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. Author manuscript; available in PMC: 2021 Apr 1.
Published in final edited form as: J Neurovirol. 2019 Nov 19;26(2):155–167. doi: 10.1007/s13365-019-00809-z

Operationalizing and Evaluating the Frascati Criteria for Functional Decline in Diagnosing HIV-associated Neurocognitive Disorders in Adults

Anastasia Matchanova a, Steven Paul Woods a,*, Victoria M Kordovski a
PMCID: PMC7234924  NIHMSID: NIHMS1544094  PMID: 31745823

Abstract

Objective

The Frascati criteria for HIV-associated neurocognitive disorders (HAND; Antinori et al., 2007) outlines a classification scheme for functional decline that – despite being over a decade old – has not heretofore been examined systematically.

Method

Participants included 307 HIV+ and 183 HIV− participants who completed self-report, clinician-rated, and performance-based measures of functional status, along with neurocognitive, psychiatric, and medical/laboratory assessments. Using the Frascati criteria, we classified participants with: 1) No functional declines; 2) Mild functional declines; or 3) Major functional declines.

Results

A multivariable logistic regression showed that HIV serostatus was associated with higher rates of Major (33.2 vs. 13.7%) but not Mild (38.8% vs. 31.7%) Frascati-defined functional decline. Within the HIV+ group, individuals with global neurocognitive impairment and affective disorders were at highest risk of Frascati-defined functional decline.

Conclusions

Findings provide some empirical support for the sensitivity and validity of the Frascati criteria for functional declines in the context of HAND. Future work is needed to determine the reliability, stability, cross-cultural validity, and down-stream health-related consequences of the Frascati-defined functional classifications.

Keywords: HIV, daily functioning, functional living skills, everyday living, activities of daily living, AIDS dementia complex

Introduction

Despite notably improved immunovirological management of individuals with HIV disease in recent decades, the prevalence of functional decline is still quite high in this population, with many estimates ranging between 50 and 75% (e.g., Blackstone et al. 2013). Functional declines are defined as the losses of ability to independently manage one’s activities of daily living due to physical, emotional, or neurocognitive changes. In HIV disease, functional declines are most commonly observed in higher-level instrumental activities of daily living (IADL), such as vocational status (e.g., unemployment; Kordovski et al. 2017), financial mis-management; (Heaton et al. 2004), social complications (e.g., social planning; Benedict et al. 2000), and difficulties with health behaviors, including poor retention in healthcare (Jacks et al. 2015). Among the most robust predictors of functional declines in HIV are sociodemographic factors (e.g., older age, lower education), HIV disease severity (Burns et al. 2006), and comorbid mood and substance use disorders (Malaspina et al. 2011; Morgan et al. 2012). By way of comparison, declines in basic activities of daily living (BADLs; e.g., grooming) are less common among HIV+ persons, but can occur in the setting of major physical disability (e.g., stroke, frailty, and extrapyramidal signs; Tierney et al. 2019) and dementia (Erlandson et al. 2014).

Neurocognitive impairment is another highly reliable predictor of HIV-associated functional declines, and its effects are not better explained by sociodemographics, HIV disease severity, medical comorbidities, mood, and substance dependence (Blackstone et al. 2013; Doyle et al. 2013). Individuals with HIV-associated neurocognitive impairment are higher risk for a wide range of functional declines, including poorer medication management (Hinkin et al. 2004; Woods et al. 2016), financial problems (Heaton et al. 2004), household shopping errors (Woods et al. 2017), unemployment (Rabkin et al. 2004; Weber et al. 2012), and automobile accidents (Marcotte et al. 2004). At the domain level, research tends to show larger associations between functional declines and HIV-associated deficits in higher-order cognitive abilities such as learning and memory (Doyle et al. 2013; Thames et al. 2011), executive functions (Heaton et al. 2004; Thames et al. 2013), and working memory (Thames et al. 2011). It is thus not surprising that the criteria for HIV-associated neurocognitive disorders (HAND) have historically incorporated functional decline into the diagnostic staging criteria. Yet while the diagnostic criteria for neurocognitive impairment in HIV has been dissected extensively (e.g., Bearden and Meyer 2016; Gisslen et al. 2011; Tierney et al. 2017; Woods et al. 2004), far less critical attention has been paid to the diagnostic criteria for functional impairment in HIV and HAND.

Early diagnostic criteria for HAND set forth by the American Academy of Neurology AIDS Task Force (Janssen et al. 1991) broadly outlined three qualitative levels of functional declines (i.e., mild, moderate, and severe). The degree of functional decline was a distinguishing feature between HIV-1-associated dementia complex, which required “conspicuous (functional) impairment,” and HIV-1-associated minor cognitive/motor disorder, wherein only the most demanding functional activities were “mildly impaired.” Mild functional decline was described as “activities of daily living are impaired but not to a degree making the person completely dependent on others,” whereas moderate and severe functional decline included “unable to function without some assistance in daily living” and “unable to perform any activities of daily living without assistance,” respectively. More recently, the fifth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5; American Psychiatric Association 2013) includes functional decline as a key criterion differentiating Mild and Major Neurocognitive Disorder due to HIV infection. Akin to the early AAN criteria, the DSM-5 outlines fairly broad specifiers for mild (i.e., difficulties with IADLs), moderate (difficulties with BADLs), and severe (i.e., fully dependent) functional declines. Thus, both the AAN and DSM-5 criteria for determining functional declines are quite broad and flexible, but are not optimally operationalized for diagnostic reliability and clarity (e.g., number and severity of ADL domains, measurement issues, and cultural considerations).

The current gold-standard diagnostic scheme for HAND outlined by Antinori et al. (2007) – more commonly known as the Frascati criteria – provide a detailed set of standards for detecting and staging functional declines. According to Frascati, HAND may be classified as either asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). One key feature distinguishing of these HAND subtypes is the presence and severity of functional declines, which are defined at three levels: functionally intact (i.e., no decline, as with ANI), mild decline (e.g., for diagnoses of MND), and major decline (as might be observed in MND or HAD, depending on the accompanying level of neurocognitive impairment). Mild functional decline is characterized by difficulty efficiently performing IADLs or work, having two or more neurocognitive symptoms in daily life, or performing in the mildly impaired range on a performance-based functional task (e.g., a laboratory test of medication management; Heaton et al. 2004). Major functional decline is characterized by a starker inability to complete tasks in everyday life (e.g., dependence in ADLs, unemployment), having four or more neurocognitive symptoms in daily life, or performing in the moderate-to-severe range of impairment on a performance-based functional task. Finally, “functional intact” is implied by the absence of both mild and major functional declines, although this term is not explicitly outlined in the Frascati criteria.

Although the Frascati diagnostic scheme is widely used (e.g., nearly 2000 citations), we are not aware of any studies that have systematically operationalized and evaluated the criteria for functional decline. This is important because the criteria and specific measures used to classify functional declines can greatly influence diagnostic prevalence estimates (e.g., rates of syndromic HAND; Blackstone et al. 2012) and feed controversies regarding the syndromic nature of HAND (e.g., Grant et al. 2014). Our review of the literature shows that the most commonly used approach to operationalizing functional declines in HAND is a single self-report ADL questionnaire, which is commonly dichotomized as “dependent” when problems are evident in two or more domains (e.g., finances, shopping, planning social activities; Heaton et al. 2010). This approach has evidence of strong inter-rater reliability in HIV (Woods et al. 2004). Others incorporate performance-based measures of functional capacity, such as medication management or vocational tasks to improve sensitivity (Blackstone et al. 2012). A few studies even use multimodal approaches, summing up the number of impaired ADL measures (i.e., self- or clinician-rated), performance-based tasks, measures of cognitive symptoms and vocational status to classify persons with and without functional declines (e.g., Blackstone et al. 2013). At present, however, we know little about: 1) the frequency of 3-level Frascati-defined functional decline subtypes among persons with and without HIV disease; 2) the clinicodemographic correlates of the 3-level Frascati-defined functional decline subtypes among persons with HIV disease; and 3) how the 3-level Frascati-defined functional decline subtypes compare to the more commonly used approach of a single ADL questionnaire.

Methods

Participants

A total of 490 individuals aged 18–83 years with (n=307) and without (n=183) HIV infection were enrolled via the University of California San Diego (UCSD) HIV Neurobehavioral Research Program, which recruits from community-based organizations, local clinics, and regional advertisements. Participants were enrolled in one of four NIH-funded studies in which a comprehensive battery of self-report, clinician-rated, and performance-based measures of everyday functioning were administered. Exclusion criteria included a prior diagnosis of any of the following: (1) severe psychiatric disorder (e.g., schizophrenia); (2) neuromedical condition involving an active central nervous system opportunistic infection; (3) seizure disorder; (4) head injury with loss of consciousness for more than 30 minutes; (5) stroke with neurological sequelae; or (6) presence of a non-HAD neurodegenerative disorder. Individuals were also excluded if they had current substance dependence or tested positive on a breathalyzer or urine toxicology screen for illicit drugs (except marijuana) on the day of testing. The demographic and clinical characteristics of the sample are shown in Table 1.

Table 1.

Demographic and clinical information for HIV− and HIV+ adults

Variable HIV+ (n = 307) HIV− (n = 183) p
Age (years) 49.6 (12.2) 47.7 (15.7) 0.667
Gender (% men) 85.7 67.2 < 0.0001
Handedness (% right) 91.2 89.1 0.438
Education (years) 13.6 (2.5) 14.2 (2.6) 0.031
Hollingshead Highest Occupation 5.6 (1.7) 5.6 (1.8) 0.704
Race/Ethnicity (%) 0.148
 Caucasian 57.3 59.1
 African American 22.8 16.9
 Hispanic 17.9 19.1
 Other 2.0 4.9
Major Depressive Disorder (%) < 0.0001
 Current 13.7 3.3
 Lifetime 62.9 33.9
Generalized Anxiety Disorder (%) < 0.0001
 Current 4.9 0.0
 Lifetime 17.9 3.8
Substance Use Disorder (%)b 73.0 59.6 0.002
Global Deficit Score (GDS) e 0.23 (0, 0.54) 0.15 (0, 0.33) 0.005
Medical
 Hepatitis C Infection (HCV,%) 22.3 10.4 0.001
 Estimated duration of infection (years) 15.8 (9.5) --
 Plasma HIV RNA (rnlog10) a 1.6 (1.6, 1.7) --
 Current CD4 count (cells/μL) a 583 (400, 784) --
 Nadir CD4 count (cells/μL) a 186 (63, 300) --
 AIDS (%) 57.7 --
 Antiretroviral therapy (% prescribed) 90.2 --
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Note. Data represent M (SD) or valid population % values. HIV = Human Immunodeficiency Virus; CD4 = cluster of differentiation.

a

Based on median and interquartile range (IQR) scores

b

Based on lifetime prevalence (no participants met criteria for current Substance Use Disorder)

Materials and Procedure

All participants provided written, informed consent prior to completing an IRB-approved medical, psychiatric, and neuropsychological research evaluation for which they received nominal financial compensation.

Assessment of Functional Decline

Individuals were assessed with seven measures of everyday functioning, including: (1) Lawton and Brody (1969) ADL Scale - Heaton Revision (see Heaton et al. 2004 and Woods et al. 2004), which is a global self-report measure of current and best functioning across 13 IADL domains; (2) Karnofsky Performance Status Scale (Karnofsky and Burchenal 1949), which is a clinician-rated measure of a patient’s overall functioning on a zero (mortality) to 100 (normal, no evidence of disease) scale; (3) Employment status, which was ascertained via a semi-structured interview; (4) Hollingshead Socioeconomic Status (SES; Hollingshead 1975) scale (n =481), which considers best and current occupational status a scale of from 1 (e.g., farm laborers, service workers) to 9 (e.g., executives, professionals); (5) Profile of Mood States (POMS; McNair et al. 1981) confusion/bewilderment scale, which is a 7-item scale measuring cognitive symptoms (e.g., “Unable to concentrate; Forgetful”) over the past week on a 5-point scale ranging from 0 (not at all) to 4 (extremely); (6) Prospective and Retrospective Memory Questionnaire (PRMQ; Smith et al. 2000), which is a 16-item, self-report scale assessing the frequency of everyday memory failures (e.g., forgetting appointments if not reminded by someone else) on a 5-point scale ranging from 1 (never) to 5 (very often); and (7) Medication Management Test-Revised (MMT-R; Heaton et al. 2004), which is a performance-based measure in which participants dispense medications according to a fictitious prescription regimen and answer questions about mock medications (NB. due to differences in the four study protocols, 291 participants received an abbreviated, four-item version of the MMT-R).

Operationalizing the Frascati Criteria for Functional Decline

As noted above, the Frascati diagnostic scheme (Antinori et al. 2007) identifies three levels of functional decline: Functionally Intact (i.e., no functional decline), Mild, and Major. To be classified with Mild or Major functional declines, participants must demonstrate two or more functional declines that are not exclusively attributable to medical symptoms or comorbid conditions. Below we reiterate those criteria and describe the specific manner in which they were operationalized for this study. The following portion of the Mild Frascati criteria was subsumed under the four criteria points outlined below.

“Although patient may maintain employment and/or full IADL independence, he or she reports less efficiency, reduced productivity, more errors in performing tasks, more difficulty meeting expectations, or greater effort expended performing the same activities. ” (e.g. work item states “I am efficient at work” as the option for maximum efficiency, and “I am not very efficient at work and have difficulty maintaining attention or finishing tasks ” as the option for reduced efficiency.)

Mild Functional Decline
  • 1

    “Self-report or other report of some increased assistance with at least two IADLs such as medication management, financial management, shopping, meal preparation, light housekeeping, laundry, driving, use of public transportation, maintaining personal schedules, understanding media events, and child care.”

Individuals were considered to have Mild functional decline in the IADL domain if they: a) endorsed a Mild decline from ‘best’ to ‘now’ on two or more items on the Heaton revision of the Lawton & Body ADL scale. Possible domains include housekeeping, home repairs, doing the laundry, financial management, medication management, shopping, buying groceries, cooking, using transportation, using a telephone, social activity planning, childcare and using reading materials/TV. For example, a Mild ADL decline was coded in the cooking domain if an individual was able to “…plan, prepare, and serve many of my own meals” at their best, but currently endorsed that they “…prepare meals if someone else provides…the right ingredients”; or b) received a clinician rating of less than 90, but greater than 70 on the KPSS.

  • 2

    “The patient is unable to perform some aspects of a previous job.”

In the current study, participants were considered to have Mild functional decline in the vocational domain if: a) they reported their current employment status as “employed” and showed a decline in the occupation rating on the Hollingshead Occupation Score, from “highest Hollingshead (HH)” to “current HH” (n =174 employed participants); or b) showed a decline from ‘best’ to ‘now’ on the “work” item from the Heaton et al. (2004) revision of the Lawton and Brody (1969) ADL scale. For example, a Mild impairment in the “work” domain was coded if the individual endorsed “I am efficient at work” at their best, but currently endorsed “I am not very efficient at work and have difficulty maintaining attention or finishing tasks.”

  • 3

    “In the absence of significant depression...patient reports that he or she is experiencing increased difficulty with ≥2 aspects of cognition in daily life.”

Individuals were considered to have Mild functional decline in the cognitive symptoms domain if: a) they did not meet criteria for current diagnoses of major depressive or generalized anxiety disorders as determined by the Composite International Diagnostic Interview (CIDI version 2.128; World Health Organization 1998); and b) had a score of ≥ 1.0 (but < 2.0) standard deviations (SDs) above the mean of normative standards on the PRMQ or POMS Confusion/Bewilderment scales (see Sheppard et al. 2019).

  • 4

    “If performance-based, standardized functional tests are administered, patient scores >1 SD below an appropriate normative mean on at least one such task”.

Individuals were classified with Mild functional decline in the performance-based domain if they obtained a score of < 10 on the MMT-R or a score of < 4 on the abbreviated MMT-R, both of which are equivalent to 1 SD below the HIV- sample’s mean. Note that, while most clinical tests of neurocognitive functioning have published normative standards, the same is not true for the vast majority of tests of everyday functioning. Instead, raw scores are more commonly used in neuroAIDS research (e.g., Blackstone et al., 2013; Heaton et al., 2004).

Major Functional Decline
  • 1

    “Patient is unable to maintain former employment and this is not due to systemic illness or other factors not related to cognitive impairment (e.g., healthcare coverage being dependent upon disability status).”

Individuals were considered to have Major functional decline in the vocational domain if: a) they reported their employment status as “unemployed” or “disabled”; or b) marked ‘I am no longer able to work’ on the Heaton et al. (2004) revision of the Lawton and Brody (1969) ADL scale.

  • 2

    “Patient requires substantially greater assistance (or is dependent) with more than two IADLs.”

Individuals were considered to have Major functional decline in the IADL domain if: a) they endorsed impairment in two or more items on the Heaton revision of the Lawton & Brody (1969) ADL scale by indicating a decline from ‘best’ to ‘now’ that was more severe than Mild (e.g., for the cooking item, individuals must have endorsed a difference between best and now, with current functioning indicating “I heat and serve meals provided by others” or “I need to have meals prepared and served to me”); or b) they received a clinician rating of less than 70 on the KPSS.

  • 3

    “Patient or a knowledgeable informant reports that he or she experiences/shows significantly greater difficulty with ≥4 aspects of cognition, as listed above. However, self-report is not sufficient (would need confirmation by another informant) if patient is significantly depressed (e.g., Beck Depression Inventory ≥ 17).”

Individuals were considered to have Major functional decline in the cognitive symptoms domain if they: a) did not meet criteria for current diagnoses of major depressive or generalized anxiety disorders on the CIDI; and b) had a score of ≥ 2.0 standard deviations above the mean of normative standards on the PRMQ or POMS Confusion/Bewilderment Scale.

  • 4

    “If performance-based, standardized functional tasks are administered, patient scores >2 SD below an appropriate normative mean on at least one such task, or >1 SD below the mean on at least two tasks.”

To further qualify for Major impairment in the performance-based domain of everyday functioning, individuals needed a score of ≤ 5 on the MMT-R or a score of ≤ 2 on the abbreviated MMT-R, which is equivalent to a 2 SD cutscore using the HIV- sample’s mean scores and is consistent with prior research (Heaton et al. 2004).

Traditional Approach for Classifying Functional Decline

In an effort to derive a comparison standard for the full Frascati diagnostic system of classifying functional declines, we also classified persons using only the Heaton revision of the Lawton & Brody (1969) ADL scale (Heaton et al. 2004). Individuals were classified as dependent if they met either criterion 1a for Mild or 2a for Major functional decline as described above.

Neuropsychological Evaluation

All participants were administered a comprehensive neuropsychological test battery by certified research assistants, which was constructed in accordance with Frascati research diagnostic criteria (Antinori et al. 2007). Ninety-seven participants received the CogState (www.cogstate.com; Woods et al. 2017), 53 received the NIH toolbox (Casaletto et al. 2015) and 340 participants received the standard clinical neurocognitive battery described in Tierney et al. (2017). Due to the fact that different test batteries were used, the data were summarized with the Global Deficit Score (GDS; see Carey et al. 2004) based on the best available normative data and collapsed across studies. Note that the GDS did not differ across the three different batteries (p = .46). The GDS ranges from 0 to 5, with higher scores reflecting greater levels of neurocognitive impairment.

Medical Evaluation

Participants underwent a brief medical evaluation led by a research nurse, which included a review of systems (nadir CD4 cells/μL), medications (e.g. antiretroviral therapies [ART]), comorbidities (e.g., Hepatitis C virus [HCV] co-infection; n = 108 of 483 total participants with data), urine toxicology, and a blood draw from which current CD4 cells/μL (n = 303 of 307 HIV+ participants) and HIV RNA (n = 295 of 307 HIV+ participants) were assessed.

Psychiatric Evaluation

Current (i.e., within the last 30 days) and lifetime diagnoses of major depressive, generalized anxiety, and substance use disorders were determined using the CIDI version 2. For primary analyses, current and lifetime diagnoses of major depressive and generalized anxiety disorders were combined into a single “affective disorders” variable to help limit the number of highly related covariates in the statistical models and minimize Type I error.

Data Analyses

A multivariable logistic regression was used to examine the association between HIV serostatus, and the frequency of functional decline as defined by the Frascati criteria (i.e., Functionally Intact, Mild, or Major). The analysis was covaried for any demographic or clinical factors in Table 1 that were significantly different between the HIV serostatus groups and were significantly associated with the Frascati-defined functional decline variable in the entire sample. This was determined by chi-square tests or Wilcoxon rank-sums tests since none of the continuous variables listed in Table 1 were normally distributed as determined by Shapiro-Wilk W Tests (ps < .05). A power analysis was conducted for the primary aims, which showed greater than 0.8 power to detect small to medium effect sizes at the univariate level for all analyses using a critical alpha level of .05. Next, within the HIV+ group we examined the demographic, psychiatric, neurocognitive, and medical correlates of Frascati functional decline groups using chi-square tests and Wilcoxon rank-sums tests, as appropriate. A final multivariable logistic regression model was then constructed in the HIV+ group that included all factors that were significantly associated with Frascati-defined functional decline at the univariable level. A kappa coefficient of agreement was computed to compare the full Frascati diagnostic system of classifying functional declines to the traditional functional criteria based on the Heaton revision of the Lawton & Brody (1969) ADL scale (Heaton et al. 2004). The data were analyzed using JMP Pro 14.0 (SAS, Cary, NC).

Results

The HIV+ group reported fewer years of education (χ2[1]=4.67, p=. 031), had a higher proportion of men (χ2[1] =23.4, p<.0001) and demonstrated worse global neurocognitive functioning (χ2[1]=8.0, p=.005, d = 0.276) than the HIV- comparison group. The HIV+ group also had greater lifetime frequency of HCV infection (χ2[1]=10.8, p=.001), as well as affective (χ2[1]=41.1, p<.0001) and substance use (χ2[1]=9.46, p=.002) disorders. No other variables listed in Table 1 differed significantly by HIV serostatus (all ps>.10). All six clinicodemographic variables that differed by serostatus also differed by Frascati-defined functional decline subtype in the full sample (ps<.05) and were thus included as covariates.

HIV Serostatus and Frascati–defined Functional Decline

Figure 1 shows the frequency of Mild and Major functional decline according to Frascati criteria by HIV serostatus and Table 2 provides descriptive data for the key functional measures for the study groups. The overall logistic regression model of HIV serostatus and six covariates predicting Frascati functional decline was significant (χ2[14]=94.5, p<.001). Within this model, HIV serostatus was an independent predictor of Frascati-defined functional decline (χ2[2]=12.1, p=.002).

Fig 1.

Fig 1.

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Frequency of Mild and Major Functional Decline According to Frascati Criteria in Persons with and without HIV disease.

Table 2.

Descriptive data for the key functional measures by HIV serostatus

Variable HIV+ (n = 307) HIV− (n = 183)
IADL Scale
 Domains declined (of 13) a 1 (0, 3) 0 (0, 1)
 Dependent (% with >/= 2 declines) 34.9 9.8
Karnofsky (of 100) e 90 (100, 80) 100 (100, 100)
 Dependent (% < 90) 28.7 6.0
Lawton & Brody Work Item (of −3) a 0 (0, −3) 0 (0, 0)
 Decline (% </= −1) 44.0 12.6
Employment (%)
 Employed 29.3 45.9
 Unemployed 25.1 30.0
 Disabled 37.1 8.7
 Retired 8.5 15.3
Hollingshead Employment Decline (%) b 10.1 12.6
PRMQ Total (of 80) 37.5 (12.2) 31.7 (9.1)
 Elevated (% >/= 1 SD) 13.4 4.9
POMS Confusion/Bewilderment (of 28) 9.3 (5.7) 6.4 (4.0)
 Elevated (% >/= 1 SD) 48.5 29.5
MMT-R (% correct) e 1 (0.9, 1) 1 (0.8, 1)
 Impaired (% < 100) 32.6 36.6
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Note. Data represent M (SD) or valid population % values unless otherwise noted. IADL = Instrumental Activities of Daily Living, MMT-R = Medication Management Test-Revised; POMS = Profile of Mood States; PRMQ = Prospective and Retrospective Memory Questionnaire.

a

Median and interquartile range (IQR) scores

b

Based on 90 HIV+ participants and 84 HIV− participants with current employment

Within our primary model, the 3-level variable for Frascati defined functional declines (i.e., Functionally Intact, Mild and Major) showed a significant omnibus association with HIV serostatus. Using the 3-level variable in the full sample (n=490), the proportion of individuals with Mild functional declines do not differ by HIV serostatus (HIV+ = 38.8% vs. HIV− = 31.7%). However, an omnibus effect on a 3-level categorical variable requires post-hoc comparisons of each pair of levels within that variable to fully understand what might driving the overall group differences. Thus, we conducted three 2-by-2 χ2 analyses comparing the HIV+ and HIV- groups on the frequencies of Functionally Intact vs. Mild (n=363; OR = 2.4 (95% CI: 1.6, 3.7)), Mild vs. Major (n=304; OR = 2.0 (95% CI: 1.2, 3.4)) and Functionally Intact vs. Major (n=313; OR = 4.7 (95% CI: 2.8, 8.0)). These sub-analyses therefore demonstrated that despite broadly comparable overall frequencies of Mild functional impairment at the population level, HIV is nevertheless associated with a heightened risk of Mild as compared specifically to Intact functioning (HIV+ = 58% vs. HIV- = 37% in the subset of 363 participants). With regard to the covariates, lower education (χ2[2]=6.16, p=.046), worse global neurocognitive functioning (χ2[2]=11.4, p=.003) and the presence of an affective disorder (χ2[2]=15.9, p<.001) were all independently associated with Frascati-defined functional decline, whereas HCV infection (χ2[2]=5.11, p=.078), gender (χ2[2]=3.55, p=.169) and substance use disorder (χ2[2]=5.17, p=.075) were not.

Clinicodemographic Correlates of Frascati-defined Functional Decline in HIV

Among HIV+ individuals (see Table 3), the severity of global neurocognitive impairment differed between the three levels of functional decline (χ2[2]=10.3, p=.006). Univariate analyses showed that the Major group had worse neurocognitive functioning than the Functionally Intact group (χ2 [1]=10.4, p=.001, d=.41), neither of which differed from the Mild group (ps >0.05, d=0.25 for Mild vs. Functionally Intact and d=0.11 for Mild vs. Major). Notably, the functional groups differed in frequency of affective disorder (χ2[2]=13.9, p=.001), such that the Major group had a higher rate than the Functionally Intact group (χ2 [1]=12.1, p<.001), who had a lower rate than the Mild group (χ2[1]=8.4, p=.004). The Mild and Major groups did not differ from each other in rates of affective disorders (p=0.450). The functional groups differed in rates of substance use (χ2[2]=6.48, p=.039) disorders, such that the Major group had a higher rate as compared to the Functionally Intact group (χ2[1]=6.4, p=.011), neither of which differed from the Mild group (ps >0.05). The three groups also differed on nadir CD4 count (χ2[2]=6.09, p=.048), AIDS diagnoses (χ2[2]=6.08, p=.048) and ART status (χ2[2]=7.05, p=.030). No other variables listed in Table 3 varied significantly across functional status (all ps>.05).

Table 3.

Demographic and clinical information for HIV+ adults by functional status.

Variable Functionally Intact (n = 86) Mild (n = 119) Major (n = 102) p
Age (years) 47.7 (12.6) 50.4 (12.1) 50.3 (11.9) 0.110
Gender (% men) 83.7 95.8 86.3 0.830
Handedness (% right) 89.5 86.5 87.3 0.067
Education (years) 14.0 (2.2) 13.6 (2.7) 13.2 (2.4) 0.058
Hollingshead Highest Occupation 5.6 (1.9) 5.7 (1.7) 5.4 (1.7) 0.599
Race/Ethnicity (%) 0.167
 Caucasian 65.1 57.1 50.9
 African American 19.8 21.1 27.5
 Hispanic 11.6 19.3 21.6
 Other 3.5 2.5 0.0
Major Depressive Disorder (%)c 0.001
 Current 5.8 21.0 11.8
 Lifetime 46.5 66.4 72.5
Generalized Anxiety Disorder (%)c 0.049
 Current 2.3 5.9 5.9
 Lifetime 9.3 21.0 21.6
Substance Use Disorder (%) e 65.1 71.4 81.4 0.039
Global Deficit Score (GDS) a,b 0.15 (0, 0.47) 0.23 (0, 0.5) 0.31 (0.15, 0.62) 0.006
Medical
 Hepatitis C Infection (HCV,%) 16.7 23.9 25.0 0.343
 Estimated duration of infection (years) 14.7 (9.9) 16.2 (9.8) 16.2 (8.7) 0.538
 Plasma HIV RNA (rnlog10) a 1.6 (1.6, 1.7) 1.6 (1.6, 1.7) 1.6 (1.6, 1.7) 0.453
 Current CD4 count (cells/μL) a 559 (397, 792) 616 (411, 800) 529 (399, 744) 0.544
 Nadir CD4 count (cells/μL) a,b 222 (108, 353) 175 (60, 259) 180 (45, 306) 0.048 b
 AIDS (%) c 46.5 62.2 61.8 0.048 c
 Antiretroviral therapy (% prescribed) d 83.7 94.9 90.2 0.030 d
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Note. Data represent M (SD) or valid population % values unless otherwise noted. HIV = Human Immunodeficiency Virus; CD4 = cluster of differentiation.

a

Median and interquartile range (IQR) scores

b

Functionally Intact > Mild, Major

c

Functionally Intact < Mild, Major

d

Mild > Functionally Intact

e

Major > Functionally Intact

Table 4 provides the descriptive data for functional measures in the HIV seropositive adults by the three levels of Frascati-defined functional declines. The overall model of HIV and clinicodemographic variables predicting Frascati-defined functional decline was significant (χ2[12]=38.7, p<.001). Within this model, worse global neurocognitive functioning (χ2[2]=9.48, p=.009) and the presence of an affective disorder (χ2[2]=13.3, p=.001) were independent contributors. The other variables, including substance use disorder (χ2[2]=4.52, p=.105), nadir CD4 count (χ2[2]=0.247, p=.884), ART (χ2[2]=5.31, p=.070) and AIDS diagnoses (χ2[2]=1.62, p=.445) were not associated with Frascati-defined functional decline in this multivariable model.

Table 4.

Descriptive data for the functional measures in HIV+ adults by functional status.

Variable Functionally Intact (n = 86) Mild (n = 119) Major (n = 102)
Lawton & Brody IADL Scale
 Domains Declined (of 13) e 0 (0, 1) 1 (0, 3) 2.5 (0, 7)
 Dependent (% with >/= 2 declines) 7.0 37.8 54.9
Karnofsky (out of 100) e 100 (90, 100) 90 (80, 100) 90 (70, 90)
 Dependent (% < 90) 2.3 30.3 49.0
Lawton & Brody Work Item (of −3) e 0 (0, 0) 0 (0, 3) 3 (0, 3)
 Decline (% </= −1) 11.6 49.6 64.7
Employment (%)
 Employed 61.6 26.9 4.9
 Unemployed 16.3 23.5 34.3
 Disabled 12.8 40.3 53.9
 Retired 9.3 9.2 6.9
Hollingshead Employment Decline (%) a 11.6 14.3 3.9
PRMQ Total (of 80) 29.7 (8.4) 38.3 (10.4) 43.1 (13.5)
 Elevated (% >/= 1 SD) 0.0 7.6 31.4
POMS Confusion/Bewilderment (of 28) 5.9 (4.2) 9.1 (5.3) 12.5 (5.4)
 Elevated (% >/= 1 SD) 19.8 47.9 73.5
MMT-R (% correct) e 1 (1, 1) 1 (0.75, 1) 1 (0.75, 1)
 Impaired (% < 100) 4.7 43.7 43.1
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Note. Data represent M (SD) or valid population % values. POMS = Profile of Mood States; PRMQ = Prospective and Retrospective Memory Questionnaire total score; IADL = Instrumental Activities of Daily Living; MMT-R = Medication Management Test-Revised.

e

Based on median and interquartile range (IQR) scores

Frequency and Correlates of Frascati-defined functional decline in HAND

Figure 2a shows the frequency of the Frascati-defined functional declines among the 90 HIV+ persons in our sample with global neurocognitive impairment (i.e., GDS > 0.5). Of these 90 participants, 21 (23%) were classified as Functionally Intact, 32 (36%) were classified as Mild, and 37 (41%) were classified as Major. By way of comparison, among HIV- individuals who were neurocognitively normal (n=148), 85 individuals (57%) were classified as Functionally Intact, 47 individuals (32%) were classified as Mild, and 16 individuals (11%) were classified with Major functional declines. Among the variables listed in Table 3, only affective disorder (χ2[2]=6.57, p=.038) was associated with Frascati-defined functional impairment among the neurocognitively impaired HIV+ subset (all other ps>.05). Post-hoc analyses showed that the Major group had a higher rate of affective disorder than the Functionally Intact group [OR = 4.1 (95% CI: 1.3, 13.0]) and the Mild group [OR = 2.4 (95% CI: 0.87, 6.7]), neither of which differed from each other (p>0.05).

Fig 2a.

Fig 2a.

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Frequency of Functional Declines According to Frascati Criteria Among HIV+ Persons with Neurocognitive Impairment (n=90).

Finally, we examined the association between the Frascati-defined functional decline criteria and the traditional two-level ADL questionnaire approach in the 90 neurocognitively impaired subset of our sample (Figure 2b). Only 31% were Functionally Dependent and 69% were Functionally Intact, which is a 0.24 rate of agreement with a simple dichotomy of the Frascati-defined criteria (95% CI: 0.19, 0.29). Among the 37 participants who were classified as Major by Frascati, 50% were classified as functionally intact by the traditional ADL approach. Seventy-two percent of the 32 participants who were classified as Mild by Frascati were classified as Functionally Intact by the standard ADL approach. By way of contrast, only 7% of the 28 participants who were classified as Functionally Dependent by the standard ADL approach were Functionally Intact according to Frascati.

Fig 2b.

Fig 2b.

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Frequency of functional decline in 90 persons with HAND according to the traditional single ADL questionnaire approach (left). Rates of Frascati-defined functional decline among persons classified as “functionally intact” by the traditional approach (right).

Discussion

The current study sought to operationalize the three levels of the detailed Frascati criteria for functional declines and characterize its frequency and clinicodemographic correlates in large, well-characterized groups of HIV+ and HIV− persons. After controlling for demographics, psychiatric diagnoses, neurocognitive impairment and medical comorbidities, HIV disease was associated with a two-fold increase in risk for any Frascati-defined functional decline in our sample. Seventy-two percent of the HIV+ participants in this sample had at least Mild functional declines according to Frascati, as compared to 45% of seronegatives. Our results are consistent with previous findings which estimate that between 50% and 75% of HIV-infected persons demonstrate “global” impairment in everyday functioning, which is present in about one-third of seronegative adults with comparable demographics and risk factors (e.g., Blackstone et al. 2013). The Frascati criteria for functional declines thus appear to be sensitive to HIV disease independent of important comorbidities and produce rates of functional problems that are consistent with prior literature, thus providing some support for their validity.

One potential advantage of the Frascati criteria for functional decline is that they differentiate Mild and Major functional problems, which are thoughtfully operationalized in the original framework (Antinori et al. 2007). In this study, the most striking effects of HIV were observed for Major Frascati-defined functional decline. Persons with HIV were nearly 5 times more likely than seronegatives to meet criteria for Major functional declines versus being classified as Functionally Intact. As compared to seronegatives in our sample, HIV+ individuals had a 2-fold risk of having Major vs. Mild Frascati-defined functional declines. Although the rates of Mild Frascati-defined functional decline were similar across serostatus groups in the full sample, pairwise comparisons nevertheless showed that persons with HIV were approximately 2 times more likely than seronegatives to meet criteria for Mild functional declines as compared to being classified as Functionally Intact. These sub-analyses therefore demonstrated that despite broadly comparable overall frequencies of Mild functional impairment at the population level, HIV is nevertheless associated with a heightened risk of Mild as compared specifically to Intact functioning (HIV+ = 58% vs HIV− = 37%) in the subset of 363 participants without Major diagnoses. To our knowledge, this is the first examination of these functional subtypes, with findings suggesting a stair-step increased risk of severity of Frascati-defined functional decline in HIV disease broadly. In this regard, Mild Frascati-defined functional declines were most frequently observed, but also the least specific (i.e., fairly high rates in the HIV- group), whereas Major Frascati-defined functional declines were less common, but had greater specificity to HIV.

Within the HIV+ group (and the full sample), neurocognitive impairment was a strong, independent predictor of Frascati-defined functional declines. Specifically, greater levels of neurocognitive impairment were associated with more severe Frascati-defined functional declines. This is commensurate with a robust literature showing that global HIV-associated neurocognitive impairment is reliably associated with everyday functioning across a range of instrumental ADLs (e.g. Heaton et al. 2004) and health behaviors (e.g., Hinkin et al. 2002). Post-hoc analyses showed that HIV+ persons with Major functional decline had moderately worse neurocognitive functioning than the Functionally Intact group (d=.41). However, the Major group did not differ from the Mild group (d=0.11), who in turn showed only a modest, non-significant difference from the Functionally Intact group (d=0.25). In fact, the highest risk for Major functional impairment in our sample was for the subset with global neurocognitive impairment. Nearly half (41%) of individuals with neurocognitive impairment were classified as having Major functional declines (vs. 36% Mild, 23% Functionally Intact). In contrast, only 11% of neurocognitively normal HIV- individuals were classified as Major (vs. 32% Mild, 57% Functionally Intact). Thus, Major functional declines, which had the greatest specificity for HIV infection, also appear to have the strongest association with global neurocognitive impairment in the setting of HIV disease. Unfortunately, our use of multiple cohort studies does not allow us to reliably dissect the domain-level associations between neurocognitive impairment and the Frascati-defined functional subcategories. Future research may wish to examine this question, particularly given the known sensitivity of executive functions and episodic memory to everyday functioning problems in HIV disease (e.g., Casaletto et al. 2017).

Affective disorders also showed a strong association with Frascati-defined functional declines in the HIV+ group, as well as in the full sample. This, despite the fact that only 10% of the sample had current (i.e., within 30 days) diagnoses of affective disorders and the Frascati criteria explicitly account for current affective distress in determining the importance of cognitive symptoms. Findings are consistent with the extant literature showing that diagnoses of GAD (Brandt et al. 2016) and MDD (Rabkin et al. 2004) increase risk of ADL dependence (e.g., unemployment) in HIV disease. Further, the odds ratios for current (2.9 [95% CI: 1.2, 7]) and lifetime (2.3 [1.3, 3.9]) affective disorders in predicting functional problems were highly comparable and had overlapping confidence intervals. Similarly, the odds ratios for GAD (2.6 [1.2, 5.0]) and MDD (2.6 [1.6, 4.3]) were highly comparable and had overlapping confidence intervals. Thus, these data suggest that the occurrence of either of these disorders at any time is a sufficient risk factor for Frascati-defined functional declines in HIV disease.

Interestingly, the rates of comorborbid affective disorders in HIV+ individuals consistently increased in step with functional decline; that is, the lowest frequency of comorbid affective disorders were in HIV+ individuals who were Functionally Intact (47% depression, 9% anxiety), followed by individuals with Mild (66% depression, 21% anxiety) and Major functional declines (73% depression, 22% anxiety). Notably, after restricting the sample to persons with global neurocognitive impairment, the presence of an affective disorder was the only clinicodemographic factor that distinguished among levels of Frascati-defined functional declines. Prior work suggests possible synergy between recent affective disorders (e.g., GAD) and neurocognitive impairment in association with ADL dependence (e.g., Brandt et al. 2016). These findings thus provide partial support for the validity of the Frascati criteria for functional decline, but again raise some concerns about the ability to distinguish between Mild and Major classifications. Future work may examine related neuropsychiatric constructs that are affected (and of clinical functional relevance) in HIV, including apathy (e.g., Kamat et al. 2014), alexithymia (McIntosh et al. 2014), post-traumatic stress disorder (O’Cleirigh et al. 2008), and other dimensions of anxiety (Brandt et al., 2017).

HIV-related disease variables including nadir CD4 count, AIDS status and antiretroviral therapy prescription were also associated with Frastacti-defined functional decline; specifically, persons classified as Functionally Intact had the highest nadir CD4 counts, lowest frequencies of AIDS diagnoses, and were more likely to be prescribed ART. This is consistent with findings that show strongest and most reliable contributing factors to everyday functioning include mood, medical comorbidity burden, and neurocognitive functioning (Heaton et al. 2004; Blackstone et al. 2013). Yet HIV disease factors did not differentiate between the Mild and Major Frascati categories of functional declines, consistent with what was observed for other demographic, psychiatric, and neurocognitive factors. Future studies may wish to determine if other HIV (e.g., CSF viral load, DNA) and non-HIV-specific (e.g., tau) biomarkers and/or disease burden indicators (e.g., comorbidity indices) are more sensitive to the differences between Mild and Major functional declines. Moreover, this finding raises questions about the possible mediating and moderating factors that might differentiate Mild and Major Frascati-defined functional declines. For example, it is possible that factors such as neurocognitive impairment, the use of compensatory strategies, or health literacy could mediate the relationship between HIV disease variables and the severity of functional declines. Likewise, HIV disease variables might have varying effects on functional declines across sociodemographics (e.g., age, gender) or levels of psychosocial support.

The 3-level Frascati-defined functional decline diagnostic criteria appear preferable to the traditional approach of using a single ADL questionnaire (see also Blackstone et al. 2012). The rate of agreement between the Frascati functional criteria and the single ADL questionnaire approach was moderately low (κ=0.24). Among the 90 HIV+ persons with neurocognitive impairment, the single ADL questionnaire approach classified 69% as functionally intact (31% functionally dependent). Meanwhile, according to the Frascati approach, only 23% of the same subset of the sample were classified as Functionally Intact (77% functionally dependent). Thus the traditional approach may miss important functional declines, which Frascati not only detects but also further breaks down into Mild (36%) and Major (41%) subtypes. Furthermore, less than a third the 69% of persons classified as “Functionally Intact” by the traditional ADL Thus the Frascati approach is arguably more sensitive and nuanced than the traditional single ADL questionnaire approach, which has clear implications for diagnosing and staging HAND.

There are multiple limitations of the current study that are important to consider. We utilized a sample that was largely comprised of white, fairly well-educated men from an urban setting. Thus, the external validity and generalizability of findings in broader national and international settings could be limited. Another possible limitation is that our performance-based task was domain specific, did not have normative data available and was limited to medication management performance, which is just one component of instrumental ADL for individuals with HIV. Therefore, performance on this task may under or overestimate real life abilities of daily functioning. Finally, the assessments used in the current study provided only cursory coverage of the “efficiency” aspect of the Frascati criteria for functional declines (e.g., an ADL functionally intact individual who is reporting being less efficient or productive or is experiencing more difficulties with managing ADLs). Notwithstanding these limitations, results of the current study extend the extant literature by providing partial support for the validity of the Frascati criteria for functional declines. Declines in everyday functioning are important predictors of health and well-being outcomes, including quality of life (Garre-Olmo et al. 2017), health status (Naseer et al. 2016), and mortality (Hoogendijk et al. in press). Therefore, the importance of correctly classifying everyday functioning decline is paramount. Future studies are needed to establish temporal stability of the Frascati criteria, sensitivity to CNS opportunistic infections, replicability, as well as linage to other manifest criterion. Additionally, investigation of the ability of the Frascati criteria to map on to quality of life will further assess the utility of these criteria in practice.

Acknowledgements

This work was supported by the National Institutes of Health under Grants R01-MH073419, P30- MH62512 and R21-MH098607. The authors are grateful to the UC San Diego HIV Neurobehavioral Research Program (HNRP) Group (I. Grant, PI) for their infrastructure support of the parent R01. In particular, we thank Donald Franklin, Dr. Erin Morgan, Clint Cushman, and Stephanie Corkran for their assistance with data processing, Marizela Verduzco for her assistance with study management, Drs. Scott Letendre and Ronald J. Ellis for their assistance with the neuromedical aspects of the parent project, and Dr. J. Hampton Atkinson and Jennifer Marquie Beck and their assistance with participant recruitment and retention. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government. The authors thank the study volunteers for their participation.

Footnotes

Disclosures

There are no conflicts of interest for the authors to disclose.

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