Abstract
Frailty is common in HIV-infected patients, but its causes are elusive. We assessed 122 clinic patients for frailty using the 5-measure Fried Frailty criteria. The prevalence of frailty was 19% (n = 23) and all frail patients reported exhaustion with a Center for Epidemiologic Studies Depression Scale score >16 indicating depression. The next most common criterion was low physical activity (expenditure of kcal/week). Markers of sarcopenia such as decreased grip strength and decreased gait speed, hallmarks of frailty in the elderly, were the least common of the 5 criteria. Frailty was reversible: 6 frail patients returned for reassessment and only 2 were frail. We conclude that frailty in the HIV-infected patients is potentially reversible and strongly associated with depression and low physical activity, whereas frailty in the elderly is associated with aging-related sarcopenia and is often irreversible.
Introduction
The use of potent antiretroviral (ARV) medications has dramatically increased the survival of HIV-infected patients, resulting in a progressively aging HIV-positive patient population. The era of potent antiretroviral therapy (ART) has led HIV-positive patients to now present with aging-related clinical problems. Growth of the aging HIV-positive population has been rapid. In 2011, approximately 30% of HIV-positive patients in the United States were aged 50 or older, having risen from just 24% in 2001. 1 In our outpatient clinic of >800 HIV-positive patients, more than half of them are now 45 years old or older. Although there is clearly a rapid increase in the number of aging HIV-positive patients, little is known about the aging issues in this population, in particular, the clinical frailty syndrome and its association with HIV.
Frailty is a recognized geriatric syndrome defined as a clinical state of increased vulnerability resulting from aging-related decline in reserve and function across multiple physiologic systems. In older adults, it is associated with multiple adverse health outcomes such as falls, fracture, disability, hospitalization, and mortality. The clinical criteria for frailty as outlined by Fried et al 2 define frailty among aging adults as a syndrome that includes at least 3 of the following 5 key aspects: unintentional weight loss (10 pound or more in the past year), weakness (as determined through grip strength), reduced walking speed, low physical activity, and self-reported exhaustion. Frailty syndrome is estimated to occur in 7% to 16% of noninstitutionalized adults aged 65 years and older, living in the community. Several studies have demonstrated that this geriatric syndrome is likewise prevalent among various generations of HIV-1-positive patients. In a large cohort study, Desquilbet et al 3 determined that younger populations of HIV-infected men had a premature frailty rate that was similar to uninfected men who are at least 10 years older than to them. Additionally, the frailty phenotype was highly associated with a low CD4 count and increased viral load (VL). 3 These studies used surrogate markers for frailty rather than the Fried criteria. Using the Fried criteria, which are validated markers of frailty, we also found a strong correlation between frailty and CD4 counts <200 cells/μL among a group of 100 HIV-1-positive patients. 4 Our initial study concluded that frailty among HIV-1-positive individuals is common (prevalence of 19%) and was often associated with an opportunistic infection being present when CD4 counts are low. However, unlike the steady, step-wise decline that is characteristic of frailty in geriatric populations, 4,5 frailty in HIV-positive patients is more transient and often disappears with reconstitution of CD4 counts and treatment of opportunistic infections. 4,6
The purpose of this study was to identify frail HIV-positive patients and determine which of the 5 Fried frailty measures were most important in predicting frailty, and possibly identify strategies to reduce frailty in the HIV-positive population.
Methods
Study Population and Recruitment
Patients were recruited from the Petersen HIV clinic within the University of Arizona Health Network which provides care at 2 campuses for more than 800 HIV-positive patients from various socioeconomic and educational backgrounds. Patients volunteered for the study during regularly scheduled clinic visits with their HIV provider. Once a written consent was obtained, evaluation of frailty indicators was performed. Recruitment occurred from August 2011 to December 2012. Eligible patients included HIV-1-infected women or men aged 18 years or older obtaining care from the HIV clinic. Demographic data were obtained from each patient. The patients’ most recent CD4 count and HIV-1 RNA VL were obtained from records. Twenty-two patients were reassessed for frailty 6 months after their first visit.
Definition of Frailty
Our study used the definition of frailty as developed by Fried et al. 2 The definition consists of 5 characteristics of which at least 3 of the criteria need to be present in order for a patient to be considered frail. These are as follows: (1) shrinking: measured as unintentional weight loss of ≥10 pounds in the prior year. (2) Slowness: decreased gait speed as defined by a timed 15-foot walk test, and time adjusted for gender and standing height. Men with a height <173 cm and women with a height <159 cm who walked 15 feet in >7 s are considered frail; men >173 cm and women >159 cm who walked 15 feet in >6 s are considered frail. (3) Weakness: decreased grip strength measured by a dynamometer, value adjusted for gender and body mass index (BMI). Men with a BMI <24 are considered frail if the grip strength (kg) is <29; for a BMI of 24.1 to 28, a man is frail if <30; and for a BMI >28, a man is frail if <32. For women, a BMI of <23 is considered frail if the grip strength (kg) is <17; a BMI of 23.1 to 26 is considered frail if <17.3; a BMI of 26.1 to 29 is considered frail if <18; and a BMI >29 is considered frail if <21. (4) Low physical activity level: a weighted score of kilocalories expended per week measured by the Minnesota Leisure Time Activity Questionnaire that asks about activities like daily living, sports, and hobbies. There is frailty when males use <383 kcal/week and females use <270 kcal/week. (5) Exhaustion: self-reported by answering 20 questions from the Center for Epidemiologic Studies–Depression Scale (CES-D). Scores for this survey can range from 0 to 60, with a score above 16 indicating that an individual has depressive symptomatology. 7
Statistics
Data were summarized with descriptive statistics. Statistical comparisons were done with chi-square for categorical variables and t tests were used to test for group statistical significance. For prediction modeling of frailty status, logistic regression analysis was used. All data were analyzed using SPSS-IBM version 22.0 (IBM Corp, Armonk, New York).
Results
One hundred and thirty-five patients were asked to participate in the study and 122 agreed to participate. Demographic and ART data were compared for frail and nonfrail HIV-positive patients, age stratified to older or younger than 50 years (Table 1). In the study, 11% (n = 14) were females and 89% (n = 108) were males. Patient ages ranged from 20 to 72 years; 53% (n = 65) were younger than 50 years and 47% (n = 57) were older than 50 years. There was no significant difference between the frail and nonfrail HIV-positive patients with respect to age older or younger than 50 years, gender, race, or ethnicity. There was no difference between frail and nonfrail HIV-positive patients whether treated with ART or not and whether or not there was a detectable VL (Table 1). When mean ages were compared, frail HIV-positive patients were significantly older than nonfrail HIV-positive patients by an average of 5 years (Table 2). Given that comparison of frail and nonfrail HIV-positive patients older or younger than 50 years was not significantly different and comparison of means was different by only 5 years, we do not think this finding is a clinically significant difference. There was also no significant difference between frail and nonfrail HIV-positive patients with respect to the mean BMI, their weight, and CD4 count (Table 2).
Demographic and Treatment Data for Frail and Nonfrail HIV-Positive Patients.
Abbreviations: ART, antiretroviral therapy; VL, viral load (>20 copies/mL).
Mean Comparison of Patient Physical Variables.
Abbreviation: BMI, body mass index.
Twenty-three (19%) patients were frail at the first visit. Six months later, a second frailty assessment was conducted on 22 patients. Six patients who were determined to be frail initially returned for reassessment. Of these 6, only 2 patients remained frail at 6-month follow-up.
Measurement of five frailty indicators (shrinking, slowness, weakness, low physical activity level, and exhaustion) forms the basis of assessment of frailty using the method of Fried (Table 3). Comparing frail to nonfrail HIV-positive patients for the specific indicators comprising frailty, all 5 characteristics were significantly different for the 2 patient groups (Table 3). Among the 23 frail HIV-positive patients, the most common variable associated with frailty was exhaustion as measured by the CES-D. 7 All frail HIV-positive patients were depressed, that is, 23 (100%) had depressive symptom scale scores that were greater than 16 at initial assessment. Of the frail HIV-positive patients who were depressed, 7 (30%) had mild to moderate depression (scores 17-21) and 16 (70%) were classified as having a major depressive disorder (scores 22-46). Among the 23 frail HIV-positive patients, 19 (83%) were found to have a low physical activity level and 15 (65%) had shrinkage (>10 pound measured weight loss within the past year). Of the frail HIV-positive patients, 10 (43%) had weakness (reduced grip strength) and 9 (39%) had slowness (reduced walking speed). The rank order of the frailty indicators among the 23 frail HIV-positive patients was exhaustion > low physical activity level > shrinking > weakness > slowness (Table 3).
Occurrence of Frailty Criteria.
Abbreviation: CES-D, Center for Epidemiologic Studies–Depression Scale (20 questions).
It is interesting to note that in comparing older patients (>50 years) with younger patients (<50 years), there are different incidences in the various indicators of frailty. For example, low physical activity and reduced grip strength were more common among patients older than 50 years, whereas slowness was more common among the patients younger than 50 years, with 44% of younger frail HIV-positive patients found to have a decreased gait speed.
Discussion
Frailty is common among patients with HIV-1 infection. In a previous study, 4 we found a frailty prevalence of 19% and this is identical to the prevalence in this study. We also confirm in this study that frailty is reversible in this patient population. Of patients who returned 6 months after the first visit, only 2 (33%) of 6 patients remained frail. In our previous study, only 1 (20%) of 5 patients on remeasurement was frail, and we attributed reversibility to the use of ART, treatment of opportunistic infections, and an improvement in CD4 count numbers. 4 In this study, there is no statistical difference between the frail and nonfrail HIV-positive individuals with respect to the CD4 counts or the presence or absence of an undetectable VL. This difference from our previous study points out the changing nature of our HIV clinic patients. During the year this study was performed, the clinic nearly doubled in size with many highly ART-experienced patients enrolling in clinic. Consequently, in this study there were about the same number of frail HIV-positive patients, but these were not associated with low CD4 counts and ongoing opportunistic infections.
This study demonstrates, we believe, important characteristics of the frail HIV-positive patients. The principal finding is 100% of the frail HIV-positive patients were depressed as determined by their score on the CES-D, 30% with mild to moderate depression and 70% with a major depressive disorder. The CES-D score not only indicates the prevalence of depression in these patients but is often an indication of deconditioning as well. Previous research has investigated the difficulty in diagnosing depression in the context of comorbid medical conditions, suggesting that one reason for the lower prevalence of depression among older adults is that this condition is often confused for or conflated with physical decline. 8 A recent review found a positive association between depressive symptoms and frailty in elder patients 9 ; however, few studies have examined the potential overlap between depression in late life and frailty. 10 It is also remarkable that 19 (83%) frail HIV-positive patients demonstrated a low physical activity level (men using <383 kcal/week and women using <270 kcal/week). There is an inverse association of depression and physical activity, and it is possible that physical activity could prevent depression. 11 The prevalence of frailty in our earlier study 4 and this study was similar, that is, 19%. The fact that 100% of the frail HIV-positive patients were depressed is concerning for the ability of these patients to manage their drug regimen, although there was no difference between CD4 numbers or VLs. It is possible that ART or the need for ART is a causative element of depression.
The frail young patients with HIV seem to be a different phenotype than the frail elderly patients without HIV. The frail elderly patients without HIV are characterized by decreased gait speed and weakness. Aging is associated with a progressive decline in muscle mass, strength, and quality, a condition known as sarcopenia of aging 12 and is highly associated with clinical frailty, loss of independence, and physical disability in older patients. 13 Measures of sarcopenia such as slowness, weakness, and shrinkage are not the most common characteristics of frail HIV-positive patients. In frail HIV-positive patients, depression and inactivity are the predominant characteristics.
In conclusion, we have shown that frailty in HIV is common (prevalence of 19% in HIV clinic patients) and often reversible. It is associated with depression and low activity levels rather than the more common irreversible, step-wise loss of function found in frail HIV-negative older adults with sarcopenia. In future studies we will focus on the treatment of depression including increasing physical activity in “frail” HIV-positive patients. As the HIV-positive cohort ages, there may be a bimodal distribution of HIV-related frailty, that is, one group, younger patients with transient frailty associated with low physical activity and depression, and an older group of HIV-positive patients with aging-related frailty and accompanying sarcopenia. The conceptual and empirical interrelationships between these conditions and treatment considerations require further research.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.