The Rakai trials enrolled uncircumcised men aged 15–49 y who provided informed consent for screening and for randomization to immediate circumcision (the intervention arm), or circumcision delayed for 24 m (the control arm). The profile of the two parallel trials is provided in , and details of trial design are reported elsewhere [1
] and described in Texts S1
. In brief, 6,461 consenting men were screened. If they were HIV-negative, had no contraindications against or medical indications for surgery, and accepted voluntary counseling and testing (VCT), they were enrolled into an NIH-funded trial of HIV-negative men. Men who were HIV-infected at screening, who did not have symptoms of AIDS (WHO stages I or II) or CD4 count < 350 cells/mm3
, and who did not have contraindications to or indications for MC, were offered VCT and were enrolled into a Gates Foundation-funded trial. There were 540 screened men who were ineligible for either trial or who failed to complete enrollment and were excluded. The trials were conducted in 50 rural communities of southwestern Uganda, thus enrollment and follow-up were decentralized, but all surgery took place in fully equipped outpatient theaters located in a central facility.
Profile of Trials for HIV-Positive and HIV-Negative Participants
In the NIH-supported trial, the primary end points were safety and HIV acquisition. A total of 2,474 participants were randomized to receive immediate circumcision. Of these, 2,328 (94.1%) received surgery within 6 m of enrollment, which was completed in August 2005. Two seronegative men who subsequently seroconverted were found to be PCR positive but antibody negative at enrollment and are excluded from the analysis, leaving 2,326 HIV-negative men who received circumcision surgery. The Gates Foundation-supported trial enrolled 925 HIV-positive men, and the primary endpoints for male participants were safety and sexually transmitted infection effects. Of these 925 HIV-positive men, 474 were randomized to immediate circumcision and 420 (88.6%) had received surgery by December 19, 2006, when enrollment was closed. The Gates Foundation trial Data Safety Monitoring Board (DSMB) closed enrollment of HIV-positive men because the NIH trial was stopped for efficacy on December 12, 2006, and it was no longer feasible to mask the HIV status of new HIV-positive participants, (since HIV-negative men could no longer be randomized to the control condition). At enrollment, 864/925 (93.4%) of circumcised HIV-positive men accepted VCT.
Enrollment and follow-up procedures were identical for HIV-positive and HIV-negative men. All men provided written informed consent for screening and trial enrollment. Men randomized to the intervention arm in either trial provided written informed consent for surgery, which described the procedure, risks of surgery, and the requirements for postoperative wound care (e.g., personal hygiene, keeping the wound dry, and recognizing signs of complications), and they were strongly advised to refrain from sexual intercourse until the wound was certified to be fully healed. Men were also advised to practice safe sex, including as appropriate sexual abstinence, monogamy with an uninfected partner, and consistent condom use. Attempts were made to contact spouses of male participants, and these female partners were also instructed on wound care, the need for sexual abstinence until wound healing was certified, and were counseled on the subsequent practice of safe sex. Free condoms were offered to all participants. Free individual and couples counseling was also offered to all participants and their spouses.
All participants had a medical examination, and any penile pathology such as genital ulcerative disease (GUD), discharge, or balanitis were treated prior to surgery. Circumcision was performed by trained physicians in fully equipped outpatient operating theaters. The physicians had completed an internship and were trained by the senior urologist (SW). Training consisted of initially observing surgeries and conducting a minimum of 15 supervised procedures prior to certification of competence. The sleeve circumcision procedure was used: details of surgery are provided in the paper reporting the results of the NIH-supported trial in HIV-negative men [1
]. All men (HIV-positive or HIV-negative) received the same surgical procedure and postoperative care. Postoperative follow-up visits were scheduled at 24–48 h, 5–9 d, and 4–6 wk. Men could access care at any time if complications occurred between scheduled visits. Follow-up was conducted by health workers (clinical officers and nurses) who were trained to diagnose and treat complications or to refer patients for specialized care if needed. Visits took place at the surgical center, in the participant's home, or at central sites (“hubs”) located in the rural communities. At each visit, a structured history was taken to detect symptoms of complications, and the wound was inspected. Wound healing was certified when there was an intact healthy scar with no residual exudate or scab formation, and all sutures had been completely absorbed.
Surgery-related adverse events (AEs) were detected at scheduled as well as at unscheduled postoperative visits. Adverse events were predefined and graded as mild, moderate, and severe. (Protocol definitions are available on request.) Grade 1 or mild AEs required no or minimal treatment, whereas grade 2 (moderate) and grade 3 (severe AEs) required medical or surgical intervention. Thus, the moderate and severe AEs are most relevant to assessment of safety. This report focuses on AEs classified as definitely, probably, or possibly related to surgery. The relationship to surgery was in most cases self evident (e.g., bleeding, wound dehiscence, or infection), but in situations where the relationship to surgery was unclear, we erred on the side of caution and assumed a relationship existed. For example, one severe AE requiring hospitalization involved acute severe herpetic ulceration involving the penile shaft and scrotum, but not the surgical wound. This episode occurred during the postoperative period, and it was assumed that surgery precipitated the reactivation of pre-existing herpes. The anatomical site of any lesion was coded as involving the frenulum or other areas of the penis, and codes were added for AEs associated with external causes such as intercourse or trauma.
All surgery-related AEs were reviewed by a medical officer at the time they were reported. The senior urologist (SW), the NIH Medical Officer (MCB), the trial Medical Officer (GK), and the principal investigator (RHG) each independently reviewed all AEs. Subsequently, a panel of physicians, nurses, and clinical officers reviewed all cases and other available records to establish a final diagnosis, severity grading, and assessment of relatedness to surgery. The panel's final assignation was achieved by consensus.
Risks of surgery-related AEs were calculated as the number of men with one or more AEs per 100 surgeries. We also assessed multiple AEs experienced by individual participants and tabulated diagnosis specific rates of AEs graded by severity. Baseline characteristics were compared via chi-squared tests of general association. In comparisons of two proportions, p-values were calculated using chi-squared test for equality of two proportions. Exact binomial confidence intervals (CIs) were calculated for risk estimates.
We compared surgery-related AE risks in HIV-positive and HIV-negative men. We also assessed AE risks by sociodemographic characteristics (age, marital status, education, and occupation), risk behaviors (number of sex partners, condom use), and sexually transmitted disease symptoms (GUD, dysuria, and urethral discharge), which differed in frequency between HIV-positive and HIV-negative men at enrollment, and thus potentially could confound the associations between HIV status and the AE outcomes. Adjusted odds ratios (AdjORs) and 95% CIs for all AEs and moderate and severe AEs were estimated by multiple logistic regression. The covariates included in adjusted analyses were age, marital status, education, sex partners in the past year, condom use, and sexually transmitted infection symptoms at enrollment, and initiation of sex before certified wound healing.
We assessed the proportion of men who achieved certified wound healing by 30 postoperative d and at 6 wk following surgery, and evaluated surgery-related AEs among men who reported intercourse prior to certified wound healing, compared with men who resumed intercourse after healing was certified or did not resume sexual activity. Analyses used Intercooled Stata 8 and R.
These trials were reviewed and approved by two Institutional Review Boards (IRBs) in Uganda (The Scientific and Ethics Committee of the Uganda Virus Research Institute, Entebbe, and the AIDS Subcommittee of the National Council on Research and Technology, Kampala) and two IRBs in the US (the Western Institutional Review Board, Bloomberg School of Public Health, Olympia, Washington, and the Johns Hopkins University, Institutional Review Board, Baltimore, Maryland). Each trial was monitored by separate independent DSMBs.