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Association Between Frailty and Components of the Frailty Phenotype With Modifiable Risk Factors and Antiretroviral Therapy: socioeconomic, neurocognitive impairment, Medicaid/Medicare - exercise, diet, smoking, obesity
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⋅ The higher burden of frailty among HIV-infected adults with socioeconomic disadvantages or neurocognitive impairment identifies individuals with high risk for hospitalizations, mobility decline, and mortality.....modifiable risk factors include lifestyle (smoking, no exercise, diet, obesity)......
⋅ In multivariable models, the odds of an increase in frailty level were significantly higher among participants aged 50-59 years (vs younger), active or prior smokers, persons with less education, lower physical activity, hepatitis C virus infection, neurocognitive impairment, and obesity, and persons who received NNRTI-based initial randomized ART therapy (vs PI; 100% EFV), but not NNRTI duration or use at time of frailty assessment.
⋅ Socioeconomic inequalities and disparities throughout a lifetime are important determinants of health, such that experiences in childhood and young adulthood, in addition to midlife and older age, all appear to contribute to frailty in older age [13]. Socioeconomic factors may, in part, be mediated by other behavioral changes such as differences in diet, leisure-time activities [14], or factors associated with chronic stress. Not surprisingly, we found that neurocognitive impairment was one of the strongest risk factors for frailty and slow gait. In contrast, no other comorbidities were associated with both outcomes.....
⋅ The odds of increased frailty were significantly lower among participants with private insurance compared with Medicare or Medicaid-based plans, higher pre-ART HIV-1 RNA levels, and any alcohol use. [from Jules: frailty & cognitive impairment contribute strongly to falls & fractures & subsequent disability. Higher rates of osteoporosis by 400% in HIV+ vs HIV-negatives reflects the dilemma of aging with HIV.
"Of 1016 participants, 6% were frail, and 38% were pre frail.......Study participants over 40 years old, so there is a large proportion of people in this study under 50 but as one ages past 50 the numbers with frailty increase. See the prevalence of frailty based on age - see table below this paragraph, most HIV+ people who were frail were between 50-59 (60%) which was triple that for those 40-49 (19%), so frailty appears to kick in on average after 50 years age in HIV+. Having neurcognitive impairment is associated with having frailty in this study meaning cognitive impairment contributes to being frail.
In a large cohort of well-characterized, HIV-infected, middle-aged and older adults who initiated ART through an ACTG randomized clinical trial, we found a significant association between frailty and initial assignment of NNRTI-based (all EFV) therapy compared with PI-based therapy, and a protective effect of baseline INSTI use compared with PI use on gait speed......
The multifactorial nature of frailty is noted by the variety of covariates that were predictive of increasing frailty, including demographic, socioeconomic, and lifestyle factors and comorbidities. Socioeconomic inequalities and disparities throughout a lifetime are important determinants of health, such that experiences in childhood and young adulthood, in addition to midlife and older age, all appear to contribute to frailty in older age [13]. Socioeconomic factors may, in part, be mediated by other behavioral changes such as differences in diet, leisure-time activities [14], or factors associated with chronic stress. Not surprisingly, we found that neurocognitive impairment was one of the strongest risk factors for frailty and slow gait. In contrast, no other comorbidities were associated with both outcomes.......
In summary, among older HIV-infected adults, we observed an association between frailty and NNRTI-based initial ART and a protective effect of INSTI therapy on gait speed. Both findings require further investigation but suggest that INSTI-based regimens may be preferred for older, HIV-infected adults at risk for frailty or mobility impairment. The higher burden of frailty among HIV-infected adults with socioeconomic disadvantages or neurocognitive impairment identifies individuals with high risk for hospitalizations, mobility decline, and mortality.
This population should constitute a priority target for frailty identification and close clinical follow-up. Lastly, modifiable factors (smoking, low physical activity, obesity) were strongly associated with increased frailty and provide ideal targets for future interventions to prevent or slow the frailty trajectory........females, nonwhites, and persons with Medicare/Medicaid health insurance were more likely to be prefrail or frail.....In multivariable models, the odds of an increase in frailty level were significantly higher among participants aged 50-59 years (vs younger), active or prior smokers, persons with less education, lower physical activity, hepatitis C virus infection, neurocognitive impairment, and obesity, and persons who received NNRTI-based initial randomized ART therapy (vs PI; 100% EFV), but not NNRTI duration or use at time of frailty assessment.
The odds of increased frailty were significantly lower among participants with private insurance compared with Medicare or Medicaid-based plans, higher pre-ART HIV-1 RNA levels, and any alcohol use. In a separate model that adjusted only for pretreatment initiation factors, the effect upon frailty of having received initial ART with an NNRTI (EFV) was unchanged (adjusted odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.15-2.16]) (not shown).....The median 4-meter walk time was 3.9 (interquartile range = 3.3-4.4) seconds. One hundred thirty-nine participants (14%) had a gait speed slower than 0.8 m/sec and 414 (41%) had a gait speed equal to or slower than 1.0 m/sec. Participant characteristics by gait speed are shown in Supplementary Table 1. The odds of slower gait speed (≤ 1 m/sec) were significantly higher among participants who were black or Hispanic, had less education, had lower physical activity, had Medicare/Medicaid versus private insurance coverage, had previously received either DDI or D4T at any time point, had gained more weight during the first year following ART initiation, or had renal disease or neurocognitive impairment; baseline use of an INSTI-based regimen and light alcohol use were protective."
Association Between Frailty and Components of the Frailty Phenotype With Modifiable Risk Factors and Antiretroviral Therapy
J Infect Dis March 2017
Abstract
The impact of antiretroviral therapy (ART) on frailty among human immunodeficiency virus (HIV)-infected adults has not been well described. HIV-infected participants aged ≥40 years with initial ART receipt through a randomized, controlled AIDS Clinical Trials Group trial completed a frailty assessment. Ordinal logistic regression models examined factors associated with frailty.
Of 1016 participants, 6% were frail, and 38% were prefrail. Frailty was associated with lower education, older age, Medicare/Medicaid, initial efavirenz, smoking, obesity, and neurocognitive impairment; physical activity and alcohol use were protective. The associations with ART require further investigation, and associations between frailty and modifiable factors provide targets for future interventions.
With combination antiretroviral therapy (ART), longer life expectancy is changing the demographics of the human immunodeficiency virus (HIV) epidemic, and an estimated 70% of the HIV-infected population will be aged >50 by 2030 [1]. Even with effective ART, frailty and physical function impairments are common and have been associated with increased risk of falls, hospitalizations, and mortality [2-6]. In addition to the composite frailty phenotype, measurement of the single, objective component of gait speed may be equally predictive of morbidity and mortality and may be easier to implement in the clinical or research setting [7]. Careful investigation of factors contributing to frailty and gait speed can guide the use of these tests in the clinical or research setting.
The impact of specific initial or ongoing ART drugs on the development of frailty has been difficult to evaluate. Although prior studies have suggested that protease inhibitors might be associated with an increased risk of frailty [8], these results may have been influenced by multiple factors that affect ART selection.
The goal of this study was to describe the impact of initial and ongoing ART selection in addition to other participant characteristics on frailty in HIV-infected adults currently enrolled in the AIDS Clinical Trials Group (ACTG) Study A5322, the HIV Infection, Aging, and Immune Function Long-Term Observational Study (HAILO).
Participants were enrolled in HAILO, an ongoing observational cohort study of HIV-infected adults who initiated ART through an ACTG randomized clinical trial and were previously followed in the ACTG A5001 study [9]. All A5001 participants aged ≥40 years were eligible. Enrollment occurred during 2014-2015 with subsequent semiannual follow-up visits. All participants signed a written informed consent before enrollment, and the study was approved by the local institutional review board at each site.
Frailty Assessment
Frailty was assessed at study entry using the criteria established by Fried et al [10]. Weakness was assessed by the average of 3 dominant hand grip strength measurements and defined by applying previously defined sex and body mass index (BMI) cutoffs [10]. Slowness was defined by the average of 2 readings on a 4-meter walk: men ≤173 cm and women ≤159 cm in height who required ≥6.22 seconds or men >173 cm and women >159 cm who required ≥5.33 seconds to complete the walk met the criterion for slowness [10]; gait speed was also dichotomized at ≤1 or >1 m/sec [7]. Weight loss was defined by self-report of an unintentional weight loss of ≥10 pounds during the past year. Low activity was defined as being "limited a lot" in response to the Short Form (SF)-36 question, "Does your health limit you in vigorous activities such as running, lifting heavy objects, or participating in strenuous sports?" Exhaustion was defined as experiencing at least 3-4 times per week the feeling that "everything I do is an effort" or "sometimes I just cannot get going." Participants were considered nonfrail if they met 0 components, prefrail if they met 1 or 2 components, and frail if they met 3-5 components. Gait speed was also evaluated individually [7].
RESULTS
Frailty
Among 1016 participants with frailty data at baseline, 62 (6%) were frail, 390 (38%) were prefrail, and 564 (56%) were nonfrail. Baseline characteristics of the study population by frailty group are shown in Table 1. Briefly, females, nonwhites, and persons with Medicare/Medicaid health insurance were more likely to be prefrail or frail. Significant differences in age and CD4 count were seen across frailty groups; years since ART initiation, nadir CD4, and baseline HIV-1 RNA at baseline were similar across groups.
Associations between greater frailty and demographic factors, comorbidities, HIV disease/treatment, and lifestyle characteristics are summarized in Table 2. In multivariable models, the odds of an increase in frailty level were significantly higher among participants aged 50-59 years (vs younger), active or prior smokers, persons with less education, lower physical activity, hepatitis C virus infection, neurocognitive impairment, and obesity, and persons who received NNRTI-based initial randomized ART therapy (vs PI; 100% EFV), but not NNRTI duration or use at time of frailty assessment.
The odds of increased frailty were significantly lower among participants with private insurance compared with Medicare or Medicaid-based plans, higher pre-ART HIV-1 RNA levels, and any alcohol use. In a separate model that adjusted only for pretreatment initiation factors, the effect upon frailty of having received initial ART with an NNRTI (EFV) was unchanged (adjusted odds ratio [OR] = 1.57; 95% confidence interval [CI] = 1.15-2.16]) (not shown). In a sensitivity analysis restricted to HAILO participants from A5202, an ART initiation study that randomized participants to EFV vs ATV/r with TDF/FTC or ABC/3TC (n = 228), similar effects were seen with age, socioeconomic variables, pre-ART HIV-1 RNA level, physical activity, and neurocognitive impairment (not shown). Efavirenz was not associated with a greater odds of frailty compared with ATV/r (univariable OR = 1.01; 95% CI = .62-1.64; P > .90), but a trend was seen for a protective effect with TDF/FTC versus ABC/3TC (multivariable OR = 0.58; 95% CI = .32-1.05; P = .07).
Gait Speed
The median 4-meter walk time was 3.9 (interquartile range = 3.3-4.4) seconds. One hundred thirty-nine participants (14%) had a gait speed slower than 0.8 m/sec and 414 (41%) had a gait speed equal to or slower than 1.0 m/sec. Participant characteristics by gait speed are shown in Supplementary Table 1. The odds of slower gait speed (≤ 1 m/sec) were significantly higher among participants who were black or Hispanic, had less education, had lower physical activity, had Medicare/Medicaid versus private insurance coverage, had previously received either DDI or D4T at any time point, had gained more weight during the first year following ART initiation, or had renal disease or neurocognitive impairment; baseline use of an INSTI-based regimen and light alcohol use were protective.
DISCUSSION
In a large cohort of well-characterized, HIV-infected, middle-aged and older adults who initiated ART through an ACTG randomized clinical trial, we found a significant association between frailty and initial assignment of NNRTI-based (all EFV) therapy compared with PI-based therapy, and a protective effect of baseline INSTI use compared with PI use on gait speed.
Although the association between initial EFV use and frailty is intriguing, several points should be considered when interpreting these findings: (1) we found no association with frailty for the duration of EFV or use of EFV at the time of the frailty assessment; (2) we found no association with frailty in a sensitivity analysis of participants randomized to only EFV- or PI-based ART, although the sample size was smaller; and 3) the time from initial NNRTI exposure to the frailty assessment was variable and spanned many years in most participants. Thus, we do not know whether merely exposure to an NNRTI-based therapy (primarily EFV) is associated with subsequent frailty or whether the association is simply a marker for a subset of participants with poor EFV tolerability (hence the lack of association with NNRTI duration), unmeasured confounders at the time of ART initiation such as time elapsed from HIV diagnosis, or loss to follow-up. In contrast, INSTI use at baseline, but not prior use or INSTI duration, was associated with a protective effect on gait speed. Baseline INSTI use included both participants initially randomized to and participants who switched to an INSTI drug. For both drug associations, the findings remained significant in multivariable models adjusted for many factors impacting baseline ART use.
The multifactorial nature of frailty is noted by the variety of covariates that were predictive of increasing frailty, including demographic, socioeconomic, and lifestyle factors and comorbidities. Socioeconomic inequalities and disparities throughout a lifetime are important determinants of health, such that experiences in childhood and young adulthood, in addition to midlife and older age, all appear to contribute to frailty in older age [13]. Socioeconomic factors may, in part, be mediated by other behavioral changes such as differences in diet, leisure-time activities [14], or factors associated with chronic stress. Not surprisingly, we found that neurocognitive impairment was one of the strongest risk factors for frailty and slow gait. In contrast, no other comorbidities were associated with both outcomes.
Limitations should be acknowledged. The participants have been continuously enrolled in ART treatment trials and observational studies for a median of 7.8 years and may not be fully representative of the overall HIV epidemic. This cross- sectional analysis precludes us from determining the temporal relationship between covariates and frailty. Frailty assessments were only available beginning at the time of HAILO enrollment, and the effect of ART on frailty, gait, and grip characteristics at the time of therapy initiation cannot be determined. Minor differences in 4-meter walk and grip strength measurement techniques across sites were likely present, although training and quality control procedures were implemented to limit variation within and between sites. Lastly, we acknowledge that self-report of physical activity is a poor measure of actual activity and hepatitis C antibody does not reflect active infection.
In summary, among older HIV-infected adults, we observed an association between frailty and NNRTI-based initial ART and a protective effect of INSTI therapy on gait speed. Both findings require further investigation but suggest that INSTI-based regimens may be preferred for older, HIV-infected adults at risk for frailty or mobility impairment. The higher burden of frailty among HIV-infected adults with socioeconomic disadvantages or neurocognitive impairment identifies individuals with high risk for hospitalizations, mobility decline, and mortality. This population should constitute a priority target for frailty identification and close clinical follow-up. Lastly, modifiable factors (smoking, low physical activity, obesity) were strongly associated with increased frailty and provide ideal targets for future interventions to prevent or slow the frailty trajectory.
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