AIDS Study Casts Doubt on AZT as a ‘Miracle Drug’

For Evan Wilder and thousands of others infected with the virus that causes AIDS, the introduction of the drug AZT six years ago was a godsend. AZT was a miraculous compound that, the U.S. government said, might extend their lives if they took it quickly, before they showed any signs of the disease.

“When AZT was made available, I went on it right away,” said Wilder, a 33-year-old New York City waiter who is attending the Ninth International Conference on AIDS here. At the time, Wilder had no symptoms of AIDS; his taking of AZT reflected the so-called “early intervention theory” that the government had adopted.

On Tuesday, that theory came under attack when a Paris scientist presented details of the longest and largest study ever of AZT in people who have no symptoms of AIDS. The results: Those who took the drug right after becoming infected lived no longer than those who waited until symptoms set in.

The Concorde Study, conducted in France, Britain and Ireland, has stirred great controversy here. Its findings contradict several earlier American studies and suggest that U.S. policy about prescribing AZT may need to be revised. The study also raises fundamental questions about when--and how--people with HIV, the virus that causes AIDS, should be treated.

The results, presented in preliminary form two months ago, have frightened patients and befuddled doctors trying to make decisions about how to care for them.

“This study has generated so much emotion, so much questioning,” said Dr. Joep Lange, director of clinical research for the World Health Organization’s Global Programme on AIDS. “This is not something that is easy to work with for practicing physicians.”

AZT is one of three approved “anti-retroviral” drugs that try to prevent HIV from replicating inside the nucleus of cells. The two other so-called “nucleoside analogs” are ddI and ddC; researchers are now studying how these drugs work in combination with one another as well as in combination with other experimental therapies.

U.S. guidelines recommend that a patient receive AZT when his or her CD4 cells--the immune-system cells that are the main target of AIDS--drop below 500 per cubic millimeter of blood. Later this month, the National Institutes of Health will address whether the policy should be changed in light of Concorde.

The Concorde results also challenge another basic assumption on AIDS research: that CD4 counts are an accurate way to measure whether drugs are effective. Scientists have long regarded CD4 cells as a good “surrogate marker”--declining counts signaled an immune system in decline and therefore a drug that did no good.

But Concorde found that while CD4 counts are a reliable way to predict how rapidly an HIV-infected person will develop AIDS, they said little about how well AZT worked. That is because patients who took the drug had counts that remained high yet developed illness at the same rate as those who took placebos.

The three-year Concorde study followed 1,749 HIV-infected people, 877 of whom were given AZT and 872 of whom were given placebos until they developed AIDS symptoms, when they were given the drug.

The study found that while there was a significant difference in patient survival after 55 weeks, this difference trailed off over time. By the study’s end, 175 patients who received AZT and 171 patients who got placebos had either progressed to AIDS or died.

The drug, declared Paris immunologist Maxime Seligmann, principal investigator for the Concorde study, offered asymptomatic patients “limited, transient benefits.”

But there may be another explanation for the Concorde results, according to Lange. He is among a group of Dutch researchers investigating a process called syncitia, in which immune cells clump together and die.

There is a point during HIV infection, Lange’s research has shown, when the virus converts to a so-called “syncitia-inducing” strain. This conversion, he says, occurs in only 50% of HIV-infected people, but when it does occur it hastens the onset of AIDS.

Lange said Tuesday that a study of 56 patients, conducted by his group in Amsterdam, found that AZT accelerated this conversion.

“My interpretation of Concorde is you’re doing good to some people and you might be doing harm to some people,” Lange said.