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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 MRKAd5 trivalent vaccine Vaccine: 1:1:1 admixture of 3 Ad5 vectors

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Circumcision and hiv vaccines what are the connections l.jpg

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


Mrkad5 trivalent vaccine l.jpg
MRKAd5 trivalent vaccine

  • Vaccine: 1:1:1 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 <200 (Dec 2004)

    • Modification: additional 1500 w/ Ad5 NAb >200 (July 2005)

    • Randomization stratified by Ad5 <18, 19-200, 201-1000, >1000

      Primary hypotheses:Ad5 <200 subset

  • Decrease in HIV acquisitionand/or

  • Lower viral load setpoint (∼3 months post-diagnosis)

    Secondary hypotheses:Total population

  • Same as primary (Ad5 <200 and Ad5 >200 combined)



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Planned Interim Analysis Results: Ad5<200

MITTAnalysis

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

p<.05

Baseline Ad5 not associated with HIV in multivariate analysis (p=0.3)


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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 foreskin riskPatterson AJP 2002

Outer foreskin

Inner foreskin


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Langerhans’ cells (LC) in foreskin risk

  • 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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Estimated Relative Risk of HIV Infection riskVaccine : 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 riskinsertive anal sexThe Step Study


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Role of baseline unprotected riskinsertive anal sex The Step Study


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Role of baseline unprotected riskreceptive anal sex The Step Study


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Role of baseline unprotected riskreceptive 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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Acknowledgments uncircumcised men be explained?

The Study Volunteers

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


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Sarah Alexander uncircumcised men be explained?

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 O’Neill

Mary Pleier

Michael Robertson

Steve Self

Rosario Leon

Amanda Vettori

Steve Wakefield

Amy Zhou

STEP Study Protocol Team


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STEP Study Sites uncircumcised men be explained?