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9th Annual International Workshop on HIV & Aging 2018 Summary / Review
Current Challenges and Solutions in Research and Clinical Care of Older Persons Living with HIV: Findings Presented at the 9th
International Workshop on HIV and Aging
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NATAP Reports
9th International Workshop on HIV and Aging
13 and 14 September 2018
New York City, NY
Published Online: 2 Aug 2019 AIDS Research and Human Retroviruses, just accepted.
Herein, we summarize the key topics discussed at the 9th Annual International Workshop on HIV & Aging 2018 including "inflammaging," mitochondrial dysfunction, exercise interventions, HIV-associated neurocognitive impairment, metabolic dysfunction, women and aging, menopause, and polypharmacy. In addition to recent developments in research and clinical care, we discuss open questions and future research directions required to better understand the interaction of HIV and aging. we summarize the key oral presentations from the Workshop and the recent developments in research pertaining to these issues. This is not a comprehensive review of issues related to HIV and aging, but, rather, a selection of timely and important issues that reflect both unique mechanisms underlying aging among PWH and potential therapeutic targets. ......
Highlights Extracted from Summaries Below
1 - Understanding the intricacies of HIV and aging at both the individual and population levels with appropriate comparison participants and research designs is necessary for both horizontal and vertical advances in HIV treatment and clinical practice....despite clear epidemiologic evidence that psychosocial differences between older PWH and HIV uninfected persons exist,14 very little remains known of the impact of factors such as loneliness, social isolation, resilience, wisdom, mental health and substance use on older PWH
2 - Impaired immune responses to vaccines, underlying mitochondrial dysfunction, alternations in skeletal muscle, metabolic dysfunction, and the age‐associated changes in hormones, particularly among women, were highlighted as important mechanisms influencing the aging process among PWH.
3 - The care of older PWH is becoming increasing complex as HIV providers are being asked to manage an increase in comorbidities, polypharmacy, increases in drug resistance and toxicity, and changes in pharmacokinetics as kidney and renal function diminish with age. It is clear that these complications necessitate a more individualized, multi‐dimensional approach to care of older PWH. Many new models of care are being proposed including geriatric consultation, novel approaches to integrating specialty medicine into HIV care, implementation of the comprehensive geriatric assessment, as well as other routine geriatric screenings and practices......Many new models of care are being proposed including geriatric consultation, novel approaches to integrating specialty medicine into HIV care, implementation of the comprehensive geriatric assessment, as well as other routine geriatric screenings and practices.116‐120 Although these approaches differ, they generally embrace some if not all of five key components, known as the 5 Ms of geriatrics.121 The 5 Ms include: 1) What Matters Most: knowing and acting upon each person's own health outcome goals and care; 2) The Mind: understanding a person's neurocognitive functioning including assessment of dementia, depression, and delirium; 3) Mobility: identifying impairments in gait and balance, implementing an individualized fall prevention program and creating an environment that promotes mobility; 4) Medications: optimal prescribing including adjusting doses, and deprescribing to reduce polypharmacy, adverse medication reaction effects and medication burden; and 5) Multi‐complexity: identifying and managing multimorbidity, and complex bio‐psycho‐social situations. By incorporating the 5Ms into routine clinical care of older PWH, providers and patients can together develop a comprehensive plan for prevention, treatment and rehabilitation, which is often accomplished using an interdisciplinary team and standardized instruments for assessment.
4 - as PWH live longer, the role for rehabilitation will increase, as the need to prevent or mitigate episodic disability among those aging with HIV continues to grow. Future research should examine the nature and extent of episodic disability, determine the effectiveness of rehabilitation interventions and models of care, while advancing the development and use of patient‐reported outcomes in the field.
5 - Menopause is thought to occur earlier in women with HIV than in the general population, but early menopause may also be a consequence of malnutrition, smoking, depression, substance use and other psychosocial factors that are disproportionately present in women with HIV.97 Although the hormonal changes associated with menopause are not thought to impact CD4 cell count or HIV‐1 viral load, they can increase the risk of age‐associated co‐morbidities such as osteoporosis, heart disease and stroke.98 Given that, the perimenopausal period may represent a period of increased risk for these comorbidities, practitioners should evaluate ART to ensure the agents are not contributing to comorbidity risk (e.g., abacavir and cardiovascular disease and tenofovir and renal disease). Menopausal symptoms are also thought to be more frequent in women with HIV and have been associated with increased rates of anxiety, depression, and sexual function dissatisfaction.
6 - Polypharmacy has been shown to be highly prevalent in older PWH, ranging from 43% up to 94%,103‐106 and is linked to an increased risk for hospitalization or mortality.105 Similarly, inappropriate prescribing appears to be frequent in older PWH and more commonly observed in patients treated with a large number of comedications
7 - PWH who suffer from metabolic syndrome or metabolic syndrome components, experience increased likelihood of neurocognitive impairment....for example, abdominal obesity was associated with neurocognitive impairment,and research by Valcour and colleagues76,88 linked higher insulin resistance to a greater degree of neurocognitive impairment among PWH. The impaired brain insulin signaling and brain glucose metabolism connected to insulin resistance may be the underlying mechanisms contributing to neurocognitive impairment. ..... It is important to note that glycolysis is a modifiable factor; anaerobic glycolysis can be promoted through exercise and intranasal delivery of insulin. Past and ongoing human intranasal insulin trials examine its safety and efficacy in improving cognitive outcomes among the general population as well as PWH
8 - Impairments in neurocognitive function persist in the era of effective ART. Approximately 30‐60% of PWH will develop neurocognitive impairment, with the majority acquiring milder forms of impairment, at some point during their lifetime..... in the Women's Interagency HIV Study (WIHS), we found that both hippocampal and prefrontal function are impaired in midlife women living with HIV versus HIV‐uninfected women67 and, in a pharmacologic challenge study, we found that hormonal mechanisms (hypothalamic‐pituitary‐adrenal axis) and inflammation68,69 may contribute to the hippocampal‐prefrontal function that underlies declarative memory.
9 - There are a host of additional predictors that may contribute to or exacerbate age‐related neurocognitive impairment in the context of HIV. These predictors include mental health factors (e.g., depressive, anxiety, and stress‐related symptoms),74 cardiovascular risk factors (e.g., arterial stiffness),75 metabolic factors (e.g., insulin resistance),76 menopause,77 substance abuse,78‐80 low educational attainment,81,82 sensory impairment,83 and neurotoxic effects of non‐antiretroviral drugs.84 Many of these factors increase with age and intervening on a number of these factors may improve cognitive aging among PWH.
10 - "There is a wealth of data linking mitochondrial dysfunction to human aging, but our understanding of the mechanisms involved has evolved in recent years. For example, the mitochondrial free radical theory of aging that suggested a 'vicious‐cycle' of mitochondrial DNA mutations and oxidative damage has been largely disproved......We observed modest deficits in gait speed, stair climb power, predicted metabolic equivalents, without deficits in leg power or strength among PWH compared to age‐matched, HIV‐uninfected controls. We also observed elevated systemic immune activation ...... among PWH compared to control participants.....we observed an unexpected increase in internalized muscle nuclei that are typically diagnostic of acute injury or advanced age.39 Also, we observed reduced levels of nuclear Peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC‐1alpha), suggesting potential downstream effects on exercise tolerance. Notably, while aging among HIV‐uninfected persons has generally been associated with declines in fast‐twitch muscle fibers and increased size variability,38,40 these features were not evident in PWH...... the premature and dysregulated expression observed in PWH may be more consistent with an asynchronous aging.....Collectively, asymptomatic PWH on effective ART were characterized by subclinical deficits in physical function, greater levels of fatigue and estimated mortality risk (by the Veterans Aging Cohort Study Index), elevated inflammation and immune activation, and increased skeletal muscle internalized nuclei with decreased PGC‐1 alpha......Physical therapy has a key role in promoting physical activity among PWH. Rehabilitation, such as physical therapy and occupational therapy, has a role in addressing episodic disability experienced by PWH.45 However, in Canada, few PWH access formalized rehabilitation services......Barriers to physical activity among PWH can be multi‐factorial including pain, depression, competing life priorities, and episodes of illness.......multimorbidity, episodic disability, readiness to engage in exercise, and accessibility to fitness centers are key considerations when implementing and prescribing community‐based exercise with PWH.58,59 Furthermore, clinicians should consider the terms 'exercise' versus 'physical activity' as a continuum of activity and health‐promoting behavior.60 Physical therapy has a key role in promoting physical activity among PWH.
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Current Challenges and Solutions in Research and Clinical Care of Older Persons Living with HIV: Findings Presented at the 9th
International Workshop on HIV and Aging
Erin E. Sundermann1, Kristine M. Erlandson2, Caitlin N. Pope3,4, Anna Rubtsova5, Jessica Montoya1, Alison A. Moore6, Catia Marzolini7, Kelly K. O'Brien8, Savita Pahwa9, Brendan A. I. Payne10, Leah H. Rubin11, Sharon Walmsley12, Norman J. Haughey11, Monty Montano13, Maile Y. Karris14, Joseph B. Margolick15, and David J. Moore1
1Department of Psychiatry, University of California, San Diego, CA, USA
2Department of Medicine and School of Public Health, Department of Epidemiology, University of Colorado‐Anschutz Medical Center, Aurora, Colorado, USA
3Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
4Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
5Department of Behavioral Sciences and Health Education, Emory University Rollins School of Public Health, GA
6Department of Medicine, Division of Geriatrics and Gerontology, University of California, San Diego, CA, USA
7Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel and University of Basel, Switzerland and the Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine,
University of Liverpool, Liverpool, UK.
8Department of Physical Therapy, University of Toronto; Institute of Health Policy, Management and Evaluation (IHPME), University of Toronto; and the Rehabilitation Sciences Institute (RSI), University of Toronto, Ontario, Canada
9Department of Microbiology and Immunology and the Miami CFAR, University of Miami Miller School of Medicine, Miami
10Wellcome Centre for Mitochondrial Research, Newcastle University, UK.
11Department of Neurology, Johns Hopkins University School of Medicine and Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
12Toronto General Hospital, University Health Network; University of Toronto, Department of Medicine.
13Department of Medicine, Harvard Medical School, Boston, MA
14Department of Medicine, Division of Infectious Diseases and Global Public Health, Unviersity of California San Diego, San Diego, CA
15Department of Molecular Microbiology and Immunology, Environmental Health and Engineering, and Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
Abstract
In the era of effective antiretroviral therapy (ART), the number of older people with HIV (PWH) is increasing, and those aging with HIV are experiencing an increasing burden of age-associated comorbidities. Life expectancy among older PWH is approaching that of demographically-comparable HIV-uninfected (HIV-) adults. With this changing demographic of PWH come new challenges for researchers and clinicians in how to identify, address, and manage the complex interplay of treated HIV infection and aging-associated factors. In response to these challenges, the annual International Workshop on HIV & Aging was initiated in 2009 as a multidisciplinary platform for scientific discourse on the research and clinical complications arising from the aging population of PWH. The multidisciplinary nature of the workshop has resulted in a wide range of topics addressed over the past nine years, from basic mechanisms in aging and HIV pathogenesis, to epidemiology of aging within large cohorts, interventions, and implementation of clinical programs. Herein, we summarize the key topics discussed at the 9th Annual International Workshop on HIV & Aging 2018 including "inflammaging," mitochondrial dysfunction, exercise interventions, HIV-associated neurocognitive impairment, metabolic dysfunction, menopause, and polypharmacy. In addition to recent developments in research and clinical care, we discuss open questions and future research directions required to better understand the interaction of HIV and aging.
Introduction
The number of people with HIV (PWH) who are 50 years old and older is increasing due to early initiation and increased effectiveness of antiretroviral therapy (ART), which have greatly improved longevity of PWH. Currently, one‐half of PWH in the United States are over 50 years of age and life expectancy among ART‐treated adults is approaching that of the general population.1‐4 Concurrently, the determinants of morbidity and mortality among PWH have shifted from AIDS‐related opportunistic infections and neoplasms to complications of aging‐related conditions including neurocognitive impairment, kidney disease, liver disease, osteoporosis, cardiovascular disease, and frailty.5‐7 Furthermore, some of these aging‐related conditions appear approximately 5 to 10 years earlier among PWH compared to demographically‐similar HIV‐uninfected populations.8. The increased frequency and earlier onset of some age‐related conditions among PWH, may suggest a 'premature aging' phenomenon. Among PWH, however, premature aging remains a matter of debate given mixed research findings, lack of an agreed‐upon definition and objective criteria, and the difficulty in obtaining a valid comparator group of HIV‐uninfected persons. Even when HIV serostatus groups are demographically matched, PWH tend to have higher rates of biopsychosocial risk factors that impact age‐related health outcomes than HIV‐uninfected controls such as poverty, lower educational attainment, comorbid conditions (e.g., diabetes mellitus and depression), co‐infections (e.g., chronic viral hepatitis), and substance use disorders (e.g., tobacco, alcohol, and illicit drugs) 9‐11 In addition, risk for aging‐related outcomes may be greater among older PWH due to less than optimal ART in the early years of the HIV epidemic, long‐term toxicity of some ART, lack of consistent viral suppression over time, and the potential interactive or compounding effects of HIV and aging on mechanisms such as chronic inflammation.5,12‐14 Thus, the aging of PWH presents new challenges in how to address, manage and treat the complex interplay of HIV and aging‐associated factors including medical comorbidities, polypharmacy, and psychosocial stressors, and how to develop the best models for clinical care and community support.
The increasing proportion of older (aged 50 years and older) adults living with HIV and the growing burden of age‐associated comorbidities create a pressing need to understand the risk and protective factors of physical and mental illness among older PWH as well as strategies for prevention and treatment of these conditions. In response to this need, the annual International Workshop on HIV & Aging was initiated in 2009 as a unique platform for scientific exchange on the increasingly‐recognized difficulties encountered in the clinical care of, and research on, persons aging with HIV. The goals of the workshop are to: 1) stimulate and guide research that will enable better treatment methods and strategies for older PWH, 2) encourage young investigators to engage in research and clinical care of older PWH, and to 3) foster collaborations among investigators working to understand HIV and aging. The workshop brings together experts in cross‐disciplinary fields including basic mechanisms of aging, HIV pathogenesis, clinical geriatrics, endocrinology, HIV biology, pharmacology, neurology, psychology, and social work to address the multidisciplinary nature of HIV and aging.
The 9th Annual International Workshop on HIV & Aging was held on September 13th and 14th, 2018 in New York, NY. Herein, we summarize the key oral presentations from the Workshop and the recent developments in research pertaining to these issues. This is not a comprehensive review of issues related to HIV and aging, but, rather, a selection of timely and important issues that reflect both unique mechanisms underlying aging among PWH and potential therapeutic targets.
Immunity and Aging: Impact of HIV infection.
Savita Pahwa, MD
Inflammation is a common feature of both HIV and biologic aging (where it is termed "inflammaging"),15‐17 and is considered to be an underlying factor in many age‐associated comorbidities. Premature immune senescence is another feature ascribed to HIV infection that is considered to be similar to the impaired immunity observed with aging. For example, in older age as well as in HIV infection, the risk for contracting influenza infection is high, but effectiveness of the influenza vaccine for protection against clinical influenza is variable. Influenza vaccination can serve as a useful tool to assess immune competence by analysis of immune response to the vaccine antigens.
We investigated responses to influenza vaccine in 151 PWH and 164 HIV‐uninfected, healthy control participants grouped as young (<40 years), middle aged (40‐59 years) and older (≥60 years) under the acronym "FLORAH" (FLu Responses Of people in Relation to Age and HIV). All PWH were receiving ART with a plasma HIV‐1 viral load of <50 copies/mL. Participants were classified as vaccine responders based on ≥4 fold change in serum antibody titers post‐vaccination compared to pre‐vaccination levels, while those who failed to achieve this change were classified as vaccine non‐responders. Young controls had the highest frequency of and most robust vaccine responders, whereas a high proportion of older controls were vaccine non‐responders. In contrast, among PWH, vaccine non‐responders were present in all age groups. The detrimental effect of HIV was most evident in the young age group wherein the PWH showed the maximum difference from controls with lower antibody titers and a higher frequency of vaccine non‐responders.18 Older PWH and older controls both showed age‐associated immune decline. A vaccine non‐responders state was commonly associated with increased inflammation and immune activation at pre‐vaccination.19
To further understand the cellular basis of these antibody responses, we investigated a subset of circulating CD4 T cells known as peripheral (p) T follicular helper cells (Tfh). The pTfh share functional and some phenotypic characteristics of Tfh cells that are found in germinal centers of lymph nodes. The interaction of germinal center Tfh cells and germinal center B cells is critically important for the generation of antibody responses to pathogens and vaccines. Study of circulating pTfh and circulating B cells provides a non‐invasive means to investigate aspects of T‐B cell interaction involved in antibody response. We investigated pTfh in project FIND (FInding Novel Determinants of Flu responses), a substudy of 103 FLORAH participants, consisting of roughly equal numbers of vaccine responders and vaccine non‐responders, grouped by age as younger (<40 yrs, 20 PWH and 18 uninfected controls), and older (≥60 yrs, 30 PWH and 35 uninfected controls).20 We compared blood samples in PWH and controls in both influenza vaccine responders and non‐responders. Samples were compared at pre‐vaccination and post‐vaccination. Briefly, younger controls who were vaccine responders had greater numbers of pTfh cells pre‐vaccination that expanded post‐vaccination and expressed predominantly the intracellular cytokine interleukin‐2120 that is critical for pTfh and B cell functions. The pTfh also expressed inducible co‐stimulator, a molecule that interacts with its ligand on B cells to promote B cell function. In contrast, among vaccine non‐responders, regardless of age, the pTfh cells were lower at pre‐vaccination, failed to expand post‐vaccination, and exhibited a much different cytokine response. This pTfh response in vaccine non‐responders was comprised of interluekin‐2, a cytokine known to inhibit Tfh, and induction of inflammatory cytokines, tumor necrosis factor alpha and interluekin‐17 as well as expression of the inhibitory molecule, programmed cell death protein 1. Vaccine non‐responder status in PWH was also often associated with defects of B cells21 and of monocyte/macrophages.22
We conclude that an impairment of serologic response to influenza vaccine in vaccine non‐responders is associated with greater inflammation and immune activation at pre‐vaccination and can manifest at any age in PWH. This state is associated with cellular immune impairment in which the pTfh play a major role. We speculate that high dose vaccines can circumvent inadequacies of pTfh, and strategies that decrease inflammation may reverse the interluekin‐2/interleukin‐21 axis in favor of interluekin‐21, with improved influenza vaccine responses in older age and in PWH.
Mitochondrial Dysfunction and aging
Brendan Payne, PhD
There is a wealth of data linking mitochondrial dysfunction to human aging, but our understanding of the mechanisms involved has evolved in recent years. For example, the mitochondrial free radical theory of aging that suggested a 'vicious‐cycle' of mitochondrial DNA mutations and oxidative damage has been largely disproved.23 Instead, mitochondrial DNA mutations exist at fairly static levels over the human lifespan, but stochastically undergo clonal expansion within individual cells during aging.24 Nucleoside/Nucleotide Reverse Transcriptase Inhibitor drugs may cause lasting mitochondrial dysfunction in PWH through an effect on clonal expansion.25 Currently, investigators are attempting to understand the subcellular processes that drive clonal expansion.26 We now recognize that mitochondrial dysfunction in aging is important, not only in post‐mitotic tissues with high energy demands (muscle, neurons), but also in replicative tissues through an effect on the maintenance of stem cell function.27 Future research is needed to determine the clinical relevance of this effect among PWH with treated HIV infection.
One key question is, "How might mitochondrial dysfunction in aging be ameliorated?" Most therapies under current investigation aim to increase mitochondrial biogenesis. Multiple signaling pathways can affect mitochondrial biogenesis, but most converge through peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha, the so‐called 'master regulator' of mitochondrial biogenesis. Recently there has been much interest in manipulating the NAD+/NADH ratio (the ratio of oxidized to reduced nicotinamide adenine dinucleotide). This nutrient‐sensing pathway regulates mitochondrial biogenesis via peroxisome proliferator‐activated receptor gamma 1‐alpha. NAD+ can be supplemented and results in increased longevity in mice. Interestingly, this effect seems to be mediated at least in part by rescuing mitochondrial function in stem cells.28 Human trials of NAD+ supplementation are ongoing in a variety of conditions. The intervention for which the most in vivo data exist, however, is exercise, with multiple human and animal studies indicating that mitochondrial function can be improved with exercise. Nevertheless, a recent study has suggested that there is a partial 'metabolic block' to exercise response in older persons that is characterized by reduced conversion of ADP (adenosine diphosphate) to ATP (adenosine triphosphate).29 We examine in vivo mitochondrial function in skeletal muscle by phosphorus magnetic resonance spectroscopy (31P‐MRS) in 24 PWH and 24 age‐matched, uninfected healthy controls. We demonstrated that PWH had elevated ADP/ATP ratio, suggesting that this metabolic block may also exist in PWH.30 Exercise studies are underway in people aging with HIV and will determine whether there are metabolic barriers to improving mitochondrial function in this population.
Preclinical Biomarkers for Functional Decline in HIV and Aging
Monty Montano, PhD
In addition to the higher rates of peripheral comorbid conditions (e.g., renal failure, diabetes, bone fracture, hypertension, cardiovascular disease and multimorbidity),31 older PWH appear to experience greater impairments in physical and cognitive function, with development of impairment in activities of daily living and frailty in multiple cohorts.32 For example, in the Multicenter AIDS Cohort Study (MACS), the percent of visits with a frailty phenotype dramatically increases at ages greater than 50 years old among PWH compared to HIV‐uninfected men,33 despite effective ART. Similarly, declines in gait speed and grip strength were observed in the MACS among men with HIV, beginning between ages 50 and 60 years.34,35 While multifactorial drivers, including HIV infection itself, ART‐related toxicities, social inequities and biobehavioral factors, likely contribute,36 an overarching question is how aging in PWH may differ from aging in people without HIV?
A current challenge is whether there are preclinical cues for risk of functional decline in the context of persons with treated but chronic HIV infection. Ideally, studies on preclinical risk would obtain concurrent physical function, immune and muscle phenotyping and mechanistic insights into drivers of functional decline, and potential accelerated aging. The Muscle and Aging in Treated Chronic HIV (MATCH) Cohort was begun to address this challenge (NCT03011957). The MATCH Cohort is composed of 170 asymptomatic men and women living with HIV and HIV‐uninfected controls, all 50‐65 years of age, recruited from the Boston metropolitan area. PWH all have an HIV‐1 RNA below the limit of detection and CD4+ T‐cell counts above 350 cells/mm3.37 Functional assessment was performed and included gait speed, leg strength and power, and predicted metabolic equivalents, and stair climb power. Multiple additional parameters were measured including fatigue, the Veterans Aging Cohort Study Index, and skeletal muscle computed tomography (CT) scans. Blood and skeletal muscle (vastus lateralis) were obtained to assess immune profiles and immunohistochemistry (muscle only). We observed modest deficits in gait speed, stair climb power, predicted metabolic equivalents, without deficits in leg power or strength among PWH compared to age‐matched, HIV‐uninfected controls. We also observed elevated systemic immune activation (cluster of differentiation 38 [CD38], human leukocyte antigen – DR subtype [HLA‐DR] expression on T cells) and inflammation (serum C‐reactive protein [CRP], soluble CD14, soluble CD163) but not serum interleukin‐6 (IL‐6) among PWH compared to control participants. CT scans did not reveal expected declines in skeletal muscle density, typically seen with increasing age, among PWH compared to control participants of similar age. Similarly, histological assessment of muscle fiber type did not reveal differences or increased size variability (both of which are expected with muscle aging38). Provocatively, however, we observed an unexpected increase in internalized muscle nuclei that are typically diagnostic of acute injury or advanced age.39 Also, we observed reduced levels of nuclear Peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC‐1alpha), suggesting potential downstream effects on exercise tolerance. Notably, while aging among HIV‐uninfected persons has generally been associated with declines in fast‐twitch muscle fibers and increased size variability,38,40 these features were not evident in PWH,37 despite the earlier than expected presence of internalized nuclei and reduced PGC‐1 alpha. This complex phenotype may suggest that PWH experience an asynchronous aging, wherein some, but not all, features of aging become evident prematurely and display dysregulated expression. Partial expression of age‐related phenotypes that occur prematurely or that are accelerated has been referred to as segmental progeria (aging).41 However, the premature and dysregulated expression observed in PWH may be more consistent with an asynchronous aging. The timing, levels and cross‐regulation of hallmarks of aging in PWH compared to the uninfected therefore remains unclear and warrants further study.
An additional finding was that, among male participants in the MATCH cohort, we did not detect differences in gait speed, despite elevated reports of fatigue. This prompted a pilot accelerometer study wherein we collected activity tracker data (Withings Pulse Ox) for three consecutive weeks.42 Interestingly, in this substudy of men living with HIV compared with HIV‐uninfected controls, we observed significant differences in average volitional gait speed by activity tracker, but not lab‐based assessment,42 (similar to results from the larger cohort).37 We also observed that the men with HIV spent significantly more time in the lowest quartile of physical activity compared to the uninfected controls.
Collectively, asymptomatic PWH on effective ART were characterized by subclinical deficits in physical function, greater levels of fatigue and estimated mortality risk (by the Veterans Aging Cohort Study Index), elevated inflammation and immune activation, and increased skeletal muscle internalized nuclei with decreased PGC‐1 alpha. Differences in men by HIV serostatus on volitional but not laboratory‐based gait measures and activity profiles, characterized by more time spent at lower activity levels, suggests potential limits on functional reserve and indicates that activity profiles may be useful as pre‐symptomatic digital biomarkers of functional decline. Future studies should distinguish the trajectory of aging in PWH compared to aging without HIV, and seek to identify biological and bio‐behavioral risk factors apparent prior to clinical presentation of physical function impairment or frailty.
Translating Exercise into the Community with Adults Aging with HIV
Kelly K. O'Brien, PhD, PT
A common comorbidity experienced by older PWH is disability defined as any physical, cognitive, mental, emotional and social‐health‐related challenges including uncertainty worrying about future health, experienced by an individual.43 Disability can be episodic in nature, characterized by unpredictable periods of wellness and illness, and exacerbated or alleviated by extrinsic contextual factors (stigma, social support) or intrinsic contextual factors (multimorbidity, age, coping strategies).43,44 Rehabilitation, such as physical therapy and occupational therapy, has a role in addressing episodic disability experienced by PWH.45 However, in Canada, few PWH access formalized rehabilitation services.46,47 A Canadian web‐based survey found that PWH tend to adopt independent living strategies such as adopting positive attitudes and beliefs, and a healthy lifestyle in which to address their disability.48
Exercise is one rehabilitation living strategy that may be adopted by PWH. Systematic review evidence indicates that performing aerobic exercise, resistive exercise, or a combination at least 3 times per week can lead to benefits of physical and mental health, specifically cardiopulmonary fitness, weight and body composition, strength, and quality of life for PWH.49,50 Nevertheless, the extent to which PWH engage in exercise or physical activity varies, with results of systematic reviews documenting inactivity in 19‐73% of PWH (n=24 studies; mean age range: 33‐47 years)51 and less than 50% achieving physical activity guidelines (n=24 studies; mean age range; 37‐58 years).52 Among a sample of 21 older PWH, mean age 66 years with an undetectable viral load in the United States, participants engaged in 35 minutes of moderate to viogorous physical activity per week.53 Barriers to physical activity among PWH can be multi‐factorial including pain, depression, competing life priorities, and episodes of illness.54 Among the 55 correlates of physical activity examined in this systematic review (n=45 studies), older age was associated with lower levels of physical activity in six of ten included studies.54 Overall, it is unclear the extent to which PWH are achieving the physical activity guidelines of 150 minutes of moderate to vigorous intensity aerobic activity per week with 2 days of muscle and bone strengthening.55 Community‐based exercise can offer an alternative strategy to enhance physical activity within a self‐management framework. Our team in Toronto, Canada is examining the effectiveness of a community‐based exercise intervention on health and disability outcomes for PWH.56 Eighty PWH initiated a six‐month exercise intervention comprised of thrice weekly exercise sessions involving a combination of aerobic, resistive, neuromotor and flexibility activity, supervised weekly by a fitness instructor.56 Results will help to establish feasible, sustainable and accessible interventions to enhance physical activity and healthy aging among PWH, and practical recommendations for physical activity among PWH have recently been published.57
In the meantime, multimorbidity, episodic disability, readiness to engage in exercise, and accessibility to fitness centers are key considerations when implementing and prescribing community‐based exercise with PWH.58,59 Furthermore, clinicians should consider the terms 'exercise' versus 'physical activity' as a continuum of activity and health‐promoting behavior.60 Physical therapy has a key role in promoting physical activity among PWH. In the Framework of Physical Therapy Role in HIV Care, deBoer and colleauges (2019) highlight the role of rehabilitation as multidimensional, focused in physical, social and psychological (mental and emotional) areas of health.61 Physiotherapists can offer goal‐oriented and person‐centered approaches while considering the influence the potentially episodic nature of HIV, stigma, aging, multi‐morbidity, social isolation, resource security, and competing priorities (e.g., housing, food insecurity) may individually or collectively have on one's ability, preferences, or priority for engaging in physical activity.61
In summary, as PWH live longer, the role for rehabilitation will increase, as the need to prevent or mitigate episodic disability among those aging with HIV continues to grow. The Canada‐International HIV and Rehabilitation Research Collaborative (CIHRRC) is a network of researchers, clinicians, PWH and representatives from community organizations working to translate evidence and identify new and emerging priorities in the field (cihrrc.hivandrehab.ca).62 Future research should examine the nature and extent of episodic disability, determine the effectiveness of rehabilitation interventions and models of care, while advancing the development and use of patient‐reported outcomes in the field.63 Disciplines of HIV, rehabilitation, primary care and geriatric medicine are well positioned to partner in collectively addressing these research priorities in order to provide timely, appropriate and effective care to optimally address disability and promote healthy aging with PWH.
Aging Considerations in HIV‐associated Neurocognitive Impairment
Leah H. Rubin, PhD, MPH
Impairments in neurocognitive function persist in the era of effective ART. Approximately 30‐60% of PWH will develop neurocognitive impairment, with the majority acquiring milder forms of impairment, at some point during their lifetime.64 Therefore, it becomes important to understand the patterns, mechanisms, and predictors of neurocognitive impairment especially as people age because, in its severe forms, neurocognitive impairment can impact daily functioning or quality of life.
Standard neuropsychological testing batteries are typically used to assess neurocognitive function .The presence of impairment in two or more domains in those living with HIV has been termed HIV‐associated neurocognitive disorders (HAND). Enthusiasm for the term HAND is mixed given the large heterogeneity in the pattern of neurocognitive impairment and age‐related neurocognitive changes.65,66 Understanding the heterogeneity of neurocognitive impairment becomes important as we work towards identifying the underlying pathophysiology of neurocognitive impairment and developing targeted interventions to improve neurocognitive impairment.
Impairment in the cognitive domain of declarative memory may be particularly important as PWH continue to age because it is common in HAND64,66 and it is a defining characteristic of Alzheimer's disease and its precursor, amnestic mild cognitive impairment. Declarative memory relies on hippocampal and prefrontal function and, in the context of HIV, has been shown to be impacted by the stress hormone, cortisol, and inflammation. In studies conducted in the Women's Interagency HIV Study (WIHS), we found that both hippocampal and prefrontal function are impaired in midlife women living with HIV versus HIV‐uninfected women67 and, in a pharmacologic challenge study, we found that hormonal mechanisms (hypothalamic‐pituitary‐adrenal axis) and inflammation68,69 may contribute to the hippocampal‐prefrontal function that underlies declarative memory. In support of this notion, strong scientific evidence supports the role of myeloid‐specific activation (e.g., serum levels of sCD163 and sCD14) and microglia70 in declarative memory71,72 and in hippocampal and prefrontal function.73
There are a host of additional predictors that may contribute to or exacerbate age‐related neurocognitive impairment in the context of HIV. These predictors include mental health factors (e.g., depressive, anxiety, and stress‐related symptoms),74 cardiovascular risk factors (e.g., arterial stiffness),75 metabolic factors (e.g., insulin resistance),76 menopause,77 substance abuse,78‐80 low educational attainment,81,82 sensory impairment,83 and neurotoxic effects of non‐antiretroviral drugs.84 Many of these factors increase with age and intervening on a number of these factors may improve cognitive aging among PWH.
Metabolic Dysfunction, Aging and Cognition
Norman J. Haughey, PhD
One factor that may play an instrumental role in neurocognitive dysfunction with aging is metabolic dysfunction. In the general population, aging is associated with increased likelihood of metabolic dysfunction. In both men and women, metabolic rate decreases and percentage of body fat increases with age. In particular, nutrition‐ and aging‐related chronic micro‐inflammation is linked to the increased hypothalamic cellular network dysfunction, which participates in the development of metabolic syndrome. Metabolic syndrome components include abdominal obesity, hypertension, dyslipidemia, and insulin resistance.73 Metabolic syndrome is associated with greater risk of type‐2 diabetes mellitus and atherosclerosis.85
Importantly, the presence of HIV infection increases the likelihood of metabolic syndrome development. Research has identified several mechanisms explaining the effects of HIV infection on metabolic syndrome. First, metabolic syndrome may develop as a possible complication of combination ART, especially regimens that include protease inhibitors.85
Second, HIV infection may itself be a contributing factor via immune dysregulation and chronic low‐level inflammation.73 Furthermore, PWH who suffer from metabolic syndrome or metabolic syndrome components, experience increased likelihood of neurocognitive impairment.85,86 For example, a study by Sattler et al87 found that abdominal obesity was associated with neurocognitive impairment,and research by Valcour and colleagues76,88 linked higher insulin resistance to a greater degree of neurocognitive impairment among PWH. The impaired brain insulin signaling and brain glucose metabolism connected to insulin resistance may be the underlying mechanisms contributing to neurocognitive impairment. In particular, increased aerobic glycolysis, one of the pathways of glucose metabolism, was found to be associated with cognitive decline among PWH.89 Conversely, a shift to anaerobic glycolysis may lead to improvements in cognitive outcomes.89 It is important to note that glycolysis is a modifiable factor; anaerobic glycolysis can be promoted through exercise and intranasal delivery of insulin. Past and ongoing human intranasal insulin trials examine its safety and efficacy in improving cognitive outcomes among the general population as well as PWH.90,91
Considerations for Women living with HIV During Menopause
Sharon Walmsley, FRCPC, MD, MSc
Dramatic shift in hormones that occurs with aging may contribute to impairments in physical and neurocognitive impairment, and these changes in hormones may manifest as unique differences in clinical manifestations among men and women. Despite the fact that the Canadian Surveillence Report estimated that about 20% of new HIV infections are diagnosed in women over the age of 50 years,92 older women are infrequently tested for HIV because of 1) lack of perceived risk, 2) failure to discuss risk factors, 3) fear of partner violence, and 4) attribution of symptoms to depression, aging or menopause.93‐96 Due to the increased lifespan of PWH in the post‐ART era, more women with HIV are experiencing menopause. Menopause is thought to occur earlier in women with HIV than in the general population, but early menopause may also be a consequence of malnutrition, smoking, depression, substance use and other psychosocial factors that are disproportionately present in women with HIV.97 Although the hormonal changes associated with menopause are not thought to impact CD4 cell count or HIV‐1 viral load, they can increase the risk of age‐associated co‐morbidities such as osteoporosis, heart disease and stroke.98 Given that, the perimenopausal period may represent a period of increased risk for these comorbidities, practitioners should evaluate ART to ensure the agents are not contributing to comorbidity risk (e.g., abacavir and cardiovascular disease and tenofovir and renal disease). Menopausal symptoms are also thought to be more frequent in women with HIV and have been associated with increased rates of anxiety, depression, and sexual function dissatisfaction.99
The use of hormone replacement therapy is controversial in the general population. The beneficial effects of hormone replacement therapy on menopausal vasomotor symptoms and on the rates of hip fracture and colon cancer need to be balanced against the small increased risk of stroke, cardiovascular disease, breast cancer, deep vein thrombophlebitis and pulmonary embolism. Hormone replacement therapy can cause adverse effects such as breast tenderness and can impact adherence to other medications. However, the studies of the risks of hormone replacement therapy are confounded by the dose, route, and timing of therapy, and there are no studies of hormone replacement therapy in women living with HIV. Concerns have been raised about the additive risk of hormone replacement therapy, HIV and ART on cardiovascular disease and stroke, and deep vein thrombophlebitis.100 If required for management of vasomotor symptoms, hormone replacement therapy should be prescribed early in the menopausal period, for as short a period as possible, and in the lowest dose possible. Additionally, clinicians need to consider drug interactions with ART when prescribing hormone replacement therapy, especially non‐nucleoside reverse transcriptase inhibitors and protease inhibitors whose induction or inhibition of cytochrome p450 enzymes might impact drug levels of the replacement therapy.
Polypharmacy and Inappropriate Prescribing in Older PWH
Catia Marzolini, PharmD, PhD
The management of HIV infection is becoming more challenging as older PWH experience age‐related chronic comorbidities101 leading to polypharmacy (defined as the use of > 5 concurrent medications) and a related higher risk for drug‐drug interactions.102 While polypharmacy is highly prevalent among older adults without HIV, the risk is likely even greater among PWH. Polypharmacy has been shown to be highly prevalent in older PWH, ranging from 43% up to 94%,103‐106 and is linked to an increased risk for hospitalization or mortality.105 Similarly, inappropriate prescribing appears to be frequent in older PWH and more commonly observed in patients treated with a large number of comedications.106 A study comparing prescriptions among PWH and age‐matched HIV‐uninfected older individuals demonstrated a higher prevalence of medication‐related problems in PWH.103 These findings suggest that HIV specialists may be less familiar with geriatric prescribing, and highlights the need for educational programs in geriatric medicine principles.
ARTs are recognized to be amongst the therapeutic agents with the highest potential for drug‐drug interactions as these drugs can be both a perpetrator and a victim of drug‐drug interactions. Common mechanisms of drug‐drug interactions involve inhibition or induction of drug metabolism enzymes or drug transporters by ART leading to toxicity or loss of efficacy of co‐administered drugs. On the other hand, co‐medications commonly used in older individuals (e.g., antacids or mineral supplements) can interfere with the absorption of certain ARTs thereby compromising their efficacy. Selected drug‐drug interactions of interest in aging PWH are represented in Table 1.107‐110
With increasing age, medication‐related problems go beyond the issue of drug‐drug interactions. The presence of age‐related comorbidities increases the risk of drug‐disease interactions whereby a medication prescribed for therapeutic use can cause medical harm due to an existing condition in the patient (e.g., prescription of corticosteroids can aggravate existing diabetes). Another issue includes age‐related physiological changes that impact drug pharmacodynamics and pharmacokinetics, thus predisposing older persons to inappropriate prescribing or incorrect dosing and consequently to adverse drug reactions.111 The latter can initiate a prescribing cascade whereby an adverse drug event is misinterpreted as a novel medical condition resulting in more medications being used to treat side effects of other medications. Prescribing cascade contributes to polypharmacy and, in turn, increases the risk of drug‐drug interactions or inappropriate prescribing and consequently adverse drug reactions, thus leading to a vicious circle.
Furthermore, medication errors can be magnified due to patient‐related communication problems as a result of deficits in vision, hearing or cognition and/or due to care coordination or communication issues among healthcare providers.
The adverse health outcomes associated with polypharmacy and inappropriate prescribing should promote interventions to minimize this risk such as 1) complete medication reconciliation, 2) periodic medication review to ensure appropriate indication, dosing and treatment duration and to check for drug‐drug interactions or drug‐disease interactions (Beers and STOPP/START criteria allow checking for inappropriate prescribing)112,113 and 3) medication prioritization according to the risk, benefit and preference for a given patient. The medication prioritization intervention highlights the issue of the applicability of treatment guidelines, mostly developed for a single disease, to multimorbid older individuals. Applying a single disease treatment model may result in care that is impractical or harmful (e.g., a tight glycemic control can expose elderly to hypoglycemia), whereas a patient‐centered treatment model may provide improved care.114 In this context, de‐prescribing, or the process of dose reduction or stopping of medications that may be harmful or no longer effective, has gained increasing attention as a means to reduce inappropriate polypharmacy in older adults.115
Comprehensive Geriatric Assessment
Alison A. Moore, MD, MPH, FACP, AGSF
The care of older PWH is becoming increasing complex as HIV providers are being asked to manage an increase in comorbidities, polypharmacy, increases in drug resistance and toxicity, and changes in pharmacokinetics as kidney and renal function diminish with age. It is clear that these complications necessitate a more individualized, multi‐dimensional approach to care of older PWH. Many new models of care are being proposed including geriatric consultation, novel approaches to integrating specialty medicine into HIV care, implementation of the comprehensive geriatric assessment, as well as other routine geriatric screenings and practices.116‐120 Although these approaches differ, they generally embrace some if not all of five key components, known as the 5 Ms of geriatrics.121 The 5 Ms include: 1) What Matters Most: knowing and acting upon each person's own health outcome goals and care; 2) The Mind: understanding a person's neurocognitive functioning including assessment of dementia, depression, and delirium; 3) Mobility: identifying impairments in gait and balance, implementing an individualized fall prevention program and creating an environment that promotes mobility; 4) Medications: optimal prescribing including adjusting doses, and deprescribing to reduce polypharmacy, adverse medication reaction effects and medication burden; and 5) Multi‐complexity: identifying and managing multimorbidity, and complex bio‐psycho‐social situations. By incorporating the 5Ms into routine clinical care of older PWH, providers and patients can together develop a comprehensive plan for prevention, treatment and rehabilitation, which is often accomplished using an interdisciplinary team and standardized instruments for assessment.
Standard instruments are available to assess each of 5 Ms. Matters Most may be assessed through advance care planning tools including Prepare for your Care,122 The Conversation Project,123 and Physician's Order for Life Sustaining Treatment (POLST).124 To quickly assess the Mind, cognitive impairment or dementia can be initially screened through simple clinical tools at the bedside such as the Mini‐CogTM,125 the Montreal Cognitive Assessment (MoCA),126 or the International HIV Dementia Scale, or screening batteries comprised of traditional neuropsychological tests127. The depression component of the mind domain is commonly screened for using the Patient Health Questionnaire‐9 (PHQ‐9).128 Mobility assessment should include an assessment of falls, in addition to tests of gait speed and balance such as the Timed Up and Go (TUG),129 the Tinetti Gait and Balance Test,130 and the Short Physical Performance Battery.131 Medication tools (further detailed above) to assess polypharmacy/inappropriate drugs include the American Geriatrics Society Beers Criteria and the STOPP/START criteria.113 Multicomplexity incorporates functional status and multimorbidity, with functional implications assessed through measures such as the Activities of Daily Living (ADLs) needed for self‐care and Instrumental ADLS (IADLs) needed for independent community living. The Veterans Aging Cohort Study (VACS) Index132 provides an assessment of the severity of underlying disease and risk for mortality. Other frailty measures such as the Fried frailty phenotype133 summarize an individual's vulnerability to additional stressors, often highly influenced by the degree of multicomplexity. Overall, the concept of multi‐complexity or multimorbidity considers the benefit versus harm of additional treatment, medication, or interventions based on a patient's current health status and goals of care, rather than strictly adhering to disease‐specific guidelines.134 In summary, distilling the discipline of geriatrics down to five key components allows development of novel, feasible and individualized models of care for older PWH that ultimately enhances implementation and dissemination of best practices.
Conclusions
The 9th Annual International Workshop on HIV & Aging 2018 discussed and showcased a wide variety of timely and important research issues in the field of HIV and Aging that spanned from neural and behavioral mechanisms and risk factors for aging‐related impairments to potential therapeutic avenues and models of care. A key takeaway from the discussions and presentations was that understanding how HIV impacts and interacts with biological aging processes is complex and will require innovative interdisciplinary teamwork from researchers, clinicians, patients and community partners. Overall, three broad research priorities emerged: (1) understanding biological and neurological mechanisms behind aging with HIV to better inform targeted and efficacious treatments and regimens for HIV; (2) investigating feasible and sustainable interventions to promote better daily function and health outcomes for PWH; and (3) enhancing clinical experience and treatment for older PWH, including women and vulnerable sub‐populations.
Impaired immune responses to vaccines, underlying mitochondrial dysfunction, alternations in skeletal muscle, metabolic dysfunction, and the age‐associated changes in hormones, particularly among women, were highlighted as important mechanisms influencing the aging process among PWH. These underlying mechanisms will guide the creation of new, targeted, therapies (e.g., medication, gene, and behavioral) aimed at improving health‐related outcomes and overall function. Therapies and interventions should be considered both for their potential biologic relevance, as well as their feasibility of long‐term sustainable uptake among PWH. For example, intranasal insulin trials are being tested to mitigate neurocognitive impairment seen with individuals with metabolic syndrome and HIV, and community‐based physical activity interventions to promote healthy well‐being for PWH experiencing episodic disability are being developed.56 Physical actictivy interventions show therapeutic promise, but is accompanied with multifactorial barriers including pain, depression, social isolation, stigma, and competing life priorities that may impact one's ability to sustain a physical activity regimen, especially in community settings.54,58,59 In terms of improving clinical experience and treatment for older PWH, talks highlighted the importance of investigating preclinical biomarkers, conducting comprehensive and geriatric‐specific assessments of health, and addressing key interactions between HIV and biological processes such as menopause to improve care. Talks also informed challenges and solutions related to the progression of other aging‐based comorbidities and issues such as polypharmacy, frailty, and Alzheimer's disease. Future research in these areas will help provide targeted treatment, promote a patient‐centered treatment model, and provide essential training and guidance for HIV specialists who may be less familiar with geriatric medicine.
This workshop summarized the current and future direction of the field; however, it is clear that more research is needed, not only at the individual‐level, but also from a cohort population‐level perspective. Previous research from Multicenter AIDS Cohort Study (MACS) has begun to inform the field on frailty phenotypes within the context of HIV. Through large multisite cohorts such as the MACS, the Women's Interagency HIV Study (WIHS), CNS HIV Antiretroviral Treatment Effects Research (CHARTER), and the National NeuroAIDS Tissue Network (NNTC), we can conduct needed complex, longitudinal investigations and begin to discern differences in aging with and without HIV. There is also a need for longitudinal cohort studies of PWH with sociodemographically‐matched control groups. The current evidence remains insufficient to determine if HIV infection leads to either accelerated or accentuated aging given that, in observational, epidemiological studies, PWH might differ from uninfected controls with respect to behavioral and lifestyle factors (e.g., smoking, alcohol, drug use) and viral co‐infections (e.g., hepatitis C) which place PWH at higher risk of age‐associated comorbidities.9 Studies with appropriately matched HIV‐uninfected control groups will provide more robust evidence and confirm the impact of HIV on the incidence of age‐associated comorbidities.
Understanding the intricacies of HIV and aging at both the individual and population levels with appropriate comparison participants and research designs is necessary for both horizontal and vertical advances in HIV treatment and clinical practice. Lastly, despite clear epidemiologic evidence that psychosocial differences between older PWH and HIV uninfected persons exist,14 very little remains known of the impact of factors such as loneliness, social isolation, resilience, wisdom, mental health and substance use on older PWH.135‐138 Recent work confirms that understanding how psychosocial factors interact with aging (both negatively and positively) and developing novel solutions to address negative factors are a major community priority.139,140 By taking a biopsychosocial approach to HIV and aging‐related research we can gain holistic insight into the clinical challenges that will ultimately translate into clinical care that promotes better health outcomes and well‐being for PWH.
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