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Integrating Frailty andFunctional Outcomes intoClinical Trials (and the Clinic)Kristine Erlandson, MD MSUniversity of Colorado, Aurora, CO. USADisclosure: [Click to add the financial relationships you have withineligible companies (previously defined as “commercialinterests”). If you have no financial relationships,specifically note "None”]

Ranges of Physical FunctionDr. Anthony Fauci, age 81David Kirby, dying of AIDS at age 32http://www.mountsinai.on.ca/about /

Physical Function or Functional Impairments Objective assessments or self-report 100s of different assessments available Examples: Activities of daily livingGait speed by 4-m, 400-m, or 6-minute walkShort Physical Performance Battery (or its components)Timed up-and-go “Impaired” can be defined differently: scale, cut-point, continuous

worse ß Function à betterWhat is Frailty?L de VilliersCMEJ.org.za

worse ß Function à betterWhat is Frailty?L de VilliersCMEJ.org.za

How is Frailty Defined?Frailty Phenotype (Fried) Reflects a vulnerability as result ofmultiple impairments: Slow gait Weak grip Low activity Fatigue Weight loss Takes 5-10 minutes to assessRequires a dynamometerMust be assessed prospectivelyScored 0-5Fried, J Gerontol A Biol Sci Med Sci 2001Jones DM, Song X, Rockwood K. J Am Geriatr Soc. 2004Mitnitski AB.Rockwood K. Mech Ageing Dev. 2002

How is Frailty Defined?Frailty Phenotype (Fried) Reflects a vulnerability as result ofmultiple impairments: Slow gait Weak grip Low activity Fatigue Weight loss Takes 5-10 minutes to assessRequires a dynamometerMust be assessed prospectivelyScored 0-5Frailty Index (Rockwood) Accumulation of deficits Variables that increase with age and areassociated with health status Can often be derived from chart review Differs by cohort/health system Expressed as ratio of # of variables impaired/# variables assessed Scored 0-1 Veterans Aging Cohort Study Index is similarconceptFried, J Gerontol A Biol Sci Med Sci 2001Jones DM, et al. J Am Geriatr Soc. 2004Mitnitski AB, et al. Mech Ageing Dev. 2002Justice, et al. JAIDS 2013

Frailty Increases with Age dijk Lancet 2019

Why do we think about frailty and functionalimpairments in HIV?Recent publications linking frailty to theaging pillars among people with HIV:Sanchez-Conde M, et al. Epigenomics 2019Shiau S, et al. Clin Infect Dis 2021Zhang, et al. Clin Epigenetics 2018Masters MC, et al. AIDS 2022De Vincentis S, et al. Euro J Endo 2021Chow DC, et al. Clin Infect Dis 2020Erlandson KM, et al. J Infect Dis 2017Johnston CD, et al. JAIDS 2021Tran T, et al. JAIDS 2022Derry HM, et al. J Geron B Psychol Sci Soc Sci 2022Edwards A, et al. Afr J AIDS Res 2020Alvarez S, et al. PLoS One 2020Sun J, et al. Clin Infect Dis 2018Margolick JB, et al. J Infect Dis 2018Tan JY, et al. J Int AIDS Soc 2021McMillan JM, et al. AIDS Patient Care STDs 2020Bisset, Howlett. Aging Medicine 2019

Frailty occurs earlier among people with HIV10% frail PWH vs 0 frail in controlsAGEhIV Cohort15% frail PWH vs 7% frail in controlsMACS CohortKooij AIDS 2016; Althoff J Gerontol A Med Sci 2014

1.2Usual Gait Speed (m/s11.051.11.95Usual Gait Speed (m/s)11.051.11.155060708090Age (years)Usual Gait Speed and Age by HIV-Status95% CIHIV .951.2Usual Gait Speed (m/s)11.051.11.15 Greater gait speed and gripstrength decline with ageamong PWH compared tocontrols40Gait Speed4050HIV-607095% CIHIV HIV-GripStrength4050607080Age (years)95% CIHIV Schrack J, et al. JAIDS 2015. Schrack, J et al. AIDS 2016; Greene, M et al. AIDS 201580Age (years).95Physical FunctionImpairments GreaterAmong Older Adultswith HIVUsual Gait Speed and Age by HIV-StatusHIV-9090

Why are frailty and function impairmentimportant? Strong association with mortality Major predictor of independence Associated with falls and fracture Associated with increased risk ofsome comorbiditiesVerheij E, et al. JAIDS 2021Pelloquin R, et al. JAIDS 2020Piggott DA, et al. AIDS 2020Kelly SG, et al. Clin Infect Dis 2019Erlandson KM, et al. Clin Infect Dis 2019Tassiopoulos K, et al. AIDS 2017

Why are frailty and function impairmentimportant? Strong association with mortality Major predictor of independent living Associated with falls and fracture Associated with increased risk ofcomorbidities A more informative vital sign?

Frailty can help us understand the expressionof diseaseVellas J, et al.Frailty Aging 2018

How can we incorporate frailty/physicalfunction in interventions?1. Interventions that change frailty/function or the trajectory offrailty/function Primary or secondary outcomesExercise in PWH over 12 weeks (n 32)Physical function% ChangeP-valueChair rise-20 (-24, -16) 0.01400-m gait speed-6 (-8, -3) 0.01Stair climb-5 (-9,-2) 0.05Grip strength 4 (0, 9)NSBench press 27 (22,31) 0.01Leg press 16 (11,22) 0.01VO2 max 11 (7, 15) 0.01Dasatinib/quercetin in people with IPF (n 14)Physical functionChangeP-value6-min walk distance (m) 21.5 280.012⁎4-m gait speed (m/s) 0.12 0.20.024⁎Timed chair-stands (s) 2.2 30.013⁎SPPB score 0.9 10.003⁎Grip strength (kg) 0.6 20.31Erlandson KM, et al. AIDS 2018. Justice JN, et al. E BioMed 2019

How can we incorporate frailty/physicalfunction in interventions?1. Interventions that change frailty/function or the trajectory offrailty/ function2. Frailty/function modifies the intervention or effect Statins Kutner et al. JAMA Intern Med 2015 benefits in stopping statins with advanced disease Campitelli et al. CMAJ 2019 no benefit of high vs moderate dose statin in long-term care Fall risk highest in PWH with both peripheral neuropathy frailtyOdds of Falling (OR [95% CI])Muscedere J, et al. J Frailty Aging 2020Tassiopoulos K, et al. AIDS 2017

How can we incorporate frailty/physicalfunction in interventions?1. Interventions that change frailty/function or the trajectory offrailty/ function2. Frailty/function modifies the intervention Statins3. Improve outcomes in those who are frail “Pre-habilitation” for frail individuals before surgeryMuscedere J, et al. J Frailty Aging 2020

Things to consider when incorporating frailty/functional outcomes in clinical trials1. Prevalence Frailty is relatively uncommon, particularly in “younger” populationsAuthorsStudy PopulationPrevalenceOnenMedian age 47; 95% on ART5%ErlandsonAged 40 , 99% on ART6%UmblejaAge 40 , substudy of REPRIEVE6%Onen 18 years; 75% on ART9%KooijAge 45 , 94% on ART11%AllavenaSEPTAVIH Study of 510 PWH aged 70 yrsPiggott 18 years; IVDU; 54% ART13.5%15%

Physical Function Impairments More Commonthan Frailty in PWHSelf-reported impairmentModMildNoimpairmentAlmost 40% of low-risk middle-aged peoplewith HIV have functional impairmentsUmbleja, et al. JID 2020Erlandson, Abstract #

Things to consider when incorporating frailty/functional outcomes in clinical trials2. Responsiveness to therapeutic interventions Ceiling or floor effect? Can it be modified?Short Physical Performance BatteryPerfect scoreTime to rise from a chair 10 timesPhysical function % ChangeChair rise-20 (-24, -16)Grip strength 4 (0, 9)P-value 0.01NSErlandson KM, et al. AIDS 2018

21Responsiveness to Intervention:Can frailty be modified?Intervention 32 non-frail/pre-frail, 50-75 years with HIV Significant improvements with exercise 246 pre-frail/frail adults 65 years Significant improvements in all arms vs controlErlandson KM, et al. AIDS 2018Ng, et al. Am J Medicine 2015

Things to consider when incorporating frailty/functional outcomes in clinical trials3. Reproducibility Existing protocolsInitial and ongoing trainingAbility to standardizeVarying cut-points/componentsSPPBGuide.com

Things to consider when incorporating frailty/functional outcomes in clinical trials4. Logistics Space Time Equipment Participant burdenTestLogisticsFrailtyPhenotypeRequires dynamometer with yearly calibration,takes 10 minutesSPPBChair and 4-m space, takes 10 min4-m walkTakes 2 minutes; minimal spaceChair rise timeTakes 2 minutes; only requires chair400-mwTakes 5-15 minutes; need long unobstructed hall

Things to consider when incorporating frailty/functional outcomes in clinical trials5. Participant-reported vs performance-based Moderately correlated What people ACTUALLY do versus what people CAN do Objective measures less vulnerable to external influences Sensitivity to changeLatham N, et al. Archives Phys Therapy Rehab 2008; Feuering, et al. Disability and Rehab 2013.

Things to consider when incorporating frailty/functional outcomes in clinical trials Are regional differences inmoderate-strenuousactivities due to culturalcontext or actualimpairments?Erlandson (CROI 2022 Abstract O34)

Things to consider when incorporating frailty/functional outcomes in clinical trials6. Mechanism of action Cardiovascular endurance vs muscle strength vs balance General vulnerabilitySemaglutide for fatty liverDeprescribing for polypharmacyImages from: Harvard Health image; Stanford Blood Center; Medical Xpress; NCT04216589; NCT04840199Letermovir in PWH

How might we use these tests in the clinic?Canales, et al. Anesthesiology 2022

How might we use these tests in the clinic? Inform general care Prioritize advance care planningIdentify patients for geriatric referralInform risk/benefit of preventive careDetermine frequency of clinic visits Treat/manage frailty Referrals to appropriate resources (i.e., nutrition, physical therapy) Deprescribing Guide treatment decisions Selecting chemotherapy Post-pone elective surgery Determine ART?

Is it Feasible? Frailty/function evaluated in manygeriatric/HIV clinics Italian guidelines suggest screening forfrailty in all PWH aged 50 Study evaluating the SPPB in 3 U.S.clinics found it feasible How do we work into the clinic flow?Guaraldi, et al. J Frailty Aging 2019; Rodiguez-Manas, et al. Trials 2014; Crane et al. OFID 2019; Levett et al. Geriatrics 2020; Lwanga et al. AIDS Care 2020

Summary

Acknowledgements Mentors and Collaborators: Thomas Campbell, Todd Brown, Wendy Kohrt, CatherineJankowski AIDS Clinical Trials Group, Multicenter AIDS Cohort Studyand Womens Interagency HIV Cohort (now MWCCS) REPRIEVE (A5332), A5322, A5371, A5383 Teams Study participants in Colorado Community for vocalizing prioritiesWant to join us in Colorado for a Post-Doc?Apply for our HIV T32!http://bit.ly/ColoradoHIVPostDoc

Extra slides

Things to consider when incorporating frailty/functional outcomes in clinical trials% improvement in objective measures after24 weeks of an exercise interventionChange in self-reported physicalfunctioning in same interventionErlandson AIDS 2018; Goulding AIDS Care 2020; Erlandson (under review)

Why do we think about frailty and functionalimpairments in HIV?Frailty, physical function impairments, andother complications of agingDeeks Lancet 2013

But what biomarker can I use instead? Biomarkers should improve risk prediction beyond these cheaper,readily available assessments In clinic, should be able to better identify a population as frailcompared to the clinical tool alone, and help to better identify a careplan than the clinical tool alone Combine clinical assessments with biomarkers? May help to identify those for whom interventions work or don’t work Example ”biomarkers” that could complement: skeletal muscle mass by MRIor CT scans

Ranges of Physical Function Dr. Anthony Fauci, age 81 David Kirby, dying of AIDS at age 32 . Rockwood K. J Am GeriatrSoc. 2004 MitnitskiAB.Rockwood K. Mech Ageing Dev. 2002. How is Frailty Defined? Frailty Phenotype . et al. Archives Phys Therapy Rehab 2008; Feuering, et al. Disability and Rehab 2013.