Chester Clinic

 

Untitled

Journal of Infectious Diseases Advance Access published June 11, 2014
Frailty in People Aging With HumanImmunodeficiency Virus (HIV) Infection Thomas D. Brothers,1 Susan Kirkland,2 Giovanni Guaraldi,3 Julian Falutz,4 Olga Theou,1 B. Lynn Johnston,5 andKenneth Rockwood6,7 1Geriatric Medicine Research, and 2Departments of Community Health and Epidemiology and Medicine, Dalhousie University, Halifax, Nova Scotia,Canada; 3Department of Medical and Surgical Sciences for Adults and Children, Clinic of Infectious Diseases, University of Modena and Reggio Emilia,Modena, Italy; 4Chronic Viral Illness Service, Division of Infectious Diseases and Division of Geriatrics, McGill University Hospital Center, Montreal, Quebec, Canada; 5Division of Infectious Diseases, and 6Division of Geriatric Medicine, Dalhousie University, and 7Centre for Health Care of the Elderly,Capital District Health Authority, Halifax, Nova Scotia, Canada The increasing life spans of people infected with human immunodeficiency virus (HIV) reflect enormous treat-ment successes and present new challenges related to aging. Even with suppression of viral loads and immunereconstitution, HIV-positive individuals exhibit excess vulnerability to multiple health problems that are not AIDS-defining. With the accumulation of multiple health problems, it is likely that many people aging withtreated HIV infection may be identified as frail. Studies of frailty in people with HIV are currently limitedbut suggest that frailty might be feasible and useful as an integrative marker of multisystem vulnerability,for organizing care and for comprehensively measuring the impact of illness and treatment on overall healthstatus. This review explains how frailty has been conceptualized and measured in the general population, crit-ically reviews emerging data on frailty in people with HIV infection, and explores how the concept of frailtymight inform HIV research and care.
Keywords. HIV; frailty; aging; risk assessment; geriatric assessment; chronic infectious disease; chronic viral illness.
AGING WITH HIV INFECTION some cancers, as well as age-associated immunologicchanges and chronic inflammation [Each involve Effective therapies have transformed human immuno- different physiological systems and etiologies yet are all deficiency virus (HIV) infection into a chronic illness strongly age-associated in the general population. While ]. As people with HIV live longer, aging-related chal- HANA conditions are more common among HIV-pos- lenges are arising. Despite complete suppression of viral itive individuals who are older, have more severe HIV load and immune recovery, HIV-positive individuals disease, and who have longer duration of antiretroviral are more vulnerable to poor health than HIV-negative treatment and toxicity, these factors do not completely individuals []. This vulnerability is characterized by explain differences in risk and survival [].
higher risk of several common, age-related health prob- Among people without HIV, aging and the accumu- lems, even after adjustment for established risk factors.
lation of age-related health problems are also highly These conditions, termed HIV-associated non-AIDS heterogeneous processes. Although people generally ac- (HANA), include cardiovascular disease, osteoporosis, cumulate health problems with age, individuals of the metabolic disorders, hepatic and renal diseases, and same age can experience very different levels of health.
Geriatricians introduced the term "frailty" to describethis variability. Frailty represents the cumulative effects Received 23 December 2013; accepted 23 April 2014.
Correspondence: Kenneth Rockwood, MD, Division of Geriatric Medicine, Dal- of age-related deterioration in multiple physiological housie University, 1421-5955 Veterans' Memorial Lane, Halifax, NS B3H 2E1, Can- systems and homeostatic mechanisms, resulting in greater vulnerability to stressors , Frail individuals The Journal of Infectious Diseases The Author 2014. Published by Oxford University Press on behalf of the Infectious often present with nonspecific health complaints, fluc- Diseases Society of America. All rights reserved. For Permissions, please e-mail: tuating disability, falls, and delirium and are at higher risk for multiple adverse outcomes, including longer Frailty in HIV Infection • JID • 1 hospital stays, postoperative complications, poor responses to cumulative deficit model The phenotype views frailty as a vaccination, functional decline, and death ].
clinical syndrome arising from a "cycle of frailty" composed With the accumulation of multiple health problems, it is like- of chronic undernutriton, sarcopenia, and weakened strength ly that many people aging with HIV may be identified as frail and exercise tolerance. It suggests that frailty pathophysiology ]. The concept of frailty could provide a useful tool to measure is distinct from aging or other disease processes ]. Other fac- and communicate the complexity of aging and vulnerability in tors, such as cognitive impairment, have been suggested as fur- people living with HIV, inform the development of therapies, ther phenotypic characteristics of frailty [].
and guide the delivery of care. This review explains how frailty The cumulative deficit model (first proposed by members of has been conceptualized and measured in the general popula- our group) views frailty as a state of vulnerability, rather than a tion, critically reviews emerging data on frailty in people living syndrome. It suggests that frailty arises from the cumulative effects with HIV, and explores how applying the concept of frailty to of nonspecific age-related health deficits and does not have a research and care might benefit people living with HIV.
unique pathophysiology but rather is related to the aging process[. As people accumulate health deficits and homeostatic mech- FRAILTY IN THE CONTEXT OF HIV anisms begin to fail, those who are frail exhibit excessive changes in health in response to even minor further insults []. Under this Investigators have begun investigating frailty among people model, frailty has been proposed to describe the overall health with HIV to identify individuals more vulnerable to disease state of an individual and therefore serve as an integrative marker progression and death and to measure the effects of illness of biologic aging, as opposed to chronological age , ].
and treatment on health status [, . However, frailty is Studies applying both frailty models have identified associa- not yet well understood in the context of the highly active tions between increasing severity of frailty and age-related dete- antiretroviral therapy (HAART) era, where most HIV-positive rioration in multiple systems, including immunosenescence and individuals now experience significant immune recovery, unde- chronic inflammation [, ], which may be particularly rele- tectable HIV viral load, and primarily HANA clinical manifes- vant in people with treated HIV [, , ].
tations , ]. Neither CD4 count nor viral load appear to beuseful surrogate markers of vulnerability in this immune-recon- MEASURING FRAILTY stituted population, whereas frailty is strongly associated with HANA conditions and disability and might be a Multiple measures exist to identify and measure frailty. Some more sensitive indicator of health changes , ]. Age-related are based on clinical judgment or a single item (eg, walking and HANA conditions have been associated with both immune speed), but most scales assess multiple domains of age-related activation (eg, soluble CD14 and CD163, CD16+ monocytes, health and grade frailty by counting the number of deficits in- HLA-DR+/CD38+ CD8+ T cells) and immune senescence dividuals have acquired One commonly used scale, based markers (eg, terminally differentiated CD45RA + CCR7− on the frailty phenotype [identifies frailty by the presence of CD4+ T cells), as well as inflammatory circulating cytokines 3 deficits out of 5 specific measures originating from the Car- (eg, interleukin 6, tumor necrosis factor α [TNF-α]) [, diovascular Health Study (an existing prospective cohort ]. Frailty is associated with both CD4 count and viral load study): self-reported unintentional weight loss >10lbs or record- ], yet relationships between frailty and markers of immune ed weight loss ≥5% in a year, measured slow walking speed, senescence and activation among HIV-positive individuals measured weak grip strength, self-reported exhaustion (3-4 have not been established. Although the clinical spectrum of days per week or most of the time), and low activity/energy ex- HIV disease differs whether individuals experience immune de- penditure (assessed by Minnesota Leisure Time Questionnaire) ficiency or immune activation, frailty might emerge in the con- [The frailty phenotype scale has been widely applied and text of both profiles. A hypothetical representation of the extensively validated in its ability to identify people at increased association between frailty, HANA, and immune system dysre- risk for a range of adverse outcomes [ gulation is depicted in Figure Causal pathways between these Another commonly used scale, the "frailty index," counts the factors are not yet understood, in part because most studies in- number of deficits individuals have accumulated out of various vestigating HANA or frailty in HIV have been cross-sectional.
health measures and presents them as a proportion [, ].
In contrast to the phenotypic approach, any measure can be included in a frailty index if it is generally related to age andpoor health, and if the group of items covers multiple physio- While "frail" is commonly used to describe vulnerable older logical systems. When at least 30 items are included, the propor- adults, there is no consensus on the best way to define and iden- tion of deficits accumulated appears more informative than the tify frailty systematically [Two conceptual models inform specific nature of those deficits. Though the effect of each indi- most approaches to frailty: the phenotype model and the vidual deficit may be small, their cumulative effects can be large.
2 • JID • Brothers et al

Hypothetical association between frailty prevalence, HANA conditions, and immune system dysregulation. Presented at 4th International Work- shop on HIV and Aging, 30–31 October Baltimore, MD ]. Abbreviations: HANA, HIV-associated non-AIDS; HIV, human immunodeficiency virus.
This reinforces the notion that health problems in the same in- accumulated diverse deficits in health; they might, however, be dividual rarely arise independently from one another [, relatively cumbersome to construct [, ]. Parsimonious Each frailty index can make use of different available measures, scales can be quicker to apply but often require specific mea- including functional limitations, comorbidities, cognition, and sures (eg, grip strength measured by dynamometer) and affect ]. This approach has been operationalized clinically might overlook people with different health problems. Modifi- using data from comprehensive geriatric assessments and rou- cations to such scales are common, especially replacing perfor- tine medical records mance-based measures (eg, walking speed) with self-reported Many other frailty scales exist, often including more items measures (eg, reported difficulty walking), or using different cri- than the 5 specified by the frailty phenotype but fewer than teria for performance-based measures (eg, loss of >10lbs in past the 30 suggested by the frailty index ]. By counting health year vs loss of >5% of body weight in past 6 months), yet the deficits across multiple physiologic systems, frailty scales are validity of such modifications is unknown each able to identify individuals vulnerable to adverse outcomesand to do so better than chronological age alone [, ]. Al-though scales differ in the number and nature of deficits they MEASURING FRAILTY IN HIV-POSITIVE count, people who have accumulated more deficits are more likely to be vulnerable and therefore more likely to be frail]. Different scales also demonstrate remarkable consistency All published studies of frailty in HIV infection use frailty scales in characteristics, including the nonlinear relationship between composed of a limited number of specific health measures, fol- frailty severity and age, greater frailty in women than same-aged lowing the phenotype approach (Table ). For instance, analyses men, and higher risk of death in men than women of equal of the Multicenter AIDS Cohort Study (MACS) used a frailty scale based on 4 self-reported deficits: weight loss, exhaustion, However, as they include different criteria, frailty scales vary impaired physical activity, and difficulty walking [One in ability to predict outcomes and in operational feasibility in study used a single measure of unexpected weight loss to define different settings ]. Frailty scales that include more measures frailty ]. No published studies of frailty in people with HIV can more sensitively grade vulnerability and track improvement have used the cumulative deficit/frailty index approach, or and decline and are less likely to overlook individuals who have scales based on clinical judgment.
Frailty in HIV Infection • JID • 3 Deficits Included in Different Frailty Scales Applied to People Living With HIV Inclusion Criteria Deficits Included in Frailty Scale Based on frailty phenotype scale: Urban, community- Age 18+; no clinical AIDS Considered frail if 3 Weight loss: ‘Since your last visit (6 mo based cohort of men ago), have you had unintentional weight who have sex with loss of at least 10 pounds?' Exhaustion: ‘During the past 4 wks, as a result of your physical health, have you had difficulty performing your work or other activities (for example, it took Low activity: ‘Does your health nowlimit you in vigorous activities, such asrunning, lifting heavy objects,participating in strenuous sports?' Slowness: ‘Does your health now limit you in walking several blocks?' Urban, community- Age 18+; either HIV−, or Considered frail if 3 Weight loss: ‘Since your last visit have HIV+ receiving ART you had unintended weight loss of at least 10 pounds?' Exhaustion: ‘During the past 4 wks, as a result of your physical health, have you had difficulty performing your work or other activities (for example, it took Low activity: ‘Does your health nowlimit you in vigorous activities, such asrunning, lifting heavy objects,participating in strenuous sports?' Slowness: Timed 4 m walk Weakness: Grip strength measuredwith dynamometer Urban, community- Age 13+; receiving ART; Considered frail if 3 Weight loss: ≥10 pounds in past year, based HIV-positive participants with ‘missing self reported and confirmed by physical female cohort in five limbs, prostheses, paralysis, or assistive Exhaustion: ‘based on responses to devices' were excluded two items from the CES-D scale' from walking speed and Low activity: A modified version of the grip strength tests and Minnesota Leisure Time Activities assigned missing values Questionnaire ‘capturing intensity andduration of 18 activities that range fromwork to child care' Slowness: Timed 4 m walk Weakness: Grip strength measuredwith dynamometer Urban, outpatient clinic Age 18+; participants with Considered frail if 3 Weight loss: >10 pounds in past year convenience sample any pain, arthritis, or ≥5% of previous year's body tendonitis, or carpal weight, unintentionally, based on tunnel syndrome were excluded from grip test Exhaustion: Answering ‘occasionally and assigned missing (3–4 d)' or ‘most of the time (5–7 d)' to values; participants with either ‘How often have you felt that missing limbs, paralysis, everything you did was an effort' or or needing assistive ‘How often have you felt that I could not device were excluded from walking speed test Low activity: Answering ‘yes, limited a and assigned missing lot', when asked ‘whether their health limits vigorous activities such asrunning, lifting heavy objects' Slowness: Timed 15 ft walk, stratifiedby gender and height Weakness: Grip strength measuredwith dynamometer, stratified by genderand body mass index 4 • JID • Brothers et al Table 1 continued.
Inclusion Criteria Deficits Included in Frailty Scale Urban, community- Age 18+; history of injecting Considered frail if 3 Weight loss: ≥5% of body weight since last visit (ranged from 5 to 12 mo), preset; ‘prefrail' if based on physical exam history of injecting Exhaustion: Answering ‘moderate' or ‘most of the time' to either ‘During the past week, I felt everything I did was an effort' or ‘During the past week, I couldnot get going' Low activity: Answering ‘limited a lot',when asked ‘Does your health nowlimit the kinds or amount of vigorousactivities you can do, like lifting heavyobjects, running, or participating instrenuous sports?' Slowness: Timed 4 m walk; deficit assigned to lowest 20% of participantsstratified by gender and height Weakness: Grip strength measuredwith dynamometer; deficit assigned tolowest 20% of participants stratified bygender and body mass index Urban, outpatient clinic Considered frail if 3 Weight loss: ≥10 pounds in past year, convenience sample unintentionally, based on physical exam Exhaustion: Answering ‘3 to 4 d' or ‘mostof the time' to either ‘How often in thelast week did you feel that everything wasan effort' or ‘ . . I could not get going.' Low activity: Weighted score ofkilocalories expended per week asmeasured by Minnesota Leisure TimeActivity Questionnaire Slowness: Timed 15 ft walk, stratifiedby gender and height Weakness: Grip strength measuredwith dynamometer, stratified by genderand body mass index Urban, community- Age 30+; no opportunistic Considered frail if 3 Weight loss: >10 pounds in past year, based HIV-positive infections or symptoms or ≥5% of previous year's body weight, unintentionally, based on clinic records participants with pain or Exhaustion: Answering ‘occasionally arthritis of dominant hand (3–4 d)' or ‘most of the time (5–7 d)' to were excluded from grip either ‘How often have you felt that strength test and everything you did was an effort' or assigned missing values; ‘ . . that I could not ‘get going'' participants with paralysis Low activity: Answering ‘yes, limited a or needing assistive lot', when asked ‘whether their health device were excluded limits vigorous activities such as from walking tests and running, lifting heavy objects.' assigned missing values.
Slowness: Timed 6 m walk, stratified bygender and height Weakness: Grip strength measuredwith dynamometer, stratified by genderand body mass index All individuals receiving Age 45–65; taking effective Considered frail if 3 Weight loss: ≥4.5 kg in past year, or ART for at least 6 mo; at ≥5% of previous year's body weight, least one clinic visit with unintentionally, self reported and outpatient clinic at a plasma HIV RNA <48 verified by records when available copies/mL, and no visit Exhaustion: 3-4 times per week of with plasma HIV RNA feeling ‘everything I do is an effort' or >200 copies/mL in prior ‘sometimes I just cannot get going.' Low activity: Self-report of being ‘limited a lot' in vigorous physicalactivities on the SF-36 questionnaire Slowness: Timed 4.5 m walk, stratifiedby gender and height Weakness: grip strength measuredwith dynamometer, stratified by genderand body mass index Frailty in HIV Infection • JID • 5 Table 1 continued.
Inclusion Criteria Deficits Included in Frailty Scale Participants recruited Age 20–40 or 50+; English Considered frail if 3 Weight loss: >10lbs unintentional for a pilot clinical trial speaking; on stable ART weight loss (time period unspecified) for 12 wks or not Exhaustion: Fatigue Severity Scale anticipating initiating ART for 6 wks; no intercurrent Low activity: POMS activity scale score acute infection, active psychiatric illness, active Slowness: Timed Gait Test (10 neurologic disease, yards × 2) >11 s current delirium or Weakness: Grip strength >1 SD below intoxication, active drug or alcohol overuse, orpregnancy Based on other frailty scales: Urban, hospital based Age 50+; receiving Considered frail if Physical Performance Test score of 18 HIV clinic outpatients antiretroviral therapy for 3+ mo and continuing; Peak oxygen uptake of 11 to 18 mL/kg able to ambulate without assistive devices; no Difficulty with one activity of daily living AIDS-defining illnesses (ADL) or two or more instrumental for 6 mo; no ‘severe cardiopulmonary illness, severe anemia, significantorthopedic orneuromuscularimpairments, renal failure,cirrhosis, significantcognitive or sensoryimpairments, untreateddepression, unstablemanic or psychoticdisorder, or active 20 patients selected Participants had identified Limitations with basic activities of daily from outpatient clinic problems in multiple severely frail if 3 Limitations with instrumental activities of dialing living moderately frail if ‘hearing and visual screening' frail if 1 deficit ‘mobility problems' All patients newly Considered frail if Unexpected weight loss diagnosed with HIV infection at tertiary care hospital inKolkata from 2008 to2012 All HIV-positive US veterans receiving care in the Veterans FIB-4 (a measure of liver fibrosis): (years of age × AST)/platelets in 100/ L × square root of ALT) Estimated glomerular filtration rate: creatinine)−1.154 × (age)−0.203 × 1.21 ifBlack Hepatitis C status Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus.
A recently introduced measure of health status in people The VACS index is a prognostic tool made up of both traditional aging with treated HIV, the Veterans Aging Cohort Study HIV-related factors, including CD4 count and viral load, as well (VACS) index, has also been proposed to measure frailty as hepatitis C coinfection, liver fibrosis (FIB-4), hemoglobin, 6 • JID • Brothers et al estimated glomerular filtration rate (eGFR), race, and age. In- Summary of Factors Associated With Frailty Among vestigators have considered adding measures to the index, in- HIV-positive Individuals on Antiretroviral Therapy cluding inflammatory markers D-dimer and soluble CD14]. As the VACS index is a measure of multisystem deteriora- Age [, ]HIV-related measures tion and vulnerability, we included it as a frailty scale. However, Longer time since diagnosis the VACS index differs from other frailty measures as it was de- Lower current CD4 count [, signed to predict mortality and includes chronological age and Lower nadir CD4 count race Most frailty scales do not include age, as they intend Low CD4/CD8 ratio [ to describe biological age-related changes independent from Detectable viral load [ chronological age, and most do not include race, because they Longer duration of HAART ] instead incorporate markers of individual physical and mental Protease inhibitor-containing HAART regimen Further work is needed to determine the best approach to Hepatitis C coinfection ] measure frailty in people aging with HIV. It is important to con- sider the intended use and setting for a frailty scale, whether as a brief screening tool or as a comprehensive evaluation, for use in the community, hospital, or long-term care. Some scales that Kidney disease [] have been used to identify frailty in people with HIV might Depressive symptoms , not be appropriate for those who are very frail or immobile, Cognitive impairment [] as they include measures of physical performance (eg, walking speed , or apply exclusion criteria based on disability Weak upper and lower extremities [] or comorbidities. One study using a modified version of the History of falls frailty phenotype scale in an HIV clinic excluded 19% of partic- ipants because time constraints prevented assessment of grip Lower education , strength and walking speed and another excluded partici- Current unemployment [ pants requiring an assistive device to walk [ Low income in past year Abbreviations: BMI, body mass index; HAART, highly active antiretroviral EPIDEMIOLOGY OF FRAILTY IN HIV INFECTION therapy; HIV, human immunodeficiency virus.
Before the introduction of HAART in 1996, men in the MACSstudy who seroconverted were 9 times more likely to be identi-fied as frail (via a modified frailty phenotype) during at least 1 [<200 cells/mm3 [], and <100 cells/mm3 []), lower study visit than men who remained uninfected (13.9% vs 1.5% nadir CD4 count [CD4/CD8 ratio ≤0.29 [detectable prevalence) Risk for frailty increased nonlinearly with age viral load history of AIDS ], and longer time since and with duration of HIV infection Frailty was also asso- diagnosis [], as well as hepatitis C coinfection [], low body ciated with CD4 count <350 cells/mm3, viral load ≥50 000 cop- mass index (BMI) , ], high BMI [], lipodystrophy [], ies/mL, and AIDS [ depressive symptoms , 1-year history of multiple falls With the introduction of HAART, the prevalence of frailty [], and lower cognitive performance ]. HIV-positive indi- appeared to decrease. Among MACS participants, frailty de- viduals who are frail are also more likely to have lower socioe- creased from 8% in 1994–1995, when <0.1% of participants re- conomic status, no more than high school education ], ceived HAART, to 5% in 2000–2005, when almost 70% were on current unemployment [and income <$10 000 in the HAART ]. Among participants presenting with AIDS, frailty prior year ]. Among people who inject drugs, those with ad- prevalence decreased from 24% to 10% []. However, from vanced HIV disease (defined as CD4 <350 cells/mm3 and de- 2007–2011, when grip strength was added to the MACS frailty tectable viral load) are more likely to be frail than uninfected scale, 25% of all participants were identified as frail during at individuals, whereas those without advanced HIV disease are least 1 study visit []. Here the use of different scales compli- not more likely to be frail ]. Frail HIV-positive individuals cates comparison of estimates between studies , are also more likely to have been on HAART for longer duration Among individuals on HAART, multiple factors have been [and on a protease inhibitor-containing HAART regimen associated with frailty in cross-sectional studies, using different and less likely to be on a non-nucleoside reverse transcriptase frailty scales (Table ). Some are traditional HIV measures, in- inhibitor-containing regimen; this disparity is not explained cluding lower current CD4 cell count (measured continuously [ by differences in adherence or successful viral suppression ] and categorically, as <500 cells/mm3 [, <350 cells/mm3 [Frail HIV-positive individuals are also more likely than Frailty in HIV Infection • JID • 7 the nonfrail to have been hospitalized in the past year and to outcomes To date, knowledge is limited regarding the have longer hospital stays prognostic characteristics of frailty in people with HIV. In 1 Also in cross-sectional studies, markers of inflammation (in- sample of people who inject drugs, having HIV or being frail terleukin-6, D-dimer, and soluble CD14) are more strongly cor- was associated with 3-fold higher likelihood of death, whereas related with VACS index scores than an index comprised only of both having HIV and being frail increased the risk 7-fold com- age, CD4 cell count, and viral load [VACS index scores are pared to those with neither [In the MACS study, the pres- also associated with upper and lower extremity strength [ ence of frailty prior to HAART initiation decreased time to and cognitive impairment ]. Although VACS index scores AIDS or death [. The prevalence of frailty at baseline was were suggestive of an association with 1-year history of multiple 8%; 36% of people who frail at baseline developed AIDS or falls in 1 study, this was not statistically significant []. As falls died, whereas 16% of people who were not frail developed are a common outcome identified among frail HIV-negative AIDS or died ].
older adults ], further research is needed to assess whether Although assessments of outcomes related to frailty in people the VACS index is measuring frailty or a different but related with HIV are limited, multiple prospective studies have evaluat- construct, including some common components.
ed outcomes in relation to the VACS index. Higher VACS index Two longitudinal analyses of frailty in people with HIV have scores are associated with all-cause mortality [coronary been published, both from the MACS cohort. One report in- heart disease-related mortality [], and fragility fractures, cluded data from before 2007 ] and the second data from suggesting that the index might indeed measure frailty as well 2007 to 2011 [. Each report used a different modification []. Compared to CD4 count and viral load, VACS index scores of the frailty phenotype scale (Table which complicates com- had better predictive ability for mortality among HIV-positive parisons between the 2 time periods. In both studies, likelihood individuals with viral load <500 copies/mL and those age ≥50 of presenting as frail at a later study visit was associated with lower CD4 count and no greater than high school education[Some risk factors for frailty identified in pre-2007 FUTURE DIRECTIONS: FRAILTY AND HIV CARE data were not replicated in the second analysis (eg, white,non-Hispanic ethnicity [), and other risk factors were as- While early data have identified the feasibility and usefulness of sessed in only 1 study. In pre-2007 data, the association between measuring frailty in people aging with HIV, the implications of frailty and low CD4 count was identified independently of low incorporating frailty concepts into HIV care are unknown. The viral load (<400 copies/mL) and hepatitis B and C coinfection.
ultimate question will be whether recognizing frailty assists in Participants with high viral load (>50 000 copies/mL) were also the clinical management of patients with HIV who are frail.
significantly more likely to become frail In the analysis of Even when immunologically stable, people with HIV accumu- data from 2007 to 2011, participants with detectable viral loads late a variety of health problems, and each individual problem were not more likely to become frail than those with undetect- likely cannot characterize overall vulnerability. As people with able viral loads, but participants with depressive symptoms, di- HIV live longer, many will survive to such an age that they abetes mellitus, and kidney disease were more likely to become might be frail in spite of –not because of –the disease. Models frail [Also in the 2007–2011 data, HIV-positive participants of care need to adapt to this changing paradigm, and principles with a history of AIDS had higher odds of becoming frail than of frailty management may be useful ]. A challenge in the HIV-negative participants, whereas HIV-positive participants management of any patient with complex needs is that many without history of AIDS did not have higher odds [ clinical interventions are intended to help people with only 1 As frailty represents an integrative marker of health and vul- problem, and such interventions can do harm in people who nerability, and the severity of frailty can worsen or improve over have many problems Interdisciplinary assessment and time [], more longitudinal research is needed. In particular, care can improve clinical outcomes for people who are frail, risk factors for frailty among HIV-positive individuals aging and screening for frailty among patients with complex needs with high CD4 counts and undetectable viral loads have not has been found to be both feasible and useful in primary care been identified. This will be critical as this profile represents settings []. Future studies should investigate comprehensive as- many HIV-positive persons currently ageing successfully with sessments and frailty screening in the delivery of care to people treated HIV infection [ aging with HIV.
Healthy aging with HIV may be promoted by early interven- FRAILTY AND HEALTH OUTCOMES IN HIV tions among those who are at risk for becoming frail. As frailty is associated with lower CD4 count, and risk appears to declineonce individuals begin HAART ], early antiretroviral treat- The clinical importance of frailty is often noted as its ability ment might delay or reduce the severity of frailty. In longitudinal to describe individuals more vulnerable to adverse health studies, some older HIV-negative adults show improvement in 8 • JID • Brothers et al frailty status over time and not simply progressive decline [].
Frailty might be an especially dynamic process in people with Financial support. This work was supported in part by a Canadian In- HIV, particularly in younger people with greater physiologic re- stitutes of Health Research (CIHR) planning grant on ‘HIV/AIDS and co- serve and greater opportunity to improve ]. However, con- morbidities', and also by the Fountain Innovation Fund of the QEII Health tributions of long-term antiretroviral treatment and toxicity to Sciences Centre Research Foundation. G. G. is supported by ‘Co-morbidityin relation to AIDS' grant agreement (305522), Seventh Framework Pro- frailty are unknown. Characteristics of frailty and opportunities gramme. O. T. is supported by a Banting Postdoctoral Fellowship. K. R. is for intervention should be investigated among the increasing pro- supported by a CIHR Operating Grant as well as the Dalhousie Medical Re- portion of treated HIV-positive individuals who demonstrate search Foundation through the Kathryn Allen Weldon Chain in AlzheimerResearch.
high CD4 counts and undetectable viral loads.
Potential conflicts of interest. J. F. has received consulting fees from Evidence is also unavailable regarding effective interventions Theratechnologies, Inc, and has received payment for lectures from Viiv for HIV-positive people who are already frail. Much of the ev- Canada, Gilead Canada, and Abbott Canada. With colleagues, K. R. has ap-plied to various Canadian government schemes to commercialize a version idence for the care of frail HIV-positive people is necessarily of a frailty index based on a Comprehensive Geriatric Assessment, and a based on trials performed on younger and fitter people. Al- company called Videx Canada was incorporated for this purpose. At present though some medical interventions developed in fit populations Videx Canada no longer exists. The version of the frailty index presented are less effective, or even dangerous, in people who are frail, oth- here was not the one that Videx aimed to commercialize. Videx Canadaplayed no role in the preparation of this manuscript. K. R. was associated ers can continue to have important benefits. Although some with Videx Canada but received no funding while it existed. All other au- treatments provide smaller risk reductions in people who are thors report no conflicts of interest.
frail, the high absolute risk for poor outcomes with frailty All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the con- might make this smaller benefit worthwhile ]. People aging tent of the manuscript have been disclosed.
while receiving HAART are also at high risk of polypharmacyand related adverse outcomes, and people who are frail are likely most vulnerable []. Better understanding of optimal prescrib-ing for frail patients on HAART is needed.
1. Deeks SG, Lewin SR, Havlir DV. The end of AIDS: HIV infection as a chronic disease. Lancet 2013; 382:1525–33.
2. High KP, Brennan-Ing M, Clifford DB, et al. HIV and aging: state of knowledge and areas of critical need for research: a report to the NIH Office of AIDS Research by the HIV and Aging Working Group. J Ac- quir Immune Defic Syndromes 2012; 60:S1–18.
The increasing life spans of people with HIV reflect enormous 3. Guaraldi G, Orlando G, Zona S, et al. Premature age-related comorbid- treatment successes and present new challenges related to aging.
ities among HIV-infected persons compared with the general popula-tion. Clin Infect Dis 2011; 53:1120–6.
Although some people with HIV live to older ages with relatively 4. Deeks SG. HIV infection, inflammation, immunosenescence, and aging.
few health problems, others accumulate multiple problems earlier Annu Rev Med 2011; 62:141–55.
in life. Risk for HANA conditions and other adverse outcomes 5. Fitch KV, Srinivasa S, Abbara S, et al. Noncalcified coronary atheroscle- rotic plaque and immune activation in HIV-infected women. J Infect vary significantly between individuals, and are not fully explained Dis 2013; 208:1737–46.
by age, HIV disease severity, or duration of antiretroviral treat- 6. Justice AC, Freiberg MS, Tracy R, et al. Does an index composed of ment and toxicity. With the accumulation of multiple health clinical data reflect effects of inflammation, coagulation, and monocyteactivation on mortality among those aging with HIV? Clin Infect Dis problems, it is likely that many people aging with HIV may be 2012; 54:984–94.
identified as frail. Emerging data suggest frailty might be a feasible 7. Clegg A, Young J, Iliffe S, Olde Rikkert M, Rockwood K. Frailty in and useful integrative marker of multisystem vulnerability in peo- elderly people. Lancet 2013; 381:752–62.
ple aging with HIV. As people with HIV live longer and with 8. Mitnitski A, Song X, Rockwood K. Assessing biological aging: the origin of deficit accumulation. Biogerontol 2013; 14:709–17.
more complex health and social care needs, the concept of frailty 9. Brothers TD, Rockwood K. Biologic ageing, frailty, and age- could be useful for identifying vulnerable individuals, for organiz- related disease in chronic HIV infection. Curr Opin HIV AIDS. 2014 ing care and for comprehensively measuring the impact of illness May 17 [Epub ahead of print].
10. Onen NF, Overton ET. A review of premature frailty in HIV-infected and treatment on overall health status.
persons; another manifestation of HIV-related accelerated aging. CurrAging Sci 2011; 4:33–41.
11. Ruiz M, Cefalu C. Frailty syndrome in patients with HIV infection. Clin Geriatr 2011; 19:46–9.
12. Onen NF, Agbebi A, Shacham E, Stamm KE, Onen AR, Overton ET.
Frailty among HIV-infected persons in an urban outpatient care setting.
We searched Cochrane Library, CINAHL, PubMed, Embase, J Infect 2009; 59:346–52.
PyschINFO, and Google Scholar using the terms "frail" or 13. Althoff KN, Jacobson LP, Cranston RD, et al. Age, comorbidities, and "frailty" along with "human immunodeficiency virus" or AIDS predict a frailty phenotype in men who have sex with men. J Ger- "HIV." Additional papers were identified from reference lists ontol A Biol Sci Med Sci 2014; 69:189–98.
14. Guaraldi G, Baraboutis IG. Evolving perspectives on HIV-associated of retrieved articles, Google Scholar linking of articles citing re- lipodystrophy syndrome: moving from lipodystrophy to non-infectious trieved articles, and personal libraries of the authors.
HIV co-morbidities. J Antimicrob Chemother 2009; 64:437–40.
Frailty in HIV Infection • JID • 9 15. Erlandson KM, Allshouse AA, Jankowski CM, et al. Association of 32. Piggott DA, Muzaale AD, Mehta SH, et al. Frailty, HIV infection, and functional impairment with inflammation and immune activation in mortality in an aging cohort of injection drug users. PLOS One 2013; 8: HIV type 1–infected adults receiving effective antiretroviral therapy. J Infect Dis 2013; 208:249–59.
33. Ianas V, Berg E, Mohler MJ, Wendel C, Klotz SA. Antiretroviral therapy 16. Desai S, Landay A. Early immune senescence in HIV disease. Curr HIV/ protects against frailty in HIV-1 infection. J Int Assoc Provid AIDS Care AIDS Rep 2010; 7:4–10.
2012; 12:62–6.
17. Desquilbet L, Margolick JB, Fried LP, et al. Relationship between a frail- 34. Pathai S, Gilbert C, Weiss HA, et al. Frailty in HIV-infected adults in ty-related phenotype and progressive deterioration of the immune sys- South Africa. J Acquir Immune Defic Syndr 2012; 62:43–51.
tem in HIV-infected men. J Acquir Immune Defic Syndr 2009; 35. Erlandson KM, Allshouse AA, Jankowski CM, et al. Comparison of functional status instruments in HIV-infected adults on effective anti- 18. Guaraldi G, Zona S, Stentarelli C, et al. Aging with HIV vs HIV sero- retroviral therapy. HIV Clin Trials 2012; 13:324–34.
conversion at older age: a diverse population with distinct comorbidity 36. Erlandson KM, Allshouse AA, Jankowski CM, et al. Risk factors for falls profiles. Antivir Ther 2013; 9:14.
in HIV-infected persons. J Acquir Immune Defic Syndr 2012; 61:484–9.
19. Walston J. Frailty-the search for underlying causes. Sci Aging Knowl- 37. Sandkovsky U, Robertson KR, Meza JL, et al. Pilot study of younger and edge Environ 2004; 2004:pe4.
older HIV-infected adults using traditional and novel functional assess- 20. Mitnitski AB, Mogilner AJ, Rockwood K. Accumulation of deficits ments. HIV Clin Trials 2013; 14:165–74.
as a proxy measure of aging. Scientific World Journal 2001; 1: 38. Shah K, Hilton TN, Myers L, Pinto JF, Luque AE, Hall WJ. A new frailty syndrome: central obesity and frailty in older adults with the human im- 21. Collerton J, Martin-Ruiz C, Davies K, et al. Frailty and the role of in- munodeficiency virus. J Am Geriatr Soc 2012; 60:545–9.
flammation, immunosenescence and cellular ageing in the very old: 39. Ruiz MA, Aguilar E, Sirisha P, Frontini M, Cefalu C. Characteristics of Cross-sectional findings from the Newcastle 85 study. Mech Ageing frail patients in a geriatric-HIV program: the experience of an urban ac- Dev 2012; 133:456–66.
ademic center at one year follow-up. J Am Geriatr Soc 2012; 60:S217–8.
22. Margolick JB, Chopra RK. Relationship between the immune system 40. Talukdar A, Khanra D, Ray S, et al. HIV among the elderly with special and frailty: Pathogenesis of immune deficiency in HIV infection and reference to mode of presentation at a tertiary care hospital in Kolkata, aging. Aging Clin Exp Res 1992; 4:255–7.
India. Trop Doct 2013; 43:100–2.
23. Theou O, Brothers TD, Mitnitski A, Rockwood K. Operationalization of 41. Womack JA, Goulet JL, Gibert C, et al. Physiologic frailty and fragility frailty using eight scales and comparison of their ability to predict all- fracture in HIV-infected male veterans. Clin Infect Dis 2013; cause mortality. J Am Geriatr Soc 2013; 61:1537–51.
24. Fried L, Tangen C, Walston J, et al. Frailty in older adults: evidence for a 42. Justice AC, Modur SP, Tate JP, et al. Predictive accuracyof the Veterans Aging phenotype. J Gerontol A Biol Sci Med Sci 2001; 56:M146.
Cohort Study index for mortality with HIV infection: a North American 25. Xue QL. The frailty syndrome: definition and natural history. Clin Ger- cross cohort analysis. J Acquir Immune Defic Syndr 2013; 62:149–63.
iatr Med 2011; 27:1–15.
43. Tate JP, Justice AC, Hughes MD, et al. An internationally generalizable 26. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A stan- risk index for mortality after one year of antiretroviral therapy. AIDS dard procedure for creating a frailty index. BMC Geriatr 2008; 8:24.
2013; 27:563–72.
27. Theou O, Brothers TD, Pena A, Mitnitski A, Rockwood K. Identifying 44. Adeyemi O, Livak B. Higher Veterans Aging Cohort Study (VACS) index common characteristics of frailty across seven scales. J Am Geriatr Soc scores in HIV-positive adults with CD4 counts <200 cells/mm3 despite 2014; 62:901–6.
viral suppression. J Acquir Immune Defic Syndr 2013; 63:e78–81.
28. Kulminski AM, Ukraintseva SV, Kulminskaya IV, Arbeev KG, Land K, 45. Marquine MJ, Umlauf A, Rooney AS, et al. The Veterans Aging Cohort Yashin AI. Cumulative deficits better characterize susceptibility Study index is associated with concurrent risk for neurocognitive im- to death in elderly people than phenotypic frailty: lessons from pairment. J Acquir Immune Defic Syndr 2014; 65:190–7.
the Cardiovascular Health Study. J Am Geriatr Soc 2008; 56: 46. Oursler K, Tate J, Gill TM, et al. Association of the VACS index with exercise capacity in HIV-infected adults. AIDS Res Hum Retroviruses 29. Desquilbet L, Jacobson LP, Fried LP, et al. HIV-1 infection is associated 2013; 29:1218–23.
with an earlier occurrence of a phenotype related to frailty. J Gerontol A 47. Mitnitski A, Bao L, Skoog I, Rockwood K. A cross-national study of Biol Sci Med Sci 2007; 62:1279–86.
transitions in deficit counts in two birth cohorts: implications for mod- 30. Desquilbet L, Jacobson LP, Fried LP, et al. A frailty-related phenotype eling ageing. Exp Gerontol 2007; 42:241–6.
before HAART initiation as an independent risk factor for AIDS or 48. Justice AC, Tate JP, Freiberg MS, Rodriguez-Barradas MC, Tracy R.
death after HAART among HIV-infected men. J Gerontol A Biol Sci Reply to Chow et al. Clin Infect Dis 2012; 55:751–2.
Med Sci 2011; 66:1030–8.
49. Greene M, Justice AC, Lampiris HW, Valcour V. Management of 31. Terzian AS, Holman S, Nathwani N, et al. Factors associated with pre- human immunodeficiency virus infection in advanced age. JAMA clinical disability and frailty among HIV-infected and HIV-uninfected women in the era of cART. J Womens Health (Larchmt) 2009; 50. Gleason LJ, Luque A, Shah K. Polypharmacy in the HIV-infected older adult population. Clin Interv Aging 2013; 8:749–63.
10 • JID • Brothers et al

Source: http://www.airn.ca/uploads/8/6/1/4/86141358/j_infect_dis_-2014-brothers-infdis_jiu258.pdf