Specter of Drug Resistance Haunts Many Being Treated for AIDS
The first time Dr. Joel Gallant laid eyes on Michael Willis, he was struck by how truly awful his new patient looked. “A skinny little emaciated creature” is what the doctor remembers.
Willis was in the full grip of AIDS, covered with eczema, partially paralyzed by a herpes infection of the spine, 140 pounds and falling. Death within a year seemed almost certain.
That was 2 1/2 years ago. Now Willis, at 37, exudes energy. He is toned, trim and handsome enough to model two or three times a week at the Maryland Institute College of Art.
As stunning as Willis’ turnaround seems, it is hardly unique. He is one of the thousands of Americans rescued from the edge of death by the AIDS cocktail, the combination of pills that changed a uniformly lethal disease into a treatable one.
However, Willis’ story is commonplace for another reason as well. Despite his look of health, he has not escaped HIV. In the brutally precise language of medicine, Willis is a treatment failure.
Estimates vary, but perhaps 30% to 60% of all people taking the AIDS cocktails are considered treatment failures, because HIV can still be found on standard tests that are sensitive enough to spot as few as 20 copies of the virus in a milliliter of blood. Either their viral levels never got that low or they rebounded after a promising start.
When Willis first learned of his disease, 600,000 bits of virus circulated in every milliliter of his blood. At the time, he had been sick for a year, often so exhausted that he could not get out of bed. He felt oddly relieved to learn the cause, even though it turned out to be HIV.
While he steadily got better on a combination of the protease inhibitor Crixivan and two other drugs, the lowest his virus level ever fell is around 1,000--far from the zero that defines success.
Most of his friends with HIV have seen their virus vanish. The failure of treatment to do the same for him is obviously disappointing.
“Sometimes I cry about it,” he admits. But mostly he focuses on his good fortune. He enjoys the pleasure of playing and singing with his rock band, the Radiant Pig, enjoys feeling well, enjoys being alive.
“I just try to ignore it,” Willis says. “I wish somebody would tell me what is going to happen, but I don’t want to ask either.”
But even if he asks, there are no clear answers.
No one knows for sure what will happen to those whose virus stays stubbornly visible despite all-out treatment. From the start of the epidemic, the amount of virus has been the surest barometer of the disease’s course. The higher the level, the faster it kills. Experts believe that if there’s enough HIV to measure, it’s probably continuing to damage the immune system, even if more slowly than before.
“Right now, we are seeing people like Michael who are having less than satisfactory virological responses. Yet, clinically, he is doing wonderfully and is as healthy as he has been in years,” says Gallant, an AIDS expert at Johns Hopkins University. “We don’t know how long that will last. But our assessment is that without complete viral suppression, it won’t last forever.”
The doctors wonder: Will these people start to go downhill in two years? Five? Ten? Or even longer? They worry that the dramatic decline in AIDS deaths of the last two years is a honeymoon, a lull before the epidemic reawakens.
“We are winning many more battles than we won before, but we still haven’t won the war,” says Dr. Michael Saag of the University of Alabama at Birmingham.
His program averaged 10 to 15 deaths a month among its 700 AIDS patients in 1995. Then came the cocktail. In 1996 and 1997, there were just one to three deaths a month. But this year, the figures are creeping up again, averaging five to eight deaths a month.
For now, though, many like Willis continue to thrive despite stable or even rising viral levels.
“You still see wonderful, wonderful things happening with this therapy,” says Dr. Lori Fantry of the University of Maryland. “People come into the clinic and they think you’re God. Their symptoms melt away before your eyes. The people aren’t failing yet. It’s the numbers.”
The numbers.
Scientists estimate that for every unit of virus in a milliliter of blood, somewhere in the body between 100,000 and 150,000 infected cells are making HIV. A viral load of 1,000, like Willis’, suggests between 100 million and 150 million virus-making cells.
Over time, these viruses may elude AIDS drugs by doing a sloppy job of reproducing themselves. No unit of HIV is exactly like its parent. With each copy it makes, HIV introduces an average of one error into its genetic code. Chances are, everyone with HIV carries a virus with a random mutation that makes it capable of resisting whatever drug comes along.
When patients start treatment, doctors give them three drugs--typically a protease inhibitor and two older medicines that they have never taken before. The idea is to hit the virus hard, knocking its production so low that lurking resistant versions never have a chance to be made in quantity.
When treatment pushes the virus below detectable levels and keeps it there, doctors feel fairly certain that patients will stay healthy for several years. If treatment fails, it’s because swarms of drug-resistant viruses have been produced.
Doctors list three main reasons for treatment failure: Patients neglect to take their medicines on schedule, they already have lots of resistant virus because of earlier exposure to medicines, or their doctors treated them inadequately.
Failure to take medicines consistently is probably No. 1. Missing just a few doses allows resistant viruses to grow explosively. Once that happens, there is no guarantee that switching drugs will do any good, since the virus may be immune to them too.
However, staying on treatment isn’t easy. It often means taking 15 or 20 pills a day on a precise schedule. Some must go down on an empty stomach, some on a full one. They must be taken at just the right time around the clock.
Many trigger nasty side effects, such as diarrhea, headaches, insomnia, stomach pains, numbness in the fingers and toes and an odd-looking rearrangement of body fat that leaves people with potbellies and wasted arms.
As the medicines do their job, HIV symptoms disappear. In time, people feel perfectly well except for the side effects of their pills. This makes sticking with them even harder.
“It was never so easy to be adherent as when I was on the brink of serious illness,” says Sean O’Brien Strub, 40, of New York City. “I couldn’t wait for my next dose. As I felt better longer, the treatment became more of an intrusion, and the side effects were more bothersome.”
Strub, who is publisher of Poz, a magazine for HIV-infected people, went on a trip in June and forgot his pills. So he decided to stop taking them for a couple of weeks, just to see what would happen. Within 10 days, he felt sick again. A blood test showed his virus level, which had been undetectable, spiked to more than a million.
Back on therapy, it’s now down to 30,000. “I definitely made a mistake,” he admits.
Some people are resistant to individual components of the AIDS cocktail, often because they took them as single drugs before the cocktail was created. Many are long-infected treatment pioneers, eager to try each new drug that comes along.
For instance, Nick Houpis, 43, of Boston, has taken 10 of the 11 approved AIDS medicines. The lowest his viral load ever dropped was 37,000. Now it’s 440,000, and this summer he had his first bout with an AIDS-related illness.
“There are an awful lot of us who are just a little bit too late,” he says. “I don’t think they will come up with something that will make miracle stories out of us.”
Some appear to suffer because of physician incompetence too. For instance, doctors may err by adding a protease inhibitor to two other medicines their patients are already taking, instead of starting them on three fresh drugs. This greatly increases the risk of rampant resistance. AIDS care has become so complicated, many believe, that it now should be done only by specialists who know how to avoid such potentially fatal mistakes.
Once someone fails AIDS treatment, the next step is what doctors call salvage therapy--the art of crafting a second attempt to knock down the virus. They may prescribe five or six drugs at once.
“You end up with a kitchen-sink approach,” says Dr. Kenneth Mayer of Brown University. “You try to pull together every possible combination to keep the virus in check.”
Willis is an extreme example of this. Gallant has him on seven anti-AIDS drugs, plus an assortment of others to ward off AIDS-related infections.
Once a week, Willis hauls out an orange crate of big white pill bottles and counts out his week’s dosage: Norvir, sequinavir, 3TC, hydroxyurea, ddI, abacavir, adefivir, Sustiva, Bactrim, acyclovir and Zithromax, plus a shot of testosterone.
He starts each day with two packets of ddI dissolved in a glass of water. Then he takes a fistful of pills with breakfast, another handful with dinner, and a couple more at bedtime, 35 in all.
“I’ve just made it part of my life,” Willis says. “I don’t really have any options. If I’m dead, I know that my options are limited.”
