1. 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

2. 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)

3. 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

4. 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

5. Ongoing/future research
• Expand on PrEP, microbicide data
– Confirmatory studies
– Feasibility/cost-effectiveness
• Optimizing combination strategies
• New modalities
– Vaccine
– Rectal microbicide
– Additional ARV options

6. HIV Prevention Trial Design
• Randomized controlled trial = gold
STUDY PARTICIPANTS
standard
Random assignment
NEW
• Placebo-controlled RCT (e.g. iPrEx, PLACEBO
MODALITY
CAPRISA 004)
– Randomization New infections
– New infections counted
– Compare study groups

7. STUDY PARTICIPANTS
Double-blind RCT
for
biomedical HIV NEW
prevention PLACEBO
MODALITY
UNAIDS/WH
O 2007: CONDOM ACCESS
“appropriate
counseling
and access RISK REDUCTION COUNSELING
to all state Background
of the art package
HIV risk STI TEST & TREAT
reduction
methods”
must be PrEP/MICROBICIDE?
provided

8. Incidence and sample size

9. Hypothetical HIV Vaccine Trial
Source: NIH Combination Prevention Workshop, 2010 (unpublished)

10. 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

11. 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

12. 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)

13. 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

14. 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

15. 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

16. 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)

17. 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

18. 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

19. 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?

20. Acknowledgments
Glenda Gray Contact:
Ken Mayer jsj@law.georgetown.edu
Ian McGowan
Liza Dawson
Collin O’Neil
Hannah Burris
Kelli Garcia
Jackie Huh