Advances in HIV treatment uncover a new issue: Aging

Thirty years ago, HIV infection was considered a death sentence. But now, because of extensive scientific research and the development of antiretroviral therapy, HIV can be considered a chronic condition, and most people with the disease are otherwise living fairly normal lives.

However, because those with HIV are living longer, they face the issues that often arise with aging, which is a new complication. There is uncertainty about how HIV and aging co-exist.

“Early in the AIDS epidemic, the thought of these patients aging never really crossed my mind,” Joel Gallant, MD, MPH, chair of the HIV Medicine Association (HIVMA), told Infectious Disease News. “We were so overwhelmed by early mortality. It would have seemed like a luxury to have to deal with complications of aging. It was hard to imagine anything different than what we were experiencing at the time.”

For Amy Justice, MD, PhD, professor of medicine at Yale School of Medicine and section chief of general medicine, VA Connecticut, the drastic transformation of HIV from a death sentence to a chronic condition is the No. 1 miracle of medicine she has witnessed throughout her career.

Joel Gallant, MD, MPH, chair of the HIV Medicine Association, said there is uncertainty about how HIV and aging interact.

Joel Gallant, MD, MPH, chair
of the HIV Medicine Association,
said there is uncertainty about
how HIV and aging interact.

Photo courtesy of Gallant J

“Nothing compares to the breakthroughs that we’ve had with HIV,” Justice told Infectious Disease News. “One of the things that is interesting about HIV is that it encapsulates a lot of modern issues in medicine. We needed a scientific breakthrough to treat this virus. Now that we have it, we need to figure out what to do with our success.”

Infectious Disease News spoke with several experts about how the issues associated with aging affect patients with HIV and whether HIV makes the aging process more complicated compared with the general population.

Longer life expectancy

In a recent study, researchers for the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) found that life expectancy for patients aged at least 20 years on ART increased from 36.1 years in 2000-2002 to 51.4 years in 2006-2007. According to the report in PLoS One, a 20-year-old patient with HIV who is on ART, who had a CD4 count of 350 cells/mm3 or higher at presentation, is now expected to live into the early 70s, which is the same life expectancy as someone without HIV.

According to the CDC, an estimated 1.1 million people in the United States are living with HIV, and those aged at least 55 years accounted for 19% of that population. Projections suggest that half of the patients with HIV in the United States will be 50 or older within the next 5 years, Justice said. Among older adults with HIV, there are two unique groups: those who were recently diagnosed with HIV, and those who have been HIV-positive since the 1980s and early ’90s.

Gallant said the latter is the more concerning of the groups, as they have received many toxic drugs over the years and have experienced complications associated with those regimens. They also have experienced complications resulting from having had low CD4 cell counts and uncontrolled HIV infection for many years.

“In that group, I see a lot of frailty and what appears to be premature complications of aging, such as loss of bone density, cognitive issues and earlier coronary artery disease,” Gallant said. “I’m more optimistic about recently 
diagnosed patients. My prediction is that people starting ART today, especially at early stages of infection, will not face the same problems as the long-term survivors.”

Comorbidities and concern

The issues surrounding HIV and aging are plentiful. To start, aging adults, in general, have a higher risk for many comorbidities, such as hypertension, diabetes, heart disease and certain cancers. But aging adults with HIV have an even higher risk of developing some of these diseases.

According to Justice, after controlling for all established risk factors, including those in the Framingham risk index, renal disease, anemia and hepatitis C coinfection, aging adults with HIV are at higher risk for cardiovascular disease compared with similarly aged adults without HIV.

“It’s about a 50% increased risk,” Justice said. “The increased risk for CV disease in people with diabetes is roughly similar.”

In addition, Justice said, aging adults with HIV have an increased risk for virus-associated cancers, such as HPV-related anal cancer, even after adjusting for risk behavior. HIV is also associated with an increased risk for lung cancer in these patients, Justice said, even after controlling for smoking. Another comorbidity that appears to be more prevalent among adults with HIV is osteoporosis and risk for fracture. However, it is unknown whether risk of fragility fractures is due to other conditions, medications or behaviors — such as smoking, alcohol use or use of proton pump inhibitors — or if it is innate to HIV.

Aside from these comorbidities, the immune systems of aging adults do not work as well, which is especially an issue in those with HIV.

“Aging people with HIV may not respond as well to ART,” Kelly Gebo, MD, MPH, associate professor of medicine at The Johns Hopkins University School of Medicine, told Infectious Disease News. “They may achieve viral suppression, but their CD4 counts may not increase as acutely as a younger person’s would. Older people, in general, have immunosenescence. Their immune systems don’t work as well, which is why they often get pneumonia and urinary tract infections and shingles. If you add HIV immunosuppression on top of that, it’s a big problem.”

With the comorbidities, many other medications are added to the mix, which raises the issue of polypharmacy and drug-drug interactions. One of the most common drug-drug interactions is that of lipid-lowering agents and protease inhibitors, Gebo said. Other medications that potentially interact with ART are benzodiazepines and pain medications.

General aging effects

The issue as adults age is not just that they accumulate diseases, according to Kevin High, MD, professor of medicine and chief of infectious diseases at Wake Forest University School of Medicine.

“As people age, their overall functional status goes down,” High told Infectious Disease News. “They are less likely to be physically independent and more likely to be cognitively impaired. Add on top of that the poor social support structures and other issues that typically plague people with HIV, such as substance abuse and mental health issues, which all become a bigger problem as you become more functionally impaired.”

Aging patients also have a higher risk for anxiety and isolation, which is further complicated by HIV, according to Michael Horberg, MD, MAS, executive director of research at Mid-Atlantic Permanente Research Institute. But medications used to treat depression and anxiety are more difficult to use in the aging population because of adverse effects. In addition, the risks for Alzheimer’s disease and dementia also are increased as people age, but this also is an issue with untreated HIV, he said.

Michael Horberg

Michael Horberg

“All of these things come together to create the perfect storm,” Horberg told Infectious Disease News.

There is a debate about whether patients with HIV experience “premature” aging, meaning that the physical comorbidities associated with aging, such as cardiovascular disease or diabetes, occur earlier in these patients due to HIV, even in those with well-controlled disease. Some would suggest that the increased incidence of these diseases at an earlier age among those with HIV is a result of the HIV infection, which causes higher levels of inflammation and immune activation. Others suggest that in studies controlling for age, there is no dramatic difference in the median age at which these diseases occur among people with HIV compared with the general population.

Gallant said there also are vast differences between untreated patients and well-treated patients in terms of complications as they age, but there is debate as to the differences between well-controlled patients and those who are HIV-negative. Justice said early studies suggest that even patients with virologic control have an increased risk for cardiovascular events.

Thinking like a PCP

Most aging adults receive general care from a primary care physician, who is the first medical point-of-contact. The PCP coordinates the care for these adults, monitoring them for diseases of aging and general health. Although these PCPs have the capability to treat patients with HIV, their knowledge of HIV and its treatment and complications is often limited.

“The HIV clinician, on the other hand, is initially more concerned with treating the HIV, increasing the CD4 count and controlling the virus,” Horberg said. “But with our aging patients, HIV clinicians also have to think like a PCP and start thinking about the other comorbidities they might not worry about in younger patients.”

This means expanding their thinking and differential diagnoses to not only consider HIV-related problems, but also other potential comorbidities that aging patients have, he said. The HIV specialist is the doctor with whom the patient has the most significant relationship, and because these specialists are most often also certified in internal medicine or family practice, they are able to handle these issues. In some cases, patients may need to be comanaged, Justice said, requiring excellent communication among providers.

Gallant said there are different models to primary care, and this one, in which the HIV specialist also serves as the PCP, has historically been the typical one for patients with HIV.

“It used to be that HIV was essentially the only medical problem these patients had,” Gallant said. “The HIV expert was the patient’s PCP because the HIV dwarfed everything else. These days, in a well-managed patient, HIV may be the least of their problems.”

Guidelines for care

Now, it is not uncommon for patients to be managed by PCPs and only visit with the HIV specialist once or twice a year. However, Gallant said there are many patients, especially in rural areas, who are taken care of only by generalists who have no HIV expertise, which can result in adverse outcomes.

The Infectious Diseases Society of America and HIVMA responded to the primary care concern last year by publishing updated guidelines in Clinical Infectious Diseases that were meant to educate HIV experts on the primary care management of patients with HIV.

Amy Justice

Amy Justice

The guidelines recommend screening for diabetes, osteoporosis and colon cancer, and they also recommend vaccinations against pneumococcal infection, influenza, varicella and hepatitis A and B. There also are recommendations for STD screening, including annual screening for trichomoniasis in women and yearly screening for gonorrhea and chlamydia for those at risk.

Physicians also are urged to consistently discuss sexual history and risky behaviors with their patients, to determine how patients are coping and whether they have a sufficient support system. The guidelines also encourage physicians to screen for other mental health issues.

“The idea of these guidelines is not to teach PCPs how to treat HIV, it’s to guide HIV physicians in the management of primary care issues in addition to monitoring viral load and CD4 counts,” Gallant said.

Besides the standard tests for illnesses, High said these patients also should undergo functional assessments, which are a critical part of aging research. Functional assessments include a battery of tests that measure balance and walking speed, among other things.

“With these tests, you can tell a lot about a person’s physical reserve beyond counting the number of deficits they have,” High said. “Walking speed at every age is a predictor of mortality, even after controlling for underlying diseases, medications, race, age and smoking. We have been trying to integrate this more into research on HIV and aging.”

Heterogeneous population

In general, the concern with HIV and aging lies with those who have already lived with their HIV infection for many years, as Gallant said, but older adults also are more commonly being diagnosed with new infections.

“Many older people do not realize that they are putting themselves at risk,” Gebo said. “They may have unprotected sex because they don’t perceive themselves or their partners as being at risk. This especially applies to older women who often don’t use condoms during sex because there is no pregnancy risk.”

High said, until recently, all of the data have suggested that as folks with HIV age, they are more socially isolated and often become dissociated from their families. However, data from a recent study suggested that older patients with HIV experience less stress than younger people with HIV.

He said this is a cohort effect, since the population of patients with HIV older than 50 years is changing to include more recently diagnosed patients.

“This cohort is no longer only including people who lived through the original epidemic, watched many friends die of AIDS and have received multiple treatment over the years,” High said. “It has expanded to include people who have been diagnosed later and have received effective therapy with no adverse effects.”

Adults diagnosed later in life are often more socially connected than young patients, who may be more likely to be experiencing problems with substance abuse, homelessness, isolation from their families, mental health or gender uncertainty, High said.

“These are two different populations because of life experiences and treatment experiences,” High said. “Cohort effects are a big issue in HIV and aging research. All people older than 50 with HIV are not the same.”
— by Emily Shafer

References:

Aberg J. Clin Infect Dis. 2013;doi:10.1093/cid/cit665.
Samji H. PLoS One. 2013;doi:10.1371/journal.pone.0081355.

For more information:

Joel Gallant, MD, MPH, can be reached at jgallant@southwestcare.org.
Kelly Gebo, MD, MPH, can be reached at kgebo@jhmi.edu.
Kevin High, MD, can be reached at khigh@wakehealth.edu.
Michael Horberg, MD, MAS, can be reached at michael.horberg@kp.org.
Amy Justice, MD, PhD, can be reached at amy.justice2@va.gov.

Disclosure: Gallant receives research support from Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Merck & Co, Sangamo BioSciences and Vertex Pharmaceuticals, and is a consultant for Gilead, Janssen Therapeutics and Merck & Co. Gebo, High, Horberg and Justice report no relevant financial disclosures.

What are the factors that contribute to the higher prevalence of age-related conditions among people with HIV?

POINT

People with HIV have higher levels of immune activation and inflammation, along with other risk factors.

I believe that the concept of "premature aging" in HIV is a misnomer. There is a significant debate in the field as to whether patients demonstrate premature aging. In my opinion, such patients do not exhibit premature aging per se, but rather exhibit a number of conditions often associated with aging, including cardiovascular disease, neurocognitive disorders and malignancies. This distinction is important. In contrast to genetic disorders associated with premature aging and a clear phenotype, patients with HIV make up a much more heterogeneous group. Though studies have shown, for example, that patients with HIV demonstrate coronary artery calcium at rates seen among patients 15 years older, such patients may exhibit increased traditional risk factors that must be accounted for. What are the mechanisms of these aging-associated phenomena in patients with HIV? One mechanism may relate to poorly controlled viremia. However, we often see such effects even among well-controlled patients on ART, and even among elite controllers who demonstrate excessive cardiovascular disease without significant viremia. A number of other potential mechanisms include early immune dysfunction, as assessed by nadir CD4, which has been shown to relate to cardiovascular disease events in patients with HIV. Other possibilities include ART itself, which may promote dyslipidemia and hyperglycemia, as well as body composition changes including abdominal fat accumulation, which may mimic those seen in older age. In addition, certain ART agents may contribute to mitochondrial dysfunction and metabolic dysregulation in key aging-related pathways. Finally, immune activation may play a role, as excessive immune activation is seen among patients with HIV, even with well-controlled viremia, potentially related to HIV infection of gut-associated lymphoid tissue, leaky gut and increased microbial translocation, as well as coinfection with cytomegalovirus or hepatitis. Excess immune activation has been shown by our group and others to occur among patients with HIV. Moreover, specific complications, including noncalcified, high-risk morphology, coronary plaque, have been related to excessive immune activation in patients with HIV, but is not related to increased traditional risk factors. In addition, arterial inflammation, as assessed by FDG-PET, has also been associated with immune activation, again independent of traditional risk. Together, these factors — early immune dysfunction, excessive traditional risk and immune activation — may contribute to an aging phenotype. Whether such heterogeneous processes can be grouped together and labeled as "premature aging" is not at all clear, but it is clear that such effects may contribute to excessive cardiovascular disease and other complications at an earlier age among patients with HIV.

Steven Grinspoon, MD, is the clinical director at the Neuroendocrine Clinical Center at Massachusetts General Hospital. He is also a professor of medicine at Harvard Medical School. Disclosures: Grinspoon consulted for Aileron, Navidea, BMS Astra Zeneca. He received research funds from BMS, Amgen, Serono, Gilead.

COUNTER

People with HIV have more risk factors, including smoking and stress.

When we say "premature aging" in HIV, you can envision a few different things. Is there a heightened risk for diseases typically associated with aging at a lower age? Or is there some type of accelerated pathogenesis that is actually increasing their risk for these diseases? We have to be clear because when patients hear this, they become upset and may believe they are going to die early. That is not accurate at all. There is clearly an elevated risk for cardiovascular disease, renal disease and other diseases that are typically associated with aging among people with HIV. However, people with HIV have an abundance of traditional risk factors for these conditions compared to those without HIV. For example, smoking is epidemic among people with HIV and many do drugs, like cocaine or marijuana, or drink excessively. Certainly, studies try to control for these factors when comparing individuals with and without HIV. But the operative word here is "try." Confounders extend beyond a handful of the most obvious and measurable risks. HIV is a disease state that leads to changes both physically and mentally and a good body of evidence often misses links between inflammation and stress. Many aging people with HIV have lived very traumatic lives. I’m certain that if one studies people with posttraumatic stress disorder, one would find that they have a higher prevalence of age-related conditions compared to people without PTSD. I’m not saying that this explains it all and that these issues are all related to smoking and stress. There are biological processes in people with HIV that could explain the higher than expected levels of chronic diseases associated with aging. But I want to make sure that we put things in perspective. Additionally, most of the work that has been done in this area has been among people who have been infected for a long time and started ART after their CD4 counts declined to around 200 cells/mcL or even lower. This is a historic population that may become obsolete as we treat people earlier. The influence of severe immunodeficiency — years of it prior to initiation of ART — on the creation of inflammatory processes and organ disease needs to be appreciated. Lastly, we must understand that not all people living with HIV are the top dots on the box and whisker graphs we see at conferences or in papers. Many with HIV infection, especially controlled HIV infection, do not have detectable elevations in the markers we use to measure inflammation. I think the majority of people with controlled HIV are not living in an inflammatory storm and are going to be fine.

David Alain Wohl, MD, is an associate professor of medicine in the Division of Infectious Diseases, University of North Carolina. Disclosure: Wohl serves on the advisory board for Gilead and Janssen and his university receives research funding from Gilead, Merck and Viiv.