HIV and Frailty

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With the widespread availability of effective antiretroviral therapy (ART) beginning in the late 1990’s, HIV infection has been transformed into a chronic disease. Survival among people living with HIV (PLWH) is now approaching that of the general population. However, there appears to be an acceleration of aging processes in PLWH. Aging-related comorbidities, such as cardiovascular disease, pulmonary disease, diabetes, heart failure, and kidney disease are more frequent and tend to occur at an earlier age in those living with HIV (Schouten et al., 2014; Guaraldi et al., 2011; Gonciulea et al., 2017; Drozd et al., 2017).  Markers of biologic aging, such as epigenetic alterations in cellular DNA – a “clock” for cellular aging – are similar to persons without HIV who are over five years older (Fülöp et al., 2017; Horvath et al., 2015).

Introduction

With the widespread availability of effective antiretroviral therapy (ART) beginning in the late 1990’s, HIV infection has been transformed into a chronic disease. Survival among people living with HIV (PLWH) is now approaching that of the general population. However, there appears to be an acceleration of aging processes in PLWH. Aging-related comorbidities, such as cardiovascular disease, pulmonary disease, diabetes, heart failure, and kidney disease are more frequent and tend to occur at an earlier age in those living with HIV (Schouten et al., 2014; Guaraldi et al., 2011; Gonciulea et al., 2017; Drozd et al., 2017).  Markers of biologic aging, such as epigenetic alterations in cellular DNA – a “clock” for cellular aging – are similar to persons without HIV who are over five years older (Fülöp et al., 2017; Horvath et al., 2015).

Among PLWH, the clinical and public health significance of frailty has become more widely recognized (Piggott et al., 2016). Multiple studies have shown a high prevalence of physical frailty is this population. In the AGEhIV Cohort Study in Amsterdam, the prevalence of frailty, using the physical frailty phenotype, was 10.6% in PLWH compared to 2.7% in age, sex, and race-matched controls. The prevalence of pre-frailty was also significantly higher in PLHW (50.7% v 36.3%). Even after adjustment for demographic factors, smoking, hepatitis C infection, comorbidities and depression, HIV-infection was associated with a doubling of the odds of frailty and pre-frailty (Kooij et al., 2016). In the Multicenter AIDS Cohort Study, a study of men who have sex with men, the prevalence of frailty was also higher in PLWH compared to demographically similar HIV-uninfected men (12% vs 9%), particularly in those who had a past history of AIDS (Althoff et al., 2014).

The Impact of HIV Infection on Frailty

The etiology of the higher prevalence of frailty in PLWH is multifactorial, with both infection and treatment contributing to the problem. Chronic inflammation, which is present in PLWH even when HIV viral load is undetectable, leads to accelerated cellular senescence, mitochondrial dysfunction, and metabolic dysregulation (Erlandson et al., 2014).  These changes in physiology are known to develop during aging and are thought to play a role in the development of frailty in the general population. Infection with HIV therefore causes a premature onset of these processes.

Antiretroviral therapy (ART) for HIV infection is likely to have both direct and indirect effects on physical function. Nucleoside analogue reverse transcriptase inhibitors (NRTI) that are thymidine analogues, including AZT and d4T, were used extensively in PLWH when combination antiretroviral therapy became available and have direct effects on mitochondrial function.  These changes result in persistent body composition alterations (subcutaneous lipoatrophy and relative central lipohypertrophy), insulin resistance, and dyslipidemia, which in turn may predispose these individuals to more accelerated aging-related declines in physical function (Kooij et al., 2016). Although in the current HIV treatment era these medications are seldom used, their adverse effects may persist in those who were previously exposed. Efavirenz, a previously widely used non-NRTI, has been linked to frailty in a study the AIDS Clinical Trial Group, although it is unclear if this association is causal (Erlandson et al., 2017).  More recently, the integrase strand transfer inhibitors (InSTI or commonly “integrase inhibitors”), which are currently a key component of most ART regimens, have been linked to significant weight gain (Eckard & McComsey, 2020). Whether these changes in adiposity will predispose PLWH to faster declines in physical function as they age is an important area of inquiry.

Impact of Frailty on those living with HIV

An increased prevalence of frailty among PLWH at a relatively young age stands to have a major impact on both health and quality of life as the HIV population ages. By 2035, an estimated 70% of the HIV population in the US will be over 50 years old, with 25% over 65 years of age (Smit et al., 2017).

Frailty among PLWH, as in the general population, is associated with multiple adverse outcomes, including falls, fractures, and mortality (Kelly et al., 2019; Erlandson et al., 2019; Sharma et al., 2019).  Frailty is also related to decreased muscle mass (sarcopenia), which is associated with mortality in PLWH, especially when coupled with accumulation of visceral fat, in a phenotype reminiscent of sarcopenic obesity (Scherzer et al., 2011; Hawkins et al, 2018).  In the FRAM study, PLWH in the lowest tertile of skeletal muscle mass had twice the mortality of those in the highest tertile, an effect that was especially prominent in those with the most (i.e., highest tertile) of visceral fat (Scherzer et al., 2011).

Applying Knowledge of Frailty in HIV

Understanding the pathogenesis of frailty in PLWH is the first step towards robust interventions.  One important research question is whether the mechanisms underlying frailty and impaired physical function are similar or different from frailty in the general population.  Are there molecular pathways that are more or less activated?  Are the physical manifestations of frailty pathways, such as immunosenescence, mitochondrial dysfunction, and hormonal dysregulation, the same as the general population in PLWH?  If differences exist between PLWH and the general population, this would suggest that the strategies to alter the physical function trajectory may also differ.

Over the past 30 years, the health of PLWH has been radically transformed with advances in our understanding of HIV, improved antiretroviral treatments, and their more widespread availability.  Advances in frailty science will help improve the health and well-being for PLWH in the next 30 years.

Primary Care

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Performing Frailty Assessment in Primary Care

Primary care doctors frequently need to help older patients make decisions in situations where knowing about frailty could, and should, influence medical choices. For example, frailty status changes risk prediction for elective surgery and alters the tolerability of side effects from aggressive cancer treatments.  Interventions to mediate such risks can only be initiated when frailty has been identified. Thus, frailty screening, followed by more comprehensive assessment when appropriate, can provide primary care physicians with important clinical information to optimize the care of older adults.

Consensus statements by both American and international leaders in aging research advocate for broad-based frailty screening in older adults for these reasons (Cesari et al., 2016; Morley et al., 2013; Turner and Clegg, 2014; Walston et al., 2019). However, individual providers seeking to implement screening in their own primary care practice often find it difficult to identify the time and the appropriate tools to measure frailty.  In addition, the limited number of interventional studies that identify effective strategies to mitigate frailty or that demonstrate benefits of frailty assessment for subsequent surgical or medical outcomes may lead care providers to consider the screening to be futile.

Clinics which have successfully implemented frailty assessment into routine, consultative or primary care, such as the Successful Aging and Frailty Evaluation clinic at the University of Chicago (Huisingh-Scheetz et al., 2019) or the Gerontopole Geriatric Frailty Clinic (Tavassoli et al., 2014), provide experience which can offer a framework for incorporating frailty into primary care.

Targeting Screening

Current expert consensus suggests that all adults age ≥70 or experiencing weight loss >5% over a year should be screened for frailty (Morley et al., 2013). This very broad approach facilitates early frailty detection. Relying on an “eyeball” test to trigger screening may identify individuals fairly late in the frailty trajectory when frailty interventions may have less impact. Providers implementing frailty screening to aid in surgical or medical treatment decision making may wish to consider screening early enough to allow frailty reduction strategies prior to the surgical or medical treatment

Choosing a Screening Method

Selecting a frailty screening method depends on the clinical or research goals.  Caution in selection of tools for clinical practice is recommended as agreement between frailty tools vary widely (Aguayo et al., 2017). A overview of screening instruments that can be utilized are provided here.  There are many validated instruments that identify a high-risk subset of older adults so that their subsequent care can be tailored effectively.  For most busy primary care physicians, selection of a quick, highly sensitive screening method may be most practical for implementation. Some assessments can be calculated using largely electronic medical record data, while others are more easily administered over the phone.   Shorter frailty screening instrument options include the FRAIL scale (Morley et al., 2012) and the Edmonton Frail Scale (Rolfson et al., 2006), but many alternatives are available.  After such high-risk frail adults are identified, they could then be referred for more complete physical frailty testing and a comprehensive geriatric assessment, conducted by either a geriatrician or a trained primary care physician.  Those screening positive on a shorter frailty instrument may be referred for a more thorough evaluation of frailty. Deficit accumulation scales with between 30 and 70 items are available, as is the physical frailty assessment instrument. This consists of gait speed (e.g., 4-meter timed walk), grip strength, weight loss calculation, physical activity energy expenditure, and self-reported exhaustion (Fried et al., 2001).

For the practitioner interested in frailty intervention, careful choice of frailty measurement methods is particularly important, because this choice determines the target of intervention. The majority of frailty intervention studies to date have assessed and targeted physical frailty, which can allow for quantified changes in function and targeting of functionality (Puts et al., 2017). Physical frailty is an appropriate endpoint for interventions that manipulate underlying biology and physiology, as it arose from a model of physiological determinants (Fried et al, 2001) having a considerable evidence base (Fried et al, 2009; Szanton et al., 2009) . The Edmonton Frail Scale highlights frailty-related domains such as cognition or medical issues, thus can be helpful in intervention strategy development in addressing and potentially treating such issues after an initial screen.  The Gerontopole Frailty Screening Tool includes measures of mobility difficulties and fatigue, and can be useful if one seeks to identify persons at risk for incident disability (Vellas et al., 2013).

Applying Knowledge of Frailty in Primary Care 

The information provided by a frailty assessment may impact clinical management of older adults in several key ways.

Risk Stratification

The prevalence of frailty is high among older adults seeking consultation for surgery and primary care physicians are often asked to medically clear these patients for procedures (Beckert et al, 2017). Knowing a patient’s frailty status can improve the pre-operative or pre-procedural risk assessment can aid in surgical risk / benefit conversations with patients. It can also support tailored education and counseling to patients and families on peri-operative and post-operative care and recovery expectations. Identifying frailty sufficiently early in the pre-operative period can provide an opportunity for more intense and time-limited frailty mitigation strategies implemented prior to procedures to reduce risk. There is limited experience, but at least one such study has shown promise in the setting of renal transplantation.

Preventative Interventions

Frailty identification should trigger frailty interventions. Such interventions aim to reverse physiologic vulnerability, improve functional status, expand the “health-span,” improve resilience to stressors of all kinds, and reduce the consequences of frailty such as falls. Although more work is needed (Walston et al., 2018), some evidence-based interventions include:

  • Strength training, general exercise, and physical activity
  • Nutrition support to prevent or reverse weight loss and micronutrient deficiencies or to aid in muscle building
  • Reduction of polypharmacy

Furthermore, those with physical frailty often have concomitant social and cognitive deficiencies which can be simultaneously addressed using multidisciplinary teams.

Framing Care Plans

Research has suggested frailty status can help frame overall care planning. For example, more aggressive medical management for chronic medical conditions might be pursued in non-frail patients, or earlier referrals for palliative care and hospice services that help optimize quality of life might be made for patients with advanced frailty (Espinoza and Walston, 2005).

Summary

Frailty assessments are increasingly relevant to the care of older adults in primary practice as care providers seek methods to better identify the most vulnerable subset of older adults.  A wide variety of instruments can be utilized, depending on the purpose in mind, to measure frailty and design potential intervention strategies.