Ethical issues in establishing the efficacy and safety of long-acting injectable pre-exposure prophylaxis for HIV prevention: the HPTN 083 trial.

Two multinational clinical trials have shown safety and efficacy of long-acting injectable cabotegravir for HIV pre-exposure prophylaxis (PrEP). These results will alter the landscape of HIV prevention and related research. Nevertheless, designing and conducting this research involved several ethical issues. This Viewpoint describes how we managed ethical issues over the duration of one of these trials (HPTN 083). Specifically, we discuss the rationale for pursuing a long-acting injectable agent in the presence of effective oral PrEP, trial design choices, site selection and local standards of prevention, data monitoring and early stopping, effects of the COVID-19 pandemic, post-trial access, and assessment of long-term safety.

Who falls between the cracks? Identifying eligible PrEP users among people with Sub-Saharan African migration background living in Antwerp, Belgium.

INTRODUCTION: This study produces an estimate of the proportion of eligible PrEP users among people of Sub-Saharan African background based on the Belgian PrEP eligibility criteria and examines associations with socio-economic and demographic characteristics. METHODS: We performed logistic regression analysis on data of a representative community-based survey conducted among Sub-Saharan African communities (n = 685) living in Antwerp. RESULTS: Almost a third (30.3%) of the respondents were eligible to use PrEP. Those who were male, single, lower educated, undocumented, and had experienced forced sex were more likely to be eligible for PrEP use. The findings highlight the importance of taking intra-, interpersonal and structural HIV risk factors into account. CONCLUSIONS: The study shows high unmet PrEP needs in this population, especially among those with high vulnerability for HIV acquisition. A better understanding of barriers to PrEP use in this population group is needed to allow for equitable access.

HIV burden and correlates of infection among transfeminine people and cisgender men who have sex with men in Nairobi, Kenya: an observational study.

BACKGROUND: Transgender people are disproportionately affected by HIV and other sexually transmitted infections (STIs) worldwide, and culturally competent prevention and treatment services are often unavailable or inaccessible. Despite recent improvements in national HIV responses for many key populations in east Africa, evidence of effective responses informed by transgender sexual health needs is sparse. We aimed to assess gender identity among men and transgender people who have sex with men in Kenya, and to explore its associations with sexual health-related outcomes, risk behaviours, and uptake of HIV prevention and care interventions. METHODS: We did a cross-sectional study in Nairobi, Kenya, and recruited adult cisgender men and transfeminine people who reported having sex with men, through respondent-driven sampling. Inclusion criteria were possession of a valid study coupon, being aged 18 years or older, having male sex assignment at birth or male gender identification currently, living within 50 km of Nairobi, and having had consensual anal or oral sexual activity with a man in the previous 12 months. Seed participants were identified by three community organisations that provide targeted health-care services to gay, bisexual, or other men who have sex with men (MSM) communities in Nairobi. We assessed gender identity, sociodemographics, sexual behaviour, and HIV prevention and care uptake, by self-completed survey. Participants were tested for HIV, syphilis, and rectal and urethral gonorrhoea and chlamydia. We compared prevalence of sexual health outcomes, risk behaviour, and HIV prevention and care service uptake among transfeminine and cisgender participants, using multivariable robust Poisson regression models, with gender identity as the independent variable. FINDINGS: Between May 4 and Dec 8, 2017, we enrolled 618 participants. Six participants did not answer the questions on sex assigned at birth and gender identity and so were excluded from the analyses. 522 (sample-weighted percentage 86%) of 612 participants were classified as cisgender men, 70 (11%) as transfeminine, and three (<1%) as transmasculine. 17 participants (2%) did not identify as male, female, or transgender. Compared with cisgender men, transfeminine people were more likely to be HIV-positive (28 [41%] of 70 transfeminine vs 151 [25%] of 521 cisgender men; p=0·0009) and to report current symptoms consistent with a rectal STI (eight [16%] of 67 vs 38 [7%] of 518; p=0·014). Transfeminine people reported higher numbers of recent male sexual partners (22 [27%] of 70 transfeminine people reported four or more male sexual partners in the past 3 months vs 112 [13%] of 522 cisgender men; p=0·042) and were more likely to report condomless anal intercourse with men (43 [62%] of 70 vs 208 [39%] of 522; p=0·0009) and receptive anal intercourse (54 [76%] of 70 vs 252 [46%] of 522; p<0·0001) in the past 3 months, and transactional sex with men (42 [57%] of 69 vs 240 [42%] of 518; p=0·023) and experience of sexual assault (16 [23%] of 69 vs 65 [11%] of 520; p=0·019) in the past 12 months. Use of pre-exposure prophylaxis and post-exposure prophylaxis was low in both groups. INTERPRETATION: Transfeminine people who have sex with men have a higher burden of HIV and associated risk behaviours compared with cisgender MSM in the same context, yet their uptake of prevention and care services is poor. Policies should acknowledge the specific needs of transfeminine people as distinct from cisgender MSM, and support health-care providers to address these needs. FUNDING: Evidence for HIV Prevention in Southern Africa (EHPSA), UK Aid.

Putting the NHS England on trial: uncertainty-as-power, evidence and the controversy of PrEP in England.

Pre-exposure prophylaxis (PrEP) (Truvada) is a medication which if taken correctly is almost entirely effective in preventing HIV infection. In regions and countries where it has been widely taken up, HIV seroconversion rates have significantly decreased. Alongside testing and treatment, it offers the very real prospect of ending HIV infections. However, in England, commissioning it has (and still is) a controversial process, where NHS England has repeatedly raised supposed 'uncertainties', first legal and then scientific. The same has not happened in Scotland, where PrEP was commissioned to anyone who needed it in April 2017. This article presents a close reading of the IMPACT trial protocol, which we conclude cannot answer the questions it sets out to answer. We then suggest that the uncertainties the trial claims to address are in fact a tool of power which is deployed to strategically ration healthcare; introduce uncertainty about commissioning PrEP; and shift the boundary between individual responsibilities and state responsibilities for public health and HIV prevention. We conclude that all the above constitute an unethical use of clinical trial rhetoric, systematically discriminate against minority and vulnerable groups, and ration healthcare for those who most need it. As such, we call on all academics, clinicians and activists to resist further unethical misuses of clinical trial rhetoric.

Lessons from PrEP: A Qualitative Study Investigating How Clinical and Policy Experts Weigh Ethics and Evidence When Evaluating Preventive Medications for Use in Pregnant and Breastfeeding Women.

This study explored how multinational HIV experts weigh clinical, evidential, and ethical considerations regarding pre-exposure prophylaxis in pregnant/breastfeeding women. Semi-structured interviews were conducted with experts in HIV policy, research, treatment, and implementation from three global regions. A constant comparative approach identified major themes. Experts noted that exclusion of pregnant women from research limits evidence regarding risks/benefits, emphasizing that underinclusion of pregnant women in RCTs shifts the onus of evidence-building to clinical care. Experts discussed approaches for weighing evidence to make decisions, including triangulating evidence from sources other than RCTs. Likelihood and severity of disease strongly influenced decisions. Less effective interventions with limited fetal risk were preferred over interventions of uncertain safety, unless the disease was serious. Experts resisted the dichotomous choice between protecting maternal and fetal interests, arguing that these interests are intertwined and that more holistic approaches to maternal-fetal balance support greater inclusion of pregnant women in research.

Ethical public health issues for the use of informal PrEP.

This article presents the phenomenon of the use of informal pre-exposure prophylaxis (PrEP), also known colloquially as 'wild PrEP'. The related ethical public health issues of the use of informal PrEP are discussed. From the approach of an ethical framework of risk reduction in public health, the main objective of this article is to encourage health-related practices and policies that do not stop the informal access to PrEP, but rather promote the wellbeing of users by providing them with the necessary knowledge and resources related to PrEP and HIV prevention (i.e. getting regularly tested for HIV if one is to take PrEP). As each country has its own policies with respect to PrEP and access to healthcare services, this article does not explore specific locations but rather highlights different global ethical key points on how to approach the use of informal PrEP with the goal of promoting HIV prevention among individuals at high risk for HIV infection.

Parents' Perspectives About Adolescent Boys' Involvement in Biomedical HIV Prevention Research.

Research on the use of pre-exposure prophylaxis (PrEP) among adolescents at high risk for HIV is urgently needed, and parents' perspectives on these studies are essential for guiding the responsible conduct of adolescent PrEP research. We conducted interviews with 30 parents of adolescent boys (50% known/presumed heterosexual; 50% sexual minority) to understand their views of research risks and benefits and parental permission regarding their son's involvement in a hypothetical PrEP adherence trial. Parents identified several health and educational benefits of the study and expressed that waiving parental permission would overcome barriers to accessing PrEP, particularly for youth who may benefit most. Among their concerns were medication non-adherence and risk compensation. Parents provided suggestions to facilitate informed, rational, and voluntary participation decisions and protect youth's safety if parental permission was waived. These findings can inform ways to increase parental trust in PrEP research and create adequate protections for adolescent participants.

The role of male partners in women's participation in research during pregnancy: a case study from the partners demonstration project.

The exclusion of pregnant women from health research remains a significant challenge globally. In settings where cultural traditions and gender norms support a more restricted decision-making role for women in general, little is known about the attitudes of male partners toward the inclusion of women in research during pregnancy. Understanding the expectations of both men and women in such cultural settings offers an opportunity to engage and address local ethical concerns to improve women's access to research during pregnancy and enhance intervention development. In this paper, we present a qualitative research ethics case study, drawn from the Partners Demonstration Project of pre-exposure prophylaxis (PrEP) in Kenya, regarding the role of male partners in decision-making to continue PrEP during pregnancy. PrEP is an effective HIV prevention tool; however, since pregnant women were excluded from early PrEP clinical trials, safety and efficacy data during pregnancy are limited. Given continued high rates of HIV infection for women, some pregnant women are now being provided with PrEP or are involved in PrEP research. Men and women in our study were equally concerned about the health risks of PrEP to the fetus and depended on healthcare provider guidance to understand these risks. Because the demonstration project enrolled couples, an implicit social expectation for many women's continuation of PrEP during pregnancy was consultation with male partners. Some women reported that consenting to participate was exclusively a woman's decision; however, many reported that they deferred to their male partner's opinion and support during the decision-making process. Most male partners believed women should not participate in research studies without their partner's permission, while a few men believed participation was ultimately a woman's decision. We suggest that relational autonomy can support a middle ground for informed consent that promotes women's autonomy while accommodating partner engagement.

Ethical considerations in developing an evidence base for pre-exposure prophylaxis in pregnant women.

Though many women in need of access to HIV preventive regimes are pregnant, there is a dearth of data to guide these care decisions. While oral pre-exposure prophylaxis (PrEP) has been shown to prevent HIV infection in numerous high-risk populations, pregnant women have been excluded from all major prospective trials. We propose for ethical examination a theoretical trial-a prospective, observational study of PrEP for pregnant women at risk for HIV in sub-Saharan Africa-highlighting an ethical tradeoff that characterizes issues faced for advancing research in pregnancy. On the one hand, an "opportunistic" study design has certain ethical advantages: as formally construed, the research activity usually begins after decisions to use PrEP during pregnancy are made in the clinical setting. This minimizes research risks and avoids ethical problems that a randomized controlled trial (RCT) comparing PrEP to placebo would entail, particularly withholding care proven beneficial in other populations. On the other hand, observational studies yield less precise information than RCTs. This raises a broader question about the pace of research with pregnant women, as it typically takes many years after a drug's approval for use in the general population to determine safety of the medication in pregnancy. Such delays can have the effect of making it impossible to ethically conduct an RCT with pregnant women, reducing the likelihood that the research community is able to obtain robust, pregnancy-specific evidence. While an observational cohort is potentially the most ethically and scientifically justified research design to study PrEP in pregnancy, earlier involvement of pregnant women in studies of newer preventives may lead to evidence that is more timely and robust.

Ethical Issues to Consider in the Design of HIV Prevention Trials Involving Transgender People.

Although transgender women have been included in HIV prevention pre-exposure prophylaxis studies, no pre-exposure prophylaxis study has focused exclusively on transgender persons. Drawing on the cardinal principles of ethics espoused in the Belmont Report, this work highlights, among other issues, that (1) the principle of Justice requires the HIV prevention field to focus exclusively on transgender persons, (2) the disclosure of potential study-related risks to study participants demonstrates Respect for Persons, and (3) devising risk mitigation plans, optimizing a proposed study's standard of care, and the provision of ancillary care satisfy the principle of Beneficence.

From subjects to relations: Bioethics and the articulation of postcolonial politics in the Cambodia Pre-Exposure Prophylaxis trial.

Controversies about global clinical trials, particularly HIV trials, tend to be framed in terms of ethics. In this article, I explore debates about ethics in the Cambodia Pre-Exposure Prophylaxis trial, which was designed to test the safety and efficacy of tenofovir as a prevention for HIV infection. Bringing together studies of public participation in science with studies of bioethics, I show how activists around the Cambodian Pre-Exposure Prophylaxis trial circulated and provoked debates about standards of research ethics, as opposed to research methodology. This postcolonial bioethics was configured through the circulation of and debate about ethics guidelines, and historically and culturally specific relations of vulnerability and responsibility between foreigners and Cambodians and between Cambodian leaders and Cambodian subjects. I argue that this shift in the object of ethical concern, from the experimental human subject to the relation between subjects and researchers, illustrates how a postcolonial field of articulation reformulates classical bioethics.

Ethical Implications of Social Stigma Associated with the Promotion and Use of Pre-Exposure Prophylaxis for HIV Prevention.

Identifying sources of and eliminating social stigma associated with the promotion and use of pre-exposure prophylaxis (PrEP) for the prevention of sexually acquired HIV infection among men who have sex with men (MSM) is both a moral imperative and necessary requirement to ensure that public health objectives of HIV prevention can be met. This article will examine and address ethical concerns and criticisms regarding the use of PrEP, barriers to its promotion, and use among MSM and examine the types of social stigma associated with PrEP. An ethical justification for both healthcare and LGBT communities to address and overcome social stigma regarding the use of PrEP among MSM is offered.

Considerations for a Human Rights Impact Assessment of a Population Wide Treatment for HIV Prevention Intervention.

Increasing attention is being paid to the potential of anti-retroviral treatment (ART) for HIV prevention. The possibility of eliminating HIV from a population through a universal test and treat intervention, where all people within a population are tested for HIV and all positive people immediately initiated on ART, as part of a wider prevention intervention, was first proposed in 2009. Several clinical trials testing this idea are now in inception phase. An intervention which relies on universally testing the entire population for HIV will pose challenges to human rights, including obtaining genuine consent to testing and treatment. It also requires a context in which people can live free from fear of stigma, discrimination and violence, and can access services they require. These challenges are distinct from the field of medical ethics which has traditionally governed clinical trials and focuses primarily on patient researcher relationship. This paper sets out the potential impact of a population wide treatment as prevention intervention on human rights. It identifies five human right principles of particular relevance: participation, accountability, the right to health, non-discrimination and equality, and consent and confidentiality. The paper proposes that explicit attention to human rights can strengthen a treatment as prevention intervention, contribute to mediating likely health systems challenges and offer insights on how to reach all sections of the population.

When the science fails and the ethics works: 'Fail-safe' ethics in the FEM-PrEP study.

This paper will explore the concept of 'fail safe' ethics in the FEM PrEP trial, and the practice of research and ethics on the ground. FEM-PrEP examined the efficacy of PrEP in African women after promising outcomes in research conducted with MSM. This was a hugely optimistic time and FEM-PrEP was mobilised using rights-based ethical arguments that women should have access to PrEP. This paper will present data collected during an ethnographic study of frontline research workers involved in FEM-PrEP. During our discussions, 'fail-safe' ethics emerged as concept that encapsulated their confidence that their ethics could not fail. However, in 2011, FEM-PrEP was halted and deemed a failure. The women involved in the study were held responsible because contrary to researcher's expectations they were not taking the oral PrEP being researched. This examination of FEM-PrEP will show that ethical arguments are increasingly deployed to mobilise, maintain and in some cases stop trials in ways which, at times, are superseded or co-opted by other interests. While promoting the interests of women, rights-based approaches are argued to indirectly justify the continuation of individualised, biomedical interventions which have been problematic in other women-centred trials. In this examination of FEM-PrEP, the rights-based approach obscured: ethical concerns beyond access to PrEP; the complexities of power relationships between donor and host countries; the operations of the HIV industry in research-saturated areas and the cumulative effect of unfilled expectations in HIV research and how this has shaped ideas of research and ethics.

Translating PrEP effectiveness into public health impact: key considerations for decision-makers on cost-effectiveness, price, regulatory issues, distributive justice and advocacy for access.

INTRODUCTION: The extraordinary feat of proving the effectiveness of oral pre-exposure prophylaxis (PrEP) in clinical trials in different populations in a variety of settings may prove to have been easier than ensuring it is used well. Decision-makers must make difficult choices to realize the promise of antiretroviral prophylaxis for their countries. This paper outlines key economic, regulatory and distributive justice issues that must be addressed for effective and acceptable PrEP implementation. DISCUSSION: In considering the role that PrEP can play in combination prevention programmes, decision-makers must determine who can benefit most from PrEP, how PrEP can be provided safely and efficiently, and what kind of health system support will ensure successful implementation. To do this, they need contextualized information on disease burden by population, analyses of how PrEP services might best be delivered, and projections of the human resource and infrastructure requirements for each potential delivery model. There are cost considerations, varying cost-effectiveness results and regulatory challenges. The principles of ethics can inform thorny discussions about who should be prioritized for oral PrEP and how best to introduce it fairly. We describe the cost-effectiveness of PrEP in different populations at higher risk of HIV exposure, its price in low- and middle-income countries, and the current regulatory situation. We explore the principles of ethics that can inform resource allocation decision-making about PrEP anchored in distributive justice, at a time when universal access to antiretroviral treatment remains to be assured. We then highlight the role of advocacy in moving the PrEP agenda forward. CONCLUSIONS: The time is ripe now for decisions about whether, how and for whom PrEP should be introduced into a country's HIV response. It has the potential to contribute significantly to high impact HIV prevention if it is tailored to those who can most benefit from it and if current regulatory and pricing barriers can be overcome. Advocacy at all levels can help inform decision-making and push the access agenda to avert HIV infections among those at highest risk of HIV exposure. The benefits will accrue beyond the individual level to slow HIV transmission at the population level.

Adolescent Self-Consent for Biomedical Human Immunodeficiency Virus Prevention Research.

PURPOSE: The Adolescent Medicine Trials Network Protocol 113 (ATN113) is an open-label, multisite demonstration project and Phase II safety study of human immunodeficiency virus (HIV) preexposure prophylaxis with 15- to 17-year-old young men who have sex with men that requires adolescent consent for participation. The purpose of this study was to examine factors related to the process by which Institutional Review Boards (IRBs) and researchers made decisions regarding whether to approve and implement ATN113 so as to inform future biomedical HIV prevention research with high-risk adolescent populations. METHODS: Participants included 17 researchers at 13 sites in 12 states considering ATN113 implementation. Qualitative descriptive methods were used. Data sources included interviews and documents generated during the initiation process. RESULTS: A common process for initiating ATN113 emerged, and informants described how they identified and addressed practical, ethical, and legal challenges that arose. Informants described the process as responding to the protocol, preparing for IRB submission, abstaining from or proceeding with submission, responding to IRB concerns, and reacting to the outcomes. A complex array of factors impacting approval and implementation were identified, and ATN113 was ultimately implemented in seven of 13 sites. Informants also reflected on lessons learned that may help inform future biomedical HIV prevention research with high-risk adolescent populations. CONCLUSIONS: The results illustrate factors for consideration in determining whether to implement such trials, demonstrate that such protocols have the potential to be approved, and highlight a need for clearer standards regarding biomedical HIV prevention research with high-risk adolescent populations.

Ensuring the Ethical Implementation of the New World Health Organization Pre-Exposure Prophylaxis Recommendations for Men Who Have Sex with Men.

The World Health Organization's (WHO) new recommendation to encourage pre-exposure prophylaxis in men who have sex with men (MSM) is an important step towards eradicating the HIV epidemic. However, the ethical issues of stigma, privacy and confidentiality, and access must be addressed in order to ensure the optimal implementation of this important recommendation.

Cultural conundrums: the ethics of epidemiology and the problems of population in implementing pre-exposure prophylaxis.

The impending implementation of pre-exposure prophylaxis (PrEP) has prompted complicated bioethical and public health ethics concerns regarding the moral distribution of antiretroviral medications (ARVs) to ostensibly healthy populations as a form of HIV prevention when millions of HIV-positive people still lack access to ARVs globally. This manuscript argues that these questions are, in part, concerns over the ethics of the knowledge production practices of epidemiology. Questions of distribution, and their attendant cost-benefit calculations, will rely on a number of presupposed, and therefore, normatively cultural assumptions within the science of epidemiology specifically regarding the ability of epidemiologic surveillance to produce accurate maps of HIV throughout national populations. Specifically, ethical questions around PrEP will focus on who should receive ARVs given the fact that global demand will far exceed supply. Given that sexual transmission is one of the main modes of HIV transmission, these questions of 'who' are inextricably linked to knowledge about sexual personhood. As a result, the ethics of epidemiology, and how the epidemiology of HIV in particular conceives, classifies and constructs sexual populations will become a critical point of reflection and contestation for bioethicists, health activists, physicians, nurses, and researchers in the multi-disciplinary field of global health. This paper examines how cultural conundrums within the fields of bioethics and public health ethics are directly implicated within the ethics of PrEP, by analyzing the problems of population inaugurated by the construction of the men who have sex with men (MSM) epidemiologic category in the specific national context of South Africa.