Standards of Prevention: Ethics in the Era of ART Prophylaxis
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Transcript of Standards of Prevention: Ethics in the Era of ART Prophylaxis
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Standards of Prevention: Ethics in the Era
of ART Prophylaxis Jonathan Jay, JD MA
O’Neill Institute for National and Global Health Law
Georgetown University National HIV Prevention Conference
August 16, 2011
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Introduction
What should researchers do to reduce HIV risk among study participants in prevention trials?
“Standards of prevention”
Answering this question: more difficult in the age of safe, effective ARV-based prevention (PrEP, microbicide)
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Biomedical HIV prevention methods
For sexual transmission
• In widespread clinical practice: – Male/female condoms – STI testing and treatment – PEP – Male circumcision – Treatment as prevention
• Proof of concept:
– PrEP – Microbicide
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ART chemoprophylaxis • Microbicide (vaginal TDF 1% gel)
– CAPRISA 004: 39% efficacy
• PrEP (oral tenofovir/Truvada)
– iPrEx: 42% efficacy among MSM
– FEM-PrEP: stopped for futility (women)
– Partners: 62/73% among men and women
– TDF2: 62% among men and women
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Ongoing/future research • Expand on PrEP, microbicide data
– Confirmatory studies – Feasibility/cost-effectiveness
• Optimizing combination strategies
• New modalities – Vaccine – Rectal microbicide – Additional ARV options
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HIV Prevention Trial Design • Randomized controlled trial = gold
standard
• Placebo-controlled RCT (e.g. iPrEx, CAPRISA 004) – Randomization
– New infections counted
– Compare study groups
STUDY PARTICIPANTS
NEW MODALITY PLACEBO
New infections
Random assignment
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Background package
STUDY PARTICIPANTS
NEW MODALITY PLACEBO
CONDOM ACCESS
RISK REDUCTION COUNSELING
STI TEST & TREAT
PrEP/MICROBICIDE?
Double-blind RCT for biomedical HIV prevention
UNAIDS/WHO 2007: “appropriate counseling and access to all state of the art HIV risk reduction methods” must be provided
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Incidence and sample size
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Hypothetical HIV Vaccine Trial
Source: NIH Combination Prevention Workshop, 2010 (unpublished)
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Current/future trials
HVTN 505:
• Combo vaccine vs. placebo – 2200 MSM in U.S.
MTN-020:
• Dapivirine ring vs. placebo – 4000 women in Southern Africa
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Methods
• Analyzed UNAIDS/WHO guidance
• Analyzed key international ethics documents – Declaration of Helsinki (WMA)
– CIOMS Ethics Guidance
– Belmont Report (USA)
• Literature review
• Consultations with HIV prevention researchers
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Approaches to standards of prevention
1. Maximum benefit to participants – Key ethical issues
• Beneficence: – Maximize benefits, minimize risks to subjectsa
– Do not withhold current, proven interventionb
• Non-exploitation – Avoid taking advantage of subjects
a: Belmont Report (U.S. Presidential Commission) b: Declaration of Helsinki (World Medical Assn)
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Approaches to standards of prevention
2. Match local clinical practice – Key ethical issues
• Public health goals – Trials which are speedier, less expensive, less complex
• Non-maleficence – Subjects are no worse off than outside study
• Sustainability – May be impossible to guarantee long-term access to some
modalities
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UNAIDS/WHO approach
• Most influential guidance on standards of prevention
• Aligned with “maximum benefits” approach – Package must include “all state of the art”
interventions
UNAIDS/WHO Ethical Considerations in Biomedical HIV Prevention Trials, 2007
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UNAIDS/WHO and ARV prophylaxis
“All state of the art” is problematic 1. Methodological/scientific issues
2. When to include • Evidence continuously emerging
• Too late/too early both ethically problematic
3. Appropriate combination approach • Ensuring benefit
• Adequacy as baseline
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Intermediate conclusions
• Both sides are right—must understand principles in light of valid concerns
• UNAIDS/WHO should be updated/revised
• A new approach would better fit the challenges posed by ARV chemoprophylaxis – Jay, Gray, Mayer, McGowan (forthcoming)
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Threshold Approach • Set threshold for presumptive inclusion
• Provide analysis of how modality might be withheld
1. Methodological/scientific issues 2. When to include
• Evidence continuously emerging • Too late/too early both ethically
problematic 3. Appropriate combination approach
• Ensuring benefit • Adequacy as baseline
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Clinically Reasonable • Background package should be clinically
reasonable – Efficacy, safety; behavioral; acceptability
1. Methodological/scientific issues 2. When to include
• Evidence continuously emerging • Too late/too early both ethically
problematic 3. Appropriate combination approach
• Ensuring benefit • Adequacy as baseline
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Three-step framework
Step 1: when validated for clinical use, should be presumptively provided
Step 2: is withholding the modality methodologically necessary?
Step 3: does the study address a compelling public health need?
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Acknowledgments
Glenda Gray
Ken Mayer
Ian McGowan
Liza Dawson
Collin O’Neil
Hannah Burris
Kelli Garcia
Jackie Huh
Contact: