Is Preexposure Prophylaxis Ready for Prime Time Use in HIV Prevention Research?

Ethan A. Cowan; Ruth Macklin

Disclosures

AIDS. 2014;28(3):293-295. 

In This Article

Placebo Controls in HIV Prevention Trials

When a proven intervention exists, the ethical principle of beneficence justifies providing this intervention to participants in control groups. In HIV prevention trials, guidance on the ethical use of placebos is covered by UNAIDS/WHO Guidance Point 15:

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.[13]

Commentary notes that 'there may be compelling scientific reasons which justify the use of a placebo rather than a known effective biomedical HIV intervention'.[13] These reasons pertain to assay sensitivity (the ability of a trial to distinguish an effective treatment from a less effective treatment), which in certain circumstances could justify the use of placebo. A detailed discussion of these issues is beyond the scope of this article.[14]

According to the UNAIDS/WHO guidance point, the following variables would have to be taken into consideration in determining whether it is ethically acceptable to use a placebo control in future PrEP studies.

  • Will the biomedical prevention method under study be an oral antiretroviral preparation?

  • Is the population on which the new method is being tested the same as the populations in which PrEP has already shown to be efficacious?

Modality of the Preexposure Prophylaxis Agent

For future studies of oral PrEP, UNAIDS/WHO guidance point 15 can be used to support the conclusion that, if the study aims to demonstrate efficacy of a product similar to oral PrEP, a placebo control could not be justified. This may include studies that test a new daily oral antiretroviral for PrEP; test a longer acting version of an antiretroviral already in use; or test a new dosing strategy of an oral antiretroviral.

In the case of agents delivered via a different route of administration, for example, a long-acting injectable, a topical microbicide or drug-impregnated intravaginal ring, the conclusions also seem clear. Arguably, a nonoral mode of drug delivery sufficiently distinguishes such new products from oral PrEP, so the use of placebo could be justified. This would not preclude the provision of oral PrEP to participants in both the active and placebo arms of the trial as part of the standard package of prevention.

Comparable Population

The UNAIDS/WHO guidance also says that a placebo control is ethically acceptable so long as the agent under study has not been scientifically validated in comparable populations or approved by relevant authorities. In this case, scientific validation is a mark of universality and implies that a single global standard is ethically appropriate for determining what the control group should receive in future PrEP trials. Performing placebo-controlled trials in populations in which PrEP has already been shown to be effective could reignite the debate over double standards in research.[15]

As PrEP has been shown to be effective for at-risk groups in more than one multicountry study, it is reasonable to assume that where individuals live makes no difference to the product's efficacy. The burden of proof in this situation – that new populations to be studied are substantially different from those where TDF/FTC has been shown to be effective – should lie with those who would defend the use of placebo in future trials.

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