Why ethics guidance needs to be updated for contemporary HIV prevention research

Why ethics guidance needs to be updated for contemporary HIV prevention research Brandon J Brown* and Jeremy Sugarman* for the HPTN Ethics Working Group Corresponding author: Jeremy Sugarman, Harvey M. Meyerhoff Professor of Bioethics and Medicine, Johns Hopkins Berman Institute of Bioethics, 1809 Ashland Ave, Baltimore, MD 21205. Tel: 410-614-5634. (jsugarman@jhu.edu) *These authors have contributed equally to the work.

Despite existing effective antiretroviral treatments and means of prevention, the human immunodeficiency virus (HIV) epidemic persists globally [1]. While efforts to scale-up access to these modalities is critical, research is needed to expand the range of options available to curb HIV incidence. Nevertheless, conducting high-quality HIV prevention research necessitates surmounting a range of obstacles. For instance, much HIV prevention research encounters ethical challenges in practice, particularly in settings with high incidence marked by weak healthcare infrastructures, poverty, laws adversely affecting key populations, inequality, discrimination and/or stigma. In addition, since HIV transmission is a high consequence, but relatively low probability event in the context of research, HIV prevention efficacy trials tend to be very large, sometimes requiring thousands of participants, making them extremely expensive. Furthermore, in order to show that an intervention is generalisable in diverse environments, these trials tend to be multisite and multinational, adding complexity.
As a result of such realities associated with conducting HIV prevention research, major funders have looked to networks and other research consortia, like the HIV Prevention Trials Network (HPTN), to coordinate these trials. Moreover because of the sensitive nature of HIV prevention research being conducted globally, ethics guidance that is universally applicable is needed.

| RECENT DEVELOPMENTS RELEVANT FOR ETHICS GUIDANCE
Practical ethics guidance for contemporary HIV prevention research must not only be sensitive to these issues, but also be responsive to numerous developments. For example, advances in HIV prevention science (e.g. treatment as prevention and oral pre-exposure prophylaxis) introduce complex ethical issues in the design of HIV prevention trials, such as selecting ethically appropriate comparator arms [2][3][4]. Here there are important tensions between the need to protect research participants by providing them with known means of HIV prevention and the ability to implement trials capable of meaningfully evaluating potentially powerful new interventions. In addition, ethicists and others increasingly emphasize the importance of addressing research questions that are relevant to local populations and responsive to host communities' health priorities [5][6][7][8], but which can complicate conventional approaches to selecting research sites that may have simply relied upon HIV incidence data within a particular locality. While community engagement and capacity building have long been part of much HIV prevention research, many guidance documents articulate specifications for robustly engaging communities and strengthening local capacity beyond health care and performing research [9][10][11][12][13][14][15][16][17], making explicit a broad range of responsibilities for HIV prevention researchers that necessitate careful attention.
Several guidelines, policies and regulations have also evolved recently, introducing a range of expectations and requirements for HIV prevention research. The updated Council for International Organisations of Medical Sciences guidelines place greater importance on the social value of research, which ought to be considered when considering whether particular research endeavours are pursued. They also delineate requirements for research among those who might become pregnant during the course of a study, which are essential to consider given the public health and ethical mandates to test HIV prevention modalities in this population [5]. The latest version of the Declaration of Helsinki emphasizes the importance of post-trial provisions "for all participants who still need an intervention identified as beneficial in the trial, " establishing privacy protections, assessing capability of giving informed consent, and providing study results to participants [18]. All of these issues are relevant to HIV prevention research. Further, the revised US federal regulations for research with  [19]. While these possibilities may be welcome and appropriate for some research, they can be problematic in internationally collaborative HIV prevention research that can encounter ethical, cultural and legal barriers in work with biospecimens and where local ethics oversight may be especially important for ensuring the social context is taken into account so that the welfare of participants is protected. Additionally, standards have changed regarding access to and dissemination of research results, such as providing participants with health-related results and third party researchers with access to raw datasets for analysis [20][21][22][23]. The HPTN and other stakeholders have also published empirically derived guidance regarding post-trial access to successful interventions [24,25]. Finally, molecular epidemiology has been increasingly playing a role in HIV prevention research and raises ethical, legal and social issues related to directionality of HIV transmission, which could result in stigma, discrimination and criminal prosecution [26].

| THE HPTN'S RESPONSE TO CHANGES IN THE CONTEXT OF HIV PREVENTION RESEARCH
The HPTN is a worldwide collaborative research network that includes researchers, community members, ethicists and others that develops and tests the safety and efficacy of interventions designed to prevent the acquisition and transmission of HIV. In 2003, to help ensure that its research was ethically sound, the HPTN developed the HPTN Ethics Guidance for Research [27,28]. The guidance was updated in 2009 [29] and is an important source document regarding the ethical issues in HIV prevention research globally.
Although there are other ethics guidance documents for HIV-related research, the HPTN guidance is intended to offer a practical approach to identifying and addressing ethical issues in the practice of HIV prevention research that is sensitive to the potentially competing claims of policies and other guidance documents.
To provide those engaged in HIV prevention research with practical guidance regarding such ethical issues, the HPTN 2009 ethics guidance document was revised following an extensive process. It was approved and posted on February 26, 2020 [30].

| ETHICS GUIDANCE POINTS AND PRIMARY STAKEHOLDERS
The revised ethics guidance document is organized according to the different stages of HIV prevention research, from research preparation, to implementation, and dissemination. The points are outlined in the Table 1; they are each explicated in the primary document. One major way that the current guidance is unique is that each guidance point identifies the primary stakeholder(s) responsible for implementing each of the ethics guidance points, and also specifies whether each guidance point is an ethical obligation that must be met or is an ethical aspiration, which is desirable but not required. Nevertheless, as described in the HPTN ethics guidance: "in general, all stakeholders in HIV prevention research are encouraged to fulfil their ethical obligations and to pursue ethical aspirations to the greatest extent possible [30, p. 10]. " The current version of the HPTN ethics guidance aims to have wide applications for the HIV prevention research field at large both inside and outside of the HPTN, and have multiple audiences. Researchers, collaborating institutions, community advisory boards, industry sponsors, ethics review committees, and other stakeholders can utilize it to reflect upon, guide or support ethical decision making in HIV prevention research. HIV prevention research is essential to developing new tools and approaches to address the HIV epidemic by decreasing HIV incidence. By expanding upon the fundamental ethical principles of research and specifying them for practical application in research, the HPTN ethics guidance document is positioned to help ensure that this it is designed and conducted responsibly. This is essential to protecting the rights, interests and welfare of those engaged in and affected by the research. It is expected that as new ethical issues emerge over time, these guidelines will be revisited.