1. A Randomized Controlled Trial of Male Circumcision to Reduce HIV Incidence in Kisumu Robert C. BaileyJ.O. Ndiny-Achola Univ. of Illinois at ChicagoUniv. of Nairobi Stephen Moses Kawango Agot University of Manitoba Moi University Ian MacleanJohn Krieger University of ManitobaUniversity of Washington Corette ParkerRichard Campbell RTI InternationalUniv. of Illinois at Chicago Supported by Division of AIDS, NIAID, and the Canadian Institute for Health Research

2. Need for Clinical Trials  “Randomized clinical trials are needed to determine the utility of circumcision as an HIV preventive measure.”  Reasons: –All epidemiological studies to date have been observational (cannot exclude residual confounding) and not all results are consistent. –Risk of too early resumption of sexual activity after circumcision or subsequent behavioural disinhibition could counteract any protective effect. –Risk of post-surgical complications must be balanced against any protective effect.

3. Hypotheses  Circumcision will reduce HIV incidence among men aged 18-24 years by 50%.  Circumcision will result in less than a 2% rate of significant post-surgical complications requiring follow-up care.  There will be no difference between circumcised men and controls in reported sexual behaviour following the circumcision procedure.

4. Study Population  Approximately 2,600,000 Luo live in Nyanza Province, western Kenya.  Luo do not practice traditional circumcision. –9.9% of Luo men are circumcised.  Kisumu District has approximately 39,000 men aged 18-24 years.  86% live within 30 minutes of central Kisumu City.

5. Study Design  Randomized, unblinded: treatment arm is circumcision, control arm is no circumcision.  Both arms: HIV testing, behavioural questionnaire, medical examination, STD testing and HIV prevention counselling at baseline, and at 6, 12, 18 and 24 months post-enrolment.  Additional HIV testing at 1 and 3 months.  Circumcision arm: Post-operative check-ups at 3 days, 8 days and 30 days after the procedure.

6. Inclusion and Exclusion Criteria  Inclusion Criteria  Uncircumcised.  HIV negative.  Sexually active.  Aged 18-24 years.  Resident of Kisumu District.  No plans to move for at least the next 2 years.  Consent to participate.  Hemoglobin over 9.0 grams per 100 ml.  Exclusion Criteria  Foreskin covers less than half of glans.  Hemophiliac or other bleeding disorder.  High Prothrombin Time Index.  Other medical condition contra-indicating surgery.  Absolute indication for circumcision.

7. Sample Size  1,388 men in each arm: provides 80% power (with alpha error 0.05) to detect a 50% protective effect of male circumcision –Assumes 5% (2.5% annual) incidencein the control group –15% loss to follow-up –5% cross-over in each direction  Plan to screen approximately 4,500 - 5,000 men to arrive at the final sample size.

8. Assumed Participant Flow from Screening to Randomization Report for VCT (Screening) N = 4,525 Excluded N = 183 Asked to enroll N = 3,470 Enrolled N = 2,776 Declined N = 694 Circumcised N = 1,388 Controls N = 1,388 95% accept 61% of screened HIV neg. N = 3,653 15%85% 5% 50% 95% 20% 80% HIV test N = 4,298 HIV pos. N = 645 HIV neg. N = 3,653

9. STD Testing  Serum for syphilis (RPR, TPHA) and HSV-2 (type-specific ELISA)  Urine for gonorrhea and chlamydia by PCR, and trichomonas by culture  Urethral, glans and shaft swabs for HPV by nucleic acid amplification  If urethral discharge, urethral swabs for gonorrhea and chlamydia by PCR  If genital ulcer present, ulcer swab for multiplex PCR

10. Circumcision Procedure  Infection control  Bleeding control  Emergency procedures  Follow-up –3 days, 8 days, 30 days

11. Potential Adverse Events  Excessive bleeding  Infection  Excessive pain  Too much skin removed  Anesthetic-related problem  Damage to the penis  Cosmetic problem  Erectile dysfunction  Psycho-behavioural problem  Penile amputation  Death

12. Adverse Events  Categories of Severity –Mild –Moderate –Severe  Categories of Relationship –Definitely related –Probably related –Possibly related –Not related

13. Recruitment of Participants  Clients of STD clinics  Clients of VCT centres  Organizations (boda boda, jua kali)  Peer recruiters  Fliers, radio, other media  Drama and musical groups

14. Willingness to Participate  86% of 18-25 year-olds said they would prefer to be circumcised.  97/103 (94%) said they want to participate in the trial.  Reasons given –Free circumcision –Free medical treatment for two years –Compensation for time and transport –Getting free counselling about safe behaviours

15. Actual Participant Proportions from Screening to Randomization Report for VCT (Screening) N = 4,525 Excluded N = 183 Asked to enroll N = 3,470 Enrolled N = 2,776 Declined N = 694 Circumcised N = 1,388 Controls N = 1,388 95% accept 61% of screened HIV neg. N = 3,653 15%85% 5% 50% 95% 20% 80% HIV test N = 4,298 HIV pos. N = 645 HIV neg. N = 3,653 (Actual - 99%) ( 89%) (Actual- 11%) (Actual - 22%) (78%) (Actual - 17%) (83%) (Actual - 60%)

16. Progress to Sept 14, 2002  1245 men screened and 1205 consented for HIV testing (97%)  HIV positive: 137 (11.0%); 5.4% in 18-20 age group, 15.3% in 21-24 age group  662 men randomized  Approximately 12 (3.6%) of those in circumcision arm have asked that procedure be delayed and are not yet re-scheduled (potential cross-overs)  No reports of cross-over from control to circumcision arm

17. Concerns  Power to detect a 50% reduction in HIV incidence. –Will HIV incidence be high enough? –Cross-over (dis-satisfaction with being randomized to control group). –Differential loss to follow-up.  Behavioural disinhibition in the MC group.  Minimizing loss to follow-up.  Use of clinic for non-essential visits.  Care for HIV positive men.