Frailty and prefrailty in people living with HIV,with focus on women living with HIV

Abstract

With the increasing lifespan of people living with HIV (PLWH), frailty and prefrailty are becoming topics which require more attention. The reciprocal interactions between chronic inflammation, comorbidities and frailty demonstrate the complex pathophysiology of frailty and its consequences. Female sex, HIV infection without antiretroviral treatment, reduced CD4 cell count, depression and cardiovascular disease are some of the risk factors for frailty among PLWH. Frailty predisposes to falls and can therefore lead to more frequent fractures, hospitalization and death, especially in women with osteoporosis. Continuous antiretroviral treatment, prevention of comorbidities such as depression and diagnosis of prefrailty are crucial interventions to slow the development of frailty. This review summarizes the literature on frailty in people living with HIV and discusses frailty management strategies in order to improve the health outcomes in women living with HIV.

Keywords

frailty people living with HIV women living with HIV chronic inflammation comorbidities

Background

Antiretroviral therapy (ART) has increased the life expectancy of people living with HIV (PLWH). It is estimated that by 2030 approximately 70% of PLWH in developed countries will be over the age of 50 years. The ageing population of patients with HIV requires a multidisciplinary approach to manage frailty and prefrailty.¹

Frailty is an age-related state of decreased homeostatic reserve resulting in increased vulnerability to endogenous and exogenous stressors which negatively affects quality of life and leads to falls, cognitive decline, disability, increased hospitalization rate and increased mortality. Frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty.^2,3

Ageing causes numerous changes in the immune system. Impaired elimination of damaged cells, increased concentration of cytokines, increased permeability of the intestines and microbial translocation all contribute to dysregulated inflammation and frailty.⁴ Chronic inflammation, which plays a central role in the pathophysiology of frailty, is defined by elevated levels of inflammatory cytokines (CRP, IL-6, TNF-α and CXCL-10) and an increased number of CCR5+ T cells.^5,6 Age-related decrease in insulin-like growth factor-1 (IGF-1) and haemoglobin, as well as changes in cortisol level, can also contribute to frailty.⁷

Frailty is defined as a clinical syndrome in which at least three of the following criteria are met (according to the Fried Frailty Phenotype, FFP): unintentional weight loss (at least 4.5 kg or ≥5% of body weight in the past year), self-reported exhaustion (positive response to questions regarding effort required for activity), weakness (grip strength assessed by a mean of three consecutive measurements of the dominant hand using a handheld dynamometer), slow walking speed (measured by the distance covered when walking for 4 min at usual pace) and low physical activity (assessed by the Minnesota Leisure physical activity questionnaire). Prefrailty (intermediate frailty status) is defined by meeting at least one, but fewer than three of these criteria.⁸

Studies have explored biochemical and immune parameters such as cytokines (IL-6, IFN-γ, TNF-α, IL-1β and RBP4) and cell free mitochondrial DNA as potential biomarkers of frailty, but further studies are needed to assess the clinical significance of these biomarkers and currently none are recommended for routine diagnosis of frailty.⁹

It is estimated that the overall prevalence of frailty and its 4-year incidence in people who are 65 years and older are 6.9% and 7.2%, respectively. Some studies have demonstrated that frailty is associated with ethnicity (more frequent in African American), low education status, low income, and multi-morbidity. Both frailty and depression affect older people and both syndromes can overlap. Studies show that the prevalence of depression in frail patients ranges from 20.7% to 53.8%.^10,11 Many studies show the reciprocal relationship between depression and frailty with depression increasing the odds of frailty and frailty predicting new-onset depression.¹²

Frailty is independently predictive (over 3 years) of falls, worsening mobility, disability in activities in daily living (ADL), hospitalization and death. Prefrailty is an intermediate risk factor for these outcomes and is a risk factor for becoming frail over a 3–4 years period.⁸

Frailty in PLWH

Studies show that frailty and prefrailty appear more often and at an earlier age in people living with HIV than in the general population and can reach up to 28.6% and 47.2% respectively.^8,13-15 This can be explained by several factors including the persistent chronic inflammation caused by HIV, other HIV-related factors such as low CD4 cell count, higher rates of comorbidities (eg. cardiovascular, metabolic, osteoporosis) than in the general population, as well as higher rates of smoking and intravenous drug use (IDU) among PLWH.^16-18

HIV infection causes chronic inflammation and immune activation, which is persistent at low levels even on antiretroviral treatment. The mechanisms driving the chronic inflammation in HIV include damage to the gut epithelium, microbial translocation, activation of toll-like receptors and co-infection with CMV. Comorbidities can be both the cause and the consequence of the chronic inflammation. Studies show that chronic inflammation predisposes to comorbidities, and comorbidities increase chronic inflammation.¹⁹

In a study by Serrao et al. the mean number of non-AIDS-related comorbidities (NARC) in a population of patients with HIV with a mean age of 59.3 years was 2.1 and 34.7% of patients had three or more NARC of which hypercholesterolemia, hypertension and depression/anxiety were the most common ones.²⁰ Treating each comorbidity might lead to polypharmacy, and polypharmacy has also been associated with frailty.²¹

The presentation of frailty in people living with HIV can be heterogenous depending on the additional comorbidities and the risk of frailty increases with severity of metabolic syndrome.²¹ A large longitudinal study showed that higher cardiovascular risk assessed by the Pooled Cohort Equations was associated with increased frailty both in men and women with and without HIV.²² On the other hand, another study showed that frailty was associated with an increased risk of cardiovascular disease and diabetes mellitus in a population of aging people living with HIV.²³ This bidirectional relationship between chronic disease and frailty was also shown in the context of depression, yet most studies regarding this topic were conducted on populations without HIV.^24,25 The mechanism of how depression increases the risk of frailty is not fully known but both depression and frailty are associated with other clinical and psychosocial factors.²⁶ People living with HIV have a 3–5 times higher prevalence of depression than the general population and thus should be screened for depression on a regular basis.²⁷

Depression often leads to discontinuation of antiretroviral treatment and detectable HIV-1 RNA and not being on antiretroviral treatment increase the risk of frailty.^28-30 Although the overall protective effect of ART on the risk of AIDS and mortality must be emphasized, some side effects of antiretroviral drugs are risk factors for frailty in PLWH. Reduction in bone mineral density has been reported with the use of ART, particularly tenofovir disoproxil (TDF), efavirenz (EFV) and protease inhibitors (PIs), especially in association with hormonal disturbances and malnutrition. PLWH have an increased risk of fracture and this risk increases about 10 years earlier compared to people without HIV. This might be the cumulative effect of HIV influence on bone cells, the effect of ART, gut microbial dysbiosis and classical risk factors.³¹ Furthermore, association between frailty and PIs has been demonstrated.²⁹

Although the European AIDS Clinical Society (EACS) recommends screening PLWH who are 50 or older for frailty using the frailty phenotype (FP) or frailty index (FI), there is no clear consensus regarding the optimal diagnostic tool for diagnosing frailty in PLWH.^2,27 Recently McMillan et al. showed a concordance of results between the Clinical Frailty Scale (CSF), a nine-point judgement-based scale, and FP and recommended using the CSF because of its ease to use.²¹ But the CSF needs to be validated in people over 50 years, as for now it is only validated for those over 65 and screening for frailty of PLWH should start at the age of 50.^2,27

Frailty in women living with HIV

The anatomical differences between men and women result in some differences in the measurement of frailty between men and women, which include various time span describing low physical activity according to sex (<2.5 h/week for men; <2 h/week for women), different walk speed time cut-offs according to sex and height, and different maximum grip strength cut-offs according to sex and BMI.⁸

Sex-related differences in the HIV-pathogenesis and immune activation, higher prevalence of some comorbidities (eg. obesity, metabolic syndrome, depression and osteoporosis) in women than in men and lower levels of adherence to ART are factors causing women living with HIV (WLWH) to have a higher risk of becoming frail than men with HIV (MWH).²

Studies show that at baseline WLWH have a lower viral load and lower levels of markers of immune activation such as CRP, LPS, sCD14 than men with HIV, whereas on antiretroviral treatment they have less reduction in key markers of inflammation and immune activation. With the same viral load women have a 1.6-times higher risk of progression to AIDS than men.³² A study by Alvarez et al. showed higher plasma levels of sCD14 in frail people with HIV than in non-frail patients, but there was no comparison done between men and women and the study group was small (45 patients, of which 9 were women).³³

An association between female gender and metabolic syndrome and raised body mass index has been shown in several studies.^34,35 Weight gain in WLWH is a multifactorial phenomenon with contributory factors including genetics, social inequalities and some antiretroviral agents. Some studies show a positive correlation between obesity and frailty, yet other studies show the opposite.^36,37 Even though a U-shape relationship between BMI and FFP has not been shown yet in women living with HIV, FFP at middle age among WLWH was predictive of 8-years mortality based on evaluation of physical frailty, metabolic health and mental health.³⁸

Studies show that women living with HIV of black African and other black ethnicities have higher odds of being obese than white WLWH.³⁹ Ethnicity is also an important factor for cardiovascular risk assessment and in the study by Kuniholm et al. the high 10-years CVD risk assessed by the pooled cohort equation showed a positive association with frailty, whereas the high coronary heart disease risk defined by Framigham score, which does not include race, did not associate with frailty.²²

Furthermore, women with HIV are at higher risk of developing depression than men, and it has been demonstrated that depression increases the risk of frailty.⁴⁰ This should also be kept in mind while choosing the ART regimens as some eg. dolutegravir (DTG), and bictegravir (BIC) increase the risk of neuropsychiatric disorders and can lead to ART discontinuation, especially when simultaneous treatment with abacavir is prescribed.^41,42 Diagnosing depression among WLWH could also improve predicting mortality, as shown in a study by Cohen et al. where adding depression and transactional sex to the Veterans Aging Cohort Study (VACS) Index analysis improved the prediction of mortality of WLWH.⁴³

Suboptimal adherence to ART has been shown to be greater in women living with HIV (WLWH) than men, especially after pregnancies or during menopause.⁴⁴ Studies show that WLWH may have menopause at an earlier age compared to the general population, which puts them at a higher risk of osteoporosis and fractures.^45,46 Frailty predisposes to falls and thus to fractures, and women have a two- to 3-fold higher fracture incidence than men.^47,48 In a prospective longitudinal cohort study by Sharma et al., frailty was a strong and independent predictor of fracture risk.⁴⁹

Possible interventions

Both prefrailty and frailty can be postponed and potentially reversed through several interventions such as management of comorbidities (including depression), avoiding polypharmacy, increased physical activity, nutritional interventions, smoking cessation, and, in the case of PLWH, successful HIV treatment.⁵⁰

The EACS guidelines recommend to screen HIV patients for depression every 1–2 years. Since women are at higher risk of developing depression then men, healthcare providers should consider screening WLWH more frequently. Since depression can be either a risk factor of frailty or its consequence, treating depression is an essential element of postponing the development of frailty and/or part of management of frailty. As menopause might appear earlier in WLWH than in the general population, and women with HIV have a lower bone mineral density than women without HIV, screening for menopause and osteoporosis and administration of hormonal replacement therapy and treatment of osteoporosis are crucial elements of frailty management for WLWH.

High C-reactive protein levels have been shown to be predictive of frailty among women without HIV, research is needed to prove whether monitoring markers of inflammation could predict incidence of frailty among women living with HIV.⁵¹ Also, further investigations are needed to assess whether anti-inflammatory therapies and CMV-specific therapies might decrease the chronic inflammation which predisposes to frailty. The influence of pre/probiotics on microbial translocation and frailty also needs further assessment.

With ART having a protective effect on frailty, adherence to ART and regular follow-ups are key elements to slowing down the appearance of frailty in PLWH. An individualized, multidisciplinary approach to each patient should be promoted (using the comprehensive geriatric assessment, CGA is recommended) More data about frailty in PLWH and WLWH is needed.

Conclusions

Frailty is an important geriatric syndrome which is more prevalent in women living with HIV. It can negatively impact the quality of life of PLWH by increasing the risk of hospitalization and mortality and thus more attention should be paid to frailty prevention. Management of PLWH requires regular screening for frailty and prefrailty, and treatment and prevention of comorbidities such as cardiovascular disease, depression and osteoporosis. The role of ART in the prevention and inhibition of the progression of frailty is undeniable.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Dagny C Krankowska

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