Different profiles among older adults with HIV according to their chronological age and the year of HIV diagnosis: The FUNCFRAIL cohort study (GeSIDA 9817)

Background People in their fifties with HIV are considered older adults, but they appear not to be a homogeneous group. Objective To evaluate the differences among older adults with HIV according to their chronological age and the year of HIV diagnosis. Methods Cross-sectional study of the FUNCFRAIL cohort. Patients 50 or over with HIV were included and were stratified by both chronological age and the year of HIV diagnosis: before 1996 (long-term HIV survivors [LTHS]) and after 1996. We recorded sociodemographic data, HIV-related factors, comorbidities, frailty, physical function, other geriatric syndromes, and quality of life (QOL). Results We evaluated 801 patients. Of these, 24.7% were women, 47.0% were LTHS, and 14.7% were 65 or over. Of the 65 or over patients, 73% were diagnosed after 1996. Higher rates of comorbidities among LTHS were found, being the more prevalent: COPD, history of cancer, osteoarthritis, depression, and other psychiatric disorders while the more prevalent among the 65 or over patients were: hypertension, diabetes, dyslipidemia, cancer, and osteoarthritis. LTHS showed a significantly worse QOL. There were no differences by the year of HIV diagnosis regarding frailty and functional impairment (SPPB <10) but they were more than twice as prevalent in the 65 or over patients compared to the other chronological age groups. Conclusions A LTHS and a 65 or over person are both “older adults with HIV,” but their characteristics and requirements differ markedly. It is mandatory to design specific approaches focused on the real needs of the different profiles.


Introduction
People in their fifties with HIV are considered older adults because at this age, the immunological recovery is lower and slower after antiretroviral treatment (ART) than in younger people [1] and age-related comorbidities, frailty, and geriatric syndromes become more prevalent [2][3][4]. Half of the people with HIV nowadays are older adults [5] and predictions point to an exponential increase of this proportion [6]. Characteristics of aging are not homogeneous. At the same chronological age, the health status can be absolutely different [7], considering the World Health Organization's (WHO) definition of health, "the process of developing and maintaining the functional ability that enables wellbeing in older age", which takes into account (beyond comorbidities) the physical function status, the presence of frailty, and the quality of life (QOL) [8]. Frailty and functional impairment have proven to be better predictors of survival than comorbidity per se, specifically of disability-free years of life in the general population [9][10][11]. Physical frailty is a clinical syndrome defined by five criteria-shrinking, weakness, poor endurance and energy, slowness, and low physical activity level-in which the whole is more than the sum of the parts in terms of predicting adverse health outcomes [12]. Frailty is prevalent in the older adults with HIV, is associated with mortality and is potentially reversible [13][14][15].Frailty is starting to be proposed as a clinical marker of biological age [7].
The growing number of older adults with HIV is due to ART's success at improving survival for people with HIV and to the increase in the number of new cases diagnosed in this age group [5]. All these people are now considered "older adults with HIV" despite appearing to have different characteristics and needs. Consequently, it is crucial to know if there are differences between older adults with HIV aged 50 years or over, according to their chronological age and the year of HIV diagnosis in terms of HIV variables, comorbidity, and social factors, but also in terms of frailty, physical function, other geriatric syndromes, and QOL. This is the main purpose of our study.

Study design and patient population
We performed a cross-sectional study of the FUNCFRAIL cohort (Spanish cohort) to study frailty and physical function in older adults with HIV. Recruitment took place between May 2018 and November 2019. The inclusion criteria were confirmed HIV infection, age �50 years at the time of recruitment, and regular follow-up at the HIV clinic. We recruited 801 patients from eleven hospitals in Spain who were then included in a random way, including patients who agreed to participate and signed the written informed consent. The study was approved by the Ethics Committee of Hospital Universitario Ramón y Cajal, Hospital Universitario Gregorio Marañón (approval was extended for the Hospital Universitario Infanta Leonor), Hospital Universitario Clínico San Carlos, Hospital Universitario de Guadalajara, Hospital Universitario La Paz, Hospital Universitario Reina Sofía, Fundación Jiménez Díaz and the Regional Ethics Committee of Galicia, Euskadi and Comunidad Valenciana. Patients were stratified into three groups according to their chronological age at the time of recruitment: 50-54 years (younger), 55-64 years (intermediate age group), and 65 years or over (65 or over). In addition, the whole sample was stratified into two groups according to the year of HIV diagnosis: 1996 or before (long-term HIV survivors [LTHS]) and after 1996 (HAART-era group).

Data collection
We recorded sociodemographic data, HIV infection-related data, medications (polypharmacy defined as taking � 5 co-medications other than ART), and comorbidity due to self-reported, physician-diagnosed chronic conditions: hypertension, type 2 diabetes, dyslipidemia, coronary heart disease, stroke, COPD, chronic kidney disease, cancer (< 5 years from the diagnosis), history of cancer (� 5 years from the diagnosis; not active disease), depression, psychiatric disease, and osteoarticular disease.
A comprehensive geriatric assessment was performed. Frailty was defined according to Fried's criteria [10]; namely, shrinking (unintentional weight loss of � 4.5 kg or � 5% of body weight during the previous year), weakness (grip strength adjusted for gender and body mass index), poor endurance and energy (self-reported exhaustion identified by two questions from the Center for Epidemiologic Studies Depression scale), slowness (based on time to walk 4.6 meters, adjusting for gender and standing height), and low physical activity level (< 383 kcal/ week in men and < 270 kcal/week in women using the Minnesota Leisure Time Activity Questionnaire). Patients were considered frail if they met at least three of the five criteria, prefrail when they met one or two criteria, and robust when they met no criteria. Physical function was assessed with the objective measures of strength, gait speed, and balance using the Short Physical Performance Battery (SPPB) [16]. Falls were evaluated by self-reporting in response to the question: "Have you fallen in the past year?" Cognitive impairment was evaluated using the Montreal Cognitive Assessment test (MOCA) [17], and depression was tested using the Short-Form Geriatric Depression Scale (SF-GDS) [18]. Each patient performed a QOL selfassessment by stratifying their QOL into one of the following categories: very good, good, fair, or poor. We also evaluated the QOL by asking the direct question of the SF-GDS: "Are you satisfied with your life?" with the dichotomous answer of yes or no [18]. We also evaluated QOL by the presence of pain because pain is considered a marker of QOL.

Statistical analysis
We used descriptive statistics to examine the participants' characteristics, which are expressed as frequencies (percent) of categorical variables, mean (SD) of normally distributed continuous variables, and median (P25-P75) of continuous variables with a skewed distribution. Continuous variables were compared using the t test for independent variables. The Mann-Whitney test was used for variables with a non-normal distribution or when the group size was small. The association between qualitative variables was assessed using the chi-square test or Fisher's exact test when a group was very small. We compared the four resulting groups from the combination of the chronological age and the year of HIV diagnosis with one another, resulting in a total of six comparisons. For that purpose, comparing three or more groups simultaneously, the Bonferroni adjustment was applied to correct for a possible increase in type 1 errors (false positives). Statistical analysis was performed with IBM SPSS Statistics for Windows software (Version 25.0. Armonk, NY: IBM Corp). All statistical tests were two-sided, and P values < .05 were considered statistically significant. The P set by Bonferroni was .05/6, as we made six comparisons, so P values < .0083 were considered statistically significant in this analysis. There was no imputation in the missing values; we worked with observed data.

Sociodemographic characteristics, HIV-related factors, and comorbidity
See Table 1 for more details.
Stratified by chronological age. Patients 65 or over were 20 years older at HIV diagnosis than the youngest patient and had been living with known HIV for fewer years at recruitment. Three in four of patients 65 or over were diagnosed after 1996. No significant differences were found between the three groups in terms of virological response to ART, but differences were found regarding immune status as measured by the CD4 T-cell nadir and the current CD4 Tcell count, which were both lower among patients 65 or over. Regarding comorbidities, the proportion of patients with no associated comorbidity decreased significantly with age, and the proportion of patients with 3-4 comorbidities was significantly higher among patients 65 or over compared to the youngest (33.9% vs 22.4% [p = 0.01]). Polypharmacy was significantly higher among patients 65 or over compared to the other two age groups. There were differences between age groups concerning some comorbidities represented in Fig 1a. No differences were found as to the history of cancer, heart attack, stroke, or COPD.
Stratified by the year of HIV diagnosis. Women represented 30.9% of the LTHS, a proportion significantly higher than in the HAART-era group with 19.1% (p <0.001). 56.2% of LTHS were 55-64 years at the time of recruitment; only 8.6% were 65 or over, while 20.5% of the HAART-era group were in the oldest group. Regarding the risk practice for HIV infection, 60.6% of the LTHS were people who used injectable drugs while 76.3% of the HAART-era group were sexual contact. No significant differences were found for immunovirological status. The mean of comorbidities was significantly higher in the LTHS, and the proportion of patients with five or more comorbidities was twice as high among LTHS as in the HAART-era group. Polypharmacy was significantly more prevalent in the LTHS, as was the use of neuroleptics, benzodiazepines, and hypnotics. There were differences between LTHS and the HAART-era group regarding some comorbidities, as shown in Fig 1b. No differences were found in relation to hypertension, diabetes, dyslipidemia, heart attack, stroke, chronic kidney disease, or cancer.

Frailty, physical function, other geriatric syndromes, and quality of life
Stratified by chronological age. Frailty was more than twice as prevalent in patients 65 or over compared to the other chronological age groups, as shown in Fig 2a. The proportion of Cognitive impairment was significantly lower among LTHS, while depressive symptoms, determined by SF-GDS � 6 points, were significantly higher than in the HAART-era group patients. QOL was significantly worse among LTHS compared to the HAART-era group patients, as shown in Fig 2b.

Comparison by groups combining chronological age and year of HIV diagnosis
We compared the four resulting groups from the combination of the chronological age and the year of HIV diagnosis with one another, resulting in a total of six comparisons. There were major differences among patients younger than 65 according to the year of HIV diagnosis regarding HIV-related factors, comorbidity and medications, function, other geriatric syndromes, and QOL. When comparing patients 65 and over with the patients younger than 65, significant differences were found, especially among those diagnosed after 1996. The results of the comparison 2, 4, 5 and 6 are shown in Table 2.

Discussion
Our study demonstrates important differences among older adults with HIV according to their chronological age and the year of HIV diagnosis concerning comorbidities, frailty, physical function, and QOL.
LTHS comprised almost half of the total patients in our study, but the proportion of patients 65 or over within the HAART-era group was twice that of the LTHS group. This is interesting because HIV care providers, when referring to the older adults with HIV, commonly assume this group is mostly formed by those diagnosed before 1996. We found that LTHS have been living with a known HIV infection for twice as many years; therefore, they were exposed to the toxicity of certain medications until the new era of ART was available. It is worth highlighting there were no differences between them regarding HIV-related factors, but important differences were found regarding comorbidity [19]. We found higher rates of not only comorbidities among LTHS, but also particular diseases: COPD, history of cancer, osteoarthritis, depression, and other psychiatric disorders. COPD is strongly linked to smoking and more prevalent among people with HIV than in general population [20]; it consumes a great deal of resources, and has been demonstrated to negatively impact the QOL of people with HIV [21]. COPD was twice as prevalent within LTHS as in the HAART-era group, and LTHS were more likely to be active smokers. Having a history of cancer was significantly more common among LTHS; in fact, one in ten LTHS in our study were not only HIV survivors, but also cancer survivors. Survival involves experiencing a life-altering event possibly leading to death, isolation, need of support, and the need of reprioritize one's life [22]. Depression is the most common psychiatric disorder among people with HIV [23] and is a well-known independent factor associated with frailty among older adults with HIV [24], as well as with worse QOL [25]. In an Australian study of 88 LTHS patients analyzed, researchers found depression to be the most common comorbidity in 45% of the patients and other psychiatric disorders were found in 25% of the patients [26]. We found that the prevalence of depression was twice as high in LTHS as in the HAART-era group and the prevalence of other psychiatric illnesses three times as high. According to these data, LTHS took more psychotropic drugs. Interestingly, in our study, benzodiazepines, neuroleptics, and hypnotics use decreased with increasing chronological age, but was twice as high among LTHS as in the HAART-era group. Depression diagnosis is included in the AIDS Survivor Syndrome description, which describes the psychological impact of living with HIV in the first years of the HIV pandemic [27,28]. In the Global Burden of Disease Study 2019 [29], COPD was the fourth most common cause of burden as measured by the disability-adjusted life-years (DALYs) in the general population aged 50-74 years, just after ischemic heart disease, stroke, and diabetes; depressive disorders and osteoarthritis were among the top 18.
Despite the increased burden of comorbidity, there were no differences between LTHS and the HAART-era group patients regarding frailty and physical function. This reveals that frailty and comorbidity are frequent but not necessarily connected [10]. The main characteristic individuals diagnosed with HIV before 1996 share is that they have survived HIV infection despite the lack of effective treatments in the early years of the pandemic while their peers died [30]. A combination of several host and immune factors must be the reason for their survival, and probably for their reduced risk for frailty. In 1995, before HAART appeared, two studies were published demonstrating that LTHS had low levels of HIV-1 in the presence of strong virusspecific immune responses [31] and that those LTHS with high levels of CD4+ cells maintained control of viral replication but lacked the CD8+ cell activities [32]. The immune system's role is one of the stress-response systems that regulates homeostasis [12], and inflammation is consistently associated with frailty [33]. Frailty is defined as a state of decreased reserves resulting in increased vulnerability to adverse outcomes when exposed to stressors. It is more common among those with low CD4 counts or a high HIV viral load [34] and is a risk factor for overall mortality [35]. People surviving HIV would have specific characteristics that made them robust and able to maintain homeostasis within the highly and severe stressful situation of an HIV infection without effective treatment.
The impact of pain on QOL is well known [36,37], and we found it was more prevalent among LTHS. Surprisingly, painkiller prescriptions were not found to be more common among those suffering more pain. This fact underscores that even when pain is assessed, in many cases it is not properly treated. As we have noted before, the comorbidities found more prevalent among LTHS largely affected the patients' QOL but are not the top comorbidities HIV care providers focus on. Much work remains to be done to seriously face the health-related QOL [38]. On the other hand, HAART-era group individuals, who are in their fifties, were never exposed to the ART's high toxicity, or the social circumstances of the early years of the AIDS pandemic. Patients 65 or over were 15% of our sample and 75% of them were in the HAARTera group. They showed no differences from the chronologically younger patients regarding virological response to ART, but did have a significantly lower CD4+ T-cell nadir count were found, which has largely been described among older adults due to the delay in the diagnosis [39] and lower current CD4+ T-cell count. This is consistent with evidence establishing a lower and slower immunological response to ART increasing with chronological age [40]. This mitigated immune response seems to have more to do with age-related aging [41] than with HIV-related immunosenescence since the years with known HIV infection were significantly lower among patients 65 or over.
HAART-era indivuals' profiles regarding comorbidity were radically different from those of LTHS. All the comorbidities that were more prevalent in those 65 or over, except for osteoarthritis, were registered in the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort study and showed an exponential increase with age among adults with HIV in the predictive model [6]. Multimorbidity increases with age [42], but as mentioned before, it is particularly important to consider the heterogeneity of chronic diseases implicated in multimorbidity to describe their specific burden of disease and impact on QOL because the number of comorbidities alone appears not to add qualitative value [43].
Frailty was twice as high in patients 65 or over than in the younger patients, which is consistent with the nature of frailty phenotype that is intrinsically related to aging and whose pathophysiological substrate is linked to inflammageing [12]. The same occurs with physical impairment, as measured by SPPB and gait speed. Nevertheless, it is worth highlighting that one in five of the patients 65 or over had a gait speed greater than 1.2m/s, which reflects a good health and functional status and suggests better-than-average life expectancy [9]. This fact supports the main objective of this study, which was intended to demonstrate that older adults with HIV are not a homogeneous group, and it is necessary to stratify them with objective measures of physical function and frailty.
Our study's limitations include the nature of observational research; it cannot establish a relationship of causality between variables. The main strength is the number of older adults with HIV included in the multicenter cohort study and the exhaustive assessment performed on all of them, covering not only comorbidity, but also frailty, physical function, other geriatric syndromes, and QOL. Older adults with HIV are currently the largest population group among people with HIV, even though most studies thus far have focused on them as a homogeneous group, which might prompt misleading conclusions.

Conclusions
An LTHS and a person 65 or older are both "older adults with HIV," but their characteristics and requirements differ markedly. The data our study provided define specific profiles of patients among older adults with HIV to aid clinicians, researchers, and health system managers to further design specific approaches focused on their real needs.