Introduction

In the United States today, the majority of people living with HIV (PLWHIV) are no longer dying of AIDS-defining illnesses. Instead, they are living longer and dying of chronic conditions similar to those of the general population, such as non-AIDS-defining cancers, cardiovascular disease, and neurodegenerative diseases [1]. The Last Gift is an end-of-life (EOL) HIV cure-related research study at the University of California, San Diego (UCSD) [2,3]. The study is part of the National Institute of Allergy and Infectious Diseases (NIAID)’s and the National Institute of Mental Health (NIMH)’s initiative to increase research involving terminally ill PLWHIV. As a rapid autopsy research study, the Last Gift enrolls altruistic PLWHIV who are terminally ill secondary to a non-AIDS-defining illness. Participants have a prognosis of less than 6 months. In the ante-mortem phase of the study, participants undergo routine blood draws and optional tissue collection. This phase also includes in-depth socio-behavioral interviews with both participants and their next-of-kin/loved ones/intimate partners (hereafter referred to as ‘NOK’) regarding their experiences and feelings toward EOL HIV cure research. In the post-mortem phase, a rapid autopsy is performed within six hours of death. Participants who enroll in the study understand that the study will not confer direct clinical benefits and will not cure them of their HIV or their terminal illness.

Antiretroviral therapy has reduced and prevented HIV mortality but cannot eliminate HIV from the body since the virus hides in latently infected cells [4]. Furthermore, studying animal models is insufficient for finding a cure for HIV because human testing remains necessary to prove safety and efficacy of interventions in humans [4]. As such, to better understand HIV persistence and potentially eliminate hidden HIV reservoirs from the human body, Last Gift researchers proposed “a perimortem translational research model” to identify where HIV persists inside the body [4]. Therefore, the rationale for enrolling terminally ill PLWHIV in HIV cure-related research is six fold: "1) the absence of any reasonable expectation of direct clinical benefits in most HIV cure-related research, 2) the manifest desire in this community to ‘give back’ to the HIV research field, 3) limited opportunities for terminally ill PLWHIV to participate in HIV clinical research in general, 4) the fact that people at the EOL may be willing to accept higher risks for research participation, 5) the possibility for donating their full body for a rapid research autopsy, and 6) the opportunity to create a new translational research model to advance HIV cure science (e.g. to test novel HIV cure-related interventions in a human model) [5].”

Using blood and tissue samples collected before and after death from six Last Gift study participants, Chaillon and colleagues found that HIV persists in blood cells and across 28 deep tissues including cardiovascular, gastrointestinal, and lymphoid tissues [6]. Rawlings et al. developed a rapid research autopsy protocol to guide the collection of fluids and tissues for interrogating HIV reservoirs [7].

NOK are an integral part of the Last Gift study. Within studies in EOL cancer research, respect and cooperation with NOK have been described as a key ethical consideration [8,9]. Similarly, understanding and respecting the attitudes and experiences of participants’ communities (including NOK) in EOL HIV cure-related research is critical for ethical study conduct [5,10]. In studying NOK perspectives, we seek to safeguard vulnerability, ensure acceptability from all stakeholders, and center the study around participants and their NOK. We conducted focus groups to better understand NOK’s perspectives of the Last Gift study and its impact on them and participants. The focus groups also sought to elucidate ethical concerns involving NOK. In this paper, we report results from small focus groups conducted with NOK in 2019, two years following the initiation of the Last Gift study in 2017.

Methods

NOK were identified by Last Gift study participants (LG) who referred them into our qualitative study. NOK provided both written and verbal informed consent for their own research involvement. A total of six NOK participated in the focus group component of the Last Gift study. Two NOK participated in each of small focus groups #1 and #2. Two remaining NOK preferred answering questions from the focus group guide via one-on-one interviews. Focus group recruitment was conducted via emails and phone calls from February 2019 through July 2019. Focus groups lasted between 60–90 minutes. One focus group and two interviews took place at the AntiViral Research Center (AVRC); however, two participants were unable to find transportation, therefore, the second focus group took place at their home. Only the participants and research staff were present during the discussions. Participants were reimbursed $50 USD for their participation.

A study staff member (K.D.) developed the focus group guide in collaboration with the AVRC Community Advisory Board and the Stakeholder Advisory Board of HIV + Aging Research Project-Palm Springs. We presented drafts of focus group guides to AVRC Community Advisory Board members and revised them using an iterative process according to their suggestions. The Last Gift Study and focus group guides were approved by the UCSD Institutional Review Board (IRB).

The small focus groups setting created an opportunity for NOK to share collective experiences in a safe environment, removing the sense of isolation following the death of a loved one, and providing richness in information gathered [11]. Smaller focus groups encourage greater depth in data collection [12]. Additionally, by limiting focus group size, discussions more accurately mirrored ordinary conversation, much like dyadic interviews [12]. Drawbacks of focus groups include the possibility of groupthink, bias in the researchers’ data interpretation, social desirability, and reluctance to share negative experiences in group settings [11].

Focus group questions covered perceptions and concerns about the Last Gift study, coping strategies to mitigate stress and grief associated with the EOL process and the study, ethical considerations for the study, and recommendations for study improvement (Table 1).

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Table 1. Small focus group question route with next-of-kin/loved ones of last gift study participants (Southern California, 2019).

https://doi.org/10.1371/journal.pone.0250882.t001

Two participants’ (NOK of Last Gift participant [LG]04 and LG08) involvement in focus groups was not possible. One participant was out of the country and the other was grieving the recent death of his loved one. Thus, out of respect to NOK, the study team remained flexible and conducted one-on-one interviews using focus group guides, as NOK had previously provided written informed consent to share their perspectives as part of a small focus group. Repeat interviews were not necessary for our study.

The members of our research team hold M.D., DrPH, MPH, and B.S. and B.A degrees. Both male- and female-identifying researchers contributed to this study. Research staff members (S.S.J. and K.M.) took detailed notes during the focus groups (and two interviews). Focus group facilitators (K.D. and S.S.J.) with prior experience in moderating focus groups ensured that participants had equal opportunities to express their thoughts. The focus groups (and two interviews) were audio-recorded and a member of the study team (S.S.J. or K.D.) uploaded audio files into a secure server. Study team members (S.S.J., K.M., and H.P.) transcribed each interview verbatim using Microsoft Word and removed identifiers. Research team members (S.S.J and H.P.) reviewed transcripts for completeness and quality assurance. We did not return transcripts to NOK for verification to avoid further distress to NOK. Study staff then deleted source audio files from the secure server in accordance with the IRB-approved informed consent form and work instructions. Socio-behavioral researchers and focus group facilitators were separate from the Last Gift study’s clinical research team and therefore did not know the participants prior to the sessions.

We followed a multidisciplinary theoretical framework integrating biomedical, socio-behavioral, ethics, and community-engaged domains that are recommended for HIV cure-related research [13,14]. Researchers (S.S.J. and K.M.) double-coded the transcripts manually for overarching themes and sub-themes using an inductive approach [15,16]. First-order codes included analyzing NOK statements by distinguishing repetitive phrases and/or ideas, identifying examples, and analyzing transitions in themes within the questions themselves [16]. We also used a phenomenological approach to study NOK narratives and understand their lived experiences without a predetermined framework [17], as very little was known about how NOK experience EOL HIV cure-related research participation. Given the novelty of EOL HIV cure-related research, our study did not use a pre-existing coding scheme. Key themes and relevant quotes were organized into a structured format in Microsoft Word. Salient quotes have been included in the Results section with supplementary quotes included in S1 Appendix. This study is reported according to Consolidating Criteria for Reporting Qualitative Research (COREQ) guidelines. Our checklist included in the S2 Appendix.

Results

This paper provides insight from six NOK (n = 5 male and n = 1 female) who consented to participate in the small focus group component of the Last Gift study. These NOK are representative of five Last Gift study participants (LG01, LG04, LG05, LG07, and LG08). Two NOK for LG07 agreed to participate in the focus group. The NOK of LG04 and LG08 participated in one-on-one interviews using focus group guides, as they were unable to attend scheduled focus group sessions. Two LG participants, LG02 and LG06, chose to forego referring a NOK to the study. Participating NOK included a grandmother, grandfather, partner, spouse, and two close friends (Table 2). The focus groups (and two interviews) were conducted between May and July 2019. Of the NOK involved with the Last Gift Study, LG03’s NOK, LG04’s second NOK, and LG05’s second NOK declined to participate in the small focus group discussions (Table 3).

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Table 2. Demographic characteristics of NOK/loved ones who responded to focus group guide questions (San Diego, California, 2019).

https://doi.org/10.1371/journal.pone.0250882.t002

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Table 3. Reasons NOK/loved ones did not participate in focus groups or one-on-one interviews (using the focus group guide).

https://doi.org/10.1371/journal.pone.0250882.t003

Our thematic analysis extracted six themes from the focus groups (and two interviews): 1) NOK had an accurate and overall positive understanding of the Last Gift clinical study; 2) NOK felt the Last Gift study was conducted in an ethical and respectful manner; 3) Support with navigating the dying and grieving process and personal growth were noted by NOK to be perceived benefits associated with their participation in the Last Gift study; 4) Perceived drawbacks for NOK included increased sadness and emotional stress, conflicted wishes between NOK and study participants, and concerns around potential invasiveness of study procedures at the EOL; 5) NOK expressed pride in their loved ones’ altruism for participating in the Last Gift study and creating further meaning in their EOL process; and 6) NOK identified suggestions to improve Last Gift study implementation, such as better communication between staff and NOK as well as a more seamless cremation process following rapid research autopsy. Fig 1 graphically illustrates these emerging themes. To capture the nuances of our discussions, we summarized common words used by participating NOK in Fig 2.

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Fig 1. Summary of the six emerging themes from discussions with NOK.

https://doi.org/10.1371/journal.pone.0250882.g001

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Fig 2. Word clouds from NOK quotes from discussions with NOK on HIV cure-related research at the EOL (San Diego, California, 2019).

https://doi.org/10.1371/journal.pone.0250882.g002

Discussion

This paper sheds light on the experiences of NOK involved in the Last Gift study at UCSD. Despite the expansion of EOL HIV cure-related research, there have only been a few studies investigating the experiences of NOK/loved ones in this setting [18]. Our initial paper on ethical considerations found that EOL HIV-cure research can be ethical when key issues are anticipated and participants’ lives are honored [5]. Our ethics paper also revealed the critical role of NOK in accepting their loved one’s EOL research participation [5]. In this paper, NOK demonstrated an accurate understanding of the clinical study and perceived the Last Gift study was conducted ethically and respectfully. Given the crucial role that NOK play in the EOL research process, their feelings and concerns, in addition to those of participants, must be considered. This qualitative study using focus group discussions (and guides) advances our understanding of the perspectives, experiences, and concerns NOK have when their loved ones elect to participate in HIV cure-related research at the EOL.

Through our discussions with NOK, we learned that NOK had an accurate and positive understanding of the Last Gift clinical study. Some mentioned that they themselves would participate in this study. While most NOK in our focus groups did not expect any clinical benefit or cure for their loved ones’ HIV or terminal illness, one NOK believed the Last Gift clinical team also served as the participant’s care team. Confusion on the distinction between clinical research and treatment, termed therapeutic misconception, may lead NOK to draw incorrect conclusions regarding their loved ones’ involvement in EOL research [19]. Therapeutic misconception is a widespread problem among research participants, often leading to the inability to obtain meaningful consent [19]. Avoiding misconception protects the integrity of the research process [20]. To combat the potential spread of misinformation, the Last Gift study team encouraged NOK to be actively involved with the study. Our study staff invited NOK to be part of the participants’ onboarding process to learn details directly from staff. Additionally, it is essential for study staff to clearly explain research study objectives to NOK, emphasizing that the research team will not be providing treatment or interfering with existing EOL care plans. While research staff do not provide palliative care, they may provide a sense of comfort to participants or NOK as a result of relationships that stemmed from the clinical study. By addressing therapeutic misconception with NOK, study staff can ensure a more ethically sound study.

NOK stated that their loved ones’ participation allowed research participants to have some control at the EOL because each participant was in charge of how they would ultimately serve their community: through their ‘last gift.’ According to Peter et al., vulnerability is defined as the state of being “incapable of protecting one’s own interests [21].” In general, NOK did not perceive Last Gift participants to be vulnerable because they considered participants to be well-informed of study implications, and participants were given the option to decline or withdraw participation in any part of the research process. Nevertheless, it was noted by NOK that HIV is still stigmatized which may contribute to vulnerability. In our cohort, we have found through separate interviews that stigma varies depending on the relationship participants have with their family [22]. HIV cure-related studies, like the Last Gift study, can also be perceived as opportunities to destigmatize HIV.

In our discussions, it was noted by a NOK that one participant did not feel comfortable declining blood draws, likely because he felt an obligation towards the study [23]. Among research participants, feelings of obligation may precipitate from a desire to reciprocate for care and attention received in the past [24]. Additionally, social desirability may compromise participants’ decisions, specifically when attempting to “look good to others,” thereby acting against their own interests [25]. It is imperative that research staff address any participants’ feelings of obligation or social desirability, explicitly stating that all aspects of the study are optional, and that there will be no repercussions for opting out.

While perceptions of benefits for participants in HIV cure-related research have previously been studied, this is the first time to our knowledge that a study is examining the perspectives of NOK specifically in small focus group settings [26]. Though the NOK of a loved one at the EOL oftentimes knows to expect an eventual death within their inner circle, they may not be prepared for the dying process [27,28]. In the Last Gift study, NOK described feeling overwhelmed by the dying process, especially because many had never cared for a loved one who was dying. NOK expressed gratitude for access to the Last Gift team, whom they could call at any hour for support. According to NOK, by calming their worries and guiding them through the EOL process, the Last Gift team gave them greater confidence and less stress. Existing literature has shown that EOL conversations between family members and physicians may contribute to reducing depression and alleviating grief during the bereavement process [23,29]. Additionally, in a study by Aoun and colleagues, family members who felt supported by palliative care staff before the death of a loved one had a more positive bereavement experience [30]. While our study did not provide palliative care, NOK expressed gratitude to Last Gift staff for remaining in contact with them and following up regularly. These efforts by Last Gift staff made NOK feel supported and valued. Thus, it is important for EOL research staff to prioritize communication with NOK, even after their formal participation in the EOL study has ended.

Research participation may be beneficial for bereaved NOK because it provides them a therapeutic opportunity to describe their experiences and voice their feelings [31]. Therefore, interviewing NOK about their experience in a research context may, in fact, serve to be beneficial in their grieving process. Similar to previous interviews with NOK, our participants also made note of the comfort they derived knowing that their loved ones’ participation gave them a sense of purpose and peace with their death [22]. Finally, in other HIV research studies, participants shed light on an unexpected benefit from their participation: increased knowledge about research [32]. NOK of Last Gift participants had a similar experience: participation as a NOK encouraged them to become more educated about living with HIV and HIV research. Serving as NOK for the Last Gift study inspired some NOK to reflect on ways they could contribute to their community and to future generations. These examples of personal growth on behalf of NOK emphasize the far-reaching and lasting impact of EOL HIV cure-related research.

Given the sensitive nature of EOL HIV cure-related research, it is important for research teams to also address the concerns and/or drawbacks of all stakeholders involved in the study. NOK participants revealed that being routinely confronted with the reminder of their loved ones’ approaching death was a source of sadness for them. Previous EOL studies have investigated the psychosocial effects of bereavement and viable mitigation strategies [33,34]. Studies have also shown that interventions such as distribution of bereavement pamphlets, professional support services, and educational palliative care interventions for families involved with the EOL can help attenuate the burden of bereavement and possibly decrease rates of depression [33–35]. Though these interventions were studied in the context of palliative care, it is still important for EOL research staff to be sensitive to NOK’s emotions and to be well-equipped to support them through the EOL process without interfering with participants’ clinical plans.

NOK in our study described potential conflicts that may arise between themselves and Last Gift participants. Previous research has shown that NOK may feel tension due to disagreements and miscommunication at the EOL [36–38]. In our study, NOK also noted feeling stressed about needing to accommodate study staff while caring for their loved one at the EOL. Having anticipated this possibility, the Last Gift research staff planned that informed consent for blood draws and rapid research autopsy would be “discussed with a next-of-kin/loved one in order to minimize concerns or conflicts during the research and at the time of death [5].” However, our discussions with NOK revealed that these interactions were not sufficient in preventing possible conflict. Thus, the Last Gift team needs to maintain diligent efforts to educate, accommodate, and involve NOK in all aspects of the study.

Oftentimes, NOK feel responsible for protecting their loved ones from pain and stress at the EOL [23,39]. In our study, while participants had provided informed consent to undergo frequent blood draws and interviews at the EOL, NOK still felt the urge to intervene when they sensed that frequent study procedures could pose a potential for discomfort, either physically due to blood draws, or emotionally due to inopportune timing of interviews. Overall, successful EOL studies require study staff to be extremely flexible and sensitive to both participants and their NOK.

Despite the potential perceived drawbacks, NOK viewed participation in an EOL HIV-cure related study as a way for participants to create further meaning in their lives by serving a higher purpose, namely participating in HIV research in hopes of helping find a cure for future generations. Altruism at the EOL has often been described similarly, as a last meaningful contribution to society [40,41]. In terms of motivation for research participation, altruism has been noted as an even greater motivator than self-gain for those at the EOL [40]. In our study, NOK expressed a sense of pride for their loved ones’ altruism. For some NOK, participants’ altruism also served as an inspiration which prompted NOK to think of ways they could also serve a higher purpose within their own means. These lessons emphasize the importance of prioritizing patient-centeredness in EOL HIV cure-related research, as research staff can ensure that participants’ altruistic wishes can be realized [42].

With regards to improving study conduct, several studies highlighted that effective communication between patients, NOK, and EOL clinical staff is critical at the EOL [43–45]. Likewise, in the research context, clear and consistent communication between NOK and study staff is key to effective and ethical implementation of EOL HIV cure-related studies. In our discussions with NOK, a perceived drawback of participating in EOL research was the potential for invasiveness. One NOK suggested that towards the participant’s EOL, it would have been helpful for study staff to consult with NOK to ensure appropriate timing of study visits. It is also known that preparing for death and funeral services are deeply important to both participants and their loved ones at the EOL [46]. Pentz et al, in their ethical considerations in EOL cancer research, reported that study staff must strive to minimize the delay of funerals and other negative effects of research with the recently dead [8]. While the Last Gift study covers cremation services for logistical purposes, the study team should still ensure the cremation process is conducted efficiently so loved ones can observe their loved ones’ death according to their plans and to reduce further distress. Additionally, our discussions with the AVRC Community Advisory Board suggested that a clear informed consent and information packet should be made available to NOK to avoid possible sources of conflict and misunderstanding. The Last Gift study staff recognize that cremation services engage with some religious traditions but not others, as such, the team will honor the wishes of the participant should they desire a traditional burial.

While our study adds to existing literature regarding psychosocial impacts of EOL research on NOK, it also emphasizes the need to better understand the challenges NOK face in the context of EOL HIV-cure related research. As such, in following ethical principles of beneficence and nonmaleficence, researchers must not only consider how to maximally reduce potential risks for NOK involvement in studies, but also how the study can serve as a positive experience [47]. A previous study demonstrated that bereavement significantly impacts the physical and mental health status of individuals who experience grief in the context of HIV-related death [48]. Another study showed that stress management interventions and social support groups not only serve to ameliorate the negative psychological impact of bereavement but also target “positive mental health and true wellness [49].” Considering previous studies on bereavement and our study results, which revealed that NOK may face increased sadness and stress when participating in EOL HIV cure-related research, we must ask the fundamental question: what considerations are needed to ensure EOL research will not exacerbate the grief NOK already face? Moving forward, we are encouraged to explore a broad range of methods to minimize the negative physical and psychological effects of EOL HIV cure-related research on NOK experiences.

We acknowledge several limitations associated with our study. First, given that six NOK responded to questions from our focus group guide, this study is limited by a small sample size at a single clinical research site. Thus, our results are not generalizable; however, the small sample size is consistent with research involving full body donations and rapid autopsies [6,8]. Given the small size of the study, we were also limited in the diversity of our sample. Most participating NOK were white and male, and as such, we were not able to study race, sex, or gender differences in perceptions; however, as more diverse NOK join, we seek to investigate these differences over time. In an effort to recruit a more diverse cohort, the Last Gift study team has recently made their website available in 10 languages. Participant and NOK brochures are now available in both English and Spanish as well. The very small sample size also limited our ability to analyze the data between NOK with Last Gift participants who were alive versus those whose participating loved ones had passed at the time of the small focus groups/interviews. Due to the small sample size, we did not achieve data saturation, and we will continue to monitor emerging themes in future research [50]. As our study grows, we will compare the perspectives and experiences of NOK at various stages of the study. Additionally, Last Gift participants had a choice of whether to refer a loved one for a small focus group. In turn, NOK had the option to decline participation in the small focus group portion of our study. Two Last Gift participants (LG02 and LG06) did not refer a NOK. Second, NOK who opted to participate in the focus group were generally more involved in the Last Gift study, giving rise to a potential for sampling bias. Therefore, results may be biased to reflect more positive or well-informed perspectives of NOK. Third, there is a potential for social desirability bias such that respondents refrained from sharing negative perspectives about the study. Fourth, our discussions posed a risk for emotional and death-related distress; therefore, our experienced focus group facilitators refrained from delving into deeply emotional topics associated with bereavement. Fifth, two research sessions had to be conducted as individual interviews due to logistical complications, but we remained flexible given the complex nature of EOL research and prioritized inclusion of as many NOK perspectives as possible; therefore, we decided to proceed with individual interviews using focus group guides.

Notwithstanding our study’s limitations, this research fostered discussions in a safe and flexible setting for NOK, thus yielding a rich source of data. Our findings may also inform other disease areas, such as EOL COVID-19-related research or EOL cancer research. We hope that our study can serve as a foundation to understanding the perspectives, experiences, and concerns of NOK in EOL HIV cure-related research and that additional literature will elaborate upon and enhance the work done in this paper.

Table 4 summarizes key themes and findings from our discussions with NOK and possible implications for future EOL HIV cure-related research.

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Table 4. Summary of findings and possible implications for future EOL HIV cure-related research studies involving NOK/loved ones (San Diego, California, 2019).

https://doi.org/10.1371/journal.pone.0250882.t004

Conclusions

In conclusion, our qualitative focus group study highlights the perspectives, experiences, and concerns of NOK involved in the Last Gift study. Progress in EOL HIV cure-related research rests on community acceptance and involvement, including participants’ loved ones. To continue accounting for the voices and concerns of NOK in a participant-centered research study, we will conduct additional focus groups in the future and provide updates on findings in the literature.

Supporting information

Acknowledgments

The authors are deeply indebted to the Last Gift study participants and their next-of-kin/loved ones. We are grateful to the UCSD AntiViral Research Center Community Advisory Board, the HIV + Aging Research Project–Palm Springs (HARP + PS) and the Palm Springs Positive Life Program.