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AIDS 2014: Untangling HIV and Aging

As people with HIV live longer, issues of aging are gaining more attention from HIV/AIDS researchers, clinicians, and advocates. Although by no means a focus of AIDS 2014, HIV and aging-related illnesses did take center stage in a mid-week “bridging session” that featured an in-depth presentation on the intersection of HIV, HIV treatment, and aging.

Peter Reiss, co-principal investigator with the AGEhiv Cohort Study in Amsterdam, was tasked by session organizers to disentangle biological aging, the inflammatory effects of long-term HIV infection, and the adverse effects of antiretroviral therapy (ART). To this end, Reiss reported on his research team’s comparison of comorbidities—simultaneously ocurring illnesses and health conditions—in people with HIV vs their HIV-negative counterparts.

“Across the board, the prevalence of a wide range of comorbidities is higher in those with HIV,” Reiss shared. Many chronic diseases of aging, such as hypertension (high blood pressure) and chronic obstructive pulmonary disease (COPD, a disease of the lungs that makes breathing difficult), are more common in the study’s HIV-positive participants, even after adjusting for lifestyle factors and use of antiretrovirals.

“What we also found in this study,” Reiss added, “is that especially the prevalence of multimorbidities—people having three or more comorbidities at the same time—is strikingly higher, especially in those individuals who are 60 years or 65 years and older.”

Multiple factors likely contribute to these higher rates of comorbidity and multimorbidity in older people with HIV, including host-related factors (like lifestyle and genetics), ART toxicity, and the persistent immune dysregulation and chronic inflammation that accompanies even well-treated HIV disease.

Researchers with the AGEhiv study found that a number of factors are independently associated with having more comorbidities. Not surprisingly, Reiss noted, known risk factors such as age, smoking, family history of disease, and waist-to-hip ratio played an important role. While having HIV was not associated with greater comorbidities, the duration of immunodeficiency (having a CD4 cell count below 200 cells/mm3) was linked with increased risk. Markers of immune activation were also associated with higher number of comorbidities, as was longer duration of exposure to high-dose ritonavir, an antiretroviral drug that today is primarily taken at smaller doses to “boost” levels of other drugs.

“We can’t stress enough the importance of lifestyle-related factors—some of which we can obviously do something about,” Reiss emphasized. Citing a fairly recent study from Denmark, he observed that among HIV-positive people, life expectancy may be shortened more by smoking than by HIV. Reiss also pointed to data suggesting that smoking causes more harm to cardiovascular health among HIV-positive people over age 50 compared with their HIV-negative counterparts.

In terms of ART toxicities, Reiss continued, “We all know about the potential effects of protease inhibitors (some more than others) and possibly abacavir on the cardiovascular system, and we know about tenofovir and its effects on the kidney and bone.” Keeping tabs on the long-term effects of these drugs is critical for protecting an aging HIV-positive population, Reiss observed: “Of course, we have been using these drugs for quite a long time, but people will be using them for much longer, and we’ll have to follow what the effect of even more prolonged use of these agents is on these organ systems.”

That said, “Aging is by far the strongest risk factor for all of these conditions.” Normal aging is characterized by progressive loss of “physiological integrity,” Reiss explained, and this deterioration is the primary risk factor for such age-related illnesses as cancer, diabetes, and cardiovascular disease. But in the setting of HIV, are these age-related conditions accentuated—occurring more commonly in those with HIV, but at the same age—or also accelerated, meaning they are occurring at a younger age than in the HIV-negative population?

To close in on an answer, Reiss presented nine “hallmarks of biological aging” and cited studies showing how HIV disease and/or its treatment affects these conditions—for example, laboratory research indicating that certain antiretrovirals can induce cells to become prematurely “senescent” and no longer divide and replicate.“We need to keep an open mind that some of the drugs that we are using may affect these mechanisms [of aging],” Reiss stated, “although we know very little about what that would mean in different tissues of the body and what it would mean long term.”

In addition, even well-controlled HIV is associated with chronic inflammation, which in turn is linked with aging of the immune system and of the body’s other cells and tissues. “Clinically, this could promote the expression and the occurrence of chronic aging-associated comorbidity and frailty,” Reiss explained.

So, does HIV (and/or HIV treatment) influence comorbidity risk by affecting the biological mechanisms of aging? While some data lend support for this hypothesis, Reiss explained, much work remains before it can be confirmed or refuted. Reiss pointed out a need for reliable markers of biological age that could be employed in longitudinal clinical studies, and also noted that animal models could help to distinguish between the effects of HIV and the effects of antiretroviral treatment on aging-related conditions.

Indeed, the Co-Morbidity in Relation to AIDS (COBRA) study, based in Amsterdam and London, is currently striving to establish a connection between HIV and diseases of aging in both human cohorts and mouse models. The study launched approximately one year ago, Reiss said, and draws on the expertise of scientists in multiple fields above and beyond HIV and aging.

Besides the need for further research to inform long-term HIV treatment, there are two clear take-home messages from Reiss’s presentation. First, controllable lifestyle factors play a part in the aging process. We can’t alter a family history of heart disease, but we can stop smoking and manage body weight to reduce risk for aging-related health problems. Second, the link between increased risk for comorbidities and length of time below 200 CD4 cells/mm3 supports starting HIV treatment sooner rather than later—and highlights the need to support people in testing for HIV earlier, before CD4 cells decline to low levels.

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