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HSV-2 is associated with HIV acquisition among both placebo & vaccine recipients in the Step Study

HSV-2 is associated with HIV acquisition among both placebo & vaccine recipients in the Step Study. Ruanne V Barnabas, MBChB DPhil HIV Vaccine Trials Network, Seattle. 5 th IAS Conference on HIV Pathogensis, Treatment & Prevention 19-22 July 2009, Cape Town. Background: HSV-2-HIV synergy.

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HSV-2 is associated with HIV acquisition among both placebo & vaccine recipients in the Step Study

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  1. HSV-2 is associated with HIV acquisition among both placebo & vaccine recipients in the Step Study Ruanne V Barnabas, MBChB DPhil HIV Vaccine Trials Network, Seattle 5th IAS Conference on HIV Pathogensis, Treatment & Prevention 19-22 July 2009, Cape Town

  2. Background: HSV-2-HIV synergy • HSV-2: most frequent cause of GUD, majority subclinical • HSV-2 and HIV • HSV-2 associated with increased risk of HIV acquisition1 • Men: RR=2.8 (95% CI: 2.1-3.7) • Women: RR=3.4 (95% CI: 2.4-4.8) • MSM: RR=1.6 (95% CI: 1.2-2.0) • HSV-2 increases HIV VL (0.3-0.55log10)2,3 1Glynnn JR, et al. (2009) Aids 2Duffus W, et al (2005) IJ STDs & AIDS 3Schacker T, et al (2002) JID

  3. Background: Step study • Step study • MRKAd5 HIV vaccine • 3000 high-risk HIV uninfected men & women in 34 sites • Primary outcome among 1,836 men1 • No difference in HIV acquisition • No difference in viral load setpoint • Subgroup analyses: increased risk of HIV acquisition among vaccinated, uncircumcised men & vaccinated Ad5 exposed men 1Buchbinder SP et al. (2008) Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet

  4. Research questions • What is the impact of HSV-2 seropositivity on HIV acquisition? (Analysis in placebo recipients; N=922) • What is the impact of HSV-2 seropositivity on the effect of the vaccine on HIV acquisition? (Analysis in placebo and vaccine recipients) • What is the effect of HSV-2 seropositivity on HIV VL? (Analysis in HIV seroconverters; N=87) • What is the effect of HSV-2 seropositivity on time to ART initiation? (Analysis in HIV seroconverters; N=87)

  5. Methods • Laboratory methods • HSV: Western blot (UWDVL)1 • Statistical analysis • 1,836 men, 88 HIV cases, infected prior to Oct 17th, 2007 • Kaplan Meier curves: HSV-2 as a risk factor for HIV acquisition & time to ART initiation • Cox proportional hazards regression: HSV-2 as a risk factor for HIV acquisition & time to ART initiation (stepwise selection of risk behavior variables) • Linear regression models: HSV-2 as a predictor of early pre-ART VL 1Ashley RL, et al (1988) Comparison of Western blot (immunoblot) and glycoprotein G-specific immunodot assay for detecting antibodies to HSV types 1 and 2 in human sera. J Clin Microbiol 26: 662-667.

  6. Q1: Impact of baseline HSV-2 seropositivity on HIV acquisition among placebo recipients; Kaplan Meier curves: Baseline HSV-2 seropositivity increased acquisition of HIV among placebo recipients Events observed HSV-2 negative: 18 HSV-2 positive: 17 *Log-rank test: p= 0.019

  7. Q1: Impact of baseline HSV-2 seropositivity on HIV acquisitionCox multivariate analysis results: HSV-2 seropositivity & age<30 increased risk of HIV acquisition among placebo recipients

  8. Q2: Impact of baseline HSV-2 seropositivity on HIV acquisition among placebo and vaccine recipients Kaplan Meier curves: HSV-2 increases risk of HIV acquisition among placebo & vaccine recipients Events observed HSV-2 negative: 50 HSV-2 positive: 36 *Log-rank test: p= 0.009

  9. Q2: Impact of baseline HSV-2 seropositivity on effect of vaccine on HIV acquisitionCox Proportional Hazards Model • Strong HSV-2 effect in univariate analysis: HR=1.7 (95% CI: 1.1- 2.7) • Adjusted for demographic, pre-specified & risk behavior variables (significant when added in a stepwise manner) • No significant interaction between HSV-2 & vaccine • Strong interaction between circumcision & vaccine (p=0.013)

  10. Q2: Impact of baseline HSV-2 seropositivity on HIV acquisition Cox results: HSV-2 positivity, N.America & Australia region, age<30, URAS£, UIAS£, Speed use in last 6 mnth^ & vaccine if uncirc’ed increased risk of HIV £UI/RAS: Unprotected insertive/receptive anal sex; ^prior to infection or last visit; * Vaccine x Circumcision Interaction significant (p=0.013)

  11. Q3: Impact of baseline HSV-2 seropositivity on HIV VL (all volunteers)Non-significant increase in HIV VL among HSV-2 seropositive compared to HSV-2 seronegative volunteers Linear regression Adjusted for vaccine, circumcision status, age, race, Ad5 immunity, & region: 0.3 log10 higher mean set point in HSV-2 seropositives (95% CI, 0.1 lower to 0.7 higher)

  12. Q4: Impact of baseline HSV-2 seropositivity on time to ART initiation; Kaplan-Meier Curves: No significant association between HSV-2 & time to ART initiation among placebo cases Cox HR for ART initiation by HSV-2 status stratified for region and circumcision status: HR=1.4 (0.5-4.5) unadjusted HR=1.5 (0.4-5.5) adjusted for age, race & Ad5 Months since infection diagnosis Num. at risk (HSV-2 negative) 18 14 (1) 12 (1) 8 (1) 1 (1) 1 0 Num. at risk (HSV-2 positive) 16 11 (3) 11 4 (3) 2 0 0

  13. Limitations • Risk behavior data • Self-reported risk behavior potentially subject to social desirability bias &/or recall bias • HSV-2 may be marker for increased behavioral (as well as biological) risk for HIV acquisition • VL, CD4 and ART initiation data are post-unblinding. • Current analysis among men only – future analyses will look at HSV-2 & HIV among women, but power will be limited

  14. Conclusions • HSV-2 infection increased HIV acquisition more than 2 fold • No significant interaction detected between HSV-2 & vaccine or circumcision • HIV viral load was not higher among HSV-2 seropositive compared to HSV-2 seronegative seroconverters • No significant association between HSV-2 serpositivity & HIV progression

  15. Thank you! Step study sites • STEP Volunteers • STEP Trial Sites Staff and Community Members • University of Washington Diagnostic Virology Laboratory • Rhoda Ashley Morrow, Stacy Selke & Anne Cent • SCHARP • Yunda Huang, Holly Janes, Maggie Wang, Alicia Sato, Liza Noonan, Peter Gilbert & Steve Self • HVTN+ • Susan Buchbinder, Jonathan Fuchs, Karen Mark, Martin Casapia, Jorge Sanchez, Ann Duerr & Larry Corey • Merck • Mike Robertson & Devan Mehrotra • University of Washington • Judy Wasserheit • HSV-2 manuscript team

  16. Q1: Risk factors for HSV-2 seropositivity at baseline Logistic regression (multivariate analysis): HSV-2 seropositivity associated with race/ethnicity, age>30, partners>4, UIAS & URAS

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