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Source: NIH Combination Prevention Workshop, 2010 (unpublished)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

Contact:

jsj@law.georgetown.edu