COLUMN ONE : The Deadly Risks of Research : One patient suddenly fell ill. Then he died. Now four are dead and three others very sick. And doctors testing a new hepatitis drug realize they are caught in a nightmare.

WASHINGTON —  It is a medical researcher’s greatest fear. And for Dr. Jay Hoofnagle, a hepatitis B expert at the National Institutes of Health, it began to take root at 11:30 p.m. Friday, June 25, when the telephone rang in his Rockville, Md., home.

Hoofnagle and his colleagues had been testing an extremely promising new drug, fialuridine, or FIAU, on a group of human subjects. They had every reason to believe the drug would be the first effective therapy for hepatitis B, an often-fatal liver disease that had defied most treatments. FIAU, after all, had appeared both effective and safe in earlier tests on humans and animals.

But that brief phone call changed Hoofnagle’s optimism to terror as he realized that something had gone horribly awry.

The late-night caller was Dr. Adrian Di Bisceglie, a colleague. He had grim news: A subject in the drug trial had become seriously ill.

“This man had been fine the week before,” Hoofnagle recalled. “Suddenly, it dawned on us that we had a catastrophe going on.”

Within two weeks, despite a quickly scheduled liver transplant and other measures, the man was dead, apparently the victim of unexpected side effects of the drug. In rapid succession, three more patients died. The last of them, on July 30, was Carlton (Sonny) Lee, 35, chief liaison officer at the National Commission on AIDS. He believed he had contracted hepatitis B in the mid-1980s while serving with the Peace Corps in Africa.

Although the drug trial was halted within hours after the first patient became seriously ill, researchers worry that more deaths may come. Before the trial was stopped, 15 of a planned 24 participants had received the drug. In addition to the four deaths, three people became so ill they required liver transplants. One has improved enough to be released from the hospital. The prognosis for the other two is uncertain. None of the subjects’ identities were released.

The team of researchers, many of them traumatized by the experience, are working around the clock to determine what went wrong. So are officials at Eli Lilly & Co., which had hoped to manufacture the drug. And so is the Food and Drug Administration, which is conducting a formal review.

So far, there is no suggestion that the scientists did anything improper in the way they conducted the trial. In retrospect, however, they realize there were early, potentially troubling signals--although, at the time, the evidence did not point to FIAU.

In the countless human drug trials performed by federal researchers in pursuit of cures for the world’s deadliest diseases, deaths like those stemming from the FIAU trial are rare. But in recent years, particularly as AIDS activists and others have pressed the research and regulatory system to speed access to new drugs, it serves as a stark reminder--both to those who run the trials and those who participate in them--that the risks are real.

“You’re never sure what’s going to happen with your first human subjects,” said Arthur Caplan, president of the American Assn. of Bioethics. “Over the years, people have tended to mash together research and therapy--when average people hear the term ‘clinical trial’ they think, ‘latest, state-of-the-art therapy.’ The reality is that ‘clinical trial’ should mean: ‘Possible dangerous substance. Beware. Could be fatal.’ ”

But, in fact, trials of experimental drugs are designed for this very purpose--to discover whether the compounds are safe and effective before they are released to hundreds of thousands of people in the marketplace. For that reason, such studies are conducted painstakingly, in stages, first on small groups of humans, then on gradually expanded numbers.

“I think what happens is that we see a trial with deaths and we wonder: How could this be?” Caplan said. “In fact, every subject recruited to a study, especially a Phase I or Phase II study, is being asked to be a hero. To face unknown risks. To put his or her life on the line.”

*

Hoofnagle, a youthful-looking 50-year-old with a shock of white hair, has devoted 15 years to finding a treatment for hepatitis B.

“It has been a major interest for me, although it has not been of major interest in this country,” he said. “In this country, it is often a disease of drug addicts and homosexuals. Unfortunately, there is not much interest in these patients.”

Nevertheless, hepatitis B is regarded as a significant global problem. An estimated 300 million people worldwide--5% of the population--is believed to be infected, primarily in Africa and Asia, particularly China. While not everyone becomes noticeably ill, all of those infected can transmit the hepatitis B virus, or HBV.

In the United States, about 300,000 new cases of infection are reported annually and 1 million people are believed to be carriers.

HBV, the most serious of the hepatitis viruses, is transmitted like the human immunodeficiency virus that causes AIDS--primarily through blood transfusions, sex and the sharing of contaminated needles--but it is considered more infectious than HIV. In this country, the highest-risk groups include gay men, intravenous drug users and health care workers exposed to blood.

While the disease is not always immediately life-threatening, it can shorten life by decades and often lead to scarring of the liver, called cirrhosis, and liver cancer.

During his career, Hoofnagle has tested several compounds against the hepatitis B virus with only modest success. Most of the drugs produced toxic side effects and were discontinued.

The latest hope seemed to lay in FIAU. Because it is in a category of drugs that includes AZT, DDI and DDC--the three antivirals used in AIDS therapy--it was first tested as a possible AIDS treatment. From 1989 to 1990, a small group of AIDS patients--who also suffered from hepatitis B--took the drug for 10 to 14 days.

FIAU had little impact on HIV but its effect on the hepatitis B virus was remarkable.

“We had never seen anything like it,” recalled Hoofnagle, his face etched with the strain of recent weeks. “Levels of virus fell within a week. They all tested negative.”

The problem, however, was that the virus usually returned once patients stopped taking the drug.

“I proposed we do a study on hepatitis B patients without HIV,” Hoofnagle said. “Also, we wanted to treat people for more than 14 days. It was not long enough to have a lasting effect. I thought we needed to treat them for a long time--months--much in the same way you cure tuberculosis.”

Hoofnagle received approval from an NIH review committee for another small study in March, 1992. This time, his team planned to give the drug for one month to patients who did not have HIV.

The goal was to find the smallest amount of the drug that would give a positive result. Researchers tried four different doses, all considerably lower than those taken earlier by AIDS patients.

“People loved the drug,” Hoofnagle said. “It could be taken by mouth, and it tasted good. There were no side effects. It looked great. The levels of virus remained low and, in some patients, the virus cleared entirely.”

Hoofnagle and his colleagues were ecstatic.

But, in retrospect, he admitted, two things happened that should have triggered concern.

The first involved Patient 1A, as he was known by his identifying code, who developed neuropathy--a painful tingling and numbness--in his feet. But that condition occurred four months after he stopped taking the drug. He also had a history of neuropathy, so researchers did not think the symptoms were FIAU-related.

But the patient did. And his condition worsened. “He got to a point where his legs were so painful that he couldn’t walk,” Hoofnagle said. “And he got very angry with us. He felt that we weren’t taking him seriously.”

In the second episode, patient 4D, a Kansas man, notified NIH last fall that his personal physician had recommended removal of his gallbladder. He had gastrointestinal problems but did not have gallstones. His NIH physicians tried to dissuade him because he had mild cirrhosis, which can worsen after surgery. But the patient ignored their advice.

At the time of surgery, it had been nearly two months since he had taken FIAU.

Two weeks after the operation, he developed ascites--fluid in his abdomen, a condition that is related to cirrhosis and can be a complication of gallbladder surgery. The development was surprising, Hoofnagle said, because “he didn’t have that much cirrhosis to have ascites.”

As his condition deteriorated, the patient developed lactic acidosis, which occurs when the liver cannot remove lactic acid from the body. Lactic acid, a waste product, results when cells produce energy by breaking down glucose without the benefit of oxygen. It occurs, for example, in cases of shock or excessive muscle use and produces the pain felt by a marathoner after a race.

“We couldn’t control it,” Hoofnagle said. “It became worse and worse, and we had no idea why he had it. His liver function (as measured through liver enzymes) looked good. His HBV was negative. Why was he falling apart? We thought the ascites was causing the lactic acidosis--that he must have had cirrhosis. So we decided to send him for a transplant.”

The man died in January, before he could receive a new liver.

Tests performed on his tissue samples showed no evidence of FIAU. The autopsy showed mild cirrhosis. It also showed that his liver cells were full of microvesicular fat, or “fat bubbles,” a condition that does not typically occur in viral hepatitis.

More often, it is seen in Reye Syndrome, a rare and often fatal disease that strikes children and teen-agers. Reye Syndrome is characterized by damage to mitochondria, the sub-units of cells where energy is produced.

“We didn’t quite know what to make of it,” Hoofnagle said. “We were stumped. But we didn’t attribute it to FIAU. His doctor performed a liver biopsy at the time of surgery that didn’t show any fat. So we decided it was something between the time of surgery to the time of death that had caused this.”

*

The final study was to involve 24 patients who would take FIAU for six months. The first 10 were enrolled in March and April; five more joined in June. Most had been part of the earlier one-month study, including Carlton Lee.

Although he suffered no symptoms, Lee had long been worried about his disease. He had participated in studies of other experimental drugs, but they had failed to help. He believed he had nothing to lose by joining this trial.

“He wanted to be involved in doing something,” said Dr. June Osborn, who chairs the AIDS commission and was Lee’s boss and close friend. “He was also a remarkably altruistic young man who felt that participating in early drug trials was a genuinely important thing to do for humanity.”

Although Lee was not infected with the AIDS virus, he was deeply involved in AIDS policy and impressed by AIDS patients’ increasingly active approach to therapy.

“His hepatitis had not made him sick, but he was living in the context of the AIDS culture, meaning that he felt he should take an aggressive approach to his illness,” said another close friend who requested anonymity. “All of us close to him now wish we had questioned this more at the time--whether people totally asymptomatic with hepatitis B should be recruited for such a trial.”

The participants all signed consent forms--used to explain the risks of a drug trial to prospective participants. Although the forms did not mention the death of Patient 4D, everyone had been told about him, according to NIH and some of Lee’s friends. The forms did warn of possible effects including nausea, insomnia, seizures and neuropathy.

By late June, 10 participants had taken the drug for periods ranging from 67 to 90 days, in addition to the earlier four weeks of therapy. The other five had taken it only for one month, including one who also participated in the earlier four-week study.

The time-frames are significant because investigators now believe the problems with FIAU stem from extended use--and the cumulative dose.

In early June, several patients began complaining of nausea, vomiting and lack of appetite. Tests on Patient 6, the only woman, showed elevated liver enzymes, a sign her hepatitis was “flaring.”

A “flare” is usually a positive signal, indicating that the body is fighting the virus. But her tests were puzzling. The virus was gone, meaning something else was happening in her liver.

Then came the fateful June 25 phone call: Patient 2 had been admitted to a Virginia hospital with multi-organ system failure. His body was overwhelmed with severe lactic acidosis. Just like Patient 4D.

At 7 a.m. Saturday, Dr. Jennifer Stotka, a Lilly scientist monitoring the study for the Indianapolis-based company, received a call from Hoofnagle.

“Jennifer, we have problems,” he told her.

Later that morning, Patient 6--the woman--began developing lactic acidosis.

“We knew something was definitely wrong,” Stotka said. “Dr. Hoofnagle told us he was going to stop the trial, and we agreed.”

The NIH researchers began calling patients immediately, ordering them to stop taking the drug.

At first, they couldn’t find Lee, who was vacationing in South Carolina. When they reached him on the Monday after the call to Hoofnagle, he told them that he had already stopped taking FIAU.

Lee had been experiencing lower abdominal cramps, but the NIH doctors had not been overly concerned. He’d had similar symptoms before he began the drug.

But “he felt there was something wrong,” Lee’s friend said. “He never wanted to frame the people at NIH as bad guys, but his anger was building. And he got increasingly scared as the days went on.”

Within a week, seven of the 15 study participants developed serious lactic acidosis. In addition to liver disease, some had other problems, including kidney dysfunction, pancreatitis and neuropathy.

“We had no idea what it was--and then we remembered Patient 4D,” Hoofnagle said. “We said: this is like Reye Syndrome--with damage to the mitochondria. And it was systemic,” meaning that the mitochondria were being poisoned in many organs.

They speculated the FIAU had disrupted the genetic workings of the mitochondria, much as it was supposed to do with the hepatitis B virus.

Recalling the neuropathy patient from the earlier study and Lee, with a history of gastrointestinal episodes, the researchers now believe that, besides the liver, the organs that apparently get hit “are the ones that are already compromised,” Hoofnagle said.

Also, it appears likely that the drug remains in the body much longer than researchers thought.

In Patient 4D, initial tests performed on his tissue samples showed no FIAU. Since then, Lilly has developed a test 250 times more sensitive. When patient 4D’s tissues were analyzed again, researchers found FIAU.

Hoofnagle theorizes the drug “hits the mitochondria--although it’s not a direct effect. It poisons their ability to make new mitochondria. That’s why you get sick a month later. In the patients who died, there was too much damage to their mitochondria for them to survive, unless we were to replace their livers.”

The researchers tried various measures in a frantic attempt to get the patients’ cells to repair themselves. And they arranged for liver transplants. But for those who died, the transplant came too late or not at all.

“The liver goes first, and it is very dependent on mitochondria,” Hoofnagle said. “Other organs have a better ability to repair themselves, but liver cells don’t turn over. We don’t quite know how FIAU gets to the mitochondria. Can it be reversed? We don’t know.”

*

Two of the patients received new livers July 4. One died the next day; the other, two days later. A third died July 16, Carlton Lee on July 30, before either could receive a transplant.

Patient 6 has received two transplants--on July 9 and again Aug. 15--and is in critical condition. Two others received livers on July 19 and Aug. 3; the first patient is stable and the second was recently discharged.

“The eight others seem to be doing fine,” Hoofnagle said, although several experienced some symptoms but are improving.

Psychologically, they also appear well, he said. “It’s amazing how cool they were. They weren’t angry. We told them everything.”

Lilly paid the medical expenses for those who became ill, as well as the bills of family members who traveled to be with them.

“It’s a tragedy,” said Stotka, the Lilly scientist. “We feel horrible for the patients’ families and for the patients themselves. The fear that they must have been experiencing, knowing that their fellow members in the trial were getting sick, getting transplants, dying.”

The FDA started its formal review in early July and is treating it as a priority. FDA Commissioner David A. Kessler will not discuss the results until the investigation is complete. But agency sources said that preliminary indications are that the researchers “proceeded very cautiously” and did not act improperly.

But that is small comfort to Hoofnagle.

“I’ve done a lot of clinical trials and I’m used to bad results,” Hoofnagle said. “It’s tough and it scares you. But usually when this happens, you can identify it early and the patient recovers--or the patients have such severe disease that they die anyway.”

“Those I can accept,” he declared. “This is a little different.”