Evaluating the psychosocial experiences of participants in HIV cure research before, during, and after analytical treatment interruptions: A longitudinal qualitative study in the United States

Abstract

The lack of socio-behavioral research on stress and psychosocial experiences among research participants who undergo analytical treatment interruption (ATI) in HIV cure studies underscores a critical gap in cure science. Existing literature acknowledges mixed and potentially adverse mental health impacts of ATIs among trial participants, but empirical insights before, during, and after clinical studies are scarce. We used longitudinal in-depth interviews with 11 participants in HIV cure-related research to explore their experiences with stress, coping, and psychological well-being before, during, and after an ATI.

Our framework analyses of participant interviews suggest an evolving interplay between person- and environment-oriented factors that shape psychosocial well-being through multiple pathways. Key emergent themes surrounding stress, coping, and psychological adaptation before the ATI encompass the stress-protective effects of pill (in)significance, curiosity in natural immunological control, and perceived support, and trust with professional help networks comprised of providers and research staff. Themes that promoted positive secondary appraisals of stressors during ATIs involved generativity and meaning-based coping, and the stress-adaptive benefits of support-seeking and actualization. Finally, a theme exposing post-ATI stress revolved around the disappointment that participants noted feeling from needing to restart their HIV medications after the ATI and accepting the permanency of HIV and medications in their lives.

Our findings emphasize the importance of building supportive and trusting relationships with research teams, and specify the stress-buffering mechanisms between emotional, informational, and appraisal support on ATI-related stress. Additionally, we outline multiple implications that advocate for the adoption of several precautionary measures in HIV cure research to mitigate psychosocial risks. By documenting the evolution of psychosocial experiences, we offer valuable insights to inform the design of future studies, ensuring their ethicality, acceptability, and inclusivity.

1. Introduction

Scientific strides toward a cure for HIV are rapidly accelerating (Deeks et al., 2021). Most HIV cure studies to date have focused on identifying biomedical mechanisms that can inform the development of a therapeutic cure. Yet, these remarkable strides raise bioethical challenges that social science disciplines are uniquely positioned to address (Dubé et al., 2019, 2021; Grossman et al., 2016; Lo and Grady, 2013). These challenges include evaluating the risks and benefits involved in complex and burdensome HIV cure studies (Dresser, 2017; Dubé et al., 2017).

Fundamentally, the ethicality of HIV cure research is tenuous because there is a questionable balance of multifaceted health and social risks to participants, compared to potential benefits (Gilbertson et al., 2019). Central to this tension is the study method of asking people with HIV who are otherwise generally healthy individuals (Dubé et al., 2018) to interrupt their HIV medication to evaluate potential biomarkers that could predict viral rebound before it occurs, or to evaluate the efficacy of a curative intervention (Julg et al., 2019). This interruption is formally called an analytical treatment interruption (ATI) and can be short (between 2 and 12 weeks and deemed relatively safe) or extended (3 months or longer). During ATIs, participants experience greater than minimal risk when it comes to a potential HIV drug resistance, heightened HIV transmission, and an increased HIV reservoir since the participant is likely to experience sustained viremia and temporarily lose the immunological benefits of ART. Some data suggest that people with HIV may receive psychological benefits from participating in HIV cure research due to reduced social isolation and the ability to learn about cutting-edge HIV research (Bilger et al., 2023; Dubé et al., 2017; Dubé et al., 2024a,b; Henderson et al., 2018; Neergaard et al., 2022). Yet, concerns regarding ATI studies remain a priority and are detailed in informed consent forms and in other published literature (Henderson, 2015; Henderson et al., 2018). Psychosocial concerns are particularly important and include increased anxiety and stress among participants who may for the first time in decades become virally unsuppressed (Bilger et al., 2023; Dubé et al., 2024a,b; Villa, 2023); the risk of HIV transmission to sex partners without HIV (Dubé et al., 2023; Dubé et al., 2024a,b; M. J. Peluso et al., 2020); the stress or anxiety stemming from experiencing the ill health effects of viremia (high viral load and replication within the body) and fear of developing resistance to HIV medications (Bilger et al., 2023; Dubé et al., 2018a,b; Dubé et al., 2024a,b). Relatedly, biomedical investigators may underestimate the psychological impacts of ATIs on participants (De Scheerder et al., 2021), as one study examining perceptions of ATIs among clinician-researchers, policymakers, bioethicists, and people with HIV found that many clinician-researchers expressed liberal opinions about ATI-related risks while people with HIV held more conservative opinions (Dubé et al., 2017). Further, if people with HIV perceived ATIs as too risky, they may not be willing to participate in HIV cure studies given the clear effectiveness of modern HIV treatment as well as its preventive benefits (e.g., Undetectable = Untransmittable, or U=U) (Dubé et al., 2017).

To date, what we know about perceptions of ATIs primarily comes from studies that are short-term, cross-sectional, and retrospective. While psychosocial concerns of ATI trial participants before, during, and after their ATIs have been explored in former research, they have yet to be documented in real-time, and fully guided by theory (Bilger et al., 2023; De Scheerder et al., 2021). The present study fills a gap by describing the (a) occurrence and (b) evolution of stress and psychosocial outcomes among participants longitudinally by conducting interviews before, during, and after their ATIs.

We used the transactional model of stress and coping to ground our analysis and interpretation. While multiple definitions of stress are noted in the literature, we use a common one that defines it as a person’s physical or psychological response to internal or external demands (defined as stressors) that disrupt homeostasis, leading to restlessness, worry, and other indicators of compromised health (Glanz and Schwartz, 2008; Manosso et al., 2022). The transactional model of stress and coping explains how perceptions and reactions to stressors – such as ATIs – affect an individual’s psychological well-being and behaviors in the context of a dynamic interaction between them and their environments (Glanz and Schwartz, 2008). According to the model, responses to stressors (e.g., worrying about being viremic) can significantly affect psychological adaptation (e.g. emotional well-being) through pathways that are mediated by coping effort and moderated by social support. The evidence strongly suggests that social support, defined by the resources (e.g. instrumental vs. emotional) that participants receive from others, will be especially impactful in removing stress and/or promoting stress management throughout ATIs (Cohen and McKay, 2020; Glanz and Schwartz, 2008; House, 1981; Thoits, 1986). Using this model, we documented (1) participants’ appraisal (primary and secondary) of a given stressor (e.g., ATI) as good/non-threatening, bad/threatening, or neutral and (2) the social support (e.g., from clinical study teams) participants had available to them. Our overall objective was to explain how individual factors and forms of environmental support interact to affect stress and psychological outcomes among participants.

2. Methods

2.1. Study setting and participants

Participants in a large parent study [study name redacted] were recruited for this qualitative study. All participants were co-enrolled in the observational cohort – a longitudinal study following over 2,000 people with HIV, some for as long as 20 years. Participants who agreed to join this ATI study provided separate informed consent before completing interviews. Our study took place between 2020 and 2024.

The parent study was designed to interrupt ART in a highly monitored setting. The goal was to identify biomarkers of viral control and to characterize proteins and nucleic acids associated with viral rebound. Frequent viral load monitoring (i.e., three times per week) allowed rapid re-initiation of ART upon confirmation of detectable values above 200 copies/mL. Some participants known as “pre-ART viral controllers,” with documented low or undetectable HIV viral loads before ART initiation had an option to extend their ATI. All participants would resume ART for 1) confirmed CD4⁺ T-cell counts below 350 cells/uL, 2) symptoms consistent with acute retroviral syndrome (ARS), or 3) a request from the participant or their clinician.

Eligibility criteria for the parent study [study name redacted] included those 18 years or older who were able to provide informed consent, with ART-suppression for at least 12 months (excluding long-acting regimens), a CD4⁺ T-cell count >350 cells/uL, and without significant pre-existing physical or mental health disorders. Participants were assessed rigorously for existing mental health illness by the physicians on the parent study team. Additionally, participants agreed to HIV transmission risk counseling before and during the ATI (Dubé et al., 2018). Interested and eligible participants were invited to a series of up to three in-depth interviews (IDIs) via videoconference or phone. Participants received $50 per interview as compensation for their time.

2.2. Procedures and data collection

The [name of institution redacted] Institutional Review Board approved the study and use of verbal consent. All interviews were conducted by one of the principal investigators. Three interviews – before, during, and after the ATI – lasted between 30 and 60 min and followed a uniform structure of open-ended questions, in the following domains: personal background, knowledge factors, decision-making factors, psychosocial and partner factors, among others. In the present analysis, we focus on the psychosocial domain, that is, the positive and negative feelings at the time of the interview about the ATI, as well as changes (if any before and after). Questions were modified to reflect the interview phase (pre-ATI, during, and after). Interviews were audio-recorded, professionally transcribed, and de-identified. De-identified transcripts were stored, managed, and analyzed through Dedoose (2023). The interview guides can be made available upon request from the corresponding authors. In this manuscript, we report data from 11 interviews before ATIs, 8 interviews during ATIs, and 5 interviews after ATIs. In total, we gathered 25 data points from participants over the course of the study, distributed as follows: 6 participants provided 3 data points each, 8 participants provided 2 data points each, and 11 participants provided 1 data point each.

2.3. Data analysis

Our analytic approach followed standard framework analysis guidance, which consists of four stages: data familiarization (reading the transcripts), indexing (applying and finalizing the codebook), charting (visually summarizing themes), and data synthesis (Goldsmith, 2021; Ritchie and Spencer, 1994). Framework analysis was designed for applied health and large-scale policy research, and for answering research questions over a brief, discrete period. This allows for both inductive reasoning, as themes emerge naturally from participant experiences, and a deductive approach, as a priori codes were applied to the data.

We developed initial codebooks a priori, based on the transactional model of stress and coping and related questions surrounding stress, coping, and psychosocial well-being in each interview guide (before, during, and post-ATI). Biweekly all-team discussions served to promote rigor, consistency, and accountability among team members involved in data collection and analysis. These meetings included the study principal investigators, coders, and code reviewers. During all-team meetings, members debriefed on study insights, clarified codes, and discussed observations. Based on these discussions, codebooks were reviewed, refined, and then applied to the transcripts by coders and coding reviewers. These all-team discussions also led to the development of additional codes inductively, that captured emerging themes in the data. Coders who participated in the all-team meetings held additional weekly regular peer check-ins while reviewing the data to ensure alignment in code categorization. Reviewers who were paired one-on-one with the coders, also reviewed newly coded transcripts and met at the end of each week as a group, and one-on-one to debrief and troubleshoot coding nuances or issues. Coder-reviewer pairs were interchanged throughout to avoid stylistic biasing. Any arising questions or disagreements were reconciled through impromptu meetings with coders, code reviewers, and the principal investigator who conducted the interviews.

We created thematic summaries of each transcript after coding the data. We utilized these summaries to populate a combined data matrix, which mapped the coded text against each domain, for each of the three interviews. This information was used to synthesize the findings into thematic outlines, organized chronologically. Additionally, we pulled illustrative quotes per domain for each of the three interview time points (before, during, and post-ATI).

2.4. Ethics statement

The [name of institution redacted] IRB reviewed and approved the parent study [name of parent study redacted], the sub-study, and the socio-behavioral research component.

3. Results

3.1. Participant demographics

Of the eleven participants interviewed, all but one identified as men and were male at birth. Participants had been living with HIV for an average of 21.2 years (SD = 9.9, range = 6.1–36.9). Seven were White/Caucasian, one was Black/African American, one was of mixed race and two were Latina/o/x (two participants declined to provide race/ethnicity data). Four participants were aged 51–60 years, three were aged 41–50 years, two were aged 30–40 years, one was in their 60s and one was in their 70s. The median age was 56 years old (ranging from 32 to 75). Participant demographic characteristics are shown in Table 1.

Table 1.

Demographic characteristics of participants.

Characteristic		N (11)
Gender
	Woman	1
	Man	10
Sex assigned at birth
	Female	1
	Male	10
Ethnicity
	Hispanic or Latina/o/x	2
	Not Hispanic or Latina/o/x	7
Race
	Black/African American	1
	White/Caucasian	7
	Mixed/Other	1
Education level
	Some high school, but no diploma	0
	High school diploma or GED	2
	Some college, but no diploma	4
	College degree (Bachelors)	0
	Graduate degree or higher	4
Relationship status
	Single	4
	Married	2
	Divorced	1
	Widowed	2
	Domestic Partnership	1
	Other	1
Age
	30 to 40	2
	41 to 50	3
	51 to 60	4
	61 to 70	1
	71 to 80	1
Household income (annual)
	Less than $25,000	4
	$25,000 - $50,000	0
	$50,001 - $75,000	1
	$75,001 - $100,000	4
	More than $100,000	2

3.1.1. Before the ATI: initial stress, anticipated stress, and the primary appraisal of the psychosocial ATI experience

Fig. 1 shows the transactional model of stress and coping for this sample of research participants before, during, and after ATIs. Participants expressed low levels of initial stress or anxiety in anticipation of study activities and the ATI. Narratives related to their feelings surrounding HIV cure research participation were saturated with expressions of optimism and excitement. When asked about the perceived health risks of being off of medications, one-third of participants self-identified or provided subjective accounts of being identified by health professionals as “controllers” or “non-progressors” – terms used to describe people with HIV who can maintain an undetectable viral load or CD4⁺ T cell counts for an extended period, without ART. The other two-thirds of participants did not express self-identifying or having been formally identified by a health professional as controllers. Controllers and non-controllers expressed similar levels of confidence that their bodies would be able to quickly recover from the ATI. We did not detect stark contrasts between the psychosocial experiences of controllers versus non-controllers before the ATI study. The main subthemes attached to low stress and positive emotions revolved around pill (in)significance, curiosity in natural immunological control, and high perceived environmental support due to rapport and trust within established personal and clinical staff relationships. These factors synergistically reinforced one another to contribute to the development of positive perceptions regarding HIV cure research participation.

Fig. 1.

Transactional model of stress and coping for HIV cure research participants before, during, and after an antiretroviral treatment interruption.

3.1.1.1. Pill (in)significance: neutral and positive expectancies associated with ATIs.

Emotions surrounding the ATI varied from neutral to eager. Many explained that they were taking medications for multiple health conditions and noted that removing ART from their regimen would have a negligible or positive impact on their overall health. For example, when asked about perceived risks associated with stopping treatment, one participant replied:

I’m not worried about it … I’m not even half worried about it … what I’d like to see in the months that I’m off of it are my kidney functions to get better … After you [I] stop taking the antiretrovirals … I’ll be able to see if my kidneys are recovering. And so, I’m very excited about seeing that. But as far as the pills that I take, I don’t have any trauma around taking pills

– Participant 1, Controller

Other participants also expressed optimism about the opportunity to “recover” from perceived medication toxicity during what they described as a temporary break. Their views on potential medication toxicity mitigated stress around the potential health-adverse risks of the ATI. The following participant described how he developed health conditions, including high cholesterol, diabetes, and hypertension since being diagnosed with HIV and how he believed that giving his body “a little vacation” could lead to overall health improvements:

Before I started the medications, I didn’t have cholesterol. I didn’t have … diabetes. So, I imagine that those … effects [are] a result of the medication that you take … by resting a little, you let the organs of your body have a little vacation type of thing to catch up with whatever they do. So, even if there is a chance that my viral load can be detectable, I don’t think it will be big numbers or a big issue to compromise my entire health. It’s just a little something temporary … I feel … very confident. I’m actually even glad. Because my own feeling is that most of the medications that you take are a little too toxic.

– Participant 2, Controller

3.1.1.2. Curiosity in natural immunological control.

Participants’ curiosity about their body’s natural immunological response to HIV intertwined with positive expectations around pausing ART to explain low initial and anticipated stress. This curiosity was also rooted in narratives about their history of sustaining a low viral load (in some participants), despite intermittent periods of voluntary ART interruptions in the past.

In the narrative below, a participant who had joined multiple research studies described how fascination with seeing how his body would react to being off of ART overruled fear-induced distress about the ATI:

I’m fascinated by this whole subject [HIV cure research]. I want to – there’s a scientist up here, going, “I’m curious what will happen.” So, I have more of a curiosity than a fear.

– Participant 3, Non-controller

The act of seeking and obtaining information about ART also pre-emptively lowered participants’ perceptions of being vulnerable to health-adverse outcomes. Most participants had been living with HIV for decades and stayed current with information on the evolving science of ART over time. One participant explained how his HIV “controller” identity and information-seeking about ART attenuated the worry about the ATI:

[K]nowing myself and the way I have taken medications and all that, I don’t think it will be too much of a problem or a big change of my regular numbers … nowadays, with proper management and care and a matching prescription … you can live a long time. But since I also have these properties in my DNA, I can afford to go off the meds.

– Participant 2, Controller

3.1.1.3. Perceived support, trust, and rapport with a research and provider network.

Perceptions of strong social support from the clinical team mitigated initial and anticipated distress while promoting positive emotions surrounding personal and research-related outcomes. When discussing the risks associated with ATIs, participants often mentioned how certain aspects of their existing relationships with study staff constituted a psychological safety net. Other support resources, including logistical or instrumental support, in the form of financial incentives, appointment scheduling, and transportation to site visits facilitated confidence and eased concerns about health risks. When asked whether he had any concerns about the study, a participant replied:

No … overall … I liked the way the study was designed. I thought it was very well crafted, compared to other studies, again, because of the built-in transportation. And obviously, there’s a lot of observation and care.

– Participant 3, Non-controller

Given their history of research participation in the parent cohort, at baseline, participants already had existing trusting relationships with the investigative team. Participants characterized the researchers and the clinicians together as a collective source of support. They described being socially integrated within a care network consisting of various health providers (e.g. pharmacists, physicians) along with the research staff. Participants frequently mentioned how the close clinical monitoring, as required by the study protocol, reduced distress concerning potential worst-case scenarios, in which their CD4⁺ count would decrease as their viral load would increase substantially. When asked to describe his feelings about seeing his viral numbers go up, a participant talked about how informational support about health scenarios and consistent supervision from the research team allowed him to embrace possible undesired outcomes of the ATI:

[T]hey [the clinical staff] are always monitoring your health, and the reactions, and the symptoms. So, I don’t [think] there will be anything bad happening to me, like any major reaction in this study. I think the only [thing] will be that my viral loads will become detectable, or my T cells might go down. So, that’s the possibilities. And I don’t think it’s as much as I put myself many years ago when I actually stopped medications for almost a year, which my T cells and my viral load went down. So, this one is controlled. Very controlled study, so I feel even much better about it.

– Participant 2, Controller

Another participant elaborated on how her existing support network of health professionals and the ones provided by the research team allowed her to mentally adjust to not taking ART after many years of adherence. She anticipated that continued support throughout the ATI would minimize distress. When asked whether she had any stress about the upcoming ATI, she replied:

I’m putting it in that little box of, you know, a medication vacation. I have my pharmacist, my doctor, and you guys all there ready … If anything happens, I know I’m in the best hands.

– Participant 4, Non-controller

Altogether, the rapport and closeness of the patient-provider and research relationships promoted open dialogue about the risks and information-seeking within an established professional health network. A participant who was initially worried about experiencing adverse health effects due to viral resistance discussed how seeking information about the study, medication, and consulting with their physician alleviated initial stress about the ATI:

I was worried about the viral resistance and creating viral loads. That one spooked me a little bit. And originally, I was going to say, “No” to it. But then, I did some research around, again, the medication, Biktarvy. And this one, I did literally consult with my private doctor, saying, Here’s a copy of the study. What do you know about it? What do you think about it? And they were like, It should be just fine. Go for it. And I know you’re closely monitored. Hence the three times a week blood draws and stuff like that.

– Participant 5, Non-controller

3.1.2. During the ATI: coping and resilience resources for regulating distress and facilitating re-appraisal

Distress due to varied life and cure-related stressors began to appear in interviews conducted during the ATI. Participants discussed the unease they felt about seeing their viral load increase and CD4⁺ T cell count decrease. Aside from one participant, most did not report feeling noticeable symptoms or ill side effects from changes in their viral load. However, multiple participants described experiencing discomfort in procedures, such as blood draws, conducted during the ATI.

Participants also identified personal challenges (e.g. break-up in a relationship, substance use relapse) and public health threats from SARS-CoV-2 and Mpox as sources of environmental distress. Nonetheless, participants maintained a curious and optimistic outlook on their health and the study, despite the co-occurrence of worry and anxiousness stemming from stressors. Meaning-based coping and generativity (see below), support-seeking, and actualization were key subthemes interwoven into narratives on sustained positive psychology amid distress.

3.1.2.1. Generativity and meaning-based coping.

Generativity, defined as the desire to make a meaningful contribution to society (Bower et al., 2021; Emlet and Harris, 2020; Villar et al., 2023), was frequently communicated by participants, who described how they felt a sense of connection with people during the 1980s HIV epidemic, and also future generations of people with HIV who could benefit from science. During the ATIs, this desire drove meaning-based coping (defined by emotional regulation strategies used to interpret stressful situations in a personally meaningful way (Glanz and Schwartz, 2008). For example, when asked about his experience during the ATI, a participant who experienced mild flu-like symptoms from viral load changes framed his continued participation as a benefit due to his ability to contribute to a greater cause:

I think I got some direct benefit … by understanding my own body and how it controls it [HIV] and the level of control that I have on it [HIV]. And … the gratification that I’m contributing to a greater global … cause.

– Participant 5, Controller

Participants’ sense of identity, as long-term survivors of the HIV epidemic, cure research advocates – through a history of participation in multiple studies, and for many, “controllers,” fostered generativity and meaning-based coping in response to stressors. For example, when describing how lending his body to a greater cause enabled resilience in coping with physical pain from multiple voluntary invasive research procedures, a participant said:

[T]he study procedures itself – was [were] a lot. And … physically, my arm was sore and stuff, so – I was, kind of like, with myself, ‘I don’t think I’ll ever do another study with leukapheresis, and frequent lab draws.’ It was just a lot. I’ve done three leukapheresis now and I think I’m kind of done … for my lifetime of giving up my white cells for somebody else.

– Participant 6, Controller

3.1.2.2. The stress-adaptive benefits of support-seeking and actualization.

Existing rapport with the study investigators deepened as researchers provided reassurance in response to mental distress triggered by increases in viral loads. This rapport was reinforced by the high level of access participants perceived to have to the study team during the ATI, as evidenced by familiar and frequent interactions with viral load monitoring. Participants specified how multiple forms of social support, including instrumental, informational, appraisal, and emotional resources, facilitated adaptation to both study- and non-study-related stressors. While some participants emphasized the importance of instrumental support, as demonstrated by the financial compensation for their time and participation in the study, and the provision of transportation via ride-sharing apps, all highlighted the critical importance of informational, appraisal, and emotional support during the ATI.

Specifically, informational and appraisal support offered by research staff assisted with positive re-appraisals of distressing events. For example, one participant found themselves worried about their health at the start of their ATI. They were quickly met with close and continued check-ins with the clinical staff that seemingly alleviated the feelings of worry.

You know, I’m not going to lie. Initially, when I stopped taking the medication, I did think, oh, my gosh, I’m immediately going to get sick, and it was a fleeting moment, honestly. And what really helped calm my nerves, if there was such a thing, at the time was the fact that there’s a three-day check-in and the fact that my blood is being drawn and double-checked every single time and the fact that [staff member X] was following up. So the people who are involved in the study who assisted me through this process made it easy. And so if I had any fears at all, they were immediately squashed.

– Participant 11, Non-controller

Overall, participants felt extremely cared for by the research staff, and considered them to be a “second, surrogate family,” given the consistent receipt of emotional support. This was aptly communicated by the following participant who talked about how having complete trust in the team, diminished fear or worry about adverse biomedical reactions:

I don’t fear that drug interactions or my HIV will be harder to treat. It’s just not even part of my mind. I’ve been with [the] SCOPE [cohort] for so long that I have absolute, complete, full, and total trust with all of the researchers. They’re like a surrogate, second family. And besides the fact that they’re totally and completely professional, and very, very careful with all research participants.

– Participant 8, Controller

A crucial component of emotional support offered by the research staff was the participants’ evaluation and recognition of this support as authentic. Participants noted that staff reinforced and emphasized their rights to withdraw from the study and resume ART in moments of distress or discomfort. Importantly, participants perceived these assurances as genuine demonstrations of care. One participant elaborated on how the staff’s consistent reinforcement of informed consent throughout the ATI supported autonomy, relieving self-inflicted pressure to continue participating, while simultaneously promoting trust. When asked to describe the beneficial aspects of continuing the study, he replied:

It’s who the [research study name redacted for de-identification] people are. And you sign the consent papers, and the consent papers say, ‘Do not do this if you feel you’re being pressured to at all. You can do this at your own pace. You can drop out at any time.’ They have all of the legal language that says exactly the same thing that [staff member X] will say when … talking to you about a study. But [staff member X] has a tone of voice and an expression on [their] face that says, ‘You’re more important than this study.’

– Participant 8, Controller

3.1.3. After the ATI: reflecting and reckoning with study revelations

When describing psychosocial experiences after the ATI, participants reflected on the exceptional support that they received throughout the ATI. Many left the study feeling a strong sense of accomplishment from contributing to HIV cure research. They reflected on how the above factors combined to buffer the impacts of stress on their mental health and allowed them to overcome difficulties encountered. However, participants described experiencing a mixture of positive and negative emotions related to life readjustment after the ATI. While on one hand, they were comforted by having clarity about how their bodies would react to being off of ART, emotional self-assessments after the ATI were generally less optimistic compared to before and during the ATI. A consistent theme noted the erosion of optimism among participants given disappointment about the permanency of HIV, viral load management, and ART in their lives. This was slightly pronounced among participants who were “controllers.”

3.1.3.1. Viral load management and ART permanency disappointment.

While many participants were curious to see how their bodies would react to pausing ART, many were disappointed about not maintaining an undetectable viral load. Summarizing his feelings after the ATI, a participant provided a bittersweet reflection about accepting the harsh reality that he would need to restart medication. He said:

I learned that unfortunately, my body is not tolerant to being off medication. And if there’s one thing that I’m bummed about, it would be that. Yeah, that’s the one big thing I learned. I learned that, for better or worse, until I’m still on this planet, I’m going to have to continue taking medication. But it doesn’t bother me because, like I said, I’ve incorporated it into my everyday life. And it’s just part of my life.

– Participant 7, Non-controller

Participants also linked their disappointment to the undesired existence of HIV, which was tied to their identities and/or ability to transmit the virus. One participant talked about how restarting ART affirmed that he had HIV:

I just felt like once I went on meds, that was it. I’d be on meds for the rest of my life. And that was hard … I guess a part of me felt like I wasn’t really HIV positive if I didn’t go on meds.

– Participant 9, Non-controller

Similarly, when describing how it felt to resume ART, another participant clarified the personal significance of medications:

It’s not taking the meds. It’s the fact that the virus is present. I don’t identify with taking the meds. I identify with the fact that it’s there somewhere. If it were eradicated from my body …, it would change my perspective. But in the 40 years I’ve been alive with this, it’s never happened. So, I know it’s there somewhere.

– Participant 10, Non-controller

In essence, post-ATI distress and disappointment were rooted in accepting the fact that participants still had the virus in their bodies which confirmed their HIV status, instead of the act of restarting their ART regimens.

4. Discussion

Leveraging theory on stress and coping, our findings suggest that personal and environmental factors interacted to influence the psychosocial experiences among HIV cure research participants. The results, along with those from prior similar research (Bilger et al., 2023; De Scheerder et al., 2021; Dubé et al., 2024a,b; Henderson et al., 2018), showed that psychosocial experiences of interrupting HIV treatment evoked a mixture of positive, neutral, and negative emotions. Additionally, stress was mitigated by the frequent health monitoring standard in these types of studies, as well as from the existing rapport between research staff and participants, and personal satisfaction in HIV cure research.

Over the course of the ATI, emotions ranged from anxious to hopeful, excited, curious, grateful, and disappointed. Retrospective qualitative data of participant experiences with ATIs in Philadelphia found that some reported positive emotions and others reported negative emotions toward the ATIs (Bilger et al., 2023). However, contrary to the aforementioned research (Fredrickson, 2001), we did not observe a strict nor clear dichotomy of positive versus negative emotions. Instead, emotions evolved as the ATI unraveled. Many participants began hopeful and intrigued by the process and ultimately found themselves disappointed at the permanency of living with HIV. Nevertheless, participants found consolation in the hope that future generations would experience a cure. The fluctuating emotions and salience of positive psychology witnessed in participants throughout their ATIs correspond with Fredrickson’s broaden-and-build theory, which describes emotions as dynamic and fluid psychological phenomena that can be overpowered by positive emotions rather than fixed states (Fredrickson, 2001). To date, empirical data describing participants’ emotions have been limited to shorter interruptions and may reflect momentary and fleeting reactions to events that happened in the past, rather than an overarching characterization of psychological states showing how dynamic the ATI experience is. The data showing mixed and predominantly positive emotions over an extended period emphasize the importance of broadening ethical considerations of stressors among participants that are inclusive of other exigent life circumstances that might emerge during a clinical trial that uses an ATI (Bilger et al., 2023; M. Peluso et al., 2022; Peluso et al., 2021a,b).

Participants’ initial optimism regarding their ATI was partially explained by their acceptance or prior use of pill holidays, which are temporary self-driven and unmonitored breaks from daily oral pills. While people with HIV may have had a pill holiday, researchers should exercise care in distinguishing ATIs (used in the context of research) from pill holidays, given the potential to transmit HIV when off ART, which is a personal and public health risk. Specifically, care must be taken to define and contextualize ATIs as temporary ART breaks that occur within the context of close clinical monitoring and research. The odds of disappointment and stress due to restarting ART may likely be lowered by situating participants’ expectations for long-term ART-free viral suppression by informing them about participant outcomes from the HIV cure literature.

The uniqueness of the study was that participants were stratified by controller and non-controller status. While controllers and non-controllers initially expressed similarly low levels of stress about the potential health adverse impacts of ATIs, we found some differences in stress about living with HIV and restarting ART between them. We may speculate that slightly higher stress and disappointment expressed by non-controllers may be due to the occurrence and risk of identity threat. Identity threat may stem from a desire to prove that one is exceptional in controlling the virus without medication, nullifying HIV status and stigmatization (Brandscome et al., 1999). Regarding identity threat, the transactional model of stress and coping details how the primary appraisal of a stressor may involve a personal assessment of self-concept threats (Lazarus and Folkman, 1984). It is possible that low stress among controllers was attached to a positive self-concept, which is tied to a special ability to control HIV without ART that buffers against any stigmatizing attributes attached to their status.

Nevertheless, the predominance of positive psychology in our data is promising given participants’ exposure to multiple stressors, as HIV is one of the clearest microcosms of intersecting social and structural inequities. Participants had unique person-environment interactions that tended to safeguard against stressors, empowering their appraisals of stressors as manageable. Using the concept of generativity, i.e., concern for others and not just the self, participants showed a person-oriented trait that has been identified as a source of psychological well-being among people with HIV (Bower et al., 2021; Emlet and Harris, 2020). It may also be viewed as an expansive form of altruism (Dubé et al., 2020) – which in the context of HIV cure research, has taken on a motivational definition regarding advancing the welfare of others (e.g. younger generations) by contributing to research (Bilger et al., 2023; Pfattheicher et al., 2022). Participants exemplified generativity inclusive of exchanging time and services to help others who helped them and pioneering through challenges of long-term HIV survivorship through research participation (Emlet and Harris, 2020). While the conceptual differences between altruism and generativity may be minor, the implication may be of great importance to research ethics. Altruistic motivations can lead people to engage in behaviors that prioritize the welfare of others over personal well-being (Pfattheicher et al., 2022). Such motivations can become problematic within the context of ATIs if feelings of obligation compel participants to continue engaging in research despite insurmountable distress, which is concealed by researchers’ positive acceptance of participants’ strong will and determination to endure challenges. This person-oriented phenomenon may, in turn, present an ethical challenge if resilience ultimately becomes psychologically costly due to disappointment and feelings of failure associated with viral rebound (Bilger et al., 2023; Dubé et al., 2024a,b). While intermittent “informed consent check-ins” from the trial staff may have lowered such risks (Sauceda et al., 2020), researchers and informed consent processes must ensure that participants’ motivations to participate are present despite the uncertainty in study outcomes – distinct from risk (Dubé et al., 2017; Henderson, 2015; Sauceda et al., 2020).

Another major finding we replicate is the importance of trusting relationships with HIV cure staff (Bilger et al., 2023; Dubé et al., 2024a, b; Gilbertson et al., 2019). The provider support system in this ATI study was a unique defining aspect of the positive psychosocial experiences. These data emphasize the importance of quality support as a mediating mechanism between support resources including effective communication, financial compensation, emotional support, transportation, and information about HIV (Barr and Jefferys, 2020; Dubé et al., 2022a; Dubé et al., 2022b; Gilbertson et al., 2019; Villa, 2023). The consistent and reassuring rapport that communicates genuine concern for participants’ autonomy should be highlighted as a best practice for future research teams.

4.1. Implications of study findings for future HIV cure research

Our findings suggest strengthening participant education and support through formalized informed consent procedures surrounding personal hopes and expectations of achieving a “cure” prognosis after an ATI. Higher hopes and expectations of long-term ART-free viral suppression – particularly among non-controllers – must be carefully assessed and managed through messaging and support regarding the restart of ART before, during, and after an ATI. Our results also suggest that mental health screening and monitoring may be a feasible, low-cost strategy to mitigate any undue harm or stress associated with these trials. The support system provided to participants in this ATI study was unique. Therefore, investigative teams should evaluate the climate of their setting and staff to ensure that systems are in place to provide quality emotional and instrumental support to research participants, as this was a main buffering factor against the stress of ATIs. Alternatively, research teams could bring on a counselor to develop and integrate a formalized plan for mental health and informed consent into longitudinal study protocols. Before ATIs, the counselor could lead psychological preparation efforts focused on informing participants of potential study-related stressors and assessing external stressors. During the ATIs, they could implement intermittent environmental scans and mental health checks geared towards evaluating emergent stressors and social support needs. Finally, post-ATI counseling procedures could further assess stress responses and promote adaptive coping.

4.1.1. Limitations

We acknowledge limitations associated with the study design, research sample characteristics, and assumptions. While qualitative research is focused on achieving depth of insights versus breadth and generalizability (Creswell, 2014), we acknowledge that our sample size decreased over the observed period and may have affected our observations of psychosocial experiences during and after ATIs. Although timing issues and scheduling conflicts were the main challenges that led to sample size reductions over time, we acknowledge the limitations of retention and our results. We also did not formally pilot-test our interview guides with potential participants nor verify our results with participants as ways to minimize bias, but the overall study aims were built in collaboration with our community representatives. The demographic composition of this study sample is generally reflective of the racial and ethnic composition of HIV cure trials in the United States (Barr and Jefferys, 2020), which largely consists of older white males. Consequently, our observations are highly representative of the psychosocial experiences of a specific subset of people with HIV and will likely contrast with the experiences and needs of groups facing HIV inequities not represented in HIV cure research (Campbell et al., 2022; Dubé et al., 2022a; Dubé et al., 2022b).

5. Conclusion

Our study findings shed light on research participants’ psychosocial experiences over the course of undergoing an ATI as part of an HIV cure-related study. Our data have clear implications for ensuring the psychosocial safety and well-being of participants being asked to pause life-saving treatment for science. We found that participants experience a range of stressors that can be navigated through trusting relationships with providers and clinical staff that offer access to tailored support.

Data availability

The authors do not have permission to share data.