Ethical Considerations in Implementing Doxycycline Post-Exposure Prophylaxis for the Prevention of Bacterial Sexually Transmitted Infections

Background

The incidence of gonorrhea, syphilis, and chlamydia have been increasing worldwide for almost a decade.^1–3 Doxycycline post-exposure prophylaxis (PEP) has been shown in three clinical trials to decrease the incidence of bacterial sexually transmitted infections (STIs) among men who have sex with men (MSM).^4–6 The off-label doxycycline PEP regimens evaluated involve taking a single dose of 200 mg of doxycycline within 72 hours of sexual exposure. If implemented effectively, doxycycline PEP could potentially not only decrease the incidence of bacterial STIs and their associated morbidity for individuals, but also their onward transmission. Consequently, some professional societies have issued statements^7–8 and several health departments have issued guidance about the use of doxycycline PEP among MSM and transgender women.^9–12 In addition, the US Centers for Disease Control recently published draft guidance regarding its use.^13–14 Nevertheless, current understanding of the potential benefits and harms of doxycycline PEP is based on studies with an average of less than a year of follow-up, leaving unanswered questions about the potential long-term effects of doxycycline PEP on the microbiome and antimicrobial resistance (AMR) as well as its public health impact, cost, equitable use, and appropriate implementation. Thus, it is important to identify and address the associated ethical issues as policies and guidelines related to doxycycline PEP are being developed and implemented.

Ethical issues

Given the existing state of knowledge and experience, implementing doxycycline PEP raises five categories of issues that are morally relevant: 1) Uncertainty regarding long-term benefits and harms; 2) Different antibiotic use paradigms; 3) Equity; 4) Shared decision-making; and 5) Engagement (See Figure). We discuss each of these in turn.

Figure.

Categories of Ethics Concerns about doxycycline PEP.

Uncertainty regarding long-term benefits and harms.

Sound treatment guidelines and quality ethical analyses are predicated on the presence and use of high-quality data. As mentioned, and reviewed elsewhere, three major randomized controlled trials have shown similar high efficacy of doxycycline PEP in reducing STIs among MSM,^14–15 prompting the development of guidelines for its use; however, there are limited specific data regarding doxycycline PEP among other populations at high risk of STIs, which necessarily restricts the scope of the guidelines. In addition, the absence of available evidence regarding the long-term benefits and harms of widespread doxycycline PEP use creates uncertainty.

The direct benefits of doxycycline PEP accrue to those who adopt it and potentially their sex partners because preventing infection in one individual also precludes transmission to other sex partners, interrupting a potential chain of transmission. Additionally, the use of doxycycline PEP could potentially reduce consumption of the antimicrobial agents used to treat STIs by preventing infections that would need to be treated with a full course of treatment. However, at least in the short-term, widespread use of doxycycline PEP will likely result in increased doxycycline use¹⁶. Ultimately, the overall effect on antibiotic use will depend upon the impact of doxycycline PEP on STI incidence and the scale of use.

Short-term risks of doxycycline PEP for those for whom it may be currently indicated include photosensitivity, gastrointestinal discomfort, esophagitis, and rarely benign intracranial hypertension. Long-term risks are uncertain, but could include changes to the microbiome with uncertain consequences. In addition, doxycycline PEP use may drive resistance to doxycycline in bacteria that can result in STIs (e.g., N. gonorrhoeae) as well as others (e.g., S. aureus, S. pneumoniae), which may ultimately have broad population implications.

Thus, given the available data, there is tension between the ethical principles of beneficence and non-maleficence.¹⁷ Beneficence supports using doxycycline PEP with the goal of decreasing bacterial STIs among individuals, communities and populations, yet the obligation of non-maleficence necessitates considering and minimizing the potential associated harms, such as changes to an individual’s microbiome and the population spread of AMR. At present there are incomplete data to assess whether doxycycline PEP will produce overall, or net, positive or negative effects. Similarly, it is unclear what effects doxycycline PEP will have on overall antibiotic use and cost, which are important policy considerations. Consequently, long term follow-up data should be collected among doxycycline PEP users and at the community and population-levels to help determine whether wide uptake of doxycycline PEP actually leads to fewer STIs, aggregate changes in antibiotic use, AMR, and changes in the microbiome. Once these data are available, policies and implementation practices should be revisited and revised as necessary.

Different antibiotic use paradigms.

Doxycycline resistance touches on the larger concern about individual and population level AMR and means of attenuating it. Substantial global attention is now being focused on the problem of AMR.^18–19 This includes efforts to minimize unnecessary antibiotic use through guidelines, pharmacy restrictions, decision aids as well as education of clinicians and patients. While there is some debate over the appropriate approach to curbing inappropriate antibiotic use for STIs,²⁰ some guidelines are premised on testing for STIs prior to treatment whereas others involve syndromic management or presumptive treatment of sexual contacts. Regardless, supporting doxycycline PEP may appear to counter critical antibiotic stewardship efforts, perhaps leading to confusion among clinicians and potential doxycycline PEP users. Clinicians are frequently reminded of the need for antibiotic stewardship whenever antibiotics are being considered and patients are frequently similarly counseled to avoid antibiotic use without a confirmed diagnosis. Nevertheless, an exception to this general stance may be warranted in the case of those who may benefit individually and collectively if STI rates decline provided that ultimately there are also not untoward effects. After all, antibiotic prophylaxis is widespread; for example, immediately preceding or following potential exposures such as tick bites, surgery, and dental procedures as well as to prevent malaria. Therefore, it is crucial that discussions about doxycycline PEP be accompanied by clear messaging about the relevance of such competing paradigms regarding antibiotic use.

Equity.

In deliberating about how doxycycline PEP should be implemented it is essential to consider that in the US STIs disproportionately affect sexual, gender, and racial/ethnic minorities.²¹ Consequently, justice requires that doxycycline PEP be equitably available to those disproportionately burdened by STIs and for whom the intervention has been shown to be effective. Recent experiences with uptake of HIV pre-exposure prophylaxis and mpox vaccination suggest the need to anticipate the possibility of racial and ethnic disparities in doxycycline PEP uptake.^22–23 Because Black and Hispanic people in the US are disproportionately at risk of STIs, doxycycline PEP uptake may prove to be helpful in reducing such health inequities. Moreover, failing to address STIs among MSM and transgender women, especially those who are also members of racial and ethnic minority populations, could lead to further disparities.

Efforts to achieve equity may be especially challenging in fragmented health systems that can be difficult to navigate for those most at need, highlighting the benefits of developing appropriate implementation strategies that are sensitive to a variety of barriers to access, such as out of pocket costs and transportation. In addition, training health care and office staff in how to provide culturally responsive and affirming care, and having nondiscrimination policies that explicitly enumerate sexual orientation and gender identity, can improve the health care experience for people of color and/or LGBTQ+ patients, increase disclosure of risk factors such as anal sex without condoms, and improve quality of care²⁴. Nevertheless, there is a need for mechanisms for monitoring access and outcomes over the long-term to ensure they are effective.

Another critical equity issue relates to the obligation to mitigate STI morbidity among other populations who can be at high risk of STIs, such as cisgender women. To date there has been only one reported study on the effectiveness of doxycycline PEP among cisgender women. The findings of this large-scale study conducted with cisgender women in Kenya found no benefit²⁵ However, insufficient doxycycline PEP use among participants assigned to the intervention arm is likely to have impacted efficacy.²⁶ Principles of health equity encourage additional research to determine if doxycycline PEP is effective if used by cisgender women and others at increased risk of STIs.

Shared Decision Making.

Early data suggest that many MSM are interested in using doxycycline PEP.^27–28 As a matter of respecting their rights and interests, if doxycycline PEP is being considered, individual potential users must have access to adequate and understandable information about its efficacy, safety, side-effects, long-term uncertainties, and alternatives to enable reflective decision-making. However, given that typical clinical encounters are time limited and the long-term uncertainties regarding doxycycline PEP (e.g., AMR, potential effects on the microbiome) are complex, this may be difficult to achieve in a busy clinical practice setting even with clinician training.²⁹ While there has been some attention directed at this issue,^30–31 additional work should be done to develop and standardize information and make sure it is accessible to those who are considering doxycycline PEP use, including the development of online tools or apps to facilitate information exchange.

Engagement.

Key to any efforts to implement and evaluate doxycycline PEP is public engagement with community members and other appropriate stakeholders who would likely be affected by them. Meaningful stakeholder engagement can help to identify relevant considerations for guideline development, contribute to equitable implementation and facilitate constructing appropriate messaging about doxycycline PEP. Moreover, engagement is central to building and maintaining trust. This is especially important for those who have been marginalized. Given the history and persistence of structural racism and anti-lesbian, gay, transgender and queer (LGBTQ+) discrimination in health care, this is of special concern in the context of doxycycline PEP. Here, failing to adopt policies supporting the use of doxycycline PEP in MSM and transgender women despite efficacy data may further erode trust. At the same time, transparency demands that the long-term uncertainties regarding doxycycline PEP be included in engagement activities so that if it turns out that negative outcomes are associated with doxycycline PEP use are encountered, this will not come as a surprise and thereby undermine trust.

Discussion

The successful development of policies and guidelines for doxycycline PEP implementation necessitates considering the associated ethical issues. Several of the issues described here may become more or less relevant as data accumulate regarding the safety, efficacy and effectiveness of doxycycline PEP as well as experiences garnered during the implementation of different policies. These data should ideally be systematically collected and considered and policies revised as appropriate. In addition, this would include monitoring for other issues that might emerge, such as interactions with other public health initiatives, unexpected interactions with medications or environmental exposures, or stakeholder concerns.

Researchers, public health scientists, and health care systems can advance the ethical imperatives related to beneficence, non-maleficence, and equity not only by rapidly conducting research related to doxycycline PEP but also by collecting and assessing data related to doxycycline PEP use. This includes deidentified sexual orientation and gender identity, race and ethnicity and other demographic data. Such data would help to ensure that doxycycline PEP is equitably implemented as well as facilitate the evaluation of longer-term outcomes. Long-term cohort studies related to these issues would also be welcome.

Good public health practice and ethics demand that implementation of doxycycline PEP programs include engagement with relevant stakeholders, clear and transparent messaging about what is known and unknown, a commitment to shared decision making and the systematic collection of data to address current uncertainties about its effect on the microbiome, rates of STIs, and AMR. More research is also needed with additional populations such as cisgender women, who could potentially benefit from doxycycline PEP.