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NEW FRONTIERS - 1st International Workshop on HIV and Aging

Baltimore, Maryland / October 4-5, 2010

Within the next 5 to 7 years, it is expected that the proportion of patients infected with HIV who are older than age 50 will surpass the proportion who are younger in several industrialized countries, including Canada and the US. This change in HIV demographics is having a profound effect on strategies for management due to the adverse impact of long-term infection on a broad array of organ systems. Rough estimates suggest that the degree of acceleration in the aging process correlates with the duration of infection. By many measures, the relative increase of aging is several-fold greater in those with HIV when compared to those without.

Frailty Risk

In raw terms, the odds ratio of demonstrating a frailty phenotype based on standardized measures of unintentional weight loss, exhaustion, slow walking speed, and low physical activity was 3.4-fold greater among older HIV patients relative to age-matched controls without HIV. This was recorded in individuals whose HIV infection had been present less than 4 years, according to data generated by the Multicenter AIDS Cohort Study (MACS). For those infected with HIV for more than 4 years, the odds ratio climbed to 13-fold and reached nearly 15-fold for those with infection for greater than 8 years.

“The risk of frailty in a 55-year-old male with HIV for less than 4 years was equivalent to a 65-year-old without HIV,” reported Dr. Joseph Margolick, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, principal investigator of MACS, one of the longest running studies in HIV. Dr. Margolick further reported that the risk of frailty increased at a much higher rate in HIV patients who were untreated, relative to those on therapy, and in those with a low CD4+ cell count relative to those with a higher count. Indeed, the correlation of increasing frailty with lower CD4+ cell count was described as non-linear, so that frailty rates climbed more steeply as CD4+ cell count fell.

HIV-accelerated Aging Present in Patients with Controlled Disease

The fact that untreated patients are at the greatest risk of accelerated aging does not lessen the concern that this process persists even when infection is controlled. Dr. Margolick suggested that the systemic changes consistent with accelerated aging, ranging from lower levels of cerebral blood flow to impaired muscle strength, are observed in essentially every organ system. He cited a study which found resting energy expenditure to be greater in patients with HIV on highly active antiretroviral therapy (HAART) relative to matched controls even after multivariate modelling (Fitch et al. Metabolism 2009;58:608-15). Dr. Margolick suggested that HIV infection, probably by driving persistent inflammation, exerts an effect that is fundamentally detrimental across body systems.

In individuals without HIV, markers of inflammation have already been isolated as predictors of key events of aging, including disability and death, according to Dr. Luigi Ferrucci, Director of Longitudinal Studies, National Institute on Aging, Baltimore. He specifically cited interleukin-6 as one of the strongest predictors of age-related events. Parallel studies in patients with HIV suggest that same kinds of inflammatory-related aging processes are at work, but the evidence indicates that they start at a much younger age and advance faster.

“Very clearly, the changes we are seeing in the immune systems of patients with HIV correspond with those of much older individuals,” stated Dr. Alan Landay, Chair of Immunology and Microbiology, Rush University Medical Center, Chicago, Illinois. According to Dr. Landay, the term that is being used to characterize this process is “immunoaging.” He suggested to delegates that the low levels of HIV replication that occur even in those on optimal HIV therapies appear to drive an inflammatory response that produces pathology across organ systems.

Organ Systems Not All Affected Equally in All Patients

In the specific areas of greatest concern, such as cardiovascular (CV) disease, neurocognitive decline, osteoporosis, renal dysfunction and generalized frailty, upregulation of inflammation keeps recurring as the primary cause. In many if not all of these cases, the presence of HIV appears to accelerate a pathology to which the patient is already susceptible. This may be an important premise for balancing risks. While diseases in each of these organ systems is increased in an HIV population overall—relative to a non-HIV-infected population—they are not evenly distributed in any individual. A treatment associated with accelerated risk of CV disease may still be the best therapy in an individual with a low baseline risk of CV pathology. Treating HIV early and effectively remains essential but the individual risk profile of the patient may define which treatments come first.

“The paradox of the need for early HIV treatment and the risks posed by specific antiretroviral drugs on organ toxicity continues,” commented Dr. Giovanni Guaraldi, Department of Clinical Infectious Diseases, University of Modena, Italy. As lead author, he presented a cross-sectional retrospective case control study that compared the prevalence of non-infected comorbidities in 2854 HIV patients on antiretroviral therapy to 8562 non-infected controls. Dr. Guaraldi reported that most major age-related diseases, such as diabetes mellitus, fractures, CV events and renal dysfunction, occurred about 10 years earlier in patients with HIV relative to controls, but baseline risk factors were important for predicting which of these diseases developed. Risks were not evenly distributed.

This last finding may be critical to the efforts to optimally suppress HIV, the first and essential goal of treatment, while minimizing the risk of the effects of HIV infection or its treatments on the events associated with accelerated aging. In this context, treatment must be individualized.

This trade-off in the context of osteoporosis was discussed in detail by Dr. Todd Brown, Division of Endocrinology and Metabolism, Johns Hopkins University, Baltimore. He concurred with other discussants that inflammation appears to be an important contributor to adverse changes in bone metabolism. However, fracture risk in patients with HIV, like those without HIV, is also strongly predicted by patient factors, such as low body weight and smoking. In terms of therapy, this baseline risk appears to be critical. Specifically, while Dr. Brown noted that there are now 5 randomized trials that have associated tenofovir with increased risk of osteoporotic fracture, it may be appropriate to avoid this otherwise effective antiretroviral agent only in those at a high baseline risk. “We recommend screening all HIV patients [for bone mineral density] who are 50 years old or older to identify those who are at risk,” Dr. Brown told delegates.

Similar strategies for early screening in order to individualize HIV therapy was advocated by other experts discussing other body systems. On the basis of screening, otherwise effective antiretroviral agents that are associated with adverse effects in specific systems at risk can be avoided, but as none of these agents are completely free of adverse effects, no regimen would be anticipated to uniformly avoid exacerbating the effects of aging across all patients.

“We need to be much more sophisticated about understanding these trade-offs in an aging population,” remarked Dr. Judith S. Currier, Associate Director, UCLA Center for Clinical AIDS Research and Education, Los Angeles, California. She indicated that relative risks of any given antiretroviral agent across a population will not be as relevant in clinical care as understanding the specific risks and benefits in the individual patient seeking an optimal regimen.

Summary

HIV accelerates aging. In rough estimates, the aging process in most organ systems is advanced by 10 years in individuals with HIV relative to those without HIV. However, the specific degree of acceleration for a specific organ system in an individual patient may be affected by a long list of variables, including the length of HIV infection, the lifetime nadir CD4+ cell count and non-HIV-related risk factors in particular. Clinically, the risk of accelerated aging, which now appears to be the greatest threat to a normal lifespan in those with HIV, suggests the need for rigorous and continuous risk assessment. Therapies can then be adjusted to match regimens with a risk profile specific to the individual patient. While persistent suppression of HIV remains the essential starting point of HIV treatment, there is strong evidence that therapies are not interchangeable for risk of accelerated aging in specific organ systems.