The tipping point: When do placebos become unethical? Bridget Haire

Overview PrEP= pre-exposure prophylaxis= HIV negative people taking antiretroviral drugs to reduce HIV risk Outline the evidentiary context for pre- exposure Critique a current French PrEP trial Consider precedents in HIV prevention research Assess the ramifications of this approach

StudyPopulationResult iPrEXMen who have sex with men 44% FTC/TDF Partners PrEPSerodiscordant couples 67% TDF 75% FTC/TDF TDF-2Heterosexual people 62% FTC/TDF FEM PrEPWomenFutility FTC/TDF VOICEWomenFutility TDF Futility TDF gel Futility FTC/TDF Bangkok PrEPPeople who inject drugs 49% TDF

PrEP (FTC/TDF) approved by US FDA for prevention of HIV From: US Food & Drug Administration When: 16 July 2012 For: Gilead Sciences oral TDF/FTC in the US What: Regulatory approval in the US for daily oral TDF/ FTC (Truvada) for PrEP in HIV-negative adults

Efficacy and adherence Bangkok: 71% in DOT participants iPrEX: 92% in high adherers (measured blood levels) FEM-PrEP: less than ¼ of participants had detectable drug levels VOICE: less than half of participants on active drug had detectable blood levels

Ipergay Tests intermittent PrEP against placebo in gay men/MSM France and Canada Began in Feb 2012 No marketing authorisation for PrEP in the European Union

Rationale Optimal design for ‘rigorous assessment’ Reduce risk of behavioural disinhibition* FTC/TDF has not been evaluated in ‘real life’ conditions in USA No detrimental in terms of prevention and health promotion Participants would be no worse off

Rationale for best practice for research participants Prevents vulnerable* participants being used to test drugs for those more privileged People enrolled in HIV prevention trials are generally at the highest risk of HIV infection Best practice standards of care recognise the contribution that research participants make to the research endeavour

Guidelines UNAIDS 2007, updated 2012 Declaration of Helsinki 2008 Council for International Organizations of Medical Sciences (CIOMS) 2002 HPTN 2009

UNAIDS, Guideline 13 … appropriate counselling and access to all state of the art HIV risk reduction methods are provided to participants throughout the duration of the biomedical HIV prevention trial. New HIV risk-reduction methods should be added, based on consultation among all research stakeholders including the community, as they are scientifically validated or as they are approved by relevant authorities…

HPTN Guideline 9 In partnership with key stakeholders, HPTN should establish a package of effective, comprehensive and locally sustainable prevention services to be offered to participants in each HPTN study.

Response to Ipergay design ANRS consulted regarding continuation of study, and concluded the study should continue as designed in October 2012 Decision based largely upon the scientific committee’s advice that the FDA approval of PrEP was not based on new information ‘Associative committee’ (community advisory board) majority requested access to daily PrEP for participants Minority disagreed

Community responses Split between ACT-UP Paris and Warning Warning called for Ipergay’s closure or change to the design on ethical grounds Other community groups ruled themselves not competent to judge scientifically or ethically AIDES demanded ‘temporary marketing approval’ of PrEP in France

Response to community critique ‘…whatever the randomization arm, the enrolment of participants is not detrimental in terms of prevention or health promotion’ ANRS Press release Research organisation is setting up a working group with non-profit organisations to discuss optimisation of HIV prevention research

History repeating Mirrors aspects of the mother-to-child prevention debate of 1997 Like the mother-to-child controversy, the argument for including a placebo in Ipergay is both methodological (getting robust data) and dependent on lack of access to the best proven prevention option in the population

How Ipergay is different form the mother- to-child debate Daily PrEP is clearly affordable and feasible in a trial context in France, though it is not yet available through the health system

Burning scientific question Would intermittent PrEP dosing work better or worse that continuous daily dosing? Positivist view: Too many confounders in a comparative study to isolate efficacy Rebuttal: the question is about situated effectiveness of the different strategies Effectiveness rather than efficacy

Why choose a placebo-controlled design? Summary Faster, cheaper, easier-to-interpret answer to the question of whether intermittent PrEP is effective Asserts the primacy of local regulations as key in what constitutes standard of care Reinforces the lowest denominator regarding what constitutes fair treatment of research subjects: leaving them no worse off