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Biologic aging, frailty, and age-related disease in chronic HIV infection
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Current Opinion in HIV & AIDS:
July 2014
Brothers, Thomas D.a,b; Rockwood, Kennetha,c
aGeriatric Medicine ResearchbFaculty of Medicine, Dalhousie UniversitycCentre for Healthcare of the Elderly, QEII Health Sciences Centre, Capital District Health Authority, Halifax, Nova Scotia, Canada
Effective therapies have transformed HIV infection into a chronic disease, and many HIV-positive people with access to treatment are living to near-normal life expectancies [1,2·]. With this success, new challenges arise related to aging with HIV and its lifelong treatment. People living with HIV exhibit higher rates of many age-related health problems, including cardiovascular disease, certain cancers, cognitive and renal impairment, bone demineralization, and age-related immune dysregulation [3]. In consequence, a contested theory has emerged that this might represent a form of 'accelerated' or 'premature' aging [4]. The purpose of this review is to discuss what aging is, its relationship with health, disease, and frailty, and how these might be affected by chronic HIV infection.
Frailty in people aging with HIV infection
Data on frailty in people with HIV are rapidly emerging from cohort and clinical studies. Reports to date use frailty scales that count a limited number of age-related health deficits; most are based on the frailty phenotype [58,59··,60]. Although methodological differences in the frailty scales used limit meaningful comparisons of frailty prevalence estimates between studies, some consistent findings reinforce the notion of frailty quantifying heterogeneity in the aging process. Similar to findings in HIV-negative individuals, frailty levels are higher in HIV-positive individuals with less formal education [61,62·,63··], who are unemployed or who have lower incomes [61,64], or who have comorbidities not included in the frailty scale, including diabetes [63··], kidney disease [63··], depressive symptoms [61,62·,63··], hepatitis C co-infection [65], and markers of chronic inflammation (IL-6, D-dimer, and sCD14) [66].
Frailty is positively associated with traditional markers of HIV disease and vulnerability, including current and nadir CD4 count [61,62·,63··,65,67-69], and presence of a detectable viral load [62·,63··]. Among a cohort of people who inject drugs, HIV-positive participants with advanced HIV disease (defined as CD4 <350 cells/μl and detectable viral load) were more likely to be frail than HIV-negative participants, whereas HIV-positive participants without advanced HIV disease were not more likely to be frail [62·]. One longitudinal analysis of the Multicenter AIDS Cohort Study (MACS) from 2007 to 2011 found that HIV-positive participants with a history of AIDS were more likely to become frail than HIV-negative participants, whereas HIV-positive participants with no history of AIDS were not [63··].
Limited data exist on frailty in relation to outcomes in HIV infection, and further work is needed. In a cohort of people who inject drugs, being HIV-positive or being frail was each associated with three times higher odds of death, whereas being both HIV-positive and frail was associated with seven times higher odds [62·]. In the MACS, participants who were frail before starting ART had shorter time to AIDS or death [70].
Of particular interest is the widely investigated Veterans Ageing Cohort Study (VACS) index. The VACS index was originally developed to assess health status and predict death in people with chronic HIV infection, and has recently been proposed as a frailty measure in this population [59··]. The index includes traditional HIV-related measures, including CD4 count and viral load, other deficits including hepatitis C virus co-infection, liver fibrosis, hemoglobin, kidney function, as well as race and age.
Data from studies employing the VACS index can help illustrate the association between deficit accumulation, frailty, and the emergence of age-related disease across multiple physiological systems. VACS index scores are associated with multiple health problems common with aging and frailty: inflammation (IL-6, D-dimer, and sCD14) [66], distal muscle weakness [71], fragility fractures [59··], cognitive impairment [72·], coronary heart disease-related mortality [73], and all-cause mortality [66,74·].
Notwithstanding these points of similarity, the VACS index differs from frailty measures developed in HIV-negative populations, as it includes chronological age and race [74·]. Most frailty scales do not include age as a variable, as they intend to describe the cumulative effects of multiple biological age-related health changes, including the possibility of improvement [75]. Most frailty scales also do not include race, which obviously does not change with age. Although it can reasonably be argued that as a measure of vulnerability, frailty scales could include all variables which improve the prediction of adverse outcomes, different patterns have been observed between the accumulation of social deficits [76] and general health deficits [43·,76]. The VACS index also includes variable weightings derived from the VACS study to optimize its prognostic abilities. Weighting of deficits is uncommon in frailty scales, as variable weights derived from one sample can limit generalizability to other populations [49·]. Even so, as described above, the VACS index has identified vulnerability for outcomes in addition to death, including many collinear with frailty, and its variable weightings have demonstrated notable stability in validation datasets [74·].
How best to measure frailty in people living with HIV?
In the current highly active antiretroviral treatment era, in which most HIV-positive people with access to therapy experience long-term immune reconstitution and suppression of viral load below detectable levels, which frailty scale is best or most informative has not been established [58]. This is not surprising, as there is also no consensus on which frailty scale is best to use in geriatric practice in general [49·]. The best frailty scale to use might also depend on the setting in which it is used, whether as a convenient screening tool to signal a need for follow-up or as a more comprehensive evaluation.
Special considerations might apply to those aging with HIV infection, however, as HIV-positive and HIV-negative people might experience characteristically different risk profiles with age. Perhaps scales measuring frailty in people aging with HIV should include measures of behavioral risk factors for illness, of chronic viral co-infections, or of surrogate laboratory measures known to be influenced by HIV infection. Although these factors might contribute to vulnerability in people aging with HIV, this might represent something else in addition to the frailty that has been identified in HIV-negative older adult populations in geriatric medicine. Here, the frailty index approach might prove useful. As noted, a frailty index can be comprised of many different variables that assess age-related health, and deficits can be included or excluded as long as there are at least around 30 included that meet the few stated criteria. No published studies have yet evaluated the frailty index among people aging with HIV.
Aging, characterized by acceleration in the accumulation of unrepaired health deficits over time, is influenced by both the rate of insults an organism sustains and the efficacy of damage maintenance and repair mechanisms. Both of these processes are likely affected in complex and heterogeneous ways among people aging with HIV infection. Differences in aging can be assessed and quantified by counting these deficits, through the concept of frailty. Patterns of aging, deficit accumulation, and frailty are not yet well understood in HIV infection, and this perspective may add to understanding about aging and age-related disease in this population.

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