A New Test for Effective AIDS Drugs: Stopping
WASHINGTON — At precisely 11 p.m. on Jan. 5, Mark Deal, a 37-year-old legal researcher and AIDS patient who lives in New Orleans, ushered in the Feast of the Epiphany by swallowing the last of the 25 daily pills that had been keeping him alive and thriving.
Deal did it for the good of science and because he believes he already has beaten the odds. “I’m beyond scared,” he said. “I should have been dead years ago.”
The last five years have seen an explosion of powerful new treatments for AIDS, which have vastly transformed the once grim prognosis of those who are infected.
Most promising, for Deal and others, have been combinations of antiviral drugs known as “cocktails,” which mix older medicines with the newest AIDS drugs, potent protease inhibitors. The drugs deliver a multi-pronged punch to the human immunodeficiency virus, making it unable to replicate and carry out its deadly search-and-destroy mission against the body’s immune system.
So effective are cocktails that many AIDS patients, Deal among them, now can lead longer, more productive lives. So revolutionary are the drugs that AIDS mortality nationwide plummeted a remarkable 46% in 1997, dropping to 16,685 deaths from 31,130 in 1996.
Using the most sophisticated tests available, researchers can find no detectable levels of virus in many patients taking the cocktails. But they know the virus probably still is there in a “resting” state, hiding out in places in the body that cannot always be reached, biding its time, waiting for a chance to make a comeback.
Thus, it is one of the most vexing questions facing AIDS researchers and the AIDS community: Must patients take these drugs for life--or can they stop? If they stop, will the virus rebound or remain dormant? If the virus returns, can patients resume therapy and stay healthy? Or will they become ill and die?
Conference to Examine Testing of AIDS Drugs
There is only one way to find out: Stop taking the drugs.
“I’ve never used the word ‘eradication’ in talking about what could happen to the virus,” says Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, or NIAID, and one of country’s leading AIDS researchers. “The key question is whether you can get it to return in such low levels that the body’s immune system is able to contain it.”
The topic is expected to be debated at the Sixth Conference of Retroviruses and Opportunistic Infections, a major scientific forum on AIDS that begins today in Chicago.
“I think it is a mistake to have this approach hyped as it has been,” said Dr. Robert T. Schooley, an AIDS specialist at the University of Colorado Health Sciences Center and an organizer of the conference. “Patients will clearly want to try it, and I don’t think it is ready for clinical application. The bulk of these individuals will see their viruses come roaring back, in some cases with an overshoot.”
So why would Deal, or anyone, risk relative health for a return to illness, possibly even death? Why stop taking drugs that have kept so many going for so long?
The drugs are expensive, costing up to $12,000 a year, and the regimen is cumbersome, requiring taking numerous pills at odd hours and often revolving around meals. And their side effects can be nasty, including diarrhea and odd deposits of body fat. Despite the benefits, many patients have considerable trouble sticking with the routine. And some in recent months have decided to quit therapy or to take drug “vacations.” Most have seen their viruses return full force.
But in a handful of cases, the virus has not returned or has returned slowly, and scientists are excited about the rich avenue of research that such a development promises.
“All patients [on these drugs] have residual virus” in their bodies, said Dr. Richard T. Davey Jr., the NIAID researcher who is conducting one of the studies. “A certain percentage of them will relapse once the drugs are stopped.” The question, said Davey, is this: “If the body’s immune system can gain control and keep the virus in check, what will that tell us about the need for therapy in future?”
Respite From Drugs Could Create Problems
The most optimistic scenario is that a respite from drugs will provoke a brief viral comeback that actually would prime critical immune system cells in the body--known as helper T cells--to do what they typically do when an invading microbe appears: recognize the enemy, in this case HIV, and signal their immune system colleagues--”killer” T cells--to attack the virus.
This is what happens when any germ invades the body. The key difference with AIDS, of course, is that cells called CD4-positive lymphocytes are HIV’s primarytarget, and often their legions are decimated early in the fight before they can gain the upper hand.
When the protease drugs first made their debut in 1994, scientists hoped that the virus could be eliminated. Today, given the virus’ talent for hiding in the body, the strategy has shifted from eradication to containment.
The current thinking is that using the drug cocktails to suppress the virus as early as possible could allow the immune system to rejuvenate. And a revved up immune system, once capable of recognizing the virus, could keep the virus under control if it returns slowly and at low enough levels.
Scientists Ponder the Possibilities
Researchers are studying numerous possibilities, among them the reasons why a very small number of HIV-infected individuals, known as “long-term nonprogressors,” already seem to have the rare ability to contain HIV naturally. These people have never taken anti-AIDS drugs or become ill and continue to have high CD4 counts.
Researchers believe that multiple genetic, immune system and other factors are responsible for this. But they are realistic about the chances of success for the majority of those who want to halt their medication permanently.
“I think it is wishful thinking,” Schooley said. “Some patients--and I think it will be a minority--might show either minimal or slow return of viral replication, but most will probably come back quickly.”
Michael Gottlieb, a physician in private practice in Los Angeles, who in 1982 was the first doctor to recognize and alert federal health officials of a strange new deadly syndrome in gay men, said that, when his patients suggest stopping therapy, “I try to talk them out of it. I try to find a regimen that is more acceptable.”
Still, experts believe there is much to be learned by studying a test group of patients who agree to give up the drugs.
Deal is among several dozen who have volunteered to do so under the watchful eyes of NIAID researchers. Until recently, Deal faithfully adhered to a rigorous schedule of taking four drugs.
The ebullient, robust-appearing man with brown eyes and salt-and-pepper hair--and with a fondness for brightly colored shirts and loud ties--has eluded the onslaught of infections that have disabled or killed most of his friends.
He is lucky. He carries a genetic mutation that researchers believe slows the progression from infection to the onset of symptoms. Even so, he has seen precipitous drops in his CD4 count, prompting him to change or alter his drug therapy on several occasions.
Two years ago, he began taking a potent four-drug combination: two protease inhibitors, Saquinavir and Viracept, and two nucleoside analogues, d4T and Lamivudine (3TC).
One Patient’s Liberation
He has done well, better than many of his friends. But he has hated the constraints of having to plan all his meals around his medications, eating lunch at 4 p.m., for example, instead of midday, and eating dinner late at night for the same reason.
“I’d go out to dinner to a restaurant with friends but wouldn’t eat a thing,” he said. “I’d take home a doggy bag for later.”
Also, he suffered persistent diarrhea and developed fat deposits on his abdomen and on the back of his neck.
He was ready to stop. And he has found doing so almost liberating.
“It’s been great. Unbelievable,” he said. “My energy level has shot through the roof. I think it’s part emotional and part not having all these chemicals floating through my body.”
Recent tests looking for the virus in the body’s known “hiding” places--key blood cells and lymph node tissue--could not find any.
Researchers attribute this to another drug, interleukin-2 (IL-2), that Deal was given earlier in conjunction with his four-drug therapy. Scientists think that IL-2, when given along with the cocktails, forces the “resting” virus out of its hiding places into replication where the drugs can attack it.
The NIAID’s Davey believes that a majority of patients will relapse to some degree--the key is how much.
Davey predicted that it will be one to two years before any conclusions are made--and possibly not that soon.
“If we see what we’re hoping to see--a percentage of individuals who do not relapse--we will want to follow them for a long period of time,” he said. But if most patients relapse quickly, “we wouldn’t need two years to determine that the approach we’re using is not feasible.”
But Deal looks toward the outcome with optimism as well as humor.
“I have lived my life on a two-year plan for the last 10 years. The bad news would be if the virus comes back and I have to go back on the pills. I hope I will still live another 10 or 15 years. The question is whether I’ll be doing that with drugs or without them. So I think I finally need a 15-year plan.”
