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  Cutting the Risk

Bloomberg School researchers working in Uganda have shown that circumcision is a surprisingly effective way to prevent HIV transmission.

By Cassandra Willyard
Illustration by Josée Masse

Maria Wawer was on vacation in Italy when the call came. She hadn't left a number where she could be reached, but her dogged assistant at Columbia University, where Wawer was then an assistant clinical professor in the School of Public Health, had tracked her to a hotel in San Gimignano. Wawer was an expert in setting up community studies, and Columbia needed her in Uganda to assess whether a small AIDS study would be feasible. Everything Wawer had heard about Uganda was beyond uninviting, but she hesitantly agreed to go.

The year was 1987. Uganda was fresh out of a series of civil wars that had lasted more than a decade; the country was barely back on its feet. Wawer landed to find the airport in shambles. "The place was a mess," she remembers. "You couldn't even get a beer." She took one look and thought, "This is hopeless. Nothing can be done, and I'm getting out of here as fast as I can."

But Wawer couldn't leave without at least finding the people she'd been sent to meet, two doctors named David Serwadda and Nelson Sewankambo. They had been among the first to identify AIDS in Uganda in the early 1980s. Since then, they had been looking for funding to figure out who was developing AIDS and why — first steps in understanding how to prevent the spread of the disease.

Mulago Hospital in Kampala, where Serwadda and Sewankambo worked, was only 30 kilometers from the airport, but it took Wawer two days to arrange transportation. "We met in this little dusty office," says Wawer. "They started talking about what they hoped to do, and they were so serious and so no-nonsense and so focused. My interest began to get piqued."

Serwadda remembers that meeting as well. At almost six feet, he towered over Wawer. "I took one look at Maria, and I said, 'Oh God, she's so small. I don't know how she's going to manage in this hard environment.'"

Serwadda took Wawer to Rakai, the district in southern Uganda where he and his colleague hoped to work. The government-run health centers there lacked even the most basic items. "There were no mattresses on the beds," says Wawer. "There weren't even rubber gloves; the midwives were delivering babies with their bare hands." Beyond all this, a sense of fatalism prevailed. "You'd hear young guys say, 'Why bother? If AIDS doesn't kill us, something else will.'"

But that didn't deter Wawer. She agreed to help the Ugandans get a study up and running. "What would be possible was not clear," she says, "but you just roll up your sleeves and start hacking away." She never anticipated that 20 years later she'd still be working on HIV in Uganda. Wawer, now a professor in the Department of Population, Family, and Reproductive Health at the Johns Hopkins Bloomberg School of Public Health (in addition to her continued appointment at Columbia), is devoted to her Ugandan colleagues and their work in Rakai. "She turned out to be a toughie," Serwadda admits.

In the mid-1990s, Wawer convinced her epidemiologist husband, Ronald Gray, a professor in the same department at the Bloomberg School, to join the team. The two have a combined 30 years of looking for ways to stop the spread of HIV in Uganda. The work has been discouraging at times, but last year they tested a surgical procedure that produced remarkable results. It's no magic bullet, but, as Serwadda once told Gray, "If you had a vaccine as efficacious as this procedure, you'd be dancing in the streets."

For reasons that aren't entirely understood, sub-Saharan Africa has borne the brunt of the HIV/AIDS epidemic. The region holds just 10 percent of the world's population, but 60 percent of the world's HIV cases — about 26 million infected people. Uganda, though it's still home to more than a million HIV-positive individuals, is often touted as the region's success story. Over the past decade, the percentage of the population infected with HIV has declined from a peak of 15 percent in the mid-1990s to about 6 or 7 percent today.

The AIDS epidemic hit Rakai harder than other parts of Uganda. The virus traveled quickly along the major highways, and slowly worked its way into more rural areas. When Wawer first arrived in the district, she found that HIV prevalence was about 39 percent in towns along the main roads, 25 percent in smaller villages on dirt roads, and only 9 percent in rural villages. Today, about 12 percent of adults in Rakai are infected, almost double the national average. And a great many people are still dying. "When you're going through the countryside you see so many graves," says Serwadda. "And many other people have yet to come full circle into the whole maturation of the disease. So that is a little bit frightening at times."

Serwadda, Sewankambo, and Wawer began their project in 1987 with only $100,000, a few hired assistants, and a couple of rented rooms at a local hotel called the Milano South View Inn. In their first year, they interviewed more than 1,000 people in 21 villages. During the day, the 10-person survey team collected personal information and drew blood samples. At night, they returned to their rooms and spun the blood using a hand-operated centrifuge. When the electricity was on, they worked by the light of a dim bulb. When it wasn't, they worked by candlelight.<>

No one had ever used surgery to combat infectious disease, and people found it hard to believe that the foreskin could be "such a risky piece of tissue,"says Gray.
Today, the Rakai Health Sciences Program operates out of a 19,000-square-foot, $2 million health center. The program employs almost 400 people and generates its own electricity. The survey team interviews 14,000 people in 50 villages every year, and has multiple studies under way outside of the annual survey. The lab is state-of-the-art. "Even some of the visitors from Hopkins are envious," says Serwadda.

The information coming out of Rakai has been invaluable to AIDS researchers around the world. "I think the Rakai collaborative program and the whole family of studies is one of the most highly valued research collaborations in Africa," says Chris Beyrer, associate director of the Center for Global Health at the Bloomberg School. "It has allowed us to ask and answer some of the most difficult questions in global AIDS."

The program's success comes, in part, from the fact that it's run by Ugandans rather than muzungus — white foreigners. Wawer and Gray devote all of their research time to the Rakai program, but they work in Uganda only two or three months out of the year. "We don't want to micromanage," says Gray. "We talk strategy, talk tactics, talk science, but we leave them to run the show."

Gray and Wawer met in 1981. Gray had recently come to Johns Hopkins from London, where his first marriage had fallen apart. Wawer was junior faculty at the time (before her stint at Columbia), and she came to Gray's office to ask him a question. "I've never seen anyone glow as she did," says Gray, "sort of radiating heat." "I had a fever," Wawer remembers. Bug bites from working in Zaire had festered, forming tropical ulcers on her legs. Fortunately she was wearing a long skirt that day. "Apparently he fell in love," says Wawer. "In lust," Gray counters. By the end of their first kiss, Wawer was hooked, too. "I remember thinking to myself, 'Don't let this be a one-night stand because he's a nice guy.'" She laughs. "Twenty-five years later, careful what you wish for."

When they're not working in Africa, Wawer and Gray spend most of their time on the fourth floor of the Bloomberg building in Baltimore. They have separate offices but share a common area. On the wall hangs a photograph of a man's foreskin, enlarged under a microscope so that individual cells are visible. An unusual bit of interior decorating to be sure, but it is at the heart of what Wawer, Gray, and their Ugandan colleagues have discovered — men who are circumcised are much less likely to contract HIV than those who aren't.

The idea that circumcision might protect against HIV infection is actually not new. In the mid-1980s, researchers began to notice that regions like sub-Saharan Africa, where circumcision is rare, typically have high rates of HIV. But most of the circumcised men were Muslim and most of the uncircumcised men weren't, which made it impossible to tease out whether the difference in HIV rates was due to a lack of foreskin or other cultural practices. Islamic men, for instance, rarely drink and tend to have limited sexual networks.

Gray and Wawer had heard the circumcision theory, but they didn't have time to study it until 1999. The Rakai team had just finished a massive study to determine whether treating other STDs would reduce the spread of HIV. The trial failed. The data showed that a person's viral load was a much better predictor of who would transmit the virus than whether or not the individual had a bacterial infection like gonorrhea or syphilis. "We were utterly depressed," says Gray. Adds Wawer, "There's no feeling like opening that envelope and finding out that something you thought was going to work didn't."

But buried in their STD data was a thread of hope. Some of the couples who had participated in the STD trial were pairs of HIV-negative men and HIV-positive women. The data from those couples showed that, over four years, none of the men who were circumcised had contracted HIV. Transmission among uncircumcised men, however, was about 16 percent per year. "That couldn't be explained by behaviors," says Gray. "The only difference was the absence of the foreskin."

Bloomberg School researchers Ronald Gray and Maria Wawer have dedicated a combined 30 years to fighting the spread of HIV in Uganda.

Wawer and Gray knew that the only way to get definitive proof would be a clinical trial. They would need to recruit thousands of HIV-negative men from the same population, circumcise half of them, and compare HIV rates between the two groups. So, a year later, they began looking for funding. "People just laughed at us when we first suggested trials," remembers Gray. No one had ever used surgery to combat an infectious disease, and people found it hard to believe that the foreskin could be "such a risky piece of tissue," says Gray. Even Wawer was pessimistic. "I frankly did not think it was going to work anywhere near this well," she says.

Finally, the National Institutes of Health (NIH) agreed to pay for a trial of 5,000 HIV-negative men. But Gray and Wawer also wanted to look at whether circumcision might reduce the chance that an HIV-positive man would pass the virus on to his HIV-negative partner. Data from their STD trial indicated that it might. At the time, the NIH wasn't funding prevention research involving people who were HIV-positive. So Wawer and Gray went to the Bill and Melinda Gates Foundation to plead their case. By 2003 they had funding for both trials.

Because circumcision had never been done en masse in a developing country, the Rakai team took special precautions to ensure that the surgery would be safe. They outfitted the operating rooms with a dizzying array of equipment — an autoclave, surge suppressors, surgical tools, operating tables — some of which had to be shipped from the States. Wawer and Gray brought the Rakai program's chief urologist and two nurses to Johns Hopkins to help train their staff. "We didn't want to take any risks," says Wawer. Back in Uganda, the team had no problem finding men willing to join the study. In Rakai, there is a "positive vibe" surrounding circumcision, says Wawer. In 2003, the surgeons began circumcising half of the men, randomly chosen from the group. Afterward, the men were advised to abstain from sex until a doctor certified that they were fully healed, about a month, because open wounds increase the chance that a man will contract HIV (if he's negative) or will infect his female partner (if he's positive).

The research team also warned the participants in both trials that circumcision might not protect either them or their partners. They offered them condoms and advised them to practice safe sex. Ethically, they had no other choice. But encouraging the use of condoms and safe sex presented them with a dilemma: If all the men heeded their advice, the HIV transmission rate would be the same in both the circumcised and uncircumcised groups — zero. "Even if you're shooting yourself in the foot," says Gray, "you always try to maximize protection." And in fact, condom use did go up in both groups. One reason the researchers used such a large sample in this study was to offset the fact that people would start to have safer sex.

Wawer and Gray conducted a blind study in which they were not allowed to see their data before the trial was finished. Not knowing the results keeps researchers from intentionally or unintentionally influencing the study's outcome. "The best way to keep you honest is to keep you blind," Gray explains. Their trial, like all trials, was overseen by an independent group, the Data and Safety Monitoring Board (DSMB). It included clinical researchers, ethicists, community representatives, and statisticians.

On December 12, 2006, Wawer, Gray, Serwadda, and Sewankambo gathered in a small room at the NIH while the DSMB pored over their data from the trial of HIV-negative men. "They made us sit a long time," Wawer remembers. Another group that had run basically the same trial in Kenya went first. The Kenyan group wasn't supposed to tell the Rakai team their results, "but of course you look at them and you read their body language," says Wawer. They'd obviously received good news. Wawer worried that Rakai's results would be negative, throwing a wrench into a promising new prevention strategy. Finally the DSMB called them in. Circumcision had reduced the study participants' chances of contracting HIV by a whopping 60 percent. The results were so convincing that the DSMB stopped the study ahead of schedule so that those men who hadn't been circumcised, the control group, could have the procedure. "By that point we were so tired we didn't even say anything," Wawer says. "But we had a very good party," Gray adds.

The preliminary results of the Gates Foundation-funded study of male-to-female transmission have been less promising and more controversial. In March, the DSMB looked at the data and found a disturbing trend. Men who had been circumcised seemed slightly more likely to transmit HIV to their partners than uncircumcised men. To be safe, the DSMB halted enrollment. "It was a very difficult judgment call," says Wawer. "They decided that if there was a risk, and enrollment continued, then harm would have been done." A closer look at the data suggests that the increased risk was due to a small group of circumcised men who had sex before their wounds healed. Then again, the finding was based on so few cases that the difference in transmission never reached statistical significance. So it could have just been bad luck. Either way, Gray and Wawer felt obliged to report their findings to the World Health Organization (WHO), which was in the process of drafting circumcision guidelines.

The results were so convincing that the study was stopped so that men in the control group could be circumcised.
Making the jump from science to policy, however, takes time. The WHO began recommending circumcision as an HIV prevention strategy and published the guidelines in late March. The Ugandan government has put together a task force to develop its own guidelines and a strategy for safely rolling out a mass circumcision campaign, but they are proceeding cautiously. They want to make sure that everyone understands that circumcision does not offer full protection against HIV and isn't a substitute for condom use or abstinence.

Meanwhile, demand for circumcision has steadily increased in Uganda. "People are very excited because, frankly, there are not many options out there," says Beyrer. "We haven't had a new prevention tool in a number of years."

The procedure is rare in Uganda — only about 15 percent of the men in Rakai are circumcised — and most physicians aren't trained. "The big concern is that if we don't move fast, we're going to have men going off to quacks, possibly suffering terrible injuries," says Wawer.

But health officials are also concerned that the men will have sex before their wounds have closed. "We shout until we are hoarse trying to emphasize the point that you [can only] resume sex after you've been certified as healed," says Serwadda. "But I'm still concerned that there will be guys who, in the heat of the moment, will have sex too soon. There's that risk that we have to manage somehow."

And then there's the cost. The Rakai team has proven the concept, but they've done it with an eye on safety rather than expense. In the trial, each circumcision cost about $65. The average Ugandan earns just $300 a year. Gray and Wawer have already moved on to their next project — figuring out how to reduce the cost of the procedure while keeping it safe. The Rakai program will also provide circumcision for free using money from the President's Emergency Plan for AIDS Relief, and will serve as a training facility where physicians learn how to perform the operation.

Working on the front lines of the AIDS epidemic isn't easy. The key, Wawer explains, is to stay focused. "You can't do this work if you get emotionally distraught," she says. Working in public health means thinking about the future of an entire community, not just a single individual. Not every sick baby can be saved. "You can't do it all," says Wawer. "And if you try to do it all, if you feel the responsibility of the whole world on you, you get paralyzed and you don't do anything." But the challenge can be addictive. "Once you get caught up in trying to do something on HIV and AIDS," says Wawer, "it's very hard to let go."

Freelancer Cassandra Willyard, A&S '07 (MA), Johns Hopkins Magazine's 2007 Corbin Gwaltney Fellow, is now based in New York City.

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