Moving on From HAND: Why We Need New Criteria for Cognitive Impairment in Persons Living With Human Immunodeficiency Virus and a Proposed Way Forward

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.

International HIV Dementia Scale for HIV-Associated Neurocognitive Disorders: A Systematic Review and Meta-Analysis

“…Recently, the validity of the Frascati criteria has been challenged [ 18 , 19 , 20 ]. Researchers disagree over the clinical relevance of ANI and the validity of neuropsychological testing in characterizing the cognitive deficits.…”

Transcriptomic and Genetic Profiling of HIV-Associated Neurocognitive Disorders

“…A recent metaanalysis of 35,513 individuals from 123 studies conducted in 32 countries identified a world-wide prevalence of 42.6% for HAND with an estimated 72% of cases occurring in sub-Saharan Africa (Wang et al, 2020). However, the attempt to widely use the current classification to assess the clinical burden of HAND has revealed a number of challenges regarding the diagnosis (Nightingale et al, 2021). One is the standardization and comparability of assessments across different observers administering the tests, different languages, ethnicities, and cultural and social backgrounds (Woods et al, 2004).…”

“…One is the standardization and comparability of assessments across different observers administering the tests, different languages, ethnicities, and cultural and social backgrounds (Woods et al, 2004). Another challenge is the fact that performance on neurocognitive tests can be affected by a variety of factors besides HIV infection and HIVE, such as brain pathology due to cerebrovascular disease, other subclinical co-morbidities, lifestyle and complex social factors beyond education (Nightingale et al, 2021). Thus, it may not be surprising that over the years the clinical relevance of HAND, and particularly the diagnosis of ANI, has become a matter of some debate as many individuals classified as having ANI show no evidence of limitations in everyday functioning (Antinori et al, 2007;Saloner and Cysique, 2017;Ciccarelli, 2020;Nightingale et al, 2021).…”

“…Another challenge is the fact that performance on neurocognitive tests can be affected by a variety of factors besides HIV infection and HIVE, such as brain pathology due to cerebrovascular disease, other subclinical co-morbidities, lifestyle and complex social factors beyond education (Nightingale et al, 2021). Thus, it may not be surprising that over the years the clinical relevance of HAND, and particularly the diagnosis of ANI, has become a matter of some debate as many individuals classified as having ANI show no evidence of limitations in everyday functioning (Antinori et al, 2007;Saloner and Cysique, 2017;Ciccarelli, 2020;Nightingale et al, 2021). On the other hand, a CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study found that participants who had ANI at baseline had a 2-to 6-fold increased risk for earlier development of symptomatic HAND than neurocognitive normal individuals (Grant et al, 2014).…”

“…Some studies have also combined GDS and HAND classification. Besides a call for better international standardization, various modifications have been proposed for a better consensus on the diagnosis of neurocognitive impairment in PLWH, such as an adjustment of the limit score used to distinguish ANI from normal performance, treating cognitive performance as a continuous variable, and including clinical history in the diagnosis (Saloner and Cysique, 2017;Ciccarelli, 2020;Nightingale et al, 2021). In any case, another challenge that remains for research is the comparison of neurocognitive and neuropsychiatric assessments made before and after the introduction of cART and before and after the establishment of HAND based on the Frascati criteria.…”