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2 Studies: Frailty Associated with 4 Times Increased Death Rates in HIV+, Associated with Comorbidities Onset, 2- Frailty and NCI (neurocognitive impairment) in study 2 Led to Increased disability, falls, in inability to Function Measuring by IADLs, independent living
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[Disability was assessed every 12 months with the Lawton-Brody Instrumental Activities of Daily Living Questionnaire, using self-reported limitations in performing 8 tasks: housekeeping, money management, cooking, transportation, telephone use, shopping, laundry, and medication management]
Frailty is an independent risk factor for mortality, cardiovascular disease, bone disease and diabetes among aging adults with HIV
Clinical Infectious Diseases 24 December 2018
Our findings support the utility of frailty assessments in the standard health maintenance of aging PWH. This may serve as a simple yet high-impact predictor of chronic, age-related diseases and better inform current predictive risk models, however further investigation is needed to determine optimal strategies to incorporate use of frailty scores in chronic disease risk stratification. Once identified, frailty development may be halted or reduced by physical activity training; such progams have been shown to increase strength, balance and physical activity among elderly HIV-negative participants, ultimately leading to reduction in frailty [44-46]. For aging PWH, structured exercise programs have been shown to improve weight, strength, and cardiorespiratory fitness, and even reduce the number of frailty criteria [47, 48]. Such interventions are low-risk and, at minimum, may improve health outcomes directly consequent to frailty. Baseline frailty was associated with an increased risk of incident CVD and DM with a trend towards a significant association with incident bone events.
Among 821 men and 195 women, 48% were white, non-Hispanic and 46% were between 40-49 years of age at study entry - 40% 50-59, 16% over 60, 44% < 50. The majority (926, 91%) were virally suppressed (HIV RNA <50 copies/mL) at baseline with a median baseline CD4 of 621 cell/μL. With the exception of seven participants, all were taking antiretroviral therapy upon study entry. At baseline, 390 (38%) were pre-frail and 62 (6%) frail. Frailty scores increased in one or more components among 194 (19%) participants from baseline to 48 weeks; among these participants, increases in the following frailty components were observed: weight loss (N=22), low physical activity (N=53), exhaustion (N=72), grip weakness (N=80), slow gait speed (N=26). An increase in frailty from baseline to week 48 was significantly associated with mortality (IRR 3.78 [1.52-9.39], p=0.004), but was not associated with incident CVD, diabetes, or bone events (Table 2). Baseline pre-frailty was not significantly associated with any of the clinical outcomes. In this large, well-characterized cohort of PWH, the vast majority of whom were virally suppressed with CD4 count >600 cells/μL, the presence of frailty at study entry was associated with greater risk for subsequent incident CVD, diabetes, and bone disease independent of traditional risk factors for such diseases, while increase in frailty over 48 weeks was associated with increased risk for death. Furthermore, the objective frailty component of slow gait, a strong predictor of mortality among older adults without HIV [14], was associated with incident diabetes and CVD (borderline), but not with mortality or bone disease event. These observations illustrate an intimate relationship between frailty, a marker of vulnerability and physiologic dysregulation, with the development of age-related chronic diseases and death among middle-aged and older PWH.
The occurrence of the frailty phenotype prior to clinical disease onset suggests that frailty is associated with the development of these chronic diseases in our cohort. The detrimental impact of frailty on many subsequent poor health outcomes (including falls, hospitalization, disability, and mortality) has been well-described among both PWH and in the general population [9-11, 15-22]. Increases in frailty score have also been shown to be associated with increased mortality risk in the general population [23], so our observed mortality association is not unexpected. Nonetheless, since PWH have a higher prevalence of frailty and progress to frailty faster than persons in the general population [7, 24], our observation underscores a potentially greater risk of mortality consequent to frailty among PWH. While our findings suggest that baseline frailty can precede certain chronic diseases among PWH, they do not establish a causal pathway between frailty and chronic disease development. Pathophysiologic mechanisms may exist, however, that are common to both. Similar to the widely-studied associations between chronic immune activation and inflammation as contributors to specific chronic diseases among PWH, elevations in levels of multiple systemic markers of inflammation have been associated with the development of frailty among PWH [33-37]. Indeed, levels of specific markers of inflammation associated with CVD among PWH, such as interleukin-6 (IL-6), high sensitivity C-reactive protein (hsCRP), sCD14 and sCD163 have been independently associated with frailty [33, 35, 37-40]. Inflammation associated with frailty and age-related chronic disease may be particularly relevant to PWH, since increased inflammation is fundamental to HIV pathophysiology. Additionally, accelerated sarcopenia and adiposity can occur in the setting of HIV [41], which may consequently contribute to sedentary lifestyle, thereby hastening metabolic derangements (such as insulin resistance) and contributing to chronic disease development. Functional impairments characteristic of frailty can further compound this process. These are especially important considerations in risk stratification for certain diseases, as traditional screening tools, such as the American College of Cardiology/American Heart Association (ACC/AHA) pooled cohort equation and the FRAX score, under-predict disease-specific clinical events for PWH [42, 43].
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Frailty, Neurocognitive Impairment, or Both in Predicting Poor Health Outcomes Among Adults Living With Human Immunodeficiency Virus
CID May 2018
As has been seen among aging HIV-uninfected persons, we found that both frailty and NCI were strong predictors of poor health outcomes.
Both frailty, or components of frailty, and NCI were strong predictors of poor health outcomes, independent of age....including more recurrent falls (47% & 33% vs 15%) and increased in IADLs (independent living disability of functioning - 40% & 53% vs 15%). Although the number of deaths was greater among those with frailty or NCI the numbers were too small to draw conclusions. Weak grip strength+NCI increased risk for bad outcomes. . Accounting for chronologic age fails to completely reflect biologic aging that can differ between individuals, particularly among PLWH with differing durations of HIV infection, severity, and ART exposure. Clinical manifestations of biologic aging are more accurately captured in measures of vulnerability, health, or functioning, such as physical frailty and cognitive capability. Frailty can also be conceptualized as an "accumulation of deficits," as described in the Rockwood model [37] and the VACS [38, 39]. Inclusion of HIV-specific variables, in addition to non-HIV comorbidities or laboratory abnormalities in these frailty indices, has demonstrated validity in predicting mortality or hospitalizations in cohorts of middle- and older-aged PLWH [38, 40, 41]. As such, we expected that a greater comorbid burden would explain most of the association between our measures of physical and cognitive frailty with poor health outcomes. In contrast, we found that education level and anxiety/depression medications, but not comorbidity burden or HIV-specific factors, partially explained the association between physical or cognitive function and poor health outcomes. Taken as a whole, our findings emphasize that other measures of economic and psychological vulnerability influence the likelihood of a frail or neurocognitively-impaired PLWH experiencing a poor health outcome to a greater extent than age, comorbidities, or HIV burden......In summary, frailty (or gait speed or grip strength), alone or in combination with NCI, is a strong predictor of a poor health outcome within 2 years. As the ideal models of care for older PLWH are established, PLWH at highest risk for adverse outcomes may benefit most from frequent clinic visits, polypharmacy reductions, geriatric consultations, rehabilitative services, or home health assistance. As the impact of "social frailty" was a strong confounder in the association between frailty, NCI, and poor health outcomes, interventions directed at improving or reducing social frailty may reduce poor health outcomes among frail or neurocognitively-impaired PLWH. Similarly, interventions that target prevention or reversal of frailty or both frailty and NCI (such as physical activity) may have the greatest potential to limit poor health outcomes among PLWH.
Poor health outcomes were most common among HIV+ persons with both frailty and NCI (74%) or frailty without NCI [Neurocognitive Impairment] (60%; Table 2). PLWH in a longitudinal, observational study of aging completed entry evaluations for frailty and NCI. Outcomes of falls (recurrent) increased limitations in independent activities of daily living (IADL), or mortality were combined. Poisson regression models estimated prevalence ratios (PR) for ≥1 outcome over 2 years: Increased IADLs (40% for those with frailty, 53% for those with both frailty & NCI vs 15% without frailty or NCI. Among 987 participants ACTG HAILO Study: the median age at entry was 51 years; 19% were female; the median CD4 count was 616 cells/μL; and HIV-1 RNA was <200 copies/mL in 94%. Most (79%) participants had neither frailty nor NCI; 2% had both; 4% frailty only; and 15% NCI only. Over 2 years of observation, 100 (10%) participants experienced recurrent falls; 175 (18%) had worsening IADL limitations; 17 (2%) died; and 254 (26%) experienced ≥1 poor health outcome. In adjusted models, frailty with NCI was associated with more than double the risk of a poor health outcome (PR 2.65; 95% CI 1.98, 3.54); a significant association was also seen with frailty alone (PR 2.26; 95%CI 1.71, 2.99) and NCI alone (PR 1.73; 95% CI 1.36, 2.20).
The cross-sectional overlap between frailty and NCI is well-described in the general population, but few studies have described the overlap among PLWH in the current ART era. As has been seen among aging HIV-uninfected persons, we found that both frailty and NCI were strong predictors of poor health outcomes. In a Colorado cohort, we previously found that both frailty and dementia (clinical diagnosis) were independently associated with an increased risk of recurrent falls [35]. Factors impacting cognition, but not cognitive complaints, were associated with an increased risk for falls, but co-occurrence of frailty was not described in this cohort [36].
In summary, frailty (or gait speed or grip strength), alone or in combination with NCI, is a strong predictor of a poor health outcome within 2 years. As the ideal models of care for older PLWH are established, PLWH at highest risk for adverse outcomes may benefit most from frequent clinic visits, polypharmacy reductions, geriatric consultations, rehabilitative services, or home health assistance. As the impact of "social frailty" was a strong confounder in the association between frailty, NCI, and poor health outcomes, interventions directed at improving or reducing social frailty may reduce poor health outcomes among frail or neurocognitively-impaired PLWH. Similarly, interventions that target prevention or reversal of frailty or both frailty and NCI (such as physical activity) may have the greatest potential to limit poor health outcomes among PLWH.
Among virally-suppressed middle-aged and older PLWH, the majority of participants had neither frailty nor NCI. NCI was more prevalent than frailty, and more than 50% of frail/pre-frail participants had NCI. Importantly, participants with both frailty and NCI had more than 2.5 times the risk of a poor health outcome over 2 years than persons with neither frailty nor NCI. Both frailty, or components of frailty, and NCI were strong predictors of poor health outcomes, independent of age. Accounting for chronologic age fails to completely reflect biologic aging that can differ between individuals, particularly among PLWH with differing durations of HIV infection, severity, and ART exposure. Clinical manifestations of biologic aging are more accurately captured in measures of vulnerability, health, or functioning, such as physical frailty and cognitive capability.
If you look at Table 2, having HIV+ with both frailty & NCI 21% had kidney disease, and 23% with frailty alone had kidney disease vs HIV+ without frailty or NCI of whom 10% had kidney disease. Same is true for diabetes: 42% with both frailty & NCI had kidney disease and 30% with frailty alone vs 23% without frailty or NCI.
Of the 1035 participants enrolled in HAILO, 987 (95%) had both frailty and neurocognitive status assessed at baseline: 40 (4%) were frail but had no NCI, 144 (15%) had NCI but no frailty, 19 (2%) had both frailty and NCI, and 784 (79%) had neither frailty nor NCI. NCI was present in 11% of non-frail, 22% of pre-frail, and 32% of frail participants at baseline (P < .001).
The cross-sectional overlap between frailty and NCI is well-described in the general population, but few studies have described the overlap among PLWH in the current ART era. In addition to our finding of greater odds of frailty in the presence of NCI among HAILO participants [17], other studies have reported worse International HIV Dementia Scores among frail (59% impaired) compared to non-frail (34%) individuals [18], slower gait speeds with increasing neurocognitive impairment [19], and greater NCI by either the mini-mental state examination or the HIV International Dementia Score among frail PLWH but not HIV-uninfected controls [20]. "Frail" PLWH also appear to have less "successful cognitive aging" (lack of IADL impairments, depressive symptoms, or NCI) [32]. A longitudinal analysis involving the Veterans Aging Cohort Study (VACS) identified a greater decline in select NCI domains with increasing VACS index scores [33]; however, there was no association between the VACS Index and NCI as assessed by the Montreal Cognitive Assessment in a cross-sectional analysis [34].
Outcome Measures
Falls were reported every 6 months (beginning at month 6), using self-reported responses obtained through interview-administered questionnaires [24]. For this analysis, the outcome was recurrent falls, defined as ≥2 falls occurring within a 12-month period. Disability was assessed every 12 months with the Lawton-Brody Instrumental Activities of Daily Living Questionnaire, using self-reported limitations in performing 8 tasks: housekeeping, money management, cooking, transportation, telephone use, shopping, laundry, and medication management [23, 26]. Disability included an increase during follow-up in 1 or more limitations on the IADL Questionnaire. Mortality included death from any cause.
Over 2 years of observation, 100 (10%) participants experienced recurrent falls, 175 (18%) experienced worsening IADL limitations, and 17 (2%) died; 254 (26%) participants experienced at least 1 of these poor health outcomes. Poor health outcomes were most common among persons with both frailty and NCI (74%) or frailty without NCI (60%; Table 2). Anxiety/depression medication changed the age-adjusted PR for the frailty without NCI exposure category by 10.5%, and was therefore included in the multivariable model as a confounder. No other variables changed the age-adjusted PR for ≥1 frailty/NCI exposure categories by ≥10%. In the models adjusted for age and use of anxiety/depression medications, the prevalence of a poor health outcome was 2.65 times greater among participants with both frailty and NCI compared to neither, 2.26 times greater among participants with frailty but no NCI, and 1.73 times greater among participants with NCI but no frailty (Table 3; all P < .001). Participants with both frailty and NCI had a significantly greater risk of poor health outcomes compared to NCI alone (PR 1.53, 95% CI 1.10, 2.13; P = .011), but not significantly greater than frailty alone (PR 1.17, 95% CI 0.8, 1.64; P = .36).
Table 2.
Frequency of Poor Outcomes Over 2 Years by Frailty/Neurocognitive Impairment Status at The Human Immunodeficiency Virus Infection, Aging, and Immune Function Long-Term Observational Study Entry
Frailty can also be conceptualized as an "accumulation of deficits," as described in the Rockwood model [37] and the VACS [38, 39]. Inclusion of HIV-specific variables, in addition to non-HIV comorbidities or laboratory abnormalities in these frailty indices, has demonstrated validity in predicting mortality or hospitalizations in cohorts of middle- and older-aged PLWH [38, 40, 41]. As such, we expected that a greater comorbid burden would explain most of the association between our measures of physical and cognitive frailty with poor health outcomes. In contrast, we found that education level and anxiety/depression medications, but not comorbidity burden or HIV-specific factors, partially explained the association between physical or cognitive function and poor health outcomes. Taken as a whole, our findings emphasize that other measures of economic and psychological vulnerability influence the likelihood of a frail or neurocognitively-impaired PLWH experiencing a poor health outcome to a greater extent than age, comorbidities, or HIV burden.
In addition to our finding of greater odds of frailty in the presence of NCI among HAILO participants [17], other studies have reported worse International HIV Dementia Scores among frail (59% impaired) compared to non-frail (34%) individuals [18], slower gait speeds with increasing neurocognitive impairment [19], and greater NCI by either the mini-mental state examination or the HIV International Dementia Score among frail PLWH but not HIV-uninfected controls [20]. "Frail" PLWH also appear to have less "successful cognitive aging" (lack of IADL impairments, depressive symptoms, or NCI) [32]. A longitudinal analysis involving the Veterans Aging Cohort Study (VACS) identified a greater decline in select NCI domains with increasing VACS index scores [33]; however, there was no association between the VACS Index and NCI as assessed by the Montreal Cognitive Assessment in a cross-sectional analysis [34].
In the AIDS (acquired immunodeficiency syndrome) Clinical Trials Group longitudinal aging study A5322 and in HAILO (The HIV Infection, Aging, and Immune Function Long-Term Observational Study), we have previously reported increased odds of frailty among PLWH with NCI [17] and an overlap between frailty and disability at baseline [23]. Furthermore, we have found increased falls over 2 years among pre-frail and frail participants and participants with baseline NCI. Of the 1035 participants enrolled in HAILO, 987 (95%) had both frailty and neurocognitive status assessed at baseline: 40 (4%) were frail but had no NCI, 144 (15%) had NCI but no frailty, 19 (2%) had both frailty and NCI, and 784 (79%) had neither frailty nor NCI. NCI was present in 11% of non-frail, 22% of pre-frail, and 32% of frail participants at baseline (P < .001). Over 2 years of observation, 100 (10%) participants experienced recurrent falls, 175 (18%) experienced worsening IADL limitations, and 17 (2%) died; 254 (26%) participants experienced at least 1 of these poor health outcomes. Poor health outcomes were most common among persons with both frailty and NCI (74%) or frailty without NCI (60%; Table 2). Anxiety/depression medication changed the age-adjusted PR for the frailty without NCI exposure category by 10.5%, and was therefore included in the multivariable model as a confounder.
Disability was assessed every 12 months with the Lawton-Brody Instrumental Activities of Daily Living Questionnaire, using self-reported limitations in performing 8 tasks: housekeeping, money management, cooking, transportation, telephone use, shopping, laundry, and medication management [23, 26]. Disability included an increase during follow-up in 1 or more limitations on the IADL Questionnaire. Mortality included death from any cause.
We also assessed the association between grip strength or gait speed with or without NCI on poor health outcomes. Similar to the frailty models, participants with weak grip or slow gait alone or in combination with NCI had a higher risk of poor health outcomes than those without the respective frailty component or NCI (Tables 4 and 5).
As this population faces more complex comorbidities in combination with physiologic aging, social vulnerability, and medication burdens, optimization of comorbidity management becomes more challenging [1–3]. Aggressive blood pressure or blood glucose treatment may not be appropriate in a patient with recurrent falls, dementia, or a limited life expectancy [4, 5]. Thus, some HIV providers have advocated for incorporation of models of geriatric care [1, 3], with a focus on recognition and management of geriatric syndromes and maximizing individual care goals.
Frailty and neurocognitive impairment (NCI) are 2 geriatric syndromes that may co-occur [6–8] and can be associated with an increased risk of poor health outcomes, including falls, disability, hospitalizations, and mortality [9–13]. NCI and frailty represent vulnerability, with the latter marked by fatigue, limitations in activity, slowness, weakness, and weight loss; these are similar symptoms to those seen among many adults with advanced dementia.
Furthermore, both cognition and motor skills (gait, grip) are highly-integrated processes that rely upon coordination and execution by the central nervous system [14]; thus, central nervous system impairment would be expected to impact both cognitive and physical functions.
The overlapping vulnerability of frailty and NCI, and the potential impact on health outcomes in older adults, is increasingly recognized as a unique syndrome termed "cognitive frailty" [15] or "motoric cognitive risk" [16]. Multiple studies have shown a strong cross-sectional association between frailty, slow gait speed, or weak grip strength and NCI, both in the general population and among people living with HIV (PLWH) [17–20]. The link between frailty and NCI is likely evidence of a common pathogenesis, driven by inflammation, immune activation, and nutritional and metabolic influences [21], and both frailty and NCI may be manifestations of vascular disease [22].
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Frailty, Neurocognitive Impairment, or Both in Predicting Poor Health Outcomes Among Adults Living With Human Immunodeficiency Virus
Abstract
Background
Neurocognitive impairment (NCI) is strongly associated with frailty in people living with human immunodeficiency virus (PLWH); the overlap of frailty and NCI and the impact on health outcomes in PLWH are unknown.
Methods
PLWH in a longitudinal, observational study of aging completed entry evaluations for frailty and NCI. Outcomes of falls (recurrent) increased limitations in independent activities of daily living (IADL), or mortality were combined. Poisson regression models estimated prevalence ratios (PR) for ≥1 outcome over 2 years.
Results
Among 987 participants, the median age at entry was 51 years; 19% were female; the median CD4 count was 616 cells/μL; and HIV-1 RNA was <200 copies/mL in 94%.
Most (79%) participants had neither frailty nor NCI; 2% had both; 4% frailty only; and 15% NCI only.
Over 2 years of observation, 100 (10%) participants experienced recurrent falls; 175 (18%) had worsening IADL limitations; 17 (2%) died; and 254 (26%) experienced ≥1 poor health outcome.
In adjusted models, frailty with NCI was associated with more than double the risk of a poor health outcome (PR 2.65; 95% CI 1.98, 3.54); a significant association was also seen with frailty alone (PR 2.26; 95%CI 1.71, 2.99) and NCI alone (PR 1.73; 95% CI 1.36, 2.20).
Conclusions
The presence of frailty with NCI was associated with a greater risk of falls, disability, or death in PLWH than NCI alone. Interventions that target prevention or reversal of both frailty and NCI (such as increased physical activity) may significantly limit poor health outcomes among PLWH.
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