REVIEW URRENT C OPINION
Multimorbidity and functional status assessment Giovanni Guaraldi a, Ana Rita Silva b, and Chiara Stentarelli a
Purpose of review This review conceptualizes multimorbidity and functional status impairment in people living with HIV and their implication in clinical and research fields. Recent findings Multimorbidity is an increasing age-related condition whose prevalence is higher in HIV-infected patients compared with the general population. It portrays the contemporary clinical complexity of HIV care. Whether multimorbidity describes an accelerated or accentuated aging process is the matter of discussion, although some HIV variables depicting immune activation and chronic inflammation are associated with multimorbidity. Multimorbidity coupled with functional status impairment are determinants of a frailty phenotype and in the frailty research setting, multimorbidity can be explored as an endpoint for clinical studies. Summary The success of highly active antiretroviral therapy has significantly changed the clinical pattern of HIV infection, with the ‘greying’ of the HIV-infected population testament to its success. This has provided new challenges relating to the care of older patients, particularly with regard to the management of multimorbidity functional status impairment. Keywords frailty, functional status assessment, HIV, multimorbidity, polypharmacy
INTRODUCTION Contemporary HIV epidemic shows a demographic aging shift among people living with HIV (PLWH). There is an increasing number of patients who are getting old because of the benefits associated with highly active antiretroviral therapy (HAART), but there is also an increasing number of people acquiring HIV at an older age, given the progressive extension of active sexual activity, but low risk perception of the elderly. The overall increase in older HIV patients is the consequence of a dramatic increase in life expectancy, observed both in industrialized and developing counties, exposing PLWH to an overlap between age-related condition and HIVassociated non-AIDS condition (HANA). The process of aging involves a continuum of changes in biological, functional, psychological, and social parameters depending on genetic factors and differences in organ function and reserves. Aging is often accompanied by: chronic comorbid conditions frequently associated in complex pictures so called multimorbidity; altered functional status and frailty [1]. The objective of this review is to describe the conceptualization of multimorbidity and functional status in PLWH and their implication in clinical and research fields. www.co-hivandaids.com
We searched PubMed for articles relevant to the description of multimorbidity and functional status assessment both in HIV and general medicine. This search strategy included articles published in English between January 2010 and December 2013.
MULTIMORBIDITY In the general population, there is no consensus in the definition of multimorbidity or how to measure it. Multimorbidity has been described as the simultaneous occurrence of several medical conditions in the same person [2]. Most of the authors would define two, three or more conditions being present at the same time [3–6]. The most commonly diagnosed medical conditions are dyslipidaemia,
a
Metabolic Clinic, Clinic of Infectious Diseases, University of Modena and Reggio Emilia, Italy and bDepartment of Infectious Diseases, Centro Hospitalar do Porto – Hospital Joaquim Urbano, Portugal Correspondence to Giovanni Guaraldi, MD, Department of Medical and Surgical Sciences for Adults and Children, Infectious Diseases Clinic, University of Modena and Reggio Emilia School of Medicine, Via del Pozzo 71, 41100 Modena, Italy. Tel: +39 059 422 5318; fax: +39 059 422 3710; e-mail: [email protected] Curr Opin HIV AIDS 2014, 9:386–397 DOI:10.1097/COH.0000000000000079 Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Multimorbidity and functional status assessment Guaraldi et al.
KEY POINTS Multimorbidity and functional status impairment are increasing age-related conditions whose prevalence are higher in HIV-infected patients compared with the general population. Whether multimorbidity and functional status describe an accelerated or accentuated aging process is the matter of discussion, although some HIV variables depicting immune activation and chronic inflammation are associated with these conditions. Multimorbidity and functional status describe the contemporary clinical complexity of HIV care. Multimorbidity and functional status are associated and possibly determinants of a frailty phenotype affecting PLWH. In the frailty research setting, multimorbidity and functional status can be explored as endpoints for clinical studies.
cardiovascular disease (CVD), diabetes mellitus, chronic obstructive pulmonary disease (COPD) [7], liver cirrhosis [8], anaemia [9], obesity, chronic kidney disease (CKD) [10], osteopenia/osteoporosis, hypothyroidism, and hypertension (HTN). According to different conditions and clinical settings, they can be diagnosed by self-report prevalence (CVD, COPD, liver cirrhosis, osteoporosis using fracture end point), clinically determined prevalence (CKD, anaemia, osteoporosis using dual energy X-ray absorptiometry), drug-tracing criteria (dyslipidaemia, type 2 diabetes mellitus, HTN) or by using administrative data set collecting International Classification of Diseases, 9th Revision clinical modification codes (ICD9-CM) [3–6,11–14]. The term multimorbidity is often used interchangeably with comorbidity, although the latter refers more specifically to conditions that occur as a consequence of one leading (‘index’) condition such as HIV in the so-called HANA conditions. HANA includes diseases in which after adjustment for established risk factors, association with HIV remains [15]. Interestingly, HANA conditions are the same as the ones used in general literature to characterize age-related condition and define MM.
Pathogenesis of multimorbidity A common mechanism for the development of multimorbidity with increasing age is its association with chronic low-grade inflammation in a process, which has been termed ‘inflammaging.’ During the aging process, changes occur in body systems,
which have a major effect upon the immune system in all individuals (with and without HIV infection). In addition to reductions in circulating growth hormones, increases are seen in the baseline levels of inflammatory cytokines [16,17 ]. Further chronic diseases and inflammation increase atherosclerosis. It is also known that aging influences the interaction between HIV infection and the immune system [18]. This starts a multifactorial process, involving immune activation through chronic infection [including cytomegalovirus (CMV)], immunosenescence, chronic inflammation [19], and the effects of HAART [20]. Evidence exists of increased expression of pro-inflammatory markers in HIV-positive patients compared with the general population [21], with higher levels of these biomarkers independently predicting risk for opportunistic diseases [22] and mortality [23]. In a recent study by our group, CD8þ T-cell activation (CD8þCD38þ) was associated with lipodystrophy (visceral adipose tissue/total adipose tissue), being itself an independent risk factor for homeostasis model of insulin resistance (r ¼ 0.364, P ¼ 0.028) and cardiovascular risk (coronary artery calcium, r ¼ 0.406, P ¼ 0.002) [24]. &
EPIDEMIOLOGY OF MULTIMORBIDITY Comorbidity is seen in non-HIV patients of all ages. A study published in Lancet found that half of the people over 65 years of age have at least three coexisting chronic conditions [25]. This phenomenon seems to be increasing over the past years. In a study of Medicare beneficiaries, the proportion of patients with more than five treated conditions increased from 31 to 50% from 1987 to 2002[26]. It is also worth noting that the diagnoses that are most rapidly on the rise are those for which new drug treatments are available [27]. This issue has also been covered in HIV medicine, with a certain number of studies assessing the prevalence of HANA conditions and multimorbidity in European and United States cohorts. Table 1 [3–6,11–14] summarizes study’s methodology and results. Data from 8844 patients in the Swiss Cohort Study showed a significantly higher incidence of clinical AIDS, mortality and of some comorbidities (including stroke, myocardial infarction, diabetes, bone fractures and non-AIDS-defining malignancies) in HIV-infected patients older than 50 years compared with younger patients [11]. Multivariable hazard ratios for stroke [17.7; confidence interval (CI), 7.06–44.5), myocardial infarction (5.89; 95% CI, 2.17–16.0), diabetes mellitus (3.75; 95% CI, 1.80–7.85), bone fractures without adequate trauma (10.5; 95% CI, 3.58–30.5), osteoporosis (9.13; 95%
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-hivandaids.com
387
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
388
www.co-hivandaids.com
2002–2019 Italy
HIV-infected persons aged >16 years who attended outpatient clinics at seven cohort centers, affiliated regional hospitals, or private practitioners collaborating with the centers. The median age was 45 years: 5761 (68%) were 65 years of age; 2464 (29%) were female, and 1963 (23%) had prior clinical AIDS. The nadir CD4 cell count was 190 cells/ml, and the latest CD4 cell count was 528 cells/ml. In persons aged >65 years and those aged 50–64 years, the median duration of HIV infection was 15.7 and 18.2 years, respectively.
Study Population
Case–control; ART-experienced HIV-infected cross-sectional patients >18 years of age who were consecutively enrolled at the Metabolic Clinic of Modena University in Italy. Control subjects were matched according to age, sex, duration of follow-up, race (all white), and geographical area and were selected from the CINECA ARNO Observational database. The mean age of the overall population was 46 (8) years; 4244 (37%) were female. Median duration of HIV infection was 196 months, median nadir CD4 cell count was 170 cells/ml, and median current CD4 cell count was 520 cells/ml. Plasma HIV RNA levels were below the limit of quantification in 71.3% patients
Study Design
Guaraldi; Premature age-related comorbidities among HIV-infected persons compared with the general population; Clin Infect Dis; 2011 [6]
Country Cross-sectional
Study Year (s)
Hasse; morbidity and 2008–2010 Switzerland aging in HIV-infected persons – The Swiss HIV Cohort Study; Clin Infect Dis; 2011 [11]
Citation (First Author; Title; Journal; Year) Number of comorbidities per age group
Concurrent presence of two or more noninfectious comorbidities
8562 HIV-negative, 2854 HIV-positive
Definition of multimorbidity
8.844
Population size (n)
Table 1. Epidemiological studies assessing the prevalence of HANA conditions and MM
Cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure
Opportunistic infections, HIV malignancies, diabetes mellitus, cardiovascular, renal and liver disease, non-AIDS malignancies, bone-related events, bacterial pneumonia, pancreatitis
Comorbidities used
Higher prevalence’s of renal failure, bone fractures, and diabetes were observed among HIVinfected patients. Independent predictors of polypathology in the overall cohort were age, male sex, nadir CD4 cell count, 200 cells/l, and ART exposure.
Hazard ratios for stroke, myocardial infarction, bone fractures with assumed adequate or inadequate trauma, osteoporosis, diabetes mellitus, and non-AIDS malignancies were higher for age groups 50–64 years and >65 years, compared with participants, 50 years of age. After multivariable adjustment for CD4 cell counts, viral load, sex, former and current injection drug use, former and current smoking, and duration of HIV infection, associations with age remained robust.
Outcome details
HIV and aging
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins Prospective
Goulet; Do patterns of comorbidity vary by HIV status, age and HIV severity?; Clin Infect Dis; 2007 [4]
1997–2004 USA
Cross-sectional
Chu; Comorbidity-related 2005–2008 USA treatment outcomes among HIV-infected adults in the bronx, NY; J Urban Health; 2011 [12] 854
The Veterans Aging Cohort Study virtual 66.840 HIV-negative cohort includes veterans receiving care 33.420, HIV-positive during the same year as the index HIVinfected; study population was matched by age, sex and race-matched. The median age was 45 years; 30% were >50 years of age; 98% were male and 60% of the study population were people of color. Models restricted to HIV-infected veterans were adjusted for CD4 cell count and viral load.
HIV-positive adults (>18 years) who initiated HIV and primary medical care at study sites. Subjects must have received all medical treatment at either the hospital-based specialty center or within the community-based network. The mean age of the population was 44 years; 360 (42.2%) were female and 45,6% were African-American. Median duration of HIV infection was 9 years. Four-hundred forty-six (52.2%) had a history of AIDS-defining conditions. Median body mass index (BMI) was 25; 233 (27.3%) were obese (BMI 30)
Presence of a comorbid condition in all three clusters
No. of comorbidities
Clusters: medical disease, substance abuse, psychiatric disorders
Hypertension, dyslipidaemia, diabetes mellitus
(Continued )
Comorbidity prevalence was 60–63%, and prevalence varied by HIV status. Differences remained when the veterans were stratified by age. In multivariable analyses, older HIV-infected veterans were more likely to have substance use disorder and multimorbidity. Renal, vascular, and pulmonary diseases were associated with CD4 cell count >200 cells/mm3; hypertension was associated with CD4 cell count >200 cells/mm3.
Prevalence rates of hypertension, dyslipidaemia, and diabetes in study population were 26% (n ¼ 223), 48% (n ¼ 414), and 13% (n ¼ 108), respectively. Furthermore, 517 subjects (61%) had any one of the three conditions, 182 (21%) had two comorbidities, and 46 (5%) had all three. Factors that significantly increased the odds of having comorbidity were: older age, obesity, relevant family history, and current protease inhibitor use. The study found no consistently significant associations between comorbidity and HIV risk factor, hepatitis C coinfection, or current tobacco and/or alcohol use. Obesity was a relatively strong predictor for comorbidity and with a prevalence of 27% in study population.
Multimorbidity and functional status assessment Guaraldi et al.
www.co-hivandaids.com
389
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
390
www.co-hivandaids.com
2010–2011 USA
Retrospective
Study Design
Kim; Multimorbidity patterns in HIVinfected patients, the role of obesity; J Acquir Immune Defic Syndr; 2012 [5]
Country Prospective
Study Year (s)
Salter; HIV infection, 2007–2009 USA immune suppression, and uncontrolled viremia are associated with increased multimorbidity among aging IVDU; Clin Infect Dis; 2011 [3]
Citation (First Author; Title; Journal; Year)
Table 1 (Continued)
Presence of at least one condition Clusters: metabolic; in two or more disease clusters behavioral; substance use in addition to HIV infection
Comorbidities used
1.844 HIV-positive HIV-infected patients who attended a primary HIV care visit at the 1917 Clinic. Inclusion criteria were: >19 years or older, currently receiving ART, with plasma HIV viral load, CD4 count, height, and weight measured between June 31, 2010 and July 1, 2011; mean age (SD) was 44 10.9 years, 46% were white, 77% male, and MSM constituted the largest HIV transmission risk group (59%, n ¼ 992). Seventy-one percent of the patients had a CD4 count >350 cells/mm3, and 65% of patients had an elevated BMI (36% overweight, 29% obese)
Definition of multimorbidity Presence of up to seven nonDiabetes mellitus, obstructive AIDS-defining chronic conditions lung disease, liver fibrosis, including diabetes, obstructive anaemia, obesity, kidney lung disease, liver fibrosis, dysfunction, hypertension anemia, obesity, kidney dysfunction, and hypertension.
Population size (n)
900 HIV-positive, 362 (ALIVE) study participants followed in a HIV-negative community-based observational cohort; >18 years of age, with a history of injection drug use. Median of age was 48.9 years; 65.1% were male, 87.5% were African-American. Among HIVinfected participants, the median CD4 T-cell count was 292 cells/mm3, 53.8% were currently receiving HAART, and 47.6% had HIV RNA >400 copies/ml.
Study Population
The prevalence of multimorbidity was 65%. Prevalence increased with progressive BMI categories from underweight (64%) to obese (79%). Three multimorbidity clusters were identified: ‘Metabolic’ including hypertension, gout, diabetes mellitus, and chronic kidney disease (range: 0.41–0.84; P < 0.001); ‘Behavioral’ including mood disorders, dyslipidaemia, chronic obstructive pulmonary disease, chronic ulcer disease, osteoarthritis, obstructive sleep apnea, and cardiac disorders (range: 0.32–0.57; P < 0.001); ‘Substance Use’ including alcohol abuse, substance abuse, tobacco abuse, and hepatitis C (range: 0.53–0.89; P < 0.001). Obesity was associated with increased odds of multimorbidity (obese vs. normal BMI category: OR ¼ 1.52, 95% CI ¼ 1.15–2.00).
HIV infection (OR, 1.50; 95% CI, 1.13–1.99) was positively associated with increased multimorbidity. Among HIVinfected participants, multimorbidity was increased with lower nadir CD4 T-cell count (OR, 1.14 per 100-cell decrease; 95% CI, 1.00– 1.29) and higher current HIV RNA (OR, 1.32 per log10 increase; 95% CI, 1.08– 1.60). Older age, being female, not using cigarettes or drugs, and having depressive symptoms were also associated with increased multimorbidity. A substantial proportion of multimorbid conditions in HIV-infected and HIV-uninfected participants were unrecognized and untreated.
Outcome details
HIV and aging
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins Europe
2010–2012 The Netherlands
Prospective
Prospective
HIV-1-infected patients 45 years from a tertiary care HIVoutpatient clinic, and concurrently recruited HIVuninfected public sexual health clinic-attendants
Ongoing recruitment goals: 500 HIV-negative, 1000 HIV-positive >50; 500 HIV positive 60 yrs
N = 542
N = 1724
N = 452
N = 136
No age-related diseases
1 comorbidity
0%
0%
0%
≤ 40 yrs
0%
41 to 50 yrs
51 to 60 yrs
> 60 yrs
N = 1626
N = 5172
N = 1356
N = 408
2 comorbidities
3 comorbidities
4 comorbidities
FIGURE 1. Polypathology prevalence among patients and control subjects, by age categories. The following comorbidities were included: hypertension, diabetes mellitus, hypothyroidism, cardiovascular disease, and bone fractures. Reproduced with permission [6]. 392
www.co-hivandaids.com
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Multimorbidity and functional status assessment Guaraldi et al.
improved because of new therapeutic interventions such as congestive heart failure and, indeed, HIV [29]. This description does not solve the question whether HIV is accelerating aging itself through pathways and mechanisms common to the aging process [30,31], or, alternatively, HIV may simply be an additional risk factor for a wide number of chronic conditions thus accentuating the prevalence of disease at every age [30,32]. Does HIV accelerate or accentuate aging? The answer is probably organ and disease/condition-specific [33]. To resolve this question, it will be important to account for differential exposure to risk factors (e.g., smoking, alcohol, non-HIV sexually transmitted diseases) between HIV-infected and uninfected populations that are likely to result in residual confounding when assessing associations of HIV with increased risk of age-related illness. This is the reason why, more recently, some cohort studies addressing prevalence of multimorbidity in HIV-selected HIVnegative control groups sharing with cases similar risk behaviour. This is the case in particular of the ALIVE cohort. The ALIVE study [3] is a prospective, community-recruited observational cohort of HIVinfected and at-risk current and former intravenous drug users followed outside clinical treatment settings in Baltimore, Maryland, USA. HIV infection (odds ratio [OR], 1.50; 95% CI, 1.13–1.99) was positively associated with increased multimorbidity. In this case, control study HIV-infected and uninfected patients displayed very similar risk behavior and demographic characteristics. Other ongoing cohorts in which cases and control are recruited in sexually transmitted diseases clinics are the POPPY study from UK [14] and HIVAGE study from The Netherlands [13]. Patients enrolled in these studies will contribute to the COBRA study, an European funded research network investigating novel aging biomarkers in HIV [34].
METHODOLOGICAL ISSUES IN COMPARING MULTIMORBIDITY Besides study population, other methodological issue should be taken into account when comparing prevalence and incidence of multimorbidity in PLWH and the general population. First, the different distribution of age categories needs mathematical adjustments to compensate differences in age group prevalence. Second, cohort studies cannot avoid a selection bias, which may result in a distortion of the results of a study based on the way in which patients are sampled, and perhaps even more important, reverse causality cannot be excluded [35]. Interestingly, this problem is quite similar to the ‘survival bias’ that complicates the interpretation of many studies on aging: the older patients,
in an observational cohort, may represent the fittest population, whereas the vulnerable individuals may be under-represented because they have already died. The same mechanism can be true for multimorbidity, being itself an item strictly associated with mortality.
CLINICAL CONSEQUENCES OF MULTIMORBIDITY One of the greatest challenges that health systems globally is facing is the increasing burden of chronic diseases [36]. Greater longevity, increasing exposure to many chronic disease risk factors, and the growing ability to intervene to keep people alive have combined to change the burden of diseases confronting health systems. Similarly, management of older HIV patients is complicated by the likelihood of comorbidities requiring treatment, resultant problems with drug toxicity, interactions on polypharmacy, and changes in pharmacokinetics (potential for drug accumulation and toxicity). In view of this, current HIV guidelines (including Department of Health and Human Services [37], European Aids Clinical Society [38], British HIV Association [39], and Italian HIV Guidelines [40]) recommend close monitoring of cardiovascular, metabolic, liver, kidney, and bone health in older patients. These guidelines also recommend the regular assessment of drug interactions, especially when starting or switching drugs. Nevertheless, no recommendation on preferred antiretroviral therapy (ART) regimens in older patients has been made so far. The delivery of improved care for older patients will require HIV experts and primary care providers to work together to optimize HAART and other pharmacotherapy, to monitor relevant health indices regularly, and to minimize toxicity. Although care is likely to require the input of a range of different medical specialists on a case-bycase basis, the HIV-treating physician will remain central to care and must balance the often competing demands of maintaining effective viral suppression while managing multimorbidity, treatment side-effects, and drug interactions. Education and involvement of the patient remain vital for the success of any treatment plan to ensure it meets the varying needs of individual patients. Multimorbidity treatment implies polypharmacy. This can be simply defined as the concomitant use of five or more medications [41 ], or the use of a potentially inappropriate drug for which the medication does not match the diagnosis [41 ,42 ]. Polypharmacy among the general population and those in care for HIV infection is common. Recent data from the Swiss HIV Cohort demonstrate that among those 65 years and older, 14% received medications
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
&
www.co-hivandaids.com
393
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIV and aging
control study, which compared direct medical care costs of comorbidities in HIV-infected and uninfected control, accounted for a cost expenditure three times higher than that of HIV infection per se, excluding HAART (US$8911 vs. US$2878) [42 ]. Figure 2 compares the direct cost of HIV outpatient, and ART and comorbidities. Increased age was associated with increased direct cost of comorbidities in both cases and controls (P < 0.001). On the contrary, the cost of HAART did not change across age categories, in HIV patients. Interestingly, the reduction of total care cost observed in increasing CD4 strata was compensated by the increase of the total care cost observed across age strata because of the increased cost of age-related conditions. We therefore believe that in the contemporary epidemiological status in which the majority of PLWHA will be older than 50 years by the year 2015, health care providers may expect an increase in total care cost for the HIV-infected population [54–56]. &
FROM MULTIMORBIDITY TO FUNCTIONAL ASSESSMENT IN THE DESCRIPTION OF FRAILTY The geriatric assessment is a multidimensional, multidisciplinary assessment designed to evaluate
6000 0
2000
4000
US dollars
8000
10,000
from four or more classes of non-HIV medications, where lipid-lowering agents were the most commonly prescribed non-ART medication [11]. These data are consistent with findings from the VACS, wherein among those 50 years and older, 55% were on five or more daily medications [43]. Because these studies report only prescription medication, they likely underestimate the prevalence of polypharmacy. Polypharmacy has also been associated with increased risk of adverse drug reactions, increased hospitalizations, poor adherence, inappropriate drugs, falls and fractures, and drug–drug interactions [44–49]. Polypharmacy can be linked to increased costs for both the patient and the healthcare system. Multiple prescriptions result in increased financial burden for older patients whose income generally consists of using savings from a retirement account and a fixed income such as Social Security [50]. Additionally, minor drug interactions can lead to increased clinic visits, a prescribing cascade wherein additional medications are given to treat new symptoms, or new lab or imaging studies. Serious adverse events from polypharmacy can lead to specialist visits, emergency department visits, and hospital admissions [51–53]. In a recently published case-
60
HIV–
60
HIV+
Mean of NICM costs
Mean of drug costs (no ART)
Mean of HIV outpatient costs
Mean of ART costs
FIGURE 2. Total cost of medical care in cases and controls stratified by age decades. Reproduced with permission [42 ]. &
394
www.co-hivandaids.com
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Multimorbidity and functional status assessment Guaraldi et al.
an older person’s functional ability, physical health, cognition and mental health, and socioenvironmental circumstances. It differs from a standard medical evaluation by including nonmedical domains, by emphasizing functional capacity and quality of life. This assessment begins with a review of two key divisions of functional ability: Activities of daily living (ADL) and instrumental activities of daily living (IADL). ADLs are self-care activities that a person performs daily (e.g., eating, dressing, bathing, transferring between the bed and a chair, using the toilet, controlling bladder and bowel functions). IADL are activities that are needed to live independently (e.g., doing housework, preparing meals, taking medications proper managing finances, using a telephone) [57]. Although these tools seem to be particularly suitable for patients with disabilities, their use in patients younger than 75 years may not reach adequate sensitivity. Several other functional assessment tools have been used in older non-HIV and in HIV populations including the Short Physical Performance Battery (SPPB), the 400-m walk test, and Fried’s frailty phenotype (FFP), all of these being associated with morbidity and mortality in elderly persons [58]. A recent article by Erlandson et al. [58] compared FFP, SPPB and 400-m walk test in a population consisting of 85% male with a median age of 50.8 years and a median CD4þ lymphocyte count of 551 cells/ml. All three instruments revealed high levels of impairment with more than 50% of participants being unable to maintain a walking speed faster than 5.5 km/h in the 400-m walk test, and more than 7% of the study population meeting criteria for frailty. Despite the finding that all three instruments detected similar frequencies of functional impairment in the study population, there was only modest agreement across instruments for the degree of impairment (61–64%; k ¼ 0.34–0.41). These discordances can be explained, in part, by the characteristics of the assessments: the FFP is a global assessment including subjective components that may overlap with depressive symptoms, the SPPB focuses on lower extremity function, and the 400-m walk test requires more endurance and incorporates the broad impact of multiple disease processes [58]. A cross-sectional study conducted in 142 HIV subjects with a median age of 57 years (range 50–74) recruited in San Francisco found that the frequency of four geriatric syndromes was common. These included falls (yes/no to fall in past year), urinary incontinence (yes/no based on the International Consultation on Incontinence Questionnaire), functional impairment (measured by ADL and IADL), and frailty (Fried’s criteria). In particular, 38 subjects (27%) reported at least one fall, 36
(25%) reported urinary incontinence, and 64 (45%) reported difficulty with at least one instrumental activity of daily living. Twelve (9%) subjects met the full criteria for frailty, whereas 79 (56%) met criteria for prefrailty. Eighty-six percent of subjects had at least one geriatric syndrome and 54% had two or more syndromes. Geriatric syndromes where associated with nadir CD4 cell count. Although the role of HIV infection in these syndromes warrants further investigation, the high frequencies of syndromes, especially difficulty with instrumental activities of daily living and prefrailty, merit consideration of new clinical care paradigms incorporating geriatric medicine principles [59]. Interestingly, in HIV setting, frailty has been used as a measurement of functional assessment. However, frailty conceptualization embraces a wider aspect of patient health issues. It is defined as a biologic syndrome of decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems, and causing vulnerability to adverse outcomes [60]. Geriatricians introduced the term ‘frailty’ to describe this variability. Although people generally accumulate health problems with age, individuals of the same age can experience very different levels of health [61 ]. Frailty represents the cumulative effects of agerelated deterioration in multiple physiological systems and homeostatic mechanisms, resulting in greater vulnerability to stressors [61 ,62 ]. Frailty scales that include more measures can more sensitively grade vulnerability and track improvement and decline, and are less likely to overlook individuals who have accumulated diverse deficits in health; they might be, however, relatively cumbersome to construct. Parsimonious scales can be quicker to apply, but often require specific measures (e.g., grip strength measured by dynamometer) and might overlook people with different health problems. Modifications to such scales are common, especially replacing performance-based measures (e.g., walking speed) with self-reported measures (e.g., reported difficulty walking), or using different criteria for performance-based measures (e.g., loss of >10 lbs in past year vs. loss of >5% of body weight in past 6 months), yet the validity of such modifications are unknown [16,63]. &&
&&
&&
RESEARCH GAPS A better understanding of the complex relationship between HIV, multimorbidity, and assessment of functional status requires the design and conduction of new clinical prospective studies on frailty in HIV. These studies will have the advantage to describe frailty phenotype[60] associated with aging
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-hivandaids.com
395
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIV and aging
affecting HIV-infected patients and demonstrate whether, as expected, the frailty measure presages adverse outcomes and multimorbidity in HIVþ patients.
CONCLUSION Future research may investigate the association between multimorbidity, functional status and frailty in PLWH as a new potential clinical marker. Researchers who study the aging process and geriatricians who care for older patients have already acquired considerable knowledge and experience on the mechanisms that lead to the aging phenotypes, frailty measurements and their consequences, and potential intervention strategies. This bulk of knowledge and experience may turn out to be extremely useful in the care of older patients. Studying this process may offer a unique observation window to better understand the aging process. Acknowledgements This work was supported by grant agreement no: 305522 COBRA (CO-morBidity in Relation to HIV/AIDS) EC 7TH framework programme for research, technological development and demonstration activities. Conflicts of interest The authors certify that there is no conflict of interest with any organization regarding the material discussed in the manuscript.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nobili A. Multiple diseases and polypharmacy in the elderly: challenges for the internist of the third millennium. J Comorbidity 2011; 1:28–44. 2. Fortin M, Lapointe L, Hudon C, Vanasse A. Multimorbidity is common to family practice: is it commonly researched? Can Fam Physician 2005; 51:244– 245. 3. Salter ML, Lau B, Go VF, et al. HIV infection, immune suppression, and uncontrolled viremia are associated with increased multimorbidity among aging injection drug users. Clin Infect Dis 2011; 53:1256–1264. 4. Goulet JL, Fultz SL, Rimland D, et al. Aging and infectious diseases: do patterns of comorbidity vary by HIV status, age, and HIV severity? Clin Infect Dis 2007; 45:1593–1601. 5. Kim DJ, Westfall AO, Chamot E, et al. Multimorbidity patterns in HIV-infected patients: the role of obesity in chronic disease clustering. J Acquir Immune Defic Syndr 2012; 61:600–605. 6. Guaraldi G, Orlando G, Zona S, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis 2011; 53:1120–1126. 7. Drummond MB, Kirk GD, Astemborski J, et al. Prevalence and risk factors for unrecognized obstructive lung disease among urban drug users. Int J Chron Obstruct Pulmon Dis 2011; 6:89–95. 8. Kirk GD, Astemborski J, Mehta SH, et al. Assessment of liver fibrosis by transient elastography in persons with hepatitis C virus infection or HIVhepatitis C virus coinfection. Clin Infect Dis 2009; 48:963–972. 9. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006; 107:1747–1750. 10. Yanik EL, Lucas GM, Vlahov D, et al. HIV and proteinuria in an injection drug user population. Clin J Am Soc Nephrol 2010; 5:1836–1843.
396
www.co-hivandaids.com
11. Hasse B, Ledergerber B, Furrer H, et al. Morbidity and aging in HIV-infected persons: the Swiss HIV cohort study. Clin Infect Dis 2011; 53:1130–1139. 12. Chu C, Umanski G, Blank A, et al. Comorbidity-related treatment outcomes among HIV-infected adults in the Bronx. NY J Urban Health 2011; 88:507– 516. 13. J. Schouten, F.W. Wit, I.G. Stolte, et al. Comorbidity and ageing in HIV-1 infection: the AGEhIV Cohort Study. 19th International AIDS Conference: Abstract no. THAB0205. Available from: http://www.iasociety.org/Abstracts/ A200746311.aspx 14. A Prospective, Observational Study to Examine the Effects of Ageing on the ‘Pharmacokinetic and Clinical Observations in People Over Fifty’ (POPPY). Available from: http://clinicaltrials.gov/show/NCT01737047. 15. Justice A. HIV Associated Non AIDS (HANA) Conditions and Inflammation. Denver: American Conference for the Treatment of HIV; 2011. 16. Franceschi C, Capri M, Monti D, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007; 128:92–105. 17. Macaulay R, Akbar AN, Henson SM. The role of the T cell in age-related & inflammation. Age (Dordrecht, The Netherlands) 2013; 35:563–572. This publication discusses the age-related dysregulation of inflammatory responses and how they may play crucial roles driving age-related pathologies, T-cell immunosenescence, and CMV reactivation. 18. Avelino-Silva VI, Ho YL, Avelino-Silva TJ, Santos Sde S. Aging and HIV infection. Ageing Res Rev 2011; 10:163–172. 19. Desai S, Landay A. Early immune senescence in HIV disease. Curr HIV/AIDS Rep 2010; 7:4–10. 20. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 2008; 214:231–241. 21. Neuhaus J, Jacobs DR Jr, Baker JV, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis 2010; 201:1788–1795. 22. Rodger AJ, Fox Z, Lundgren JD, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis 2009; 200:973–983. 23. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203. 24. Guaraldi G, Luzi K, Bellistri GM, et al. CD8 T-cell activation is associated with lipodystrophy and visceral fat accumulation in antiretroviral therapy-treated virologically suppressed HIV-infected patients. J Acquir Immune Defic Syndr 2013; 64:360–366. 25. Barnett K, Mercer SW, Norbury M, et al. Epidemiology of multimorbidity and implications for healthcare, research, and medical education: a cross-sectional study. Lancet 2012; 380:37–43. 26. Thorpe KE, Howard DH. The rise in spending among Medicare beneficiaries: the role of chronic disease prevalence and changes in treatment intensity. Health Aff (Millwood) 2006; 25:w378–w388. 27. Mangin D, Heath I, Jamoulle M. Beyond diagnosis: rising to the multimorbidity challenge. BMJ 2012; 344:e3526. 28. Justice AC, Landefeld CS, Asch SM, et al. Justification for a new cohort study of people aging with and without HIV infection. J Clin Epidemiol 2001; 54 (Suppl 1):S3–S8. 29. Guaraldi G. Morbidity in older HIV-infected patients: impact of long-term antiretroviral use. AIDS Rev 2014; 16:. [Epub ahead of print] 30. 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 Acquir Immune Defic Syndr 2012; 60 (Suppl 1):S1–18. 31. Martin J, Volberding P. HIV and premature aging: A field still in its infancy. Ann Intern Med 2010; 153:477–479. 32. Effros RB, Fletcher CV, Gebo K, et al. Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis 2008; 47:542–553. 33. Pathai S, Bajillan H, Landay AL, High KP. Is HIV a model of accelerated or accentuated aging? J Gerontol A Biol Sci Med Sci 2013. [Epub ahead of print] 34. FP7-COBRA Co Morbidity in Relation to AIDS [cited 2014 27/02/2014]. Available from: http://fp7-cobra.eu/. 35. Greenberg RS, Flanders WD, Eley JW, Boring JR. Variability & bias. In: Medical epidemiology. 4th ed New York: Lange; 2004. 36. Global Health and Aging. World Health Organization, 2011 NIH Publication no. 11-7737. 37. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents [Guidelines]. AIDSinfo website2013 [cited 2014 09 APR]. Available from: http://aidsinfo.nih.gov/guidelines. 38. European AIDS Clinical Society Guidelines: European AIDS Clinical Society (EACS); 2013 [updated October 2013; cited 2014 09 APR]. Guidelines]. Available from: http://www.eacsociety.org/Portals/0/Guidelines_Online_ 131014.pdf. 39. Writing Group. Williams I, Churchill D, Anderson J, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy. HIV MedV 15 2014; 1–85. 40. Antinori A, Marcotullio S, Ammassari A, et al. Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. New Microbiologica 2012; 35:113–159.
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Multimorbidity and functional status assessment Guaraldi et al. 41. Gleason LJ, Luque AE, Shah K. Polypharmacy in the HIV-infected older adult population. Clinical interventions in aging 2013; 8:749–763. This article provides an overview of polypharmacy with a focus on its impact on the HIV-infected older adult population. 42. Guaraldi G, Zona S, Menozzi M, et al. Cost of noninfectious comorbidities in & patients with HIV. Clinicoecon Outcomes Res 2013; 5:481–488. This paper provides estimates of and describes factors contributing to direct costs for medical care among HIV-infected patients, focusing on HANA care expenditure. 43. Justice A. Overview of Ageing: a. How Can We Optimize Care in the Context of Multimorbidity? Amy C. Justice, MD, PhD Professor, Yale University. Schools of Medicine. 2011. 44. Barat I, Andreasen F, Damsgaard EM. Drug therapy in the elderly: what doctors believe and patients actually do. Br J Clin Pharmacol 2001; 51:615–622. 45. Franceschi M, Scarcelli C, Niro V, et al. Prevalence, clinical features and avoidability of adverse drug reactions as cause of admission to a geriatric unit: a prospective study of 1756 patients. Drug Saf 2008; 31:545–556. 46. Gnjidic D, Le Couteur DG, Kouladjian L, Hilmer SN. Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes. Clin Geriatr Med 2012; 28:237–253. 47. Lin CF, Wang CY, Bai CH. Polypharmacy, aging and potential drug-drug interactions in outpatients in Taiwan: a retrospective computerized screening study. Drugs Aging 2011; 28:219–225. 48. Secoli SR, Figueras A, Lebrao ML, et al. Risk of potential drug-drug interactions among Brazilian elderly: a population-based, cross-sectional study. Drugs Aging 2010; 27:759–770. 49. Tamura BK, Bell CL, Inaba M, Masaki KH. Outcomes of polypharmacy in nursing home residents. Clin Geriatr Med 2012; 28:217–236. 50. Madden JM, Graves AJ, Zhang F, et al. Cost-related medication nonadherence and spending on basic needs following implementation of Medicare Part D. JAMA 2008; 299:1922–1928. 51. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011; 365:2002–2012. 52. Miller RR. Hospital admissions due to adverse drug reactions. A report from the Boston Collaborative Drug Surveillance Program. Arch Intern Med 1974; 134:219–223. &
53. Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ 1997; 315:1096–1099. 54. Gebo KA, Fleishman JA, Conviser R, et al. Contemporary costs of HIV healthcare in the HAART era. AIDS 2010; 24:2705–2715. 55. Luther VP, Wilkin AM. HIV infection in older adults. Clin Geriatr Med 2007; 23:567–583; vii. 56. Mandalia S, Mandalia R, Lo G, et al. Rising population cost for treating people living with HIV in the UK, 1997–2013. PLoS One 2010; 5:e15677. 57. Elsawy B, Higgins KE. The geriatric assessment. Am Fam Physician 2011; 83:48–56. 58. Erlandson KM, Allshouse AA, Jankowski CM, et al. Comparison of functional status instruments in HIV-infected adults on effective antiretroviral therapy. HIV Clin Trials 2012; 13:324–334. 59. Greene M, Valcour V, Miao Y, et al. Geriatric syndromes are common among older HIV-infected adults: in this group over age 50, 50% of participants had frailty or prefrailty ay higher frequencies than HIV-negatives 21st Conference on Retroviruses and Opportunistic Infections2014 [cited 2014 18/03/2014]. Available from: http://www.croiwebcasts.org/console/player/22199?media Type=audio&. 60. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56:M146–M156. 61. Mitnitski A, Song X, Rockwood K. Assessing biological aging: the origin of && deficit accumulation. Biogerontology 2013; 14:709–717. This article proposes a general model to explain how the number of deficits present in individuals can be represented by the product of the intensity of environmental stresses to the average recovery time. 62. Clegg A, Young J, Iliffe S, et al. Frailty in elderly people. Lancet 2013; && 381:752–762. This article describes frailty as state of vulnerability and as consequence of cumulative decline in physiological systems during a lifetime. It also approaches the need to develop methods to detect frailty and measure its severity in routine clinical practice, in order to properly select elderly people for invasive procedures or drug treatments. Can you send this to Leanne and check if it problem with my computer? 63. Guaraldi G, Stentarelli C, Zona S, et al. Lipodystrophy and antiretroviral therapy as predictors of sub-clinical atherosclerosis in human immunodeficiency virus infected subjects. Atherosclerosis 2010; 208:222–227.
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-hivandaids.com
397
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Multimorbidity and functional status assessment Giovanni Guaraldi a, Ana Rita Silva b, and Chiara Stentarelli a
Purpose of review This review conceptualizes multimorbidity and functional status impairment in people living with HIV and their implication in clinical and research fields. Recent findings Multimorbidity is an increasing age-related condition whose prevalence is higher in HIV-infected patients compared with the general population. It portrays the contemporary clinical complexity of HIV care. Whether multimorbidity describes an accelerated or accentuated aging process is the matter of discussion, although some HIV variables depicting immune activation and chronic inflammation are associated with multimorbidity. Multimorbidity coupled with functional status impairment are determinants of a frailty phenotype and in the frailty research setting, multimorbidity can be explored as an endpoint for clinical studies. Summary The success of highly active antiretroviral therapy has significantly changed the clinical pattern of HIV infection, with the ‘greying’ of the HIV-infected population testament to its success. This has provided new challenges relating to the care of older patients, particularly with regard to the management of multimorbidity functional status impairment. Keywords frailty, functional status assessment, HIV, multimorbidity, polypharmacy
INTRODUCTION Contemporary HIV epidemic shows a demographic aging shift among people living with HIV (PLWH). There is an increasing number of patients who are getting old because of the benefits associated with highly active antiretroviral therapy (HAART), but there is also an increasing number of people acquiring HIV at an older age, given the progressive extension of active sexual activity, but low risk perception of the elderly. The overall increase in older HIV patients is the consequence of a dramatic increase in life expectancy, observed both in industrialized and developing counties, exposing PLWH to an overlap between age-related condition and HIVassociated non-AIDS condition (HANA). The process of aging involves a continuum of changes in biological, functional, psychological, and social parameters depending on genetic factors and differences in organ function and reserves. Aging is often accompanied by: chronic comorbid conditions frequently associated in complex pictures so called multimorbidity; altered functional status and frailty [1]. The objective of this review is to describe the conceptualization of multimorbidity and functional status in PLWH and their implication in clinical and research fields. www.co-hivandaids.com
We searched PubMed for articles relevant to the description of multimorbidity and functional status assessment both in HIV and general medicine. This search strategy included articles published in English between January 2010 and December 2013.
MULTIMORBIDITY In the general population, there is no consensus in the definition of multimorbidity or how to measure it. Multimorbidity has been described as the simultaneous occurrence of several medical conditions in the same person [2]. Most of the authors would define two, three or more conditions being present at the same time [3–6]. The most commonly diagnosed medical conditions are dyslipidaemia,
a
Metabolic Clinic, Clinic of Infectious Diseases, University of Modena and Reggio Emilia, Italy and bDepartment of Infectious Diseases, Centro Hospitalar do Porto – Hospital Joaquim Urbano, Portugal Correspondence to Giovanni Guaraldi, MD, Department of Medical and Surgical Sciences for Adults and Children, Infectious Diseases Clinic, University of Modena and Reggio Emilia School of Medicine, Via del Pozzo 71, 41100 Modena, Italy. Tel: +39 059 422 5318; fax: +39 059 422 3710; e-mail: [email protected] Curr Opin HIV AIDS 2014, 9:386–397 DOI:10.1097/COH.0000000000000079 Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Multimorbidity and functional status assessment Guaraldi et al.
KEY POINTS Multimorbidity and functional status impairment are increasing age-related conditions whose prevalence are higher in HIV-infected patients compared with the general population. Whether multimorbidity and functional status describe an accelerated or accentuated aging process is the matter of discussion, although some HIV variables depicting immune activation and chronic inflammation are associated with these conditions. Multimorbidity and functional status describe the contemporary clinical complexity of HIV care. Multimorbidity and functional status are associated and possibly determinants of a frailty phenotype affecting PLWH. In the frailty research setting, multimorbidity and functional status can be explored as endpoints for clinical studies.
cardiovascular disease (CVD), diabetes mellitus, chronic obstructive pulmonary disease (COPD) [7], liver cirrhosis [8], anaemia [9], obesity, chronic kidney disease (CKD) [10], osteopenia/osteoporosis, hypothyroidism, and hypertension (HTN). According to different conditions and clinical settings, they can be diagnosed by self-report prevalence (CVD, COPD, liver cirrhosis, osteoporosis using fracture end point), clinically determined prevalence (CKD, anaemia, osteoporosis using dual energy X-ray absorptiometry), drug-tracing criteria (dyslipidaemia, type 2 diabetes mellitus, HTN) or by using administrative data set collecting International Classification of Diseases, 9th Revision clinical modification codes (ICD9-CM) [3–6,11–14]. The term multimorbidity is often used interchangeably with comorbidity, although the latter refers more specifically to conditions that occur as a consequence of one leading (‘index’) condition such as HIV in the so-called HANA conditions. HANA includes diseases in which after adjustment for established risk factors, association with HIV remains [15]. Interestingly, HANA conditions are the same as the ones used in general literature to characterize age-related condition and define MM.
Pathogenesis of multimorbidity A common mechanism for the development of multimorbidity with increasing age is its association with chronic low-grade inflammation in a process, which has been termed ‘inflammaging.’ During the aging process, changes occur in body systems,
which have a major effect upon the immune system in all individuals (with and without HIV infection). In addition to reductions in circulating growth hormones, increases are seen in the baseline levels of inflammatory cytokines [16,17 ]. Further chronic diseases and inflammation increase atherosclerosis. It is also known that aging influences the interaction between HIV infection and the immune system [18]. This starts a multifactorial process, involving immune activation through chronic infection [including cytomegalovirus (CMV)], immunosenescence, chronic inflammation [19], and the effects of HAART [20]. Evidence exists of increased expression of pro-inflammatory markers in HIV-positive patients compared with the general population [21], with higher levels of these biomarkers independently predicting risk for opportunistic diseases [22] and mortality [23]. In a recent study by our group, CD8þ T-cell activation (CD8þCD38þ) was associated with lipodystrophy (visceral adipose tissue/total adipose tissue), being itself an independent risk factor for homeostasis model of insulin resistance (r ¼ 0.364, P ¼ 0.028) and cardiovascular risk (coronary artery calcium, r ¼ 0.406, P ¼ 0.002) [24]. &
EPIDEMIOLOGY OF MULTIMORBIDITY Comorbidity is seen in non-HIV patients of all ages. A study published in Lancet found that half of the people over 65 years of age have at least three coexisting chronic conditions [25]. This phenomenon seems to be increasing over the past years. In a study of Medicare beneficiaries, the proportion of patients with more than five treated conditions increased from 31 to 50% from 1987 to 2002[26]. It is also worth noting that the diagnoses that are most rapidly on the rise are those for which new drug treatments are available [27]. This issue has also been covered in HIV medicine, with a certain number of studies assessing the prevalence of HANA conditions and multimorbidity in European and United States cohorts. Table 1 [3–6,11–14] summarizes study’s methodology and results. Data from 8844 patients in the Swiss Cohort Study showed a significantly higher incidence of clinical AIDS, mortality and of some comorbidities (including stroke, myocardial infarction, diabetes, bone fractures and non-AIDS-defining malignancies) in HIV-infected patients older than 50 years compared with younger patients [11]. Multivariable hazard ratios for stroke [17.7; confidence interval (CI), 7.06–44.5), myocardial infarction (5.89; 95% CI, 2.17–16.0), diabetes mellitus (3.75; 95% CI, 1.80–7.85), bone fractures without adequate trauma (10.5; 95% CI, 3.58–30.5), osteoporosis (9.13; 95%
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-hivandaids.com
387
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
388
www.co-hivandaids.com
2002–2019 Italy
HIV-infected persons aged >16 years who attended outpatient clinics at seven cohort centers, affiliated regional hospitals, or private practitioners collaborating with the centers. The median age was 45 years: 5761 (68%) were 65 years of age; 2464 (29%) were female, and 1963 (23%) had prior clinical AIDS. The nadir CD4 cell count was 190 cells/ml, and the latest CD4 cell count was 528 cells/ml. In persons aged >65 years and those aged 50–64 years, the median duration of HIV infection was 15.7 and 18.2 years, respectively.
Study Population
Case–control; ART-experienced HIV-infected cross-sectional patients >18 years of age who were consecutively enrolled at the Metabolic Clinic of Modena University in Italy. Control subjects were matched according to age, sex, duration of follow-up, race (all white), and geographical area and were selected from the CINECA ARNO Observational database. The mean age of the overall population was 46 (8) years; 4244 (37%) were female. Median duration of HIV infection was 196 months, median nadir CD4 cell count was 170 cells/ml, and median current CD4 cell count was 520 cells/ml. Plasma HIV RNA levels were below the limit of quantification in 71.3% patients
Study Design
Guaraldi; Premature age-related comorbidities among HIV-infected persons compared with the general population; Clin Infect Dis; 2011 [6]
Country Cross-sectional
Study Year (s)
Hasse; morbidity and 2008–2010 Switzerland aging in HIV-infected persons – The Swiss HIV Cohort Study; Clin Infect Dis; 2011 [11]
Citation (First Author; Title; Journal; Year) Number of comorbidities per age group
Concurrent presence of two or more noninfectious comorbidities
8562 HIV-negative, 2854 HIV-positive
Definition of multimorbidity
8.844
Population size (n)
Table 1. Epidemiological studies assessing the prevalence of HANA conditions and MM
Cardiovascular disease, hypertension, diabetes mellitus, bone fractures, and renal failure
Opportunistic infections, HIV malignancies, diabetes mellitus, cardiovascular, renal and liver disease, non-AIDS malignancies, bone-related events, bacterial pneumonia, pancreatitis
Comorbidities used
Higher prevalence’s of renal failure, bone fractures, and diabetes were observed among HIVinfected patients. Independent predictors of polypathology in the overall cohort were age, male sex, nadir CD4 cell count, 200 cells/l, and ART exposure.
Hazard ratios for stroke, myocardial infarction, bone fractures with assumed adequate or inadequate trauma, osteoporosis, diabetes mellitus, and non-AIDS malignancies were higher for age groups 50–64 years and >65 years, compared with participants, 50 years of age. After multivariable adjustment for CD4 cell counts, viral load, sex, former and current injection drug use, former and current smoking, and duration of HIV infection, associations with age remained robust.
Outcome details
HIV and aging
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins Prospective
Goulet; Do patterns of comorbidity vary by HIV status, age and HIV severity?; Clin Infect Dis; 2007 [4]
1997–2004 USA
Cross-sectional
Chu; Comorbidity-related 2005–2008 USA treatment outcomes among HIV-infected adults in the bronx, NY; J Urban Health; 2011 [12] 854
The Veterans Aging Cohort Study virtual 66.840 HIV-negative cohort includes veterans receiving care 33.420, HIV-positive during the same year as the index HIVinfected; study population was matched by age, sex and race-matched. The median age was 45 years; 30% were >50 years of age; 98% were male and 60% of the study population were people of color. Models restricted to HIV-infected veterans were adjusted for CD4 cell count and viral load.
HIV-positive adults (>18 years) who initiated HIV and primary medical care at study sites. Subjects must have received all medical treatment at either the hospital-based specialty center or within the community-based network. The mean age of the population was 44 years; 360 (42.2%) were female and 45,6% were African-American. Median duration of HIV infection was 9 years. Four-hundred forty-six (52.2%) had a history of AIDS-defining conditions. Median body mass index (BMI) was 25; 233 (27.3%) were obese (BMI 30)
Presence of a comorbid condition in all three clusters
No. of comorbidities
Clusters: medical disease, substance abuse, psychiatric disorders
Hypertension, dyslipidaemia, diabetes mellitus
(Continued )
Comorbidity prevalence was 60–63%, and prevalence varied by HIV status. Differences remained when the veterans were stratified by age. In multivariable analyses, older HIV-infected veterans were more likely to have substance use disorder and multimorbidity. Renal, vascular, and pulmonary diseases were associated with CD4 cell count >200 cells/mm3; hypertension was associated with CD4 cell count >200 cells/mm3.
Prevalence rates of hypertension, dyslipidaemia, and diabetes in study population were 26% (n ¼ 223), 48% (n ¼ 414), and 13% (n ¼ 108), respectively. Furthermore, 517 subjects (61%) had any one of the three conditions, 182 (21%) had two comorbidities, and 46 (5%) had all three. Factors that significantly increased the odds of having comorbidity were: older age, obesity, relevant family history, and current protease inhibitor use. The study found no consistently significant associations between comorbidity and HIV risk factor, hepatitis C coinfection, or current tobacco and/or alcohol use. Obesity was a relatively strong predictor for comorbidity and with a prevalence of 27% in study population.
Multimorbidity and functional status assessment Guaraldi et al.
www.co-hivandaids.com
389
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
390
www.co-hivandaids.com
2010–2011 USA
Retrospective
Study Design
Kim; Multimorbidity patterns in HIVinfected patients, the role of obesity; J Acquir Immune Defic Syndr; 2012 [5]
Country Prospective
Study Year (s)
Salter; HIV infection, 2007–2009 USA immune suppression, and uncontrolled viremia are associated with increased multimorbidity among aging IVDU; Clin Infect Dis; 2011 [3]
Citation (First Author; Title; Journal; Year)
Table 1 (Continued)
Presence of at least one condition Clusters: metabolic; in two or more disease clusters behavioral; substance use in addition to HIV infection
Comorbidities used
1.844 HIV-positive HIV-infected patients who attended a primary HIV care visit at the 1917 Clinic. Inclusion criteria were: >19 years or older, currently receiving ART, with plasma HIV viral load, CD4 count, height, and weight measured between June 31, 2010 and July 1, 2011; mean age (SD) was 44 10.9 years, 46% were white, 77% male, and MSM constituted the largest HIV transmission risk group (59%, n ¼ 992). Seventy-one percent of the patients had a CD4 count >350 cells/mm3, and 65% of patients had an elevated BMI (36% overweight, 29% obese)
Definition of multimorbidity Presence of up to seven nonDiabetes mellitus, obstructive AIDS-defining chronic conditions lung disease, liver fibrosis, including diabetes, obstructive anaemia, obesity, kidney lung disease, liver fibrosis, dysfunction, hypertension anemia, obesity, kidney dysfunction, and hypertension.
Population size (n)
900 HIV-positive, 362 (ALIVE) study participants followed in a HIV-negative community-based observational cohort; >18 years of age, with a history of injection drug use. Median of age was 48.9 years; 65.1% were male, 87.5% were African-American. Among HIVinfected participants, the median CD4 T-cell count was 292 cells/mm3, 53.8% were currently receiving HAART, and 47.6% had HIV RNA >400 copies/ml.
Study Population
The prevalence of multimorbidity was 65%. Prevalence increased with progressive BMI categories from underweight (64%) to obese (79%). Three multimorbidity clusters were identified: ‘Metabolic’ including hypertension, gout, diabetes mellitus, and chronic kidney disease (range: 0.41–0.84; P < 0.001); ‘Behavioral’ including mood disorders, dyslipidaemia, chronic obstructive pulmonary disease, chronic ulcer disease, osteoarthritis, obstructive sleep apnea, and cardiac disorders (range: 0.32–0.57; P < 0.001); ‘Substance Use’ including alcohol abuse, substance abuse, tobacco abuse, and hepatitis C (range: 0.53–0.89; P < 0.001). Obesity was associated with increased odds of multimorbidity (obese vs. normal BMI category: OR ¼ 1.52, 95% CI ¼ 1.15–2.00).
HIV infection (OR, 1.50; 95% CI, 1.13–1.99) was positively associated with increased multimorbidity. Among HIVinfected participants, multimorbidity was increased with lower nadir CD4 T-cell count (OR, 1.14 per 100-cell decrease; 95% CI, 1.00– 1.29) and higher current HIV RNA (OR, 1.32 per log10 increase; 95% CI, 1.08– 1.60). Older age, being female, not using cigarettes or drugs, and having depressive symptoms were also associated with increased multimorbidity. A substantial proportion of multimorbid conditions in HIV-infected and HIV-uninfected participants were unrecognized and untreated.
Outcome details
HIV and aging
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins Europe
2010–2012 The Netherlands
Prospective
Prospective
HIV-1-infected patients 45 years from a tertiary care HIVoutpatient clinic, and concurrently recruited HIVuninfected public sexual health clinic-attendants
Ongoing recruitment goals: 500 HIV-negative, 1000 HIV-positive >50; 500 HIV positive 60 yrs
N = 542
N = 1724
N = 452
N = 136
No age-related diseases
1 comorbidity
0%
0%
0%
≤ 40 yrs
0%
41 to 50 yrs
51 to 60 yrs
> 60 yrs
N = 1626
N = 5172
N = 1356
N = 408
2 comorbidities
3 comorbidities
4 comorbidities
FIGURE 1. Polypathology prevalence among patients and control subjects, by age categories. The following comorbidities were included: hypertension, diabetes mellitus, hypothyroidism, cardiovascular disease, and bone fractures. Reproduced with permission [6]. 392
www.co-hivandaids.com
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Multimorbidity and functional status assessment Guaraldi et al.
improved because of new therapeutic interventions such as congestive heart failure and, indeed, HIV [29]. This description does not solve the question whether HIV is accelerating aging itself through pathways and mechanisms common to the aging process [30,31], or, alternatively, HIV may simply be an additional risk factor for a wide number of chronic conditions thus accentuating the prevalence of disease at every age [30,32]. Does HIV accelerate or accentuate aging? The answer is probably organ and disease/condition-specific [33]. To resolve this question, it will be important to account for differential exposure to risk factors (e.g., smoking, alcohol, non-HIV sexually transmitted diseases) between HIV-infected and uninfected populations that are likely to result in residual confounding when assessing associations of HIV with increased risk of age-related illness. This is the reason why, more recently, some cohort studies addressing prevalence of multimorbidity in HIV-selected HIVnegative control groups sharing with cases similar risk behaviour. This is the case in particular of the ALIVE cohort. The ALIVE study [3] is a prospective, community-recruited observational cohort of HIVinfected and at-risk current and former intravenous drug users followed outside clinical treatment settings in Baltimore, Maryland, USA. HIV infection (odds ratio [OR], 1.50; 95% CI, 1.13–1.99) was positively associated with increased multimorbidity. In this case, control study HIV-infected and uninfected patients displayed very similar risk behavior and demographic characteristics. Other ongoing cohorts in which cases and control are recruited in sexually transmitted diseases clinics are the POPPY study from UK [14] and HIVAGE study from The Netherlands [13]. Patients enrolled in these studies will contribute to the COBRA study, an European funded research network investigating novel aging biomarkers in HIV [34].
METHODOLOGICAL ISSUES IN COMPARING MULTIMORBIDITY Besides study population, other methodological issue should be taken into account when comparing prevalence and incidence of multimorbidity in PLWH and the general population. First, the different distribution of age categories needs mathematical adjustments to compensate differences in age group prevalence. Second, cohort studies cannot avoid a selection bias, which may result in a distortion of the results of a study based on the way in which patients are sampled, and perhaps even more important, reverse causality cannot be excluded [35]. Interestingly, this problem is quite similar to the ‘survival bias’ that complicates the interpretation of many studies on aging: the older patients,
in an observational cohort, may represent the fittest population, whereas the vulnerable individuals may be under-represented because they have already died. The same mechanism can be true for multimorbidity, being itself an item strictly associated with mortality.
CLINICAL CONSEQUENCES OF MULTIMORBIDITY One of the greatest challenges that health systems globally is facing is the increasing burden of chronic diseases [36]. Greater longevity, increasing exposure to many chronic disease risk factors, and the growing ability to intervene to keep people alive have combined to change the burden of diseases confronting health systems. Similarly, management of older HIV patients is complicated by the likelihood of comorbidities requiring treatment, resultant problems with drug toxicity, interactions on polypharmacy, and changes in pharmacokinetics (potential for drug accumulation and toxicity). In view of this, current HIV guidelines (including Department of Health and Human Services [37], European Aids Clinical Society [38], British HIV Association [39], and Italian HIV Guidelines [40]) recommend close monitoring of cardiovascular, metabolic, liver, kidney, and bone health in older patients. These guidelines also recommend the regular assessment of drug interactions, especially when starting or switching drugs. Nevertheless, no recommendation on preferred antiretroviral therapy (ART) regimens in older patients has been made so far. The delivery of improved care for older patients will require HIV experts and primary care providers to work together to optimize HAART and other pharmacotherapy, to monitor relevant health indices regularly, and to minimize toxicity. Although care is likely to require the input of a range of different medical specialists on a case-bycase basis, the HIV-treating physician will remain central to care and must balance the often competing demands of maintaining effective viral suppression while managing multimorbidity, treatment side-effects, and drug interactions. Education and involvement of the patient remain vital for the success of any treatment plan to ensure it meets the varying needs of individual patients. Multimorbidity treatment implies polypharmacy. This can be simply defined as the concomitant use of five or more medications [41 ], or the use of a potentially inappropriate drug for which the medication does not match the diagnosis [41 ,42 ]. Polypharmacy among the general population and those in care for HIV infection is common. Recent data from the Swiss HIV Cohort demonstrate that among those 65 years and older, 14% received medications
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
&
&
&
www.co-hivandaids.com
393
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIV and aging
control study, which compared direct medical care costs of comorbidities in HIV-infected and uninfected control, accounted for a cost expenditure three times higher than that of HIV infection per se, excluding HAART (US$8911 vs. US$2878) [42 ]. Figure 2 compares the direct cost of HIV outpatient, and ART and comorbidities. Increased age was associated with increased direct cost of comorbidities in both cases and controls (P < 0.001). On the contrary, the cost of HAART did not change across age categories, in HIV patients. Interestingly, the reduction of total care cost observed in increasing CD4 strata was compensated by the increase of the total care cost observed across age strata because of the increased cost of age-related conditions. We therefore believe that in the contemporary epidemiological status in which the majority of PLWHA will be older than 50 years by the year 2015, health care providers may expect an increase in total care cost for the HIV-infected population [54–56]. &
FROM MULTIMORBIDITY TO FUNCTIONAL ASSESSMENT IN THE DESCRIPTION OF FRAILTY The geriatric assessment is a multidimensional, multidisciplinary assessment designed to evaluate
6000 0
2000
4000
US dollars
8000
10,000
from four or more classes of non-HIV medications, where lipid-lowering agents were the most commonly prescribed non-ART medication [11]. These data are consistent with findings from the VACS, wherein among those 50 years and older, 55% were on five or more daily medications [43]. Because these studies report only prescription medication, they likely underestimate the prevalence of polypharmacy. Polypharmacy has also been associated with increased risk of adverse drug reactions, increased hospitalizations, poor adherence, inappropriate drugs, falls and fractures, and drug–drug interactions [44–49]. Polypharmacy can be linked to increased costs for both the patient and the healthcare system. Multiple prescriptions result in increased financial burden for older patients whose income generally consists of using savings from a retirement account and a fixed income such as Social Security [50]. Additionally, minor drug interactions can lead to increased clinic visits, a prescribing cascade wherein additional medications are given to treat new symptoms, or new lab or imaging studies. Serious adverse events from polypharmacy can lead to specialist visits, emergency department visits, and hospital admissions [51–53]. In a recently published case-
60
HIV–
60
HIV+
Mean of NICM costs
Mean of drug costs (no ART)
Mean of HIV outpatient costs
Mean of ART costs
FIGURE 2. Total cost of medical care in cases and controls stratified by age decades. Reproduced with permission [42 ]. &
394
www.co-hivandaids.com
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Multimorbidity and functional status assessment Guaraldi et al.
an older person’s functional ability, physical health, cognition and mental health, and socioenvironmental circumstances. It differs from a standard medical evaluation by including nonmedical domains, by emphasizing functional capacity and quality of life. This assessment begins with a review of two key divisions of functional ability: Activities of daily living (ADL) and instrumental activities of daily living (IADL). ADLs are self-care activities that a person performs daily (e.g., eating, dressing, bathing, transferring between the bed and a chair, using the toilet, controlling bladder and bowel functions). IADL are activities that are needed to live independently (e.g., doing housework, preparing meals, taking medications proper managing finances, using a telephone) [57]. Although these tools seem to be particularly suitable for patients with disabilities, their use in patients younger than 75 years may not reach adequate sensitivity. Several other functional assessment tools have been used in older non-HIV and in HIV populations including the Short Physical Performance Battery (SPPB), the 400-m walk test, and Fried’s frailty phenotype (FFP), all of these being associated with morbidity and mortality in elderly persons [58]. A recent article by Erlandson et al. [58] compared FFP, SPPB and 400-m walk test in a population consisting of 85% male with a median age of 50.8 years and a median CD4þ lymphocyte count of 551 cells/ml. All three instruments revealed high levels of impairment with more than 50% of participants being unable to maintain a walking speed faster than 5.5 km/h in the 400-m walk test, and more than 7% of the study population meeting criteria for frailty. Despite the finding that all three instruments detected similar frequencies of functional impairment in the study population, there was only modest agreement across instruments for the degree of impairment (61–64%; k ¼ 0.34–0.41). These discordances can be explained, in part, by the characteristics of the assessments: the FFP is a global assessment including subjective components that may overlap with depressive symptoms, the SPPB focuses on lower extremity function, and the 400-m walk test requires more endurance and incorporates the broad impact of multiple disease processes [58]. A cross-sectional study conducted in 142 HIV subjects with a median age of 57 years (range 50–74) recruited in San Francisco found that the frequency of four geriatric syndromes was common. These included falls (yes/no to fall in past year), urinary incontinence (yes/no based on the International Consultation on Incontinence Questionnaire), functional impairment (measured by ADL and IADL), and frailty (Fried’s criteria). In particular, 38 subjects (27%) reported at least one fall, 36
(25%) reported urinary incontinence, and 64 (45%) reported difficulty with at least one instrumental activity of daily living. Twelve (9%) subjects met the full criteria for frailty, whereas 79 (56%) met criteria for prefrailty. Eighty-six percent of subjects had at least one geriatric syndrome and 54% had two or more syndromes. Geriatric syndromes where associated with nadir CD4 cell count. Although the role of HIV infection in these syndromes warrants further investigation, the high frequencies of syndromes, especially difficulty with instrumental activities of daily living and prefrailty, merit consideration of new clinical care paradigms incorporating geriatric medicine principles [59]. Interestingly, in HIV setting, frailty has been used as a measurement of functional assessment. However, frailty conceptualization embraces a wider aspect of patient health issues. It is defined as a biologic syndrome of decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems, and causing vulnerability to adverse outcomes [60]. Geriatricians introduced the term ‘frailty’ to describe this variability. Although people generally accumulate health problems with age, individuals of the same age can experience very different levels of health [61 ]. Frailty represents the cumulative effects of agerelated deterioration in multiple physiological systems and homeostatic mechanisms, resulting in greater vulnerability to stressors [61 ,62 ]. Frailty scales that include more measures can more sensitively grade vulnerability and track improvement and decline, and are less likely to overlook individuals who have accumulated diverse deficits in health; they might be, however, relatively cumbersome to construct. Parsimonious scales can be quicker to apply, but often require specific measures (e.g., grip strength measured by dynamometer) and might overlook people with different health problems. Modifications to such scales are common, especially replacing performance-based measures (e.g., walking speed) with self-reported measures (e.g., reported difficulty walking), or using different criteria for performance-based measures (e.g., loss of >10 lbs in past year vs. loss of >5% of body weight in past 6 months), yet the validity of such modifications are unknown [16,63]. &&
&&
&&
RESEARCH GAPS A better understanding of the complex relationship between HIV, multimorbidity, and assessment of functional status requires the design and conduction of new clinical prospective studies on frailty in HIV. These studies will have the advantage to describe frailty phenotype[60] associated with aging
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-hivandaids.com
395
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
HIV and aging
affecting HIV-infected patients and demonstrate whether, as expected, the frailty measure presages adverse outcomes and multimorbidity in HIVþ patients.
CONCLUSION Future research may investigate the association between multimorbidity, functional status and frailty in PLWH as a new potential clinical marker. Researchers who study the aging process and geriatricians who care for older patients have already acquired considerable knowledge and experience on the mechanisms that lead to the aging phenotypes, frailty measurements and their consequences, and potential intervention strategies. This bulk of knowledge and experience may turn out to be extremely useful in the care of older patients. Studying this process may offer a unique observation window to better understand the aging process. Acknowledgements This work was supported by grant agreement no: 305522 COBRA (CO-morBidity in Relation to HIV/AIDS) EC 7TH framework programme for research, technological development and demonstration activities. Conflicts of interest The authors certify that there is no conflict of interest with any organization regarding the material discussed in the manuscript.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Nobili A. Multiple diseases and polypharmacy in the elderly: challenges for the internist of the third millennium. J Comorbidity 2011; 1:28–44. 2. Fortin M, Lapointe L, Hudon C, Vanasse A. Multimorbidity is common to family practice: is it commonly researched? Can Fam Physician 2005; 51:244– 245. 3. Salter ML, Lau B, Go VF, et al. HIV infection, immune suppression, and uncontrolled viremia are associated with increased multimorbidity among aging injection drug users. Clin Infect Dis 2011; 53:1256–1264. 4. Goulet JL, Fultz SL, Rimland D, et al. Aging and infectious diseases: do patterns of comorbidity vary by HIV status, age, and HIV severity? Clin Infect Dis 2007; 45:1593–1601. 5. Kim DJ, Westfall AO, Chamot E, et al. Multimorbidity patterns in HIV-infected patients: the role of obesity in chronic disease clustering. J Acquir Immune Defic Syndr 2012; 61:600–605. 6. Guaraldi G, Orlando G, Zona S, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis 2011; 53:1120–1126. 7. Drummond MB, Kirk GD, Astemborski J, et al. Prevalence and risk factors for unrecognized obstructive lung disease among urban drug users. Int J Chron Obstruct Pulmon Dis 2011; 6:89–95. 8. Kirk GD, Astemborski J, Mehta SH, et al. Assessment of liver fibrosis by transient elastography in persons with hepatitis C virus infection or HIVhepatitis C virus coinfection. Clin Infect Dis 2009; 48:963–972. 9. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006; 107:1747–1750. 10. Yanik EL, Lucas GM, Vlahov D, et al. HIV and proteinuria in an injection drug user population. Clin J Am Soc Nephrol 2010; 5:1836–1843.
396
www.co-hivandaids.com
11. Hasse B, Ledergerber B, Furrer H, et al. Morbidity and aging in HIV-infected persons: the Swiss HIV cohort study. Clin Infect Dis 2011; 53:1130–1139. 12. Chu C, Umanski G, Blank A, et al. Comorbidity-related treatment outcomes among HIV-infected adults in the Bronx. NY J Urban Health 2011; 88:507– 516. 13. J. Schouten, F.W. Wit, I.G. Stolte, et al. Comorbidity and ageing in HIV-1 infection: the AGEhIV Cohort Study. 19th International AIDS Conference: Abstract no. THAB0205. Available from: http://www.iasociety.org/Abstracts/ A200746311.aspx 14. A Prospective, Observational Study to Examine the Effects of Ageing on the ‘Pharmacokinetic and Clinical Observations in People Over Fifty’ (POPPY). Available from: http://clinicaltrials.gov/show/NCT01737047. 15. Justice A. HIV Associated Non AIDS (HANA) Conditions and Inflammation. Denver: American Conference for the Treatment of HIV; 2011. 16. Franceschi C, Capri M, Monti D, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007; 128:92–105. 17. Macaulay R, Akbar AN, Henson SM. The role of the T cell in age-related & inflammation. Age (Dordrecht, The Netherlands) 2013; 35:563–572. This publication discusses the age-related dysregulation of inflammatory responses and how they may play crucial roles driving age-related pathologies, T-cell immunosenescence, and CMV reactivation. 18. Avelino-Silva VI, Ho YL, Avelino-Silva TJ, Santos Sde S. Aging and HIV infection. Ageing Res Rev 2011; 10:163–172. 19. Desai S, Landay A. Early immune senescence in HIV disease. Curr HIV/AIDS Rep 2010; 7:4–10. 20. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 2008; 214:231–241. 21. Neuhaus J, Jacobs DR Jr, Baker JV, et al. Markers of inflammation, coagulation, and renal function are elevated in adults with HIV infection. J Infect Dis 2010; 201:1788–1795. 22. Rodger AJ, Fox Z, Lundgren JD, et al. Activation and coagulation biomarkers are independent predictors of the development of opportunistic disease in patients with HIV infection. J Infect Dis 2009; 200:973–983. 23. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203. 24. Guaraldi G, Luzi K, Bellistri GM, et al. CD8 T-cell activation is associated with lipodystrophy and visceral fat accumulation in antiretroviral therapy-treated virologically suppressed HIV-infected patients. J Acquir Immune Defic Syndr 2013; 64:360–366. 25. Barnett K, Mercer SW, Norbury M, et al. Epidemiology of multimorbidity and implications for healthcare, research, and medical education: a cross-sectional study. Lancet 2012; 380:37–43. 26. Thorpe KE, Howard DH. The rise in spending among Medicare beneficiaries: the role of chronic disease prevalence and changes in treatment intensity. Health Aff (Millwood) 2006; 25:w378–w388. 27. Mangin D, Heath I, Jamoulle M. Beyond diagnosis: rising to the multimorbidity challenge. BMJ 2012; 344:e3526. 28. Justice AC, Landefeld CS, Asch SM, et al. Justification for a new cohort study of people aging with and without HIV infection. J Clin Epidemiol 2001; 54 (Suppl 1):S3–S8. 29. Guaraldi G. Morbidity in older HIV-infected patients: impact of long-term antiretroviral use. AIDS Rev 2014; 16:. [Epub ahead of print] 30. 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 Acquir Immune Defic Syndr 2012; 60 (Suppl 1):S1–18. 31. Martin J, Volberding P. HIV and premature aging: A field still in its infancy. Ann Intern Med 2010; 153:477–479. 32. Effros RB, Fletcher CV, Gebo K, et al. Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis 2008; 47:542–553. 33. Pathai S, Bajillan H, Landay AL, High KP. Is HIV a model of accelerated or accentuated aging? J Gerontol A Biol Sci Med Sci 2013. [Epub ahead of print] 34. FP7-COBRA Co Morbidity in Relation to AIDS [cited 2014 27/02/2014]. Available from: http://fp7-cobra.eu/. 35. Greenberg RS, Flanders WD, Eley JW, Boring JR. Variability & bias. In: Medical epidemiology. 4th ed New York: Lange; 2004. 36. Global Health and Aging. World Health Organization, 2011 NIH Publication no. 11-7737. 37. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents [Guidelines]. AIDSinfo website2013 [cited 2014 09 APR]. Available from: http://aidsinfo.nih.gov/guidelines. 38. European AIDS Clinical Society Guidelines: European AIDS Clinical Society (EACS); 2013 [updated October 2013; cited 2014 09 APR]. Guidelines]. Available from: http://www.eacsociety.org/Portals/0/Guidelines_Online_ 131014.pdf. 39. Writing Group. Williams I, Churchill D, Anderson J, et al. British HIV Association guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy. HIV MedV 15 2014; 1–85. 40. Antinori A, Marcotullio S, Ammassari A, et al. Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons. New Microbiologica 2012; 35:113–159.
Volume 9 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Multimorbidity and functional status assessment Guaraldi et al. 41. Gleason LJ, Luque AE, Shah K. Polypharmacy in the HIV-infected older adult population. Clinical interventions in aging 2013; 8:749–763. This article provides an overview of polypharmacy with a focus on its impact on the HIV-infected older adult population. 42. Guaraldi G, Zona S, Menozzi M, et al. Cost of noninfectious comorbidities in & patients with HIV. Clinicoecon Outcomes Res 2013; 5:481–488. This paper provides estimates of and describes factors contributing to direct costs for medical care among HIV-infected patients, focusing on HANA care expenditure. 43. Justice A. Overview of Ageing: a. How Can We Optimize Care in the Context of Multimorbidity? Amy C. Justice, MD, PhD Professor, Yale University. Schools of Medicine. 2011. 44. Barat I, Andreasen F, Damsgaard EM. Drug therapy in the elderly: what doctors believe and patients actually do. Br J Clin Pharmacol 2001; 51:615–622. 45. Franceschi M, Scarcelli C, Niro V, et al. Prevalence, clinical features and avoidability of adverse drug reactions as cause of admission to a geriatric unit: a prospective study of 1756 patients. Drug Saf 2008; 31:545–556. 46. Gnjidic D, Le Couteur DG, Kouladjian L, Hilmer SN. Deprescribing trials: methods to reduce polypharmacy and the impact on prescribing and clinical outcomes. Clin Geriatr Med 2012; 28:237–253. 47. Lin CF, Wang CY, Bai CH. Polypharmacy, aging and potential drug-drug interactions in outpatients in Taiwan: a retrospective computerized screening study. Drugs Aging 2011; 28:219–225. 48. Secoli SR, Figueras A, Lebrao ML, et al. Risk of potential drug-drug interactions among Brazilian elderly: a population-based, cross-sectional study. Drugs Aging 2010; 27:759–770. 49. Tamura BK, Bell CL, Inaba M, Masaki KH. Outcomes of polypharmacy in nursing home residents. Clin Geriatr Med 2012; 28:217–236. 50. Madden JM, Graves AJ, Zhang F, et al. Cost-related medication nonadherence and spending on basic needs following implementation of Medicare Part D. JAMA 2008; 299:1922–1928. 51. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med 2011; 365:2002–2012. 52. Miller RR. Hospital admissions due to adverse drug reactions. A report from the Boston Collaborative Drug Surveillance Program. Arch Intern Med 1974; 134:219–223. &
53. Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ 1997; 315:1096–1099. 54. Gebo KA, Fleishman JA, Conviser R, et al. Contemporary costs of HIV healthcare in the HAART era. AIDS 2010; 24:2705–2715. 55. Luther VP, Wilkin AM. HIV infection in older adults. Clin Geriatr Med 2007; 23:567–583; vii. 56. Mandalia S, Mandalia R, Lo G, et al. Rising population cost for treating people living with HIV in the UK, 1997–2013. PLoS One 2010; 5:e15677. 57. Elsawy B, Higgins KE. The geriatric assessment. Am Fam Physician 2011; 83:48–56. 58. Erlandson KM, Allshouse AA, Jankowski CM, et al. Comparison of functional status instruments in HIV-infected adults on effective antiretroviral therapy. HIV Clin Trials 2012; 13:324–334. 59. Greene M, Valcour V, Miao Y, et al. Geriatric syndromes are common among older HIV-infected adults: in this group over age 50, 50% of participants had frailty or prefrailty ay higher frequencies than HIV-negatives 21st Conference on Retroviruses and Opportunistic Infections2014 [cited 2014 18/03/2014]. Available from: http://www.croiwebcasts.org/console/player/22199?media Type=audio&. 60. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56:M146–M156. 61. Mitnitski A, Song X, Rockwood K. Assessing biological aging: the origin of && deficit accumulation. Biogerontology 2013; 14:709–717. This article proposes a general model to explain how the number of deficits present in individuals can be represented by the product of the intensity of environmental stresses to the average recovery time. 62. Clegg A, Young J, Iliffe S, et al. Frailty in elderly people. Lancet 2013; && 381:752–762. This article describes frailty as state of vulnerability and as consequence of cumulative decline in physiological systems during a lifetime. It also approaches the need to develop methods to detect frailty and measure its severity in routine clinical practice, in order to properly select elderly people for invasive procedures or drug treatments. Can you send this to Leanne and check if it problem with my computer? 63. Guaraldi G, Stentarelli C, Zona S, et al. Lipodystrophy and antiretroviral therapy as predictors of sub-clinical atherosclerosis in human immunodeficiency virus infected subjects. Atherosclerosis 2010; 208:222–227.
1746-630X ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
www.co-hivandaids.com
397
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
