Update: HIV Vaccines and other Prevention Research

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Update HIV Vaccines and other Prevention Research

• Susan Buchbinder, MD
• HPPC Presentation
• August 14, 2008

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Topics

• Process of vaccine development
• Background on the Step Study
• Results of the Step Study
• The road forward

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Impact of Vaccines in the U.S.
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Duration between discovery of cause of infectious
diseases and development of a vaccine
Source Modified from H. Markel, NEJM, August
25, 2005
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How do you test an HIV vaccine?
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The Step Study Merck Vaccine
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The Step Study

• 3000 men and women
• 1500 with low levels of Ad5 antibodies
• 1500 with high levels of Ad5 antibodies
• Randomized, double-blind, placebo-controlled
• Approved by regulatory authorities
• Data Safety Monitoring Board

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Step Study sites
?
?
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Scientific Questions

• Primary Study Questions
• Safety Is this vaccine well-tolerated?
• Efficacy Does this vaccine prevent HIV
  infection?Does this vaccine reduce the amount of
  HIV in the blood of people who become infected
  with HIV?

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Step Study Results

• Scheduled DSMB look at the data 18 Sept 2007
• Evaluate data from 1500 volunteers who had low
  Ad5 antibody levels
• The vaccine did not protect against HIV infection
• The vaccine did not reduce the viral load in
  people who became infected
• Met futility criteria and should stop
  vaccinations

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Cumulative Number of HIV Infections Men with
Ad5 200
Cases accrued as of Oct 17, 2007
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More Analysis

• Disappointing that vaccine did not protect
• Moved to post-hoc analyses to explore potential
  reasons, BUT
• Small numbers, multiple comparisons, so cant
  draw definitive conclusions
• Limited to men (only 1 infection in a woman)

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Cumulative Number of HIV Infections Men
Overall
Ad5 gt 200
Cases accrued as of Oct 17, 2007
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The vaccine CANNOT cause HIV infection

• (No live or killed HIV)
• (Not enough genetic information to form a virus)

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Three questions

• Could the different number of infections be due
  to other differences between those who got
  vaccine vs. placebo?
• Are all vaccinees at increased risk, or just some
  subgroups?
• Is the increased risk transient or does it last?

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1. HIV risk in vaccine group

• Even after controlling for these factors,
  vaccinees still had higher HIV infection rates
• Age
• Race
• Location
• Behaviors (sex, drug use)
• Medical (sexually transmitted infections, male
  circumcision)

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2. Subgroups?

• Vaccine risk seemed only to apply to men who were
  uncircumcised and/or had Ad5 antibodies
• If both uncircumcised and with antibodies before
  getting vaccine, increased HIV risk
• If both circumcised and no antibodies, no
  increased risk
• If only one risk factor but not other,
  intermediate risk
• Why increased risk in these subgroups?

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3. Does the effect last?
Time interval of estimated HIV infection in weeks
relative to randomizationSummaries exclude 1
female infection (placebo group with Ad5 18).
MITT population includes all HIV cases diagnosed
after baseline.
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HIV Vaccine Research GoalWhats Next?

• To find a vaccine that works in the populations
  most affected by HIV disease today

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Research that Could Re-define Prevention, 9/06
See also http//www.avac.org/timeline-website/inde
x.htm
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Research that Could Re-define Prevention, 2/08

Vaccines Prime/Boost Merck Adeno 1
Female Barrier Diaphragm
Microbicides Carraguard
HSV-2 Treatment Infectiousness
Microbicides CS-1 CS-2
Community VCT and HIV Support
Male Circumcision Susceptibility
Oral PrEP IDU
Vaccine VRC PAVE 100
Vaccine Merck Adeno 2

• Microbicides
• BG/Pro2000
• Pro2000
• TDF

Male Circumcision Infectiousness
HSV-2 Treatment Susceptibility

• Oral PrEP
• MSM
• Heterosexual

Index Partner Treatment
Oral PrEP West Africa
2011
2006
2010
2008
2009
2007
See also http//www.avac.org/timeline-website/inde
x.htm
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How Many Molecules Does it Take to Develop an
Approved Drug?

• 10,000 molecules screened for activity in vitro
• 250 evaluated in full preclinical tests
• 5 enter phase I testing
• 1 approved drug
• Pharmaceutical Manufacturers of America, 2006

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What happened to PAVE?

• Partnership in AIDS Vaccine Evaluation (NIH,
  CDC, IAVI, USMHRP)
• PAVE 100 designed to evaluate 2 vaccines
• DNA Ad5 vector (different from Merck)
• Originally 3 trials, 8500 total
• Revised was to focus on MSM in US, 2400
  circumcised, Ad5 negative men
• NIH decided not to fund asked HVTN to create
  smaller, more focused study

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Stepping forward

• Continuing to follow study volunteers
• gt90 retention since unblinded everyone
• Lots of important data from STEP study
• Learning why it didnt work
• Exploring whether true increase in risk and if it
  lasts
• Intriguing leads about potential protection in
  subgroups
• Step provided new information that could never
  have come from animal studies
• Back to basics includes lab, animal studies,
  and clinical trials

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Other strategies

• 2 Pre-exposure prophylaxis studies in SF
• Part of global effort to test PrEP
• Combined approaches needed
• Substance use treatment
• ART, HSV2 for positives?
• Testing, disclosure, improved sero-adaptation?
• Male circumcision?
• Behavioral interventions
• PUMA (Prevention Umbrella for MSM in Americas)

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Success is

• A clinical trial that produces a scientifically
  accurate result and protects participant
  well-being
• We cant guarantee what studies will find, but we
  can promise rapid communication of results
• Community input has been critical to our
  decision-making throughout our trials
• If studies are well-designed, they will move us
  forward, regardless of the result

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The Study Volunteers
Acknowledgments

• For their dedication and commitment in the search
  for an HIV vaccine