Frailty and Aging in HIV–Status post 13 years of National Awareness

Abstract

People aged 50 years and above comprise over 50% of people living with HIV (PLWH) in the US. Despite the advances made with anti-retroviral therapy in increasing their life span, PLWH are plagued with non-AIDS associated conditions which increase their risk for morbidity and mortality. Frailty, a decline in physical and functional reserve is one of the manifestations of aging, has a prevalence of 5–30%, and occurs up to 2 decades earlier in people aging with HIV (PAWH). The majority of providers for PAWH have minimal experience with the concept of gerontology, frailty, and aging. Hence, there is a gap in clinicians’ knowledge on how to address frailty and aging in PAWH. This review will focus on the clinical interventions that mitigate frailty and aging in PAWH as well as highlight areas of investigation towards achieving these mediations. Beyond the identification of the roles of exercise and nutrition, more studies are needed on the pragmatic approach to apply these resources to routine care. There should be continued reinforcement of the proven strategy of combination antiretroviral therapy as well as treatment of co-infections and age-appropriate health and cancer screening in PAWH.

1. Introduction

On September 18^th 2008, the National HIV/AIDS and Aging Awareness day (NHAAD) was launched by the National AIDS institute to bring the aging-related challenges of HIV management to light. As of 2018, people aged 50 years and above comprised over 50% of people living with HIV (PLWH) in the U.S. [1]. Despite the advances made with anti-retroviral therapy (ART) towards increasing the life span and quality of life of PLWH, people aging with HIV (PAWH) are burdened with non-AIDS associated conditions which increase their risk for morbidity and mortality including cardiovascular, cognitive, and functional deficits which occur at an earlier age compared to those without HIV infection [2]. Although the pathogenesis of the relationship between HIV and these non-AIDS comorbidities has not been fully understood, chronic immune stimulation, ART toxicity, co-infections, and health care disparities in PLWH have been identified as some of the driving factors [3].

Frailty, a decline in physical and functional reserve is one of the manifestations of aging which occurs up to two decades earlier in PAWH, starting around 40 years of age, with a prevalence varying from 5–30%, depending on the tool of measure [4, 5]. This accelerated aging is said to be a result of systemic immune activation in response to the HIV virus which involves a complex interplay of pro-inflammatory cytokines and lymphocyte dysregulation which leads to immunosenescence [6]. This culminates in disability, falls, multi-morbidity, and mortality in PAWH. The earlier occurrence, phenotypic and clinical manifestation of frailty, and other non-AIDS defining comorbidities as a result of HIV-related accelerated aging in PLWH is referred to as premature aging. Hence, PLWH may be biologically older than their chronological age. Several strides have been made with research to understand the pathogenesis and also to determine interventions that mitigate or prevent this accelerated and premature aging in PLWH.

The majority of providers for PAWH have minimal experience with the science of gerontology or the concept of frailty and aging. There remains a gap in clinicians’ knowledge of addressing frailty and aging in PAWH. This review will focus on the clinical interventions that mitigate frailty and aging in PAWH, and areas of investigation towards achieving these mediations. The goal of this review is to provide clinicians taking care of PAWH with implementable strategies that will enable them to provide holistic care to their patients.

2. Methods:

A PubMed search was undertaken on May 7, 2021, to identify English language peer-reviewed articles using the MeSH terms “Frailty” or “Aging” and “HIV”. A free text search was also made for “prevention of frailty in HIV”. A total of 293 articles were found, reviewed for relevance, and included where relevant. There was no year limit for the search. Articles were considered to be relevant if they addressed aging with HIV, frailty, or prevention of frailty in patients infected with HIV. A broader internet search, using the same terms, was also conducted using the Google search engine. The most relevant of the 2,278,000 hits were assessed for accuracy and authenticity (as far as possible) and included as appropriate. Additional articles found to be relevant from the references of the initial articles selected were also included. A total of 99 articles were deemed to be relevant by the authors and included in the paper.

3. Frailty-Definition and components

Frailty is a clinical syndrome in which there is a decline in physical and functional reserve, which creates an enhanced vulnerability to the usual stressors of life that would otherwise not affect the non-frail person, leading to adverse outcomes, such as falls, disability, institutionalization, and death.

The most widely used description of frailty is a frailty-related phenotype (FRP) that is measured by 5 components including 1) weight loss of 10 lb or more over a year; 2) self-reported exhaustion; 3) slow walking speed; 4) weakness as determined by grip strength, and 5) low physical activity. The presence of three or more of these is a diagnosis of frailty, whereas individuals with one or two elements are diagnosed as pre-frail [7]. However, several investigations have shown that the concept of frailty goes beyond a phenotype [8, 9]. Some scholars have adapted the use of multidimensional frailty indices to describe frailty as an accumulation of deficits over time, which eventually leads to disability, falls, hospitalization, institutionalization, and mortality among other adverse outcomes [8, 10]. The varying prevalence of frailty depends on the tool used to describe frailty, with a lower prevalence (~10%) reported by methods using the FRP, versus a higher prevalence (~30%) reported with the FI, which captures some of those categorized as pre-frail by the FRP [11].

Screening for frailty involves the use of frailty assessment tools, most commonly based on the FRP or frailty index (FI),) in order to identify individuals who are frail or at risk for developing frailty as well as individuals who may benefit from a complete geriatric assessment [12]. While the FRP focuses on activity and physical measures with scores that span from robust to, pre-frail to frail, the FI provides a frailty score based on the number of accumulated conditions or deficits as a ratio of the total number of conditions assessed [10, 12]. In the clinical setting, some quick assessment tools have been used, such as the clinical frailty scale (CFS) observed by the physician, which ranges from 1–9, depending on an individual’s fitness and ability to perform activities of independent daily living [13]. The FRAIL score, on the other hand, is based on a patient’s self-reported fatigue, illness, ambulation, and weight loss, and is scored from 0–5 [12]. In each of these tools, 0–1 represents non-frail while the highest numbers represent severe frailty. A diagnosis of frailty is made when the CFS score is ≥ 4 or when the FRAIL score is ≥ 3. Another quick assessment is gait speed measured over 4 meters, where a speed of <0.8m/s is associated with adverse outcomes and <0.2m/s is associated with severe frailty [12]. The identification of individuals at risk for frailty or in their pre-frail state could provide the opportunity to offer interventions that may mitigate its progression or outcomes.

4. Who among PAWH are at the greatest risk of frailty and its complications?

Although frailty occurs in higher proportions in older persons with multiple comorbidities, frailty and its adverse outcomes also occur irrespective of chronological age, multimorbidity and disability. In essence, comorbidity is a risk factor for frailty, while disability is a result of frailty [7]. In PLWH, CD4 count <200, history of AIDS-defining illness, low albumin, elevated D-dimer, hepatitis C co-infection, injection drug use (IDU), depression, smoking, unemployment, and low income are some of the factors associated with frailty (Figure 1) [5, 14–17]. Middle-aged and older women with HIV may also be at increased risk of frailty, compared to younger women or men across ages, which may be a result of the increased impact of lifestyle stressors and comorbidities in women compared to men [5, 18–20]. In addition, pre-frail (defined as those who have 1–2 of the FRP) PLWH, share some of the risk factors as PLWH with frailty and present an important patient population to address ways to intercept and alleviate frailty [7, 16].

Figure 1.

Frailty schematic showing HIV and other contributing factors.

Abbreviations: HCV, hepatitis C virus; IDU, injection drug use

5. Interventions:

The identification of the risks predisposing to frailty has led to the fundamental mission to determine ways to mitigate or prevent frailty and its adverse outcomes in PAWH (Table 1). Although some of these factors appear to be modifiable, there is still insufficient data to prove that some interventions, for instance, smoking cessation, treatment of co-infections, nutrition support, or drugs that counter systemic inflammation and immunosenescence slow down the occurrence of frailty in PAWH.

Table 1:

Contributors to Frailty in HIV and their Mitigation

Condition	Mitigation
HIV disease and progression	1. Early initiation of ART
Multimorbidity	1. Cardiovascular disease-Yearly BP, ASCVD score determination, statin, and aspirin therapy if indicated. 2. Fasting blood glucose, every year 3. Lipid panel every year 4. eGFR and spot urine creatinine yearly 5. Hepatic function panel yearly 6. Mammogram, Pap smear, Anal Pap smear, low radiation CT thorax yearly, and colonoscopy 1 7. Smoking cessation
Mood disorders and Mental Health	1. GAD-7 and PHQ-9 at every visit 2. OUD treatment 3. Psychosocial support
SDOH adverse outcomes-Missed appointments, non-adherence, and lack of durable viral suppression	1. Measures to address poverty, unemployment, housing, and food insecurity. 2. Provide access to healthcare, including transportation. 3. Psychosocial support and education to address stigma.
Polypharmacy	1. Medication review at every visit and medication reconciliation annually 2. Deprescribing
Cognitive decline	1. Early initiation of cART 2. Multidimensional measures that improve cognitive reserve e.g., leisure activities, physical activity, literacy, 3. Cognitive behavioral rehabilitation
Sarcopenia, falls, and disability	1. Identify pre-frail and frail individuals using the FRIED phenotype or frailty index 2. Multicomponent exercises for at least 30–45 minutes, 3 times/week, preferably in group settings. 3. Protein supplementation 4. Diet rich in fruits and vegetables
Nutrition	1. Emphasis on energy, protein, fruits and vegetables intake.
Low BMD, Osteoporosis, Fractures	1. FRAX in men 40–49 and premenopausal women≥40 2. DXA in men ≥50 and post-menopausal women 3. Replace calcium, phosphate, and Vitamin D if low. 4. Alcohol and cigarette cessation counseling 5. Yearly height measurement 6. Exercise and physical activity
HCV and/or HBV Co-infection	1. Treat co-infection 2. Liver ultrasound with or without AFP for those with cirrhosis every 6 months

Abbreviations: ART, antiretroviral therapy; BP, blood pressure; ASCVD, atherosclerotic cardiovascular disease; eGFR, estimated glomerular filtration rate; GAD, general anxiety disorder; PHQ, patient health questionnaire; OUD, opioid use disorder; SDOH, social determinants of health; cART, combination antiretroviral therapy; BMD, bone mineral density; FRAX, fracture risk assessment tool; DXA, dual X-ray absorptiometry; HCV, hepatitis C virus; HBV, hepatitis B virus.

5.1. Early initiation of antiretroviral therapy:

The most consistent evidence-based factor that mitigates HIV latency and immune activation with resultant reduction in systemic inflammation, is the initiation of ART during the acute phase of HIV infection [21–23]. Early introduction of ART results in reduced destruction of CD4+ T cells and preservation of gut lymphoid homeostasis which in turn reduces microbial translocation and systemic inflammation [24, 25]. Although this may not seem to be helpful in PAWH since a majority acquired HIV in their earlier years, people above the age of 50 still comprise a substantial percentage (17% in 2018) of new HIV diagnoses. [1]. Therefore, it is important that providers adhere to the Centers for Disease Control and Prevention (CDC) guidelines to test everyone 13–64 years of age for HIV infection as part of routine health care [26]. This will improve the chances of early diagnosis and early initiation of therapy. In addition, starting ART early (when CD4+ count is >500) is associated with fewer AIDS and non-AIDS associated complications including malignancies, tuberculosis, and other bacterial infections which contribute to frailty and mortality [27, 28].

The limitation of ART, however, is that systemic inflammation, morbidity, and mortality from HIV infection are not eradicated even in patients with viral suppression. Studies of ART intensification with integrase strand inhibitors like raltegravir were unsuccessful in eliminating residual HIV viral replication as determined by an increase in the level of two long terminal repeat (2-LTR) circles and HIV1-DNA. Also, this approach was not associated with any significant change in the markers of T-cell activation, though d-dimer levels were reduced in one study [29, 30]. The use of maraviroc, a CCR5 inhibitor for intensification also did not result in any significant decrease in HIV residual viremia [31, 32]. Hence, besides the prospects of initiating ART early, there have been no additional therapeutic interventions of benefit against the HIV and its milieu of systemic inflammation.

5.2. Treatment of co-infections

Due to shared routes of transmission, up to a third of PLWH in the U.S. are co-infected with hepatitis C (HCV), which leads to a faster progression of HCV to cirrhosis and mortality, despite combination antiretroviral therapy (cART) [33–35]. HIV/HCV co-infection heightens early T-cell immune-senescence in injection drug users as determined by reduced T-cell telomere length [36]. This multidimensional impact on frailty in this population warrants the need to treat both viruses early in co-infected PAWH. Similarly, a substantial 6–10% of PLWH are also co-infected with hepatitis B (HBV) in the US, with up to 20% affected globally resulting in worse outcomes in liver disease and mortality, despite the increased and early introduction of HBV-active cART in these patients [37]. The availability of the direct-acting antiviral agents for HCV and the nucleoside reverse transcriptase inhibitors with potent activity against HBV have simplified the treatment of these viruses during routine HIV care. However, liver disease continues to progress in 10–20% of co-infected patients with HBV despite being treated with tenofovir-containing HBV-active regimens [37]. HCV co-infection has been associated with frailty in some PLWH cohorts, but HBV has not been consistently shown to have the same effect [16, 38]. However, the fact that both these hepatitis viruses can accelerate the progression to cirrhosis, hepatocellular carcinoma (HCC), and death in PLWH represents a potential frailty threat that can be avoided by recognizing and treating these co-infections promptly. Surveillance ultrasound monitoring for HCC should be continued in HCV and HBV co-infected PAWH, especially in those with cirrhosis [39].

5.3. Other therapeutics

Studies have looked at drugs that counter systemic inflammation, immunosenescence, and aging, but the majority of this work is still investigational and none of the findings have impacted policies or treatment guidelines. For instance, the use of statins with ART was associated with a lower occurrence of non-AIDS cancers, Hodgkin’s lymphoma, and mortality but these findings have not been replicated [40]. Another study with statins resulted in reduced number of activated T cells without any effect on HIV viral load [41]. These results, if validated, may provide the rationale to recommend the use of statins in PAWH with low or borderline-risk ASCVD scores who ordinarily would not qualify for the use of statins for primary prevention of cardiovascular disease [42].

HIV infection damages the intestinal mucosa and gut microbiome resulting in bacterial translocation, immune activation, and chronic inflammation [43, 44]. Several studies have shown promising results with the administration of probiotics in humans in an attempt to preserve the gut microbiome and immune homeostasis thereby reducing leaky gut syndrome and microbial translocation. Some studies are evaluating the applicability of fecal transplant for this same goal [43, 44]. However, further research is needed to identify if these are interventions that are feasible and beneficial to mitigate frailty and aging by reducing chronic inflammation.

Homeostatic biomarkers like IL-7, administered to lymphopenic HIV-infected adults on ART resulted in a dose-dependent increase in naïve and memory CD4+ and CD8+ T cell numbers and function [45, 46]. Although this suggests a possible path to immunotherapy and adjunct to ART in HIV-infected patients, another study showed that IL-7 therapy promotes viral persistence by increasing the number of latently infected T-cells in the blood circulation [47]. Investigators are still looking at the prospect of reducing the CD4+ HIV-infected T-cell reservoir by blocking IL-7 and IL-7 receptor signaling [48]. The use of senolytic agents that selectively destroy senescent cells by inducing apoptosis in animal studies mitigated premature aging and rejuvenated muscle stem cells [49]. By reducing the cascade of inflammation promoted by these senescent cells, these agents could be instrumental in mitigating frailty and other phenotypes of aging in people with HIV and other chronic diseases.

5.4. Multimorbidity

HIV and aging are both associated with multimorbidity. Characterized by the presence of two or more chronic conditions in an individual, multimorbidity is associated with frailty, polypharmacy, socio-economic deprivation, and adverse outcomes in adults without HIV [50]. The prevalence of multimorbidity in PLWH is ~22–25% which increased by 60% between 2000–2009 in a large North American population study even after adjusting for age, with a less robust increase of 10% demonstrated in a smaller study within the last decade [51–53]. The multimorbid conditions that are often studied in PLWH are hypertension, type 2 diabetes, hypercholesterolemia, chronic kidney disease, end-stage renal disease, and non-AIDS associated cancer. Others include cardiovascular diseases, cognitive impairment, depression, anxiety, falls, and liver cirrhosis. The challenge with the management of multimorbidity is the paucity of guidelines for the management of patients with multiple comorbidities compared to those for individual conditions. A system-based, multidisciplinary approach with effective communication among providers and the implementation of several patient safety checkpoints will be a minimum requirement to combat multimorbidity and its associated complications.

5.4.1. Screening and Health Maintenance

From a PAWH provider perspective, effective screening for these chronic medical conditions and health maintenance becomes a very useful and proactive way to prevent and mitigate aging. The practical approach is to follow guidelines for age-matched non-HIV infected individuals where data specific for PLWH is insufficient. The first randomized study on the use of statin for primary prevention of cardiovascular disease in PLWH (REPRIEVE) is still ongoing [42]. The determination of atherosclerotic cardiovascular disease (ASCVD) scores would help determine a patient’s risk for cardiovascular disease and need for statin therapy for primary prevention. Tobacco use should be assessed at every visit with an implementable plan to advise and assist patients to quit. Screening for hypertension, diabetes, hypercholesterolemia, and liver disease yearly and renal dysfunction at least twice a year is routinely performed in PAWH and are endorsed by society guidelines [54, 55]. Age-appropriate cancer screening should also be implemented with systems and reminders in place, particularly for patients who are not compliant with office visits. Judicious medication reconciliation and deprescribing are paramount in the systemic approach to managing PAWH with the expertise of HIV-specialized pharmacists.

5.4.2. Polypharmacy

Polypharmacy is the use of multiple medications (generally classified as taking 5 or more medications) that may increase drug-drug interactions or severe adverse outcomes [56]. It is associated with multimorbidity and is a burden in PLWH and PAWH. Polypharmacy begins at least one decade earlier in PLWH than their non-HIV-infected counterparts, with a prevalence of 48–55% in those ≥50 years of age. [57, 58]. This is because as people age with HIV, their need for non-ART medications increases, such that potentially problematic polypharmacy in PAWH may be better defined as taking 5 or more medications that are not ART. The complications that arise from polypharmacy in PLWH result from a combination of high pill burden, non-compliance with ART and progression of HIV disease, adverse drug effects, drug-drug interactions, medication administration errors, and mental health stress and deterioration, among others, all of which contribute to frailty. Furthermore, the chronic inflammation of HIV and the direct effect of HIV on organs make PAWH even more susceptible to the complications of polypharmacy [57]. In addition to frailty, falls and cognitive decline, polypharmacy is also associated with an increased risk of hospitalization and mortality in this population [59, 60].

The management of polypharmacy is a challenge in PLWH. Pharmacovigilance is an essential component of clinical care for PLWH which should emphasize and prioritize medication review at every opportunity a patient comes in contact with the healthcare provider and medication reconciliation should be conducted annually. However, there is limited and conflicting data on if these interventions provide significant reduction of polypharmacy and its adverse outcomes [61]. Nonetheless, practical approaches include the establishment of an accurate medication list for every patient, discontinuing unnecessary medications (deprescribing), consolidating ART by taking advantage of single pill combination regimens, use of only one pharmacy per patient, if possible, aan HIV specialist pharmacy with an integrated network with patient’s providers, and adjustment of patient’s medication for kidney and hepatic function [62]. A clinical HIV pharmacist provides excellent expertise to the multidisciplinary approach needed to manage polypharmacy in PAWH. Validated instruments such as the Beers criteria and the STOPP/START (Screening Tool of Older Person’s Prescriptions/Screening Tool to Alert to Right Treatment) are useful to reduce inappropriate prescribing in the elderly [63, 64]. While the Beer’s criteria address medications to avoid in the elderly such as benzodiazepines, STOP addresses inappropriate condition-medication combinations. Finally, START focuses on medications that may have benefit but are under-prescribed. Due to the complexities in the care of PLWH, polypharmacy is difficulty to navigate successfully but doing so, could impact frailty in these individuals.

5.4.3. Mental Health

Mood disorders including suicidal ideation and anxiety remain a substantial problem in PLWH and PAWH despite ART, with an excess burden of depression that is up to 3 times that in non-HIV infected individuals [65–67]. Substance use disorders including opioids, alcohol, tobacco, and methamphetamines, either current or past use are common in PAWH, compared to their non-HIV infected peers [68]. Mental health services should be readily available for patients, with a system in place to integrate these into routine patient care. Anxiety disorder and depression screening at every visit using validated measures, such as the General Anxiety Disorder-7 questionnaire (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) should be implemented. Substance use counseling and treatment services should also be provided. These will help identify and mitigate the impact of these conditions in HIV management outcomes and social determinants of health including poor adherence, disease progression, homelessness, poor quality of life, access to health care, and mortality [67].

5.4.4. Social Determinants of Health (SDOH)

HIV outcomes are influenced by SDOH. According to the CDC, SDOH refers to the condition of the environment where people live, learn, worship, play, and work and how these affect a wide range of their health risks and quality of life outcomes. PLWH who are 50 years are disproportionately people of color (39% non-Hispanic blacks and 18% Hispanics), male (over 77%), sexual minorities, and over 50% live in poverty with low levels of employment and unstable housing [68]. A large population-based US study revealed that over 80% of PLWH had at least one unfavorable indicator of SDOH, the commonest of which was poverty (43%). Other common indicators seen were intimate partner violence, food insecurity, and need for transportation. This study showed a cumulative increase in the risk of adverse outcomes including missed appointments, non-adherence to ART, and inability to achieve durable viral suppression as the number of SDOH indicators increased. These adverse outcomes were more associated with PLWH who identified as being black or Hispanic [69].

The concentration of HIV in poor and socially disenfranchised minority US populations and these resultant adverse outcomes contribute to multimorbidity and frailty in PAWH [15, 70, 71]. HIV-associated stigma is another SDOH factor that limits access of PLWH to healthcare [68, 72]. PAWH may suffer stigma not only from HIV infection but also the stigma of accelerated aging [68]. This increases the risk of social isolation, mental stress, loneliness, and depression all of which also impact multimorbidity and frailty. Therefore, interventions that address these social and structural disparities and their associated stigma will be necessary to reduce frailty in PAWH [68, 72].

5.4.5. Geographic variations in Multimorbidity and Mortality

Since approximately 70% of the world’s HIV-infected population reside in sub-Saharan Africa, it would be important to understand their SDOH and how these affect access to healthcare, morbidity, and mortality compared to the US [73]. In US PLWH, despite the advances in ART and increase in life span, a recent study showed a substantial burden of years of comorbidities (a gap of 15 years) compared to those without HIV, with a smaller difference ~9 years, in those who started ART at CD4 ≥500/ul [74]. Cardiovascular disease (CVD) is one of the major comorbidities implicated, such that in the US and Europe, HIV has been considered a risk factor for CVD and its complications including myocardial infarction, heart failure, and death [75, 76]. US studies have also shown faster atherosclerosis progression measured by carotid intima thickness in PLWH [77].

In comparison, recent studies in Sub-Saharan Africa have shown that atherosclerosis progression, measured by carotid intima thickness over time was not associated with HIV infection in PLWH who were virally suppressed [76, 78]. In contrast to PLWH in the US, those in Sub-Saharan Africa appear to have more access to primary care as part of their HIV care, such that compared to those without HIV in the same location, they had lower blood pressure and fewer smokers [76, 78]. Although HIV-related mortality decreased about 48% in 2020 compared to 2010, 67% (460,000) of people who died from HIV in 2020 reside in Africa [79]. Hence, there needs to be continued vigilance and interventions to prevent HIV-associated morbidity and mortality in this population.

5.5. HIV and Cognitive decline

Cognitive impairment has been identified as a major contributor to frailty and frailty-associated disability [80–82]. The systemic inflammation due to HIV causes accelerated aging, resulting in neuroinflammation which in turn leads to neuronal death. Unfortunately, this neuroinflammation persists despite antiretroviral therapy and causes advanced brain aging in PLWH [83, 84]. The prevalence of HIV Associated Neurocognitive Disorders (HAND) remains as high as 50% in US HIV populations of median age ~40 and over 40% globally [85, 86]. CD4 nadir <200 cells/mm³, detectable HIV viral load, and duration of HIV infection >10 years are some of the risk factors for HAND [85–87]. Although HIV-associated dementia has significantly reduced from pre-cART level of 10–20% to about 2%, mild neurocognitive disorder (MND) in executive function, memory and learning remains common among PLWH and is more prevalent in PAWH [88–90]. While the diagnosis of neurocognitive impairment in HIV has not been fully optimized, it relies on the use of standardized neuropsychological tests [91]. One such test, the Montreal cognitive assessment (MoCA), is a 30-point standardized rapid screening test that measures visuospatial skills plus executive function, memory, language, abstract thinking, calculation, attention, concentration, and orientation and has been used to identify MND in HIV patients [92, 93]. Early initiation of cART may mitigate the development of HAND given its consistent association with a low CD4 nadir [86, 89].

Interventions that optimize cognitive reserve have been shown to mitigate HIV-associated cognitive decline [94]. Cognitive reserve is the innate and acquired brain feature that enables one brain to continue to function well despite certain brain damage or degeneration, compared to another brain whose function declines significantly with similar exposures [95]. Computerized cognitive rehabilitation therapy using culturally adapted video game training sessions was found to be efficacious in improving immediate recall, working memory, verbal fluency, and timed gait among PLWH 50 years and older [96]. Adaptive cognitive working memory training (Cogmed) also improved working memory in older PLWH [97]. For the HIV provider, among other interventions, enhancing cognitive reserve will involve a multidimensional approach that includes advocating for literacy, physical activity, cognitively stimulating leisure activities, adequate nutrition and sleep, self-care, management of comorbidities, and reduction of stress in their PAWH.

Hence, interventions to mitigate frailty must take cognitive impairment into account due to its association with frailty in PLWH.

5.6. Exercise

Four of the five FRP components involve physical ability and activity. Hence, a process that enhances cardiorespiratory performance and physical endurance will diminish frailty. In the general population, physical exercise is associated with improved cardiovascular, metabolic, and mental health [98, 99]. It has also been shown to reduce mortality and the risk of conditions like stroke, diabetes, and cancer which are associated with aging in HIV [98, 100]. Recent studies of PLWH ≥50 years of age demonstrated that moderate to high-intensity aerobic exercise increased endurance and walking distance, while high-intensity exercise increased cardiorespiratory fitness [101, 102]. Progressive resistive exercise also appears to be safe in PLWH and improves depressive symptoms [103]. The success of exercise as an intervention in frailty requires consistency, and the type, optimal duration, and frequency is yet to be determined as studies have used durations ranging 4 to 16 weeks [103, 104]. However, multi-component exercises comprising resistance, aerobic, balance, and flexibility, performed 3–4 times per week, lasting 30–45 minutes per session, for at least 5 months, improved or delayed frailty with respect to muscle strength, gait speed and physical performance in frail and prefrail individuals [105, 106]. Evidence suggests that these interventions are more successful when conducted in group settings than in individual or one-on-one basis [107]. However, there need to be more exercise studies among women and PAWH to determine the generalizability of these findings.

5.7. Sarcopenia and Nutrition

Sarcopenia, a determinant of frailty, is at the forefront of the causes of falls and disability in aging, with a prevalence of 10% in adults ≥60 years of age [108, 109]. However, in PLWH ≥50 years of age, sarcopenia has a prevalence as high as 25% and appears to be more prevalent and progresses faster in women than men [110, 111]. Although there is still a debate on the appropriate definition of sarcopenia, it is characterized by the loss of muscle mass and strength, assessed by grip strength and mobility disability-gait speed less than 0.8 m/s over 4–6m. [112]. Therefore, interventions, including exercise and nutrition, targeting the attenuation and alleviation of sarcopenia are a priority in PAWH. Data suggest that when multicomponent exercise is combined with protein supplementation in the form of amino acids, sarcopenia is improved to a greater extent than exercise alone [113, 114].

Since nutrition is a major contributor to sarcopenia and frailty and is a modifiable factor, it is an important target for interventions that diminish or abate frailty. Food insecurity and low protein intake are more common in frail PLWH than in their non-frail counterparts [115]. This is a problem in marginalized populations to which a majority of PAWH belong [116, 117]. Some studies have evaluated nutrition in PLWH with albumin levels and BMI. One study found that 25% of PLWH ≥75 years of age were nutritionally deficient [19]. Other assessments of nutrition have depended on self-reported diet intake recall, with emphasis on protein and energy [115, 116]. The Healthy Eating Index score, which assesses how well the diet quality aligns with the dietary guidelines for Americans was used in a large US study to determine that people who met dietary guidelines for intake of proteins, whole grains, vegetables, or whole fruits had 20–30% lower odds of having a low grip strength than those who did not [118]. A diet of fruits and vegetables was also associated with a lower risk of sarcopenia among older adults in a large Korean study [119]. There are still several questions in this area with respect to defining adequate versus poor nutrition, validation of its measurement by way of reproducibility of results, and how best to replenish nutritionally deficient PAWH. Studies of protein supplementation in PAWH are needed to determine if nutrition can change sarcopenia status.

5.8. Bone Disease

Osteoporosis and fractures are more prevalent among PLWH and occur at a younger age compared to their HIV-uninfected counterparts [120, 121]. This is attributed to chronic inflammation due to HIV, ART, dietary, and nutritional deficiencies including calcium and vitamin D [122]. A low muscle mass has also been shown to be associated with osteoporosis in older PLWH [123]. Fracture rates are 30–70% higher in PLWH than among matched controls [122]. A fracture risk assessment tool (FRAX) specific to a particular geographic region is recommended in HIV-infected men 40–49 years of age and pre-menopausal women ≥40 to assess their 10-year risk of developing a fragility fracture. Dual Energy Absorptiometry (DXA) is recommended in men ≥50 and post-menopausal women, those with prior fragility fractures, on chronic steroid treatment (≥5mg prednisone or its equivalent for >3 months), and at high risk for falls. Yearly height measurements with vertebral plain radiographs when there is a height loss of at least 2cm is useful to diagnose silent vertebral fractures [124, 125]. Dietary supplementation and replacement of calcium, phosphate, and vitamin D are recommended in those patients with inadequate levels and treatment with bisphosphonates in those with osteoporosis, fragility fractures, and high FRAX scores (≥20%) [122, 126, 127]. The use of testosterone among older HIV-infected men was associated with higher bone mineral density scores as measured by DXA [128]. More studies are needed to determine if this is a feasible approach in PAWH.

6. Conclusion

Although several strides have been made in the identification and impact of frailty in PLWH, knowledge gaps remain on various aspects of frailty management in this rapidly growing patient population. For instance, how often frailty should be assessed, the rate of its progression, and what efficient, practical measure/s that could be easily applied during routine care remain uncertain. In addition, viable ways to mitigate aging from an intervention perspective still require further study. Beyond the identification of the roles of exercise and nutrition, more studies are needed on the pragmatic way to apply these resources to routine care. This should be as basic as a “prescription” suitable for each particular patient’s deficiency or need for a certain exercise strategy and/or nutrition. Hence, multidisciplinary collaboration is the most effective way to success in the care for our PAWH. There should be continued reinforcement of the proven strategy of cART which has given our patients the ability to age with HIV, treatment of co-infections as well as age-appropriate health and cancer screening.

PAWH are at high risk for frailty and its complications. In addition to the interventions recommended to the patients by their providers during clinical encounters, these patients should also be educated and made aware of their risk for frailty and its consequences. Furthermore, they should be provided the resources they need to combat and abate frailty, especially those which they can safely apply on their own.