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On the analysis of viral load endpoints in HIV vaccine trials

On the analysis of viral load endpoints in HIV vaccine trials Michael Hudgens, Antje Hoering and Steve Self Fred Hutchinson Cancer Research Center Seattle, WA USA VE S effect on susceptibility Primary objective of preventive efficacy trials Possible Vaccine Effects

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On the analysis of viral load endpoints in HIV vaccine trials

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  1. On the analysis of viral load endpoints in HIV vaccine trials Michael Hudgens, Antje Hoering and Steve Self Fred Hutchinson Cancer Research Center Seattle, WA USA

  2. VES effect on susceptibility Primary objective of preventive efficacy trials Possible Vaccine Effects • VEP effect on disease progression • Requires long term follow-up of infected participants • VEI effect on infectiousness • Requires partner study or community randomization Barcelona , 10 July 2002

  3. How do we draw inference regarding VEP or VEI within the framework of a classic efficacy trial design? Question • Consider vaccine effects on surrogate markers of disease progression or secondary transmission • E.g., viral load, CD4+ count Barcelona , 10 July 2002

  4. 2. Accounting for ART Challenges 1. Viral load is a surrogate marker 3. Intent-to-treat vs. condition on infection Barcelona , 10 July 2002

  5. + Preserves randomization Intent-To-Treat • Compare VL in all participants according to randomization assignment - Requires assigning VL to uninfected participants - Potential loss of power - Does not separate vaccine effects Barcelona , 10 July 2002

  6. Compare VL in infected participants only according to randomization assignment Condition on Infection • Subject to selection bias since comparing two groups that are defined by a post - randomization event, infection • Most relevant selective mechanism: VES • Participant immune system • Infecting viral strain Barcelona , 10 July 2002

  7. Suppose vaccine protects recipients with stronger immune systems Selection bias – Example I • Infected vaccinees have weaker immune systems on average than infected controls • Vaccine may appear to enhance VL due solely to selection bias Barcelona , 10 July 2002

  8. Suppose vaccine protects recipients against relatively innocuous strains Selection bias – Example II • Vaccinees infected by more virulent strains on average than infected controls • Vaccine appears to enhanceVL due solely to selection bias Barcelona , 10 July 2002

  9. Test for a vaccine effect on viral load beyond possible selection bias Goal Barcelona , 10 July 2002

  10. Define difference in mean VL: =mean VLV – mean VLC Testing for VE on VL • Due to selection bias replace H0:   0 by H0 :  VL where threshold VL is determined by amount of selection Barcelona , 10 July 2002

  11. Assume: Integrity of randomization, blinding VES0 Vaccine has no effect on VL (null hypothesis) Selection bias - model • Then: • VL distribution for infected vaccinees can be represented as a rescaled subdistribution of the VL distribution for infected controls Barcelona , 10 July 2002

  12. Barcelona , 10 July 2002

  13. Assume extreme selection bias model Testing for VE on VL • Then testing H0 : VL is simply testing for a difference in means greater than VL between two groups • E.g., t-test • Bootstrap procedure employed to assess significance Barcelona , 10 July 2002

  14. VES: 0%, 30%, 50%, 80% Simulated Efficacy Trial • Randomized, placebo control: NV=NC=1000 • Number of infected controls: nC=90 • Three scenarios • H0: =VL • HA: =VL + 1/3 • HA: =VL + 1/2 • VL distribution: =4.5, 2=0.4 Barcelona , 10 July 2002

  15. Simulation Results - Power Barcelona , 10 July 2002

  16. Intent-to-treat vs Conditional Test for difference in mean VL using bootstrap VES=0 Simulation results - Power Barcelona , 10 July 2002

  17. Comparing post-infection endpoints (VL, CD4+) in infected vaccinees vs infected controls subject to selection bias Conclusions • Statistical methods have been developed to test for vaccine effects on post-infection endpoints beyond possible selection bias • Adequate power remains to detect clinically meaningful effects Barcelona , 10 July 2002

  18. Dichotomous outcomes Disease/death Secondary transmission Other Applications • Monkey studies • Mother to child transmission studies • Condition on survival of the child beyond birth Barcelona , 10 July 2002

  19. Hudgens, Hoering, and Self. On the analysis of viral load endpoints in HIV vaccine trials. Statistics in Medicine, In press. Gilbert and Bosch. Sensitivity analysis for the assessment of vaccine effects on viral load in HIV vaccine trials. Submitted. References Barcelona , 10 July 2002

  20. Steve Self, FHCRC, Seattle Antje Hoering, Insightful Corp, Seattle Peter Gilbert, FHCRC, Seattle M. Elizabeth Halloran, Emory Univeristy, Atlanta NIAID Acknowledgments Barcelona , 10 July 2002

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