Ethics and Pre-Exposure Prophylaxis for HIV-infection

Abstract

There is increasing evidence that the use of antiretroviral agents (ARVs) can be a safe and effective means of preventing HIV-infection. In fact, a combination of ARVs, tenofovir-emtricitabine, was recently approved by the United States Food and Drug Administration (FDA) for use as “pre-exposure prophylaxis”(PrEP) and the US Centers for Disease Control and other regulatory authorities have issued guidance concerning PrEP use. Clinicians and policy makers are now faced with questions about the appropriateness of prescribing ARVs to healthy persons who are at risk for becoming infected with HIV and those at risk for being infected must decide whether to use PrEP. In addition, researcher stakeholders must grapple with determining whether and how PrEP should be included in future HIV prevention research. In addressing such issues, it is important that their ethical dimensions are identified. When using PrEP, two broad ethical domains are of special relevance: well-being and justice. Ethical issues related to well-being include: safety, parameters of use, risk behaviors, resistance, stigma, and diversion. Those related to justice include: access and competing priorities. In research involving PrEP, ethical issues include determining the appropriate control arm as well as whether PrEP should be included as a part of the prevention package provided to all at risk participants. While PrEP could play an important role in HIV prevention, understanding and addressing the related ethical issues is critical to its safe, effective, and appropriate use in practice and future research.

There is increasing evidence that the use of antiretroviral agents (ARVs) can be a safe and effective means of preventing HIV-infection. Despite mixed data from efficacy trials, the United States Food and Drug Administration (FDA) recently approved co-formulated tenofovir-emtricitabine for daily use as “pre-exposure prophylaxis” (PrEP)¹. In addition, the United States Centers for Disease Control², the World Health Organisation³, and other normative bodies have issued guidance regarding PrEP⁴. Clinicians and policy makers are now faced with questions about the appropriateness of prescribing ARVs to healthy persons who are at risk for becoming infected with HIV and those at risk for being infected must decide whether to use PrEP. In addition, research stakeholders must grapple with determining whether and how PrEP should be included in future HIV prevention research. In addressing such issues, it is important that their ethical dimensions are identified, yet to date there have been limited discussions on point, most focusing on population-level issues^5–7. Accordingly, after briefly delineating current evidence and guidance regarding PrEP, we describe some of the ethical challenges that are associated with PrEP.

Evidence and Guidance Regarding PrEP

While a comprehensive review of the research related to PrEP is beyond the scope of this paper, having a sense of the major lessons from this research, especially as they have been interpreted by those with particular expertise in HIV prevention^8–10, is essential to analyzing the ethical issues associated with PrEP. Data from three major clinical trials support the safety and efficacy of oral PrEP; one conducted among men who have sex with men in several countries¹¹, one among serodiscordant heterosexual couples in Africa, and the other among young high risk heterosexuals in Botswana^{12, 13}. Nevertheless, in two other major trials involving women in Africa, these results have not been confirmed^{14, 15}. One study of peri-coital vaginal use of use of a 1% tenofovir gel demonstrated a 39% decrease in HIV incidence compared to a placebo gel among South African women¹⁶, but a study of daily use of the same product in a similar population did not demonstrate efficacy¹⁵. A third vaginal gel study is underway in South Africa to see if the initial findings can be confirmed, but currently, the only approved PrEP regimen involves a single oral daily tablet containing tenofovir-emtricitabine.

The discordant results seem to at least be due in part to different patterns of adherence to PrEP regimens¹⁰. Further, it is important to note that the studies published to date have all used either tenofovir alone or in combination with emtricidabine. While the agents are well-tolerated there can be mild gastrointestinal side-effects and concerns have been raised about the possibility of renal toxicity and bone density in a minority of patients, particularly in those with pre-existing medical conditions, who were not included in the earlier trials. In addition, there are not yet data regarding the long-term safety and efficacy of PrEP. Finally, data are currently unavailable regarding the safety and efficacy of PrEP for those at risk for HIV infection due to injection drug use, although it is anticipated that data from a Thai study should be available soon¹⁷.

Nevertheless, the US FDA approved tenofovir-emtricitabine for PrEP to decrease transmission of HIV among both men who have sex with men and heterosexuals. In addition, guidance regarding oral PrEP has been issued. For example, the US CDC has provided interim guidance for PrEP among men who have sex with men² and heterosexual adults¹⁸. The World Health Organisation has issued guidance for PrEP among both men who have sex with men and heterosexuals in the context of demonstration projects, that is, translational projects to assess real world implementation of PrEP in diverse settings³. Each of these documents makes clear the need for PrEP to be accompanied by behavioral counseling, safer sex practices, HIV testing and safety monitoring.

Using PrEP for Prevention

When using PrEP for prevention, two broad ethical domains are of special relevance: well-being and justice.

Well-being

The use of PrEP promises to help meet the strong moral claim to prevent infection with HIV. However, meeting this claim must be balanced against an array of other threats to the well-being of individuals and communities.

Safety

Safety is a critical consideration in the provision of PrEP. First, the willingness of individuals to consistently use ARVs for prevention raises concerns about safety, in light of adherence challenges when ARVs are used to treat infected persons. In fact, suboptimal adherence has been observed in several of the PrEP efficacy trials¹⁹. The extent to which adherence is linked to the side-effect profiles is unclear, but it is conceivable that this plays at least some role. For example, PrEP with TDF/FTC may be associated with mild gastrointestinal symptoms, which could result in non-adherence. If a person used PrEP erratically to mitigate side effects, or because of intercurrent psychosocial issues, such as depression or substance use, and continued to engage in unprotected sex, HIV transmission and selection for a drug resistant viral strain could occur, compromising future treatment options. Second, there are known adverse effects associated with ARVs, such as renal toxicity with tenofovir. Participants in efficacy trials are typically selected because of their lack of concomitant medical conditions, but as PrEP becomes more widely accessible, it is conceivable that side effects could become more common. These safety issues underscore the need to monitor adherence as well as potential adverse effects of PrEP.

Parameters of Use

Data regarding the safe and effective use of PrEP are currently limited with respect to particular ARVs, dosing, and populations. As the recent history of randomized trials of PrEP make clear, at present it would be imprudent to use PrEP outside of the parameters in which data are available since doing so could prove harmful. Along these lines, it is relevant that existing data about safe and effective use were obtained in settings where routine testing and counseling services were available, which may be challenging, but necessary, to reproduce outside of the setting of clinical trials to achieve similar results.

Risk behaviors

While PrEP can be effective in preventing HIV-infection, it obviously does not prevent the transmission of other sexually transmitted infections, such as gonorrhea, chlamydia, viral hepatitis, and syphilis. Thus, an important concern is that the administration of PrEP in practice does not lead to an increase in risk behaviors, sometimes termed either “risk compensation” or “behavioral disinhibition” that would be expected to enhance the likelihood of acquiring other STIs^{7,20, 21}. Risk behaviors might include unprotected sex, having additional sexual partners, or engaging in riskier behaviors such as unprotected receptive anal intercourse. Further, it is conceivable that increased risk behaviors might overwhelm the ability of PrEP to prevent HIV infection itself, particularly if adherence is suboptimal, and/or amplifying factors, such as concomitant sexually transmitted infections, mucosal trauma, or a highly infectious partner are present. While there does not seem to be reported evidence of such changes in risk behaviors in the context of the efficacy trials, whether this will remain true outside the research setting is unclear. Consequently, it is critical that effective messages about safer sex practices accompany the use of PrEP.

Resistance

Current treatment of HIV-infection involves the use of HAART (highly active anti-retroviral therapy), which entails the use of several ARVs to combat the virus and prevent the development of viral resistance. In contrast, one or two ARVs are currently used for PrEP. Accordingly, there is a worry that if a person using PrEP becomes infected with HIV and continues to using these ARVs, resistance may develop. This could have implications not only for treatment of the individual, but also to the transmission of resistant HIV to others. These concerns highlight the need for frequent high-quality HIV testing among users of PrEP. To this end, the Boxed Warning for tenofovir-emtricitabine, includes cautionary language regarding the need to ensure that those using the product for PrEP are HIV-uninfected before initiating use and that they are regularly tested. In addition, the FDA is requiring the manufacturer to test HIV isolates for resistance from those who become infected while using tenofovir-emtricitabine for PrEP.

Stigma

PrEP may be associated with stigma due to the mistaken belief that the use of ARVs indicates that the PrEP user is HIV-infected, subjecting that person to the stigma sometimes associated with HIV-infection. Further, stigma might arise from moral or cultural attitudes and beliefs about risk behaviors and the character of those who engage in them. It is easy to imagine that those who use PrEP may be assumed to be irresponsible because of perceived promiscuity, despite the responsibility inherent to taking preventive measures. Of related concern is that those using PrEP in some settings may face difficulty with respect to obtaining insurance and employment given its association with risk behaviors. Obviously, whether and how stigma arises is an empirical matter that will need to be tracked carefully. Successful PrEP implementation may require culturally tailored stigma mitigation strategies that would need to be developed by public health and community leaders.

Diversion

Since the ARVs used for PrEP can be components of HAART, drug diversion is a possible sequel, especially in settings where access to ARVs is limited. Diversion might arise from the well-intended desire to help treat those who are sick or more nefariously from a desire to profit, assuming a market for these ARVs exists. Nevertheless, the incomplete and likely unmonitored treatment of those who are sick may in the long-run be harmful to patients and be associated with the development, and perhaps transmission, of resistant virus.

Justice

As a matter relevant to clinical practice and public health, PrEP involves issues related to justice. In its broadest sense, justice is concerned about fairness, both in terms of processes and the distribution of benefits. Of special importance are the ethical tensions related to access to PrEP as well as adjudicating competing priorities for the allocation of resources.

Access

For any HIV prevention modality to realize its effectiveness, it must be acceptable to potential users. To date, there are limited data concerning the acceptability and desirability of PrEP among those it would be expected to benefit²². Further, it is unclear how acceptability might be related to the delivery systems for PrEP. On the one hand, a delivery system based in a hospital or clinic may be well-suited to address medical aspects of PrEP, but be less capable of conducting effective behavioral counseling than a non-clinical system (e.g., a community based organization). Moreover, a clinical setting may be costly and pose barriers to access for healthy persons, who may perceive health care providers as insensitive to their concerns. Such factors need to be considered in designing appropriate delivery systems. Nonetheless, assuming that PrEP is a desirable part of a local HIV prevention effort, it would arguably be reasonable to prioritize access to PrEP regimens for populations for which there are adequate data about safety and efficacy. Where such data do not exist appropriate research trials should be conducted. Finally, there is a critical set of unanswered questions related to accessing underserved populations (e.g., what should be included in the package of essential PrEP services)^6,7, the cost of PrEP and who should and will pay for it²³, that directly affect access.

Competing Priorities

While PrEP offers an important option for HIV prevention, there are now other safe and effective methods that can decrease HIV transmission⁹. Accordingly, justice demands considering the fairness in the distribution of resources for the range of prevention modalities and their expected benefits in reducing the burden of infection among populations and subgroups. After all, the fundamental moral claim for using any of these approaches relates to decreasing the burden of new HIV infections. As a related matter, is the distribution of resources not only for the prevention of new infections, but also for the treatment of those already infected with HIV⁵. Given the very promising results of early treatment for HIV prevention²⁴, determining how best to allocate resources is especially complex. Assuming that funding for ARVs is limited and insufficient to treat those who are infected, some have argued for prioritizing the use of ARVs first to those in certain need of treatment, next for treatment as prevention, and finally for PrEP²⁵. In contrast, others have argued at a broader level for privileging prevention over treatment, given that effective prevention will ultimately decrease the numbers of individuals needing treatment²⁶. However, given the host of unanswered empirical assumptions regarding the safety, efficacy and cost of both early treatment for prevention and PrEP among population subgroups, a simple conclusion is not feasible at this time^6,27. In moving forward, the range of benefits and possibilities should be considered^20,21. Furthermore, the distribution of such health related resources must also be sensitive to a variety of other prevalent diseases and conditions that are common among individuals at risk for HIV, and among the general population.

HIV Prevention Research and PrEP

The emerging data regarding the safety and efficacy of PrEP raise important scientific and ethical questions about future HIV prevention research, for both other forms of oral PrEP²⁸ and other modalities.

New PrEP Research

While there is currently strong evidence regarding the specific use of certain ARVs for prophylaxis in some groups, there is arguably a need for additional research to: 1) explain the disparate results from earlier research (i.e., African women); 2) establish alternative dosing strategies that might be both effective and associated with improved adherence (e.g., peri-coital oral use, or topical gels, rings, and injectable delivery mechanisms); 3) determine the safety and efficacy of alternative ARVs for PrEP (e.g., dapivirine and maraviroc); and 4) determine the safety and efficacy of PrEP in other populations (e.g., people who inject drugs). A key ethical issue that will be faced in such trials relates to the selection of an appropriate comparator arm. Assuming that most of the study populations will be similar to those in which PrEP has been shown to be safe and effective, there could be a presumption favoring the use of established PrEP regimens as the comparator arm. However, this could create challenges in trial design. For example, providing oral TDF-FTC to all participants in a study that compared an ARV-containing gel to a placebo gel could be associated with drug interactions and the need to enroll a much larger sample, given that all participants would have access to chemoprophylaxis. None of the potential scenarios are simple, but the ethical principles of well-being and justice must be factored into decisions about trial designs.

Other HIV Prevention Research

Despite recent considerable progress in HIV prevention, additional research will be directed at combination prevention and HIV prevention among hard to reach populations. As in all HIV prevention research, all participants in these trials would be expected to be provided with a “prevention package”. That is, a set of established methods of preventing infection with HIV such as counseling and male condoms. Therefore, it will be essential to consider whether PrEP should be included in the prevention package for HIV prevention trials going forward. While determining the correct “standard of prevention” to be provided is always complex, this issue will become increasingly knotty given the advances in HIV prevention science and the associated number of possible modalities that could be incorporated in such packages. While an extensive discussion of this issue is beyond the scope of this paper, a fundamental tension arises when providing preventive modalities besides what is being tested in the trial because while doing so may protect participants, it may also undermine the ability of the trial to answer the research question at hand. Further, should participants be provided with preventive methods that are not available outside the trial, questions of fairness to those outside the trial arise. Finally, even if individual methods of prevention are known to be safe and effective, the effects of combining them may remain unclear. Ethics guidance on what should be included differs^29,30,31. Given the complexities of these issues, and the likelihood that knowledge will continue evolve, it is critical to engage stakeholders when determining the standard of prevention for each new study, and to periodically revisit study designs as new information becomes available.

If PrEP is not provided to study populations where it is known to be effective, researchers need to account for the possibility that some participants may access PrEP outside of the trial, which could affect the integrity of the trial. Furthermore, the informed consent process for enrollment should clearly articulate that PrEP will or will not be provided and should discuss any limitations on use among participants while they are enrolled. It will be important for trial staff to create a supportive environment for trial participants, so that any subsequent use of chemoprophylaxis will be reported.

One extant example of adaptive trial design is HVTN 505, a phase IIB study involving HIV vaccines in high risk American MSM. The study was conceptualized and implemented prior to the announcement of the iPrEX results, so access to PrEP was not part of the protocol. However, once the results were available, the protocol was subsequently modified to allow participants to use PrEP, but it was not provided routinely. In addition, participants were educated about the iPrEX study results, asked about PrEP use at subsequent study visits, and the sample size of the study was increased in anticipation of a partial PreP impact on HIV incidence.³²

Concluding Comments

PrEP is positioned to play an important role in HIV prevention, but its ultimate optimal implementation will require further evaluation. In the meantime, clinicians who prescribe PrEP have an ethical obligation to not only be keenly aware of the current and emerging data concerning PrEP, but also of the ethical issues associated with its use. Moreover, learning how to address and manage these issues is central to providing competent care. Accordingly, consideration should be given to developing educational and training programs that include explicit consideration of these ethics issues and their management so that clinicians may be appropriately prepared. That is, there is a tangible need for capacity building in many clinical settings. Similarly, those crafting policies regarding PrEP need to be sensitive to these issues so that resulting programs might be optimally designed. Finally, given the ethical complexities that will be invariably faced regarding PrEP in future research efforts concerning PrEP as well as those evaluating other promising means of preventing HIV it is essential that appropriate ethics expertise is incorporated into this work from its outset. Continued analyses of the ethical issues related to PrEP in clinical practice and research will need to accompany evolving data and policies concerning PrEP if its promise is to be fully realized.