Aging of the HIV Population: Epidemiology
In Canada, like many other countries where antiretroviral agents are readily available, the ability of current therapies to sustain control of human immunodeficiency virus (HIV) has led to a growing number of patients who are 50 years old or older.(1-2)This age stratification, used by the Public Health Agency of Canada for tracking the epidemiology of HIV and acquired immunodeficiency syndrome (AIDS),(3)is a potentially useful threshold because of increasing evidence that HIV may pose unique challenges in aging patients. Older patients have long been over-represented among AIDS cases relative to their total representation among patients with HIV,(1)but there is growing concern that HIV infection may complicate or even accelerate the co-morbidities common to the aging process,(4)such as cardiovascular disease (CVD),(5)renal impairment,(6)osteoporosis,(7)liver disease,(8)and neurocognitive decline.(9)
The aging of the HIV population in Canada can be understood in two different ways. One is the increasing proportion of new infections in patients who are 50 years old or older. Individuals over the age of 50 now represent close to 15% of new infections in Canada, a proportion that has almost doubled since the late 1990s.(3)The other is the prolonged survival made possible with highly active antiretroviral therapies (HAART). While the proportion of HIV-positive patients who are older than age 50 years increased very modestly in Canada over the last 10 years because the majority of new infections still occur in younger individuals,(10)the absolute number of older individuals with HIV is increasing along with the increasing estimated number of total infections, which exceeded 70,000 persons by the end of 2010.(1)
While persistent and sustained suppression of HIV remains critical to the survival of patients with HIV, AIDS deaths are now infrequent in Canada. In 2009, there was a total of 25 deaths attributed to AIDS, which represented an 84% reduction since 2003 despite a substantial increase in the number of individuals living with HIV.(10) (Fig. 1). Similar reductions have been recently reported in other countries with ready access to antiretroviral therapies, such as Switzerland.(11)In the Swiss HIV Cohort Study (SHCS), less than 20% of all deaths in 2005 through 2009 were due to AIDS. Rather, non-AIDS malignancies followed by CVD were the most common causes of death in patients without hepatitis C virus (HCV) infection. Liver disease, followed by non-AIDS infections were the most common causes of mortality in HIV patients co-infected with HCV. Over this study period, the median age at death climbed from 45 to 49 years while the median CD4 count at time of death increased from 257 to 321 cells/mm3 (Fig. 2).
These data suggest that prolonging survival in patients with HIV is becoming less dependent on developing better therapies for suppressing HIV than controlling disease processes that are exacerbated by the presence of HIV or its treatments. The risks for specific diseases, such as those affecting the CV system, the central nervous system (CNS), or the skeleton, may range substantially among HIV-infected individuals due to an array of variables that affect specific risk, including familial susceptibility, lifestyle choices, and medication history, but current data suggest that the treatment of these co-morbid conditions will be increasingly critical to the effort to extend the life span of individuals infected with HIV.
The association between HIV infection and an increased risk of CVD, which is well described and one of the first signals that age-related diseases occur earlier in patients with HIV,(12-14)was not initially recognized as a manifestation of accelerated aging. Rather, the initial focus was on the dyslipidemias associated with protease inhibitors (PIs) and the high prevalence of conventional heart disease risk factors, such as smoking, in the HIV-infected population.(15-16)Those factors remain relevant, but numerous other factors appear to be contributing, including a direct influence of HIV on CV risk, and that this risk may in part be mediated by immunosenescence.(17)The concept of immunosenescence, which is relevant to natural aging, is based on a decline in the adaptive immune system that, among other effects, leads to upregulation of inflammatory mediators.(18)In CVD, it is now believed that inflammation participates in promoting both atherosclerosis and thrombotic events.(19-20)
A similar interplay between an upregulation of the immune system and accelerated senescence may be relevant to other organ systems in patients with HIV.(21)The aging process, which is generally recognized as a progressive cumulative deterioration in normal physiologic molecular and cellular functions resulting in organ damage, has been linked to expression of several specific inflammatory cytokines, such as interleukin-6 (IL-6), in normal as well as HIV-associated aging.(22-23)This has led to the hypothesis that HIV patients are aging more quickly simply because the persistent infection exhausts the immune system at a more rapid pace.(17) (Fig. 3).
In normal aging, the rate of impairment in specific organs depends on multiple factors, particularly genetics. Genetic variables that affect risk have been defined for CVD,(24)neurocognitive impairment,(25)osteoporosis,(26)and renal impairment.(27)Although lifestyle choices may have an important influence on the relative risk of all of these processes, suggesting that genetic predisposition can be exacerbated or reduced, the risk of death from any single cause of death appears to vary widely. Current efforts to determine the relative contribution of DNA damage and repair, telomere shortening, and mitochondrial dysfunction may all provide insight on individual differences in the rate of aging in specific organs.(28)All of these factors are likely to be relevant to the relative rate of deterioration in specific organ systems in those who are HIV infected.
The cumulative effect of the aging process in normal individuals is a generalized frailty, which is also observed in individuals with HIV. As anticipated by an accelerated rate of aging, the increasingly well-defined frailty phenotype occurs at a much younger age in individuals who are HIV positive. (Fig. 4) In new data from the Multicenter AIDS Cohort Study (MACS), pre-defined frailty characteristics were almost twice as common in men with HIV relative to men without HIV between the ages of 50 and 59 (14.8 vs. 8.1%; P=0.006) and 60 and 69 (19.9 vs. 10.0%; P=0.01).(29)In this study, individuals were considered to have frailty if they had three or more of the following: low grip strength (20th percentile for age), slow four-meter walk (<20th percentile for age), low physical activity, exhaustion as defined by the Short-Form 36 (SF-36), and unintentional weight loss of >10 pounds.
Traditionally, the goals of HIV therapy have been to suppress viremia while minimizing the potential for adverse effects from the medications. The evidence of accelerated aging, suggests a new paradigm that includes attention to target organs at risk.(30)While a specific definition of frailty in the HIV-positive patient may be helpful to better understand this phenomenon, criteria for early recognition of the process is supported by the association of frailty with adverse outcomes in individuals who are HIV-negative.(31)
Diagnosis and Monitoring
The evidence that HIV accelerates aging promotes a proactive approach to patient care. Unlike acute health complaints, age-related deterioration in organ systems can be subtle and insidious. Many of the processes, including CVD and renal impairment, may not elicit direct complaints but remain asymptomatic up until life-threatening complications occur. It is therefore appropriate to consider an organized approach to gathering baseline information about CV risk factors, renal function, cognitive function, and bone mineral density. It is essential to recognize that aging processes in all of these organ systems are multifactorial. For example, while dyslipidemias were once considered to be most likely explanation for the relationship between antiretroviral therapy and CVD,(32)exposure to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) specifically and antiretroviral agents overall have also been associated with increased insulin resistance, an independent risk factor for CVD.(33-34)
HIV-infected individuals face the same health risks as non-infected individuals, but the interrelationship of normal health risks, accelerated aging, and the effects of antiretroviral therapy defines a need to initiate more rigorous monitoring of age-related risks at a much earlier timepoint than would be appropriate in individuals without HIV infection. Due to the multiple pathophysiologic processes at work in HIV-infected individuals, each risk factor may threaten a greater impact than anticipated in an individual without HIV. For example, therapeutic agents designed to reverse the complex effect of HIV infection on visceral fat, insulin resistance, and lipodystrophy, are being pursued for their potential to circumvent a synergy between these risk factors.(17)
Evidence of risk in specific organ systems can be addressed with targeted therapies according to evidence-based guidelines, such as those provided by the Canadian Cardiovascular Society for CV risk factors or the Canadian Society of Nephrology for the management of chronic kidney disease.(35-36)However, the best opportunity for reducing the morbidity and mortality in aging patients with HIV may be to intervene in advance of pathology. Although strategies must be individualized for the individual risk profiles, aggressive interventions at a relatively young age, including lifestyle changes, may have a large impact on subsequent risk.
In this setting, family history, in addition to baseline monitoring, can be helpful for anticipating risks. Although no objective takes precedence over sustained suppression of HIV, the relative safety of antiretroviral agents for lipid metabolism or kidney function may be relevant in patients with elevated risk for CVD or kidney disease, respectively. Recent attention to the relative penetration of antiretroviral agents into the CNS compartment may prove relevant to relative risk reduction for neurocognitive impairment,(37)although more studies are required to understand the potential for neurotoxicity among antiretroviral agents and to confirm the relative clinical value of agents that do or do not have a high central nervous system penetration effectiveness (CPE) score. Ultimately, strategies for optimal management of age-related diseases are likely to evolve as the growing number of older HIV-positive patients expands the scope of this clinical challenge.
With the identification of numerous effective antiretroviral combinations that provide sustained control of HIV, age-related diseases will increasingly represent the primary obstacle to a normal lifespan among infected individuals. The relative risks of specific organ diseases appear to be patient-specific, but the vulnerability may have a common pathway related to immunosenescence and the persistent upregulation of the inflammatory response induced by the presence of HIV. Strategies for an individualized but proactive approach to slowing decline in susceptible organs are emerging, but this is a dynamic area which is expected to evolve.
1. HIV/AIDS Epi Updates – July 2010. Public Health Canada, 2010. (Accessed March 7, 2011, 2011, at http://www.phac-aspc.gc.ca/aids-sida/publication/epi/2010/1-eng.php.)
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6. Winston J, Deray G, Hawkins T, Szczech L, Wyatt C, Young B. Kidney disease in patients with HIV infection and AIDS. Clin Infect Dis 2008;47(11):1449-57.
7. Thomas J, Doherty SM. HIV infection–a risk factor for osteoporosis. J Acquir Immune Defic Syndr 2003;33(3):281-91.
8. Weber R, Sabin CA, Friis-Moller N, et al. Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006;166(15):1632-41.
9. McArthur JC. HIV dementia: an evolving disease. J Neuroimmunol 2004;157(1-2):3-10.
10. HIV and AIDS in Canada. Surveillance Report to December 31, 2009. In: Canada PHAo, ed. Ottawa; 2009.
11. Ruppick M, Ledergerber B, Rickenbach M, Furrer H, Battegay M. Changing patterns of causes of death: SHCS, 2005 to 2009. In: Conference on Retroviruses and Opportunistic Infections; 2011; Boston; 2011.
12. Sackoff JE, Hanna DB, Pfeiffer MR, Torian LV. Causes of death among persons with AIDS in the era of highly active antiretroviral therapy: New York City. Ann Intern Med 2006;145(6):397-406.
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14. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis 2007;44(12):1625-31.
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17. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med 2011;62:141-55.
18. Molina-Pinelo S, Vallejo A, Diaz L, et al. Premature immunosenescence in HIV-infected patients on highly active antiretroviral therapy with low-level CD4 T cell repopulation. J Antimicrob Chemother 2009;64(3):579-88.
19. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352(16):1685-95.
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23. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008;5(10):e203.
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Chapter 2: Cardiovascular Disease
Early death from cardiovascular (CV) complications in aging individuals infected with HIV is a growing challenge in chronic HIV management. There are numerous factors that have converged to increase CV risk in individuals infected with HIV compared to age-matched individuals without infection. These include a greater prevalence of CV risk factors, the adverse effects of several antiretroviral agents that appear to contribute to CV risk, and a direct or indirect effect of HIV itself. In HIV patients with otherwise well controlled viremia, CV disease is expected to become an increasingly important cause of preventable death. The effort to modify the impact of this potential crisis depends on heightened awareness of the risks in HIV patients and aggressive monitoring and intervention for modifiable risk factors. Individualization of therapy will be increasingly important when attempting to reduce CV risks in the context of sustained HIV suppression.Show review
Chapter 3: Renal Impairment
Chronic kidney disease (CKD) is a significant threat to the long-term survival of individuals infected with human immunodeficiency virus (HIV). Although the introduction of highly active antiretroviral therapy (HAART) dramatically reduced the risk of end stage renal disease (ESRD) from HIV-specific causes, as it did many of the other complications of uncontrolled HIV, it attenuated but did not eliminate the development of compromised renal function from causes indirectly related to HIV infection. Until recently, the risk of renal failure as a complication of HIV has been concentrated in African-Americans, who have demonstrated an increased susceptibility to HIV-associated nephropathy, but the incidence of renal impairment in aging individuals with otherwise well-controlled HIV infection is climbing. In the setting of HIV infection, therapies traditionally employed to preserve renal function, such as renin-angiotensin-aldosterone system (RAAS) inhibitors, are appropriate, but other steps should be considered. This may include preferential use of antiretroviral agents with the least potential to exacerbate renal dysfunction. Close monitoring of renal function is appropriate because of variability in the individual risk for renal disease and progression of nephropathy once it is established.Show review
Chapter 4: Neurocognitive Deficit
Cognitive decline is an insidious and frequently progressive complication of human immunodeficiency virus (HIV) infection. While the introduction of highly active antiretroviral therapy (HAART) largely eliminated the dementia associated with end-stage acquired immunodeficiency syndrome (AIDS), cognitive impairment remains a common complication of HIV even in those with well controlled viremia. The incidence and the severity of HIV-associated neurocognitive disorders (HAND) are rising with an aging HIV population – a potential consequence of both increased susceptibility in older individuals and progressive impairment with longer duration of infection. The clinical challenges posed by this complication are substantial. The relative ability of specific antiretroviral therapies to cross the blood brain barrier to reduce central nervous system (CNS) viral load, and the specific, perhaps genetic, susceptibility of individual patients are among factors that may explain the variable risk of cognitive impairment. In addition, HIV-independent variables may also be important in some individuals. Clinical sensitivity to changes in cognitive function through periodic assessments is appropriate in the context of strategies to understand and prevent HAND.Show review
Chapter 5: Osteoporosis
The accelerated loss of bone density in patients with HIV infection threatens a significant health crisis in Canada and other countries with aging HIV-infected populations. There appears to be an important interaction between traditional osteoporosis risk factors and bone loss related specifically to HIV and its therapies. Consistent with accelerated aging across other organ systems, HIV-related loss of bone mineral density is a progressive condition detected soon after infection. It may persist independent of HIV suppression, and it can be exacerbated by some antiretroviral drugs. Strategies to diminish the impact of bone mineral loss depend on early screening and aggressive efforts at preventing or modifying the underlying processes. The rising rates of fracture in aging individuals with HIV infection have intensified attention on this complication, but the scope of this complication is expected to enlarge with the demographic shift that is increasing the proportion of HIV-infected individuals in the age range of vulnerability.Show review