|Home | About | Journals | Submit | Contact Us | Français|
HIV risk behaviors, susceptibility to HIV acquisition, progression of disease after infection, and response to anti-retroviral therapy all vary by age. In those living with HIV, current effective treatment has increased the median life expectancy to > 70 years of age. Biologic, medical, individual social and societal issues change as one ages with HIV infection, but there has been only a small amount of research in this field. Therefore, the Office of AIDS Research of the National Institutes of Health commissioned a working group to develop an outline of the current state of knowledge and areas of critical need for research in HIV and Aging; the working groups’ findings and recommendations are summarized in this report. Key overarching themes identified by the group included: multi-morbidity, poly-pharmacy and the need to emphasize maintenance of function; the complexity of assessing HIV vs. treatment effects vs. aging vs. concurrent disease; the inter-related mechanisms of immune senescence, inflammation and hypercoagulability; the utility of multi-variable indices for predicting outcomes; a need to emphasize human studies to account for complexity; and a required focus on issues of community support, caregivers and systems infrastructure. Critical resources are needed to enact this research agenda and include expanded review panel expertise in aging, functional measures and multi-morbidity, as well as facilitated use and continued funding to allow long-term follow-up of cohorts aging with HIV.
The development and application of effective antiretroviral therapy (ART) for HIV has allowed many infected persons to live to an older age. In addition, an increasing proportion of incident HIV infections are occurring in older adults as members of this age group are the least likely to practice safe sex and late-life changes in the reproductive tract and immune system may enhance susceptibility to HIV acquisition in seniors. Thus, by 2015, half the people living with HIV infection in the United States will be 50 years of age or over. Research in Sub-Saharan Africa suggests that these trends are also occurring in more resource limited settings (1,2). Further, there is an emerging consensus that HIV and/or its treatment affecs the process of aging and/or the development of illnesses typically associated with advanced age. When compared to behaviorally and demographically similar HIV-uninfected individuals, people with HIV infection, even those receiving effective ART with suppression of virus to levels below typical detection limits, experience excess morbidity and mortality (3,4). On average, a 20 year old initiating ART may have already lost 1/3 of the expected remaining years of life compared to demographically similar HIV-uninfected persons (5).
While AIDS-defining illnesses are increasingly rare in those with ART-suppressed HIV, the list of HIV-associated, Non-AIDS (HANA) conditions is growing. A common theme among currently identified HANA conditions is their association with advancing age and chronic inflammation. These include cardiovascular disease (6), a number of infectious and noninfectious cancers (7,8), osteopenia/osteoporosis (9), liver disease (10), renal disease (11,12) and neurocognitive decline. It is uncertain whether people with HIV infection develop these conditions earlier in their life course because the aging process itself is accelerated (i.e., is HIV speeding pathways of aging in every organ?) (13) or whether HIV is an additive risk factor (i.e., is HIV similar to high cholesterol which does not make one “age” faster, but increases the risk of cardiovascular events?).
Any comparison between people with and without HIV infection must be accomplished with careful study design as these populations tend to differ in a number of behavioral and biologic factors that are known to affect the aging process. People aging with HIV infection are more likely to continue substance use (tobacco, alcohol, opioids, and other psychoactive substances) (14). People with HIV infection are also more likely to be co-infected with chronic viruses such as hepatitis C, which interacts with HIV or with alcohol use to lead to more rapid cirrhosis and more rapid development of hepatocellular carcinoma. People with HIV infection differentially represent sexual and racial minorities with constrained economic and social resources. As a result, issues of homelessness, food insecurity, and social isolation may exacerbate substance use and complicate the aging process broadly – physically, emotionally, and socially.
The pathophysiology leading to morbidity and mortality among those aging with HIV is only beginning to be elucidated. Evidence from the Strategies for Management of Antiretroviral Therapy (SMART) trial and other observational studies suggests that HIV infection and ART influence morbidity and mortality through effects on inflammation, treatment-related toxicity (which includes abnormal fat distribution, renal and kidney dysfunction and neuropathy), interactions with other chronic viral infections and co-morbid diseases typically associated with advanced age. This complex and often subtle pathophysiology also interacts with prolonged substance use and other psychosocial and health behaviors more commonly experienced by those with HIV infection. As a result, aging HIV-infected persons exhibit an excess burden of co-morbid conditions and the premature onset of a number of clinical symptoms and syndromes that are often associated with advanced aging, multi-morbidity, poly-pharmacy, limited reserve and functional (physical and cognitive) decline (Figure 1). Addressing these aspects of heath care is the primary domain of the subspecialty of Geriatric Medicine which can help inform the research agenda for HIV and the clinical management of those aging with HIV infection (15).
Recognizing the issues and needs of the evolving HIV-infected population and the potential insights provided through the pathophysiology of aging (Gerontology) and the care of older adults (Geriatrics), September 18th has been designated National HIV/AIDS and Aging Awareness Day since 2008, and a White House Conference on HIV and Aging was held in 2010 (16). However, the extent to which Geriatric principles can be directly applied to HIV-infected individuals is unknown. While parallels with other chronic diseases such as cardiovascular disease or diabetes are compelling, several factors set apart those aging with HIV. At the moment, the population aging with HIV infection is predominantly middle aged. Many geriatric syndromes of greatest concern in the general population, including dementia, frailty, and falls, are not common among those under 65 years of age and are frequently seen only in those 80+ years of age. Thus, we may not fully appreciate the importance of these conditions until a larger proportion of the population of those aging with HIV infection reaches older thresholds. The Geriatric concepts of multi-morbidity, personalized care, maximizing function, and deriving integrated management strategies are, however, very likely relevant to the care of the growing middle to older age adult population with HIV.
To further address the issues of aging with HIV infection, the NIH Office of AIDS Research assembled a working group with the goal of assessing what is known and unknown, and what the priorities should be for research at the interface of HIV, aging, and multi-morbidity. The task force met in a face-to-face meeting in April 2011, and assigned breakout groups to address four specific areas – 1) Triggers and Underlying Mechanisms of Aging in those with HIV; 2) Biomarkers/Prognostic Indices of Aging and Illness; 3) Design and Conduct of Observational and Intervention Studies; and 4) Societal, Mental Health, Behavioral and Care giving Issues. The working group force findings are summarized in this white paper.
Several common themes emerged during the discussions:
Although the priority for research on HIV and aging vs. other important issues in HIV research is a question well beyond the purview of this working group, the working group members believe the issues outlined here are high priority as more than 50 percent of individuals affected by HIV in the U.S will be age 50 years or greater by 2015. A common theme from the geriatric literature is that proactive prevention of geriatric syndromes is preferred to interventions aimed to reverse diseases which have already occurred; hence, interventions aimed at addressing concerns outlined in this report will need to be implemented soon if the large population of aging HIV-infected adults are to benefit. Further, as outlined in the White House Conference (16), issues regarding HIV in aging people is a high priority area among a large and diverse community of advocacy groups active in the area of HIV. Finally, as was true of immunology research in the early days of HIV, studies in this area of AIDS research are likely to have dramatic impact on other fields. Compression of disease development and functional decline in HIV-infected individuals offers a unique model of multi-morbidity that should be applicable to many populations (e.g. the aged, dialysis patients, chronic inflammatory conditions such as rheumatoid arthritis). Thus, research on multiple, coexistent conditions and the preservation of function in aging HIV-infected individuals is likely to pay dividends for the wider field of healthcare. Specific areas of active research in the larger community that may benefit from knowledge gained studying HIV and aging include the biology of inflammation and disease development, the identification and validation of clinically relevant biomarkers, the comparative effectiveness of various interventions to optimize clinical outcomes and preserve function in complex populations, and the role of community-based research and systems-based delivery of healthcare.
Human aging is associated with substantial changes in both the innate and adaptive immune response and occur at the phenotypic, functional, and molecular levels. It is now recognized that immune changes that occur during normal aging may occur earlier in chronically HIV-1 infected individuals. There also may be synergistic effects of aging and HIV in this population resulting in complex pathologies and precipitous immune decline. Studies focused specifically on the impact of aging and HIV on immune function will therefore likely remain central to research in this area.
A number of priority areas of research exist. Research in the areas of aging and immune dysfunction in HIV-infected persons should focus on mechanisms and triggers in human populations, although the use of primate models for combined aging and HIV/SIV research may prove to be useful. Most studies on aging and HIV have utilized peripheral blood which contains approximately 2 percent of the host immune cells. It is critical for HIV and aging research to expand work to the analysis of tissue sites including bone marrow, gut mucosa, and lymph nodes. There are also significant needs in developing imaging technologies to evaluate sites such as the central nervous system since these areas are not easily accessible for study. Imaging tools such as advanced computed tomography (CT), functional magnetic resonance imaging (MRI), and position emission tomography (PET) may provide platforms for expanded assessment of multiple tissues. These tools will clearly provide important resources for pathogenesis studies and will be likely to improve the clinical evaluation of antiretroviral-induced immune reconstitution (18–30).
Cellular senescence is an important mechanism that contributes to organismal aging. There are numerous aspects of immune and cellular senescence that have been documented in the elderly but only a few of them have been extended to studies in HIV-infected individuals (31,32). The senescent phenotype is complex and involves the activation of gene programs that have important clinical implication for the prevention of cancer, but are thought to also result in cumulative damage to tissues and organs.
Many of the pathways known to affect cellular aging may be affected by HIV or its treatment. Shortening of telomeric sequences and structural changes to the telomere are believed to be major drivers of the senescence program in all individuals. Telomere length decreases with age in all hematopoietic lineages that have been studied, including circulating CD38 hematopoietic precursor cells, neutrophils, and naïve and memory T cells. HIV-associated inflammation and/or exposure to nucleoside analogues have been associated with changes in these and other key biologic pathways (33–40).
Emerging data from a number of groups suggest that HIV-infected individuals demonstrate features of immunologic aging including accumulation of terminal stage, effector CD8+ T cells (most often identified by the absence of CD28 expression) with shortened telomeres, absence of telomerase activity, and limited T cell proliferation potential. The biologic consequence for the accumulation of these cells is controversial, but their presence has been associated with clinical problems in seniors including reduced vaccine responses, bone loss, neurocognitive decline and cardiovascular disease.
It is also important to note that the immunology of aging is thought to be influenced by other chronic viral pathogens, particularly cytomegalovirus (CMV). CMV infection is characterized by the oligoclonal expansion of a CMV specific T cell population that comprises a large fraction of the T cell repertoire. It is not clear how the human host can compensate for so much anti-CMV T cell reactivity over so many years without having persistent problems in immune control. The impact of HIV disease on this process is not known, but emerging data suggest that these co-infections interact in a potential negative manner (41–44).
The role of dysregulation of the immune system among those with HIV requires careful study. Specifically, age-associated T cell changes include an increase in the number of regulatory T cells both within the CD4 and CD8 subsets, and a generalized chronic inflammatory state (which may reflect the combined effects of senescent T cell cytokine secretion), a shift in the balance of Th1, Th2, Th17, and T-regulatory responses, and alterations in cells of the innate immune system. This so-called “inflammaging” is associated with frailty and increased mortality risk in the very old, HIV-uninfected population. The role that this process has in causing HIV-associated morbidity remains only theoretical and deserves investigation.
Humoral immunity is affected by aging as well, as evidenced by the dramatic decline in antibody responses to a variety of vaccines and markedly increased risk of pathogens typically controlled by antibody-based mechanisms (e.g. Streptococcus pneumoniae). The major intrinsic B cell defects include a reduction in both somatic hypermutation of the immunoglobulin genes and in class switching, which undoubtedly contribute to the blunted titer and affinity of antibodies in the elderly. Aging is also associated with diminished numbers and sizes of the lymph node germinal centers, which may impact affinity maturation and antibody quality, as well as a reduction in the number of B cells migrating out of the bone marrow. All of these immune alterations merit investigation in HIV-infected persons, both young and old, and are clearly relevant to vaccine development.
There is only minimal information on innate immunity changes associated with HIV/AIDS, but recent information from studies in the elderly can provide a preliminary road-map for future HIV studies. Most prominent among the age-associated changes are functional alterations in Toll-Like Receptors (TLR), a family of invariant pattern recognition receptors specific for highly conserved portions of pathogens. There is evidence of age-associated defects in TLR-induced production of IL-6 and TNF-alpha, particularly in response to engagement of TLR1/2, as well as a generalized defect in TLR-induced CD80 upregulation in monocytes from older individuals (45). The proinflammatory cytokine production by cells of the monocyte/macrophage lineage is hypothesized to be influenced by the complex interplay of immunologic, hormonal, and neuroendocrine factors. Circulating levels of adipokines and adrenal hormones are altered during aging. These systemic influences on both innate and adaptive immunity are key areas that have not yet been addressed with respect to HIV/AIDS.
Other cell types within the innate immune system that undergo age-related changes include natural killer (NK) cells, which show defects in cytotoxicity and signal transduction, and natural killer T (NKT) cells, which have some overlapping phenotypic features with senescent CD8 T cells. In both cases, research in the context of HIV is lacking and should be considered a priority. Diminished neutrophil function that accompanies aging (e.g. reduced phagocytic capacity and intracellular killing) clinically manifested by high morbidity and mortality due to bacterial infections is another area worthy of more extensive research. Finally, studies on dendritic cells, which bridge the gap between innate and adaptive immunity, are clearly critical both in terms of immune function in general, and development of vaccine formulations that compensate for immunosenescence effects.
We can also learn a significant amount of information on aging and how it applies to HIV by studying other clinical conditions. In rheumatoid arthritis, lymphocytes display a phenotype consistent with accelerated immune aging including accelerated telomere attrition, accumulation of differentiated effector T cell populations that have lost the CD28 marker and contraction in T cell receptor repertoire diversity. Compared to normal age-matched controls, T lymphocytes from patients with rheumatoid arthritis have increased numbers of DNA double-strand breaks and increased spontaneous apoptosis rates; repair of radiation-induced DNA breaks is reduced and delayed. There is significant information that can be gained for the aging and HIV fields by studies on autoimmune disease.
Focus should be on investigator-initiated research. We should also take advantage of existing cohorts or research networks for supplemental funding opportunities (See Part 3 - Aging with HIV Infection: Multimorbidity and Clinical Research). There are other cohorts outside the HIV field that could be utilized to provide normative data for age-matched or senior populations. Examples include the Alzheimer’s Disease Neurological Initiative (ADNI) that is collecting a very large population data base and ASPREE, currently accruing senior subjects. It will be critical to continue to accrue subjects and data in cohorts aging with HIV (e.g. the VACS, the MACS, and the WIHS) as comparator groups. Women’s issues require particular attention as there are substantial sex differences in immune response, menopause leads to changes in immune response, vaginal/cervical changes in epithelium and secretions that may influence HIV acquisition and/or progression.
The objective of this section is to identify and prioritize areas of research relevant to the characterization and validation of biomarkers and clinical indices associated with the development of conditions that lead to morbidity and mortality.
Although combination antiretroviral therapy is highly effective in suppressing HIV replication, it does not fully restore health. When compared to HIV-uninfected persons, long-term treated HIV-infected adults have excess risk of a number of HIV-associated, non-AIDS (HANA) conditions, including many typically associated with advancing age (e.g., cardiovascular disease, kidney disease, liver disease, osteoporosis, cancer, and cognitive impairment) (46). The mechanisms accounting for this excess risk likely include persistent immune dysfunction/inflammation, treatment toxicity, co-infections such as CMV, HCV and hepatitis B virus (HBV) and traditional risk factors (including use of alcohol, tobacco, and psychoactive drugs) (15,47,48).
Many studies of biomarkers reported to date have included untreated and treated individuals, despite the fact that HIV replication is known to be major a determinant of inflammation, immune function and overall health. Even those studies that focused on long-term treated individuals rarely controlled for the degree of viral suppression. Further, use of alcohol, tobacco, and psychoactive drugs affects both biomarker behavior and the risk of non-AIDS morbidity and mortality; the lack of precise data regarding these factors in most cohorts prevents a careful assessment regarding mechanisms.
The impact of HIV and its treatment on the biology of aging is also likely an important factor in premature development of typical age-associated diseases (see Figure 1). HIV infection results in chronic activation/dysfunction of the innate and adaptive immune responses, leading to inflammation and perhaps the development of most non-AIDS conditions. HIV infection also causes a loss of effective immune surveillance, which may contribute to cancer and other complications. The cumulative burden of these complications reduces a person’s ability to compensate and respond to many events, which collectively results in onset of frailty and other geriatric syndromes (15, 17, 48).
Advances in our knowledge of these areas will almost certainly be driven by the use of biomarkers. Many putative HIV-associated biomarkers have established prognostic significance in HIV-uninfected populations. To what degree these biomarkers or indices have unique performance characteristics in HIV-infected adults independent of established risk factors is often unknown because of the difficulties in identifying cohorts of behaviorally and demographically similar infected and uninfected adults. The interaction between certain biomarkers appears to be different in HIV-infected and HIV-uninfected infected individuals. In the SMART study, C reactive protein (CRP) only exhibited an IQR odds ratio of 3.1, much lower than what one might expect given the IL-6 data. In the Study of Fat Redistribution and Metabolic Change in HIV Infection (FRAM), CRP was considerably lower than anticipated in HIV and HCV co-infected individuals than in either controls or in HIV mono-infected patients. In a combined analysis from WIHS and MACS, the initiation of effective antiretroviral therapy was associated with the expected decline in IL-6 and D-dimer, but an apparent increase in CRP (49). It is likely that some of these unusual trends and interactions relate to the complex effect HIV and its treatment and co-infection with other viruses, such as HCV, has on the ability of the liver and perhaps other organs to regulate biomarker levels.
There is accumulating evidence that the behavior of certain biomarkers in the context of treated HIV disease is different from that in general population. Many (but not all) biomarkers associated with inflammation (e.g., IL-6, sCD14) and end-organ diseases common in seniors (e.g., cystatin C as a marker of declining renal function) are higher in antiretroviral-treated adults than uninfected adults (50). The association between these biomarkers and subsequent morbidity/mortality appears to be stronger in those with HIV infection compared HIV-uninfected individuals. For example, in the SMART studies, the fully adjusted odds ratios of mortality (fourth versus first quartile; IQR) in HIV disease were 8.0, 12.4, and 41.2 for sCD14, IL-6 and D-dimer, respectively (47); these odds ratios are higher than those observed in the general population. The ability of these biomarkers to predict outcome has been observed in most patient populations, including those with preserved immune function (51).
The durability in terms of prognostic significance of certain biomarkers also appears to be unique among HIV-infected adults. In the Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPIRIT) study, high plasma D-dimer was associated with continued excess risk four to seven years after the measurement of a single level. This stability in terms of prognosis is years longer than that which has been observed in the general population.
Despite the tremendous amount of research in this area, the precise role these biomarkers have in the causal pathway is largely unknown. The ability of these markers and indices to provide prognostic significance beyond traditional markers (e.g., CD4+ T cell count, HIV RNA level, and routine cardiovascular risk markers) is also largely unknown. Finally, how a clinician should use these emerging markers or measures of multiple co-morbidities has yet to be addressed in any prospective clinical study. It is expected that high-quality basic, translational and clinical research in this area will advance our understanding of the pathogenesis of HIV infection during treatment It is also expected that research in this area could inform clinical management of HIV disease and perhaps even of other diseases that might be affected by similar pathways (e.g., chronic inflammation and “aging”).
Biomarkers progress through several stages: a) initial discovery; b) translation into small human populations; c) application to larger more generalizable populations; and d) testing for clinical relevance. A handful of these are then incorporated into larger, more comprehensive clinical indices like the Framingham Index for cardiovascular disease. For eventual clinical applicability, biomarkers and indices would likely begin by demonstrating significant associations with the specific outcome of interest, using standard epidemiological criteria. The most promising ones would demonstrate consistent and independent associations with important clinical outcomes across a broad and representative population. Further, these associations should be independent of other biomarkers already in routine clinical use. Tests of prediction generally compare a known set of clinical risk factors, such as the Framingham equation for coronary heart disease, with and without the addition of the new biomarker. Metrics for determining added value include the c-statistic (area under the curve) and the Net Reclassification Index (52, 53).
Biomarkers and clinical/biomarker indices intended for use as surrogate outcomes are held to an even higher standard, as they become proxies for the underlying disease process. Not only must the biomarker or index indicate increased risk factor for adverse outcomes, but they must rise and fall in step with the disease process. The impact of clinical intervention on the target disease must be captured by proportional changes on the candidate biomarker and differentiate between two treatments of differing benefit. If the differential effects of treatment options on mortality are reflected by parallel changes in the biomarker, then it is considered a good surrogate outcome and can be used as an endpoint in clinical trials. The measurement of HIV RNA in plasma is a well-accepted example of a surrogate marker.
A brief summary regarding what is known and not known about existing non-specific integrated biomarkers and indices is provided below. Given the effects of HIV infection on immune function, much of the emphasis in the past several years have been on inflammatory biomarkers.
The priority areas for focus in the development of biomarkers and clinical prognostic indices are: (1) identifying biomarkers indicative of residual disease; (2) characterizing the link between chronic inflammation and immunodeficiency during treatment-mediated viral suppression on biomarkers and outcomes; and (3) comparing and contrasting the risk and modifiable risk factors for non-AIDS conditions among those with and without chronic HIV infection. Some examples of specific high-priority questions are listed below.
A greater investment in novel cohorts aimed at studies on specific end-organ diseases is needed. Most cohorts have focused on collecting clinical information and specimens which can inform issues related to HIV disease. Novel approaches including multi-disciplinary teams should be formed to develop needed cohorts to advance our knowledge in cardiovascular function, metabolism and other chronic diseases, especially those that have a high impact on HIV-infected individuals either because of their association with HIV infection itself or because of their severity and prevalence among those with HIV. For example, hepatitis C is common among those with HIV and has a different disease trajectory in the face of HIV co-infection.
Most of the early work in novel cohorts is expected to be observational. Initially analyses may be cross-sectional and involve the identification of biomarkers associated with important clinical outcomes that can be measured in stored samples. This work should then rapidly move into longitudinal studies to characterize how modifiable a biomarker may be and to identify treatments and behavior changes associated with improvements in biomarker levels over time. These analyses would be invaluable to the design of strategic intervention studies and to inform ongoing clinical management.
Eventually, randomized clinical trials will need to fully test the utility of the biomarker--possibly as ancillary studies to ongoing clinical trials. Then full scale intervention studies aimed at preserving end-organ function could be launched using the biomarker or a panel or index of biomarkers as the primary outcome (much as earlier antiretroviral treatment studies used CD4 cell count and HIV-1 RNA). As an example, drugs that protect kidney disease from inflammation-associated or treatment-associated injury could be studied in the context of smaller, focused studies that use accepted biomarkers of injury as an outcome.
A key related objective of future research is to determine when we can apply principles developed in non-HIV infected adults to those with HIV disease. Examples might include angiotensin-converting-enzyme (ACE) inhibitors in protecting against kidney disease, or bisphosphonates for osteoporosis. Validated markers from the general population known to be mediators of outcome could be investigated in HIV disease to determine that these markers are at least responsive to an intervention.
Finally, the most important work yet to be done is the process of translating biomarker research from pathogenesis-oriented studies into the clinic. Such work will require phase II and eventually phase III clinical trials. Resources may need to shift from pilot correlative studies to larger definitive interventional studies in which a therapeutic intervention improves health. The role of a biomarker in mediating this therapeutic effect can only be defined in such resource-intensive studies. Although multiple interventions might be considered, it is reasonable to first advance into clinical studies therapies which in other disciplines have proven to be safe, well-tolerated, and are aimed at unifying hypotheses (e.g., inflammation). Also of high priority is the study of drugs which affect development of common non-AIDS conditions, but which might be affected by HIV disease. As an example, adults with insulin resistance and metabolic syndromes appear to derive remarkable clinical benefit from the use of oral insulin-sparing interventions. Such drugs could conceivably have a number of positive benefits in HIV-infected adults with subclinical metabolic conditions, including chronic inflammation, early insulin resistance, and the presence of the metabolic syndrome.
HIV Associated Non-AIDS (HANA) conditions are increasingly common and associated with aging and chronic inflammation. These include cardiovascular disease, a number of infectious and noninfectious cancers (7,8), osteopenia/osteoporosis(9), liver cirrhosis (10), and renal disease (11, 12). It remains to be seen whether people with HIV infection develop these conditions earlier in their life course or are simply at greater risk of developing aging associated conditions at ages observed among those without HIV infection (13).
Of many useful geriatric concepts, three are particularly relevant to intervention research among those aging with HIV infection: frailty (which encompasses the concepts of multi-morbidity and functional decline and vulnerability to illness); chronic inflammation; and personalized care. These concepts are highly related to each other in that all three recognize the complex overlapping effects of multi-morbidity in aging, the need to measure cumulative injury from multiple causes, and the need to identify modifiable mediators of common pathways of injury.
Frailty is a syndrome characterized in HIV-uninfected adults, typically in their 7th, 8th, or 9th decade, by muscle weakness, weight loss, fatigue, and low levels of physical activity signifying a decreased ability to withstand further injury (65). It indicates vulnerability to diverse adverse health outcomes including treatment toxicity, functional decline, hospitalization, surgical complications, and mortality. While few middle aged individuals with HIV infection demonstrate the full frailty phenotype (66), there is a concern that those with HIV infection may have significantly decreased physiologic reserve at younger ages than those without HIV infection. Association studies among older HIV uninfected patients have demonstrated high levels of inflammatory mediators, high levels of cortisol, activated sympathetic nervous system, and activated clotting cascades in frail compared to non-frail older adults.
The etiology of frailty is thought to be age-related and multi-systemic in nature. However, as among those without HIV infection, a likely driving force behind this vulnerability to injury is chronic inflammation (67–69). Chronic inflammation and hypercoagulability occur when the body is exposed to chronic antigen stimulation through a number of possible mechanisms including chronic viral infection and microbial translocation. It is thought to play an important role in many diseases of aging including cardiovascular and rheumatologic diseases. Biomarkers of chronic inflammation and hypercoagulability such as IL-6, sCD14, and D-dimer are elevated among those with HIV infection compared with demographically matched uninfected controls and are higher still among HIV-infected individuals with unsuppressed levels of HIV-1 RNA (70,71). These biomarkers were correlated with non-AIDS events observed in the SMART study. Thus, the concept appears relevant for those aging with HIV infection. As noted in the prior section, those aging with HIV have many reasons to have chronic antigen stimulation including infection with HIV and common co-infection with HCV, HBV, HPV, and CMV; microbial translocation from HIV (72) and from alcohol (73), and oxidative stress from smoking, obesity, and ART toxicity. These factors must also be considered when evaluating biomarkers of chronic inflammation.
Interest in understanding chronic inflammation and hypercoagulability and its role in the excess burden of disease experienced among those aging with HIV infection stems from a desire to evaluate diverse therapeutic approaches shown to mitigate inflammation in other settings. These include pharmacologic treatment and behavioral interventions. If these interventions are to be grouped and prioritized effectively, we need a means of comparing their effectiveness for important patient outcomes. Outcomes of primary interest remain morbidity, mortality, and cost. However, clinical and experimental biomarkers might offer important insight and prove useful intermediate outcomes for some studies, especially if they are considered as part of an integrated risk index such as the VACS Index (see prior section) (52).
The concept of personalized care rests on the observation that those at greatest risk of a particular disease often reap the largest benefit from screening and prevention thereby justifying the risks and/or costs associated with the intervention (screening test or preventative therapy). It requires an accurate assessment of individual risk that accounts for all important sources of risk. An example of this approach is the use of the Framingham Index in cardiovascular disease management. The Framingham Index is used to determine the patient’s individual risk of disease, to indicate whether or not diagnostic tests such as a stress test are indicated, and to tailor the approach to hypertension and cholesterol treatment, and to monitor progress over time. Patients at low risk of cardiovascular disease are not given further diagnostic workup nor treated with cholesterol lowering agents even if the cholesterol is elevated since this would more likely result in toxicity rather than in averting a very low probability cardiovascular event. Similarly, hypertension is managed more aggressively in those with diabetes than without. In both cases, this risk assessment allows providers to identify those most likely to benefit from an intervention and those for whom toxicity, polypharmacy, or simply being distracted from more beneficial interventions is a greater concern. Of note, newly developed biomarkers of cardiovascular disease are compared with the current standard (the Framingham Index) rather than in isolation (52). Only biomarkers that substantially improve the accuracy of the Index are likely to be adopted whether they are based on genetics, proteomics, biochemistry, biometrics (e.g., blood pressure), or patient behaviors (53).
The number of interventions shown effective among those aging without HIV infection that may have benefit among those aging with HIV is large and diverse. Their applicability to this population will likely evolve as the population with HIV continues to age. Most require substantial time and resources. Further, with every intervention chosen for implementation, time and attention is taken from other clinical activities. Several kinds of outcomes must be considered to inform this prioritization:
The geriatric literature has called into question the wisdom of following all applicable primary and secondary prevention guidelines among those with multi-morbidity, polypharmacy, and reduced life expectancy (74). These arguments likely apply to those aging with HIV infection. For example, the incremental benefit of aspirin, bisphosphonates, vitamin D, and/or testosterone for osteoporosis based on low BMD among men with HIV has yet to be demonstrated. The cost of competing attention to guidelines needs to be characterized in terms of what is not accomplished in the clinical encounter.
Interventions that have several types of beneficial effects need to be comprehensively evaluated to characterize their multiple beneficial effects.
There is a need for methodologic studies, observational data analyses, and carefully designed clinical randomized trials:
Better observational data are needed characterizing polypharmacy, nutritional status, and multi-morbidity among those with HIV infection and comparing its associated outcomes among those with HIV infection and demographically and behaviorally similar controls. This information can then immediately inform intervention studies.
By studying “natural experiments” (i.e. studies in which the treatment assignment is haphazard and not made by the investigator) in observational data, we can determine what interventions and intervention strategies may appear the most promising among those aging with HIV infection.
Ultimately randomized clinical trials will need to test central approaches to aging with HIV infection. These will likely need to focus on key strategies rather than individual interventions and, likely, should represent a combination of behavioral and therapeutic approaches. The wisdom of combining behavioral and therapeutic approaches has already been demonstrated in the treatment of depression, alcohol addiction, and smoking cessation. For example,
Due largely to the advances of antiretroviral therapy (ART), in industrialized countries HIV has been transformed into a manageable, chronic condition leading to the emergence of a large population aging with this disease. However, the quality of life in adults aging with HIV is in question due to medical complications, co-morbidities, polypharmacy, substance use, poorer mental health, social isolation, as well as stigmatization from healthcare providers and society at larger (75).
Likewise, the burgeoning population of older adults with HIV also faces considerable psychosocial challenges with regard to social engagement and interaction, adequacy of informal social supports and care giving resources, and utilization of community-based services to meet their growing needs. Numerous studies have documented that those aging with HIV tend to have limited and inadequate social networks, especially with regard to traditional familial support (76). These truncated social networks result from a variety of reasons, including HIV-stigma and resultant social isolation due to rejection from social network members, as well as self-protective withdrawal. Social network insufficiency may also be attributed to histories of incarceration and use of alcohol, tobacco, and psychoactive drugs. Such isolation has been linked to high levels of loneliness and depression and insufficiency of instrumental and emotional support from both family and friends. These limited social networks also have negative implications for care giving resources for an aging population with HIV since caregivers are typically drawn from these networks. As a result, this population will need to rely on formal community-based services in the near future, yet this is complicated by frequent service barriers (e.g., knowledge and access to services, ability to afford services) as well as cultural competency issues of mainstream service providers interacting with an HIV-infected population (77). Furthermore, some community-based resources, such as faith-based organizations, may have resources to meet the needs of older adults with HIV, but are likely underutilized due to stigma issues as well as a lack of understanding of the service needs of these older adults (78).
The primary objective of this component of the research program is to enhance our understanding of the socio-behavioral influences on aging with HIV in order to enhance positive outcomes (e.g., quality of life, adherence, and “successful aging”). Aging is a complex process physically, mentally, and socially which takes place within societal infrastructures such as the medical community; this complexity increases with HIV disease. Those who have aged with HIV are often very different from those who have contracted HIV in later life. Additionally, HIV affects those from a variety of social and ethnic backgrounds, some who have more competencies and resources to cope with the disease (79). Therefore, exploring the basis for health disparities among those aging with HIV remains a priority. Finally, because of the complex nature of aging with this disease, a trans-disciplinary, multi-professional team approach is encouraged to investigate how to improve functioning and quality of life for these individuals.
Although many topics can be studied in relation to aging with HIV, objectives focus on, but are not limited to, the topics outlined below. Future research projects should use a wide variety of scientific methods to address these objectives including cross-sectional and longitudinal survey designs, translational research, and secondary data analysis. Studies should also place special emphasis on participation of women, minorities, and rural populations.
Sources of Support: Office of AIDS Research, National Institutes of Health
Mark Brennan-Ing, Ph.D., Senior Research Scientist, AIDS Community Research Initiative of America (ACRIA), ACRIA Center on HIV and Aging, 230 West 38th Street, 17th Floor, New York, NY 10018, 212-924-3934, ext. 131, mbrennan/at/acria.org
David B. Clifford, M.D., Melba and Forest Seay Professor of Clinical, Neuropharmacology in Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid, Saint Louis, MO 63110, 314-747-8423, cliffordd/at/neuro.wustl.edu
Mardge H. Cohen, M.D., Professor of Medicine, Rush University, Women Interagency HIV Study (WIHS), Medical Director, Women’s Equity in Access to Care and Treatment (WE-ACTx), 2255 W Harrison, Chicago, IL 60612, 312-925-5660, mardge.cohen/at/gmail.com
Judith Currier, M.D., M.Sc., Professor of Medicine, Chief, Division of Infectious Diseases, Associate Director, Clinical AIDS Research and Education (CARE) Center, David Geffen School of Medicine at University of California, Los Angeles, 9911 W. Pico Blvd., Suite 980, Los Angeles, CA 90035, 310-557-2273, jscurrier/at/mednet.ucla.edu
Steven G. Deeks, M.D., Professor of Medicine, University of California, San Francisco, Ward 84, Building 80, 995 Potrero Avenue, San Francisco, CA 94110, 415-476-4082 x404, sdeeks/at/php.ucsf.edu
Sherry Deren, Ph.D., Director, Center for Drug Use and HIV Research, Senior Research Scientist, New York University College of Nursing, 726 Broadway, 10th Floor, New York, NY 10003, 212-998-9015, shd2/at/nyu.edu
Rita B. Effros, Ph.D., Professor of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, 310-825-0748, reffros/at/mednet.ucla.edu
Kelly Gebo, M.D., M.P.H., Associate Professor of Medicine, Epidemiology, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Room 435, Baltimore, Maryland 21287, 410-502-2325, kgebo/at/jhmi.edu
Jörg J. Goronzy, M.D., Ph.D., Professor of Medicine, Department of Immunology and Rheumatology, Stanford University School of Medicine, 269 Campus Drive West, Mail Code 5166, Stanford, CA 94305-5166, 650-723-9027, jgoronzy/at/stanford.edu
Kevin P. High, M.D. , M.S., Co-Chair, Professor of Medicine and Translational Science, Chief, Section on Infectious Diseases, Associate Dean, Clinical Research, Wake Forest University Baptist Medical Center, 100 Medical Center Boulevard, Winston Salem, NC 27157-1042, 336-716-4584, khigh/at/wfubmc.edu
Amy C. Justice, M.D., Ph.D., Professor of Medicine, Yale University, Section Chief of General Internal Medicine, Veteran Affairs Connecticut Healthcare System, 950 Campbell Avenue (11-ACSL-G), West Haven, Connecticut 06516, 203-932-5711 x3541, amy.justice2/at/va.gov
Alan Landay, Ph.D., Professor and Chairman, Department of Immunology/Microbiology, Rush University Medical Center, 1735 W. Harrison Street, Room 616 Cohn, Chicago, IL 60612-3823, 312-942-2849, alanday/at/rush.edu
Jules Levin, Executive Director, National AIDS Treatment Advocacy Project (NATAP), 580 Broadway, Suite 1010, New York, NY 10012, 212-219-0106, JuLev/at/aol.com
Paolo G. Miotti, M.D., Executive Secretary, Natural History and Epidemiology Coordinator, Office of AIDS Research, Office of the Director, National Institutes of Health, DHHS, 5635 Fishers Lane, Suite 4000, Rockville, MD 20852, 301-435-7699, pm122m/at/nih.gov
Robert J. Munk, Ph.D., Project Coordinator, AIDS InfoNet, P.O. Box 810, 34A Percilla Lane, Arroyo Seco, NM 87514, 575-776-8032, bobmunk/at/ix.netcom.com
Heidi Nass, J.D., Madison, WI, 608-263-9219, hmnass/at/uwalumni.com
Charles R. Rinaldo, Jr., Ph.D., Professor and Chairman, Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, A427 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261, Ph: 412-624-3928, Fax: 412-624-4953, rinaldo/at/pitt.edu
Michael G. Shlipak, M.D., M.P.H., General Internal Medicine Division Chief, Veteran Affairs Medical Center, Professor of Medicine, Epidemiology & Biostatistics, University of California, San Francisco, 4150 Clement St. Rm. 111A1, 415-221-4810 x3381, San Francisco, CA 94143, Michael.shlipak/at/ucsf.edu
Russell Tracy, Ph.D., Professor of Pathology and Biochemistry, University of Vermont College of Medicine, 208 South Park Drive, Suite 2, Colchester, VT 05446, 802-656-8968, russell.tracy/at/uvm.edu
Victor Valcour, M.D., Associate Professor of Geriatric Medicine, Division of Geriatric Medicine and Department of Neurology, Memory and Aging Center, University of California, San Francisco, 350 Parnassus Avenue, Suite 905, San Francisco, CA 94143-1207, 415-476-3746, vvalcour/at/memory.ucsf.edu
David E. Vance, Ph.D., Associate Professor, School of Nursing, University of Alabama at Birmingham, 1701 University Boulevard, Room 456, Birmingham, AL 35294-1210, 205-934-7589, devance/at/uab.edu
Paul Volberding, M.D., Co-Chair, Professor and Vice Chair, University of California, San Francisco, Chief of the Medical Service, San Francisco Veterans Affairs Medical Center, 4150 Clement Street, VAMC 111, San Francisco, CA 94121, 415-750-2037, Paul.volberding/at/ucsf.edu
Jeremy D. Walston, M.D., Raymond and Anna Lublin Professor of Geriatric Medicine, Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Suite 1A.62, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, 410-550-1003, jwalston/at/jhmi.edu