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Frailty in People Living with HIV - new review following several CROI reports on frailty, mitochondrial damage & brain function & frailty
  Current HIV/AIDS Reports - June 2020 -
Julian Falutz1
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at CROI 2020:
MITOCHONDRIAL DNA, COGNITIVE FUNCTION, AND FRAILTY IN OLDER ADULTS WITH HIV - (03/17/20)....Older PLWH experience more comorbidities and geriatric syndromes, including cognitive impairment and frailty. Mitochondrial DNA (mtDNA), released from dying cells, is a biomarker of inflammation, a mediator of immune activation and has been detected at elevated levels in the plasma of PLWH. We hypothesized that in older PLWH, plasma mtDNA would be associated with lower cognitive performance, frailty, and higher serum IL-6 level.. Age was not related to MoCA score (=-0.1, p=0.19), but was associated with frailty status by Jonckheere-Terpstra (JT) test (p=0.008). Plasma mtDNA level was higher in those with low MoCA score (p=0.028) by t-test [Figure 1]. Higher plasma mtDNA level was associated with slow walk (p=0.007) and exhaustion (p=0.04), but not weight loss (p=0.62), grip strength (p=0.06), low physical activity (p=0.71) or composite frailty score (p=0.98). Serum IL-6 levels were associated with frailty status (p=0.018) but not with low MoCA score (p=0.89 by JT).
50% PREVALENCE OF PHYSICAL FUNCTION IMPAIRMENT AND FRAILTY IN MIDDLE-AGED PWH - age 46-55 -(03/27/20) ......31% reported not being able to perform one or more instrumental activities of daily living (DASI). median age was 51 (Q1, Q3: 46, 55) years. "Older age, Black race, 10 years on ART, history of thymidine analog (TA), greater BMI, high waist circumference, hypertension and physical inactivity were associated with physical function impairment in univariate analyses (figure). Black race, greater BMI and physical inactivity remained associated with physical function impairment in the multivariate model. Physical function impairment and pre-frailty were common among middle-aged PWH; greater BMI and physical inactivity are important modifiable factors that may prevent further decline in physical function with aging."



EFFECTS OF HIV, AGE, AND SEX ON SKELETAL MUSCLE MASS AND DENSITY (04/01/20) "Older age and being a woman was associated with smaller and fattier muscle, while obesity was associated with larger and fattier muscle. Detrimental effects of HIV on the psoas density and area, particularly among men, may have important implications on balance, trunk stability, and mobility." The psoas muscle is located in the lower lumbar region of the spine and extends through the pelvis to the femur. This muscle works by flexing the hip joint and lifting the upper leg towards the body. A common example of the movement created from this muscle is walking.
Immuno-senescence plays a key role..... Women's Interagency HIV Study (WIHS), consisting of mostly low-income, African-American non-Hispanic women, most with secondary education and a mean age of 39, 17.3% of seropositives were FP+ versus 10.0% of uninfected women....Disability, determined as impairments in IADLs, was investigated in the HAILO (HIV Infection, Aging, and Immune Function Long-Term Observational Study) Cohort, a prospective, observational, long-term study of treatment naïve PLWH starting cART, with median age 51. The prevalence of pre-frailty and being FP+ was 37% and 6% respectfully. There was minimal overlap between frailty and disability, although 52% of frail PLH had at least 1 disability [79]. Frailty was associated with increased incidence of CVD, type II diabetes, and with increased mortality [80]. Modifiable risk factors for frailty including neurocognitive impairment, obesity, smoking, choice of initial cART (with NNRTI [non-nucleoside reverse transcriptase inhibitor]-based cART increasing risk of frailty), and level of education. Physical activity and moderate alcohol use were protective [81].
The MACS initially investigated similarities between frailty in the elderly and PLWH using a four-item adapted frailty-related phenotype (aFRP). In untreated, seropositive, Caucasian, college-educated men, with a mean age of 55, the prevalence of frailty, 3.4%, was similar to that of HIV seronegative males older than 65 from the same cohort [73]. An association between frailty and immuno-virologic parameters was demonstrated by an increasing risk of being FRP+ relative to a CD4 count < 500/mm3 and an HIV viral load > 50,000 copies/mL [74]. Frailty, regardless of HIV status, occurred without concurrent co-morbidities. Risk factors included older age and non-Hispanic black ethnicity. Potentially manageable risks included a history of AIDS, cigarette smoking, hepatitis C infection, depression, diabetes, and kidney disease. Higher education was protective. Although frailty is dynamic, PLWH who became frail were more likely than controls to remain frail at follow-up. [76]. The AIDS Linked to the Intravenous Experience (ALIVE) cohort showed that 12% of mostly male, African-American injection drug users with a median age of 49 were FP+. Risk factors for frailty included HIV infection, older age and female sex, while potentially controllable risks, as in the MACS, included advanced HIV disease, lower education, depression and multimorbidity. Being frail, regardless of HIV status, was a risk factor for overall mortality [77], all-cause hospitalizations, as well as chronic conditions such as psychiatric, cardiovascular, and pulmonary diseases [78].
It is essential that the assessments and interventions discussed in regard to frailty in aging PLWH go beyond increasing survival and shift the focus to maintaining and improving functional status and QoL, as in the geriatric population. Quality of life represents an ongoing hurdle to fulfilling the proposed "fourth 90" of the UNAIDS 90-90-90 goals for PLWH [127]. The paradigm of successful aging emphasizes better understanding of physical, social, and cognitive resilience as well as the evolving interactions between HIV, frailty, and intrinsic capacity [128, 129].
More seropositive women than men are FP+ [82, 83], as in the general population [84]. In the Women's Interagency HIV Study (WIHS), consisting of mostly low-income, African-American non-Hispanic women, most with secondary education and a mean age of 39, 17.3% of seropositives were FP+ versus 10.0% of uninfected women [85]. Impaired bone health is more common in FP+ PLWH [80, 86, 87]. Functional impairment, determined by reduced gait speed and poor performance on the Short Physical Performance Battery (SPPB), occurred in 20% and 55%, respectively, in a cohort of Spanish PLWH with a median age of 61, of whom 51% were pre-frail and 15% were FP+ [61]. In an analysis of mostly non-Caucasian Brazilian PLWH with a median age of 55, the 19% who were FP+ were more likely to have a poor quality of life determined using the 36-item Short Form Survey [82]. In a study of younger, treated PLWH in South Africa with a mean age of 41, 19.4% were frail using an adapted FP, compared with 13.3% of seronegative controls [83]. This finding in a low-income country highlights the economic burden and impact on healthcare delivery that frailty will have as the prevalence of aging PLWH increases in all regions.
Frailty and Other Clinical Conditions in PLWH
Several studies have shown an association between measures of abdominal obesity and being FP+, regardless of HIV status, [72, 97, 98] highlighting this as a potentially reversible lifestyle factor for frailty. Potentially treatable mild-to-moderate depression is diagnosed in about 50% of frail PLWH [99, 100], and occurs often in PLWH with neurocognitive impairment. Asymptomatic neurocognitive impairment (NCI) is a feature of aging PLWH [101]. Studies have investigated whether physical frailty is a risk factor for NCI in PLWH. A higher VACS-I, suggestive of frailty, predicted the presence of NCI in a cohort with a mean age of 41 [99] . The Italian MHMC cohort study found that a lower FI was associated with successful cognitive aging, defined as the absence of depression, cognitive, and functional impairment [102]. Participants in the HAILO study who were both FP+ and had NCI had an increased risk of adverse health events including falls, disability, and overall mortality [103]. Being FP+ has also been associated with NCI in PLWH in diverse geographic regions including China [98] and Mexico [104]. These consistent findings using different metrics support the emerging construct of cognitive frailty as an important condition in PLWH.
Frailty determined using the FI has been extensively studied by the Modena HIV Metabolic Clinic (MHMC) cohort. Using a 37-item-derived FI, which importantly did not include any HIV-related variables, the median FI was 0.30 in the cohort of treated, mostly male PLWH with a mean age of 46. The FI was a significant predictor of survival and development of new multi morbidity.
Studies Comparing Frailty Metrics in PLWH
As in the general population [105], studies have compared frailty classifications in PLWH. In a subgroup of the MHMC cohort with a mean age of 46, the VACS-I, compared with the FI, more accurately predicted 2-year but not 5-year mortality [92]. The FI was compared with the FP in a different subgroup of the MHMC cohort with a mean age of 54, of whom 52% were pre-frail and 3.1% were FP+. The FI had a greater association than the FP with baseline factors of age, nadir CD4 count and with adverse events including co-morbidities, falls, and disability [106]. Overall, it is premature to recommend a particular frailty metric as more reliable to use for all PLWH.
Biology of Frailty
General Population

A progressive loss of normal homeostatic processes in diverse physiologic systems occurring in response to environmental and biologic stressors leads to frailty. This results in adverse outcomes which can be characterized at the cellular, tissue, organ and whole person level [34]. Although these changes also occur in physiologic aging, a heightened degree of dysfunction is central to the development of frailty [35]. Immuno-senescence plays a key role, as determined by activation of the multiple cellular components of the innate immune system, plus changes in the adaptive immune system. This results in a chronic inflammatory state [36] characterized by reduced numbers of naïve T cells, an increase in terminally differentiated CD8+ and CD28− T cells and a low CD4+/CD8+ T-cell ratio [37]. Chronic CMV infection contributes to both immune-senescence and frailty [38]. The combination of immune features plus CMV seropositivity is referred to as the Immune Risk Profile (IRP) and increases risk of mortality in the very old [39, 40]. Interestingly most centenarians have a normal CD4/CD8 T cell ratio [41]. The term inflammaging encompasses the aging-related dysregulation between the innate and adaptive immune systems [42]. Triggers include accumulation of damaged cells and their impaired elimination, entry of microbial products into the circulation via an aging and leaky gastrointestinal tract alongside changes in the gut microbiome, accumulation of senescent cells secreting proinflammatory cytokines, increased activation of the coagulation system, impaired regulation of the complement cascade, and mitochondriopathies [43].
Commonly determined serum markers of these processes include increased levels of proinflammatory cytokines, particularly C-reactive protein (CRP), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and coagulation factors including fibrinogen, Factor VIII, and D-dimer [44]. A meta-analysis confirmed the increased levels of these markers in both frail and pre-frail elderly subjects [45].
Contributing hormonal changes include decreased insulin-like growth factor-1 levels, decreased testosterone and dehydroepiandrosterone-sulfate levels, and abnormalities in cortisol secretion characteristic of a chronic stress response [46]. An important consequence is sarcopenia, a geriatric syndrome characterized by progressive loss of muscle mass and power which occurs frequently in persons with physical frailty [47]. Other fundamental contributors include epigenetic changes [48], telomere shortening associated with the frailty phenotype [49], genetic regulation of fundamental biologic pathways controlling apoptosis, transcription and biosynthesis [50], and age-related body composition changes. These include abdominal obesity, itself contributing to chronic inflammation, and loss of lean muscle mass [51].
Pre-frailty and frailty affect more than 50% of effectively treated older PLWH. These states represent the clinical expression of the multifactorial decline of normally coordinated biologic systems to maintain physiologic homeostasis. Regardless of the tools used to diagnose them, they are associated with an increased risk of adverse health outcomes which contribute to the overall reduced survival and QoL of PLWH. Both pre-frailty and frailty are potentially preventable and reversible. Risk factors increasing progression to, and importantly, promoting reversion from frailty, are under investigation. Encouragingly, several are lifestyle related and amenable to prevention and change, which does not need to be financially burdensome. Just as early cART was the main driver behind turning HIV/AIDS from a fatal disease into a chronic condition, so current cART may also be a key factor in reducing the progression along the frailty continuum. The vital lessons learned in providing humane and effective holistic patient-centered care to the elderly can be adapted to meet the latest challenges to confront aging PLWH. These will surely be met with the same vigorous determination which has marked the last 40 years struggle against HIV.
Screening for Frailty and Management Principles

Diagnosing an older individual as frail has relevance beyond simply identifying a condition associated with adverse outcomes. For example, frailty is an important risk factor for perioperative complications. Pre-habilitation clinics, where identified preoperative risks for postoperative morbidity can be modified, improve outcomes [107]. An interdisciplinary geriatric approach is increasingly recommended for selected aging PLWH, particularly those diagnosed as frail [108]. Other surrogates besides frailty can help to identify those PLWH who may benefit from a geriatric evaluation. These include polypharmacy, which is more common in PLWH compared to controls [109], impaired functional status as determined by gait speed or the comprehensive SPPB, and the presence of geriatric syndromes. Although distinct conditions, important interactions occur in PLWH between frailty, functional status, and disabilities [110]. Both functional impairment and disabilities occur in PLWH [111], especially in those with concurrent geriatric syndromes [110]. A combination of immune parameters, (e.g., a low nadir CD4 count < 200, a 'plateau' CD4 < 500 on suppressive cART, and a CD4/CD8 ratio < 1.0) may also identify frail PLWH requiring a geriatric evaluation [60, 61].
Frailty is a dynamic state. In a study of over 300 treated PLWH over a 12-month follow-up period, most non-frail and pre-frail persons maintained their status, whereas most who were frail reverted to prefrailty [91]. Pre-frailty, occurring in 30–60% of PLWH, is important to identify, as it is also associated with adverse outcomes. Factors associated with progression to frailty in PLWH in the MACS have been described above. Only younger age was associated with reversion from frailty [76]. Guaraldi investigated predictors of frailty transition over 4 years in the MHMC Cohort. Baseline FI, female sex, duration of HIV infection and cART exposure, and smoking history independently predicted FI at follow-up [93].
At present, the clinical utility of geriatric referrals remains untested, and no guidelines are in place regarding which PLWH to refer. In the general population, persons older than 70 should be screened for frailty [112]. Based on data suggesting age-advancement of PLWH, it is reasonable to consider screening PLWH older than 50. The role of geriatricians as either expert consultants or as active members of the managing team is being clarified.
Management of Frail PLWH
An algorithm to identify PLWH who may benefit from an HIV-geriatrics assessment, including a Comprehensive Geriatric Assessment (CGA), has been proposed [113]. The goals of the CGA in the general population, in addition to assessing and managing multimorbidity and geriatric syndromes, are also to ensure follow-up with primary care providers and evaluating the impact of recommended interventions. The CGA has been evaluated in diverse clinical settings. Collectively, and accounting for logistic differences, the CGA improves quality of life, decreases the need for emergency room visits and hospitalization, and maintains independence [114]. However, outcomes in one type of setting (e.g., acute care unit) do not necessarily translate to a different one (e.g., community clinic) [115]. Importantly, the process of performing a CGA need not be uniform, while maintaining the recommended "5 M's" approach, assessing the following: mind and mood; mobility; medications; multimorbidity; and matters most (e.g., discharge from hospital, end-of-life planning) [116]. Rather than simply adopting the CGA model to PLWH, it is essential to determine how best to adapt it to this population. A modification applicable to PLWH has been recently been suggested [117]. Various locally responsive models of providing care to older PLWH have been organized [118]. An early report reviewed the first 76 older PLWH (median age 67) referred to a dedicated academic geriatric-HIV clinic for a CGA on the basis of perceived need, but with no specific referral criteria. Adherence to recommendations was about 30% [119].
The general approach to managing frailty in the geriatric population includes specific recommendations arising from a CGA, exercise and appropriate rehabilitation interventions, nutritional support, and cognitive care. The long-term effectiveness of regular, multicomponent, long-duration exercise programs on reducing frailty remains to be established but a targeted approach is often successful [120]. PLWH with more impaired baseline functional status may achieve similar or greater improvements in exercise domains compared with controls [121]. Priorities for rehabilitation interventions to limit disability in PLWH have been established and early outcomes have been encouraging [122]. Sarcopenia, diagnosed most reliably by dual energy X-ray absorptiometry, is increasingly recognized in PLWH [123] and may respond to judicious exercise and nutritional supplements [124], awaiting the introduction of more specific pharmacotherapies.
cART reduces the prevalence of frailty [74]. A recent modeling analysis showed that the burden of frailty using the FI model has decreased in PLWH older than 50 over the past 10 years and is projected to decrease further from 26% to 7% between 2015 and 2030. However, frailty will increase from 43 to 52% in PLWH older than 75. This was interpreted as the "compression of frailty" in older age, a successful feature of current therapies [125]. These results support the current recommendations of the early diagnosis of HIV and prompt initiation of cART in older PLWH. A post hoc analysis of the START study showed that older PLWH were the main beneficiaries of early initiation of cART [126].
It is essential that the assessments and interventions discussed in regard to frailty in aging PLWH go beyond increasing survival and shift the focus to maintaining and improving functional status and QoL, as in the geriatric population. Quality of life represents an ongoing hurdle to fulfilling the proposed "fourth 90" of the UNAIDS 90-90-90 goals for PLWH [127]. The paradigm of successful aging emphasizes better understanding of physical, social, and cognitive resilience as well as the evolving interactions between HIV, frailty, and intrinsic capacity [128, 129].

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