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Aging with HIV - Lessons from CROI 2009
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Victor Valcour MD
Memory and Aging Center, UCSF
Hawaii AIDS Clinical Research Program, U. Hawaii
"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......much 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
Some of the worlds 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 US 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 from researchers in Senegal1.
In the US, the prevalence of HIV in people who are over sixty-five years of age has increased more than ten-fold in the past decade2. In some regions, more than half of HIV patients are currently over 50 years 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 near 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, brought quickly to light in large studies, such as that presented in abstract #1453. With the occasional outlier (two paper suggest a signal that prostate cancer rates may be lower that 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 concerning 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.
Cardiovascular Disease
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 study6; but promising data were noted from the California Kaiser Permanente database where rates of MI decreased in recent years and are now similar to background rates, possibly owing to aggressive management of risk factors7. Risk for cardiovascular outcomes and intermediate markers of cardiovascular change can be predicted with the Framingham risk scores8; however, HIV-specific changes (not necessarily associated with traditional risk factors) are also noted. One study identified changes in endothelium-dependent vasodilatation in treatment naïve HIV patients to the extent that would be anticipated in HIV-negative controls who were 25 years older, suggesting vascular changes akin to accelerated aging9.
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 diabetes3, 10. The relationship between abacavir use and cardiovascular outcomes was discussed in several papers with some11-13 but not all14 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 topic15.
Osteoporosis and Renal Diseases
Osteoporosis is largely a disease associated with age in HIV-negative populations, but has also been demonstrated to be more frequent with HIV16, 17 (from Jules: 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 men18. As with other complications, the presence and pattern of osteoporosis may suggest age-related changes19, such as its association with increased markers of t-cell senescence20.
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 plasma viremia21. Age was also shown to increase risk for renal tubular disease in association with tenofovir use22, 23. New advances in medications that may eventually replace ritonavir as a boosting agent were presented and are thought to have improved gastro-intestinal profiles compared to ritonavir, a factors likely to greatly impact quality of life for HIV elders24, 25.
Malignancies and mortality
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+ 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, Kidney, lung and 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 well5.
Although aging is associated with increased mortality, modifiable risk factors, such as smoking, also predict morbidity and mortality, providing opportunities to potentially decrease risk10, 26. These studies and others mark the need to address non-AIDS mortality risk in order to reduce rates in HIV patients. An evaluation of thirteen cohort studies identified non-AIDS-related causes of death to be more frequent than AIDS deaths27. Some leading causes include non-AIDS malignancies, renal failure, non-AIDS infections, violence, liver disease, and cardiovascular disease.
Immunology
The debate on initiating ARV 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 CD4<500 negatively impacted survival28. Another group noted that age impacts the beneficial effects seen when HAART is initiated during primary HIV infection29. 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 # 40731. These findings could inform future research designed to determine if age-specific treatment recommendations would improve outcomes for older HIV-infected individuals.
Cognitive Impairment
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 1000 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 therapy33. As with the CHARTER group, co-morbidities 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 HAART34. The CHARTER group also identified a risk for neuropathy associated with diabetes and age, the later was also noted in resource-limited settings35-37.
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 Consortium38. 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 flow39. 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, there findings suggests that cerebral blood flow in HIV-infected 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 _4 allele, a marker known to be associated with Alzheimer's disease40. This paper and another note a relationship between posterior corpus callosum volume and cognitive impairment, a relationship that was not described in the pre-HAART era40, 41. These finding suggest a possible change in phenotype of cognitive impairment in HIV and may suggest a risk for neurodegenerative processes.
Closing Remarks
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 much 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.
This work should not be considered solely an HIV issue, as papers presented at the 16th CROI suggest that HIV may be a model of accelerated aging. Thus, much of the information gained is likely to impact older Americans regardless of serostatus. For example, new knowledge relating to immune system senescence (and, perhaps, accelerated senescence with HIV) will largely inform the aging process in general and aging-related susceptibility to poor outcomes in non-HIV infections. Likewise, uncovering mechanisms by which inflammation may accelerate atherosclerosis or neurodegeneration may have broad non-HIV implications. In other words, findings from the 16th CROI lend credence to HIV as a model of accelerated aging, suggestive that findings from this population may have broad applicability.
The mandate is clear. The unprecedented successes of HIV treatments and the incessant process of aging have had the inevitable result and welcomed 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 need 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.
Abstracts cited
1. Sow P, Debaudrap P, Etard J, et al. Abstract # 596a: AIDS as a chronic disease in Africa: a 10-year follow-up of patients under ART in Senegal. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
2. Stoff DM, Khalsa JH, Monjan A, Portegies P. Introduction: HIV/AIDS and Aging. Aids. Jan 1 2004;18 Suppl 1:S1-2.
3. Smith C. Abstract #145: Association between modifiable and non-modifiable risk factors and specific causes of death in the HAART era: The Data Collection of Adverse Eventes of Anti-HIV Drugs study (D:A:D). Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
4. Silverberg M, Leyden W, Chao C, et al. Abstract #30: Infection-related non-AIDS-defining cancer risk in HIV-infected and uninfected persons. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
5. Grulich A. Abstract # 178: HIV, immune deficiency, and malignancy. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
6. Grunfeld C, Delaney J, Wanke C, et al. Abstract # 146: HIV infection is an independent risk factor for atherosclerosis similar in madnitude to traditional cardiovascular disease risk factors. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
7. Hurley L, Leyden W, Xu L, et al. Abstract # 710: Updated surveillance of cardiovascular event rates among HIV-infected Californians, 1996 to 2008. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
8. Falcone L, Mangili A, Skinner S, Polak J, Wanke C. Abstract #726: Framingham risk score and markers of early atherosclerosis in a cohort of HIV-infected subjects. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
9. Van Guilder G, Stauffer B, Mestek M, et al. Abstract #731: HIV-1 infection is associated with accelerated vascular aging. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
10. Morcroft A, Reiss P, Gasoprpwslo K, et al. Abstract # 707: Serious fatal and non-fatal AIDS-defining illnesses in Europe. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
11. Lang S, Mary-Krause M, Cotte L, et al. Abstract # 43 LB: Impact of specific NRTI and PI exposure on risk of myocardial infarction: a case-control study nested within FHDH ANRS CO4. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
12. Lundgren J, Reiss P, Worm S, et al. Abstract 44LB: Risk of myocardial infarction with exposure to specific ARV from the PI, NNRTI, and NRTI drug classes: the D:A:D study. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
13. Hsue P, Wu Y, Schnell A, et al. Abstract # 723: Association of abacavir and HIV disease factors with endothelial function in patients on long-term suppressive ART. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
14. Benson C, Ribaudo H, Zheng E, et al. Abstract #721: No association of abacavir use with risk of myocardial infarction or severe cardiovascular disease events: results from ACTG A5001. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
15. Reiss P. Abstract # 152: Abacavir and cardiovascular risk. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
16. Short C, Shaw S, Fisher M, Walker-Bone K, Gileece Y. Abstract# 753: Evaluation of peripheral dual energy x-ray absortiometry as a tool for identification of low bone mineral density in HIV-infected men. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
17. Sharma A, Cohen H, Freeman R, Santoro N, Schoenbaum E. Abstract # 757: Prospective evaluation of bone mineral density among middle-ages HIV-infected women. Paper presented at: Abstract #754: Gender and gonadal function; February 2009; Montreal, CA.
18. Guaraldi G, Zona S, Vescini G, et al. Abstract #754: Gender and gonadal function differences in the prevalence of bone mass reduction. Paper presented at: Abstract #754: Gender and gonadal function; February 2009; Montreal, CA.
19. Falutz J, Rosenthall L. Abstract # 755: Preferential bone demineralization at the hip in treated HIV+ males: another example of premature aging? Paper presented at: Abstract #754: Gender and gonadal function; February 2009; Montreal, CA.
20. Gazzola L, Cicconi P, Comi L, et al. Abstract #752: Osteopenia and osteoporosis in HIV-infected patients are associated with reduced frequency of central memory CD8+ CD127+ T cells. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
21. Choi A, Shlipak M, Hunt P, Martin J, Deeks S. Abstract # 38: HIV-infected persons continue to lose kidney function despite successful ART. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
22. Novoa S, Labarga P, Soriano V, et al. Abstract # 37: Predictors of kidney tubulopathy in HIV patients treated with tenofovir: a pharmacogenetic study. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
23. Fux C, Opravil M, Cavassini M, et al. Abstract # 743: Tenofavir and PI use are associated with an increased prevalence of proximal renal tubular dysfunction in the Swiss HIV Cohort Study. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
24. Mathias A, Lee M, Callebaut C, et al. Abstract # 40: GS-9350: a pharmacoenhancer without anti-HIV activity. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
25. Gulnik S, Eissenstat M, Afonina E, et al. Abstract #41: Preclinical and early clinical evaluation of SPI-452, a new pharmacokinetic enhancer. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
26. Modrich L, Scherzer R, Zolopa A, et al. Abstract # 706: Factors associated with mortalit in the study of fat redistribution and metabolic change in HIV infection. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
27. Gill J, May M, Lewden C, et al. Abstract # 708: Causes of death in patients treated with ART, 1996 to 2006: collaborative analysis of 13 cohort studies. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
28. Kitahata M, Gange S, Moore R. Abstract # 71: Initiating rather than deferring HAART at a CD4 count >500 cells/mm3 is associated with improved survival. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
29. Steingrover T, Jurriaans S, Grijsen M, de Wolf F, Lange J, Prins J. Abstract #70b-LB: Transient HAART during PHI prolongs the total time off HAART in patients presenting with PHI: Data from the Dutch PRIMO SHM Cohort. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
30. Kalinowska M, Bazdar D, Lederman M, Sieg S. Abstract # 315: Both age and HIV infection are associated with diminished CD4 t-cell responsiveness to IL-7. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
31. Sankaran S, MacAl M, Grishina I, et al. Abstract # 407: Effects of aging on HIV-1 pathogenesis. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
32. Heaton R, Franklin D, Clifford D, et al. Abstract #154: HIV-associated neurocognitive impairment remains prevalent in the era of combination ART: The CHARTER Study. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
33. Dulioust A, Lerolle N, Dolphin P, et al. Abstract # 459: High frequency of neurocognitive disorders in older HIV-infected patients despite a sustained virological and immunological response on cART: The Sigma Study. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
34. Valcour V, Shikuma CM, Shiramizu BT, et al. Diabetes, Insulin Resistance, and Dementia Among HIV-1-Infected Patients. J Acquir Immune Defic Syndr. Jan 1 2005;38(1):31-36.
35. Cherry C, Affandi J, Yunihastuti E, et al. Abstract # 161: Predicting neuropathy risk before stavudine prescriptions: an algorithm for minimizing neurotoxicity in resource-limited settings. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
36. Ellis R, Rosario D, Clifford D, et al. Abstract # 461: Persisting high prevalence of HIV distal sensory peripheral neuropathy in the era of combination ART: correlates in the CHARTER study. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
37. Ances B, Rosario D, Vaida F, et al. Abstract #463: metabolic syndrome components as risk factors for distal sensory polyneuropathy. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
38. Everall I, Lassaretto D, Letendre S, et al. Abstract # 155: The neuro-epidemiology of HIV in the US in the era of ART, from the National NeuroAIDS Tissue Consortium. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
39. Ances B, Yeh J, Vaida F, et al. Abstract # 157: Additive effects of aging and HIV serostatus on cerebral blood flow. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
40. Kallianpur K, McMurtray A, Valcour V, Shiramizu B, Shikuma C. Abstract #460: Reduced region-specific corpus collosum volumes correlate with low nadir CD4 and decreased cognition in HIV-infected carriers of the Apo E4 allele. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February 2009; Montreal, CA.
41. Russell T, Sampat M, Tate D, et al. Abstract # 481: Gross and regional morphometry of the midsagital corpus collosal areas in HIV-infected patients on stable HAART. Paper presented at: 16th Conference on Retroviruses and Opportunistic Infections; February, CA; Montreal, CA.
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