HSV2 is associated with HIV acquisition among both placebo

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
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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 RR2.8 (95 CI 2.1-3.7)
• Women RR3.4 (95 CI 2.4-4.8)
• MSM RR1.6 (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
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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
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Research questions

• What is the impact of HSV-2 seropositivity on HIV
  acquisition? (Analysis in placebo recipients
  N922)
• 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 N87)
• What is the effect of HSV-2 seropositivity on
  time to ART initiation? (Analysis in HIV
  seroconverters N87)

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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.
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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
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Q1 Impact of baseline HSV-2 seropositivity on
HIV acquisition Cox multivariate analysis
results HSV-2 seropositivity agelt30 increased
risk of HIV acquisition among placebo recipients

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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
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Q2 Impact of baseline HSV-2 seropositivity on
effect of vaccine on HIV acquisition Cox
Proportional Hazards Model

• Strong HSV-2 effect in univariate analysis
  HR1.7 (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
  (p0.013)

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Q2 Impact of baseline HSV-2 seropositivity on
HIV acquisition Cox results HSV-2 positivity,
N.America Australia region, agelt30, URAS,
UIAS, Speed use in last 6 mnth vaccine if
uncirced increased risk of HIV

UI/RAS Unprotected insertive/receptive anal
sex prior to infection or last visit
Vaccine x Circumcision Interaction significant
(p0.013)
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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)
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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 HR1.4 (0.5-4.5) unadjusted HR1.5
(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
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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

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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

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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

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Q1 Risk factors for HSV-2 seropositivity at
baseline Logistic regression (multivariate
analysis) HSV-2 seropositivity associated with
race/ethnicity, agegt30, partnersgt4, UIAS URAS