Lessons learned from the Last Gift study: ethical and practical challenges faced while conducting HIV cure-related research at the end of life.

The Last Gift is an observational HIV cure-related research study conducted with people with HIV at the end of life (EOL) at the University of California San Diego. Participants agree to voluntarily donate blood and other biospecimens while living and their bodies for a rapid research autopsy postmortem to better understand HIV reservoir dynamics throughout the entire body. The Last Gift study was initiated in 2017. Since then, 30 volunteers were enrolled who are either (1) terminally ill with a concomitant condition and have a prognosis of 6 months or less or (2) chronically ill with multiple comorbidities and nearing the EOL.Multiple ethical and logistical challenges have been revealed during this time; here, we share our lessons learnt and ethical analysis. Issues relevant to healthcare research include surrogate informed consent, personal and professional boundaries, challenges posed conducting research in a pandemic, and clinician burnout and emotional support. Issues more specific to EOL and postmortem research include dual roles of clinical care and research teams, communication between research personnel and clinical teams, legally required versus rapid research autopsy, identification of next of kin/loved ones and issues of inclusion. Issues specific to the Last Gift include logistics of body donation and rapid research autopsy, and disposition of the body as a study benefit.We recommend EOL research teams to have clear provisions around surrogate informed consent, rotate personnel to maintain boundaries, limit direct contact with staff associated with clinical care and have a clear plan for legally required versus research autopsies, among other recommendations.

Ethical and practical considerations for cell and gene therapy toward an HIV cure: findings from a qualitative in-depth interview study in the United States.

BACKGROUND: HIV cure research involving cell and gene therapy has intensified in recent years. There is a growing need to identify ethical standards and safeguards to ensure cell and gene therapy (CGT) HIV cure research remains valued and acceptable to as many stakeholders as possible as it advances on a global scale. METHODS: To elicit preliminary ethical and practical considerations to guide CGT HIV cure research, we implemented a qualitative, in-depth interview study with three key stakeholder groups in the United States: (1) biomedical HIV cure researchers, (2) bioethicists, and (3) community stakeholders. Interviews permitted evaluation of informants' perspectives on how CGT HIV cure research should ethically occur, and were transcribed verbatim. We applied conventional content analysis focused on inductive reasoning to analyze the rich qualitative data and derive key ethical and practical considerations related to CGT towards an HIV cure. RESULTS: We interviewed 13 biomedical researchers, 5 community members, and 1 bioethicist. Informants generated considerations related to: perceived benefits of CGT towards an HIV cure, perceived risks, considerations necessary to ensure an acceptable benefit/risk balance, CGT strategies considered unacceptable, additional ethical considerations, and considerations for first-in-human CGT HIV cure trials. Informants also proposed important safeguards to developing CGT approaches towards an HIV cure, such as the importance of mitigating off-target effects, mitigating risks associated with long-term duration of CGT interventions, and mitigating risks of immune overreactions. CONCLUSION: Our study identified preliminary considerations for CGT-based HIV cure across three key stakeholder groups. Respondents identified an ideal cure strategy as one which would durably control HIV infection, protect the individual from re-acquisition, and eliminate transmission to others. Known and unknown risks should be anticipated and perceived as learning opportunities to preserve and honor the altruism of participants. Preclinical studies should support these considerations and be transparently reviewed by regulatory experts and peers prior to first-in-human studies. To protect the public trust in CGT HIV cure research, ethical and practical considerations should be periodically revisited and updated as the science continues to evolve. Additional ethics studies are required to expand stakeholder participation to include traditionally marginalized groups and clinical care providers.

"We are looking at the future right now": community acceptability of a home-based viral load test device in the context of HIV cure-related research with analytical treatment interruptions in the United States.

BACKGROUND: People with HIV (PWH) and community members have advocated for the development of a home-based viral load test device that could make analytical treatment interruptions (ATIs) less burdensome. OBJECTIVE: We assessed community acceptability of a novel home-based viral load test device. METHODS: In 2021, we conducted 15 interviews and 3 virtual focus groups with PWH involved in HIV cure research. We used conventional thematic analysis to analyze the data. RESULTS: PWH viewed the home-based viral load test device as a critical adjunct in ongoing HIV cure trials with ATIs. The ability to test for viral load at home on demand would alleviate anxiety around being off ART. Participants drew parallels with glucometers used for diabetes. A preference was expressed for the home-based test to clearly indicate whether one was detectable or undetectable for HIV to mitigate risk of HIV transmission to partners. Perceived advantages of the device included convenience, sense of control, and no puncturing of veins. Perceived concerns were possible physical marks, user errors and navigating the logistics of mailing samples to a laboratory and receiving test results. Participants expressed mixed effects on stigma, such as helping normalize HIV, but increased potential for inadvertent disclosure of HIV status or ATI participation. Increasing pluri-potency of the device beyond viral load testing (e.g., CD4+ count test) would increase its utility. Participants suggested pairing the device with telemedicine and mobile health technologies. CONCLUSIONS: If proven effective, the home-based viral load test device will become a critical adjunct in HIV cure research and HIV care.

Ethical and practical considerations for HIV cure-related research at the end-of-life: a qualitative interview and focus group study in the United States.

BACKGROUND: One of the next frontiers in HIV research is focused on finding a cure. A new priority includes people with HIV (PWH) with non-AIDS terminal illnesses who are willing to donate their bodies at the end-of-life (EOL) to advance the search towards an HIV cure. We endeavored to understand perceptions of this research and to identify ethical and practical considerations relevant to implementing it. METHODS: We conducted 20 in-depth interviews and 3 virtual focus groups among four types of key stakeholders in the United States (PWH, biomedical HIV cure researchers, HIV clinicians, and bioethicists) to obtain triangulated viewpoints because little was known about the ethics of this topic. Each group was queried as to ethical considerations, safeguards, and protections for conducting HIV cure-related research at the EOL to ensure this research remains acceptable. RESULTS: All four key stakeholder groups generally supported HIV cure-related research conducted at the EOL because of the history of altruism within the PWH community and the potential for substantial scientific knowledge to be gained. Our informants expressed that: (1) Strong stakeholder and community involvement are integral to the ethical and effective implementation, as well as the social acceptability of this research; (2) PWH approaching the EOL should not inherently be considered a vulnerable class and their autonomy must be respected when choosing to participate in HIV cure-related research at the EOL; (3) Greater diversity among study participants, as well as multi-disciplinary research teams, is necessitated by HIV cure-related research at the EOL; (4) The sensitive nature of this research warrants robust oversight to ensure a favorable risk/benefit balance and to minimize the possibility of therapeutic misconception or undue influence; and (5) Research protocols should remain flexible to accommodate participants' comfort and needs at the EOL. CONCLUSION: Because of the ethical issues presented by HIV cure-related research at the EOL, robust ethical safeguards are of utmost importance. The proposed ethical and practical considerations presented herein is a first step in determining the best way to maximize this research's impact and social value. More much inquiry will need to be directed towards understanding context-specific and cultural considerations for implementing EOL HIV cure research in diverse settings.

Considerations for Increasing Racial, Ethnic, Gender, and Sexual Diversity in HIV Cure-Related Research with Analytical Treatment Interruptions: A Qualitative Inquiry.

Despite disproportionate incidence and prevalence of HIV among transgender individuals, cisgender women, and racial and ethnic minority groups, all remain underrepresented in HIV cure research. As HIV cure trials are scaled up, there is emerging research on ways to mitigate risks of HIV acquisition for sexual partners of analytical treatment interruption (ATI) trial participants. As such, it is imperative that HIV cure researchers consider the implications of implementing ATIs in populations that are disproportionately affected by HIV, but largely underrepresented in trials to date. In this qualitative study, we sought to derive triangulated perspectives on the social and ethical implications regarding ATIs and partner protection strategies during ATIs among under-represented populations. We conducted 21 in-depth interviews with 5 types of informants: bioethicists, community members [people living with HIV (PLWH) and their advocates], biomedical HIV cure researchers, sociobehavioral scientists, and HIV care providers. We analyzed the data using conventional content analysis and reduced the data to important considerations for implementing ATI trials in diverse communities and settings. Our study revealed the following key themes: (1) attention must be paid to gender and power dynamics in ATI trials; (2) ATI trials should be designed and implemented through the lenses of intersectionality and equity frameworks; (3) ATI trials may have both positive and negative effects on stigma for PLWH and their partners; and (4) partnership dynamics should be considered when designing ATI protocols. Our study generated actionable considerations that could be implemented in ATI trials to promote their acceptability to communities that have been underrepresented in HIV cure research to date. Research teams must invest in robust community and stakeholder engagement to define best practices. Paying attention to representation and equity will also promote better and more equitable implementation of HIV cure strategies once these become ready for rollout.

Considerations for designing and implementing combination HIV cure trials: findings from a qualitative in-depth interview study in the United States.

BACKGROUND: An increasing number of HIV cure trials involve combining multiple potentially curative interventions. Until now, considerations for designing and implementing complex combination HIV cure trials have not been thoroughly considered. METHODS: We used a purposive method to select key informants for our study. Informants included biomedical HIV cure researchers, regulators, policy makers, bioethicists, and community members. We used in-depth interviews to generate ethical and practical considerations to guide the design and implementation of combination HIV cure research. We analyzed the qualitative data using conventional content analysis focused on inductive reasoning. RESULTS: We interviewed 11 biomedical researchers, 4 community members, 2 regulators, 1 policy researcher, and 1 bioethicist. Informants generated considerations for designing and implementing combination interventions towards an HIV cure, focused on ethical aspects, as well as considerations to guide trial design, benefit/risk determinations, regulatory requirements, prioritization and sequencing and timing of interventions, among others. Informants also provided considerations related to combining specific HIV cure research modalities, such as broadly neutralizing antibodies (bNAbs), cell and gene modification products, latency-reversing agents and immune-based interventions. Finally, informants provided suggestions to ensure meaningful therapeutic improvements over standard antiretroviral therapy, overcome challenges of designing combination approaches, and engage communities around combination HIV cure research. CONCLUSION: The increasing number of combination HIV cure trials brings with them a host of ethical and practical challenges. We hope our paper will inform meaningful stakeholder dialogue around the use of combinatorial HIV cure research approaches. To protect the public trust in HIV cure research, considerations should be periodically revisited and updated with key stakeholder input as the science continues to advance.

Ethics of HIV cure research: an unfinished agenda.

BACKGROUND: The pursuit of a cure for HIV is a high priority for researchers, funding agencies, governments and people living with HIV (PLWH). To date, over 250 biomedical studies worldwide are or have been related to discovering a safe, effective, and scalable HIV cure, most of which are early translational research and experimental medicine. As HIV cure research increases, it is critical to identify and address the ethical challenges posed by this research. METHODS: We conducted a scoping review of the growing HIV cure research ethics literature, focusing on articles published in English peer-reviewed journals from 2013 to 2021. We extracted and summarized key developments in the ethics of HIV cure research. Twelve community advocates actively engaged in HIV cure research provided input on this summary and suggested areas warranting further ethical inquiry and foresight via email exchange and video conferencing. DISCUSSION: Despite substantial scholarship related to the ethics of HIV cure research, additional attention should focus on emerging issues in six categories of ethical issues: (1) social value (ongoing and emerging biomedical research and scalability considerations); (2) scientific validity (study design issues, such as the use of analytical treatment interruptions and placebos); (3) fair selection of participants (equity and justice considerations); (4) favorable benefit/risk balance (early phase research, benefit-risk balance, risk perception, psychological risks, and pediatric research); (5) informed consent (attention to language, decision-making, informed consent processes and scientific uncertainty); and (6) respect for enrolled participants and community (perspectives of people living with HIV and affected communities and representation). CONCLUSION: HIV cure research ethics has an unfinished agenda. Scientific research and bioethics should work in tandem to advance ethical HIV cure research. Because the science of HIV cure research will continue to rapidly advance, ethical considerations of the major themes we identified will need to be revisited and refined over time.

Ethical and practical considerations for interventional HIV cure-related research at the end-of-life: A qualitative study with key stakeholders in the United States.

BACKGROUND: A unique window of opportunity currently exists to generate ethical and practical considerations presented by interventional HIV cure-related research at the end-of-life (EOL). Because participants would enroll in these studies for almost completely altruistic reasons, they are owed the highest ethical standards, safeguards, and protections. This qualitative empirical ethics study sought to identify ethical and practical considerations for interventional HIV cure-related research at the EOL. METHODS AND FINDINGS: We conducted 20 in-depth interviews and three virtual focus groups (N = 36) with four key stakeholder groups in the United States: 1) bioethicists, 2) people with HIV, 3) HIV care providers, and 4) HIV cure researchers. This study produced six key themes to guide the ethical implementation of interventional HIV cure-related research at the EOL: 1) all stakeholder groups supported this research conditioned upon a clearly delineated respect for participant contribution and autonomy, participant understanding and comprehension of the risks associated with the specific intervention(s) to be tested, and broad community support for testing of the proposed intervention(s); 2) to ensure acceptable benefit-risk profiles, researchers should focus on limiting the risks of unintended effects and minimizing undue pain and suffering at the EOL; 3) only well-vetted interventions that are supported by solid pre-clinical data should be tested in the EOL translational research model; 4) the informed consent process must be robust and include process consent; 5) research protocols should be flexible and adopt a patient/participant centered approach to minimize burdens and ensure their overall comfort and safety; and 6) a participant's next-of-kin/loved ones should be a major focus of EOL research but only if the participant consents to such involvement. CONCLUSIONS: To our knowledge, this empirical ethics study generated the first ethical and practical considerations for interventional HIV cure-related research at the EOL. The ethical complexities of such research must be considered now. We must navigate this ethical conundrum so that we are good stewards of the participants' extremely altruistic gifts by maximizing the impact and social value of this research. We hope that this study will serve as the foundation for future research and discussion on this topic.

Ethical and practical considerations for mitigating risks to sexual partners during analytical treatment interruptions in HIV cure-related research.

BACKGROUND: Background: Analytical treatment interruptions (ATIs) in HIV cure-related research can result in trial participants becoming viremic with HIV, placing HIV-negative sexual partners at elevated risk of acquiring HIV. OBJECTIVE: Objective:Our study aimed to generate ethical and practical considerations for designing and implementing appropriate risk mitigation strategies to reduce unintended HIV transmission events during ATIs. METHODS: Methods: We conducted 21 in-depth interviews with five types of informants: bioethicists, community members, biomedical HIV cure researchers, socio-behavioral scientists/epidemiologists, and HIV care providers. We used conventional content analysis to analyze the data and generate considerations. RESULTS: Results: Key findings include: 1) Ethical permissibility of ATI trials depends on due diligence and informed consent to mitigate risks to participants and their sexual partners; 2) Participants should receive adequate support and/or counseling if they choose to disclose ATI participation to their partners; 3) Measures to protect sexual partners of trial participants from HIV transmission during ATIs should include referral to and/or provision of pre-exposure prophylaxis, as well as other available means of preventing HIV transmission; 4) There is uncertainty regarding the appropriate management of emerging sexually transmitted infections during ATI trials and possible protection measures for multiple and/or anonymous partners of ATI trial participants. CONCLUSION: Conclusion: While there is no way to completely eliminate the risk of HIV transmission to sexual partners during ATIs, HIV cure trialists and sponsors should consider the ethical concerns related to the sexual partners of ATI participants. Doing so is essential to ensuring the welfare of participants, their partners and the trustworthiness of research.

The LAIs Are Coming! Implementation Science Considerations for Long-Acting Injectable Antiretroviral Therapy in the United States: A Scoping Review.

Long-acting injectable antiretroviral therapy (LAI-ART) is one of the latest advancements in HIV control with the potential to overcome oral ART barriers to adherence. The objective of this article is to anticipate and examine implementation considerations for LAI-ART using components of the PRISM model, a Practical, Robust Implementation and Sustainability Model for integrating research findings into practice. We conducted a scoping review from January to August 2020 of the growing literature on LAI-ART implementation and other fields using LAI therapies. Key considerations regarding LAI-ART were parsed from the searches and entered into the PRISM implementation science framework. The PRISM framework posed multiple questions for consideration in the development of an optimal implementation strategy for LAI-ART in the United States. These questions revealed the necessity for more data, including acceptability of LAI-ART among many different subgroups of people living with HIV (PLWH), cost effectiveness, patient satisfaction, and patient-reported outcomes, as well as more detailed information related to the external environment for optimal LAI-ART implementation. Ethical considerations of LAI-ART will also need to be considered. The anticipation of, and excitement for, LAI-ART represent the hope for a new direction for HIV treatment that reduces adherence barriers and improves prognoses for PLWH. We have a unique window of opportunity to anticipate implementation considerations for LAI-ART, so this new therapy can be used to its fullest potential. Outstanding questions remain, however, that need to be addressed to help achieve HIV suppression goals in diverse populations.

Altruism: Scoping review of the literature and future directions for HIV cure-related research.

INTRODUCTION: The question of what motivates people to participate in research is particularly salient in the HIV field. While participation in HIV research was driven by survival in the 1980's and early 1990's, access to novel therapies became the primary motivator with the advent of combination antiretroviral therapy (cART) in the late 1990s. In the HIV cure-related research context, the concept of altruism has remained insufficiently studied. METHODS: We conducted a scoping review to better contextualize and understand how altruism is or could be operationalized in HIV cure-related research. We drew from the fields of altruism in general, clinical research, cancer, and HIV clinical research-including the HIV prevention, treatment, and cure-related research fields. DISCUSSION: Altruism as a key motivating factor for participation in clinical research has often been intertwined with the desire for personal benefit. The cancer field informs us that reasons for participation usually are multi-faceted and complex. The HIV prevention field offers ways to organize altruism-either by the types of benefits achieved (e.g., societal versus personal), or the origin of the values that motivate research participation. The HIV treatment literature reveals the critical role of clinical interactions in fostering altruism. There remains a dearth of in-depth knowledge regarding reasons surrounding research participation and the types of altruism displayed in HIV cure-related clinical research. CONCLUSION: Lessons learned from various research fields can guide questions which will inform the assessment of altruism in future HIV cure-related research.

Re-examining the HIV 'functional cure' oxymoron: Time for precise terminology?

For over a decade, the binary concepts of 'sterilizing' versus 'functional' cure have provided an organizing framework for the field of HIV cure-related research. In this article, we examine how the expression 'functional cure' is employed within the field, published literature, and community understanding of HIV cure research. In our synthesis of the different meanings attributed to 'functional cure' within contemporary biomedical discourse, we argue that employing the 'functional cure' terminology poses a series of problems. The expression itself is contradictory and inconsistently used across a wide array of HIV cure research initiatives. Further, the meaning and acceptability of 'functional cure' within communities of people living with and affected by HIV is highly variable. After drawing lessons from other fields, such as cancer and infectious hepatitis cure research, we summarize our considerations and propose alternative language that may more aptly describe the scientific objectives in question. We call for closer attention to language used to describe HIV cure-related research, and for continued, significant, and strategic engagement to ensure acceptable and more precise terminology.

Reasons People Living with HIV Might Prefer Oral Daily Antiretroviral Therapy, Long-Acting Formulations, or Future HIV Remission Options.

A growing body of research is beginning to elucidate reasons people living with HIV (PLWHIV) might prefer oral daily antiretroviral treatment (ART) compared with emerging long-acting ART (LA-ART) or HIV remission strategies under investigation. Our objective is to provide qualitative insights into the reasons why PLWHIV might prefer one of these HIV control therapies over others. From May to August 2018, we implemented a semistructured cross-sectional survey of PLWHIV in the United States to better understand patient preferences around various HIV treatment and remission options. Using free text, respondents were asked to explain why they preferred one HIV control option over the other two. We analyzed responses to the open-ended survey questions on reasons for preferring oral daily ART versus LA-ART versus HIV remission strategies using conventional content analysis. The results showed that PLWHIV preferred oral daily ART because of its familiarity and known safety and efficacy profile, whereas those who preferred LA-ART would value the convenience it offers. Finally, HIV remission strategies would be preferred to avoid taking ART altogether. The qualitative results provide insights into reasons why PLWHIV in the United States might prefer oral daily ART versus novel therapies. More importantly, they provide information to better align HIV virological control strategies with end-user perspectives. To make informed choices around evolving HIV therapeutics, PLWHIV and HIV care providers would benefit from decision tools to better assess options and trade-offs. More research is needed on how best to effectively support PLWHIV and HIV care providers in shared decision-making.

The Dose Response: Perceptions of People Living with HIV in the United States on Alternatives to Oral Daily Antiretroviral Therapy.

There are two concurrent and novel major research pathways toward strategies for HIV control: (1) long-acting antiretroviral therapy (ART) formulations and (2) research aimed at conferring sustained ART-free HIV remission, considered a step toward an HIV cure. The importance of perspectives from people living with HIV on the development of new modalities is high, but data are lacking. We administered an online survey in which respondents selected their likelihood of participation or nonparticipation in HIV cure/remission research based on potential risks and perceived benefits of these new modalities. We also tested the correlation between perceptions of potential risks and benefits with preferences of virologic control strategies and/or responses to scenario choices, while controlling for respondent characteristics. Of the 282 eligible respondents, 42% would be willing to switch from oral daily ART to long-acting ART injectables or implantables taken at 6-month intervals, and 24% to a hypothetical ART-free remission strategy. We found statistically significant gender differences in perceptions of risk and preferences of HIV control strategies, and possible psychosocial factors that could mediate willingness to switch to novel HIV treatment or remission options. Our study yielded data on possible desirable product characteristics for future HIV treatment and remission options. Findings also revealed differences in motivations and preferences across gender and other sociodemographic characteristics that may be actionable as part of research recruitment efforts. The diversity of participant perspectives reveals the need to provide a variety of therapeutic options to people living with HIV and to acknowledge their diverse experiential expertise when developing novel HIV therapies.