December 13, 2006

1.		Who funded and who conducted the two adult male circumcision trials in Africa?
		The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), supported two clinical trials, one in Rakai, Uganda, and the other in Kisumu, Kenya, designed to determine whether adult male circumcision is safe and can prevent men from acquiring HIV infection in geographic areas where heterosexual transmission of the virus is most common. The Ugandan study, led by Drs. Ronald Gray and Maria Wawer of Johns Hopkins Bloomberg School of Public Health and Drs. David Serwadda and Nelson Sewankambo of Makerere University in Kampala, Uganda, enrolled 4,996 men since the trial began in August 2003. The Kenyan trial, also known as the UNIM trial (Universities of Nairobi, Illinois and Manitoba trial), opened in February 2002, in a collaborative effort between U.S., Canadian and Kenyan researchers. Drs. Robert Bailey, University of Illinois, Chicago, Stephen Moses, University of Manitoba, Jeckoniah Ndinya-Achola, University of Nairobi, and Kwango Agot, UNIM, are funded by NIAID and the Canadian Institute of Health Research. This trial enrolled 2,784 men.
2.		What is a Data and Safety Monitoring Board, and how does it monitor this study?
		A Data and Safety Monitoring Board (DSMB) is an independent committee composed of clinical research experts, statisticians, ethicists and community representatives. The DSMB reviews data while a clinical trial is in progress to ensure the safety of participants. The DSMB may recommend that a trial, or part of a trial, be stopped if there are safety concerns or if the trial objectives have either been achieved or are unlikely to be achieved. During the trial, the DSMB looks at analyses that are not available to the investigators or to anyone else.
3.		What were the results of the most recent DSMB review of the two circumcision trials?
		The NIAID adult male circumcision trials have been under the review of the NIAID Prevention DSMB. On December 12, 2006, the NIAID DSMB reviewed an interim data analysis of the trials and determined the following: Adult male circumcision performed by trained medical personnel and with appropriate post-surgical follow-up to ensure management of any infections or other problems with wound healing was shown to be safe. Among men in these trials, adult male circumcision reduced the risk of acquiring HIV infection by 48 percent in the Ugandan study and by 53 percent in the Kenyan study. Given these results, both trials will offer men in the control group circumcision. In order to understand the long term impact of adult male circumcision, the studies will continue to measure HIV infection rates and to study the risk-taking behavior and attitudes of participants.
4.		What is adult male circumcision and how was it performed in these studies?
		Adult male circumcision is a surgical procedure to remove the foreskin (prepuce) of the male penis. The NIAID-supported trials tested whether there is a decreased risk of HIV infection among men who were circumcised, in which their foreskin has been nearly or completely removed, compared with men who were not circumcised. Both studies performed the circumcision in a surgical room with local anesthesia. The circumcision procedure used in the Kenyan trial was the foreskin clamp method. The Kenyan trial procedure took about 25 minutes and used stitches to control bleeding and improve wound closure. The circumcision procedure used in the Ugandan trial is known as the sleeve method and takes about 30 minutes. The Ugandan trial used cauterization of the blood vessels to control bleeding and stitches to close the wound. Both methods are commonly used throughout the world.
5.		How were the studies designed?
		Both trials recruited healthy, HIV-negative uncircumcised men who planned to remain near the study site for the duration of the trial. The trial in Uganda recruited men between 15 and 49 years old; the trial in Kenya recruited men between 18 and 24 years old. After an initial HIV screening and a medical exam, eligible men were randomly assigned either to receive circumcision immediately or to wait two years before circumcision. All participants were closely followed for two years to collect information about their health, sexual activity, and theirs and their partners’ attitudes about circumcision; to counsel participants in HIV prevention and safe sex practices; and to check the HIV status of the volunteer. Participants in the Kenyan study were scheduled for six visits over the two-year follow-up, compared with four visits for the Ugandan trial participants. In addition to the study visits, men enrolled in the Kenyan trial were encouraged to receive all of their outpatient health care at the study clinics, which enabled researchers to collect information on the safety of the procedure and the number of other sexually transmitted diseases the men had during follow-up.
6.		What were the primary objectives of the adult male circumcision trials?
		The primary objectives of these studies were to determine whether adult male circumcision 1) can be administered safely, and 2) reduce the risk of acquiring HIV infection through heterosexual contact.
7.		Why were these studies done?
		Previously published studies on male circumcision found a protective effect against HIV acquisition ranging from 40 to 88 percent. However, since male circumcision is closely tied to culture, it was not possible to rule out other cultural factors as the reason for the lower HIV rates in circumcised men. Scientists concluded that there was insufficient evidence from these observational studies to support adult male circumcision as a means of reducing HIV acquisition in men, and therefore, called for randomized controlled trials of adult male circumcision.
8.		What other trials have been conducted?
		The first randomized controlled trial of adult male circumcision was funded by the French government’s research agency, Agence Nationale de Recherches sur la SIDA (ANRS). The trial, ANRS-1265, was conducted in South Africa to test the effect of adult male circumcision on HIV acquisition. Led by Dr. Bertran Auvert, the investigators found a 60 percent reduction in HIV acquisition for the men enrolled in the circumcised arm of the trial. (Auvert B, et al. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Med. 2005 Nov;2(11):e298. Epub 2005 Oct 25.) There were a total of 69 HIV infections among participants: 20 were among the 1,546 circumcised men and 49 among the 1,582 uncircumcised men. Despite these results, there was still debate among clinicians, policy makers and the international community over whether these results could be generalized to different populations. These NIAID-sponsored trials provide additional scientific evidence for the role of adult male circumcision in HIV prevention.
9.		How could male circumcision prevent HIV infection?
		There are several proposed mechanisms for how male circumcision might reduce a man’s risk of HIV infection. The foreskin’s inner mucosal surface is more susceptible to HIV because it has more immune cells vulnerable to HIV infection than the external surface. Furthermore, the foreskin acts as a physical barrier, trapping HIV next to the mucosal surface of the penis for a longer period of time. In this moist environment, the virus can also survive longer, potentially increasing the risk of infection. Small tears in the foreskin as a result of intercourse could also promote entry of the virus. After circumcision the penile shaft and glans develops more epithelial keratinization, a process which makes the penis less susceptible to viral invasion.
10.		What are possible negative biological and behavioral complications associated with adult male circumcision?
		Male circumcision is a surgical procedure with recognized risks. There have been multiple reports of serious complications and adverse events following improperly performed male circumcision, including serious infection, severe loss of blood, mutilation, penile amputation and death. These serious complications are due to poor training of those performing circumcision, lack of appropriate surgical equipment, and lack of patient follow-up. Furthermore, the procedure requires some time for healing, and during that time there is a break in the epithelial (skin) surface of the penis. This incision site may be a portal for HIV entry and until fully healed, it may increase the risk of HIV infection. For this reason, men in the trials were cautioned to not resume sexual activity until the incision was fully healed and checked by the physician. As with most prevention strategies, adult male circumcision is not completely effective at preventing HIV transmission. Millions of circumcised men have become infected with HIV through heterosexual exposure to the virus. Men who receive adult male circumcision may perceive that they are at decreased risk for transmission and, therefore, may not maintain other risk reduction strategies. Modest increases in the number of sexual partners could negate the protective effect and increase the rate of HIV transmission in a community. Adult male circumcision will be most effective when integrated into a comprehensive prevention strategy which includes the ABCs (Abstinence, Be Faithful, and Condoms) of HIV prevention.
11.		How common is male circumcision in Africa?
		Studies have shown that overall, 62 percent of adult males in Africa are circumcised. However, there are significant differences in these rates by region and tribal groups. In particular, male circumcision is strongly tied to religious beliefs. In Southern Africa, where the HIV epidemic is the most severe, rates of male circumcision are less than 20 percent.
12.		How acceptable is adult male circumcision in Africa?
		Surveys conducted in Africa in both men and women have found that adult male circumcision is acceptable (50 to 86 percent), provided that the procedure is safe, affordable and has minimal side effects or pain. Among the reasons cited include better hygiene, lower sexually transmitted disease rates, more modern/urban appearance, peer pressure and perceived attractiveness to women. However, because of varying religious and cultural norms, not all groups or communities practice adult male circumcision.
13.		How might these new findings affect future HIV prevention strategies?
		These results indicate that HIV transmission to men could be lowered, though not eradicated, by increased rates of male circumcision. Adult male circumcision is only one component of a comprehensive prevention strategy. As a partially effective procedure, it can be an important component of a comprehensive prevention strategy that also stresses the ABCs: abstinence and delay of sexual debut, overall partner reduction and reduction in number of concurrent partners and correct and consistent use of condoms. These studies looked only at risk of heterosexual HIV transmission from females to males. The risks associated with other modes of transmission, such as male-to-male and male-to-female sexual transmission, are not addressed, and risks associated with needle sharing are not affected.
14.		How will these findings influence other prevention trials already under way?
		Other trials and research are under way to evaluate methods and strategies (e.g., microbicides, pre-exposure prophylaxis, vaccines and behavioral interventions) for HIV prevention. These studies are being conducted in a variety of different populations and settings. These results indicate that adult male circumcision may play an important role in the prevention of heterosexual HIV transmission to males in some areas of the world. In areas where international and country-specific HIV prevention recommendations are adapted to include male circumcision, research trials will need to determine how to ensure that education about, and access, to safe male circumcision is incorporated into comprehensive trial prevention services.
15.		Will these results have an effect on policy in Africa and other regions?
		United Nations agencies, including the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO), are multinational organizations that guide health ministries and aid organizations in determining how research findings should be applied to recommendations for and provision of health services in different parts of the world. These agencies will review the data from these studies and develop appropriate policy guidelines. In preparation for the possibility of these findings, WHO and UNAIDS are working with key stakeholders in several countries to host country consultations and conduct needs assessments to help prepare for any change in policy that may result from the findings of these studies. To learn more about the international response to the study findings, visit the WHO website at www.who.int/hiv and the UNAIDS website at www.unaids.org.
16.		How will these results affect the U.S. epidemic?
		These NIH studies have focused on populations in Africa, where the infection rate is high and where heterosexual sex is the predominant mode of HIV transmission. In the United States, the majority of adult men are already circumcised. According to the U.S. Centers for Disease Control and Prevention (CDC), in a 1992 survey, 77 percent of men in the United States reported being circumcised. In addition, there is a lower prevalence of HIV in this country, and the men at greatest risk have been those who have sex with other men. The degree of protection that circumcision may afford for men who have sex with men is unknown. For all of these reasons, the study findings will likely have less of an impact in the United States. Information about circumcision is available from the CDC at http://www.cdc.gov/hiv/resources/factsheets/circumcision.htm.
17.		Are other studies of male circumcision being conducted?
		In addition to the NIAID trials in Uganda and Kenya, a randomized trial led by researchers at Johns Hopkins University is studying whether male circumcision reduces male-to-female HIV transmission. (In contrast, the NIAID trials studied whether male circumcision reduces female-to-male transmission.) The Johns Hopkins-led trial, which is supported by a grant from the Bill & Melinda Gates Foundation, is scheduled for completion in 2007.

For media inquiries about this trial, please contact Victor Zonana at Global Health Strategies at vzonana@ghstrat.com.

Media inquires also can be directed to the NIAID OCPL media group at 301-402-1663, niaidnews@niaid.nih.gov.

NIAID is a component of the National Institutes of Health. NIAID supports basic and applied research to prevent, diagnose and treat infectious diseases such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis, malaria and illness from potential agents of bioterrorism. NIAID also supports research on basic immunology, transplantation and immune-related disorders, including autoimmune diseases, asthma and allergies.

The National Institutes of Health (NIH)—The Nation's Medical Research Agency—includes 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov

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