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Accelerated Longitudinal Gait Speed Decline in
HIV-Infected Older Men. (MACS) - just published
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Download the PDF here
State & Federal officials OWE this patient population, older/aging HIV+ !
"The 57% increased hazard of developing slowed gait holds significant implications for the care of those aging with HIV+ who may be at increased risk of lower extremity limitations, hospitalization, and death. Accordingly, efforts to prevent and treat mobility loss in those aging with HIV should be a major public health focus. Given recent evidence from the general population, promoting physical activity and a healthy lifestyle are the best current options41."
from Jules: it is clear that older HIV+ are facing significant hardships, both medically & non-medically (housing, depression, suicide, mobility, healthcare, income & more). WHEN Will NYS & Federal officials wake up & begin to discuss the infrastructure needs of this abandoned population. The federal & state govt HIV/AIDS programs are supported by tax income & federal funding, they owe an obligation to provide attention & funding to this patient population, aging HIV+, govt officials & advocates have no right to deny the requisite attention this group needs & deserves!)
"Although a link between reduced functional performance and HIV infection has been hypothesized, the majority of previous research on the syndrome of frailty 32,33, or on composite measures of performance"
"we analyzed gait speed measurements collected over a 6-year period in the Multicenter AIDS Cohort Study (MACS), an ongoing study of the history of HIV infection that includes HIV+ and HIV- men who have sex with men (MSM)......The current study demonstrates a statistically significant difference in the trajectory of gait speed decline between men aging with HIV and demographically similar HIV- men. Given the increased risk of frailty and comorbidity burden that has been noted in those aging with HIV32, 35, 36, this raises the concern that greater morbidity and disability among those aging with HIV may be forthcoming......Gait speed declined significantly faster in non-white men than in white men, and this was true for both HIV+ and HIV- participants. This difference could not be explained by HIV infection, education, or peripheral neuropathy. Race-related differences in functional and mobility decline in the general aging population have been reported.....life-long differences in socio-economic status (from Jules: and comorbidities prevalence)"
"The current study also was limited in its ability to assess the effect of HIV status on gait speed decline in those over age 65. As of September 2013, 24% of HIV- MACS participants were 65 or older and 11% were 70 or older. Among HIV+ participants, the corresponding figures were 9% and 3%. However, given the separation of the gait speed trajectories at age 50 and the steeper rate of decline among the HIV+ observed in this study, it is likely that the negative association between HIV infection and decline in gait speed would be amplified with advancing age. Future analyses of this cohort as it continues to age will help confirm this hypothesis."
"The capacity to walk independently is a central component of independent living and essential to maintaining quality of life. To our knowledge, this study is the first to evaluate age-related gait speed decline prospectively in a large HIV+ population and compare these observations to a demographically similar HIV population. In the general aging population, it has been suggested that a change in gait speed of 0.05 m/s or more is clinically meaningful27. In the current study, gait speed at age 50 was on average 0.05 m/s slower among HIV+ men compared to HIV- men, suggesting that a clinically meaningful difference in speed by HIV status exists in middle age. Moreover, the significant interaction between HIV and age indicate that the rate of gait speed decline intensifies with age among those with HIV. Overall, these results strongly support the hypothesis that HIV+ individuals experience earlier and faster gait speed decline than their HIV- peers." (from Jules: supporting the notion that HIV accelerates & intensifies aging in HIV+)......."A typical 65-year-old lives with two or more comorbid conditions31. The addition of chronic HIV infection to this comorbidity burden adds another layer of complexity to an aging system, even among the virologically controlled."
Gait speeds were similar by HIV status among those aged 40-49, but after age 50 there was clear separation between the HIV- and HIV+ men, as indicated by the non overlapping confidence intervals of the respective curves, with unadjusted gait speed at age 50 averaging 1.24 m/s in HIV- participants and 1.19 m/s in HIV+ participants (p <0.001). In the fully adjusted model including HIV+ and HIV- men (Table 2), gait speed declined 0.009 m/s for each one-year increase in age after age 50 (p<0.001). There was a significant negative association with HIV status, in which gait speed declined 0.025 m/s more per year in HIV+ men, on average, than in HIV- men (p <0.001). Further, the interaction between age and HIV status was also significant (ß= -0.002 m/s, p= 0.007), indicating that the magnitude of the difference between HIV+ and HIV- men increased with age (from Jules: as I have said before & this is supported by data that in older years HIV+ age-related declines are more steep, this has been shown in CVD & bone studies where the graphically depicted declines are more steep, the graph lines separate between HIV+ & HIV- whereby the HIV+ have greater steepness declines in bone & CVD disease after age 50 & worsen with increase in age, suggesting damage to immune system by HIV & senescence in HIV+ may be causing or at least contributing strongly to this finding). Other significant predictors of gait speed included: weight, height, race, education, hepatitis C status, and peripheral neuropathy.......In the HIV+ model, there was a significant association between nadir CD4 T-cell count and gait speed decline (ß = 0.002 m/s per year for each 50 cell/ul increase, p = 0.029), but suppressed viral load (<200 copies/ml) did not have a significant effect. (from Jules: this is important, that nadir CD4 contributes to gait sped decline & also supports that immune damage is cause & that early ART is important & that having undetectable HIV viral load did not improve outcome!). .......To provide clinical perspective, we examined the effect of HIV status on the time to development of slow gait speed (<1.0 m/s). As shown in Figure 2, the trajectories of time to slow gait were significantly different between HIV+ and HIV- men (p < 0.001), with 50% of the HIV+ men exhibiting slow gait by age 57 compared to age 66 among the HIV- men. In Cox proportional hazard models using age as the time metric and adjusting for the variables that were significant in the continuous analysis (height, weight, race, education, peripheral neuropathy, and hepatitis C), the hazard of developing slow gait was 57% greater for HIV+ compared with HIV- men (aHR 1.57; 95% CI, 1.27 - 1.91)."
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Accelerated Longitudinal Gait Speed Decline in HIV-Infected Older Men.
JAIDS Journal of Acquired Immune Deficiency Syndromes:
June 20 2015
Schrack, Jennifer A PhD, MS; Althoff, Keri N. PhD, MPH; Jacobson, Lisa P. PhD; Erlandson, Kristine M. MD; Jamieson, Beth D. PhD; Koletar, Susan L. MD; Phair, John MD; Ferrucci, Luigi MD, PhD; Brown, Todd T. MD, PhD; Margolick, Joseph B. MD, PhD; for the Multicenter AIDS Cohort Study
Abstract
Background: Gait speed predicts functional decline, disability, and death and is considered a biomarker of biological aging. Changes in gait speed in persons aging with HIV may provide an important method of gauging health and longevity in an under assessed population. The objective of this study was to evaluate and quantify the rate of gait speed decline in HIV infected (HIV+) men compared to HIV uninfected (HIV-) men.
Methods: The study was nested in the Multicenter AIDS Cohort Study (MACS). The primary outcome was usual gait speed in meters per second (m/s) measured between 2007 and 2013. Differences in the rate of gait speed decline and the incidence of clinically slow gait (<1.0 m/s) were assessed using multivariate linear regression models and Cox proportional hazards models, respectively.
Results: A total of 2,025 men (973 HIV+ and 1,052 HIV-) aged 40 and older contributed 21,187 person-visits (9,955 HIV+ and 11,232 HIV-) to the analysis.
Average gait speeds at age 50 years were 1.24 m/s and 1.19 m/s in HIV- and HIV+ men, respectively (p <0.001).
In fully adjusted models, gait speed decline averaged 0.009 m/s per year after age 50 (p <0.001); this decline was 0.025 m/s per year greater in HIV+ men (p <0.001). Moreover, HIV+ men had a 57% greater risk of developing clinically slow gait (aHR=1.57, 95% CI: 1.27 - 1.91).
Conclusions: These findings indicate a faster rate of functional decline in HIV-infected men, suggesting greater risks of disability and death with advancing age.
Introduction
Over 1.1 million people living in the United States are HIV-infected (HIV+)1. Due to highly active antiretroviral therapy (HAART), those living with HIV now have the potential to live a long life2; however, the long-term consequences of treated HIV infection on health and quality of life are unknown. It has been postulated that HIV infection may lead to an accelerated aging phenotype regardless of HIV virology suppression3, due to a pro-inflammatory state4 and greater comorbidity burden present in those aging with HIV5-7. As life expectancy of those living with HIV continues to increase8, these factors may contribute to an accelerated rate of functional decline and disability.
Slow gait speed is a well-established predictor of functional decline, disability, and death in older adults9-11. It has been associated with clinical progression of several chronic diseases in the general population, including diabetes, dementia, and congestive heart failure12, and has been proposed as a method to distinguish between normal and pathological aging13. Among HIV+ persons, slowed gait and an increased risk of poor functional performance have been observed compared to HIV- populations 14-17, yet larger sample sizes, a control group of similar HIV- adults, and longitudinal data are needed to better describe the trajectory of functional decline, and the risk of poor functional performance, by HIV status. Moreover, until recently the HIV+ population has not been old enough to observe the onset and trajectory of the age-related decline in gait speed.
Given the established prognostic power of gait speed11, 12, 18, a systematic examination of the onset and rate of gait speed decline in a large population of HIV+ middle- and older-aged adults, relative to HIV- adults of similar demographics and lifestyle behaviors, may help define whether those living with HIV experience accelerated aging19. Therefore, the purpose of this study was to test the hypothesis that HIV+ persons experience earlier and faster gait speed decline than HIV- persons. To this end, we analyzed gait speed measurements collected over a 6-year period in the Multicenter AIDS Cohort Study (MACS), an ongoing study of the history of HIV infection that includes HIV+ and HIV- men who have sex with men (MSM).
Results
The study population consisted of the 2,025 men (973 HIV+ and 1,052 HIV-) aged 40 and older who had two or more study visits between October 1, 2007 and September 30, 2013. These men contributed 21,187 person-visits (9,955 HIV+ and 11,232 HIV-) to the analysis. The mean number of visits per participant was 10.2 (range: 2-17) for HIV+ men and 10.7 (range 2-17) for HIV- men (p=0.35). Baseline characteristics of these men are shown in Table 1. HIV+ participants were on average 3.4 years younger than HIV- participants and had lower BMIs (p-values <0.001); and HIV+ participants were more likely to have liver disease, peripheral neuropathy, hepatitis B, and hepatitis C infection, be non-white, report a history of drug use, and have fewer years of education, and were less likely to consume alcohol (p-values <0.001). There was a wide range of gait speeds, from less than 0.14 m/s to more than 1.9 m/s (supplemental Figure 1), which is consistent with previous studies12, 26.
Figure 1 displays the unadjusted mean and 95% confidence interval association between age and gait speed by HIV status using a quadratic fit plot. Gait speeds were similar by HIV status among those aged 40-49, but after age 50 there was clear separation between the HIV- and HIV+ men, as indicated by the non overlapping confidence intervals of the respective curves, with unadjusted gait speed at age 50 averaging 1.24 m/s in HIV- participants and 1.19 m/s in HIV+ participants (p <0.001). In the fully adjusted model including HIV+ and HIV- men (Table 2), gait speed declined 0.009 m/s for each one-year increase in age after age 50 (p<0.001). There was a significant negative association with HIV status, in which gait speed declined 0.025 m/s more per year in HIV+ men, on average, than in HIV- men (p <0.001). Further, the interaction between age and HIV status was also significant (ß= -0.002 m/s, p= 0.007), indicating that the magnitude of the difference between HIV+ and HIV- men increased with age. Other significant predictors of gait speed included: weight, height, race, education, hepatitis C status, and peripheral neuropathy. There was no interaction between race and peripheral neuropathy or education. Smoking, history of drug and alcohol use, diabetes, liver disease, hypertension, arthritis, MCS score, and hepatitis B infection were not significant and were not included in the final model.
In analyses stratified by HIV status, there were strong negative associations between gait speed and age in both the HIV+ (ß = -0.012 m/s per year, p <0.001) and HIV- (ß = -0.011 m/s per year, p <0.001) groups (Table 3).
Height, weight, race, education, and peripheral neuropathy contributed significantly to both HIV+ and HIV- models, but hepatitis C infection was significant only in the HIV- model. In the HIV+ model, there was a significant association between nadir CD4 T-cell count and gait speed decline (ß = 0.002 m/s per year for each 50 cell/ul increase, p = 0.029), but suppressed viral load (<200 copies/ml) did not have a significant effect.
To provide clinical perspective, we examined the effect of HIV status on the time to development of slow gait speed (<1.0 m/s). As shown in Figure 2, the trajectories of time to slow gait were significantly different between HIV+ and HIV- men (p < 0.001), with 50% of the HIV+ men exhibiting slow gait by age 57 compared to age 66 among the HIV- men. In Cox proportional hazard models using age as the time metric and adjusting for the variables that were significant in the continuous analysis (height, weight, race, education, peripheral neuropathy, and hepatitis C), the hazard of developing slow gait was 57% greater for HIV+ compared with HIV- men (aHR 1.57; 95% CI, 1.27 - 1.91).
To examine the potential effects of treatment on the risk of slow gait, HIV+ men were stratified into three groups: (i) those who never had slow gait, (ii) those who had slow gait at baseline, and (iii) those who had incident slow gait during the study. There were no meaningful or statistically significant differences among these groups by cumulative years on HAART or by cumulative years on ddI, d4T, AZT, or efavirenz.
Discussion
The capacity to walk independently is a central component of independent living and essential to maintaining quality of life. To our knowledge, this study is the first to evaluate age-related gait speed decline prospectively in a large HIV+ population and compare these observations to a demographically similar HIV population. In the general aging population, it has been suggested that a change in gait speed of 0.05 m/s or more is clinically meaningful27. In the current study, gait speed at age 50 was on average 0.05 m/s slower among HIV+ men compared to HIV- men, suggesting that a clinically meaningful difference in speed by HIV status exists in middle age. Moreover, the significant interaction between HIV and age indicate that the rate of gait speed decline intensifies with age among those with HIV. Overall, these results strongly support the hypothesis that HIV+ individuals experience earlier and faster gait speed decline than their HIV- peers.
Multiple factors have been associated with gait speed decline including decreased aerobic capacity, changes in body composition, threats to biomechanics (e.g., arthritis, balance difficulty), and compromised energy utilization28-30, signifying that slowed gait speed is a reflection of underlying biological and physiological challenges that develop with age. A typical 65-year-old lives with two or more comorbid conditions31. The addition of chronic HIV infection to this comorbidity burden adds another layer of complexity to an aging system, even among the virologically controlled.
Although a link between reduced functional performance and HIV infection has been hypothesized, the majority of previous research on the syndrome of frailty 32,33, or on composite measures of performance 15,34. Richert et al analyzed gait speed over 10 meters, along with the five times sit-to-stand test and six-minute walk distance, in 354 middle-aged HIV+ participants (median age at baseline 46 years) and compared it to published data from the general aging population. After a two-year follow-up period, findings included greater deterioration in the five times sit-to-stand test and six-minute walk distance, but no difference in median 10-meter gait speed. In a study of injection drug users, Greene et al17 found that after five years of follow-up, HIV+ participants had reduced physical performance and greater risk of mortality than HIV- participants, but the rate of decline was not quantified or compared. The current study demonstrates a statistically significant difference in the trajectory of gait speed decline between men aging with HIV and demographically similar HIV- men. Given the increased risk of frailty and comorbidity burden that has been noted in those aging with HIV32, 35, 36, this raises the concern that greater morbidity and disability among those aging with HIV may be forthcoming.
Gait speed declined significantly faster in non-white men than in white men, and this was true for both HIV+ and HIV- participants. This difference could not be explained by HIV infection, education, or peripheral neuropathy. Race-related differences in functional and mobility decline in the general aging population have been reported. In the Health, Aging and Body Composition study older blacks showed higher rates of mobility loss than whites, with greater risk of developing mobility limitations over follow-up even after accounting for poor mobility at baseline37. The mechanism of these differences is not known, but is generally believed to be related to life-long differences in socio-economic status37, 38
It is unclear from the current results how long-term antiretroviral treatment may affect gait speed decline. This is an important question, as nearly all of the HIV+ men in this study were receiving HAART, and the vast majority were virologically suppressed, characteristics which are likely to be similar in most populations aging with HIV. In the present study, analyses of HIV+ men with and without slow gait at baseline, or with incident slow gait, yielded no evidence that cumulative exposure to specific antiretroviral drugs (ddI, d4T, AZT, efavirenz) was associated with slower gait speed. These findings should be replicated in other, more diverse populations with greater power to detect differences by treatment. Moreover, the association between lower nadir CD4 cell count and faster decline in gait speed is consistent with previous research linking HIV with frailty32, 33, 39 and underscores the importance of early initiation of therapy, and maintaining virologic suppression and sufficient CD4 cell count, particularly with advancing age.
The development of age-related chronic diseases in people with chronic HIV infection may be driven by a state of chronic inflammation. Although not having data on inflammatory markers is a limitation, stored samples will provide opportunities for future research. The negative association between hepatitis C and gait speed among the HIV- participants may in part be explained by increased inflammatory burden, and also warrants future investigation.
The current study also was limited in its ability to assess the effect of HIV status on gait speed decline in those over age 65. As of September 2013, 24% of HIV- MACS participants were 65 or older and 11% were 70 or older. Among HIV+ participants, the corresponding figures were 9% and 3%. However, given the separation of the gait speed trajectories at age 50 and the steeper rate of decline among the HIV+ observed in this study, it is likely that the negative association between HIV infection and decline in gait speed would be amplified with advancing age. Future analyses of this cohort as it continues to age will help confirm this hypothesis.
The HIV+ men in the MACS may not be generalizable to other aging HIV+ populations, as longstanding participants of HIV cohort studies are likely to be different from the general HIV+ population. Moreover, 9% of MACS participants are age 65 or older compared with 5% of persons living with HIV in the United States40, and many of these participants survived a period of time without effective treatment (i.e prior to 1996) and/or exposure to less effective and more toxic ART regimens, before achieving virology suppression. Our results do not show a difference in gait speed and disability by experiences prior to effective treatment (specifically by d-drug usage); if there is, however, an unmeasured effect, the difference in gait speed and disability by HIV status may decrease in an era of effective, accessible treatment and ART initiation at higher CD4 counts. Further, the current study did not include women, limiting its generalizability to women aging with HIV.
As the treatment of HIV expands globally, the need to manage and treat age-related conditions in persons living with HIV will grow exponentially. The 57% increased hazard of developing slowed gait holds significant implications for the care of those aging with HIV+ who may be at increased risk of lower extremity limitations, hospitalization, and death. Accordingly, efforts to prevent and treat mobility loss in those aging with HIV should be a major public health focus. Given recent evidence from the general population, promoting physical activity and a healthy lifestyle are the best current options41.
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