particularly true for low-resource settings where access to neuroimaging can be scarce. In many cases, a diagnosis of HIV brain pathology would rely on the trajectory of symptoms and exclusion of other illnesses. This might necessitate a possible/probable/definite hierarchy. Nevertheless, we feel that such classification is realistic and achievable in a low-resource research setting, more accurately reflects the true nature of the problem, and is more aligned to the clinical scenario.
We hope this framework will lead to the development of new consensus criteria to classify cognitive impairment in PLWH, appropriate for the modern era of widespread effective ART. Based on this framework we feel it is achievable to develop criteria for diverse global populations that are applicable to both research and clinical settings. The development of such criteria will require further refinement and validation of our framework and the involvement of different clinical specialities, academic disciplines, and geographic regions, as well as the wider community of PLWH.
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