Facing Old AIDS

Facing Old AIDS
A growing body of research shows age-related diseases for those with HIV
by Larry Buhl

The face of HIV, now in its early thirties, is getting old.

By 2015, the average age of an HIV patient in the United States will be fifty, according to the Centers for Disease Control and Prevention. The CDC also says that right now, a third of the nearly 1.2 million people living with HIV in the U.S. are over fifty years-old, and by 2020 half will be over fifty.

Even in sub-Saharan Africa, home to most of the world’s HIV-infected population, studies suggest 3 million people living with HIV are over fifty. Dr. Joel Negin of the University of Sydney in Australia told attendees at this year’s International AIDS Conference that by 2040 that number could reach 9 million.

Those figures are the best news the scientific community could hope for, short of a cure that eliminates HIV completely. An aging group of HIV-positive people means the medications and treatments are working in prolonging lives. But what’s not so clear is, once the lives are lengthened, how well can the body stand living with the virus (and the meds).

Until very recently there has been little data on the long-term effects of HIV, and the therapies to keep it in check, twenty, thirty or forty years after the initial infection. The research so far suggests HIV-positive people may suppress the virus only to succumb to diseases normally associated with old age—many years younger than they ordinarily would.

HIV survival and new health risks
For the first years that therapies like protease inhibitors and other antiretrovirals began helping people live longer with HIV, the bulk of the research and treatment was on the virus itself: How do the meds reduce the viral load and increase T cells? Now that it’s clear that the meds have made manageable what was an exclusively deadly disease, a growing field of research is exploring how the human body copes with the virus, even when it’s kept at undetectable levels. The results so far suggest that even when HIV is kept in check, it’s still doing damage, even if it isn’t clear why.

Two of the first wave of studies to look at the health effects of HIV-positive people as they age were described in the December 2011 issue of Clinical Infectious Diseases. An Italian study showed that HIV-positive people were more likely to have multiple health problems at an earlier age. In that same issue, a Swiss study showed that HIV-positive people, over time, had a higher rate of non-AIDS-related conditions including cardiovascular disease, cancer, bone loss, and diabetes.

The Italian study compared risk factors for non-infectious co-morbidities in a cohort of 2,854 HIV-positive adults receiving antiretroviral therapy (ART) at Modena University during 2002–2009, and 8,562 matched control subjects in an Italian general population database. Just under two-thirds were men, the average age was forty-six years, and HIV-positive patients had been on ART for an average of about ten years.

This case-control analysis looked at age-related non-infectious conditions including cardiovascular disease, hypertension (high blood pressure), diabetes, bone fractures, and kidney failure; because these conditions are not caused by infectious pathogens, they are not directly linked to immune function (CD4 T-cell count) and are considered non-AIDS related.

Researchers found that co-morbidity was significantly higher among HIV-positive patients compared with HIV-negative controls and that prevalence of hypertension, cardiovascular disease, diabetes, kidney failure and bone fractures among HIV-positive people in their forties was similar to that of HIV-negative control subjects in their fifties.

The study did not conclude why the bodies of people with HIV were in some ways, but not others, ten years “older” than people without HIV. The researchers did have a recommendation: an aggressive approach to the screening, diagnosis, and treatment of non-infectious co-morbidities as part of routine healthcare for HIV-infected patients. They added that their data suggest such screening in HIV-positive people should start as much as a decade earlier than in HIV-negative people.

The Swiss HIV Cohort Study assessed the influence of aging on the epidemiology of non-AIDS diseases. This large prospective observational cohort was established in 1988 and continues to enroll new participants. Researchers calculated the incidence of clinical events from January 2008, when a new non-AIDS-related morbidity questionnaire was introduced, through December 2010. There were 994 new non-AIDS events observed during the study period, including 201 cases of bacterial pneumonia, 123 trauma-associated fractures, 115 non-AIDS defining malignancies, seventy cases of diabetes, fifty-five heart attacks, and thirty-nine strokes. Based on these findings, the investigators concluded, non-AIDS diseases, particularly diabetes mellitus, cardiovascular disease, and osteoporosis, “become more important in care of HIV-infected persons and increase with older age.”

Since those studies were released, more research has concluded that the aging body with HIV does have more non-AIDS related problems.

The latest and largest study, co-led by Yale, the VA Healthcare System, and the North American Cohort Collaboration built on older indices that measured biomarkers for HIV such as CD4 cell count, HIV-1 RNA levels, and patient age in order to better predict mortality as patients with HIV age. Appearing in the Journal of Acquired Immune Deficiency Syndromes (JAIDS), the study shows that there have been reductions in AIDS-related deaths in regions where ART is easily accessible, but people with HIV infection continue to experience a higher rate of mortality due not just to HIV-related factors. Specifically, the authors say that chronic HIV infection appears to make people more vulnerable to aging-related organ system injury.

One study discussed at the 2013 CROI, underscored the risk of non-HIV related health problems for HIV-positive adults. Matthew Freiberg, MD, from the University of Pittsburgh, compared people who have sustained low viral loads to uninfected people, and found a significant increase in heart attack risk—nearly fifty percent higher—for HIV-infected people.

Freiberg’s data came from 84,459 participants from the Veterans Aging Cohort Study over a median follow-up period of 5.9 years, and he used a control group “that was as similar to HIV-infected people as possible so we saw that our results were due to HIV and not something else, such as smoking,” he said. His team found that 41.7 percent of the 871 myocardial infarctions occurred in the HIV-positive group.

Long-term survival, long term damage?
Long-term HIV survivors are not only finding themselves at risk of more age-related diseases than the average person, but they are also the focus of research that can help both experts on HIV and aging, as well as the patients themselves.

“It is clear that adults with HIV are developing some of the diseases we associate with very old people at a younger age,” says Dr. Steve Karpiak, senior director of research at AIDS Community Research Initiative of America (ACRIA).

Instead of using the term “co-morbidity” for long-term, aging people with HIV, researchers are using “multi-morbidity,” which stands for several serious health conditions that can’t be cured to a great extent, only managed. Multi-morbidity is a term historically used only by geriatricians, who often have to play medical whack-a-mole with their patients who develop one disease after another. Often, when those diseases overlap, they take an exponential toll on the body.

There are several hypotheses that researchers on aging and HIV are working with now. One is that the virus causes acute inflammatory response. From the onset of acute infection HIV creates an inflammatory response and an excessive activation of the immune system, like putting the body on constant high alert. The inflammation continues, even in people with undetectable viral loads. Another hypothesis, is that AZT and early protease inhibitors were causing something called cellular senescence, or aging cells.

A third hypothesis, floated by other researchers, is that those who were infected early and managed to survive with HIV before the most successful treatments were available suffered irreversible damage to their immune systems.

These hypotheses are not mutually exclusive, according to Judith Campisi, a scientist with the Buck Institute for Research on Aging. “Often in biology there can be multiple causes for something, but scientists unfortunately tend to raise one hypothesis above the other. The fact is, we don’t know exactly what’s causing the risk of age-related diseases [in HIV-positive people].”

Karpiak, for his part, has been studying the effect that HIV has on telomeres, which are stretches of DNA that protect chromosomes from deteriorating rapidly. Each time a cell divides, telomeres shorten, and when they get too short, the cell becomes inactive or senescent. He believes that there is enough evidence to show that HIV causes telomeres to shorten rapidly, and that is another piece of the puzzle.

All of these competing, non-exclusive hypotheses might sound familiar, just as in the early days of HIV when doctors and researchers were trying to find out how the virus actually replicates and degrades the immune system. This time, the need to find answers is less dire, since HIV has been knocked off its throne of death.

“What you have to understand is, HIV goes beyond causing the immune system to collapse,” Karpiak tells A&U. “It does damage to the body even when it’s suppressed, and we’re uncovering exactly what that is and how it happens.”


The impact of chronic inflammation
Peter Hunt, MD, Assistant Professor of Medicine, HIV Division, San Francisco General Hospital, is working the theory of chronic inflammation, probably brought on by the effects of latent, inactive HIV that remains in the body even during antiretroviral treatment. He believes that chronic inflammation caused by HIV in the body, even at low levels, does cause the body to “age” more rapidly, and that aging becomes more pronounced over time.

“It certainly is possible that the older HIV meds caused some of the multi-morbidities that we’re seeing today, years later, but it’s more likely that the virus itself is much worse for the body than any drug,” Hunt tells A&U.

Inflammation is the body’s mechanism for fighting viruses or bacteria, and repairing injured tissues. The cells that fight the problem swell and become sore. For an acute infection, this inflammation wanes as the body heals. With HIV the immune system is constantly fighting the virus, even when HIV is being suppressed by meds. That’s a problem, because an over-stimulated immune system can become burned out or weakened. So, even though a lab result may show a high CD4 count, the amount of inflammation in the body may be causing damage on a cellular level, which can, in turn, damage tissues of the heart, liver, kidney, and bone.

The first, and still seminal, study on inflammation caused by HIV is the 2009 SMART study, conducted by the National Institute of Allergy and Infectious Diseases (NIAID). In this study, people who stopped their HIV meds when their CD4 count rose above 350 had higher rates of AIDS-defining opportunistic infections and non-AIDS conditions, as compared with those who stayed on HIV therapy. They had higher amounts of virus in their blood, and those higher levels were associated with inflammation.

The SMART trial also showed the dangers of interrupting ART. For subjects who stopped the meds and restarted them, levels of inflammation decreased but never became normal. The subjects with higher residual inflammation, had more cardiovascular events, as well as higher rates of heart, liver, and kidney disease among people with HIV at younger ages, even after controlling for differences in age and gender.

But the SMART study also showed residual inflammation in the body even for those who didn’t interrupt their drug regimen. And that has researchers concerned.

Hunt says the link between inflammation and premature aging is strong enough that it can be assumed that, even if it isn’t the primary cause of early onset of some non-HIV diseases, that research into therapies that decrease inflammation should be a top priority.

Some of that research is underway, and Hunt is working on uncovering the effectiveness of promising treatments involving statins, a class of drugs commonly used to lower cholesterol and prevent cardiovascular disease. The NIH is considering funding a long-term (seven to eight-year study) on the effectiveness of statins in reducing the inflammatory response caused by HIV.

Until the results of that and other studies give a clearer picture of the link between HIV and body “aging,” Hunt has some safe, cautious recommendations for people living with the virus. “Diet and exercise will go a long way toward preventing inflammation. We know exercise decreases it, as does a diet without sugar and fat.” Whether doctors should prescribe statins to HIV-positive patients is a “gray area” until the results of studies are back.

Hunt and other researchers have some treatment suggestions for doctors and health providers as well.

“Because we’re seeing increased risk in osteoporosis, kidney disease, liver disease, and frailty in long-term HIV patients, doctors need to first be aware that those risks exist,” Hunt says. Proper screening for age-related diseases is warranted for HIV-positive patients, he adds.

Karpiak, who was a member of a panel led by the AAHIVM and joined by ACRIA and AMG (American Geriatrics Society) which crafted guides for the management of older adults with HIV, says that multi-morbidity is becoming the norm rather than the exception for people with HIV infection.

“Aging itself is a heterogeneous process. Many factors go into it. And we’re finding that HIV damage is similar.” The challenge, he adds, is getting healthcare providers to move from a silo approach to treatment, that is, treating CD4 and viral loads, to see the bigger picture managing the health of the entire person.

And with the new waves of research in the link between HIV and premature aging, the picture is becoming much bigger.

Larry Buhl is a radio news reporter, screenwriter, and novelist living in Los Angeles. His young adult novel, The Genius of Little Things, debuted in January 2013. His comic mystery novel, We’re Here to Help, will be available later in 2013.