Current Challenges, Solutions, and Novel Directions in Research and Clinical Care: Proceedings From the 14th Annual International Workshop on HIV and Aging

Abstract

Integrating antiretroviral therapy into HIV care dramatically extended the lifespan for people living with HIV. Improving the health span requires understanding aging, HIV, associated comorbid conditions, and concurrent treatments. The 14th annual International Workshop on HIV and Aging on October 26–27, 2023 included podium presentations on: Sarcopenia: Biology, Pathophysiology, Prevention and Treatment; Long-acting ART; Central Nervous System (CNS) complications; Asymptomatic Neurocognitive Impairment (ANI); Mental Health; Loneliness; and Resilience. Presentations highlighted persistent concerns for people living with HIV including sarcopenia and frailty, mental health, loneliness, and cognition. Presenters encouraged prioritizing mental health treatment, reducing social isolation, and research on resiliency.

The integration of antiretroviral therapy (ART) into HIV care dramatically extended the lifespan of people living with HIV (PWH) and changed the demographics of the HIV epidemic. Currently, over half of PWH are aged 50 years or older, and recent projections in the United States and Europe suggest that over 70% of PWH will be over the age of 50 by 2030 (1,2). In comparison to populations without HIV, PWH on effective ART experience a near normal life expectancy but an early onset of aging complications, including neurocognitive impairment, osteoporosis and fractures, and frailty (2).

Improving the health span of older PWH requires a deep understanding of the interface between aging, HIV, associated comorbid conditions, and treatments. Additionally, research must address the unique psychosocial challenges faced by PWH. While many age successfully with HIV, older PWH are vulnerable to social stigma, depression, and anxiety, which in turn can compromise medication adherence and reduce overall health and quality of life (3).

The International Workshop on HIV and Aging took place in a hybrid format on October 26–27, 2023, in Washington, DC, in the United States. In its 14th year, the Workshop remains the only platform (to our knowledge) worldwide for international, cross-disciplinary scientific exchange on the difficulties encountered in clinical care and research on aging among PWH. The Workshop creates opportunities for HIV and aging trainees and junior investigators from diverse clinical and social science backgrounds to present research, network, and learn. The meeting gathered 177 researchers, healthcare professionals, government officials, and community advocates to foster dialogue and prompt solutions to benefit older PWH. To share current challenges, knowledge, and future research directions with the broad community of HIV and aging scholars and practitioners who were unable to attend the Workshop, we present a summary of major topics covered in podium presentations: Sarcopenia: Biology, Pathophysiology, Prevention and Treatment; Long-acting ART; Central Nervous System (CNS) complications; Asymptomatic Neurocognitive Impairment (ANI); Mental Health; Loneliness; and Resilience.

Sarcopenia: Biology, Pathophysiology, Prevention, and Treatment

Gustavo Duque, Kristine M. Erlandson, and Jing Sun

Muscle biology and mitochondrial disruptions

Skeletal muscle comprises a complex structure throughout the body that goes from the fiber bundle to myofibrils and myofilaments. The stability and function of these components depend on fiber quality and their interactions with adjacent tissues such as neurons (neuromuscular junction), blood vessels, and intermuscular fat and with other organs and systems such as the CNS, gut, and bone (4,5). In addition to biological factors and interorgan communication systems, muscle performance is determined by lifestyle and psychological factors (eg, nutrition, level of activity, depression, resilience) (6–8). These factors interact to maintain muscle health and function, providing mobility and functional independence and regulating glucose metabolism.

Multiple cellular changes (eg, epigenetic alterations, mitochondrial dysfunction), defined as hallmarks of aging also affect muscle cells (9), impacting the capacity to respond to stressors and regulate glucose metabolism. In addition, other external factors such as the chronic low grade inflammatory status observed with aging (inflammaging), malnutrition, and excessive fatty infiltration of muscle potentiate changes and affect skeletal muscle and its interactions with other organs.

Mitochondria, found in greatest density within skeletal muscle, play a crucial role in energy production, and mitochondrial dysfunction is also an aging hallmark (10). Mitochondrial dysfunction is linked to age-related diseases such as cardiovascular and kidney disease, diabetes, and metabolic disorders (11,12).

Research on the effect of mitochondrial function and genetics on aging and comorbidity among PWH is limited. For example, mitochondrial dynamics is a key process in maintenance of skeletal muscle health and aging (13,14), especially among PWH. PWH may be more prone to mitochondrial damage due to chronic inflammation, prolonged ART, smoking, and drug use (15–19). Older nucleoside reverse transcriptase inhibitors (NRTIs) are known for their mitochondrial toxicity, causing severe side effects like hepatic failure and lactic acidosis (15–17). Although modern ARTs exhibit significantly less mitochondrial toxicity, many older PWH had prior exposure to older NRTIs, with lasting side effects. Mitochondrial nuclear genetics and epigenetics may influence muscle function. For example, certain mitochondrial DNA haplogroups, such as African haplogroup L3, are linked to an increased risk of age-related comorbidities (20). Exposure to mitochondrial-toxic ARTs (eg, d4T, ddC, ddI) might exacerbate risks, particularly in individuals with haplogroup L3, leading to higher incidence of diabetes (20). Exercise may improve muscle mitochondrial bioenergetics, although such responses were blunted among older adults with HIV (21).

Sarcopenia and frailty

A progressive decline in mitochondria, muscle mass, and function is observed with aging (1%/year after age 50), and is called sarcopenia. Sarcopenia is more pronounced among those aging with underlying risk factors (eg, sedentarism, obesity, alcohol abuse, malnutrition). Compared to people without HIV, PWH may experience sarcopenia at a faster rate and an earlier age (22–25). Many older adults with sarcopenia also experience frailty, an increased vulnerability to stressors resulting from age-associated declines in multiple physiologic systems. Like sarcopenia, frailty also appears to occur more commonly and at an earlier age among PWH (26,27). Sarcopenia and frailty are both associated with an accumulation of comorbidities, and both contribute to falls, hospitalization, skilled nursing placement, and mortality (4).

Sarcopenia prevention and intervention

Intervening early to prevent the subsequent development of sarcopenia and frailty is imperative. Although there are currently no FDA-approved therapies that have resulted in improvements in both muscle mass and function among people with or without HIV, numerous therapies have been tested with limited success (28,29). Many therapies target pathways that may overlap between sarcopenia and frailty (30), and may have particular relevance among PWH, including treatments for excess adiposity or body fat.

With aging, fat can deposit both within and surrounding skeletal muscle. Adipose tissue within skeletal muscle has been associated with poor muscle function among both people with and without HIV (31) and appear to accumulate to a greater extent among PWH (5) and in the setting of ART initiation (32). The glucagon-like peptide 1 receptor agonists are a particularly attractive option to decrease overall adiposity, skeletal muscle adiposity, and improve function among those with both sarcopenia and obesity. However, similar to other interventions leading to rapid weight loss, these agents are associated with significant declines in lean mass (a proxy measure of skeletal muscle mass) (33). Furthermore, although some studies have suggested improvements in self-reported physical function, objective data for improved muscle strength are limited (33,34).

Ideally, interventions should simultaneously increase skeletal muscle mass and prevent further declines in function accompanying aging and obesity. Several studies demonstrated decreases in overall adiposity and simultaneous increases in lean mass with a combination of cardiovascular and resistance training among PWH (35,36). Although exercise can be difficult to maintain, novel strategies combining newer weight-loss therapies with exercise will likely provide the greatest long-term benefits on overall weight, muscle strength, and physical function with aging, particularly among PWH. A recent clinical trial suggests that exercise can also enhance mitochondrial efficiency, potentially improving long-term physical function and quality of life in PWH (21). Future research should focus on identifying optimal exercise strategies (combined with weight loss, when appropriate) for PWH, which ultimately could lead to improvements in treatment and long-term care strategies for people aging with HIV.

Long-Acting ART

Charles Flexner

With the development of safer and more effective ART, newer therapies have shifted towards the development of long-acting (LA) injectables. LA injectables currently available in the United States include the combination of cabotegravir + rilpivirine (administered every 1–2 months) or lenacapavir (administered every six months). LA injectables decrease daily pill burden and may increase viral suppression, particularly in populations struggling with adherence. However, many initial studies of LA therapies excluded or included only very small numbers of older PWH. Furthermore, whether sarcopenia or frailty impact optimal use of LA injectables has not been studied (37,38).

From other research, there are several possible effects of aging to alter the pharmacokinetics of LA injectables: (i) reduced subcutaneous tissue and altered ratio of fat-to-muscle due to aging-related obesity, or weight loss and sarcopenia; (ii) reduced blood circulation/perfusion to major organs, including liver, muscles, and subcutaneous tissues in aging; (iii) reduction in some hepatic drug metabolizing enzymes; and (iv) drug–drug interactions secondary to polypharmacy and aging-related multi-comorbid conditions (39,40).

Fortunately, most aging-associated physiologic changes have little overall impact on drug distribution and clearance. Some changes balance each other out, for example, a reduction in hepatic drug metabolizing enzyme capacity, but also a reduction in portal blood flow, thus delivering less drug to the liver (41). Therefore, no significant age-related effects would be seen for most parenterally administered LA drugs and formulations. In fact, there are no marketed LA injectable drugs for any condition for which dosing or method of administration, are recommended to be modified exclusively as a function of older age. This is reassuring for the use of LA injectables in older PWH (42).

Central Nervous System

Beau Ances

PWH continue to experience changes to the integrity of the CNS despite ART (43). As PWH age, it becomes increasingly important to identify factors that may impact CNS integrity to successfully identify therapeutic targets to improve health and quality of life. Research suggests that these factors may be multifaceted, including initial changes seen early after infection (ART delay, virological failure), as well as comorbidities, social determinants of health, interactions with aging, and medication management or polypharmacy. Improving CNS health in aging PWH may depend on bridging the gap between biology, comorbidities, and social determinants of health. Clinicians may need to consider multifactorial complications when assessing current and future CNS health among PWH.

Time, legacy effects of the virus, and virological control

HIV affects the CNS soon after infection. Research using neuroimaging methods, including brain volumes and cortical thickness, has observed reduced structural brain integrity in PWH who are within the acute and early stages of HIV compared to people without HIV (44,45). Initiation of ART and remaining virally suppressed (<50 copies/mL) prevents a continued downward trajectory in cortical thickness and is associated with improvements in brain volume and cognitive performance compared to PWH with uncontrolled virus (45,46).

Interactions between HIV and comorbidities

PWH are also at greater risk for comorbidities that may interact with CNS integrity compared to people without HIV. A recent study identified a significant effect of both cardiovascular disease, as measured by the Framingham risk score, and Hepatitis C co-infection on brain-predicted age (47). Brain-predicted age was derived using a publicly available model (DeepBrainNet) (48) that is trained on over 11 000 structural MRI scans from a diverse, normative cohort. Structural T1-weighted images (80 axial slices) from PWH were input into this model, and a median brain-age estimate is generated. Individuals with these comorbidities had a higher brain age gap, or a brain-predicted age greater than their chronological age. A higher Framingham risk score was also associated with reduced cerebral blood flow in PWH (49). Importantly, Alzheimer’s disease (AD) pathology was not associated with cognitive impairment in PWH.

Social determinants of health

Emerging research has indicated the importance of social determinants of health on CNS health in PWH. The Area Deprivation Index is a measure incorporating income, education, employment, and housing quality at the census-tract-level. It provides a proxy of how advantaged or disadvantaged a neighborhood is and its associations with access to healthcare and health outcomes. A higher Area Deprivation Index (ie, more disadvantage) has been linked to higher brain age gap in people with and without HIV (47,50).

Aging and Alzheimer’s disease

HIV may be associated with an accelerated brain aging pattern, as evidenced by a greater decline in cerebral blood flow in PWH with a detectable viral load compared to people without HIV (51). Whether accelerated aging is associated with neurodegenerative diseases remains unknown. As PWH age, it is important to distinguish between HIV-associated neurocognitive disorders (HAND) and AD to better direct treatment decisions (52). Among people who did not have AD, neither positron emission tomography-measured amyloid or tau or plasma measures of amyloid significantly differed in PWH compared to people without HIV (53–55).

Medications and polypharmacy

Certain medications commonly prescribed to PWH may also affect CNS integrity. For example, anticholinergic medications have been associated with worse cognition and reduced brain volumes in PWH (56). Increased prevalence of comorbidities in aging PWH may also lead to polypharmacy, or having a large number of medications prescribed, and could increase the risk of medication effects.

Asymptomatic Neurocognitive Impairment

April D. Thames

ANI is the mildest form of HAND, characterized by impaired performance on neuropsychological tests while maintaining independence in performing everyday functions, compared to mild neurocognitive disorder (MND defined as neurocognitive impairment plus impairments in daily functioning) or HIV-associated dementia (HIV-associated dementia defined as severe cognitive impairment plus the inability to perform daily functions independently) (52). Factors such as depression and unreliability of self-reported data create difficulties in accurately assessing and identifying everyday functioning, and the resulting diagnosis of ANI as compared to MND. Similarly, there are challenges in distinguishing ANI from mild cognitive impairments that may be overlapping and are associated with neurodegenerative diseases such as AD (eg, amnestic mild cognitive impairment). Globally, studies have shown variability in the associations between cognitive functioning and reported activities of daily living in countries such as India, Mexico, and South Africa as compared to the United States (57). Given current debates about the utility of an ANI diagnosis (52,58,59), it remains important to consistently revisit the HAND nosology to account for the changing landscape of scientific HIV knowledge, although evidence exists that the sensitivity and specificity of current HAND impairment thresholds are appropriately set for detecting brain impairment by neuroimaging (60). Neuroimaging studies support the idea that markers of HIV-associated brain injury, such as smaller brain volumes and abnormal white matter, can be useful in predicting worsening cognitive status among individuals with normal cognitive function (45,52,61). The heterogeneity of HAND suggests multiple underlying pathologies. Studies that focus on mechanistic pathways of persons who transition from neuropsychologically unimpaired to ANI or those with ANI who transition to more severe forms of HAND, or studies that predict stability of cognitive status, may help to identify treatment targets and interventions.

Mental Health

Brian W. Pence

Depression and other mental health disorders are among the most common comorbidities in PWH (3,62,63). Furthermore, these conditions have a major impact on health, presenting challenges to HIV care engagement and leading to HIV disease progression and early mortality (64–66). Treating mental illness, particularly in tandem with HIV care engagement skills building, improves HIV outcomes (67–71). Widespread integration of mental healthcare for PWH yields a measurable and meaningful improvement in viral suppression (72). Tools for addressing mental health among PWH include: measurement-based care to guide antidepressant prescription by nonspecialists (73–75), collaborative care models (76), and evidence-based psychosocial counseling protocols tailored for lay personnel delivery (77–79).

What can we learn from the HIV treatment field to encourage the integration of mental health treatment into the HIV care setting? The HIV treatment cascade (80) and the resulting “90-90-90” goals have led to worldwide gains in ART coverage and viral suppression. In comparison, the status of the depression treatment cascade is sobering. Half of patients with depression are not diagnosed, half of those diagnosed go untreated, and very few of those treated receive evidence-based treatment leading to remission (81). Based on the above evidence, the time is ripe for defining “90-90-90” goals for mental health treatment for PWH (82) and for using these tools to achieve 90% of patients in need of mental healthcare being identified, 90% of those identified starting mental health treatment, and 90% of those starting treatment achieving clinical remission. Achieving these goals will have a major impact on mental health and HIV outcomes for PWH. Strategies that are commonly used in mental health treatments may need additional consideration in the aging PWH population. For example, psychosocial counseling may be less effective in older PWH (83,84); side effects of pharmacotherapy may be more pronounced in aging PWH (85); depression may present as pseudo-dementia and need additional screening (86); and there is an increased importance of involving caregivers in treatment plans (87).

Loneliness

Ronald J. Ellis

Prevalence and impact of loneliness

Social isolation refers to the objective isolation from others, encompassing quantifiable features like the level of social engagement and social support, living arrangements (ie, living alone vs with others), number of social contacts, and relationship status. Loneliness, on the other hand, is a perceived emotional state characterized by a sense of dissatisfaction with the quality or quantity of social relationships (88). Although the 2 concepts overlap, they are distinct; one can experience loneliness without being objectively isolated and vice versa (89). As individuals age, medical issues, relocation, and death of those in their networks increase the risk for social isolation. The existing literature has found loneliness to be linked to higher rates of illness and death in the general population (88,90); a recent paper (91) found consistent evidence that loneliness and social isolation increase cardiovascular disease, mental health outcomes, and all-cause mortality, and recommended developing prevention strategies. PWH are particularly affected by loneliness, social isolation and mortality within social networks (92–96), though literature describing associations between these factors, socioeconomic determinants, and health outcomes remains a significant knowledge gap.

Substantial research supports the concept that during evolution, brain circuits originally involved in processing physical pain were co-opted to deal with disruptions to normal social interactions (97–99). Inflammation is a well-understood source of physical pain and can affect how social interactions are neurally processed (99,100). Reciprocally, disturbances in social interactions can amplify inflammation (101). PWH, despite viral suppression, continue to experience chronic low-grade inflammation (102). Ellis et al. studied the relationships between social isolation and inflammatory biomarkers measured in blood and CSF. Among both PWH and people without HIV, poorer social support was associated with higher serum levels of inflammatory factors such as MCP-1, IL-8, VEGF, and IL-6 (103). Future research should investigate the causal relationship between social isolation and inflammation. It is possible that anti-inflammatory medications could improve social functioning or that social interventions might reduce inflammation.

Interventions to lessen loneliness and improve health outcomes

Many PWH are restricted in their activities outside the home due to physical and other limitations. Social interactions in the home (eg, telephone calls) might mitigate adverse effects of loss of mobility. To determine if daily social interactions might modify mood in populations with restricted time outside the home, Kamalyan et al. studied “life-space” using electronic activity monitoring and Global Positioning Systems methods to track location sampled at multiple times during the day (104). Participants’ sleeping location was considered home. Additional assessments included the number of social interactions (“more than 5 minutes talking/communicating with someone else”), self-reported mood (happiness, sadness, anxiety), fatigue, and pain. Older PWH were more likely to have lower ratings of happiness, live alone, and spend more time at home than older people without HIV. Poorer daily happiness ratings correlated with restricted life space and fewer social interactions; however, restricted life space reduced happiness only through its association with fewer social interactions for both groups. Thus, the negative impact on happiness of being physically isolated from others (“home-bound”) might be mitigated by interventions such as visiting community health workers or home-based, virtual interactions.

There are very few interventions to improve social functioning in PWH. A comprehensive meta-analysis of the literature on social interventions in people without HIV evaluated 44 studies, including 33 involving community-dwelling persons and 11 in long-term care facilities (105). When seen, improvements in social outcomes and loneliness were modest for numerous interventions, including animal therapy, cognitive behavioral therapy, exercise, music therapy, and technological interventions (eg, videoconferencing). When provided in the context of long-term care, animal therapy showed the most robust benefits.

Resilience

Michael Plankey and John David Mullins

Resilience is defined as the process through which an individual makes use of available resources to positively adapt following an adverse experience. Masten et al. conceptualize resilience as a dynamic process that is rooted in basic human adaptational systems (106). Complex interactions between internal and external factors influence how individuals react to adversity, showing resilience in some situations and not others. The internal factors that influence resilience include character traits as well as physical, cognitive, and emotional states. External factors include social-, family-, and community-level influences. The combination of factors across different levels of influence impacts the resilience process, even if the relevance and expression of specific factors varies between different populations (107).

Sexual minority communities have exhibited remarkable resilience despite high rates of stigma and discrimination (108). Until now, most research on the health and well-being of these communities has focused on the things they lack, rather than the strengths they possess. Identifying and harnessing resiliencies, which have been underexplored to date, may be a more acceptable and successful way to promote health and wellness rather than only targeting vulnerabilities.

The Multicenter AIDS Cohort Study and Women’s Interagency HIV Study Combined Cohort Study represent the longstanding longitudinal observational study of HIV treatment and prevention among men and women living with and without HIV in the United States. This cohort was leveraged for an R01 grant (MD010680 PIs: Plankey/Friedman), Understanding Patterns of Healthy Aging Among Men Who Have Sex with Men, funded by the National Institute on Minority Health Disparities. The study aimed to identify individual, interpersonal, community, and structural resiliencies to promote health in the Multicenter AIDS Cohort Study (109). This study led to numerous new findings on associations between resiliency and various health outcomes. For example, socially resilient older men who have sex with men, as defined by the levels of social support, social networks, and social cohesion using latent class analysis, were less likely to experience loneliness than those who were not socially resilient over time (110). The inventoried work in progress with publication links are here: https://macshealthyaging.library.georgetown.edu/current-concepts. Identified strengths may form the basis for interventions to better support older PWH.

Discussion

Workshop presentations demonstrated cutting edge research at the intersection of HIV and aging, how to better address the needs of older PWH, and how to support intervention development across physical and psychosocial domains. Scholars called on the field to prioritize mental health treatment, reduce social isolation, and enhance resiliency. Insights are consistent with the desires of the HIV advocacy community to develop and implement such innovative and needed models of care (111,112). This requires, as Pence suggests, expanding the traditional “90-90-90” goals of broad HIV testing, treatment, and viral load suppression, to include as the next “90” measuring the optimal mental healthcare and quality of life for PWH (113,114).

Presentations highlighted how some processes experienced by older PWH are part of normal aging. Others pointed out specific and persistent concerns including sarcopenia and frailty, mental health challenges, loneliness, and cognition. For example, Ellis laid out the need for research to study the longitudinal associations between social isolation and inflammation in older PWH. Such agendas indicate that next phase of research must consider the cross-cutting dynamic and bidirectional influences of biology on social life and functioning. Interventions are needed to address multiple comorbid conditions, such as sarcopenia and depression, or ANI and frailty. Subgroup analyses can examine differences in experiences, biophysical processes, and outcomes based on length of time living with HIV, as long-term survivors with long-term exposure to different ART drugs may have different biophysical trajectories than those recently diagnosed or with exposure to only modern ART.

Another takeaway is the need for facilitative or asset-based approaches to health. Plankey and Mullins note the evidence of positive adaptation and resilience by strengthening social networks and support in populations experiencing high levels of adversity. Ellis cites recent evidence that increasing social interactions can mitigate the negative effects of social isolation. Variability in HAND diagnosis and the influence of social determinants of health on CNS trajectories also suggest the need to consider how we facilitate coping, offer strength-based supports, and continue to reduce barriers to social and economic resources.

We take these insights as a call to action to advance science and clinical care to improve the lives of those aging with HIV. We must work collaboratively and equitably with older PWH, clinicians, researchers, governments, and funders. We must continue to pursue novel, therapeutic pathways targeting multiple co-occurring conditions. Working with national and international agencies, we can expand the integration of components into clinical models of care, supported by ongoing community and advocacy engagement.

Funding

None.

Conflict of Interest

C.F. declares consulting relationships with Gilead, Merck, ViiV Healthcare, and TheraTechnolgies, and is a named inventor on 5 issued patents related to the development of technologies for long-acting delivery of antiretroviral therapy. The other authors have no conflict to declare.

Author Contributions

We would like to acknowledge the following contributions to the manuscript: A.B.-L., S.C., M.Y.-J., D.J.M., and K.M.E. conceptualized, drafted the introduction and discussion, synthesized each summary, and reviewed, edited and finalized; B.A., G.D., K.M.E., R.J.E., C.F., B.W.P., M.P., J.D.M., J.S., and A.D.T. drafted the summaries they presented at the Workshop as listed and reviewed; J.B.M. provided funding and review.