For a long, dark time in the 1980s and '90s, the Shanti Project and other agencies like it provided hospice-like services to the thousands of men suffering, and dying, from AIDS in San Francisco.
And then there was monumental success: new drugs to fight the virus and lift the death sentence of HIV infection. With the virus under control in their bodies, patients were healthy and active. They had decades of living ahead of them.
Many of them left the supportive care of places like Shanti, said Kaushik Roy, executive director of the program.
"Now they're coming back," he said.
More than a decade after the first truly successful AIDS drugs became available, a new image of HIV is emerging: People with the virus appear to be aging prematurely. After years of feeling healthy and recharged with the new drugs, they're suddenly slowing down not from the effects of AIDS, but from old age - a decade or two earlier than their noninfected peers.
"When we have clients passing away now, it's from cancer or heart disease," Roy said. "It used to be AIDS."
Patients are coming down with diseases and conditions most associated with aging even when their HIV is well controlled - even when the antiretroviral drugs used to treat it make the virus essentially undetectable in the blood, and by nearly all accounts a patient's immune system is strong and stable.
They are having heart attacks and strokes in their 50s or 60s. They're developing dementia and arthritis a decade earlier than they should be. They're getting cancers that tend to strike only people in their 70s or 80s.
"In the last 18 months, in my clinic I've had four people under age 60 who've had either bypass surgery or heart attacks," said Dr. Brad Hare, medical director of the HIV/AIDS ward at San Francisco General Hospital. "One of them was 37 years old. That's something that would be more typical in somebody 70 or older."
It is, Hare and other doctors admit, a good news-bad news scenario.
The drugs discovered to fight HIV have saved millions of lives and given patients decades' more time. By 2015, the average age of an HIV patient will be 50 in the United States, according to the Centers for Disease Control and Prevention. That figure alone is a sign of how widely successful the work toward treating HIV has been.
But it's come at a cost that has caught patients and doctors off guard. In the United States, AIDS patients now are more likely to die of cancer, heart disease, liver disease or other effects of premature aging than they are of AIDS itself, according to multiple studies.
Researching a cause
"They call it the graying of the AIDS epidemic," Hare said. "We do expect people with HIV to live long, healthy lives now. But there's still a big cost to your health."
Clinicians like Hare who work closely with HIV-positive patients first started noticing the effects of premature aging five or 10 years ago, and in the past year or two, scientists have begun work in the lab to determine what it is that's causing the accelerated aging and how it might be stopped.
Some of the causes for early aging may be behavioral and may apply mostly to people who were diagnosed at the height of the epidemic. For example, smoking and heavy drinking often can cause early aging, and many people who were diagnosed in the '80s or even '90s kept their bad habits because they didn't think they had long to live. Now, many years later, they may still be smoking or drinking, and suffering the ill effects of it.
"I'm living with HIV, and I have been for 10 years," said Justin Jones, program manager of Positive Force, part of the San Francisco AIDS Foundation. "When I was first diagnosed, my primary-care doctor told me I really needed to quit smoking. He also told me he used to encourage people to not quit smoking, because he figured, 'Hey, you've got HIV, if smoking brings you even a modicum of pleasure, do it.'
"There was this huge period where people were making choices based off of, 'Well, I'm going to die.' "
Damage early on
It's also possible, doctors say, 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. In San Francisco, public health officials now recommend that people diagnosed with HIV start treatment immediately instead of waiting for signs that the immune system has started to suffer.
Another culprit of early aging could be the drugs used to treat HIV. Antiretroviral drugs include what are known as protease inhibitors, which attack key proteins associated with viral replication. But some of those inhibitors also may attack a natural protease in the body, which could, in the long run, cause premature aging.
But the prevailing theory is that early aging is caused primarily by chronic inflammation, probably brought on by the effects of latent, inactive HIV that remains in the body even during antiretroviral treatment.
It's been clear to scientists for some time that chronic inflammation is tied to aging, and especially to the decline in the immune system known as cellular senescence, the process by which the body loses cells critical to fighting infections. What's not clear is whether inflammation is a cause or effect of the deterioration of the immune system.
Scientists have, in HIV patients and in the elderly, identified signs of both senescence and inflammation. And, in turn, they've noted a susceptibility to certain "old-age" diseases in both older patients and HIV-positive patients. But how those processes are causing disease isn't quite understood.
A new look at aging
"All of this raises the broader question of what is aging," said Dr. Eric Verdin, associate director of virology and immunology at the Gladstone Institutes and a professor at UCSF.
"We used to think about aging as slowly falling apart, like an old car. But there's a huge difference between us and a car. We constantly get fixed up by our cells. What happens is you have a defect in repairing that damage as you get old," Verdin said. "It may be that we can use HIV as a model system for what we know about aging."
Scientists have long been hunting for models to study aging, but because humans age slowly and at roughly the same pace, a scientist can't hope to study a group of people for a lifetime, if only because that scientist will probably die before his or her study group does.
But HIV patients who are aging faster than the average person provide some opportunity for research.
"What these patients are going through is not so different from what a lot of old people go through," said Judith Campisi, a scientist with the Buck Institute for Research on Aging in Novato. "The way a lot of us look at it, there's some natural aging process that's being accelerated.
"Of course, it may be we're wrong, and maybe there's something specific to AIDS going on with these people," Campisi added. "But I still think we could learn something about normal aging by studying the incidents of accelerated aging."
Turning to mice
Along a similar vein, a scientist at the Gladstone Institutes is developing what's known as a humanized mouse - a rodent whose native immune system has been stripped out and replaced with a human one.
If the model works, scientists hope to use those mice to study the aging effects of HIV infection, among other areas of research. Because mice have so much shorter lives than humans, a mouse with a human immune system could provide a fantastic, birth-to-death example of cellular senescence and inflammation.
And, ultimately, researchers believe the mouse model could help scientists develop treatments to fight the decline of the immune system - both in HIV patients and in the general population.
"As we age the animals, it'll be interesting to see how quickly their immune system ages too. We can look at whether the effect of the aging is caused by the virus, by the HIV drugs, or by a combination or something else entirely," said Shomyseh Sanjabi, an assistant investigator at Gladstone. "You can really try to address some of the questions that no one's been able to address right now in the field."
Someday, scientists hope to develop drugs that will slow the effects of aging in HIV patients. They are looking at anti-inflammatory drugs, many of which are already on the market, to target the specific types of inflammation associated with HIV infection. Scientists at Gladstone are hopeful that clinical trials of those drugs could begin in one or two years.
Researchers also are looking for ways to refine protease inhibitors so they only attack the virus and not naturally occurring cells. That could mean developing entirely new drugs, or changing dosage requirements so that only the virus is affected.
In the meantime, doctors are treating HIV patients with an eye on aging. Many are screening for age-related cancers like colon cancer a decade earlier than what's currently recommended, or they're paying closer attention to blood pressure and cholesterol than they ordinarily would in patients in their 30s.
The advocacy agencies are devoting their resources not so much toward hospice and other end-of-life care, but toward support networks for people living with a chronic illness, or psychological help for those who are still dealing with the effects of having survived a deadly epidemic.
And for many of the patients, aging is just another dip in the roller coaster of living with HIV.
"It's just being on pins and needles all the time," said Anna, 42, an Oakland woman who was diagnosed with HIV in 1995 and asked that her last name not be published. "Sometimes you feel something, and you wonder if it's a side effect from the drugs or if it's aging or if it's the disease itself. And you don't know. You just have to wait and see.
"I do have a few more gray hairs," she added with a laugh. "But I think that's just normal aging."
Erin Allday is a San Francisco Chronicle staff writer. E-mail: firstname.lastname@example.org