Randomized and controlled studies have shown that male circumcision (MC) can reduce the lifetime risk of HIV infection by 53%–60%,1–4 and results of the 4-year longitudinal study (2007–2010) carried in Orange Farm, South Africa, indicate a reduction in HIV incidence of 76%.5 The World Health Organization (WHO) and UNAIDS recommend that MC be considered as an HIV prevention means in addition to other HIV prevention means in countries with predominantly heterosexual epidemics.6 There are more than 38 million adolescent and adult males in Africa that could benefit from MC for HIV prevention.7,8
About 15% of all men in the Republic of Rwanda have been circumcised.9 The government plans to implement a nation-wide circumcision program with the objective of facilitating voluntary circumcision of 2 million adult men in Rwanda within 2 years to achieve a goal of decreasing HIV incidence rate by 25% in the fifth year from scale-up initiation, calculated by a national task force. However, given current resource limitations, such a goal is unattainable using standard surgical methods, the only approved method by the WHO. Today in Rwanda, there are a total of 21 surgeons, assuming each surgeon will be able to provide 20% of his work time for MC and assuming 15 minutes for 1 MC, there can be maximum 32,256 MCs done per year in Rwanda by surgical means. Government sought to investigate solutions for nonphysicians in nonsterile settings, thus minimizing the burden on the existing health care system, which is already strained handling life-saving procedures.
This prospective, randomized, controlled study was sponsored by Rwanda to measure the performance of the nonsurgical PrePex device compared with a WHO-approved method of surgical MC for rapid scale-up in resource-limited settings.
This was a single-center nonmasked randomized controlled trial to compare the performance of nonsurgical MC using the PrePex device versus an approved WHO method of surgical MC in adults, over a period of 9 weeks with an allocation ratio of 2:1, allocation ratio is based on WHO recommendation.10 The study was carried out in the Nyamata District Hospital, Rwanda, a rural area 35 kilometers from Kigali City. Study period per subject was 9 weeks. This study was approved by the Rwanda National Ethics Committee on January 13, 2011, approval number N0 001/RNEC/2011.
Participants were eligible if they were male, aged 21–54 years, and a resident of Bugesera District in Rwanda, the lower age of 21 was selected because in Rwanda this age is considered as legally adult for clinical studies, the upper age of 54 was selected according to the target upper age of the Ministry of Health for nation-wide MC campaign. A localized demand creating effort was done around the Hospital area, calling men to participate in the study. Men who arrived to the hospital arrived with the intention to be circumcised as part of the study and only then went through inclusion exclusion investigation and HIV testing. Subjects had to be uncircumcised, wanted to be circumcised, agree to being circumcised by either study method, and be capable of understanding study procedures and requirements. In addition, subjects had to agree to abstain from sexual intercourse for 9 weeks, agree to return to the health care facility for follow-up visits, and agree to anonymous video and photographs of the procedure and follow-up visits.
Exclusion criteria for the trial included active genital infection, anatomic abnormality, or according to the investigator, any condition preventing the subject from being circumcised; any of the following diseases/conditions: phimosis, paraphimosis, warts under the prepuce, torn or tight frenulum, narrow prepuce, hypospadias, and epispadias; known bleeding/coagulation abnormality, or uncontrolled diabetes; abnormal penile anatomy or any penile diseases; refusal to take HIV test; or any subject considered by the investigator to be an unsuitable candidate, such as mental condition or inability to return for follow-up visits.
After signing the informed consent form (ICF), patients were enrolled into the trial by randomly assigning them to 1 of the 2 arms. All subjects went through the national voluntary counseling and testing program for HIV after enrollment to the study.
All surgical MCs were conducted by surgeons experienced in circumcision. All nonsurgical MC procedures were performed by surgeons who participated in prior safety and efficacy studies using PrePex in Rwanda.11 Surgeons of each arm did not perform MC procedures in the other arm, and all surgeons had the same level of MC experience.
PrePex Nonsurgical MC Arm
Procedure was bloodless and performed without anesthesia or sutures and in a standard inspection room. Subjects of both arms were instructed to remain in the hospital under supervision for 16 hours and return 3 days after device placement for the first follow-up visit. About 400 mg of Ibuprofen was administered post PrePex placement only. On day 7, the device and foreskin were removed. The treated area was dressed with sterile gauze for 2 days. On day 9, the subject returned for a follow-up visit, and the dressing was removed. The subject returned for a weekly visits (days 14, 21, 28, 35, 42, 49, 56, and 63) for 8 weeks (total of 9 weeks from placement).
Surgical MC Arm
All surgical MC procedures used the dorsal slit method12 performed by the same surgeon who was highly experienced in this surgical technique for adults. Surgery was performed under local anesthesia according to WHO guidelines.8 For light bleeders, the surgeon used a monopolar diathermia device; for heavy bleeders, a knot with a stitching thread was made. The first follow-up visit was 1 week later with subsequent visits per the nonsurgical arm.
The primary endpoint was total MC skin-to-skin procedure time (Table 1). Secondary outcomes were as follows: procedure preparation time; clinical adverse event (AE) rates; surgical procedure-related and device-related incident rates; expected side effects; pain at key time points and during erection on day 3 and day 9; loss of productivity; patient satisfaction; and time to complete healing (Table 1). Time intervals were measured using a stopwatch; as a backup, a video of each procedure was recorded.
It was determined that a sample size of 144 would provide 80% power with alpha set to 0.05 based on a mean PrePex time of up to 10 minutes, reference procedure time of 18 minutes. Using an allocation ratio of 2:1 (PrePex/reference procedure)10 and a dropout rate of ∼25%, the target sample size was set to 180 subjects.
Randomization, Sequence Generation, Allocation Concealment, Masking and Implementation
A randomized number table was created by the study PI using the RAND algorithm in Excel (Microsoft Corp, Redmond, WA) in which each randomized number was distributed between 1.00000 and 0.00000. To achieve an allocation ratio of 2:1, each random number below 0.33333 was assigned to the surgical arm and each number higher than 0.333334 was assigned to the PrePex arm. Randomized numbers and study arms were marked with study numbers (1, 2, 3, etc.) and notes were prepared containing the study number, random number, and assigned intervention by the study principal investigator. Study envelopes each containing the folded note were prepared, sealed, and the study number written on each before enrollment by the principal investigator solely who was not involved in the enrollment and allocation process. It was validated that assigned intervention could not be seen through the sealed envelope.
Each subject who met the inclusion exclusion criteria, signed the informed consent, and passed screening was enrolled by co-investigator and assigned a study number, which was documented. Only then the subject received a sealed envelope from a co-investigator with his study number on it. The subject opened the envelope in front of the co-investigator and intervention assignment was documented, the randomization note was attached to the study file.
Statistical analyses were performed using SAS v 9.2 statistical software (SAS Institute, Cary NC).
Although primary outcome analysis was originally intended to be intention to treat, the placement time for 1 patient in the PrePex arm was not recorded, therefore it was decided to proceed with a as treated analysis with 1 missing subject.
Categorical parameters were summarized by frequencies and percentage, whereas quantitative variables were described using the mean, median, SD, and range. Nominal categorical parameters were analyzed by Fisher exact/χ2 tests, ordinal categorical parameters by the Wilcoxon rank sum test, and continuous variables by t test. Logistic regression was used to compare rates adjusted for major demographic covariates. An alpha of 0.05 was used to define statistical significance.
The original protocol and ICF called for a stay of 4–6 hours after the procedure. However, patients did not return for their 4–6 hours follow-up after the procedure, making it difficult to monitor their post procedure pain levels. As a result, after 38 enrolled subjects, it was decided to continue the study by incorporating an overnight stay (16 hours) for all subjects with a nurse monitor who administered pain medication on demand to better ensure their safety and well being. Patients subsequently verbally notified and consented to the overnight stay before the procedure was conducted. A WHO MC Technical Advisory Group retroactively requested that these first 38 subjects be included in the final analysis because all 9-week safety data were collected anyway. Therefore, primary outcome analysis includes data on 217 patients. Sixteen-hour pain analysis and patient satisfaction data occurred starting with the 39th patient.
Men that arrived to the Hospital with intention to be circumcised were asked if they will consider joining the study and then screened, including HIV test. Of 265 candidates screened, 226 were found eligible. There were 8 cases of subjects that were randomized, but before MC the treating physician found that they do not meet the inclusion exclusion criteria, and one subject who did not show up for MC. In total, 217 subjects were eligible and treated; 144 were randomized to the PrePex nonsurgical arm and 73 to the surgical arm (Fig. 1 for detailed description). Eight patients were lost to follow-up for the last scheduled visit (1 in the surgical arm and 7 in the PrePex arm).
Recruitment, Baseline Data, and Numbers Analyzed
The entire study was carried out between February 17 and April 8, 2011.
All subjects were HIV negative. The mean age of subjects in the 2 arms was similar (PrePex: 26 years, SD: 5.17; surgical MC: 24 years, SD: 4.10).
For the primary per protocol analysis, 73 patients in the surgical arm and 143 patients in the PrePex arm (For 1 subject, we failed to document the PrePex placement time) were analyzed. The number of subjects who were analyzed for each of the secondary outcomes are listed in Table 2.
The mean PrePex skin-to-skin procedure time, combining placement and removal, was significantly shorter at 3.1 minutes (SD: 1.1) compared with a mean surgical skin-to-skin MC time of 15.4 minutes (SD: 3.1) (P < 0.0001). Mean PrePex preparation time was also significantly faster at 3.4 minutes (SD: 1.13) in comparison to the mean surgical MC preparation time of 8.8 minutes (SD: 1.97) (P < 0.0001).
In the PrePex arm, there were zero device-related AEs and 4 non–device-related AEs (no subject had more than 1 AE) (Table 3). In the MC surgical group, there were 7 AEs related to surgery and 1 AE unrelated to surgery (Table 3); in each arm, the scrotal abscess was determined as unrelated due to it's distance from the MC site and lack of evidence of laceration and or dermal damage before the abscess appeared. All AEs were resolved. The total AEs rates (related and unrelated) were 2.7% in the PrePex arm compared with 11% in the MC surgical arm (P = 0.029). Sixteen percent of PrePex subjects experienced expected side effects, the most common which was localized edema, compared with 45% of subjects in the surgical group (P < 0.0001) (Table 3). Side effects were defined as regular expected appearance of a healing MC wound and included very common signs such as clear exudates, localized mild edema in the wound area, oozing, and slough. All AEs and side effects were categorized and graded by the study investigators and relied on recommendations from the WHO framework.10
Procedure pain was measured by visual analog scale (VAS), by presenting to subjects a scale of 0–10 where each level has a relevant faces with increasing degrees of pain and description in words and asking them to select the most representative level. Pain by VAS is summarized in Table 4. Mean pain level by subject was higher at time of MC anesthesia administration compared with PrePex placement with no anesthesia (2.4 vs. 0.8; Table 4). Pain levels 1–8 hours after procedures in the surgical arm were lower than in the PrePex arm. The 2 points of higher pain in the PrePex arm were 1 hour post PrePex procedure (mean 5.6 SD 1.8) and during PrePex removal (mean 4.7 SD 1.9) which lasted 2–5 seconds, and decreased to 1.4 immediately after removal.
Pain during erection on day 3 in the surgical arm was 5.2 (SD: 2.2) compared with 2.5 (SD: 1.8) for the PrePex arm, additional pain during erection was gathered for the PrePex arm on day 9 [2 days after removal and resulted in 1.9 (SD: 1.5)]. The pain scores during erection for the surgical group was significant higher compared with the PrePex group (P < 0.0001).
On average, a patient in the MC surgical arm lost significantly more days (1.15 days) compared with a patient in the PrePex arm (0.07 days) (P < 0.0001).
Six weeks after circumcision, there was no significant difference in satisfaction of subjects in both arms, 91 of 92 patients (99%) in the PrePex group were satisfied with the aesthetics of circumcision compared with 55 of 55 patients (100%) in the surgical group. Ninety-one of 92 (99%) patients in the PrePex group would recommend the procedure compared with 54 of 55 patients (98%) in the surgical group. Six weeks after circumcision, they were asked if they would recommend the MC procedure to their friend and why. The key reasons selected by the PrePex subjects were the cosmetic outcome and the hygiene benefits. The key reasons selected by the surgical subjects were that the healing process is fast and that the hygiene benefits.
The number of days required for complete healing in the PrePex group was 31 days post device removal (SD: 12.1) compared with 23 days post surgery (SD: 7.50) for the surgical group (P < 0.0001).
The low or no pain reported by subjects during the placement of the PrePex on the penis can be attributed to the fact that PrePex is designed in a manner that allows controlled radial elastic pressure that does not crush the foreskin to achieve hemostasis, different than all other devices which require anesthesia at placement.13–15
After this comparative study, a yet to be published study examined ways to reduce the discomfort 1 hour post placement. It was discovered that the discomfort is superficial and not deep. Therefore, we studied applying 1g of Lidocaine 5% dermal anesthetic cream at placement. The cream takes about 30–45 minutes to kick in, and therefore it averted the 1-hour post placement discomfort. The anesthetic cream is now part of the standard PrePex procedure and placement of the device is pain free.
PrePex, the nonsurgical MC, was statistically significantly faster (almost 5 times) compared with surgical MC as measured by procedure time and had significantly fewer AE. Surgical preparation time was 2.5-fold longer compared with PrePex preparation time—also a statistically significant result. The surgical procedure time in our study (15.4 minutes) was below typical of conventional surgical procedures.13,16–19 Our finding that nonsurgical MC took significantly less time than surgical MC is especially noteworthy, considering that the average surgical MC procedure time in our study was less than the time reported in the WHO MOVE model.7 The MOVE model’s shortest surgical circumcision time was 19 minutes, whereas the average time for surgical MC in our study was 15 minutes, we cannot speculate the reasons for those time differences.
PrePex time was shorter than other reported MC devices used in developing countries when preparation and device placement and removal time are taken into account.14,15
Our study was performed in a district hospital, but we have reason to believe that it is applicable in the same manner in any other clean clinical setting such as a classroom or tent, as the room had no special sterile settings.
In the PrePex group, subjects reached first complete healing 31 days after the device removal (38 days from initial device placement), whereas the surgical arm subjects reached complete healing after 23 days, which represents an advantage to the surgical technique, this finding should be considered in the decision to use the nonsurgical device. A second consecutive healing verification visit was conducted in both arms. WHO suggests that patients may resume to protected sex (using condoms) 6 weeks post procedure, which would be applicable to both the device and surgical arm. During the study, all men were asked weekly if they were abstaining from sex, and all complied with the WHO voluntary counseling and testing program suggestions.
The biggest obstacle to scale-up MC in Rwanda is lack of surgeons and surgical infrastructure. A nonsurgical technique may help change current government policies and facilitate task shifting of MC to nurses. Rwanda has embarked upon a field study to test the safety profile of PrePex in the hands of nurses (clinicaltrials.gov NCT01434628) in large numbers as the third and final step outlined by WHO.7 A 3 days training course should be sufficient to enable low cadre nurses with no experience with PrePex MC to become PrePex MC Experts and perform safe and efficient PrePex procedures. Only 3% of the eligible men for MC in Africa have been reached since the WHO and UNAIDS issued their MC HIV prevention suggestions.20,21 The findings of our study demonstrates that PrePex has the potential to transform circumcision programs in resource-limited countries prevalent in sub-Saharan Africa and can likely be deployed by nurses rather than requiring surgeon or physician deployment. The procedure has been scientifically validated as safe, effective, and faster than surgical technique. The procedure is bloodless, requires no injected anesthesia, no sutures, and no sterile settings and accordingly has the potential to enable rapid scale-up of MC in Rwanda in sub-Saharan Africa.
Based on the results of our study, Rwanda officially approved the device for use in the country and is updating its national scale-up plan to use PrePex instead of the surgical method.
Dr Marissa Carter (Strategic Solutions, Inc, Cody, WY) edited the article and has also given permission to have her name and information included in the acknowledgment.
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