Operation Hope

To paraphrase Shakespeare, the course of true research never did run smooth. Consider the recent rollercoaster ride of Bloomberg School researchers Maria Wawer and Ron Gray. In February, the husband and wife team made headlines around the world with a study from Uganda showing that circumcision dramatically reduced men's chances of contracting HIV from infected female partners. Their randomized trial, involving 4,996 HIV-negative men in the hard-hit Rakai region of the country, found the surgery more than halved the infection rate among participants. Fast-tracked for publication in the February 24 issue of The Lancet, the results echoed similar studies in South Africa and Kenya and sent a much-needed charge of hope to AIDS-ravaged sub-Saharan countries.

Then, on March 6, Wawer and Gray presented preliminary results from a separate circumcision trial of HIV-infected men to a WHO and UNAIDS consultancy meeting in Montreux, Switzerland. Representatives of the agencies had convened to help develop policies for national circumcision programs. The Rakai trial showed preliminary evidence that circumcised men who fail to wait until their wounds heal may have a heightened risk of infecting their female partners. In addition, having sex before the end of a healing period of about four to five weeks makes them more likely to incur post-surgical complications. (Follow-up of these men and their partners is continuing to test the hypothesis, based on observational data, that male circumcision may actually reduce HIV transmission in the long run. Wawer and Gray, in conjunction with an independent data and safety monitoring board that oversees the study, will be closely examining the data about healing and sexual activity and how best to protect women.)

Concerned about how the findings would be portrayed in the media, the investigators organized an international press conference. "It was sobering," Gray says. "We were obviously concerned that the press not blow [the preliminary findings] out of proportion, saying that circumcision is harmful to wives and derailing the scale-up of programs."

Wawer and Gray, both professors of Population, Family and Reproductive Health, were relieved when the international media accurately reported the new information. And, on March 28, the WHO concluded that there was compelling evidence to recommend that male circumcision be made part of a comprehensive HIV prevention package for HIV-negative men. "Countries with high rates of heterosexual HIV infection and low rates of male circumcision now have an additional intervention which can reduce the risk of HIV infection in heterosexual men," noted Kevin De Cock, director of WHO's HIV/AIDS Department. "Scaling up male circumcision in such countries will result in immediate benefit to individuals."

Policy development will now move ahead on a country-by-country basis. The President's Emergency Plan for AIDS Relief (PEPFAR) is considering paying for circumcisions in high-risk countries. Before any programs can be put in place, however, health officials will evaluate everything from surgical technique and the costs of upgrading facilities to training for practitioners and post-operative care.

Much is at stake. As the findings of the initial Rakai study showed, investing in large-scale male circumcision programs could mitigate the epidemic. In the study, HIV-negative men were either circumcised at the beginning of the randomized trial or asked to wait two years. Early results were so clearly beneficial that, in December 2006, an NIH data safety and monitoring board halted the Ugandan trial, as well as one in Kenya, so that the surgery could be offered to men in the control groups. The data showed that male circumcision reduces the infection rate by 50 to 60 percent.

But the experts caution that circumcision is not a quick fix for sub-Saharan Africa's AIDS epidemic. One significant hurdle is developing operating facilities to perform circumcision hygienically and on an ambitiously large scale. In addition, Gray underscores the importance of making sure all circumcised men wait until their wounds heal before resuming sex, because post-surgical complications can occur in those who are HIV-positive or -negative.

Money is also a consideration. Individual ministries of health, as well as the WHO, UNAIDS and PEPFAR, are studying the potential costs of implementing a widespread program. In Uganda, the cost per circumcision was $69, but expenses will go down as countries develop service programs.

The good news, says Gray, is that the Rakai trials proved that circumcision can be done safely and that men are receptive to having the operation. A small percentage in the control group even dropped out mid-trial in order to seek the surgery elsewhere. Infant circumcision, which is cheaper and safer, is "the ultimate goal," says Gray, MBBS, MSc. But the current focus remains on slowing the spread of HIV in the short term by reaching adults.

The researchers stress that any national effort will have to fit into safe-sex education programs already in place, like the one in Uganda which has been effective in containing the spread of AIDS. "We say ABC," says Wawer, "Abstinence, Be Faithful and Condoms. Now we have another C. It's like a four-legged stool instead of a three-legged one."

She and Gray will follow up with a five-year study to investigate how circumcision affects risk behaviors. One concern is that men may view the surgery alone as sufficient protection against HIV and disregard the ABC warnings.

But as part of an infection-reduction regimen, the researchers believe circumcision holds great promise. "A single procedure done once in a person's life conferring a lifelong reduction in risk?" says Wawer, MD, MHSc. "In countries with high levels of HIV, if this becomes standard, the effect could be very significant."