aDepartment of Emergency Medicine and Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Jacobi Medical Center
bDepartment of Epidemiology & Population Health, Dr Shoshanah Trachtenberg Frackman Faculty Scholar in Biomedical Ethics, Albert Einstein College of Medicine, Jack and Pearl Resnick Campus, Bronx, New York, USA.
Correspondence to Ethan A. Cowan, MD, MS, Department of Emergency Medicine and Department of Epidemiology & Population Health, Albert Einstein College of Medicine, Jacobi Medical Center, 1400 Pelham Parkway South, Building 6, 1B25, Bronx, NY 10461, USA. Tel: +1 718 918 3050; fax: +1 718 918 7459; e-mail: email@example.com
Received 26 June, 2013
Revised 19 August, 2013
Accepted 30 August, 2013
Four clinical trials have demonstrated that the antiretroviral drug emtricitabine/tenofovir disoproxil fumarate (TDF/FTC), normally reserved for treatment in infected persons, can provide protection from HIV when taken daily by uninfected individuals at high risk of acquiring HIV [1–4]. The results of these studies of preexposure prophylaxis (PrEP) prompt the question of when – if not already – PrEP will be ready for prime time in research. Other authors have addressed the ethics of PrEP in clinical care, but the discussion of PrEP's role in future HIV prevention studies has been limited [5–9]. We contend that barring exceptional circumstances, PrEP is ready for ‘prime time’ in future HIV prevention research trials. We support this conclusion with reference to the UNAIDS/WHO ethical guidance document for HIV biomedical prevention trials the principle of beneficence.
Implications of preexposure prophylaxis for future research
Athough problems with adherence have plagued several trials, what seems clear is that oral PrEP, when taken correctly, can provide greater than 90% protection from HIV acquisition [10–12]. The demonstrated success of PrEP as a biomedical prevention for HIV brings two ethical challenges for future research. The first is the controversy over the ethics of placebo controls, and the second is what the UNAIDS/WHO ethical guidance document for HIV biomedical prevention trials calls ‘standard of prevention’ .
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 .
Commentary notes that ‘there may be compelling scientific reasons which justify the use of a placebo rather than a known effective biomedical HIV intervention’ . 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 .
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.
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 .
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.
Is preexposure prophylaxis ready to be considered a standard of prevention in research?
The second ethical issue concerns standards of prevention described in UNAIDS/WHO Guidance Point 13:
Researchers, research staff and trial sponsors should ensure, as an integral component of the research protocol, that 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 .
If PrEP were to qualify as a standard of prevention, it would ostensibly mean that all participants in future HIV prevention studies who want it should receive PrEP. To reach this conclusion, three elements must be examined: ‘scientific validation’, ‘approval by relevant authorities’ and ‘consultation among stakeholders’.
Evidence demonstrates that TDF/FTC for PrEP, when used as directed, protects against HIV acquisition and should be considered ‘scientifically validated’. The second element concerns approval by relevant authorities. In countries where TDF/FTC for PrEP has not been approved by a relevant authority but HIV prevention studies are being conducted in populations in which this product has already been scientifically validated, should approval by a relevant authority be necessary for PrEP to qualify as a standard of prevention?
Requiring approval by relevant authorities and product registration could result in substantial delays in offering PrEP as part of the standard package of prevention. In the case of product registration, the US Food and Drug Administration has given TDF/FTC a formal product indication for PrEP. This imprimatur has meaning, both scientific and ethical, as it comes from a normative body that has analysed trial results independently from the researchers. Globally, TDF/FTC is registered for HIV treatment but could be used ‘off-label’ at any time for PrEP. It is not uncommon for HIV medications with significant public health impact to be used without formal label indication for both research and clinical care [16–18].
The weight given to formal guidelines, such as those issued by the WHO, can also impact the speed at which oral PrEP is introduced as part of the standard package of prevention. On one hand, WHO's position on PrEP is important because many countries look to WHO before deciding on public health interventions. On the other hand, waiting for WHO guidelines could cause unwarranted delay given the procedures that WHO must undergo before producing such guidelines . It would be inappropriate to insist that investigators wait for WHO to produce guidelines before offering something they consider to have been scientifically validated. It is also ethically problematic to suggest that an effective product remains unavailable simply because research participants live in areas where the product has not been registered or because WHO has not produced guidelines for its use.
The third element refers to consultation among stakeholders. It is not unrealistic to foresee objections to adding oral PrEP to the prevention package. Researchers might claim that it would be scientifically impossible to analyse the resulting data from a study in which most participants were using PrEP. This opening could be viewed as a loophole, enabling methodologists to assert that providing PrEP to all participants in a future HIV prevention trial would make it impossible to isolate efficacy. Moreover, as the process of negotiation involves all stakeholders, sponsors would likely argue that the greater sample size needed to make results interpretable would make the cost of the trial prohibitive, take too long and expose more people to risk.
Another concern is safety. Drug–drug interactions could result in unsafe drug doses that might increase the risk of side effects and toxicities. There may also be concerns about prolonged antiretroviral use in low to moderate risk participants in whom the risks of taking antiretrovirals might outweigh its protective benefits .
These methodological and practical considerations will almost certainly lead some stakeholders to conclude that it is currently impossible to include PrEP in the standard package of prevention in future HIV prevention trials. That conclusion cannot be justified by appealing to either the UNAIDS ethics guidance document or the basic tenets of research ethics. So long as safety concerns are satisfied, maximizing the protective benefits for future HIV prevention trial participants supports the conclusion that PrEP is ready for ‘prime time’ in future HIV prevention research trials.
E.C. is supported by a career development award from the National Institute of Allergy and Infectious Diseases (5K23AI078755-05).
Reprints not available from the authors.
Conflicts of interest
No authors have any financial arrangements that may represent conflict of interest.
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