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Phambili/HVTN 503 Interim Efficacy Analysis A multicenter double-blind randomized placebo-controlled Phase IIB

Phambili/HVTN 503 Interim Efficacy Analysis A multicenter double-blind randomized placebo-controlled Phase IIB test-of-concept study to evaluate the safety and efficacy of a 3-dose regimen of the Clade B-based Merck Adenovirus serotype 5

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Phambili/HVTN 503 Interim Efficacy Analysis A multicenter double-blind randomized placebo-controlled Phase IIB

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  1. Phambili/HVTN 503 Interim Efficacy Analysis A multicenter double-blind randomized placebo-controlled Phase IIB test-of-concept study to evaluate the safety and efficacy of a 3-dose regimen of the Clade B-based Merck Adenovirus serotype 5 HIV-1 gag/pol/nef vaccine in HIV-1-uninfected adults in South Africa Gray G, Allen M, Churchyard G, Bekker L, Nchabeleng M, Mlisana K, Moodie Z, Metch B, Nicholson O, & Kublin J

  2. Background • Designed as a companion trial to the STEP study • Evaluate the efficacy of a clade B HIV vaccine in a region where the predominant circulating clade is C • Heterosexual population with a high proportion of women and young adult population targeted for enrollment • Original sample size was 3000 adults at high risk of HIV acquisition (120 HIV-1 infection end-points within 3 years of first participant enrolled) • In September 2007, post STEP DSMB, decided to discontinue vaccination, unblind participants and continue follow-up

  3. Study Design Test of concept phase IIb double blind randomized controlled study of the MRK ad5 HIV-1 gag/pol/nef vaccine conducted at five study sites in RSA • 18-35 year old healthy HIV uninfected adults • Sexually active within last 6 months • Sites: Soweto (PHRU), Cape Town, KOSH, eThekwini, MEDUNSA

  4. Major Findings • Good cross clade immune reactivity • 0.57 log reduction in viral load at set-point in women who received the vaccine • Early differences seen in CD4 decline between vaccine and placebo • Risk reduction behaviour sustained over time in both vaccine and placebo arms (P15-08) • Good uptake of circumcision post-enrollment (P14-07 Guy de Bruyn) • Minimal social harm (P14-02 Mary Allen)

  5. Statistical Analysis • Data frozen on 31st August 2009 • Safety analysis (reactogenicity events and adverse events) • Efficacy endpoint analysis are based on MITT cohort • Efficacy Assessments: • Two co-primary endpoints • 1) HIV-1 infection • 2) Viral load set-point • ELISpot assay analysis using both Clade B and C peptide pools:

  6. Maximum Local Reactogenicity by Treatment Arm

  7. Maximum Reactogenicity by Treatment Arm

  8. Baseline Participant Characteristics by Treatment Arm

  9. Baseline Participant Characteristics by Treatment Arm

  10. Vaccinations

  11. Cumulative probability of early study termination ( HIV-1 negative Participants) 92.8% retention

  12. Baseline Risk Behaviors for Men by Treatment Arm

  13. Baseline Risk Behaviors for Men by Treatment Arm

  14. Baseline Risk Behaviors for Men by Treatment Arm

  15. Baseline Risk Behaviors for Women by Treatment Arm

  16. Baseline Risk Behaviors for Women by Treatment Arm

  17. Baseline Risk Behaviors for Women by Treatment Arm

  18. Pregnancy Outcomes by Treatment Arm (13/66 occurred during vaccination)

  19. Post Enrollment Circumcision

  20. Post Enrollment Circumcision by site

  21. Post−enrollment Sexually Transmitted Infections

  22. HIV-1 infections

  23. HIV− 1 Infections by Treatment Arm (MITT)

  24. HIV− 1 Infections by Treatment Arm (MITT)

  25. HIV− 1 Infections by Treatment Arm (pre and post unblinding)

  26. Cumulative Number of HIV-1 infections

  27. Cumulative Number of HIV-1 Infections by Gender & Treatment

  28. Cumulative Number of HIV – 1 infections by Treatment Arm (Ad5>18)

  29. Cumulative Number of HIV-1 Infections by Gender and Treatment Arm (Ad5>18)

  30. HIV−1 Incidence Rates by Treatment Arm Vaccine:Placebo hazard ratio adjusted for gender: 1.26 95%CI (0.76-2.10) 2-tailed Wald p-value (unadjusted for dual endpoints)=0.37

  31. Cumulative Probability of Being HIV- 1 Infected by Treatment Arm and Number of Study Vaccinations Received

  32. Log Hazard Ratio of infections (V:P) Over Time

  33. Viral Load Setpoint

  34. Viral Load Setpoint by Treatment Arm: MITT Cohort

  35. Viral Load Setpoint by Gender

  36. Viral Load Setpoint: Women in MITT cohort 0.57 log reduction

  37. Viral Load Setpoint by Baseline Ad5 Titer

  38. Log10 Viral Load Over Time

  39. CD4 count and ART initiation

  40. CD4 Counts Over Time

  41. Rate of CD4 decline to <350 over time

  42. HIV−1 Infected Participants who have Initiated ART * PMTCT

  43. Immunogenicity • first 186 participants (93v/93p) • IFN-ϒ ELISpot from week 8 (4 weeks post 2nd vaccination) • HIV-1 negative at day 84 (week 12) • received the 2nd vaccination • Clade B peptide pools were synthetic peptide pools spanning Clade B proteins encoded by the vaccine constructs (1Gag, 1Nef and 2 Pol pools) • Clade C peptide pools were from Southern African isolates (2 Gag PTE-C, 1 Nef PTE-C and 3 Pol PTE-C pools)

  44. ELISpot Response Rates for Clade B Synthetic Peptide Pools by Treatment Arm (day 56) Placebo (n=93) Vaccine (n=93)

  45. ELISpot Response Rates for Clade C PTE Peptide Pools by Treatment Arm (Day 56) Placebo (n=93) Vaccine (n=93)

  46. ELISpot Response Rates for Clade B Synthetic Peptide Pools by Baseline Ad5 Titer for Vaccinees (Day 56) Ad5≤18=18 Ad5>18=75

  47. ELISpot Response Rates for Clade C PTE Peptide Pools by Baseline Ad5 Titer for Vaccinees (Day 56) Ad5≤18=18 Ad5>18=75

  48. Magnitude of ELISpot Response Among Responders

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