standards of prevention: ethics in the era of art prophylaxis
TRANSCRIPT
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
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)
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
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
Ongoing/future research • Expand on PrEP, microbicide data
– Confirmatory studies – Feasibility/cost-effectiveness
• Optimizing combination strategies
• New modalities – Vaccine – Rectal microbicide – Additional ARV options
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
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
Incidence and sample size
Hypothetical HIV Vaccine Trial
Source: NIH Combination Prevention Workshop, 2010 (unpublished)
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
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
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)
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
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
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
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)
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
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
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?
Acknowledgments
Glenda Gray
Ken Mayer
Ian McGowan
Liza Dawson
Collin O’Neil
Hannah Burris
Kelli Garcia
Jackie Huh
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