Circumcision and HIV Vaccines: What are the connections

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Circumcision and HIV Vaccines What are the
connections?

• Susan Buchbinder, MD
• HIV Research Section
• San Francisco Department of Public Health
• International AIDS Society Meeting
• Mexico City
• August 4, 2008

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MRKAd5 trivalent vaccine

• Vaccine 111 admixture of 3 Ad5 vectors
• Encoded transgenes codon-optimized,
  near-consensus clade B HIV-1 sequences
• Placebo vaccine dilution buffer without Ad5

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Trial Design

• 3000 high-risk HIV uninfected men and women
• Initial study 1500 pts w/ Ad5 NAb 2004)
• Modification additional 1500 w/ Ad5 NAb 200
  (July 2005)
• Randomization stratified by Ad5 201-1000, 1000
• Primary hypotheses Ad5
• Decrease in HIV acquisition and/or
• Lower viral load setpoint (3 months
  post-diagnosis)
• Secondary hypotheses Total population
• Same as primary (Ad5 200 combined)

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Step Study sites
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Planned Interim Analysis Results Ad5Analysis
HIV Acquisition
Early viral RNA
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Incidence (95 CI) of HIV Infection MITT
population (males)
18 is the LOQ for the Ad5 titer assay includes
all HIV cases thru Oct 17, 2007
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Baseline characteristics by Ad5 status
pBaseline Ad5 not associated with HIV in
multivariate analysis (p0.3)
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Variables included in univariate/multivariate
analyses

• Vaccine vs. placebo
• Baseline Ad5
• Circumcision (self-report)
• Age
• Race
• Region
• Baseline risk factors (previous 6 months)
• male sex partners
• Unprotected receptive anal sex
• Unprotected insertive anal sex
• Substance use
• Self-reported sexually transmitted infection

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Variables included in univariate/multivariate
analyses

• Vaccine vs. placebo
• Baseline Ad5
• Circumcision (self-report)
• Age
• Race
• Region
• Baseline risk factors (previous 6 months)
• male sex partners
• Unprotected receptive anal sex
• Unprotected insertive anal sex
• Substance use
• Self-reported sexually transmitted infection

significant interaction with vaccine vs. placebo
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Estimated Relative Risk of HIV Infection Vaccine
Placebo(95 CI)
Circumcision status was unknown for 49 (2.7)
men. All univariate and multivariate analyses
are based on the Cox proportional hazards
regression model for time-to-event data.
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Estimated Relative Risk of HIV Infection Vaccine
Placebo(95 CI)
Circumcision status was unknown for 49 (2.7)
men. All univariate and multivariate analyses
are based on the Cox proportional hazards
regression model for time-to-event data.
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Estimated Relative Risk of HIV Infection Vaccine
Placebo(95 CI)
Circumcision status was unknown for 49 (2.7)
men. All univariate and multivariate analyses
are based on the Cox proportional hazards
regression model for time-to-event data.
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Estimated Relative Risk of HIV Infection Vaccine
Placebo(95 CI)
Men with unknown circumcision status (49, 2.7)
were excluded from analyses. All analyses are
based on the Cox proportional hazards regression
model for time-to-event data.
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Association of male circumcision (MC) with HIV
acquisition risk

• Observational studies demonstrate association of
  MC with reduced HIV acquisition
• Many studies confirm in heterosexual men
• Mixed data on role of MC in MSM
• 3 RCT demonstrate adult MC reduces HIV
  acquisition risk by 50
• Laboratory studies demonstrate role of foreskin
  in HIV acquisition
• Keratin layer thin in inner mucosa
• Target cells abundant in foreskin
• Possibilities for micro-abrasions

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Keratin in outer and inner foreskinPatterson AJP
2002
Outer foreskin
Inner foreskin
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Langerhans cells (LC) in foreskin

• In the penis
• LC most superficial of all target cells
• Foreskin has greatest concentration of LC
• LC most superficial in the inner foreskin
• Most other target cells also most superficial in
  the inner foreskin

McCombe AIDS 2006
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Likely locations of HIV acquisition in
uncircumcised penis
McCombe AIDS 2006
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Estimated Relative Risk of HIV Infection Vaccine
Placebo(95 CI)
Men with unknown circumcision status (49, 2.7)
were excluded from analyses. All analyses are
based on the Cox proportional hazards regression
model for time-to-event data.
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Role of baseline unprotected insertive anal
sexThe Step Study
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Role of baseline unprotected insertive anal sex
The Step Study
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Role of baseline unprotected receptive anal sex
The Step Study
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Role of baseline unprotected receptive anal sex
The Step Study
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How might these associations of increased risk in
uncircumcised men be explained?

• (As yet) unmeasured confounders
• HSV-2, host genetics
• Sexual networks
• Sexual risk over time
• Hypothetical targeting of activated target cells
  to mucosa in Ad5 seropositives
• Make less risky sexual practice (insertive anal
  sex) riskier
• Next steps
• Analyze potential confounders
• Evaluate cellular and mucosal specimens to
  explore enhancement
• Follow study volunteers to evaluate long-term
  effects

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The Study Volunteers
Acknowledgments

• For their dedication and commitment in the search
  for an HIV vaccine

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STEP Study Protocol Team

• Sarah Alexander
• Gail Broder
• Susan Buchbinder
• Lisa Bull
• Danny Casimiro
• Ann Duerr
• Cheryl Ewing
• Dan Fitzgerald
• Paula Frew
• Lori Gabryelski
• Peter Gilbert
• Tirzah Griffin
• Soyon Im
• Dale Lawrence

• Rosario Leon
• David Li
• Ellen MacLachlan
• Julie McElrath
• Devan Mehrotra
• Robin Mogg
• Dewayne Mullis
• Gabriela ONeill
• Mary Pleier
• Michael Robertson
• Steve Self
• Rosario Leon
• Amanda Vettori
• Steve Wakefield
• Amy Zhou

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STEP Study Sites