aDepartment of Internal Medicine, Yale University and the Veterans Affairs Healthcare System, West Haven, CT 06516, USA
bChronic Viral Illness Service and Division of Geriatrics, McGill University Health Center, Montreal, Quebec, Canada
Correspondence to Amy Justice, MD, PhD, Professor of Medicine and Public Health, Yale School of Medicine, Building 35A, Room 2-212 (11-ACSLG), 950 Campbell Avenue, West Haven, Connecticut 06516, USA. Tel: +1 203 932 5711 x3541; fax: +1 203 937 4926; e-mail: firstname.lastname@example.org
The increasing availability of effective antiretroviral treatment (ART) has dramatically extended life expectancy for those with HIV infection . As a result, people are aging with HIV , but data on this new phenomenon remain somewhat limited and opinions vary. Some experts contend, now that we are successful at suppressing HIV-1 RNA, that HIV research and healthcare resources should be exclusively dedicated to ensuring access to ART and developing an effective vaccine. They argue against spending limited resources on complex issues of aging with HIV because many of these issues have bedeviled aging researchers for decades. Some also suggest that routine care of virologically suppressed patients can be managed in more patient-centered and financially less-expensive primary care settings . Others take a different view, suggesting that the pathophysiologic processes and socioeconomic supports of aging are substantially altered among those with HIV and that these alterations offer unique opportunities for scientific discovery and improved clinical management. They suggest that aging with HIV is an untapped laboratory for discovery that offers unique insights into larger issues of aging. They point out that treatment strategies among those aging with HIV are only beginning to take shape, offering a unique opportunity to use evidence to inform care. Many clinicians also argue that enough unique and challenging aspects related to the ongoing management of HIV remain, suggesting a continuing role for the HIV specialist .
Probably the strongest data in support of the view that patients aging with HIV in the context of virologic suppression and adequate immune recovery are no different than aging-uninfected persons come from a recent meta-analysis of HIV life expectancy data. Among those with HIV-1 RNA suppression and CD4 cell counts above 500 cells/mm3, the studies find no difference in life expectancy compared with demographically similar uninfected individuals . Importantly, the majority of those in care with HIV infection do not achieve this level of immune reconstitution. According to recently updated analyses from the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD), a cross-cohort study encompassing most of the large HIV cohort studies in North America, more than 95% of whom are on ART, have a median CD4 cell count in 2011 below 500 cells. Thus, less than half of those aging with HIV have a normal life expectancy (www.naaccord.org/dossier/NA-ACCORD_Dossier20140325.pdf). Further, whether long-term HIV effects of microbial translocation, viral reservoirs, and chronic inflammation among suppressed patients will alter these estimates with time is not yet known [5,6].
Another common argument from HIV and aging ‘skeptics’ is that any increased risk we observe for non-AIDS conditions among those with HIV compared with demographically similar uninfected individuals can be explained by differential health behaviors (more smoking, drinking, and drug use) or by suboptimal antiretroviral therapy (exposure to mono and dual therapy as well as exposure to antiretrovirals with known toxicity collectively known as the ‘D drugs’, i.e., the thymidine nucleoside analog reverse-transcriptase inhibitors). Certainly, alcohol use, smoking, and both illicit and prescription drug abuse are more common among those aging with HIV [7,8]. Similarly, mental health issues play a role . However, the SMART study  and a number of observational studies controlling for important health behaviors such as smoking, alcohol, and drug use [11–14] have demonstrated that ART, on average, decreases risk for and progression of non-AIDS-defining organ system disease including anemia, cardiovascular disease, liver disease, and renal disease. Although ART toxicity continues to play a more minor role in adverse outcomes, it does not appear to be a major driver of excess risk for the so-called HIV-associated non-AIDS-defining conditions [15–19].
At least some of the incident metabolic complications occurring after ART initiation, previously attributed to ART toxicity, may be partially explained by a general return to health characterized by weight gain  and inevitable increases in lipids and glucose intolerance or frank diabetes . Determining what is healthy and unhealthy weight gain after ART is a unique challenge.
A further possibility that has yet to be carefully explored is that toxicity from non-HIV medications may explain some of the observed excess risk for organ system disease and adverse outcomes seen among those aging with HIV . In resource-rich settings, those aging with HIV are also taking a growing number of non-ART medications that likely interact with ART and easily cross the numeric threshold for polypharmacy established in the geriatric literature. As a result, they are at increased risk for adverse drug reactions further [22–24]. Whether decreasing the number of non-ART medications through prioritization and consideration of behavioral alternatives to medications for common aging-related conditions such as sleep disorders, reflux esophagitis, and chronic pain improves outcomes remains to be seen.
Claims of ‘accelerated aging’ are largely overstated and heighten concern and anxiety in many older patients. Increased risk of complications at all ages is not the same as premature aging. Many HIV-infected and uninfected patients complain of feeling ‘old beyond their time’ , but the characterizations of aging with HIV as accelerated are largely based on biomarker data and/or clinical data employing inappropriate comparators [25,26]. Age differences that at first appeared pronounced diminish substantially when the underlying distribution of age in the samples compared is matched . Comparing community-based controls with clinic-based patients is always biased toward higher estimates of disease in the clinic sample. Although those with HIV infection appear to have more co-occurring conditions  (also called multimorbidity) including hepatitis C, substance use addiction to tobacco, alcohol, and psychoactive drugs, and to have somewhat higher levels of the frailty-related phenotype , it is not clear that HIV patients infection achieving immunovirologic control are subject to greater levels of frailty  or functional compromise. Further, the current understanding of HIV-associated neurologic disease is problematic because many factors included are not unique to HIV. For example, many measures of neurocognitive performance are strongly associated with organ system components of the Veterans Aging Cohort Study (VACS) Index, but are not associated with CD4 cell count or HIV-1 RNA . These risks will increase as the HIV population ages beyond 65 years of age, an age after which cerebrovascular disease, dementia, both vascular and nonvascular related, and affective disorders occur more often .
An important subgroup among those supporting the relevance of aging concerns in HIV focuses on aging with and without HIV in resource -limited settings . In this setting, aging, among the general population, is a relatively new phenomenon and the HIV epidemic is a generalized one. How limited resources can be used to effectively address the growing population of both aging HIV-infected individuals and newly infected older individuals will provide a unique and important challenge . Among these challenges is that of simply characterizing aging with, and without, HIV in this data-limited setting.
We are only beginning to comprehend aging and HIV. The median age among those living with HIV has crossed 50 years in specific settings such as the United States Veterans Administration Healthcare System, New York City, and San Francisco. More will follow. Whether investments in this line of research will lead to important biologic insights and improved clinical management remains uncertain. There are tantalizing clues about overlapping roles of chronic viral infection, hypercoagulability, inflammation, immune dysregulation, and senescence [5,6,34,35] as well as the critical importance of more integrative scientific thinking across diseases, medical and research disciplines, and ages [22,36,37]. Outside HIV research, there is a growing appreciation for the importance of other chronic viral infections including hepatitis C and cytomegalovirus. Perhaps the questions at this juncture are: can studying aging with HIV inform the study of aging more generally; can this focus provide unique insights into modifiable roles of chronic inflammation, multimorbidity, and frailty in the course of particular disease processes and in the overall aging process; and can it improve care of those aging with HIV? We believe that the answers to these questions will be a resounding, ‘yes,’ but only time will tell.
To further inform the discussion, we invited 18 articles from colleagues with diverse backgrounds who think that there is something special about the study of aging and HIV. Some of these articles focus on particular organ systems including the immune system , gastrointestinal system , liver , cardiovascular system , kidney , skeletal system , and central nervous system . Some focus on health behaviors and substance use [8,9]. Others are focused on more integrated issues of aging including metabolism , multimorbidity , geriatric syndromes , frailty , and functional status . Still others focus on systems and approaches to care . Finally, we begin the collection with an updated description of the demographics of aging with HIV  and end with a cautionary article on how to identify appropriate uninfected comparators  and an article focused on pressing research questions .
J.F. discloses a consulting association with Theratechnologies Canada Inc. (April 2014).
Conflicts of interest
There are no conflicts of interest.
1. Sabin CA. Do people with HIV infection have a normal life expectancy in the era of combination antiretroviral therapy? BMC Med 2013; 11:251.
2. Costagliola D. Demographics of HIV and aging. Curr Opin HIV AIDS 2014; 9:294–301.
3. Chu C, Selwyn PA. An epidemic in evolution: the need for new models of HIV care in the chronic disease era. J Urban Health 2011; 88:556–566.
4. High KP, Brennan M, Clifford D, et al. HIV and Aging: State of Knowledge and Areas of Critical Need for Research. A Report to the NIH Office of AIDS Research by the HIV and Aging Working Group. J Acquir Immune Def Syndr 2012; 60 (Suppl 1):S1–S8.
5. Hunt PW. HIV and aging: emerging research issues. Curr Opin HIV AIDS 2014; 9:302–308.
6. Wang H, Kotler DP. HIV enteropathy and aging: gastrointestinal immunity, mucosal epithelial barrier, and microbial translocation. Curr Opin HIV AIDS 2014; 9:309–316.
7. Green TC, Kershaw T, Lin H, et al. Patterns of drug use and abuse among aging adults with and without HIV: A latent class analysis of a US Veteran cohort. Drug Alcohol Depend 2010; 110:208–220.
8. Edelman EJ, Tetrault JM, Fiellin DA. Substance use in older HIV-infected patients. Curr Opin HIV AIDS 2014; 9:317–324.
9. Rueda S, Law S, Rourke SB. Psychosocial, mental health and behavioral issues of aging with HIV. Curr Opin HIV AIDS 2014; 9:325–331.
10. El-Sadr W, Lundgren J, et al. Strategies for Management of Antiretroviral Therapy (SMART) Study GroupCD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283–2296.
11. Anderson JP, Tchetgen EJ, Lo RV III, et al. Antiretroviral therapy reduces the rate of hepatic decompensation among HIV- and hepatitis c virus-coinfected veterans. Clin Infect Dis 2013; 58:719–727.
12. Wyatt CM, He C, Parikh C, et al. VACS diabetes and CKD. J Acquir Immune Defic Syndr in press.
13. Moore RD, Forney D. Anemia in HIV-infected patients receiving highly active antiretroviral therapy. J Acquir Immune Defic Synd 2002; 29:54–57.
14. Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med 2013; 173:614–622.
15. Calvo M, Martinez E. Update on metabolic issues in HIV patients. Curr Opin HIV AIDS 2014; 9:332–339.
16. Nadkarni GN, Konstantinidis I, Wyatt CM. HIV and the aging kidney. Curr Opin HIV AIDS 2014; 9:340–345.
17. So-Armah K, Freiberg MS. Cardiovascular disease risk in an aging HIV population: not just a question of biology. Curr Opin HIV AIDS 2014; 9:346–354.
18. Cysique LA, Brew BJ. The effects of HIV and aging on brain functions: proposing a research framework and update on last 3 years’ findings. Curr Opin HIV AIDS 2014; 9:355–364.
19. Rockstroh JK, Mohr R, Behrens G, Spengler U. Liver fibrosis in HIV: which role does HIV itself, long-term drug toxicities and metabolic changes play? Curr Opin HIV AIDS 2014; 9:365–370.
20. Lakey W, Yang LY, Yancy W, et al. Short communication: from wasting to obesity: initial antiretroviral therapy and weight gain in HIV-infected persons. AIDS Res Hum Retroviruses 2013; 29:435–440.
21. Vigouroux C, Bastard J-P, Capeau J. Emerging clinical issues related to management of multiorgan comorbidities and polypharmacy. Curr Opin HIV AIDS 2014; 9:371–378.
22. Edelman EJ, Gordon K, Akgun K, et al. HIV+ individuals on ART are at risk of polypharmacy: More medication increases mortality. 51st Infectious Diseases Society of America (IDSA) ID Week, San Francisco, California, 2s–6 October 2013.
23. Edelman EJ, Gordon KS, Glover J, et al. The next therapeutic challenge in HIV: polypharmacy. Drugs Aging 2013; 30:613–628.
24. Holtzman C, Armon C, Tedaldi E, et al. Polypharmacy and risk of antiretroviral drug interactions among the aging HIV-infected population. J Gen Intern Med 2013; 28:1302–1310.
25. Pathai S, Bajillan H, Landay AL, High KP. Is HIV a model of accelerated or accentuated aging? J Gerontol A Biol Sci Med Sci 2013; [Epub ahead of print].
26. Wong C, Althoff K, Gange SJ. Identifying the appropriate comparison group for HIV-infected individuals. Curr Opin HIV AIDS 2014; 9:379–385.
27. Shiels MS, Althoff KN, Achenbach C, et al. Age at cancer diagnosis in HIV-infected individuals in North America compared to the general U.S. population. XIX International AIDS Conference. 2012.
28. Guaraldi G, Silva AR, Stentarelli C. Multimorbidity and functional status assessment. Curr Opin HIV AIDS 2014; 9:386–397.
29. Desquilbet L, Jacobson LP, Fried LP, et al. HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. J Gerontol A Biol Sci Med Sci 2007; 62:1279–1286.
30. Althoff KN, Jacobson LP, Cranston RD, et al. Age, comorbidities, and AIDS predict a frailty phenotype in men who have sex with men. J Gerontol A Biol Sci Med Sci 2014; 69:189–198.
31. Marquine MJ, Umlauf A, Rooney AS, et al. The Veterans aging cohort study index is associated with concurrent risk for neurocognitive impairment. J Acquir Immune Defic Syndr 2014; 65:190–197.
32. Mills EJ, Barnighausen T, Negin J. HIV and aging – preparing for the challenges ahead. N Engl J Med 2012; 366:1270–1273.
33. Justice AC, Braithwaite RS. Lessons learned from the first wave of aging with HIV. AIDS 2012; 26 (Suppl 1):S11–S18.
34. Tsoukas C. Immunosenescence and aging in HIV. Curr Opin HIV AIDS 2014; 9:398–404.
35. Chirch LM, Hasham M, Kuchel GA. HIV and aging: a clinical journey from Koch's postulate to the chronic disease model and the contribution of geriatric syndromes. Curr Opin HIV AIDS 2014; 9:405–411.
36. Brothers TD, Rockwood K. Biologic aging, frailty, and age-related disease in chronic HIV infection. Curr Opin HIV AIDS 2014; 9:412–418.
37. Boyd CM, Lucas GM. Patient-centered care for people living with multimorbidity. Curr Opin HIV AIDS 2014; 9:419–427.
38. Mallon PWG. Aging with HIV: osteoporosis and fractures. Curr Opin HIV AIDS 2014; 9:428–435.