McIntyre CROI 2005

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Phase IIB HIV Vaccine Trials viral load
endpoints looking for efficacy Glenda
Gray Perinatal HIV Research UnitUniversity of
the WitwatersrandChris Hani Baragwanath
HospitalJohannesburg, South Africa
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Scope Rational for a phase IIB TOC vaccine trial
vs Phase III HIV vaccine trial Viral load
endpoints in a phase IIB TOC HVTN 503 phase IIB
trial
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• A preventive vaccine should
• Mimic the effects of natural exposure to microbes
• Provide long lasting protection against infection
• Serve as a free standing prevention method
• Presently
• There is a lack of knowledge of the quality and
  quantity of immune responses required for
  protection against HIV or the development of
  disease

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Features of a Phase IIB Test of Concept HIV
Vaccine Trial

• Provide a rapid preliminary assessment of whether
  a vaccine concept is sufficiently promising to
  warrant advancement to a pivotal phase III trial
  (intended to inform the stop-go decisions)
• Be a randomised double blind placebo controlled
  trial in an at risk population
• Directly evaluate efficacy using selected
  endpoints that augment immunogenicity
• Virological and Immunological follow up
  participants that become infected on the trial
  will provide valuable information on the effect
  of vaccine on disease progression

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Potential Differences between a phase IIB-TOC and
phase III pivotal trial design
WHO/UNAIDS/IAVI International Expert Group, AIDS,
2007
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Phase IIB-TOC and Phase III pivotal trials
WHO/UNAIDS/IAVI International Expert Group, AIDS,
2007
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Phase II Screening Test of Concept Trials (STOC)

• Novel approach to gather preliminary efficacy
  data in a short period of time in fewer trial
  participants
• STOC 30 incident HIV infections to detect a 1
  log reduction of viral load which would require a
  4 HIV incidence and 500 subjects with 18 months
  post-vaccination follow up

Wayne Koff, IAVI 2007
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HIV-1 Virologic and Immunologic Progression and
Initiation of ART among HIV-1 infected subjects
in a trial of the efficacy of rgp120 Vaccine
Gilbert PB, JID, 2005
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CTL-based vaccines
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• Role of CTL/CMI based HIV vaccines
• A vaccine that may induce a strong T-cell
  mediated immune response in the absence of
  broadly neutralizing antibodies that may prove
  beneficial even if infection is not completely
  prevented
• Vaccine-induced T-cell responses may blunt
  initial viraemia and prevent the early and
  massive destruction of memory CD4T cells that
  help control infection and prolong disease-free
  survival
• Such a vaccine may impact on secondary
  transmission of HIV if the vaccine helps control
  viral replication

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• Evaluating CTL-based vaccines
• Vaccine efficacy-susceptibility (VEs) reduction
  in risk of acquiring HIV infection
• Vaccine efficacy-disease progression (VEp) Need
  to demonstrate that the initial reduction in
  viral load set-point results in a clinical
  benefit
• Vaccine efficacy-disease progression (VEp) Need
  to demonstrate the durability of T-cell mediated
  control of infection
• Vaccine efficacy-infectiousness (VEi) Need to
  demonstrate that vaccination reduced the spread
  of HIV in the community

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Johnston M, Fauci A. N Engl J Med
20073562073-2081

• Vaccine efficacy-disease progression (VEp)
• Reduce peak viremia
• VL set-point
• CD4 count
• Durability of VL reduction
• Time to initiate ART

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Course of HIV Infection in Unvaccinated Persons
and the Hypothetical Course of Infection in
Vaccinated Persons
Johnston M, Fauci A. N Engl J Med
20073562073-2081
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• Viral Load as a measure of efficacy may be
  affected by
• Gender
• Age
• Sub-type
• Region
• HLA (HLAB5701 allele)
• Route of infection

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Impact of Early HIV RNA and T-lymphocyte Dynamics
during Primary HIV-1 infection and the Subsequent
Course of HIV-1 RNA levels and CD4T-Lymphocytes
in the first year of HIV-1 infection Kaufmann GR,
JAIDS, 1999
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Review of early natural history of HIV infection
by region, sub-type, gender in cohort studies
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Disease Progression in Sero-Convertors
predictors of undetectable viremia without ART
(France). Madec Y, Clin Infect Dis, 2005
NOTE.     Data are median (range), unless
otherwise indicated.      a In multivariate
logistic regression, adjusted for the 6
variables.     b     26 years (33rd
percentile) vs. gt26 years.     c For each 100
cells/mm3.     d     3.76 log10 copies/mL
(33rd percentile) vs. gt3.76 log10
copies/mL.     e Data available for 31 subjects
with undetectable viremia and 343 subjects with
detectable viremia.     f     2.61 log10
copies/mL (33rd percentile) vs. gt2.61 log10
copies/mL.     g Data available for 35 subjects
with undetectable viremia and 369 subjects with
detectable viremia during follow-up.
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FACTORS ASSOCIATED WITH SPONTANEOUS CONTROL OF
VIRAL LOAD AND CD4 CELL COUNT PROGRESSION AMONG-1
HIV SERO-CONVERTORS (CASCADE COLLABORATION)
Median duration of undetectable viremia was 11,2
months
MADEC Y, AIDS, 2005
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Viral Load and CD4 Count following HIV-1
sero-conversion (sub-type B) impact of gender
and region
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Viral Load and CD4 post sero-conversion in Asia
Impact of Region
Cascade Median Age to AIDS was 11 years Lancet
2000
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Disease Progression in Sero-Convertors in Africa
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HAZARD RATIOS FOR PROGRESSION TO AIDS IN MEN AND
WOMEN
Sterling TR, NEJM, 2001
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Gender, Age and Route of Infection
Touloumi G, AIDS, 2004 Cascade Collaboration
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Age and Sex
Touloumi G, AIDS, 2004 Cascade Collaboration
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HVTN 503 Primary Hypotheses

• Primary Safety
• The MRKAd5 HIV-1 gag/pol/nef vaccine will be safe
  and well tolerated in 18 to 35-year old HIV-1
  seronegative adults.
• Co-Primary Efficacy
• Infection endpoint
• Subjects who receive the vaccine will have a
  lower likelihood of acquiring HIV-1 infection
  than those who receive placebo
• AND/OR
• Viral load endpoint
• Among subjects who become HIV-1 infected, those
  who receive the vaccine will have a smaller
  average viral load set-point at 3 months post
  seroconversion than those who receive placebo
• Ensure sufficient power for efficacy analysis in
  subgroup with baseline Ad5 titers lt 200

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Key questions addressed by the HVTN 503
phase IIB TOC trial

• Will CMI responses elicited by the vaccine
• Prevent persistent HIV infection and/or
• Control HIV viral replication if infection does
  occur
• What is the impact of pre-existing Ad5 titer on
  immunogenicity
• What is the role of clade in vaccine protection?
• That is, will a clade B-based vaccine designed to
  elicit cellular immunity demonstrate efficacy in
  non- Clade B regions?
• It is likely not feasible to develop a different
  vaccine targeted against each HIV-1 clade.
• Our ability as a scientific community to provide
  tailor-made vaccine for specific regions and
  ensure specificity is not realistic.

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HVTN 503 phase IIB TOC

• A Test-of-Concept South African Study
• Address efficacy Merck Ad 5 trivalent vaccine in
  a
• Subtype C region
• Predominantly heterosexual populations
• The key question addressed by the RSA Study
• Will the efficacy of the vaccine be influenced by
  HIV-1 subtype
• South Africa has studied non-Clade C vaccines
  (IAVI, HVTN)
• Other questions addressed by the RSA Study
• Markedly enhance the information on efficacy in
  women
• Refine the assessment of the impact of
  pre-existing Ad5 titers
• More than double the number of endpoints to
  enhance the evaluation of correlates of
  protection.

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Conclusion

• Results from properly designed phase IIb TOC
  trials will help with the decision to move ahead
  with a pivotal trial or go back to the drawing
  board
• Phase IIB TOC will provide further data on viral
  dynamics in early infection.
• Phase IIB TOC trials will further elucidate the
  interaction between virus and the immune system
  that will inform vaccine design and development

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Acknowledgments HVTN Core Larry Corey Ann
Duerr Niles Eaton HVTN 503 Investigators Jim
Kublin Linda Gail Bekker Gavin Churchyard Koleka
Mlisani Mophashane Nchabeleng
NIAID Peggy Johnston Jorge Flores Alan
Fix PHRU Guy de Bruyn James McIntyre Eftyhia
Vardas