1. The safety of adult male circumcision in HIV-infected and uninfected men in Rakai, Uganda (WEAC101) Godfrey Kigozi Rakai Health Sciences Program 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention Sydney, Australia July 25 th 2007

2. Acknowledgement Ron GrayStephen Watya Maria WawerNoah Kiwanuka David SerwaddaVictor Ssempijja Nehemia KighomaFred Wabwire-Mangen Nelson SewankamboFred Makumbi Fred NalugodaKiggundu Valerian James NkaleJackson Musuuza Denis BuwemboPius Opendi Joseph KagaayiTom Lutalo Dan Namuguzi Trial Participants Funders – Gates and NIH Rakai Program staff

3. Objective To assess the safety of adult male circumcision (MC) by comparing rates of adverse events (AEs) related to circumcision among HIV+ and HIV- men.

4. Background 1 3 RCTs have shown that male circumcision reduces the risk of HIV acquisition in men by 50-60%. WHO/UNAIDS has recommended MC as an additional strategy for preventing heterosexual HIV infection in men. The safety of surgery is a paramount consideration in planning future circumcision programs, –to minimize surgical risks and –to provide guidelines for best practices in surgical procedures and postoperative care.

5. Background 2 Some information is available on postoperative complications in children and in HIV-negative men (rates range from 2-10%), However, little information exists on the safety of MC in HIV-infected men. If surgery was found to be unsafe in HIV+ men, these individuals might have to either –be excluded from programs, which would be potentially stigmatizing, or –they might require specialized services for postoperative care which could add to program costs and complexity.

6. Methods 1 Two separate but complementary RCTs of adult MC were conducted in Rakai district, Uganda. One trial, supported by the NIH, Enrolled HIV-negative men who agreed to know their HIV status Was stopped for efficacy on December 12, 2006. The other trial, supported by Gates Foundation Enrolled HIV-positive men without AIDs symptoms or CD4 > 350, and HIV-negative who declined to know their HIV status Enrollment was closed on December 19, 2006.

7. Methods 2 In the two trials, 2,326 HIV-negative men and 420 HIV- positive men were circumcised Circumcision was done by physicians using the sleeve circumcision procedure. All men who were circumcised –provided written informed consent for surgery, –were strongly advised to refrain from sexual intercourse until the wound was certified to be fully healed, –advised to practice safe sex (ABC) Post-operative follow up was done by medical health workers, at ~ 1 day, 7 days, and 1 month, –assessed surgery-related adverse events (AEs), wound healing and resumption of intercourse

8. Methods - 3 AEs graded as: Grade 1 (mild), required no treatment Grade 2 (moderate) Grade 3 (severe) required medical care/surgical intervention All surgery related AEs were reviewed and summarized by a medical officer at the time they were reported Chi-square or Fisher’s exact tests were used to compare AE rates and wound healing between HIV-positive and HIV-negative men Multiple logistic regression was used to assess factors associated with surgery-related AEs.

9. RESULTS

10. Table 1: Characteristics of HIV-positive and HIV-negative men at enrollment-1 Characteristics, behaviors and STI symptoms HIV-positive men HIV-negative men P value N%N% All 420100.02326100.0 Marital status Currently married 29169.3110047.3 <0.0001 Previously married 8520.251375.9 Never married 4410.5108946.8 Education None 235.51396.0 < 0.0001 Primary 32677.6154566.4 Secondary 5112.155023.6 Tertiary 204.8924.0 HIV+ men were more likely to be married and less educated

11. Characteristics, behaviors and STI symptoms HIV-positive men HIV-negative men P value N%N% Sex partners in past year 0 317.444219.0 < 0.0001 1 18744.5107946.4 2 11928.351422.1 3+ 8319.829112.5 Table 2: Characteristics of HIV-positive and HIV-negative men t enrollment - 2 HIV+ men reported more sexual partners

12. Table 3: Characteristics of HIV-positive and HIV-negative men - 3 Characteristics, behaviors and STI symptoms HIV-positive men HIV-negative men P value N%N% Sexually active population 3891001884100 Condom use in past year Consistent condom use 297.531016.5< 0.0001 Inconsistent use 17745.565534.8< 0.0001 No use 18347.091948.8 STD symptoms in past year GUD 11830.31688.9< 0.0001 Urethral discharge 5313.6814.3< 0.0001 Dysuria 6817.51286.8<0.0001 HIV+ men reported less consistent condom use and had higher rates of STD symptoms.

13. Table 4: Surgery related adverse events by severity Adverse events (AEs) HIV-positive (n = 420) HIV-negative (n = 2326) NRate/100 surgeries N Any AE related to surgery Grade 1 122.9944.0 Grade 2 133.1793.4 Grade 3 00.050.2 Total AEs 256.01787.7 (p=0.26) No significant difference in rates of moderate or severe surgery- related AEs between HIV-positive and HIV-negative men (p=0.7).

14. Table 5: Common cause-specific surgery related adverse events by severity -1 Adverse events (AEs) HIV-positive (n = 420) HIV-negative (n = 2326) NRate/100 surgeries N Infection Grade 1 30.7150.6 Grade 2 81.9532.3 Grade 3 0010.04 All infections 112.6693.0 Infections were the most common AEs: the rates of moderate or severe infections were 1.9% in HIV-positive versus 2.3% in HIV-negative men.

15. Table 6: Common cause-specific surgery related AEs - 2 Adverse events (AEs) HIV-positive (n=420) HIV-negative (n = 2326) N Rate/100 surgeriesN Bleeding/hematoma Grade 1 30.7311.3 Grade 2 51.2150.6 Grade 3 0030.13 All bleeding/hematoma 81.9492.1 Wound dehiscence Grade 1 112.6281.2 Grade 2 0020.09 Grade 3 0010.04 All dehiscence 112.6311.3 Rates of mod-severe bleeding/hematoma and wound dehiscence complications were similar in the two groups.

16. Table 7: Surgery-related adverse events by timing of resumption of intercourse in HIV+ and HIV-negative men - 1 HIV-positive menHIV-negative men Rate/ 100 surgeries Risk ratio early vs late sex (95%CI) Rate/ 100 surgeries Risk ratio early vs late Sex (95%CI) All AEs Resumed sex after healing 5.1 (15/292)1.00 6.7 (123/1847) 1.00 Resumed sex before healing 7.8 (7/90) 1.51 (0.64-3.60) 11.8 (45/382) 1.77 (1.28-2.44) AE rates were higher in men who resumed intercourse before wound healing. Significant among HIV negative men

17. HIV-positive menHIV-negative men Rate/ 100 surgeries Risk ratio early vs late sex (95%CI) Rate/ 100 surgeries Risk ratio early vs late sex (95%CI) Grade 2 and 3 AEs Resumed sex after healing 2.4 (7/292) 1.003.4 (63/1847) 1.00 Resumed sex before healing 4.4 (4/90) 1.85 (0.56-9.19) 4.5 (17/382) 1.31 (0.77-2.20) Grade 2 and 3 infections Resumed sex after healing 1.0 (3/292) 1.002.2 (40/1847) 1.00 Resumed sex before healing 3.3 (3/90) 3.3 (0.67-15.80) 2.9 (11/382) 1.32 (0.69-2.57) Table 7: Surgery-related adverse events by timing of resumption of intercourse in HIV+ and HIV-negative men - 1 AE rates were higher in men who resumed intercourse before wound healing. But differences were not significant.

18. Other findings The proportion of men with completed healing by 30 days post-surgery was lower in HIV-positive (71.2%) than HIV-negative men (80.7%, p <0.0001). Multiple regression identified no significant sociodemographic, behavioral or STI symptoms predictive of moderate/severe AEs.

19. Conclusion Overall, the safety of circumcision was comparable in HIV-positive and HIV-negative men The rates of moderate or severe AES are acceptably low Wound healing was somewhat slower among the HIV-infected Resumption of sex before wound healing was associated with higher complication rates (though not statistically significant)

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