Some of the world's leading HIV researchers converged on Montreal in February of this year for the 16th Conference on Retroviruses and Opportunistic Infections (CROI). This year's conference continued to document the unfolding world-wide access to antiretroviral therapy, with large advances noted, despite some set-backs. These accomplishments rightly find their place centrally in the agenda for this premier international conference. The conference also relayed new findings on the risk factors for HIV and non-HIV-related complications. Presentations related to new therapies were less frequent and research related to vaccines continued to detail great challenges.
Attendees interested in emerging issues related to aging with HIV infection would be largely disappointed, as the emphasis on aging was notably scant. Despite many papers describing age-related vulnerability and a general agreement that this population is rapidly expanding, there continues to be a large gap in research specifically addressing this population. This is quite disappointing to clinicians who are witnessing the graying of their clinic populations across the U.S. while they have few guidelines by which to direct specialized care. Even resource-limited settings will soon be facing the challenges related to the management of chronic HIV in populations that will inevitably age with infection, as was noted in data presented by researchers in Senegal.1
In the U.S., the prevalence of HIV in people who are over 65 years of age has increased more than 10-fold in the past decade.2 In some regions, more than half of HIV patients are currently over 50 and it is broadly acknowledged that this distribution is likely to be noted nationwide by 2015. Numerous articles have already been published demonstrating a detrimental effect of aging on HIV and non-HIV outcomes, rendering the age-related findings from many of the 16th CROI papers to be confirmatory rather than enlightening as to underlying mechanisms. There were no papers (and probably little-to-no data) that tried to address the controversy related to age-specific treatment recommendations, despite nearly universal detrimental outcomes associated with age. This striking deficit may reflect the relative infancy of this topic in the minds of researchers, and we can only hope it will change in the years ahead.
With few exceptions, aging was considered as a potential modifying factor in models for clinical studies presented at the 16th CROI. Depressingly, the impact is almost universally unfavorable, which was brought quickly to light in large studies, such as that presented in abstract #145.3 (Visit www.retroconference.org.) With the occasional outlier (two papers suggest a signal that prostate cancer rates may be lower than anticipated in HIV compared to age match controls, #30, 178)4, 5, older HIV patients can typically anticipate higher rates and worse outcomes for nearly all complications. These poorer outcomes should be worrisome enough, but become even more striking when one considers that most participants in these trials are not old. Typically, the reported mean age is in the mid? to upper 40s, representative of the HIV epidemic in resource-richer countries, in general. Thus, outcomes for truly old HIV populations remain under-studied and largely unknown.
What follows is a brief synopsis of papers that highlight aging or complications with particular relevance to the aging HIV population.
Over the past decade, it has become increasingly clear that cardiovascular complications are frequent among patients treated for HIV. Accordingly, the 16th CROI included a broad array of papers on the topic. HIV infection was confirmed to be an independent risk factor for cardiovascular disease based on data from the FRAM study;6 but promising data were noted from the California Kaiser Permanente database, where rates of myocardial infarction (MI) decreased in recent years and are now similar to background rates, possibly owing to aggressive management of risk factors.7 Risk for cardiovascular outcomes and intermediate markers of cardiovascular change can be predicted with the Framingham risk scores;8 however, HIV-specific changes (not necessarily associated with traditional risk factors) are also noted. One study identified changes in endothelium-dependent vasodilatation (a measure of cardiovascular risk) in treatment-na?ve HIV patients to the extent that would be anticipated in HIV-negative controls who were 25 years older, suggesting vascular (blood vessel) changes akin to accelerated aging.9
While age negatively impacts cardiovascular outcomes, several papers also identified modifiable risk factors that influence cardiovascular (as well as all-cause) mortality, including intravenous drug use, smoking, hypertension, and diabetes.3, 10 The relationship between abacavir use and cardiovascular outcomes was discussed in several papers with some,11-13 but not all,14 studies identifying associations. This controversy is beyond the scope of this review, but was the subject of paper #152, for readers interested in more information on the topic.15
Osteoporosis is largely a disease associated with age in HIV-negative populations, but has also been demonstrated to be more frequent with HIV16, 17 (50% osteopenia in HIV and 5-20% osteoporosis at the average age of 45). Some of this risk is explained by hypogonadal status in HIV-infected men.18 As with other complications, the presence and pattern of osteoporosis may suggest age-related changes,19 such as its association with increased markers of T-cell senescence (when cells lose the ability to divide).20
Renal function decreases with age, regardless of HIV status, often requiring medication adjustments. One paper identified that the rate of decline is increased with HIV and this increase is not arrested by control of viral load.21 Age was also shown to increase risk for renal tubular disease in association with tenofovir (Viread) use.22, 23 New advances in medications that may eventually replace ritonavir (Norvir) as a boosting agent were presented and are thought to have improved gastrointestinal profiles compared to ritonavir, a factor likely to greatly impact quality of life for HIV elders.24, 25
Cancer rates are elevated with HIV and with age. The California Kaiser Permanente database identified a rate of 29.7/10,000 person-years for infection-related non-AIDS-defining cancers in HIV-positive people compared to a background rate of 4.4/10,000 (RR = 6.8).4 This rate has remained essentially unchanged in the last decade. Cancers found to be elevated in HIV include anal cancer, Hodgkin's lymphoma, head and neck cancers, gynecological cancers, and kidney, lung, and skin melanomas. The notable exception was prostate cancer, where the authors noted an early signal of decreased relative risk (0.7).4 This trend was noted by another group as well.5
Although aging is associated with increased mortality, modifiable risk factors, such as smoking, also predict morbidity and mortality, providing opportunities to potentially decrease risk.10, 26 These studies and others mark the need to address non-AIDS-related mortality risk in order to reduce rates in HIV patients. An evaluation of 13 cohort studies identified non-AIDS-related causes of death to be more frequent than AIDS-related deaths.27 Some leading causes include non-AIDS-related malignancies and/or infections, renal failure, violence, liver disease, and cardiovascular disease.
The debate on initiating ARV (antiretrovirals) at a higher CD4 count continued at CROI 2009. While not specifically addressed in presentations, it was noted that both age and starting ARV at less than 500 CD4s negatively impacted survival.28 Another group noted that age impacts the beneficial effects seen when HAART is initiated during primary HIV infection.29 Two groups presented evidence demonstrating altered immunological responses associated with age and HIV infection, independently, as measured by IL-7 responsiveness of memory CD4 cells in poster #31530 and T-cell activation in poster #407.31 These findings could inform future research designed to determine if age-specific treatment recommendations would improve outcomes for older HIV-positive individuals.
Dementia and milder degrees of cognitive impairment have obvious implications for older individuals, given the strong predisposition for dementia associated with age in seronegative populations. Although dementia affects less that 1% of HIV-negative individuals younger than sixty, nearly one-half of HIV patients in this age group can expect to experience cognitive impairment. At the 16th CROI, investigators from the CHARTER study evaluating over 1,000 individuals confirmed cognitive impairment in nearly 50% of enrollees (the mean age of the CHARTER cohort is only 43.2 years).32 Despite optimism that HAART would eradicate cognitive impairment, this group confirmed that the prevalence rates have not changed with HAART. Specifically, they note rates of mild, moderate, and severe impairment in the CHARTER that are strikingly similar to past University of California?San Diego HIV cohorts evaluated before antiretroviral medications were available. They further note that co-morbidity frequently confounds cognitive diagnoses. Since many of these confounds are modifiable, there is hope that future work may identify treatment options for individuals with impairment.
Perhaps one of the first studies to report on cognition in patients over 60 years of age, the Neurosigma study from France reported that half of subjects over 60 had neurocognitive impairment despite sustained response to antiretroviral therapy.33 As with the CHARTER group, co-morbidities (other diseases) were common in these impaired subjects, including diabetes (27%), hypertension (49%), and dyslipidemia (43%). This study and the CHARTER findings confirm previous work published from the Hawaii Aging with HIV Cohort, identifying metabolic disturbances in HIV as a correlate to cognitive impairment, providing a possible framework for intervention trials in the era of HAART.34 The CHARTER group also identified a risk for neuropathy associated with diabetes and age; the latter was also noted in resource-limited settings.35-37
The presence of co-morbidities may partially explain the puzzling report that the presence of HIV brain pathology at autopsy does not correlate to pre-death cognitive impairment, based on specimens in the National NeuroAIDS Tissue Consortium.38 Despite this phenomenon, HIV brain pathology remains frequently identified at autopsy and correlates to CD4 nadir count and plasma HIV RNA. More work is needed to clarify clinical-pathological correlations, an area of great importance to informing treatment opportunities.
Two papers are particularly noteworthy in relation to aging. Ances and colleagues evaluated cerebral blood flow within the visual cortex of HIV compared to non-HIV cases, noting that both age and HIV factors influence cerebral blood flow.39 In their models, the slope of change in cerebral blood flow by age is similar for HIV cases and HIV-negative controls, but HIV appears to add 10-15 years, displacing the slope to the right. Stated in a different way, their findings suggest that cerebral blood flow in HIV-positive individuals appears similar to that of HIV-negative individuals who are 10-15 years older. This finding, if confirmed, would add credence to a concern for accelerated brain aging in HIV. A second paper by Kallianpur and colleagues identified an interaction effect between CD4 nadir, a factor shown in several cohorts to relate to dementia, and the presence of an apolipoprotein e4 allele, a marker known to be associated with Alzheimer's disease.40 This paper and another note a relationship between posterior corpus callosum (the part of the brain which connects the left and right hemispheres) volume and cognitive impairment, a relationship that was not described in the pre-HAART era.40, 41 These findings suggest a possible change in phenotype of cognitive impairment in HIV and may suggest a risk for neurodegenerative processes.
One need look no further than a typical HIV clinic in the United States to recognize the graying of the HIV population. However, we will have to look beyond the 16th CROI to develop tools specific to this aging population, since many of the age-related presentations at this conference do not successfully transition from correlations of detrimental outcomes in aging to mechanism-related discovery of modifiable targets. This finding likely exposes the infancy of HIV-aging research and uncovers a need to move beyond the recognition that aging detrimentally impacts a broad and diverse set of outcomes, to determining precise underlying mechanisms whereby aging exerts its impact.
The mandate is clear. The unprecedented successes of HIV treatments and the incessant process of aging have had the inevitable and welcome result of HIV-infected populations who are now in their seventh, and older, decade of life. Without better information regarding the potential interactions between aging and HIV to inform treatment options, clinicians will have to approach older patients with inadequate tools. Aging-HIV research must transition from confirmatory observations of detrimental outcomes to meaningful, informative, mechanism-based reports that will offer researchers and clinicians treatment options aimed to improve these outcomes. (Referenced footnotes available online)
Victor Valcour, M.D. is an adjunct clinical instructor at the Memory and Aging Center at the University of California, San Francisco; Associate Professor of Geriatric Medicine at the University of Hawaii, Manoa; and Director of the Office of Neurology and Aging Research (ONAR), which is part of the Hawaii AIDS Clinical Research Program (HACRP) at the Pacific Center for AIDS Research in Honolulu. Reprinted with permission from www.natap.org.
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