David Hardy has been treating HIV-infected patients since the early 1980s, when the epidemic began. In those days, people newly diagnosed with AIDS lived for only about six months. Hardy, an infectious-disease specialist and internist, was ecstatic when powerful new drug combinations came into widespread use in 1996, enabling HIV-infected people to measure their lives in decades rather than months. But in recent years, his euphoria has turned bittersweet.
“Most people assume that the medicines have worked and that everything has gone back to normal, and that’s not really true,” says Hardy, who directs research for Whitman-Walker Health in Washington and who still sees patients weekly. “While we have suppressed HIV very well, we’ve now discovered that the medicines only treat part of the problem.”
Many HIV-infected people, now in their 50s and 60s, who have lived for years with HIV under control, are developing aging-related conditions — heart, liver and kidney disease, certain cancers and frailty, for example — at a rate significantly higher than uninfected people of the same age. “These are things that people develop all the time as they get old, but they are occurring at an earlier age in HIV-positive people,” Hardy says.
“The first goal was to save someone from dying of HIV infection,” agrees Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) and a leading researcher involved in developing the AIDS drug combinations. “After we started successful therapy that suppressed the virus and extended lives, we began to notice that people were getting diseases associated with aging sooner than their chronological age would indicate they should be getting them.”
An aging HIV population
In 2014, an estimated 45 percent of Americans living with HIV were older than 50, amounting to 428,724 people, according to the Centers for Disease Control and Prevention, while 27 percent were older than 55 and 6 percent were 65 and older. These include people diagnosed a decade or more before life-prolonging drugs became available, as well as older Americans diagnosed with late-stage AIDS who did not begin HIV drug therapy until then.
Experts believe this timing — the point at which someone starts therapy after infection — is key to understanding what is happening now. It involves how the body’s immune system behaves following infection with HIV.
“If you are in your 50s today and you were infected when you were 20, you had about 10 years of living without therapy before the drugs came along and helped you survive,” says Carl Dieffenbach, director of NIAID’s AIDS division. In this group, and in older people diagnosed with late-stage AIDS, the period without treatment “led to a tremendous amount of damage to their immune system.”
HIV not only damages the immune system, it also turns on that system indefinitely, meaning the immune response triggered by HIV never really shuts down, even once drugs have begun to quell the virus. “With most infectious invaders, the immune system responds and then is supposed to rest, like a fire engine waiting to come out when there is a fire to be fought,” Dieffenbach says. “With HIV, those firetrucks keep driving around looking for fires, even when there are none.”
Fauci agrees. “It isn’t only the [initial] immune response against HIV,” he says. “It’s a global turning-on of the immune system — and the longer you wait to take drugs, the more robust the immune activation.”
Many AIDS researchers believe that this “immune activation” is the primary mechanism underlying the accelerated rate of age-related diseases. HIV-infected patients must take multiple medications daily, some with side effects, but experts believe the AIDS drugs aren’t a major contributor to these conditions. “It’s much less the drugs; it’s the immune activation,” Fauci says.
Medications don't cure
HIV medications control HIV, but they don’t cure it. The virus persists in numerous reservoirs in the body, including the lymph nodes, which prompt immune activation as well as chronic inflammation. “Inflammation and immune activation accelerate heart disease and stroke, and chronic HIV infection results in both,” says Robert T. Schooley, a longtime AIDS researcher and professor of medicine in the infectious-diseases division at the University of California at San Diego. “One can calculate a given patient’s risk for stroke or heart attack based on how elevated laboratory markers of inflammation are.”
Several studies have shown the heightened risk of cardiovascular disease among those with HIV. They have a 50 percent higher risk of heart attack compared with noninfected controls, and a more than fourfold higher rate of sudden cardiac death compared with the general population. They also are in greater danger from complications associated with heart failure.
Certain cancers are increasing among them as well. Early in the epidemic, some cancers — Kaposi’s sarcoma, non-Hodgkin’s lymphoma and invasive cervical cancer, for example — often developed in HIV-infected individuals, signaling the onset of full-scale AIDS. These “AIDS-defining” cancers initially decreased with the introduction of anti-HIV drugs and have remained relatively steady during the past two decades. However, the burden of non-AIDS-defining cancers — anal cancer, lung cancer, Hodgkin’s lymphoma, liver cancer and head and neck cancers, among others — has grown during that period. Many of these are caused by viruses other than HIV.
(These include hepatitis B and C viruses and liver cancer; human papillomavirus and head, neck and anal cancers; and Epstein Barr virus and Hodgkin’s lymphoma.)
Experts believe these arise in HIV-infected people predominantly because their impaired immune systems can’t effectively fight the viruses responsible. Lung cancer is an exception because it is not caused by a virus. But many HIV-infected people smoke, and also suffer lung infections and other assaults.
These cancers account for a growing number of cancer-related deaths among the HIV population. “As people are dying less often of AIDS and opportunistic infections, cancer is becoming one of the most common causes of death in people with HIV,” says Robert Yarchoan, chief of the National Cancer Institute’s HIV and AIDS malignancy branch. “Also, the incidence of most cancers increases as people age, and HIV-infected people are becoming more susceptible, just like the rest of us.”
One ongoing study has shown that patients who start AIDS antiretroviral drug therapy early generally fare better than those who wait, including significantly reducing their chances of developing full-scale AIDS. But even a brief period between infection and the onset of therapy can harm the immune system and cause problems, experts say.
“Very shortly after someone is infected, the lymphatic system in the gastrointestinal tract undergoes a major transformation” known as microbial translocation, often called “leaky gut,” a condition where microbes from the GI tract escape and enter the bloodstream, according to Amy Justice, a professor of medicine at Yale University who studies HIV among veterans. “It happens quickly after infection, and we’re not very good at preventing it. Even when we treat them [with anti-HIV drugs] early, they still have more microbial translocation than people who don’t have HIV — and it feeds the chronic inflammation.”
Moreover, drinking alcohol exacerbates leaky gut, “so drinking when you have HIV is not a good thing,” she says.
In fact, drinking, smoking, recreational drug use and obesity — a common side effect of antiretroviral therapy — also probably contribute to the medical problems of HIV patients, experts say. “The challenge is to try to get them to change ingrained health behaviors at midlife,” Justice says. “This is hard for anyone, with or without HIV, but probably more important if you’ve got HIV.”
While the risk of developing age-related conditions “is substantially increased” for people with HIV, the situation isn’t necessarily all grim, Justice says. “Not everyone is miserable and sick,” Justice says. “Many are doing incredibly well. A lot is in their control, if they can change their health behaviors.”
The NIAID’s Dieffenbach agrees. “Everybody has his or her own set of risk factors, and what HIV infection tends to do is magnify your lifestyle choices, or your genetics,” he says. “What we are grappling with now is defining this. Aging occurs, and with it the risk of getting one or more of these diseases. What is it about HIV that hastens the process? Can we do anything about it? Those are the things we are trying very hard to address.”