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“The Foreskin Saga” (Ron’s title)

Male Circumcision: Research on implications for men and women, and programmatic challenges, Rakai, Uganda (Maria’s title). “The Foreskin Saga” (Ron’s title). Meta-analysis Observational Studies (Weiss Geneva 05). General populations (10 studies) RR = 0.57 (0.47-0.70),

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“The Foreskin Saga” (Ron’s title)

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  1. Male Circumcision: Research on implications for men and women, and programmatic challenges, Rakai, Uganda(Maria’s title) “The Foreskin Saga” (Ron’s title)

  2. Meta-analysis Observational Studies(Weiss Geneva 05) • General populations(10 studies) • RR = 0.57 (0.47-0.70), • High risk populations(10 studies) • RR = 0.31 (0.23-0.42)

  3. Randomized trials of MC for HIV prevention in men • Three trials: • South Africa (ANRS), Auvert et al PLos 2005 • Kenya (NIH), Bailey et al Lancet 2007 • Uganda (NIH), Gray et al, Lancet 2007 • Similar research design: • Enroll HIV-negative uncircumcised men, randomize to: • Immediate MC (Intervention) • MC delayed 21-24 months (Control) • Endpoints: • HIV incidence • Safety • Behavioral disinhibition • STIs and STI symptoms

  4. HIV Incidence and Efficacy of Circumcision in 3 Randomized Trials Efficacy 53% (CI 22-72%) Efficacy 60% (CI 32-76%) Efficacy 60% (CI 30-77%) Meta-analysis of the three trials: Circumcision reduced HIV acquisition in men by 57%

  5. Plausibility • Three trials show consistent protection despite variation in design and populations • Trials consistent with prior observational studies Why did MC work so consistently?

  6. Foreskin anatomy and histology and increased risk of HIV acquisition McCoombe & Short, AIDS 2006 20:1491-1495 Inner surface: - susceptible to minor trauma and abrasion - trauma facilitates entry of pathogens - retracted during intercourse- mucosal surface exposed to vaginal secretions Area under foreskin is warm and moist, suitable for pathogen replication and survival

  7. Role of Keratin Inner mucosa of foreskin has a thin keratin layer: vulnerable to HIV and ulcers Outer skin has a thick keratin layer: much less vulnerable toHIV and ulcers Circumcision removes tissues vulnerable to HIV infection

  8. Foreskins contain HIV target cells (esp dendritic cells) and CD4 CD8 cells(enable HIV replication and dissemination) HIV-infected dendritic cell in foreskin mucosa

  9. Inflammation Foreskin is vulnerable to inflammation due to balanitis, HSV-2 and other infections. Inflammation recruits HIV target cells Dermis CD8 focal cell density Dermis CD8 focal cell density No Inflammation Inflammation

  10. HIV Incidence increases with foreskin surface area: Size matters(Kigozi et al, AIDS 2009) IRR = 2.44 CI 1.1-4.8 Men who had a larger foreskin prior to MC were more likely to have acquired HIV prior to surgery

  11. Male CircumcisionHerpes (HSV-2), Syphilis Genital Ulcer Disease (GUD)Human papilloma virus (HPV)Secondary trial end points

  12. Control Arm Intervention Arm Cumulative Probability of HSV-2 detection Total follow-up time (months) Cumulative probabilities of HSV-2 acquisition by MC status, Rakai TrialTobian et al, NEJM 2009 Adj HR = 0.73 (0.49-0.98)

  13. Syphilis Incidence by MC status, Rakai Trial Tobian et al, NEJM 2009

  14. Circumcision and Genital Ulcer Disease (GUD), Rakai Trials(Gray et al CROI 2009) Circumcision protects against GUD, irrespective of HIV

  15. MC effects on the prevalence of penile High Risk (HR) HPV infectionin HIV-neg men

  16. Incidence and Clearance of High Risk-HPV over 24 months in HIV-neg men, Rakai MC Trial RR = 1.16 (1.05-1.28) IRR = 0.65 (0.41-0.86)

  17. Circumcision and HR-HPV prevalence at 24 months in HIV-infected men, Trial of MC in HIV+ men, Rakai

  18. Circumcision and sexual risk behaviors • Concern that an exaggerated belief in MC efficacy may lead to increased sexual risk behaviors (risk compensation) • No differential risk behaviors seen in Kenya and Ugandan trials • Some increased risk behavior seen in South African trial • All trials had intensive health education during follow up, so programmatic generalization is problematic

  19. Circumcision, sexual satisfaction/ dysfunction in men; Rakai Trial(Kigozi et al Brit J Urol 2008) No adverse effects on satisfaction or function

  20. Summary: Effects of circumcision in men • Circumcision prevents: • HIV, HSV-2, HPV infections and GUD • Behaviors and sexual satisfaction • No major behavioral disinhibition • No effect on sexual satisfaction and function

  21. Safety of Male Circumcision

  22. Rates of surgery-related complications HIV+ and HIV-negative men; Rakai (Kigozi et al PLos 2008)

  23. Completed wound healing by HIV status; Rakai *P < 0.001, **P = 0.006 Postoperative healing is slower in HIV+. Most men healed by 6 weeks

  24. Next steps • Scale up services • Training, upgrade facilities • Operations research on surgical procedures, physician vs non-physician providers • Assess effectiveness of circumcision: • Population-level HIV incidence, acceptance, risk behaviors

  25. Operation research • Training • Sleeve vs dorsal slit procedures • Physician vs non-physician performance of surgery

  26. Number of MC procedures needed to achieve competency following training: Sleeve MC method, Rakai (Kigundu BJU 2009) Practitioner needs to perform ~ 100 MCs to reduce duration of surgery below 30 minutes

  27. Moderate/severe complications by number of surgeries performed after training, Rakai Risk of complications is higher immediately after training

  28. MC performed by Physician vs Clinical Officers • Based on >1000 MCs performed by physicians and >1500 performed by clinical officers • Moderate/severe adverse events • Physicians 0.8% • Clinical officers 0.8%

  29. Experience with two MC surgical methods, Rakai, Uganda Dorsal slit Sleeve method

  30. Sleeve vs dorsal slit • Assessment based on ~ 1000 of each type of procedure • Moderate/severe adverse events • Sleeve 0.9% • Dorsal slit 0.6% • Time for surgery • Sleeve 28.5 minutes • Dorsal slit 24.4 minutes

  31. Modeling impact of circumcision on the HIV epidemic (Hankins et al PLoS 2009 accepted) • Circumcision can mitigate the epidemic by: • Direct reduction of male HIV acquisition • Probable lifelong protection • Indirect benefit to women: Fewer men acquire HIV so less women exposed to HIV+ partners • In areas with high HIV prevalence, need ~ 15 circumcisions per HIV infection averted over 10 years

  32. Effects of Male Circumcision in Women

  33. Design, Rakai MC trials in men, women and the community 4,996 HIV-neg men * whoaccepted VCT HIV/STI acquisition MC safety, behaviors, satisfaction 922 HIV+ men * STI acquisition, MC safety, behaviors satisfaction 450 HIV-neg men * who declined VCT HIV/STI acquisition MC safety, behaviors satisfaction Consenting spouses* HIV/STI acquisition, behaviors, MC acceptability Community surveys, 50 Rakai MC trial catchment communities* Trends in HIV/STI rates, behaviors, MC acceptability Pls note: ALL participants were offered health education, VCT, couples VCT, condoms * NIH* Gates Foundation

  34. Complementary trial of MC in HIV+ males, their partners, and the community Rakai, RCT of 922 HIV+ men Why? Can’t deny MC to HIV+ men - Stigma - Behavioral disinhibition in MC’ed HIV-neg men Followed women partners Why? Anything sexual affects both genders! Followed the community (and have funds for 5 more years) Why: Ultimate question: does MC help control the HIV epidemic?

  35. HIV+ Male circumcision status and HIV transmission to womenGray et al AIDS 2000 Male Viral load 47 couples in which circumcised male partner was HIV+ AND whose viral load was <50,000 copies, no female partners infected, vs. 26 of 143 female partners of uncircumcised HIV+ men (9.6/100 py) (p = 0.02).

  36. Male-to-Female HIV transmission by MC study arm for concurrently enrolled couples(Wawer et al CROI 2008, Wawer et al, Lancet forthcoming 2009)

  37. Male-to-Female HIV Transmission, Rakai Trial(Wawer et al Lancet, 2009) Figure 2 Cumulative probability of Female HIV acquisition M+F- couples with concurrent enrolment Intervention 0.24 0.20 Control 0.16 0.12 Prob. of HIV-Acquisition 0.08 0.04 0.00 0 6 12 24 Total follow-up visit (month) # HIV incident cases/# at risk Control 0/67 5/67 2/60 1/31 Intervention 0/92 10/92 4/79 3/40 Adj HR = 1.49 (0.62-3.57)

  38. HIV transmission to female partner in relation to resumption of sex and wound healing after MC Early resumption of sex after MC was associated with increased HIV transmission

  39. Viral load in HIV+ circumcised men pre- and post-surgeryWawer et al Lancet 2009

  40. BV, Trichomonas and GUD in female partners of HIV-negative men by MC status(Gray et al Amer J Obstet Gynecol 2008) • Women married to HIV-negative male trial participants • 825 wives of intervention and 783 wives of control men • Women followed at one year to detect: • Self-reported vaginal symptoms • Trichomonas by culture • BV by Gram stain (Nugent’s score)

  41. Vaginal symptoms at follow up by HIV-negative husband’s study arm PRR 0.99 CI 0.89 – 1.12 PRR 0.76 CI 0.60 – 0.97 PRR 0.97 CI 0.75 – 1.21 Significant reduction of GUD in wives of circumcised men (p = 0.03). No effect on discharge or dysuria.

  42. Vaginal infections at follow up by HIV-negative husband’s study arm PRR 0.80 CI 0.71 – 0.89 PRR 0.53 CI 0.33 – 0.85 PRR 0.31 CI 0.18 – 0.54

  43. Prevalence of Multiple Female HPV Infections by Husband’s Circumcision Status (analysis in progress) RR 0.96 RR 0.74 (0.57-0.97)

  44. MC versus HPV vaccines • Vaccines • To date, evidence of high rates of efficacy in reducing HPV prevalence and cervical dysplasia: long term effects not yet known • Primarily directed at HPV 16 and 18; partial cross-protection with other HPV types • Cost: ~$375 for three doses • 3 doses over 6 months; may need boosters • Male circumcision: • Reduces male HPV prevalence (any oncogenic) by ~35% • Reducea female HPV prevalence in partner of MC’ed male ~25% • Cost ~$35-50, no booster dose needed, effective after sexual debut

  45. Women’s sexual satisfaction and MC, Rakai MC trials Reported sexual satisfaction status in women, after versus before their husband’s circumcision More satisfied 39.8% No change 57.3% Less satisfied 2.9%

  46. Summary: Male circumcision effects in female partners • Observational data: • MC in childhood is associated with lower HIV acquisition in female partners • Trial findings: • Adult MC does not reduce HIV transmission from HIV+ men to their wives over 24 months • Resumption of sex before wound healing is potentially associated with increased in male-to-female HIV transmission • MC up-regulates viral load in HIV+ men • MC prevents BV, Trich and GUD in female partners • MC increased female sexual satisfaction in the Rakai RCT

  47. Basic science research • What can we learn from MC and preserved foreskins regarding • Mucosal immune responses • Factors which increase susceptibility to HIV/STIs • Factors which increase resistance to HIV/STIs • Interactions between HIV, STIs, genital microbiome • Rakai already has >7,000 foreskins from HIV-neg and 1,300 from HIV+ participants and patients • ~half have pre-MC penile swabs, with vaginal swabs from female partners

  48. HIV incidence by reported # of sex partners, past 6 months, by arm, Rakai MC trialin HIV-neg men IRR 0.30 IRR 0.55 Number of sex partners Hypothesis: Effect of MC and partial acquired mucosal immunity potentiate each other (Wawer et al, AIDS, 2004)

  49. CD3 expression in cells isolated from adult male foreskin Jessica Prodger, U of T, work in progress on Rakai samples (other assays: DC-SIGN, Langerin, CD1A, etc…)

  50. Penile bacterial flora before and after circumcision(L Price CROI 2009) • Penile swabs from 13 Ugandan men prior to circumcision and 12 months after circumcision. • Broad-range PCR primers to amplify the V3 and V4 hypervariable regions of the 16S rRNA gene. • Analyzed by high-throughput pyrosequencing

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