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G. Guaraldi1, S. Marcotullio2, R. Maserati3, M. Gargiulo4, J. Milic1, I. Franconi1,  A. Chirianni4, M. Andreoni5, M. Galli6, A. Lazzarin7, A. D’Arminio Monforte6, G. Di Perri8, C.-F. Perno5, M. Puoti9, S. Vella10, A. Di Biagio11, L. Maia12, C. Mussi13,
M. Cesari14, A. Antinori15


1. Modena HIV Metabolic Clinic, University of Modena and Reggio Emilia, Modena, Italy; 2. Nadir Onlus, Rome, Italy;3. Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;
4. Azienda Ospedaliera D. Cotugno, Napoli, Italy; 5. Università degli Studi di Roma Tor Vergata, Roma, Italy; 6. Università degli Studidi Milano, Milano, Italy; 7. Università Vita-Salute San Raffaele, Milano, Italy; 8. Università degli Studi di Torino, Torino, Italy;9. Azienda Ospedaliera Ospedale Niguarda Ca’ Granda, Milano, Italy; 10. Istituto Superiore di Sanità – Dipartimento del Farmaco, Roma, Italy; 11. Azienda Ospedaliera San Martino, Genova, Italy; 12. Department Infectious Diseases, Centro Hospitalar do Porto, Porto, Portugal; 13. Geriatrics Division, University of Modena and Reggio Emilia, Modena, Italy; 14. Department of Clinical and Community Sciences, Università di Milano, Milan, Italy, Geriatric Unit, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy; 15. Istituto Nazionale Malattie Infettive L. Spallanzani, Roma, Italy. All members of the Italian HIV Guidelines Working Group are listed in the acknowledgment section.
Corresponding author: Giovanni Guaraldi, Department of Medical and Surgical Sciences for Children & Adults, University of Modena and Reggio Emilia, Via del Pozzo 71, 41124 Modena, Italy. Tel: +39-0594225318; Fax: +39-0594333710; E-mail: giovanni.guaraldi@unimore.it

J Frailty Aging 2018;in press
Published online November 29, 2018, http://dx.doi.org/10.14283/jfa.2018.42



Objective: This article deals with the attempt to join HIV and geriatric care management in the 2017 edition of the Italian guidelines for the use of antiretrovirals and the diagnostic-clinical management of HIV-1 infected persons. Methods: The outlined recommendations are based on evidence from randomized clinical trials and observational studies published in peer-reviewed journals and/or presented at international scientific conferences in recent years. The principles of starting antiretroviral therapy in elderly patients and the viro-immunological goals are the same as in the general HIV population. However, there are some specificities to consider, related to the host as well as the therapy itself. HIV care in elderly patients must shift from a combined AntiRetroviral Therapy specific approach to a more comprehensive management, and from a disease-based model (list of co-morbidities) to a multi-morbidity and frailty standpoint. The implementation of a geriatric approach, based on the Comprehensive Geriatric Assessment, is essential and consists of a broader evaluation of health status. This multidimensional and multidisciplinary evaluation is focused on the development of a tailored intervention plan. Polypharmacy is a frequent condition in the older population and an independent risk factor for negative health-related outcomes. This can be overcome with a multidisciplinary and cooperative approach involving HIV specialists, geriatricians and primary care physicians. Conclusion: The inclusion of geriatric care becomes necessary due to the novel needs of an evolving patient population. It is important to underline that the HIV specialist will continue to lead multidimensional interventions and optimize quality of care for HIV-positive people.

Keywords: Comprehensive geriatric assessment, frailty, HIV, guidelines.



In the context of the global ageing epidemic, HIV infection is not an exception, but rather a paradigm of this relatively new phenomenon. The greying of people living with HIV is – everywhere – part of the HIV landscape (1), arising from two phenomena: the general effectiveness of antiretroviral therapy and the increasing mean age of HIV acquisition (2).
Future projections of the evolving demographics clearly indicate that HIV care will intersect with geriatric medicine (3). This is not merely the result of an age shift. In fact, antiretroviral drugs, patients and, consequently, the disease itself have changed and continue to evolve:
1. Antiretroviral treatment has changed. Drug potency, genetic barriers as well as short- and long-term toxicities have been the determinants of HIV-therapy success/failure during the early Highly Active AntiRetroviral Therapy (HAART) era. Antiretroviral regimens have become more effective and less toxic. Thus, in HIV-negative people aware of their HIV risk, the probability of morbidity and mortality might be lower in the future. This is due to early detection through the efficient continuum of care resting on wise networking strategies.
2. Patients have changed. HIV-infected people have experienced a dramatic improvement in life expectancy during the modern combined antiretroviral therapy (cART) era, particularly those who initiated therapy at earlier stages of the disease (4). Several recent cohort studies have suggested that the life expectancy of HIV-infected individuals may soon approach that of the general population (5). At the same time, an increasing number of people is seroconverting HIV at an older age because of a lower perception of sexual risk in the elderly (6). The net result is that nowadays HIV-people display a heterogeneous clinical presentation with a substantially increased risk for comorbidities in the former group (i.e., ‘HIV-aged people’) compared to the latter (i.e., aged HIV-people) (2).
3. HIV disease itself is changing. A rapid progressive disease is evolving into a chronic condition with a substantial variation in the immunopathological driver of the disease. Immune-deficiency is leaving the room for immune-activation.
Although there is now a broad consensus that immune-activation and inflammation persist in the majority of HIV-infected individuals maintaining long-term ART-mediated viral suppression (even in those that restore normal CD4+ T cell counts) (7), the degree to which inflammation is a direct cause of morbidity and mortality remains controversial.
In this context, in the current edition of the Italian guidelines for the use of antiretroviral agents and the diagnostic-clinical management of HIV-1 infected persons (IHIVGL), the Italian Society of Infectious and Tropical Diseases, in collaboration with the Italian Ministry of Health, have included a chapter entitled: “Management of the ageing, geriatric and frail individuals with HIV”. This could be interpreted as a momentous report, given that specific sections regarding the management of geriatric HIV patients do not exist in other European guidelines.
The objective of the present article is to introduce a first attempt to join HIV and geriatric care management for all the involved healthcare professionals (in particular, geriatricians and HIV-specialists) as well as for people living with HIV and their communities. Such effort reflects the emergence of a novel “Geriatric-HIV” clinical know-how similar to what has previously occurred in other medical specialities like ortho-geriatrics (8), cardio-geriatrics (9), or onco-geriatrics (10).
These guidelines are addressing clinical needs of older adults living with HIV, in the geriatric age definition, over 65 years (according to geriatric age definition) or rather any age but only if they meet frailty criteria.
To conceptualize the age-related increase of vulnerability, the term “frailty” has been commonly used in the medical literature over the past two decades. Frailty is defined as a condition caused by the reduction of homeostatic reserves exposing the individual to higher risk of negative outcomes (11).
Frailty can be considered either as a specific syndrome (12) or as state with degrees of risk for adverse outcomes (13). It might represent much more than a mere condition to be screened for but rather an interval parameter reflecting the “biological age” of the individual. The argument further is that this could replace the obsolete criterion of chronological age in clinical decision algorithms.
In HIV setting, frailty has been operationalized both with a frailty phenotype and frailty index tools. The frailty phenotype (FP) is based on a predefined set of five criteria exploring the presence/absence of signs or symptoms (involuntary weight loss, exhaustion, slow gait speed, poor handgrip strength, and sedentary behavior). The number of criteria (a six-level ordinal variable ranging from 0 to 5) is categorized as a three-level variable depicting robustness (meets none of the criteria), pre- frailty (meets one or two criteria) and frailty (meets three or more criteria) (14).
The only frailty index tool validated in HIV cohorts comprises 37 health variables that are routinely collected at each visit (15). Each variable included in the FI is coded with a value of 1 when a deficit is present, and 0 when it is absent. Missing values are removed from both the numerator and the denominator of the FI (16). FI>0.3 has been used to identify frail individuals.
Frailty as well as falls, urinary incontinence, polypharmacy and delirium describe the so called geriatric syndromes which are multifactorial health conditions that occur when the accumulated effects of impairments in multiple systems render an older person vulnerable to situational challenges (17), posing some special clinical considerations. First, for a given geriatric syndrome, multiple risk factors and multiple organ systems are often involved. Second, diagnostic strategies to identify the underlying causes can sometimes be ineffective, burdensome, dangerous, and costly. Finally, therapeutic management of the clinical manifestations can be helpful even in the absence of a firm diagnosis or clarification of the underlying causes (18).
Geriatric syndromes are more predictive of self-reported health and mortality than diagnoses of chronic diseases or MM alone (19, 20). The majority of existing guidelines, however, remain organ system-based and do not include formal assessment for geriatric conditions (21).



The recommendations issued in IHIVGL are based on evidence from randomized clinical trials and observational studies published in peer-reviewed journals and/or presented at international scientific conferences in recent years. Controlled studies were critically evaluated, in particular by analysing their design, power, sample representativeness, primary and secondary objectives, duration of follow-up, criteria of superiority, non-inferiority and equivalence, methodology, and analytical approach. Information from safety reports drafted by regulatory authorities (FDA – Food and Drug Administration, EMA – European Medicines Agency, AIFA – Italian Medicines Agency) was also considered.
Following governance directions, the IHIVGL expert panel (subdivided into working groups) established a work-plan and drafted a preliminary text after a progressive assessment of electronic contents. Later, in a plenary session, agreements on the contents and degrees of recommendation were reached.
The experts declared their conflicts of interest specifically indicating every potential association (i.e., financial interests, research grants, participation in advisory boards, commissioned lectures at sponsored events) with companies involved in the production of antiretroviral drugs and/or diagnostic materials and/or tools for the monitoring of therapy and disease, over the last five years. LM, CM, JM, IF and MC, co-authors of this paper, are not members of the IHIVGL panel, but helped in the critical revision of the manuscript.
The present text complies with the aims in the methodological introduction to the full text of the Italian Guidelines for the use of antiretroviral drugs and the diagnostic-clinical management of people with HIV-1 infection. The present article should not be considered exhaustive compared to the full text version of the Guidelines (11) available at the website: http://www.salute.gov.it/imgs/C_17_pubblicazioni_2696_allegato.pdf.

Table 1 Degree of recommendation and level of evidence

Table 1
Degree of recommendation and level of evidence


Ageing, geriatric and frail patients

The principles of starting antiretroviral therapy in elderly patients and the viro-immunological goals are the same as in the general HIV population. However, there are some specificities to consider, related to the host as well as the therapy itself.
In particular, polypharmacy, defined as the concomitant use of five drugs or more, is a very frequent condition in the older population and an independent risk factor of negative health-related outcomes (e.g., hospitalization, institutionalization, functional impairment, malnutrition and adverse drug events) (30, 31). Moreover, age-associated physiological changes altering pharmacokinetics (i.e., decreased GI transit, increased fat-to-lean body ratio, reduced hepatic metabolism and renal elimination) (32) and pharmacodynamics may result in increased sensitivity to medications and a higher risk for adverse side effects.
Consequently, drug-drug interactions in ageing patients with polypharmacy are unavoidable. Nevertheless, they can be curtailed and managed by adopting ad hoc strategies.
In elderly HIV infected patients, a broader evaluation of health status is clearly necessary as part of a multidimensional approach characterizing the Comprehensive Geriatric Assessment (CGA). This methodology is not limited to the evaluation of the individual’s clinical conditions. Rather, it is focused on the development of tailored intervention plans. The geriatric approach is based on a multidimensional and multidisciplinary evaluation of the individual, to which every professional brings his/her own expertise and background in patient management. Consequently, functional capacity, fall risk, neurocognitive disorders and/or dementia, mood, polypharmacy, social support, and economic issues remain of special relevance in optimizing treatment goals according to personal needs (33, 34).

Table 4 reports evidence about specific points to consider in the management of older HIV patients.

Table 2 Specificities of elderly HIV patients

Table 2
Specificities of elderly HIV patients



Table 3 Specificities of the most common clinical conditions in elderly HIV patients

Table 3
Specificities of the most common clinical conditions in elderly HIV patients


Table 4 Evaluation and additional behaviours in the approach to elderly HIV patients

Table 4
Evaluation and additional behaviours in the approach to elderly HIV patients



The debate regarding accentuated or accelerated ageing processes affecting HIV patients is ongoing (41). Several factors have been proposed as detrimental contributors to the ageing process of HIV patients, including chronic inflammation, long-term ART drug toxicity, neurocognitive impairment, and a high prevalence of social and behavioural risk factors. Regardless of the causes, it is evident that HIV-positive persons are characterized by an older biological age compared to the HIV-negative population. Moreover, because elderly HIV patients are generally excluded from clinical trials (42), there is limited information on the efficacy and safety of antiretroviral regimens in this particular population.
As the HIV-positive population grows, the healthcare needs to evolve, especially for the purpose of targeting chronic and disabling conditions more effectively. HIV care must therefore enrich the straightforward ART-specific approach with elements broadening older patients’ assessment to capture their heterogeneity and complexity more accurately. Recommendations are provided to improve the so-called “HIV continuum of care”, which defines the sequential steps that people living with HIV should go through from the initial diagnosis to the achievement of viral suppression. These actions include the optimization of the HIV care environment, an increase in HIV testing and care network, treatment coverage and monitoring of viral suppression (42). It is noteworthy that HIV care is a continuum going beyond the traditional goal of viral un-detectability. So far, no guidelines have included such new paradigms in HIV management.
The new section of the IHIVGL trying to introduce a new cultural paradigm in the management of elderly HIV patients based on the following shifts in clinical perspective:
1. from the assessment of single co-morbidities to the management of multi-morbidity
2. from the assessment of organ impairment to the evaluation of functional capacity
3. from age assessment to frailty evaluation.

Taken together, clinical evaluation is not a list of multiple organ impairments to be considered as a disease status, but rather a wider and more detailed image of health status described in functional capacities.
This change in health perspective is extremely important to adapt care models to the emerging needs of HIV-infected individuals characterized by a complex composition of multi-morbidity, frailty, geriatric syndromes and disability.
The geriatric approach, based on a CGA, establishes a multidimensional and multidisciplinary evaluation of the individual, to which every professional brings his/her own expertise and background in patient management. Therefore, the interdisciplinary team members (including nurses, social workers, pharmacists, psychologists, physical therapists) concur in the evaluation of ageing patients to objectivize their needs and resources to complete a multidimensional evaluation. This work is essential to identify frail patients and to develop tailored intervention plans, indicating priorities and setting goals. The objectives of the evaluation are also changing, shifting from a restricted focus on life expectancy (i.e., the estimated number of years to live) to a broader consideration of quality of life (e.g., expected life free from disability). From this perspective, the active empowerment of patients (through improved information and involvement) becomes crucial to the prevention of negative health-related events.
This multidimensional management can be integrated in “Total Patient Care” (TPC), which results in a more comprehensive patient approach, considering their physical, emotional, social, economic, and spiritual goals (43), as well as personal reactions to illness (including the ability to meet self-care needs). It implies the transition from a model based on a single referral care centre to a coordinated and multidisciplinary network providing primary and specialized support to people living with HIV.
Central to this paradigm shift is the recognition of the need for an active partnership with primary care physicians, who remain in charge of providing proactive, preventive, and chronic care management through all stages of life. Primary care physicians could also be key players in the management of polypharmacy. This condition is common in elderly HIV patients. Consequently, these are at higher risk of drug-drug interactions between antiretroviral drugs and concomitant medications, which may compromise medication effectiveness and can be responsible for serious adverse drug events (including organ system injury, hospitalization, geriatric syndromes, and mortality). Interventions to address polypharmacy in the HIV setting are still missing and primary care physicians can help in this multidimensional approach to elderly patients, because they can share all clinical information across the entire healthcare system, using of registries, information technologies, and health information exchanges.
To conclude, it is also crucial to ensure that patients and their families receive proper education and support to actively participate in the planned care program. Patient risk factors may include social vulnerability, a predictor of mortality and disability in elderly people. In this context, HIV and Ageing stigma plays a crucial role and requires urgent action. HIV stigma is a well-known barrier for HIV testing and treatment in numerous settings, particularly in low-and-medium income countries, contingent on inequalities in social, economic, and political power (44). At the same time, many stereotypes (the so-called “Ageing Stigma”) are typically associated to the older population (e.g., needy, unhappy, senile, inactive, useless to society, not receptive). Apparently, we are indeed in the presence of an augmented risk of stigmatization due to the overlap of two detrimental phenomena, the HIV and Ageing stigmas. This aspect also requires urgent consideration.
Finally, it is important to underline that the HIV specialist will continue to lead multidimensional interventions and optimize quality of care for HIV-positive people. The progress made over the years in the fight against HIV are not underestimated here. HIV care will remain an outstanding example of healthcare management. The inclusion of geriatric care becomes necessary due to the novel needs of an evolving patient population. The collaboration between HIV specialists, geriatricians and general practitioners will follow the already existing (and successful) paradigms developed in other interdisciplinary models of geriatric care, with an utmost respect for each and every stakeholder’s expertise and background.


Acknowledgments: Institutional referees: Andreoni Massimo, Università degli Studi di Roma Tor Vergata, Roma; Chirianni, Antonio, Azienda Ospedaliera D Cotugno, Napoli. Coordinators: Antinori Andrea, Istituto Nazionale Malattie Infettive L. Spallanzani, Roma; Galli Massimo, Università degli Studi di Milano, Milano; Lazzarin Adriano, Università Vita-Salute San Raffaele, Milano. Executive commitee: d’Arminio Monforte Antonella, Università degli Studi di Milano, Milano; Di Perri Giovanni, Università degli Studi di Torino, Torino; Perno Carlo-Federico, Università degli Studi di Roma Tor Vergata, Roma; Puoti Massimo, Azienda Ospedaliera Ospedale Niguarda Ca’ Granda, Milan; Vella Stefano, Istituto Superiore di Sanità, Roma. Editorial coordinators: Di Biagio Antonio, Azienda Ospedaliera San Martino, Genova; Marcotullio Simone, Nadir Onlus, Roma. Italian HIV Guidelines Working Group: Ammassari Adriana, Istituto Nazionale Malattie Infettive L. Spallanzani, Roma; Angarano Gioacchino, Università degli Studi di Bari, Bari; Antinori Andrea, Istituto Nazionale Malattie Infettive L. Spallanzani, Roma; Armignacco Orlando, Ospedale Belcolle, Viterbo; Babudieri Sergio, Università degli Studi di Sassari, Sassari; Bini Teresa, Azienda Ospedaliera – Polo Universitario San Paolo, Milano; Bonfanti Paolo, Azienda Ospedaliera della Provincia di Lecco, Lecco; Bonora Stefano, Università degli Studi di Torino, Torino; Borderi Marco, Azienda Ospedaliera Sant’Orsola Malpighi, Bologna; Breveglieri Michele, Arcigay, Verona; Bruno Raffaele, Policlinico San Matteo, Pavia; Calza Leonardo, Università di Bologna, Bologna; Capobianchi Maria Rosaria, Istituto Nazionale Malattie Infettive L. Spallanzani, Roma; Cagarelli Roberto, Regione Emilia-Romagna, Prevenzione Collettiva e Sanità Pubblica, Bologna; Calcagno Andrea, Università degli Studi di Torino, Torino; Castagna Antonella, Ospedale San Raffaele, Milano; Castelli Francesco, Università degli Studi di Brescia, Brescia; Cattelan Anna Maria, Azienda Ospedaliera-Universitaria, Padova; Cauda Roberto, Università Cattolica del Sacro Cuore, Roma; Cingolani Antonella, Università Cattolica del Sacro Cuore, Roma; Cinque Paola, Ospedale San Raffaele, Milano; Corbelli Giulio Maria, Plus Onlus, Bologna; d’Arminio Monforte Antonella, Università degli Studi di Milano, Milano; d’Ettorre Gabriella, Università degli Studi di Roma La Sapienza, Roma; De Carli Gabriella, Istituto Nazionale Malattie Infettive L. Spallanzani, Roma; De Luca Andrea, Azienda Ospedaliera Universitaria, Siena; Università Cattolica del Sacro Cuore, Roma; Di Biagio Antonio, Azienda Ospedaliera San Martino, Genova; Di Perri Giovanni, Università degli Studi di Torino, Torino; Di Pietro Massimo, Azienda Sanitaria di Firenze, Firenze; ElHamad Issa, Azienda Ospedaliera Spedali Civili, Brescia; Errico Margherita, NPS Italia Onlus, Napoli; Gaeta Giovanni Battista, II Università di Napoli, Napoli; Galli Massimo, Università degli Studi di Milano, Milano;Gargiulo Miriam, Azienda ospedaliera D. Cotugno, Napoli; Gervasoni Cristina, Azienda Ospedaliera L. Sacco, Milano; Giacomet Vania, Azienda Ospedaliera L. Sacco, Milano; Giannini Adriana, Regione Emilia-Romagna, Prevenzione Collettiva e Sanità Pubblica, Bologna; Gianotti Nicola, Ospedale San Raffaele, Milano; Giaquinto Carlo, Azienda Ospedaliera di Padova, Padova; Girardi Enrico, Istituto Nazionale Malattie Infettive L. Spallanzani, Roma; Gori Andrea, Ospedale San Gerardo, Università di Milano-Bicocca, Monza; Grossi Paolo, Università degli Studi dell’Insubria, Varese; Guaraldi Giovanni, Università degli Studi di Modena e Reggio Emilia, Modena; Lichtner Miriam, Sapienza Università di Roma Polo Pontino, Roma; Liuzzi Giuseppina, Istituto Nazionale Malattie Infettive L. Spallanzani, Roma; Lo Caputo Sergio, Policlinico di Bari, Bari; Maggi Paolo, Policlinico di Bari, Bari; Maggiolo Franco, Ospedali Riuniti di Bergamo, Bergamo; Marchetti Giulia, Università degli studi di Milano, Milano; Marcotullio Simone, Nadir Onlus, Roma; Maserati Renato, Policlinico San Matteo, Pavia; Mastroianni Claudio, Università degli Studi di Roma La Sapienza, Roma; Matteelli Alberto, Università degli Studi di Brescia, Brescia; Mazzotta Francesco, Azienda Sanitaria di Firenze, Firenze; Menichetti Francesco, Azienda Ospedaliero-Universitaria Pisana, Pisa; Mussini Cristina, Università degli Studi di Modena e Reggio Emilia, Modena; Nozza Silvia, Ospedale San Raffaele, Milano; Oldrini Massimo, Lega Italiana per la Lotta contro l’AIDS, Milano; Parruti Giustino, Azienda Sanitaria Locale di Pescara, Pescara; Pascucci Maria Grazia, Regione Emilia-Romagna, Prevenzione Collettiva e Sanità Pubblica, Bologna; Parrella Roberto, Azienda Ospedaliera D. Cotugno, Napoli; Perno Carlo-Federico, Università degli Studi di Roma Tor Vergata, Roma; Prestileo Tullio, Ospedale Civico-Benfratelli, Palermo; Puoti Massimo, Azienda Ospedaliera Ospedale Niguarda Ca’ Granda, Milano; Puro Vincenzo, Istituto Nazionale Malattie Infettive L. Spallanzani, Roma; Rancilio Laura, Caritas Italiana, Milano, Ravizza Marina, Azienda Ospedaliera – Polo Universitario San Paolo, Milano; Rezza Gianni, Istituto Superiore di Sanità – Dipartimento di Malattie Infettive P.I., Roma; Rizzardini Giuliano, Azienda Ospedaliera L. Sacco, Milano; Rusconi Stefano, Università degli Studi di Milano, Milano; Santoro Maria, Università degli Studi di Roma Tor Vergata, Roma; Sighinolfi Laura, Azienda Ospedaliero – Universitaria di Ferrara, Ferrara; Stagnitta Maria, Coordinamento Nazionale delle Comunità di Accoglienza, Firenze; Starnini Giulio, Ospedale Belcolle di Viterbo, Viterbo; Tamburrini Enrica, Università Cattolica del Sacro Cuore, Roma; Tambussi Giuseppe, Ospedale San Raffaele, Milano; Tavio Marcello, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona; Torti Carlo, Università Magna Graecia, Catanzaro; Vaccher Emanuela, Centro di Riferimento Oncologico di Aviano, Aviano; Viscoli Claudio, Università di Genova, Genova; Visintini Raffaele, Ospedale San Raffaele, Milano; Vullo Vincenzo, Università degli Studi di Roma La Sapienza, Roma; Zaccarelli Mauro, Istituto Nazionale di Malattie Infettive L. Spallanzani, Roma; Zuccotti Gian Vincenzo, Università degli Studi di Milano, Milano;
Special Acknowledgments: Rastrelli Elena, Ospedale Belcolle di Viterbo, Viterbo; Sticchi Laura, Università degli Studi di Genova, Genova.



1.    Michel S, ed. THE GAP REPORT. September 2014:1-422. http://www.unaids.org/sites/default/files/media_asset/UNAIDS_Gap_report_en.pdf. Accessed July 2018.
2.    Guaraldi G, Zona S, Brothers TD, et al. Aging with HIV vs. HIV Seroconversion at Older Age: A Diverse Population with Distinct Comorbidity Profiles. PLOS ONE. 2015;10(4):e0118531.
3.    Smit M, Brinkman K, Geerlings S, et al. Future challenges for clinical care of an ageing population infected with HIV: a modelling study. The Lancet Infectious Diseases. 2015;15(7):810-818.
4.    Samji H, Cescon A, Hogg RS, et al. Closing the Gap: Increases in Life Expectancy among Treated HIV-Positive Individuals in the United States and Canada. PLOS ONE. 2013;8(12):e81355.
5.    Rodger AJ, Lodwick R, Schechter M, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS. 2013;27(6):973-979.
6.    Cooperman NA, Arnsten JH, Klein RS. Current sexual activity and risky sexual behavior in older men with or at risk for HIV infection. AIDS education and prevention: official publication of the International Society for AIDS Education. 2007;19(4):321-333.
7.    Justice AC, Freiberg MS, Tracy R, et al. Does an index composed of clinical data reflect effects of inflammation, coagulation, and monocyte activation on mortality among those aging with HIV? Clin Infect Dis. 2012;54(7):984-994.
8.    Ramason R, Chong MS, Chan W, Rajamoney GN. Innovations in Hip Fracture Care: A Comparison of Geriatric Fracture Centers. Journal of the American Medical Directors Association. 2014;15(4):232-233.
9.    Dodson JA, Matlock DD, Forman DE. Geriatric Cardiology: An Emerging Discipline. Canadian Journal of Cardiology. 2016;32(9):1056-1064.
10.    Bugat M-ER, Gerard S, Balardy L, et al. Impact of an oncogeriatric consulting team on therapeutic decision-making. J Nutr Health Aging. 2013;17(5):473-478.
11.    Cesari M, Calvani R, et al. Frailty in Older Persons. Clin Geriatr Med. 2017 Aug;33(3):293-303
12.    Althoff KN, Jacobson LP, Cranston RD, et al. Age, comorbidities, and AIDS predict a frailty phenotype in men who have sex with men. J Gerontol A Biol Sci Med Sci. 2014 Feb;69(2):189-98.
13.    Brothers TD, Kirkland S, Guaraldi G, et al. Frailty in people aging with human immunodeficiency virus (HIV) infection. J Infect Dis. 2014 Oct 15;210(8):1170-9.
14.    Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):M146-56
15.    Guaraldi G, Brothers TD, Zona S, et al. A frailty index predicts survival and incident multi-morbidity independent of markers of HIV disease severity. AIDS. 2015 Aug 24;29(13):1633-41.
16.    Guaraldi G, Malagoli A, Theou O, et al. Correlates of frailty phenotype and frailty index and their associations with clinical outcomes. HIV Med. 2017 Nov;18(10):764-771
17.    Inouye SK, Studenski S, Tinetti ME, Kuchel GA. Geriatric syndromes: clinical, research, and policy implications of a core geriatric concept. J Am Geriatr Soc. 2007;55:780–91.
18.    G. Guaraldi et al. (eds.), Managing the Older Adult Patient with HIV. Springer International Publishing, Switzerland 2016
19.    Erlandson KM, Schrack JA, Jankowski CM, Brown TT, Campbell TB. Functional impairment, disability, and frailty in adults aging with HIV-infection. Curr HIV/AIDS Rep 2014; 11:279–290.
20.    Koroukian SM, Schiltz N, Warner DF, Sun J, Bakaki PM, Smyth KA, et al. Combinations of chronic conditions, functional limitations, and geriatric syndromes that predict health outcomes. J Gen Intern Med 2016; 31:630–637.
21.    Guaraldi G, Palella F. Clinical implications of aging with HIV infection: perspectives and the future medical care agenda. AIDS 2017, 31 (Suppl 2):S129–S135
22.    Althoff K.N., Justice Ac, Gange SJ for the NA-ACCORD. Virologic and immunologic response to HAART by age and regimen class. AIDS 2010, 24:2469–2479.
23.    Ingle SM May M, Gill MJ et al for the Antiretroviral Therapy Cohort Collaboration. Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients. Clin Inf Dis 2014;59(2):287-97
24.    Edwards J.K., Cole R.S., Westreich D.I. Age at entry into care, timing of antiretroviral therapy initiation and 10-years mortality among HIV-seropositive adults in the United States. Clin Inf Dis 2015, 60(12):1-7.
25.    The Antiretroviral Therapy Cohort Collaboration. Durability of first ART regimen and risk factors for modification, interruption or death in HIV-positive patients starting ART in Europe and in North-America 2002-2009 AIDS 2013, 27:803-813.
26.    Greene M., Steinmann M., McNicholl IR et al Polipharmacy, drug-drug interactions, and potentially inappropriate medications in older adults with human immunodeficiency virus infection. J Am Ger Soc 2014; 62:447-453.
27.    Edelman EJ, Gordon KS, Glover J, McNicholl IR, Fiellin DA, Justice AC. The next therapeutic challenge in HIV: polypharmacy. Drugs Aging. 2013;30:613–28.
28.    Post FA, Tebas P, Clarke A, Cotte L, Short W, Abram ME, et al. Switching to Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Adults With Renal Impairment. J Acquir Immune Defic Syndr.2016;1–16.
29.    Ortolani E, Meloni E, Onder O. Linee Guida evidence-based di appropriatezza prescrittiva nel paziente anziano complesso. Giornale Italiano di Farmacoeconomia e Farmacoutilizzazione 2014; 6: 30-37.
30.    Wastesson JW, Fastbom J, Johnell K. Expanding the Proportion of Life With Polypharmacy in Sweden: 2006–2013. Journal of the American Medical Directors Association. 2016;17(10):957-958.
31.    Wastesson JW, Canudas-Romo V, Lindahl-Jacobsen R, Johnell K. Remaining Life Expectancy With and Without Polypharmacy: A Register-Based Study of Swedes Aged 65 Years and Older. Journal of the American Medical Directors Association. 2016;17(1):31-35.
32.    McLachlan AJ, Pont LG. Drug metabolism in older people–a key consideration in achieving optimal outcomes with medicines. J Gerontol A Biol Sci Med Sci. 2012;67(2):175-180.
33.    Stuck AE, Aronow HU, Steiner A, et al. A Trial of Annual in-Home Comprehensive Geriatric Assessments for Elderly People Living in the Community. N Engl J Med. 1995;333(18):1184-9
34.    Caplan GA, Williams AJ, Daly B, Abraham K. A Randomized, Controlled Trial of Comprehensive Geriatric Assessment and Multidisciplinary Intervention After Discharge of Elderly from the Emergency Department—The DEED II Study. Journal of the American Geriatrics Society. 2004;52(9):1417-1423.
35.    Guaraldi G, Silva AR, Stentarelli C. Multimorbidity and functional status assessment. Current Opinion in HIV and AIDS. 2014;9(4):386–97.
36.    30. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Oxford University Press; 2010. 412–423.
37.    Greene M, Covinsky KE, Valcour V, Miao Y, Madamba J, Lampiris H, et al. Geriatric Syndromes in Older HIV-Infected Adults. J Acquir Immune Defic Syndr. 2015 ;69(2):161–7
38.    Wit FW, Kootstra NA, Geerlings SE, Prins M, Reiss P, for the AGEhIV Cohort Study Group, et al. Cross-sectional Comparison of the Prevalence of Age-Associated Comorbidities and Their Risk Factors Between HIV-Infected and Uninfected Individuals: The AGEhIV Cohort Study. Clin Infect Dis. 2014;59(12):1787–97
39.    Guaraldi G, Orlando G, Zona S, Menozzi M, Carli F, Garlassi E, et al. Premature age-related comorbidities among HIV-infected persons compared with the general population. Clin Infect Dis. 2011;53(11):1120-6
40.    Camoni L, Raimondo M, Urciuoli R, Iacchini S, Suligoi B, Pezzotti P & the CARPHA Study Group. People diagnosed with HIV and in care in Italy in 2014: results from the second national survey. AIDS Care. 2018;30(6):760-764
41.    Pathai S, Lawn SD, Gilbert CE, et al. Accelerated biological ageing in HIV-infected individuals in South Africa: a case–control study. AIDS. 2013;27(15):2375-2384.
42.    International Advisory Panel on HIV Care Continuum Optimization. IAPAC Guidelines for Optimizing the HIV Care Continuum for Adultsand Adolescents. J Int Assoc Provid AIDS Care. 2015;14 Suppl 1:S3-S34.
43.    Kogan AC, Wilber K, Mosqueda L. Person-Centered Care for Older Adults with Chronic Conditions and Functional Impairment: A Systematic Literature Review. Journal of the American Geriatrics Society. 2016;64(1).
44.    Mahajan AP, Sayles JN, Patel VA, et al. Stigma in the HIV/AIDS epidemic: A review of the literature and recommendations for the way forward. AIDS. 2008;22(Suppl 2):S67–S65.





1. Faculty of Science, Department of Exercise Science, Université du Québec à Montréal, Montréal, Canada; 2. Centre de recherche de l’Institut universitaire de gériatrie de Montréal, Montréal, Canada

Corresponding author: Mylene Aubertin-Leheudre, Faculty of Science, Department of Exercise Science, Sciences Biologiques Building, SB-4615, 141 av president Kennedy, Montréal, Quebec, Canada, H3C 3P8, Phone: 514-987-3000 #5018, Fax: 514-987-6166, Email: aubertin-leheudre.mylene@uqam.ca



The life expectancy of older individuals continues to increase with persons aged 70 years and more representing the fastest growing proportion of the western population (1). At the same time, this extended life should involve the preservation of autonomy through the maintenance of physical and cognitive function. However, with normal aging, people will develop frailty. Thus, identifying cost-effective interventions, which prevent frailty, is one of the most important challenges of health care systems. The difficulty in developing specific interventions to prevent or delay frailty is due to the complexity of the phenomenon, which involves many different physiological, cognitive, and psychological systems. Because no single manifestation of frailty can encompass the whole of the symptoms or signs present, consensual exercise training guidelines remain paradoxically difficult. Therefore, the aim of this review is to address an overview of the literature regarding the effect of exercise/physical activity in the prevention of physical and cognitive frailty.


Exercise and physical frailty  

Although there is not a universally accepted operational definition of frailty, the most commonly used definition of a physical phenotype of frailty comes from the Fried Frailty Index (FFI). Fried proposed identifying frailty in the individual by observing the presence of at least three of the five following symptoms: shrinking (nutritional/metabolic component assessed by unintentional weight loss), weakness (indicated by muscle strength), poor endurance and energy (per self-reported exhaustion), slowness (demonstrated by slow walking speed) and low amounts of physical activity (2).

There is evidence to suggest that history of leisure time physical activity (LTPA) is related to frailty. In fact; Savela et al. showed that people with high LTPA had up to 80% lower risk of frailty compared to sedentary subjects (3). This conclusion has been confirmed by others who observed that regularly engaged exercise activities in elderly individuals were less likely to develop frailty through a 5 year period than those who were sedentary (4, 5).

The benefits of exercise in improving functional capacities which include daily living activities, falls and quality of life of frail older adults has been considerably reported through reviews or meta-analyses (6-9). Regarding the literature, low intensity resistance training (10, 11) , power resistance training (12), multimodal (13, 14); could be recommended to older frail individuals but not flexibility home programs or chair based exercises alone (10, 15, 16). In addition, aerobic exercise could also counteract physical frailty through the improvement of the maximal oxygen uptake (Vo2max)(17) and increased muscle mass(18, 19).


Exercise and Cognitive frailty 

It is not satisfactory to define frailty in the physical domain alone since there are other factors that have not yet been examined, but are recognized as part of the frailty syndrome such as cognition. While physical frailty is a widely recognized problem in the elderly, cognitive frailty has only recently become the focus of inquiry. Recently, the International Academy of Nutrition and Aging (IANA) and the International Association of Gerontology and Geriatrics (IAGG) summarized cognitive frailty as a heterogeneous clinical manifestation characterized by the simultaneous presence of physical frailty and cognitive impairment, in the absence of dementia (20).

It is well establish that aerobic exercises such as walking may prevent the decline in cognitive function in non-frail older adults (21-23). However, few studies have examined the effect of other types of exercises (tai-chi, body and mind, resistance training) on cognitive function. For example, it has been observed that resistance training contributes positively and significantly in the improvement of brain functional plasticity, executive function and response inhibition (24, 25). There is also evidence to suggest that home based exercises may improve executive function, specifically response inhibition, after 6 months (26). Moreover, studies have shown that Tai Chi could positively affect cognitive performance in older adults (27). It should also be noted that combining aerobic training to resistance training is more efficient in improving cognitive function in older adults than aerobic or resistance training alone (28, 29). However, current evidence is limited, and research is needed on the role of exercise parameters (e.g. volume, types, and intensity) on specific cognitive functions. Indeed, it has been reported that the volume, intensity and variation of physical activities as well as the history of practice was positively associated with processing speed, memory, mental flexibility, executive function and overall cognitive function (30, 31). Finally it has been proposed that exercise could prevent cognitive frailty through an improvement on brain plasticity, structural brain reserves and cerebral blood flow (32-34).

Thus, even if exercise is promising to improve cognitive decline with age in non-frail individuals, to our knowledge only one study has been conducted to improve cognitive function using exercise alone in frail older adults (35). This study concluded that aerobic training combined to resistance training is efficient to improve executive functions, processing speed and working memory. Thus, RCT using exercise training to counteract cognitive frailty are needed in frail elderly because this population is poorly studied.


Practical guidelines 

Overall, it is important to propose an exercise program reproducible at home including gradual increases in the volume, intensity, complexity and type of all of the exercises through resistance, aerobic, as well as body and mind training. Since 64 % of older people are considered as sedentary, increasing the long-term adherence is important in order to create a specific training program that includes regular changes in the intensity and type of exercises and is feasible at home (counteract the transportation). 

More specifically, resistance-training programs should be performed two to three times per week, with two sets of 8–12 repetitions at an intensity that starts at 20%–30% and progresses to 80% of 1RM. In addition, progressively, we could increase the tempo to turn on power training, which is more efficient to improve or maintain muscle quality. All these exercises should be realized in exercise rooms under supervision or at home using for example Swissball; free-weight, elastic band, chair and others with occasional supervision. To optimize the functional capacity of individuals, resistance/power training programs should be combined with exercises in which daily activities are simulated, such as the sit-to- stand, tandem foot standing, heel–toe walking, line walking, stepping practice, standing on one leg, weight transfers (from one leg to the other). These exercises are often offered through body and mind activities such as tai chi and pilates. Aerobic training should include walking with changes in pace and direction, treadmill walking, step-ups, stair climbing, and stationary cycling. Aerobic exercise may start at 5–10min during the first weeks of training and progress to 15–30 min for the remainder of the program. The Rate of Perceived Exertion scale should be used for prescribing the exercise intensity, and an intensity of 12–14 on the Borg scale appears to be well tolerated.  

In General, to prevent physical and cognitive frailty adverse effects, frail older adults could practice multimodal physical activity programs (resistance/power, aerobic and body and mind exercise) at least twice a week during 30-45 min per session at moderate to high intensity. In addition, to optimize the physical training prescription and meet these goals in subjects with physical and/or cognitive frailty, the most effective type of exercise program should be identified by considering the optimal combination of intensity, volume, and frequency training that would promote neuromuscular, muscular and cardiovascular adaptations and thus result in improved functional and cognitive capacity in the frail elderly.


Conflict of Interest: None



1. Manton KG, Vaupel J. Survival after the Age of 80 in the United States, Sweden, France, England, and Japan. N Engl J Med 1995;333:1232-5.

2. 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:M146-56.

3. Savela SL, Koistinen P, Stenholm S, et al. Leisure-Time Physical Activity in Midlife Is Related to Old Age Frailty. J Gerontol A Biol Sci Med Sci 2013;68:1433-8.

4. Brach JS, Simonsick EM, Kritchevsky S, Yaffe K, Newman AB. The Association between Physical Function and Lifestyle Activity and Exercise in the Health, Aging and Body Composition Study. J Am Geriatr Soc 2004;52:502-9.

5. Peterson MJ, Giuliani C, Morey MC, et al. Physical Activity as a Preventative Factor for Frailty: The Health, Aging, and Body Composition Study. J Gerontol A Biol Sci Med Sci 2009;64:61-68.

6. Cadore EL, Moneo AB, Mensat MM, et al. Positive Effects of Resistance Training in Frail Elderly Patients with Dementia after Long-Term Physical Restraint. Age (Dordr) 2014;36:801-11.

7. Chou CH, Hwang CL, Wu YT. Effect of Exercise on Physical Function, Daily Living Activities, and Quality of Life in the Frail Older Adults: A Meta-Analysis. Arch Phys Med Rehab 2012;93: 237-44.

8. Gine-Garriga M, Roque-Figuls M, Coll-Planas L, Sitja-Rabert M, Salva A. Physical Exercise Interventions for Improving Performance-Based Measures of Physical Function in Community-Dwelling, Frail Older Adults: A Systematic Review and Meta-Analysis. Arch Phys Med Rehabil 2014;95:753-69 e3.

9. Weening-Dijksterhuis E, de Greef MHG, Scherder EJA, Slaets JPJ, van der Schans CP. Frail Institutionalized Older Persons: A Comprehensive Review on Physical Exercise, Physical Fitness, Activities of Daily Living, and Quality-of-Life. Am J Phys Med Rehab 2011;90:156-68.

10. Brown M, Sinacore DR, Ehsani AA, Binder F, O Holloszy J, Kohrt WM. Low-Intensity Exercise as a Modifier of Physical Frailty in Older Adults. Arch Phys Med Rehab 2000;81:960-65.

11. Chandler JM, Duncan PW, Kochersberger G, Studenski S. Is Lower Extremity Strength Gain Associated with Improvement in Physical Performance and Disability in Frail, Community-Dwelling Elders? Arch Phys Med Rehab 1998;79:24-30.

12. Izquierdo M, Lusa Cadore E. Muscle Power Training in the Institutionalized Frail: A New Approach to Counteracting Functional Declines and Very Late-Life Disability. Curr Med Res Opin 2014;30:1385-90.

13. Gill TM, Baker DI, Gottschalk M, Peduzzi PN, Allore H, ByersA. A Program to Prevent Functional Decline in Physically Frail, Elderly Persons Who Live at Home. New Engl J Med 2002;347:1068-74.

14. Pahor M, Guralnik JM, Ambrosius WT, et al. Effect of Structured Physical Activity on Prevention of Major Mobility Disability in Older Adults: The Life Study Randomized Clinical Trial. JAMA 2014;311:2387-96.

15. Anthony K, Robinson K, Logan P, Gordon AL, Harwood RH, Masud T. Chair-Based Exercises for Frail Older People: A Systematic Review. BioMed Res Int 2013 (2013).

16. Binder EF, Schechtman KB, Ehsani AA, et al. Effects of Exercise Training on Frailty in Community-Dwelling Older Adults: Results of a Randomized, Controlled Trial. J Am Geriatr Soc 2002;50:1921-28.

17. Ehsani AA, Spina RJ, Peterson LR et al. Attenuation of Cardiovascular Adaptations to Exercise in Frail Octogenarians. J Appl Phys 2003;95:1781-88.

18. Harber MP, Konopka AR, Douglass MD, et al. Aerobic Exercise Training Improves Whole Muscle and Single Myofiber Size and Function in Older Women. Am J Physiol Regul Integr Compar Physiol 2009;297:R1452-R59.

19. Sugawara J, Miyachi M, Moreau KL, Dinenno FA, DeSouza CA, Tanaka H. Age-Related Reductions in Appendicular Skeletal Muscle Mass: Association with Habitual Aerobic Exercise Status. Clin Physiol Functional Imaging 2002;22:169-72.

20. Kelaiditi E, Cesari M, Canevelli M, et al. Cognitive Frailty: Rational and Definition from an (I.A.N.A./I.A.G.G.) International Consensus Group. J Nutr Health Aging 2013;17:726-34.

21. Hindin SB, Zelinski EM. Extended Practice and Aerobic Exercise Interventions Benefit Untrained Cognitive Outcomes in Older Adults: A Meta-Analysis. J Am Geriatr Soc 2012;60: 136-41.

22. Landi F, Onder G, Carpenter I, Cesari M, Soldato M, Bernabei R. Physical Activity Prevented Functional Decline among Frail Community-Living Elderly Subjects in an International Observational Study. J Clin Epidemiol 2007;60:518-24.

23. Smith PJ, Blumenthal JA, Hoffman BM, et al. Aerobic Exercise and Neurocognitive Performance: A Meta-Analytic Review of Randomized Controlled Trials. Psychosomatic Med 2010;72:239.

24. Cassilhas RC, Viana VAR, Grassmann V, et al. The Impact of Resistance Exercise on the Cognitive Function of the Elderly. Med Sci Sports Exer 2007;39:1401.

25. Liu-Ambrose T, Nagamatsu LS, Graf P, Beattie BL, Ashe MC, Handy TC. Resistance Training and Executive Functions: A 12-Month Randomized Controlled Trial. Arch Intern Med 2010;170:170-78.

26. Liu-Ambrose T, Donaldson MG, Ahamed Y, et al. Otago Home-Based Strength and Balance Retraining Improves Executive Functioning in Older Fallers: A Randomized Controlled Trial. J Am Geriatr Soc 2008;56:1821-30.

27. Chang YK, Nien YH, Tsai CL, Etnier JL. Physical Activity and Cognition in Older Adults: The Potential of Tai Chi Chuan. J Aging Phys Act 2010;18:451-72.

28. Bherer L, Erickson KI, Liu-Ambrose T. A Review of the Effects of Physical Activity and Exercise on Cognitive and Brain Functions in Older Adults. J Aging Res 2013;657508.

29. Rolland Y, Abellan van Kan G, Vellas B. Physical Activity and Alzheimer’s Disease: From Prevention to Therapeutic Perspectives. J Am Med Dir Assoc 2008:9:390-405.

30. Arab L, Sabbagh MN. Are Certain Life Style Habits Associated with Lower Alzheimer Disease Risk? J Alzheimer Dis 2010;20:785.

31. Voelcker-Rehage C, Niemann C. Structural and Functional Brain Changes Related to Different Types of Physical Activity across the Life Span. Neurosci Biobehavioral Rev 2013;37:2268-95.

32. Angevaren M, Vanhees L, Wendel-Vos W et al. Intensity, but Not Duration, of Physical Activities Is Related to Cognitive Function. Eur J Cardiovasc Prev Rehab 2007;14:825-30.

33. Cotman CW, Berchtold NC. Exercise: A Behavioral Intervention to Enhance Brain Health and Plasticity. Trends Neurosci 2002;25:295-301.

34. Ide K, Secher NH. Cerebral Blood Flow and Metabolism During Exercise. Progr Neurobiol 2000;61:397-414.

35. Langlois F, Minh Vu TT, Kergoat MJ, Chassé K, Dupuis G, Bherer L. The Multiple Dimensions of Frailty: Physical Capacity, Cognition, and Quality of Life. Int Psychogeriatr 2012;24:1429-36.