Gait Speed Decline Is Associated with Hemoglobin A1C,Neurocognitive Impairment,and Black Race in Persons with HIV

Introduction

Although routine use of virally suppressive combination antiretroviral therapy (ART) has dramatically extended the life expectancy of persons with HIV (PWH), this population now experiences both earlier onset and higher rates of chronic noninfectious aging-related comorbidities than the general population. ^{1 –3} Compared with seronegative controls, PWH exhibit an accelerated decline in physical function and higher than expected rates of frailty. ^{4 –6} Such declines in functional status have been associated with poor health outcomes such as disability, falls, and reduced quality of life in this population. ^{7 –10}

Slow gait speed is a simple, easily obtainable measure in the clinical setting that requires minimal equipment, training, and time. ¹¹ Slow gait speed is highly predictive of disability and mortality in older adults, ^{12 –14} and we have similarly found that slow gait speed is associated with subsequent poor outcomes including disability, falls, and mortality in middle-aged PWH. ¹⁵ Schrack et al. previously observed that gait speed declines more rapidly with increasing age in men with HIV compared with demographically similar men without HIV. ⁵ Proposed mechanisms for this accelerated decline in gait speed among PWH include those observed with general aging, such as changes in energy utilization and body composition, decreased aerobic capacity, and worsened biomechanics ^{16 –19} and characteristics specific to HIV infection, including exposure to ART, prolonged immune suppression, chronic inflammation and immune activation, and mitochondrial dysfunction. ^{20 –23} Multiple studies among PWH have found associations between decreased gait speed and increasing age, socioeconomic factors (such as nonwhite race, less education, public insurance, and social support), obesity, lower physical activity, tobacco or intravenous drug use, certain mitochondrial DNA haplogroups, and medical comorbidities [particularly renal disease, peripheral neuropathy, neurocognitive impairment (NCI), and diabetes]. ^{21,24 –30} However, many of these studies have been limited to cross-sectional analyses.

The goal of this investigation was to identify baseline characteristics associated with development of slow gait speed among participants currently enrolled in AIDS Clinical Trial Group (ACTG) A5322/HAILO (HIV Infection, Aging, and Immune Function Long-term Observational Study). This cohort of both men and women has well-defined ART exposure and detailed history of immune and clinical health. Through investigation of this diverse and well-characterized cohort, we aim to better understand risk factors for slow gait to guide strategies to screen for and prevent functional impairment among persons aging with HIV.

Methods

Results

Of 929 participants included in this analysis, the median age at baseline was 51 years [interquartile range (IQR) = 46–56]. Eighty-one percent were men, 31% black, and 20% Hispanic. Most individuals had well-controlled HIV infection at study entry: 92% had undetectable plasma HIV-1 RNA (viral load <50 copies/mL) with median CD4 631 cells/mm³ (IQR = 458–840). At study entry, 7% of participants had slow gait.

Over the 3 years of observation, 87% maintained normal gait speed, 3% maintained a slow gait, 6% developed a slow gait, and 4% improved from slow to normal gait speed. The prevalence of each gait speed trajectory group is given in Figure 1. Median time to complete the 4-m walk in each gait speed trajectory group at baseline and at each year of follow-up in the study is given in Supplementary Table S1. Characteristics of participants by gait speed trajectory group are given in Table 1. In brief, age, sex, race, HbA1C, BMI, waist circumference, level of physical activity, peripheral neuropathy, alcohol and illicit drug use, use of anxiolytic or antidepressant medications, TDF use at HAILO study entry, neurocognitive function, presence of kidney or liver disease, hypertension, and diabetes differed across groups. Between HAILO participants included in and excluded from this analysis, there were no significant differences in age; sex; HIV virologic control; current or nadir CD4; ART treatment history; BMI; reported physical activity; or use of alcohol, cigarettes, other substance use, or antidepressants or anxiolytics. Black non-Hispanic, white non-Hispanic, and Hispanic participants were more likely to be included in the analysis than Asian, Pacific Islander, and American Indian, Alaskan native participants. In addition, excluded participants had a higher median HbA1C (5.6 vs. 5.5, p = .01).

OPEN IN VIEWER

FIG. 1.

Prevalence of slow gait within each gait speed trajectory group. Over 3 years of observation, 87% of HAILO participants maintained normal gait speed, 3% maintained a slow gait speed, 6% developed a slow gait, and 4% improved from a slow to a normal gait speed. HAILO, HIV Infection, Aging, and Immune Function Long-term Observational Study.

Discussion

Gait speed declines more rapidly with age among PWH than in HIV-uninfected individuals, but a longitudinal assessment of characteristics related to this functional outcome have previously been limited. In this large cohort of men and women living with HIV, we found that development of slow gait speed was significantly associated with higher HbA1C, NCI, and black race. These findings reveal a modifiable risk factor (HbA1C) and vulnerable populations (individuals who have NCI or black race) that may benefit from early screening and intervention to preserve physical function in PWH.

Associations between impaired neurologic and physical function have been noted among older populations of people with and without HIV. ^35,36 Previous cross-sectional analysis in PWH have shown a relationship between slowed gait and more advanced AIDS dementia complex stage. ³⁰ Structural changes in brain regions involved in both cognitive and motor function may provide a mechanistic explanation for this relationship. Both gait and cognition are vulnerable to impaired communication between brain regions in long white matter tracts. A small cross-sectional study of men and women (average age 50.6 years) in the Hawaii Aging with HIV cohort showed volumetric changes in brain regions (cerebellar white matter and subcortical gray matter) linked to cognition and motor control. ³⁷ In a previous cross-sectional analysis of the HAILO cohort, we reported an association between impaired cognitive function and gait speed. ²⁵ This study adds longitudinal evidence from this large, well-characterized cohort of PWH, where we similarly find that NCI is strongly associated with development of slow gait.

Similarly, abnormal glucose metabolism has been associated with gait speed decline in the general population. ^{38 –42} Decreased muscle quality and strength and mitochondrial dysfunction have been identified as potential causes of this relationship. ^43,44 Among diabetic participants, inflammation has been linked to increased risk of functional decline. ⁴⁵ Among men with HIV compared with seronegative controls, inflammation and insulin resistance have previously been associated with frailty, a complex phenotype of which gait speed is a key component. ²⁰ We found that the association between increased HbA1C and development of slow gait was most apparent among diabetic participants. These results suggest that individuals with both diabetes and HIV represent a particularly high-risk group for development of functional impairment.

In addition, studies of the general population have noted a complex interplay between insulin resistance and cognitive and physical dysfunction. ⁴⁶ Hyperglycemia, insulin resistance, and hyperinsulinemia have been associated both with frailty and cognitive performance in HIV cohorts. ^20,47,48 A recent study of MACS participants showed HIV and diabetes interact to produce white matter changes and that the extent of these structural alterations was significantly associated with psychomotor speed. ⁴⁹ Previous studies have shown that cerebral white matter disease links these three characteristics. White matter T2/FLAIR hyperintensities and abnormal diffusion tensor imaging are present in conditions such as cerebral microvascular disease and HIV. ^50,51 Because of the relatively low incidence of marked slowness as defined for this cohort, we were not sufficiently powered to detect interactions between A1C and NCI and the development of impaired gait speed. Additional analyses as this cohort continues to age will help to further characterize these relationships.

Our findings suggest that strategies to prevent and treat hyperglycemia may help avert functional impairment in PWH. Pharmacologic interventions, including metformin, to improve glucose control have shown some promise in elderly individuals with diabetes. ^{52 –54} However, the risks and benefits of such therapies must be carefully considered. Because of an increased risk of hypoglycemia, intensive glucose treatment may not be appropriate for aging PWH who are vulnerable to other geriatric syndromes such as polypharmacy and falls. ^{55 –57} Lifestyle interventions may help prevent insulin resistance in PWH and lead to improved glucose control and functional outcomes in individuals with known diabetes. ^58,59 Dietary and exercise interventions to thwart excess weight gain and reduce obesity are essential to prevent development of diabetes and physical limitations. ⁶⁰ In addition to weight benefits, exercise-based interventions promote physical function in older diabetic and nondiabetic participants alike. ^{29,61 –63} Indeed, in our analysis of participants with diabetes, physical activity was significantly associated with resolution of slow gait. This finding suggests that physical activity is a key intervention to maintain gait speed in older PWH, particularly those with diabetes.

In this study, we also found that black race had a significant association with development of slow gait. A previous analysis of gait trajectories among participants in the Multicenter AIDS Cohort Study also found significantly faster declines in nonwhite men with and at risk for HIV. ⁵ Higher rates of impaired physical function among older individuals of black race have been previously noted in the general aging population. ^64,65 These differences are incompletely understood but have been linked to increased disease burden and socioeconomic inequalities. ⁶⁶ Indeed, increased education (completion of high school or beyond) was protective against development of slow gait among black participants, suggesting that socioeconomic disparity may in part be driving this difference. Furthermore, among black participants in this study, increasing HbA1C was significantly associated with development of slow gait, suggesting that black PWH should be prioritized for early screening and interventions for insulin resistance.

Several limitations of this study must be acknowledged. Although the HAILO cohort is diverse, its participants have been continuously enrolled in ACTG trials and observational studies since at least 2009. As a result, they may be more adherent and not be fully representative of the general population of older PWH. In addition, women remain underrepresented in this cohort and only account for 19% of participants included in this study. Similarly, the restricted number of participants in each subgroup analysis limits the power of our findings. As such, our preliminary study did not allow for more complex analysis of the relationship between NCI and gait speed. Without a control group of participants who do not have HIV, it remains unclear whether our findings are specific to or accentuated among PWH. Furthermore, there are limitations in obtaining some of the characteristics considered in this analysis. Minor differences in gait speed measurement may have persisted across sites, although all sites receive regular training and quality control procedures. Physical activity was assessed by self-report, which may be unreliable. Although the 4-m gait speed test is a useful screening tool, it is an acute stressor test and does not capture physiologic reserve and exercise tolerance in the setting of prolonged stressor conditions such as the 400-m walk test. Finally, the A5001 Neuroscreen is a limited assessment of neurocognitive function and may not capture all cognitive domains affected in participants.

The growing number of older PWH are vulnerable to poor health outcomes such as disability and reduced quality of life. ^7,22,67 Targeted interventions to preserve physical function and independence and promote resiliency is imperative in this population. As decline in gait speed was associated with increased HbA1C, NCI, and black race, we have identified those at the highest risk for physical function impairment who may benefit most from screening, prevention, and early intervention. Moreover, the association between baseline HbA1C and development of slow gait speed highlights an intervenable target to prevent progression of physical function limitations.