Warning considers that, given the current international scientific consensus, the placebo arm of the IPERGAY study does not meet ethical standards and must be immediately interrupted in the interest of protecting the health of gay men participating in study. Warning also requests that a temporary authorization for the use of oral PrEP be granted in France by the medication regulatory body.

In what follow, Warning, a community health organisation, responds to the opinion issued by the independent monitoring committee [1] of the IPERGAY study as well as to the news release of the ANRS (the French Aids Research Agency) regarding IPERGAY where they announce that the trial will be continued as originally planned.

Two competing “scientific truths”

Following the decision of U.S. Food and Drug Administration (FDA) to authorize the marketing of Truvada to prevent HIV infection in HIV-negative people, the ANRS requested the opinions of the various committees of the IPERGAY study on various issues including the placebo arm design. Each committee has delivered its opinion. This was followed by a recent ANRS press release deciding to continue IPERGAY as is.

To justify the continuation of the IPERGAY study with its current design (including a placebo arm), the Independent Monitoring Committee (IMC) states that the evidence of the effectiveness of PrEP among MSM comes from a single study [iPrEx] and is therefore inconclusive. Furthermore, the evidence from studies of heterosexual transmission has provided mixed results. The IMC therefore considers that the effectiveness of daily oral PrEP hand not been effectively and sufficiently demonstrated.

In late August, the study’s scientific committee stated that the FDA’s [2] decision is not based on new evidence and therefore doesn’t change the scientific relevance of the project. This somewhat convoluted statement was aligned with the IMC’s statement, notably that the findings of the iPrEx trial are insufficient in the opinion of French scientists.

The validity of the first daily oral PrEP trials has been discussed and compared to international standards in this field [3]. The World Health Organization has recognized the effectiveness of these strategies (evidence of effectiveness) [4]. The results of the iPrEx were deemed solid by the Centers for Disease Control and Prevention [5] for the use of Truvada [6] in a population similar to the study population. The results of iPrEx also convinced the experts of the Food and Drug Administration, who authorized its use on July 16th 2012.

Over time, experts from the ANRS seem to have changed their minds. In their argument at the beginning of the study protocol, they stated that the results of the iPrEx study have confirmed proof of concept of the effectiveness of PrEP in preventing HIV infection.

This shift, which goes against the advice of experts and of reputable agencies, has obvious implications for the IPERGAY study and its continuation. Namely, it affects the ethical standards expected of such a study and reflects the moral attitude of the researcher towards enrolled participants. By denying the efficacy of daily oral PrEP and by considering that its approval in the United States does not change anything, the study researchers are questionably and falsely claiming that there is no established reference method just to justify pursuing the study.

An erroneous statement

When the ANRS says that the IPERGAY trial is crucial for prevention among gays since it seeks to validate a hypothesis that scientists have not yet explored – namely a comprehensive prevention package based on the combination of all validated methods (condoms, screening and treatment of common sexually transmitted infections) to which is added the study of the additional benefit from taking Truvada on demand – they fails to mention that this “offer of enhanced prevention” has nothing innovative about it (it has already been tested as such) and that it constitutes the minimum required for any ethical biomedical research in prevention according to recommendations issued by international organizations.

UNAIDS and WHO, in particular, recommend that a comprehensive counselling and prevention package that includes the most effective state of the art risk reduction interventions be fully integrated and offered to participants in prevention study protocols [7].

We begin to better understand the “turnaround” of the ANRS since recognition of the effectiveness of daily oral PreP would integrate it into the standard required for any preventive biomedical prevention. Especially since the UNAIDS document states that “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.”

The IPERGAY study is no longer ethical

This implies that the placebo arm of the IPERGAY study is no longer ethical, if it ever was. It blatantly violates the general recommendations of the Helsinki Declaration [8], confirmed by UNAIDS and WHO, as well other guidelines [9] and Good Participatory Practices [10] in the context of HIV and AIDS. UNAIDS has very clear guidance on control groups in biomedical prevention trials :

Participants in both the control arm and the intervention arm should receive all established effective HIV risk reduction measures. The use of a placebo control arm is ethically acceptable in a biomedical HIV prevention trial only when there is no HIV prevention modality of the type being studied that has been scientifically validated in comparable populations or approved by relevant authorities. [11]

The IPERGAY study obviously does not meet these conditions ; the placebo arm should be stopped without delay : it reduces the chances of participants in this arm to avoid HIV infection and therefore puts their health at risk.

The Independent Monitoring Committee estimates, with incredible lightness, that since participants in either arm of the study are receiving a prevention package, they are not being denied prevention and health promotion methods.

Given all the international evaluations and recommendations on this type of trial, the sponsors, investigators, operators and experts in charge of monitoring the study could be held collectively responsible for the circumstances in which any contamination occur unnecessarily in the placebo arm of the study due to a protocol not providing the « standard of prevention » required.

We are not guinea pigs !

Is biomedical prevention creating a “crisis of trials” already described in the clinical trials of the first ARVs in the mid-1990s [12] ? Trials pitted supporters of a “strict line” (advocates of randomized, double-blind placebo trials : the gold standard), to those of a more “open” approach allowing faster access to new molecules and flexible methods that are adapted to the needs of those involved.

Recognizing the effectiveness of daily oral PrEP and its ethical implications is tantamount to foregoing the IPERGAY study in its current form. The researchers would have to revise the protocol and resubmit it to the necessary agencies for approval. This would delay publishing the expected results in prestigious periodicals. Furthermore, integrating a daily PreP arm in the study would considerably complicate the methodology of the trial. The difference between the two arms would be much lower in comparison to the current primary endpoint (i.e. the number of seroconversions observed in each arm of a trial that plans to eventually include 1,900 people). This would force the ANRS to significantly expand the size of the sample, and thus further increase the budget of the study.

This alternative posits a moral dilemma : should the focus be the health of the participants enrolled in the trial, or should we favor the public interest in maintaining a design that is more “productive” yet more “expensive” in terms of collateral outcomes ? Study sponsors, investigators and operators seem to have settled the issue, with the consent of the supervisory board : they chose a universalist approach considered more profitable, scientifically and financially.

Therefore, gay men enrolled in the study are “exploited” and collectively made into guinea pigs facing potential negative effects on their personal health.

Immediate action is required

Despite a system of HIV/AIDS research that seems in disarray, the ANRS (and its satellites) are probably not as monolithic as it seems. In this sense, the agency would benefit from greater transparency on the governance of IPERGAY and the use of its budget in monitoring the study [13] ; on any conflicts of interest involved [14] and on its European commitment on PrEP [15].

The IPERGAY study protocol needs an urgent overhaul. Daily oral Prep needs to be integrated in its standard of prevention. If this is not methodologically or financially possible, the study should be stopped and the remaining budget should be redirected to other avenues of research.

In its statement, the ANRS promised to create a working group charged with exploring new avenues of research to optimize the use of different preventive measures, including pre-exposure prophylaxis (PrEP). This group should not be constituted only by scientists ; it must include a space for independent community stakeholders.

Foremost, to respond the urgent needs of gay men in France, the temporary authorisation for use of daily oral Truvada for prevention (among MSM and other population groups) should be considered without delay. This will pave the way for open label trials [16] that can collect data on the daily or “on demand” preventive use of this drug [17].

Warning believes that there is great interest in studying the intermittent, “on demand” use of PrEP but stresses that such a goal cannot be subject to the abandonment of ethical principles and the endangering of participants’ health. Accordingly, Warning has decided to leave the associative committee of the IPERGAY study.

 

1 – The following associations asked for the position of the Independent Monitoring Committee on October 5th and received their answer on October 25th 2012 : Warning, Keep Smiling, Boucle Rouge-Marseille, Fédération LGBT.

2 – On July 16th 2012, the FDA approved the sale of Truvada daily oral regimen as an HIV prevention method following a largely favorable expert panel recommendation.

3 – Haire Bridget, Kaldor John, Jordens Christopher, « How good is “good enough” ? The case for varying standards of evidence according to need for new interventions in HIV prevention », The American Journal of Bioethics, 12(6), 2012, p. 21-30.

4 – WHO, Guidance on pre-exposure oral prophylaxis (PrEP) for discordant couples, men and transgender women who have sex with men at high risk of HIV : Recommendations for use in the context of demonstration projects, Geneva, WHO, July 2012.

5 – CDC, Interim guidance : preexposure prophylaxis for the prevention of HIV infection in men who have sex with men, MMWR bulletin, Vol.60, n.3, CDC, 28 January 2011.

6 – Made by Gilead Sciences, the combination of Tenofovir/emtricitabine is also used for treatment of HIV

7 – Ethical considerations in biomedical HIV prevention trials. UNAIDS/07.28E / JC1349. 2012. P. 45

8 – Association médicale mondiale, Déclaration d’Helsinki. Principes éthiques applicables à la recherche médicale impliquant des êtres humains, Ferney-Voltaire, AMM, 1964-2008.

9 – HIV Prevention Trials Network, Ethics Guidance for Research, Revised June 10, 2009

10 – UNAIDS and AVAC, Good participatory practice. Guidelines for biomedical HIV prevention trials, 2011.

11 – 10 – UNAIDS and AVAC, Good participatory practice. Guidelines for biomedical HIV prevention trials, 2011.

12 – Ethical considerations in biomedical HIV prevention trials. UNAIDS/07.28E / JC1349. 2012. P. 51

13 – Nodier Nicolas et Barbot Janine, « Le temps des tensions épistémiques. Le développement des essais thérapeutiques dans le cadre du sida », Revue française de sociologie, 41(1), 2000, p. 79-118.

14 – The membership of the independent surveillance committee is not public.

15 – The conflicts of interests of experts engaged in IPERGAY are not public. Financial ties between Gilead and IPERGAY stakeholders have been mentioned in the media (Aujourd’hui en France, 12 octobre 2012).

15 – According to the expert committee on PrEP, the EU has asked France to coordinate a scientific discussion on the subject.

16 – For examples of open label study see Proud study in the UK and forthcoming studies in the USA.

17 – See Anderson Peter L. et al., « Emtricitabine-Tenofovir Concentrations and Pre-Exposure Prophylaxis Efficacy in Men Who Have Sex with Men », Science Translational Medecine 4, 151ra125 (2012).