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The association between physical frailty and injurious falls and all-cause mortality as negative health outcomes in people living with HIV: A systematic review and meta-analysis

  • Qionggui Zhou
    Affiliations
    Department of Epidemiology, School of Public Health and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China

    Yi-Wu Research Institute, Fudan University, Shanghai, China
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  • Jiayu He
    Affiliations
    Department of Epidemiology, School of Public Health and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
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  • Xuan Yang
    Affiliations
    Department of Epidemiology, School of Public Health and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
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  • Hao Yin
    Affiliations
    Department of Epidemiology, School of Public Health and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
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  • Zhiyi Zhang
    Affiliations
    Department of Epidemiology, School of Public Health and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
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  • Na He
    Correspondence
    Corresponding author: Na He, Professor of Epidemiology, Dean, School of Public Health, Fudan University, Tel/Fax: (86)-21-54237519
    Affiliations
    Department of Epidemiology, School of Public Health and the Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China

    Yi-Wu Research Institute, Fudan University, Shanghai, China
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Open AccessPublished:November 28, 2022DOI:https://doi.org/10.1016/j.ijid.2022.11.030

      Highlights

      • Physical frailty is a risk factor for health outcomes in people living with HIV.
      • People living with HIV with physical frailty were at increased risk for falls.
      • HIV–seropositive individuals with physical frailty were at higher risk of mortality.
      • Routine screening and intervention for physical frailty may improve health outcomes.

      Abstract

      Objectives

      Physical frailty is one of the major concerns among older people living with HIV (PLWH). This meta-analysis aimed to explore the association between physical frailty and negative health outcomes among PLWH.

      Methods

      We systematically searched six electronic databases including PubMed, Embase, Web of Science, the Cochrane Library, and Chinese databases up to April 10, 2022, for studies examining the association between physical frailty and risk of negative health outcomes among PLWH. Risk ratios (RRs), odds ratios, and hazard ratios with 95% CIs were extracted, and meta-analyses were conducted by using a fixed or random-effects model.

      Results

      In total, 10 studies incorporating 7755 HIV–seropositive patients (mean age 49.4 years) were included in the meta-analysis. Overall, five studies with 3434 participants reported the effect of physical frailty on falls. Results showed that physical frailty in HIV–seropositive individuals demonstrated a higher risk of future falls (pooled RR 3.74, 95% CI 1.42-9.86) compared with robust HIV–seropositive patients. In addition, a meta-analysis of five studies (4321 participants) reporting the frailty-mortality association showed that physical frailty was significantly associated with a higher risk of all-cause mortality (RR 1.70, 95% CI 1.32-2.19) among PLWH.

      Conclusion

      Physical frailty is a significant risk factor for negative health outcomes in PLWH, including falls and all-cause mortality, underscoring the need for routine screening and early intervention of physical frailty among PLWH.

      Keywords

      Introduction

      The life expectancy of people living with HIV (PLWH) has notably improved because of potent combination antiretroviral therapy [
      • Lewden C
      • Chene G
      • Morlat P
      • Raffi F
      • Dupon M
      • Dellamonica P
      • et al.
      HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population.
      ,
      • Rodger AJ
      • Lodwick R
      • Schechter M
      • Deeks S
      • Amin J
      • Gilson R
      • et al.
      Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and Esprit trials compared with the general population.
      ], non–AIDS-defining comorbidities and chronic age-related diseases predominantly caused morbidity and mortality among PLWH [
      • Palella FJ
      • Jr Baker RK
      • Moorman AC
      • Chmiel JS
      • Wood KC
      • Brooks JT
      • et al.
      Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study.
      ]. Further compromises health among aging HIV–seropositive patients is frailty, a geriatric phenotype characterized by dysregulation of multiple biologic systems that leads to reduced physiological reserve and loss of resistance to stressors. Prevalence of physical frailty increases with age in community-dwelling older adults and has been associated with a greater risk of multiple adverse health consequences [
      • Fried LP
      • Tangen CM
      • Walston J
      • Newman AB
      • Hirsch C
      • Gottdiener J
      • et al.
      Frailty in older adults: evidence for a phenotype.
      ,
      • Ofori-Asenso R
      • Chin KL
      • Mazidi M
      • Zomer E
      • Ilomaki J
      • Zullo AR
      • et al.
      Global incidence of frailty and prefrailty among community-dwelling older adults: a systematic review and meta-analysis.
      ]. A previous meta-analysis has found an association between physical frailty status and risk of negative health outcomes including falls, disability, hospitalization, and death in the general geriatric population [
      • Kojima G
      • Iliffe S
      • Walters K.
      Frailty index as a predictor of mortality: a systematic review and meta-analysis.
      ,
      • Liu HX
      • Ding G
      • Yu WJ
      • Liu TF
      • Yan AY
      • Chen HY
      • et al.
      Association between frailty and incident risk of disability in community-dwelling elder people: evidence from a meta-analysis.
      ,
      • Vermeiren S
      • Vella-Azzopardi R
      • Beckwée D
      • Habbig AK
      • Scafoglieri A
      • Jansen B
      • et al.
      Frailty and the prediction of negative health outcomes: a meta-analysis.
      ,
      • Veronese N
      • Cereda E
      • Stubbs B
      • Solmi M
      • Luchini C
      • Manzato E
      • et al.
      Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: results from a meta-analysis and exploratory meta-regression analysis.
      ].
      Physical frailty has been shown to occur up to a decade earlier among HIV–seropositive individuals [
      • Desquilbet L
      • Jacobson LP
      • Fried LP
      • Phair JP
      • Jamieson BD
      • Holloway M
      • et al.
      HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty.
      ], and HIV–seropositive patients with physical frailty have a higher comorbidity burden than lifestyle-comparable HIV–seronegative participants [
      • Schouten J
      • Wit FW
      • Stolte IG
      • Kootstra NA
      • van der Valk M
      • Geerlings SE
      • et al.
      Cross-sectional comparison of the prevalence of age-associated comorbidities and their risk factors between HIV-infected and uninfected individuals: the AGEhIV cohort study.
      ]. Previous studies have reported the association between physical frailty and the risk of poor health outcomes among HIV–seropositive patients [
      • Brothers TD
      • Kirkland S
      • Theou O
      • Zona S
      • Malagoli A
      • Wallace LMK
      • et al.
      Predictors of transitions in frailty severity and mortality among people aging with HIV.
      ,
      • Kelly SG
      • Wu K
      • Tassiopoulos K
      • Erlandson KM
      • Koletar SL
      • Palella FJ.
      Frailty is an independent risk factor for mortality, cardiovascular disease, bone disease, and diabetes among aging adults with human immunodeficiency virus.
      ,
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey MW
      • Tien PC
      • et al.
      Frailty as a predictor of falls in HIV-infected and uninfected women.
      ]. However, meta-analysis evidence is scarce, and the effects of physical frailty on negative health outcomes among PLWH remains unclear. Identifying the association between physical frailty and health outcomes has important implications for the management and care of PLWH as the progression of physical frailty could be prevented or delayed by appropriate screening and interventions.
      Therefore, we conducted a systematic review and meta-analysis of observational studies to comprehensively examine the association between physical frailty and relevant negative health outcomes including falls and mortality among PLWH.

      Methods

      Search strategy

      We conducted this meta-analysis per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [
      • Moher D
      • Liberati A
      • Tetzlaff J
      • Altman DG
      • Group PRISMA
      Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement.
      ]. PubMed, Embase, Web of Science, the Cochrane Library, and Chinese databases (Chinese National Knowledge Infrastructure [CNKI], Wanfang data) were searched up to April 10, 2022, for studies examining the association between physical frailty and risk of negative outcomes among PLWH by using various combinations of medical subject headings terms and free text: frailty, HIV, falls, mortality, and adverse effects (details in Supplementary Table1). We did not limit our search by language. We also reviewed the reference lists of eligible studies and previous evidence summaries to identify additional literature.

      Study selection

      Studies were included if (i) they were observational studies (i.e., cohort or cross-sectional); (ii) the exposure of interest was physical frailty; (iii) outcomes were falls and all-cause mortality; (iv) the study population was HIV–seropositive adults; and (v) they provided multivariate-adjusted risk ratios (RRs), odds ratios (ORs) or hazard ratios (HRs) with 95% CI or reported sufficient data to derive these. In the case of multiple publications related to the same study, we included the one with the most informative reporting and/or the largest sample size. We excluded reviews, comments, letters, editorials, and studies that used only a single indicator for frailty diagnosis (e.g., only low gait speed).

      Data extraction and quality assessment

      We extracted the following information using a predesigned collection form: first author, publication year, country, study design, sample size, age, frailty measurement method, outcome, follow-up period, adjustment factors, and ORs/RRs/HRs with 95% CI (adjusted by the most confounders).
      The quality of included cohort studies was evaluated with respect to bias using the nine-item Newcastle-Ottawa Scale [
      • Stang A.
      Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.
      ], which summarizes eight aspects of each study. The quality of cross-sectional studies was evaluated by the Agency for Healthcare Research and Quality scale [
      • Rostom A
      • Dubé C
      • Cranney A
      • Saloojee N
      • Sy R
      • Garritty C
      • et al.
      Celiac disease.
      ], which includes 11 items answered by “Yes” “No” or “Unclear”. An item was scored 0 for “No” or “Unclear” and 1 for “Yes”. We assigned scores of 0-3, 4-7, and 8-11 for low, moderate, and high quality [
      • Hu J
      • Dong Y
      • Chen X
      • Liu Y
      • Ma D
      • Liu X
      • et al.
      Prevalence of suicide attempts among Chinese adolescents: a meta-analysis of cross-sectional studies.
      ].

      Statistical analysis

      We did separate meta-analyses to determine the association between physical frailty and the risk of different health negative outcomes. RRs were used as the common measure of association across studies, and HRs and ORs were regarded as approximate to RRs because of the low incidence rates [
      • Pan A
      • Wang Y
      • Talaei M
      • Hu FB
      • Wu T.
      Relation of active, passive, and quitting smoking with incident type 2 diabetes: a systematic review and meta-analysis.
      ,
      • Zhang J
      • Yu KF.
      What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes.
      ]. Statistical heterogeneity was examined by Cochran Q and I2 statistics, with P <0.1 considered statistically significant for the Q statistic, and the I2 value threshold of 25%, 50%, or >75% considered as low, moderate, or substantial heterogeneity, respectively. If moderate or substantial heterogeneity was identified, we used random-effects models to pool outcomes. Otherwise, a fixed-effects model was used. We performed sensitivity analyses to assess the stability of results and potential sources of heterogeneity by excluding one study at a time and by restricting studies with the same measurements of frailty. Publication bias was assessed by Egger's test and visual inspection of funnel plots [
      • Begg CB
      • Mazumdar M.
      Operating characteristics of a rank correlation test for publication bias.
      ]. All analyses involved using Stata 12.1 (Stata Corp, College Station, TX), with two-sided P <0.05 considered statistically significant.

      Results

      Study selection

      We identified 1213 articles from six electronic databases, and three from the reference list search. After excluding duplicates (n = 282) and title or abstract screening (n = 875), we assessed 59 full-text articles. We further excluded 49 articles because the study population was not HIV–seropositive individuals (n = 5), exposures or outcomes were not of interest (n = 32), and there was a lack of available data (n = 12). Finally, 10 studies were included for quantitative synthesis by meta-analysis. The flow chart of the literature search is summarized in Figure 1.

      Characteristics of included studies

      The sample size of 10 eligible studies ranged from 359 participants to 1385 participants, with a total of 7755 HIV–seropositive patients (Table 1). Of these studies, nine were prospective cohort studies [
      • Brothers TD
      • Kirkland S
      • Theou O
      • Zona S
      • Malagoli A
      • Wallace LMK
      • et al.
      Predictors of transitions in frailty severity and mortality among people aging with HIV.
      ,
      • Kelly SG
      • Wu K
      • Tassiopoulos K
      • Erlandson KM
      • Koletar SL
      • Palella FJ.
      Frailty is an independent risk factor for mortality, cardiovascular disease, bone disease, and diabetes among aging adults with human immunodeficiency virus.
      ,
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey MW
      • Tien PC
      • et al.
      Frailty as a predictor of falls in HIV-infected and uninfected women.
      ,
      • Pelloquin R
      • Abdo M
      • MaWhinney S
      • Jankowski CM
      • Erlandson KM.
      Physical function and frailty tools in mortality prediction of middle-aged adults with HIV.
      ,
      • Erlandson KM
      • Allshouse AA
      • Jankowski CM
      • Duong S
      • MaWhinney S
      • Kohrt WM
      • et al.
      Risk factors for falls in HIV-infected persons.
      ,
      • Gustafson DR
      • Shi Q
      • Holman S
      • Minkoff H
      • Cohen MH
      • Plankey MW
      • et al.
      Predicting death over 8 years in a prospective cohort of HIV-infected women: the Women's Interagency HIV Study.
      ,
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey M
      • Tien PC
      • et al.
      High frequency of Recurrent Falls among prefrail and frail women with and without HIV.
      ,
      • Tassiopoulos K
      • Abdo M
      • Wu K
      • Koletar SL
      • Palella FJ
      • Jr Kalayjian R
      • et al.
      Frailty is strongly associated with increased risk of recurrent falls among older HIV-infected adults.
      ,
      • Verheij E
      • Kirk GD
      • Wit FW
      • van Zoest RA
      • Verboeket SO
      • Lemkes BA
      • et al.
      Frailty is associated with mortality and incident comorbidity among middle-aged human immunodeficiency virus (HIV)-positive and HIV-negative participants.
      ] and one was a cross-sectional study [
      • Guaraldi G
      • Malagoli A
      • Theou O
      • Brothers TD
      • Wallace LMK
      • Torelli R
      • et al.
      Correlates of frailty phenotype and frailty index and their associations with clinical outcomes.
      ]. The follow-up period of the included cohort studies ranged from 1-10 years. The participants included in the sample had a mean age of 49.4 years. Seven studies were conducted in the United States [
      • Kelly SG
      • Wu K
      • Tassiopoulos K
      • Erlandson KM
      • Koletar SL
      • Palella FJ.
      Frailty is an independent risk factor for mortality, cardiovascular disease, bone disease, and diabetes among aging adults with human immunodeficiency virus.
      ,
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey MW
      • Tien PC
      • et al.
      Frailty as a predictor of falls in HIV-infected and uninfected women.
      ,
      • Pelloquin R
      • Abdo M
      • MaWhinney S
      • Jankowski CM
      • Erlandson KM.
      Physical function and frailty tools in mortality prediction of middle-aged adults with HIV.
      ,
      • Erlandson KM
      • Allshouse AA
      • Jankowski CM
      • Duong S
      • MaWhinney S
      • Kohrt WM
      • et al.
      Risk factors for falls in HIV-infected persons.
      ,
      • Gustafson DR
      • Shi Q
      • Holman S
      • Minkoff H
      • Cohen MH
      • Plankey MW
      • et al.
      Predicting death over 8 years in a prospective cohort of HIV-infected women: the Women's Interagency HIV Study.
      ,
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey M
      • Tien PC
      • et al.
      High frequency of Recurrent Falls among prefrail and frail women with and without HIV.
      ,
      • Tassiopoulos K
      • Abdo M
      • Wu K
      • Koletar SL
      • Palella FJ
      • Jr Kalayjian R
      • et al.
      Frailty is strongly associated with increased risk of recurrent falls among older HIV-infected adults.
      ], two in Italy [
      • Brothers TD
      • Kirkland S
      • Theou O
      • Zona S
      • Malagoli A
      • Wallace LMK
      • et al.
      Predictors of transitions in frailty severity and mortality among people aging with HIV.
      ,
      • Guaraldi G
      • Malagoli A
      • Theou O
      • Brothers TD
      • Wallace LMK
      • Torelli R
      • et al.
      Correlates of frailty phenotype and frailty index and their associations with clinical outcomes.
      ], and one in Netherlands [
      • Verheij E
      • Kirk GD
      • Wit FW
      • van Zoest RA
      • Verboeket SO
      • Lemkes BA
      • et al.
      Frailty is associated with mortality and incident comorbidity among middle-aged human immunodeficiency virus (HIV)-positive and HIV-negative participants.
      ]. In terms of frailty criteria, eight studies used a phenotype model (or modified version) of Fried's Frailty Phenotype (FP) for defining frailty [
      • Kelly SG
      • Wu K
      • Tassiopoulos K
      • Erlandson KM
      • Koletar SL
      • Palella FJ.
      Frailty is an independent risk factor for mortality, cardiovascular disease, bone disease, and diabetes among aging adults with human immunodeficiency virus.
      ,
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey MW
      • Tien PC
      • et al.
      Frailty as a predictor of falls in HIV-infected and uninfected women.
      ,
      • Erlandson KM
      • Allshouse AA
      • Jankowski CM
      • Duong S
      • MaWhinney S
      • Kohrt WM
      • et al.
      Risk factors for falls in HIV-infected persons.
      ,
      • Gustafson DR
      • Shi Q
      • Holman S
      • Minkoff H
      • Cohen MH
      • Plankey MW
      • et al.
      Predicting death over 8 years in a prospective cohort of HIV-infected women: the Women's Interagency HIV Study.
      ,
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey M
      • Tien PC
      • et al.
      High frequency of Recurrent Falls among prefrail and frail women with and without HIV.
      ,
      • Tassiopoulos K
      • Abdo M
      • Wu K
      • Koletar SL
      • Palella FJ
      • Jr Kalayjian R
      • et al.
      Frailty is strongly associated with increased risk of recurrent falls among older HIV-infected adults.
      ,
      • Verheij E
      • Kirk GD
      • Wit FW
      • van Zoest RA
      • Verboeket SO
      • Lemkes BA
      • et al.
      Frailty is associated with mortality and incident comorbidity among middle-aged human immunodeficiency virus (HIV)-positive and HIV-negative participants.
      ,
      • Guaraldi G
      • Malagoli A
      • Theou O
      • Brothers TD
      • Wallace LMK
      • Torelli R
      • et al.
      Correlates of frailty phenotype and frailty index and their associations with clinical outcomes.
      ], one used the Veterans Aging Cohort Study Index (VI) [
      • Pelloquin R
      • Abdo M
      • MaWhinney S
      • Jankowski CM
      • Erlandson KM.
      Physical function and frailty tools in mortality prediction of middle-aged adults with HIV.
      ] and one used the Frailty Index (FI) [
      • Brothers TD
      • Kirkland S
      • Theou O
      • Zona S
      • Malagoli A
      • Wallace LMK
      • et al.
      Predictors of transitions in frailty severity and mortality among people aging with HIV.
      ]. The mean quality score of the included studies was 7, which indicates moderate quality (Supplementary Table 2).
      Table 1Characteristics of the included studies.
      StudyYearRegionStudy designSample sizeAge (years)Female (%)Frailty measurementsFrailty (%)OutcomeFollow-up period (years)AdjustmentNewcastle-Ottawa Quality Assessment Scale /Agency for Healthcare Research and Quality
      Guaraldi et al.
      • Guaraldi G
      • Malagoli A
      • Theou O
      • Brothers TD
      • Wallace LMK
      • Torelli R
      • et al.
      Correlates of frailty phenotype and frailty index and their associations with clinical outcomes.
      2017ItalyCross-sectional48253.925The Fried FP3.1Falls-Age and gender5
      Sharma et al.
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey M
      • Tien PC
      • et al.
      High frequency of Recurrent Falls among prefrail and frail women with and without HIV.
      2021United StateProspective cohort89753100The Fried FP9Falls1WIHS site, race, smoking status, cocaine, crack, or heroin use, recent alcohol use, renal dysfunction, depressive symptoms, and CNS active medication currently used7
      Erlandson et al.
      • Erlandson KM
      • Allshouse AA
      • Jankowski CM
      • Duong S
      • MaWhinney S
      • Kohrt WM
      • et al.
      Risk factors for falls in HIV-infected persons.
      2012United StateProspective cohort3595215The Fried FP7.5Falls1Age, gender, and CD4 lymphocyte count8
      Tassiopoulos et al.
      • Tassiopoulos K
      • Abdo M
      • Wu K
      • Koletar SL
      • Palella FJ
      • Jr Kalayjian R
      • et al.
      Frailty is strongly associated with increased risk of recurrent falls among older HIV-infected adults.
      2017United StateProspective cohort9675118.9The Fried FP6Falls1Age (categorical), race/ethnicity, alcohol use, current substance use, neurocognitive function.7
      Sharma et al.
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey MW
      • Tien PC
      • et al.
      Frailty as a predictor of falls in HIV-infected and uninfected women.
      2019United StateProspective cohort72942100The Fried FP14Falls10Age, enrollment year, WIHS Site, smoking status, cocaine, crack, or heroin use, marijuana use, recent alcohol use, comorbidities, CNS active medication currently used and number of current CNS active medication types8
      Gustafson et al.
      • Gustafson DR
      • Shi Q
      • Holman S
      • Minkoff H
      • Cohen MH
      • Plankey MW
      • et al.
      Predicting death over 8 years in a prospective cohort of HIV-infected women: the Women's Interagency HIV Study.
      2017United StateProspective cohort138542.6100The Fried FP17.5Mortality8Race/ethnicity; education less than or equal to versus greater than high school; smoking current versus no; income less than versus greater than or equal to $ 12,000 annually; alcohol use: low, moderate or high versus none; and BMI <30 vs >30 kg/m27
      Verheij et al.
      • Verheij E
      • Kirk GD
      • Wit FW
      • van Zoest RA
      • Verboeket SO
      • Lemkes BA
      • et al.
      Frailty is associated with mortality and incident comorbidity among middle-aged human immunodeficiency virus (HIV)-positive and HIV-negative participants.
      2020NetherlandsProspective cohort598≥ 45NAThe Fried FP7.5Mortality6Age, HIV, smoking status, alcohol status and log-transformed soluble CD1637
      Kelly et al.
      • Kelly SG
      • Wu K
      • Tassiopoulos K
      • Erlandson KM
      • Koletar SL
      • Palella FJ.
      Frailty is an independent risk factor for mortality, cardiovascular disease, bone disease, and diabetes among aging adults with human immunodeficiency virus.
      2019United StateProspective cohort10165119The Fried FP6Mortality1Age, sex, history of diabetes, and route of HIV transmission7
      Pelloquin et al.
      • Pelloquin R
      • Abdo M
      • MaWhinney S
      • Jankowski CM
      • Erlandson KM.
      Physical function and frailty tools in mortality prediction of middle-aged adults with HIV.
      2020United StateProspective cohort3595215The Veterans Aging Cohort Study Index8Mortality8Physical activity7
      Brothers et al.
      • Brothers TD
      • Kirkland S
      • Theou O
      • Zona S
      • Malagoli A
      • Wallace LMK
      • et al.
      Predictors of transitions in frailty severity and mortality among people aging with HIV.
      2017ItalyProspective cohort96346.829The Frailty IndexNAMortality4Current CD4 cell count, nadir CD4 cell count, injection drug use and hepatitis C virus co-infection7
      WIHS: the Women...s Interagency HIV Study; HIV, human immunodeficiency virus; BMI, body mass index; CD, clusters of differentiation; CNS, central nervous system; CVD, cardiovascular disease; FP, Frailty Phenotype; NA, not available

      Injurious falls

      Overall, four prospective cohort studies [
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey MW
      • Tien PC
      • et al.
      Frailty as a predictor of falls in HIV-infected and uninfected women.
      ,
      • Erlandson KM
      • Allshouse AA
      • Jankowski CM
      • Duong S
      • MaWhinney S
      • Kohrt WM
      • et al.
      Risk factors for falls in HIV-infected persons.
      ,
      • Sharma A
      • Hoover DR
      • Shi Q
      • Gustafson DR
      • Plankey M
      • Tien PC
      • et al.
      High frequency of Recurrent Falls among prefrail and frail women with and without HIV.
      ,
      • Tassiopoulos K
      • Abdo M
      • Wu K
      • Koletar SL
      • Palella FJ
      • Jr Kalayjian R
      • et al.
      Frailty is strongly associated with increased risk of recurrent falls among older HIV-infected adults.
      ] and one cross-sectional study [
      • Guaraldi G
      • Malagoli A
      • Theou O
      • Brothers TD
      • Wallace LMK
      • Torelli R
      • et al.
      Correlates of frailty phenotype and frailty index and their associations with clinical outcomes.
      ] with a total of 3434 participants reported the effect of physical frailty on injurious falls. The frailty assessments in these five studies were based on the FP. Meta-analysis showed that HIV–seropositive individuals with physical frailty demonstrated a significantly higher risk of future falls, compared with robust HIV–seropositive patients, the summary RR was 3.74 (95% CI 1.42-9.86), with high heterogeneity (I2=90.3%, Pheterogeneity <0.001) (Figure 2). No publication bias was observed by funnel plots (Supplementary Figure 1) or Egger's test (P-value = 0.083). Sensitivity analysis suggested that the source of heterogeneity was most likely because of a cross-sectional study by Guaraldi et al. [
      • Cheng MH
      • Chang SF.
      Frailty as a risk factor for falls among community dwelling people: evidence from a meta-analysis.
      ] (Supplementary Figure 2), so we excluded that study and recombined the data. Results showed the effect of physical frailty on future falls remained significant (RR 5.11, 95% CI 1.43-18.32, I2 = 89.0%, Pheterogeneity <0.001) (Supplementary Figure 3).
      Figure 2
      Figure 2Forest plot of the association between physical frailty and injurious falls.
      FP, Frailty Phenotype; RR, risk ratio.

      All-cause mortality

      A total of five cohort studies [
      • Brothers TD
      • Kirkland S
      • Theou O
      • Zona S
      • Malagoli A
      • Wallace LMK
      • et al.
      Predictors of transitions in frailty severity and mortality among people aging with HIV.
      ,
      • Kelly SG
      • Wu K
      • Tassiopoulos K
      • Erlandson KM
      • Koletar SL
      • Palella FJ.
      Frailty is an independent risk factor for mortality, cardiovascular disease, bone disease, and diabetes among aging adults with human immunodeficiency virus.
      ,
      • Pelloquin R
      • Abdo M
      • MaWhinney S
      • Jankowski CM
      • Erlandson KM.
      Physical function and frailty tools in mortality prediction of middle-aged adults with HIV.
      ,
      • Gustafson DR
      • Shi Q
      • Holman S
      • Minkoff H
      • Cohen MH
      • Plankey MW
      • et al.
      Predicting death over 8 years in a prospective cohort of HIV-infected women: the Women's Interagency HIV Study.
      ,
      • Verheij E
      • Kirk GD
      • Wit FW
      • van Zoest RA
      • Verboeket SO
      • Lemkes BA
      • et al.
      Frailty is associated with mortality and incident comorbidity among middle-aged human immunodeficiency virus (HIV)-positive and HIV-negative participants.
      ] with a total of 4321 participants reported the effect of physical frailty on all-cause mortality in PLWH. Among these five studies, three used FP for defining physical frailty, one used VI and one used FI. The presence of physical frailty was significantly associated with a higher risk of all-cause mortality in PLWH as compared with robust HIV–seropositive patients, the pooled RR was 1.70 (95% CI 1.32-2.19), with moderate heterogeneity (I2 = 67.0%, Pheterogeneity = 0.016) (Figure 3). No publication bias was observed by funnel plots (Supplementary Figure 4) or Egger's test (P = 0.153). Sensitivity analysis showed that the main result changed after excluding a study by Brothers et al. [
      • Brothers TD
      • Kirkland S
      • Theou O
      • Zona S
      • Malagoli A
      • Wallace LMK
      • et al.
      Predictors of transitions in frailty severity and mortality among people aging with HIV.
      ] (Supplementary Figure 5). Thus, we excluded this study and found that the effect of physical frailty on all-cause mortality remained significant (RR 1.78, 95% CI 1.50-2.11), with low heterogeneity (I2 = 41.9%, Pheterogeneity = 0.160) (Supplementary Figure 6). In addition, we explored the role of physical frailty on mortality separately according to frailty measurements. Results showed that the relationship between frailty and all-cause mortality was significant across the different frailty measures, with pooled RRs of 2.37 (95% CI 1.74-3.22) and 1.40 (95% CI 1.25-1.56) for FP and FI/VI, respectively (Supplementary Figure 7).
      Figure 3
      Figure 3Forest plot of the association between physical frailty and all-cause mortality.
      FP, Frailty Phenotype; FI, Frailty Index; RR, risk ratio; VI, Veterans Aging Cohort Study Index.

      Discussion

      This systematic review and meta-analysis included 10 observational studies with 7755 HIV–seropositive patients to quantitatively examine the association between physical frailty and adverse health outcomes among PLWH including injurious falls and all-cause mortality. We found a significant association between physical frailty and a high risk of injurious falls and all-cause mortality in HIV–seropositive individuals.
      A previous meta-analysis including 11 studies incorporating 68,723 individuals to explore the association between physical frailty and falls among community-dwelling older adults found that physical frailty was significantly associated with a higher risk of future falls (pooled OR 1.84, 95% CI 1.43-2.38) [
      • Kojima G.
      Frailty as a predictor of future falls among community-dwelling older people: a systematic review and meta-analysis.
      ]. Another meta-analysis including 10 studies in community residents revealed that compared with robust older adults, older adults with frailty demonstrated the greatest risk for falls [
      • Cheng MH
      • Chang SF.
      Frailty as a risk factor for falls among community dwelling people: evidence from a meta-analysis.
      ]. Our findings were consistent with these studies. However, in contrast to the previous meta-analysis, the present study focused on HIV–seropositive individuals and found that the pooled RR of frailty related to future falls (RR 3.74, 95% CI 1.42-9.86) was higher than that reported in the above-mentioned studies. This is probably because frailty has a greater impact on PLWH than on the general population, or HIV–seropositive individuals have more comorbidities and affected health conditions that may lead to a higher prevalence of falls [
      • Erlandson KM
      • Allshouse AA
      • Jankowski CM
      • Duong S
      • MaWhinney S
      • Kohrt WM
      • et al.
      Risk factors for falls in HIV-infected persons.
      ,
      • Althoff KN
      • Smit M
      • Reiss P
      • Justice AC.
      HIV and ageing: improving quantity and quality of life.
      ,
      • Pathai S
      • Bajillan H
      • Landay AL
      • High KP.
      Is HIV a model of accelerated or accentuated aging?.
      ].
      A previous meta-analysis investigating the relationship between frailty and mortality in community-dwelling individuals reported that frailty was associated with a higher risk of all-cause mortality [
      • Kojima G
      • Iliffe S
      • Walters K.
      Frailty index as a predictor of mortality: a systematic review and meta-analysis.
      ,
      • Vermeiren S
      • Vella-Azzopardi R
      • Beckwée D
      • Habbig AK
      • Scafoglieri A
      • Jansen B
      • et al.
      Frailty and the prediction of negative health outcomes: a meta-analysis.
      ]. This significant frailty-mortality association was also observed in patients with diabetes [
      • Ida S
      • Kaneko R
      • Imataka K
      • Murata K.
      Relationship between frailty and mortality, hospitalization, and cardiovascular diseases in diabetes: a systematic review and meta-analysis.
      ], hypertension [
      • Hu K
      • Zhou Q
      • Jiang Y
      • Shang Z
      • Mei F
      • Gao Q
      • et al.
      Association between frailty and mortality, falls, and hospitalization among patients with hypertension: a systematic review and meta-analysis.
      ], and chronic kidney disease [
      • Mei F
      • Gao Q
      • Chen F
      • Zhao L
      • Shang Y
      • Hu K
      • et al.
      Frailty as a predictor of negative health outcomes in chronic kidney disease: a systematic review and meta-analysis.
      ]. In the present meta-analysis, our result was consistent with the previous studies and found a significant relationship between physical frailty and all-cause mortality in PLWH.
      Sensitivity analyses were conducted by excluding one study at a time and by restricting studies with the same frailty measurements. Results of sensitivity analysis suggested that the main result changed after excluding the studies of Guaraldi et al. [
      • Guaraldi G
      • Malagoli A
      • Theou O
      • Brothers TD
      • Wallace LMK
      • Torelli R
      • et al.
      Correlates of frailty phenotype and frailty index and their associations with clinical outcomes.
      ] and Brothers et al. [
      • Brothers TD
      • Kirkland S
      • Theou O
      • Zona S
      • Malagoli A
      • Wallace LMK
      • et al.
      Predictors of transitions in frailty severity and mortality among people aging with HIV.
      ], indicating that the source of heterogeneity is likely because of the differences in study design and frailty measurements. As there is currently no gold standard measure of physical frailty, urgent action is needed to standardize frailty measurements to establish a more precise relationship between physical frailty and falls and mortality.
      Our findings may have important implications for practice given the aging PLWH and rising levels of physical frailty. PLWH experience a high burden of comorbidities earlier in life that is typically associated with aging, including geriatric syndromes such as frailty, falls, and fractures. Previous research found that HIV–seropositive individuals had a higher prevalence of physical frailty [
      • Levett TJ
      • Cresswell FV
      • Malik MA
      • Fisher M
      • Wright J.
      Systematic review of prevalence and predictors of frailty in individuals with human immunodeficiency virus.
      ,
      • Yamada Y
      • Kobayashi T
      • Condo A
      • Sangarlangkarn A
      • Ko F
      • Taniguchi Y
      • et al.
      Prevalence of frailty and prefrailty in people with human immunodeficiency virus aged 50 or older: a systematic review and meta-analysis.
      ]. Given that physical frailty is a risk factor for several negative health outcomes among PLWH and is more likely to be reversed by appropriate intervention, clinicians caring for HIV–seropositive patients need to be aware of the risks of frailty, routinely provide frailty screening for PLWH and timely initiate appropriate interventions.
      Our meta-analysis contains several strengths. Primarily, to the best of our knowledge, this is the first systematic review and meta-analysis exploring the association of physical frailty with falls and mortality as negative health outcomes in PLWH. In addition, we employed a comprehensive search strategy involving multiple electronic databases as well as a manual search for relevant articles for all available studies. However, some limitations must also be noted. First, although extracted risk estimates were adjusted for some confounding factors, other unmeasured risk factors could not be ruled out completely. Second, the definitions of frailty used in the included studies were heterogeneous, which may have affected the results. But our sensitivity analysis showed that the combined results were consistently based on different definitions of frailty. Finally, we did not conduct subgroup analyses due to the limited number of studies available. However, we performed sensitivity analyses to explore possible causes of heterogeneity among included studies.

      Conclusion

      This meta-analysis indicated that physical frailty was a significant risk factor for injurious falls and all-cause mortality in PLWH. Given that physical frailty is a dynamic state and is prevalent in HIV–seropositive patients, routine screening and prompt intervention are needed for PLWH to reverse frailty and improve health outcomes in the clinical setting. Further longitudinal studies are required to validate the association between physical frailty and negative health outcomes among HIV–seropositive patients.

      Declaration of competing interest

      The authors have no competing interests to declare.

      Funding

      This study was supported by the National Natural Science Foundation of China (Grant No. 82173579) and Yi-Wu Research Institute of Fudan University, China (Grant No. KCF201512).

      Ethical approval

      Approval was not required for this study.

      Author contributions

      Q.Z.: literature search, study quality assessment, data extraction, formal analysis, and writing (original draft preparation). N.H.: methodology, writing (review and editing), and supervision. J.H., X.Y., H.Y., and Z.Z.: revised the manuscript. All authors read and approved the final manuscript.

      Appendix. Supplementary materials

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