The Pathologist Who Struck Gold

By Anne Bennett Swingle

Brooks Jackson's huge clinical trial in Uganda made him the subject of a public attack. It also cut the transmission of HIV from mother to infant by almost 50 percent.

There are far easier ways to make a living than by running a clinical trial in the developing world. Just building the infrastructure, making the contacts and training the staff can take years of toil and require millions in grant funding. Then, when all the groundwork is laid, so me catastrophe—a revolution, a coup—can wipe out everything. Still, scientists generally agree that the key to finding better treatments for the diseases that batter struggling nations can lie in testing promising drugs on their stricken populations.

When Brooks Jackson opened his big AIDS clinical trial in Uganda four years ago, none of the usual obstacles stood in his way. The Hopkins HIV researcher had hefty funding from the National Institute of Allergy and Infectious Diseases (NIAID), several key government contacts, a well-trained staff and a state-of-the-art lab. What's more, Uganda, after years of deadly guerrilla warfare and brutal dictators, was relatively calm. Government officials in other African countries had turned their backs on the tens of thousands dying around them from AIDS, but Uganda's government was spending time and money educating people about how HIV is transmitted. Jackson's study moved smoothly into its first stages. But within months his protocol had thrust him into the midst of a worldwide melee.

Remarkably, Jackson is not a typical international-health type. He's neither a specialist in public health nor infectious disease, but a pathologist—interim chairman, no less, of Hopkins' huge, historic department. For him, directing a clinical trial overseas is all the more formidable because the work must be blended with the grinding demands of academic medicine to teach, publish and see patients. Still, since the early 1980s, when he was a resident in transfusion medicine, and AIDS was first identified, Jackson's been committed to helping rid the world of this scourge. There was no more obvious place for him to make an impact than in the downtrodden nations of Africa, where the disease was striking up to one in three people.

By the early '90s, Jackson was keen to find a simple, affordable way to cut the spread of AIDS from mother to child in the developing world. Transmission of HIV from a woman to her newborn takes place about 700,000 times a year, usually during the birthing process or through breast-feeding. Yet, in the United States, because infected pregnant women are given AZT starting early in pregnancy, only about 200 babies annually develop the AIDS virus. At $1,700 a case, however, the AZT regimen used in this country is too costly to sustain in developing nations.

Jackson had two drug regimens he wanted to try in Uganda, both considerably less expensive than the U.S. method. The first was a much shorter course of AZT which he would give to infected women and to their infants, the second, a course of the anti-retroviral drug nevirapine, a drug used in combination "cocktail" treatments that have proven so successful in staving off the disease in this country.

By 1997, Jackson's clinical trial—known as HIVNET 012 because it was part of the NIH-sponsored network of HIV prevention trials—was ready to go. It would enroll more than 600 mother/infant pairs. Some would receive AZT, some nevirapine, and some—and this would eventually prove the fire keg—a placebo.

Laura Guay who did the day-to-day work on the 012 study.

Giving a placebo or sugar pill to one group of subjects in a clinical trial while others receive drugs is a tried and true approach. In "double-blind" studies like this one, neither the subjects nor the physicians who direct the trial—in this case Jackson, two Ugandan physicians from Makerere University in Uganda and Laura Guay, an American pediatrician who'd been in Uganda since 1988—know who receives what. At the end of the trial, when the information is "unblinded," though, they are able to assess the success of each drug by comparing the outcomes of patients in the different groups. Jackson's protocol was approved by review boards in Uganda and the United States, and the trial enrolled its first subjects in November 1997.

The study worked like this: Mothers in the AZT group received either AZT or a placebo when labor began and every three hours until delivery. Their babies received AZT or a placebo twice a day for seven days after birth. Mothers in the nevirapine group took just one dose of the drug, or a placebo, at the start of labor. Their babies received one dose of nevirapine or placebo in the first three days after birth.

Then, early in 1998 something unexpected happened. Harvard researchers in Thailand demonstrated that a short, four-week course of AZT could reduce transmission of HIV between mother and infant by 51 percent. Jackson knew, though, that the regimen would be unaffordable in Uganda and decided to forge ahead with his own protocol. It would allow him to compare nevirapine's results with AZT's and also show how subjects treated with both drugs fared in contrast to those who received nothing—the standard of care at that point in Uganda.

Within weeks, he was attacked by a watchdog group called Public Citizen. For Brooks Jackson to continue to use a placebo on some subjects in the 012 study after knowing the results of the Thai study, Public Citizen wrote in the prestigious British medical journal Lancet, was deeply unethical.

At 47, Brooks Jackson is a mild- mannered, amiable man known as a superb collaborator. Unethical is not a word that's ever been used to describe him. Still, Jackson felt strongly that he didn't want to drop the placebo part of his protocol. Testing the two drugs against nothing, instead of only against each other, was the only way to make a valid scientific assessment of the worth of both medications.

It had taken Jackson nearly a decade to get his big HIV trial off the ground. When he first arrived in Uganda in the late 1980s, he had been an associate professor at Case Western Reserve. Mulago Hospital in Uganda's capital city of Kampala had no running water, erratic electrical power and few supplies. Almost no HIV testing was being done, and clinicians weren't even allowed to tell patients they were HIV positive for fear they would commit suicide. Before Jackson could even think of starting a clinical trial, he knew he'd have to establish a modern laboratory to support his research.

Over the next few years, he imported practically every single piece of equipment—generators, water distillers, computers—necessary for a health care clinic. He did it all without a reliable airline, customs or refrigerated shipping. In the meantime, he had to train Ugandan technicians to perform sophisticated assays and make certain that each technician became familiar with US concepts like informed consent, follow-up, data management and quality control. Now, just as all that was about to pay off, it looked as though the meticulously planned study might have to be canceled.

As pressure mounted, Jackson dropped the two placebo arms of his clinical trial, a step that still riles him today. "I could have completed the trial a year earlier, and we could have saved as many as 300,000 kids," he says. As it was, he had to go back to the IRBs and rewrite the protocol.

"The real nub of the issue," he says, "is this: Should a clinical trial be obliged to provide the same drug regimens in developing nations as we do in the United States, even though those regimens won't be affordable or easy to administer in those countries once the trial is over?

The placebo controversy is another frustration. "No researcher," Jackson says, "can assess a drug's effectiveness with scientific certainty without testing it against a placebo. That's the only way we can know for sure if a short course of AZT or nevirapine is better than nothing."

Working abroad in a study like his can present a Catch-22 dilemma for American investigators, Jackson says. "If the trial had been done exclusively by Ugandan investigators who had decided simply to test nevirapine against a placebo, no one would have batted an eye. But because we're Americans and NIH-funded, all of a sudden we're unethical. These kinds of barriers can make it almost impossible to find good solutions for medical dilemmas facing developing nations."

 

The clinic in Kampala, built by Makerere University and Hopkins.

As the 012 study lurched on, Jackson was resigned to simply producing enough preliminary data to determine which of the two drugs he would ultimately test against other potential drug regimens. In the summer of 1999, after the trial had enrolled more than 600 mothers, the NIH got ready to unblind the data. Jackson and the other researchers would now discover which subjects had received AZT, which nevirapine and which a placebo. They would be able to clearly compare the effect of both AZT and nevirapine on the transmission of HIV from mother to child.

The data proved stunning. It showed that nevirapine was 47 percent more effective than AZT and had reduced the number of infected infants from 25 to 13 percent. Best of all, nevirapine was inexpensive—just $4 for both doses. If implemented widely, the drug could prevent HIV transmission in more than 300,000 newborns a year.

Jackson's findings were announced jubilantly in Kampala, by the Ugandan Minister of Health. In the United States, on July 14, 1999, Vice President Gore broadcast the news around the world. Today, Hopkins AIDS researcher Tom Quinn, of the Division of Infectious Diseases, defines Jackson's study as a breakthrough in the prevention of mother-to-infant transmission. "Make no mistake about it," he says. "What made it so important is that nevirapine is affordable and sustainable." Many would call the study a perfectly constructed clinical trial by a superb academician.

And yet, academic medicine appeared late on Jackson's radar screen. After graduating from Kenyon College with a degree in history, he earned an MBA at Dartmouth, then joined the family coal-mining business in Cincinnati. "That lasted less than a year. It was 1977, and after six months on the job, there was a violent United Mine Workers strike that dragged on. "I thought, this is not the life I want to have," he remembers.

Jackson returned to Dartmouth, this time to round out premed requirements. To support himself, he took a job as administrative manager of the pathology lab at Mary Hitchcock Hospital. It was a life-defining decision. Even before entering medical school at Dartmouth he knew his subspecialty would become transfusion medicine.

By the time he'd entered the pathology residency at the University of Minnesota in 1982, the worldwide problem was AIDS and Jackson had jumped with both feet into HIV research. By 1986, he was providing laboratory support for the national AIDS Clinical Trials Group (ACTG). "You know," he says, "you're in all these conference calls for these clinical trials, and you start to realize, Boy, I could do a clinical trial."

By the early 1990s, Jackson was jetting back and forth between Kampala and Cleveland. A year before his big trial in Uganda opened, he and his wife and three young sons moved to Baltimore, where he'd been recruited to become Johns Hopkins' deputy director of pathology for clinical affairs. Jackson arrived at Hopkins with all the underpinnings for studying a kind of HIV research—mother-to-infant transmission—that had never been practiced here. He brought Guay, his HIV lab, a couple of staff and a sky-high pile of research dollars. (This year, he was introduced at the Alpha Omega Alpha honors dinner as the Hopkins researcher with the most grant funding. That may well be true—if no one else brings in more than $30 million as a principal investigator.)

Jackson in his Hopkins HIV Specialty Lab.

Jackson has one more big asset: he has the energy of someone half his age. He's been known to arrive on the other side of the world at midnight after a 15-hour flight, check into a hotel and be out on the streets jogging 10 minutes later. He's a marathon runner and has completed nearly a dozen races, though these days, with a raft of departmental responsibilities in addition to his overseas projects, he has little time in which to train. He continues as an attending on the blood-bank service. "It's a way to keep involved with patients and residents and see how things are working administratively," he says. Through it all, he projects tranquillity.

But what really sets him apart, says Sue Eshelman, an HIV basic science researcher Jackson recruited from Case Western, "is his ability to see long-range. He looks into the field of HIV, sees the problems that need exploring and knows what needs to be done."

Today, Jackson's HIV Specialty Lab provides a staggering number of services every month for the Hospital, for industry, for the ACTG and for clinical trials at medical centers around the country. It processes samples and performs some 40,000 tests in the diagnosis and monitoring of HIV infection. And it is now the central lab for HIVNET's successor, the HIV Prevention Trials Network, or HPTN, the NIH worldwide trials network that will test non-vaccine preventions at 16 international and nine domestic sites.

Today Jackson is on the move with nevirapine. He wants to test the drug's power to prevent HIV transmission among IV drug users in China. According to Hopkins HIV researcher Hua Shan, about half of the drug users in China still use needles, and some 40 to 70 percent of them admit to sharing needles. Shan, born in Beijing 40 years ago and fluent in Mandarin, will do the day-to-day work on Jackson's study, much as Guay did on the 012 trial.

This phase III, placebo-controlled trial is supposed to take place in two of China's poorest areas, Xinjiang and Guangxi. It's a daring plan, one that leaves even the likes of Tom Quinn, an investigator who has worked in 20 different countries, gasping for breath. "Brooks is going out on a little more of a limb here. He'll be bearing some risk until he can prove benefit, and that will be tough."

There will be the concerns that widespread use of nevirapine will create resistant virus, that the drug will be toxic, particularly to liver function, if used over a long period. (The long-term effects of nevirapine still are unknown.) The chief criticism, though, will be that if the drug is proven effective, people will think they're protected from becoming infected with HIV and continue risky behaviors like IV drug use. Participants receive intense counseling when they enroll in the study, but that, some will say, is hardly sufficient. In fact, NIAID, the study sponsor, recently suggested that Jackson's subjects in China should have access to a full array of established treatment programs, just like those in America.

Now, with the cumbersome review process coupled with new, controversial international doctrines involving human subjects research threatening to cripple his clinical investigation, Jackson again is exasperated. "American-style treatment programs are impractical at this point in China," he protests. "It's unrealistic—even unethical—to think that we could provide Western standards of care to everyone in the world." He is mulling alternative venues, funding sources and subjects, even as he continues to negotiate with the NIH. For Brooks Jackson, dealing with the United Mine Workers is starting to look easy after all.

There's a place in Kampala where kids come for their vaccinations and to be treated for all the illnesses of childhood, a clean, bright clinic with rooms for medical care, and a reception area where mothers and children watch health videos while they wait. It's called the MU-JHU Research House, for Makerere University and Johns Hopkins, and it is here that those who participated in the landmark 012 trial are followed.

"You know," says Jackson, "one of the things I'm most proud of is building that clinic. Even if we had accomplished nothing in terms of the HIV research, we would have saved literally thousands of lives just in providing day-to-day care for the kids and mothers too. Even after we're gone, they're going to have the clinic."

It's been 12 years since Jackson started working here, and in that time Uganda has done more to slow the spread of AIDS than any other country in Africa. It's also become a center for AIDS research. With Jackson turning his attention to China, Guay, now an associate professor of pathology at Hopkins, remains in Kampala and is principal investigator on her own trials. Supporting these studies is the lab that Jackson established, now manned by experienced Ugandan technicians. All of Guay's work is aimed at mother-to-child HIV transmission and the implementation of nevirapine.

The controversy over placebo-controlled trials has died down and shifted to the arena of third-world drug costs. The World Health Organization, meanwhile, has recommended that all HIV-infected pregnant women receive nevirapine as an option. Thanks to the landmark 012 study, the drug's manufacturer, Boehringer Ingelheim Pharmaceuticals, now provides nevirapine free for five years to governments that request it.

"It was high risk, but it was also high return," says Jackson, as he thinks back to the clinical trial. "For me, it's personally been very satisfying. But you know, we were just so lucky. We struck gold with nevirapine."