HIV Cure Research

Abstract

Despite doing well on antiretroviral therapy, many people living with HIV have expressed a willingness to accept substantial risks for an HIV cure. To date, few studies have assessed the specific quantitative maximal risk that future participants might take; probed whether, according to future participants, the risk can be offset by the benefits; and examined whether taking substantial risk is a reasonable decision. In this qualitative study, we interviewed 22 people living with HIV and used standard gamble methodology to assess the maximum chance of death a person would risk for an HIV cure. We probed participants’ reasoning behind their risk-taking responses. Conventional inductive content analysis was used to categorize key themes regarding decision-making. We found that some people would be willing to risk even death for an HIV cure, and some of their reasons were plausible and went far beyond the health-related utility of an HIV cure. We contend that people’s expressed willingness to take substantial risk for an HIV cure should not be dismissed out of hand.

People with HIV can expect a nearly normal life span and a high quality of life with antiretroviral therapy (ART).¹ Some people living with HIV have nevertheless expressed a willingness to accept substantial risks from research interventions being tested that might cure HIV even though these individuals would be unlikely to benefit from the interventions.² This expressed willingness raises an ethical question: what kind of research risks should researchers and clinicians allow people living with HIV to undertake in order to either achieve a cure or contribute to research aimed at developing one?

Some people might think the ethical question is easily answered, concluding that the decision to receive a research intervention should be the autonomous right of the individual, as long as they understand the risks and benefits and accept or reject them freely, without undue influence. But what does it mean to understand the risks and benefits of interventions? In a previous study, we surveyed people living with HIV and asked them to state the highest risk of death they would accept to be cured of it. This risk question derives from a common way economists measure the health-related utility of illness or disability and freedom from those states—the standard gamble method.³ In that study, expressed willingness to risk death varied widely across people living with HIV, with some expressing an unwillingness to risk even a 1% chance of death and others indicating that they would accept risks greater than even 70%, 80%, or 90%.⁴ One question raised by this methodology is whether people’s stated risk preferences reflect their actual attitudes or instead result from their misunderstanding of probabilities.⁵

To address ethical concerns about HIV cure trials, we need to understand potential participants’ beliefs and values related to the risks and benefits of potential HIV cure interventions. Some ethicists have raised the question of whether participating in HIV cure trials is a bad gamble for people living with HIV because the risks of participation are not outweighed by the benefits.⁶ But the risk-benefit ratio could depend on what people living with HIV value about seeking a cure. For example, one study performed in Thailand found that participants in HIV cure research were motivated by giving back to their community and by the potential benefits not only to themselves but also to the investigators and others with HIV.⁷ Additional studies have found similar other-oriented motivations.⁸

People’s willingness to take risk for an HIV cure also goes beyond the clinical or health benefit, and the fact that people living with HIV are often quite healthy does not preclude the possibility that a cure would significantly improve their overall quality of life.⁹ The value of a cure may lie in quality-of-life factors such as destigmatization, liberation from concerns of transmitting HIV to others, and freedom from the burden of daily medication.¹⁰ The risk-benefit analysis of a participant must be viewed in the larger context of the individual’s life experiences, rather than be dismissed as irrational or unrealistic.¹¹

Can the risk be offset by the personal and societal benefits of an HIV cure, and can one argue that taking substantial risk (even near-certain death) is a reasonable decision? In our study, we presented hypothetical scenarios about HIV cure research to people living with HIV and asked them about the risk of death they might be willing to take if recruited to enroll in these types of studies.

STUDY METHODS AND OVERALL FINDINGS

We conducted 22 semistructured interviews with people living with HIV. Using standard gamble methodology to assess cure utility, we asked them what risk of death they would take for an HIV cure and why.¹² The respondents were 16 men and 6 women, ranging in age from 33 to 61, with an average age of 49; 14 were African American, and eight were Caucasian. Respondents had been HIV positive for six months to 27 years at the time they were interviewed. Study staff members performed interviews to probe the rationales behind responses, which could not be elucidated using surveys or other quantitative methods.

The interviews took place between May and November 2016, with a convenience sample of people living with HIV in North Carolina and Washington, D.C. We recruited individuals in North Carolina from a community organization for people living with HIV and individuals in the Washington, D.C., area by distributing a recruitment flyer at a community HIV clinic. All interviews were conducted in English in a private setting. Interviews were audio recorded and transcribed, with personal information deidentified during the transcription process to protect participant identities.

To assess individuals’ willingness to assume research risks for an HIV cure, we asked them to imagine the following scenario: “Medical experts have developed what they believe is a promising treatment, but they need to conduct a research trial to test it. The trial is risky. Some people will die as a side effect; the rest will be cured of HIV.” We used this hypothetical research scenario for the first 10 interviews. For the subsequent 12 interviews, we reframed the scenario to better understand respondents’ willingness to accept risk for an HIV cure, apart from their feelings toward research per se. Reframed, the scenario was as follows: “Medical experts have developed a successful treatment, but the new treatment is risky. Some people who receive the treatment will die because of a fatal side effect; the rest will be cured of HIV.” Some participants who received this latter framing still seemed to assume a research trial context in their answers.

We then asked all respondents two risk questions and used pictographs to assist in risk comprehension: “If there was a 1 in 100 chance you would die by taking this HIV treatment and a 99 in 100 chance you would survive and be cured of HIV, would you take this treatment?” and “If there was a 99 in 100 chance you would die by taking this HIV treatment and a 1 in 100 chance you would survive and be cured of HIV, would you take this treatment?” These two questions were designed to familiarize respondents with the standard gamble question—the extreme values help people recognize whether their risk tolerance lies between 1% and 99% or, instead, on one of those extremes.¹³ Finally, we assessed the maximal risk they would take, asking, “If asked to take a treatment that included a chance of causing death, what is the largest chance of death (0–100 out of 100) you would accept in order to be cured of HIV?” (see table S1, which is available online, along with table S2; see the “Supporting Information” section at the end of this article). (We realize that including 100 as the top of this range may have led respondents to speak of a 100% chance of death as a “risk” when it would be not a risk but a certainty.)

We performed conventional inductive content analysis of the interviews to categorize key themes regarding risk decision-making (the “why” explanations behind willingness or unwillingness to take risk).¹⁴ Researchers trained in qualitative research techniques double coded all interviews. We resolved coding discrepancies by consensus. This study was approved by the Partners Human Research Committee in Boston, MA, and the Duke University Human Subjects review board.

For the 22 respondents, expressed willingness to risk death in the hypothetical scenarios ranged from 0% to 100%,¹⁵ with more than half of participants skewing toward either extreme (see table S2). When respondents explained their responses, several common themes emerged concerning why people would risk death for an HIV cure, as did themes for why they would not. We describe each theme, first those illuminating why people believe they would risk death by enrolling in HIV cure research and then those about why they would take this risk (see table 1).

Table 1.

Reasons for Expressed Willingness or Unwillingness to Risk Death for an HIV Cure

Category	Example	Illustrative quotation
Altruism	Contribute to the scientific community	“There’s so many things that you can do. I am a donor to the HIV research, so I want any organs that can be removed from my body to be studied to help someone else” (Interviewee 19, 100% risk).
	Contribute to the HIV community	“When it is time for me to die, I am going to die happy, because when I think of all of [the] kids that I have educated and mentored about HIV, the blessings that it has brought upon them, their families—I am just as happy” (Interviewee 11, 100% risk).
	Sacrifice self for others	“You’re going to think I’m a nut. I would volunteer to be the one to die if 99 could be cured. Really. I know that you’re probably going to say, ‘I’m a nut.’ But no. It’s humanity. It’s human compassion” (Interviewee 9, 99% risk).
Nothing to lose	Lived life to the fullest	“I feel I ain’t got nothing to lose. I think I’ve got to think positive about things like that. But I got to be positive that I might die, and I would be—I’d be content with that” (Interviewee 18, 99% risk).
Psychosocial benefit	Decrease stigma	“That would probably be the only reason I would want to take a cure, is to remove that element, to not feel in any way disadvantaged or stigmatized” (Interviewee 13, <1% risk).
	Gain recognition	“I’d want to go on the news. I would want to just talk all over the world, on the news, to let them know what I had been through my twenty-some years.… And now I’m finally cured” (Interviewee 19, 100% risk).
	Avoid future health changes from HIV	“I think HIV is going to shorten my life” (Interviewee 18, 99% risk). “My quality of life is not what it used to be, or what I would like it to be. I worry about, what if I were to live 5 or 10 more years? How much more physical disability would I be having to deal with?” (Interviewee 3, 30% risk).
Attitudes toward health research	Positive	“I love [research trials]. I don’t think I’ve been offered or found out about a trial that I didn’t—if I fit the criteria for it—that I didn’t want to do” (Interviewee 19, 100% risk).
	Negative	“I do not do clinical trials .… I am not a guinea pig. … There are studies that I have studied in the past of different [people] going through these trials, and [the] things that got them killed” (Interviewee 20, <1% risk).
Cure not worth it	Nothing to gain from cure	“I would not do it because I am good the way that I am” (Interviewee 15, 0% risk).
	Effects of cure uncertain	“We can very easily simplify the image of a drug trial, for example, and just take a pill and swallow it and walk away. But frequently, it’s a lot more than that.… If it’s a very complicated kind of therapy, and then the treatment can go wrong in a very bad way” (Interviewee 5, <1% risk).
	Unwilling to risk death	“If I am going to die, let me die. A cure would be wonderful, but going through it … and then I might croak. … I cannot risk that” (Interviewee 15, 0% risk).
	Uncertainty about risk taking	“I’d be scared. And most likely, I probably wouldn’t. But I would like to say that I would. But I most likely wouldn’t. Because I still [have] my life ahead of me” (Interviewee 8, 60% risk).

REASONS TO RISK DEATH FOR AN HIV CURE

Altruism (other oriented).

Several respondents explained their willingness to take a risk of death in terms of altruism. Although this was a common theme, people invoked altruism for several reasons. Some expressed altruism in general terms, for example, “If I passed away, at least I tried to help somebody else” (Interviewee 19, 100% risk). Others tied their altruistic desire to furthering scientific knowledge and contributing to the scientific community. As one respondent explained, “There’s so many things that you can do. I am a donor to the HIV research, so I want any organs that can be removed from my body to be studied to help someone else” (Interviewee 19, 100% risk). Others expressed this desire to contribute to science as paying forward favors they had received from past trial participants. “Because somebody did a clinical trial for the medicine I’m on now, I’m sure,” a participant said (Interviewee 9, 99% risk).

Finally, some explained that their altruism arose because their identity as HIV positive made them part of a community, defining their life in such a way that they were willing to take substantial risk to help their community. “When it is time for me to die,” a respondent declared, “I am going to die happy, because when I think of all of [the] kids that I have educated and mentored about HIV, the blessings that it has brought upon them, their families—I am just as happy” (Interviewee 11, 100% risk). Some claimed a willingness for extreme social altruism, a willingness to sacrifice themselves for others. “You’re going to think I’m a nut,” one said. “I would volunteer to be the one to die if 99 could be cured. Really. I know that you’re probably going to say I’m a nut. But no. It’s humanity. It’s human compassion” (Interviewee 9, 99% risk).

Nothing to lose (personal).

Less than half of respondents stated that they had nothing to lose from a change in their current situation. Sometimes, they felt they had lived their life to the fullest and were content. For example, one stated, “I feel I ain’t got nothing to lose. I think I’ve got to think positive about things like that. But I got to be positive that I might die, and I would be, I’d be content with that” (Interviewee 18, 99% risk). For others, their negative experiences with HIV made them feel as if the risk of death was preferable to their potential future. One respondent explained, “I’ve seen the negative side of what can happen to people with HIV, which we don’t see anymore for the most part in this country. So, if [the negative side of HIV] were the option versus this, I would definitely consider dying as an option” (Interviewee 5, <1% risk).

Psychosocial benefits (personal).

Several respondents explained that a cure would benefit them personally, in ways unrelated to their health. Some felt that being HIV positive had caused them to lose a part of themselves, and they wanted to rid themselves of what HIV had brought upon them. As one respondent put it, “I would feel like I’m a whole person again. I would [try the cure]. I think HIV was positive in my life; then again, it stopped part of my life … you know, emotional love” (Interviewee 18, 99% risk). Others explained the personal benefit in terms of a decrease in stigma: “That would probably be the only reason I would want to take a cure, is to remove that element, to not feel in any way disadvantaged or stigmatized” (Interviewee 13, <1% risk). Others hoped to gain recognition, either from other people or from God. “I’d want to go on the news,” a respondent declared. “I would want to just talk all over the world, on the news, to let them know what I had been through my twenty-some years. … And now I’m finally cured” (Interviewee 19, 100% risk). Those seeking recognition by God sometimes cited a feeling that if they did a good deed for others, a good deed would come back to them.

Avoid future health changes from continued HIV infection (personal).

Several respondents said they were willing to risk death to avoid potential future health changes they may encounter from continued HIV infection. This included concerns about medication side effects, ways prolonged HIV infection may affect the body, or social issues that may arise from continued health problems. One respondent expressed it quite simply: “I think HIV is going to shorten my life” (Interviewee 18, 99% risk). Another explained, “My quality of life is not what it used to be, or what I would like it to be. I worry about, what if I were to live 5 or 10 more years? How much more physical disability would I be having to deal with?” (Interviewee 3, 30% risk). Another person described how they would no longer have to endure the negative health side effects of having HIV: “I wouldn’t feel so tired. I wouldn’t have like all these problems, medical problems that I have related to the virus” (Interviewee 17, 50% risk).

Positive attitudes toward health care research.

Less than one quarter of study participants expressed willingness to take a high risk of death because of positive feelings about health care research: “I love [research trials]. I don’t think I’ve been offered or found out about a trial that I didn’t, if I fit the criteria for it, that I didn’t want to do” (Interviewee 19, 100% risk). Another respondent also already participated in many trials: “I already do a lot of clinical trials to help people [like] doctors, specialists understand living with HIV” (Interviewee 11, 100%). Others tied their positive feelings about the health care system to the fact that it provides education to themselves and others. “I am 100 percent behind, you know, any type of research. I’ve done a lot of clinical trials, and the education that I learned from those clinical trials is helping me, and if it doesn’t help me it’ll help the younger generation and the people to come” (Interviewee 17, 50%).

Multiple reasons for risk of death.

Almost one quarter of respondents expressed willingness to take a 99% to 100% risk of death. When questioned further about their sense of willingness to assume such risks, some of these individuals responded with thoughtful insights. For one person, it was about personal drive and altruism. The interviewer said, “You said a 100% risk of death. Why would it not be a lower risk?” and this respondent answered, “When I give myself [I give] 300 to 400% plus. It’s my drive. I am a strong person, and I am not going to live forever. It is about the next man, the next woman, and you have to have the mindset to care about people, which I do” (Interviewee 11, 100% risk). For another individual, it was their community that pushed them to take such a high risk. In response to the interviewer’s question, “Is there an upper limit to the risk you would be willing to take?,” the respondent said, “Me personally, for the sake of research and helping a population, I don’t have a limit. I’m willing to go the course for the cure and for the HIV community. I can’t imagine how many people’s lives would change if there was a cure” (Interviewee 9, 99% risk). These responses show that, upon further questioning, respondents who expressed willingness to take very high levels of risk had thoughtful rationales for wanting to do so.

REASONS NOT TO RISK DEATH FOR AN HIV CURE

Negative attitudes toward health care research.

One third of respondents did not want to take any risk of death because of negative feelings toward the health care system—either toward researchers, providers, medications, or the health care system as a whole. One respondent described his mistrust of clinical trials: “I do not do clinical trials . … I am not a guinea pig. … There are studies that I have studied in the past of different [people] going through these trials, and [the] things that got [them] killed” (Interviewee 20, <1% risk). For others, their HIV diagnosis was a drawn-out process, leaving them with a distrust of the health care system. “Before I found out about HIV,” one explained, “I had been going to the hospital one, two, almost six months before they could even find out what was going on with me” (Interviewee 14, 0% risk). For this individual, and others, a previous difficult experience with the medical system led them to be unwilling to take risk in the future.

Cure not worth it (personal).

Half of respondents expressed either that they had nothing to gain from a cure or that the unknown effects of a cure were not worth the risk. Some expressed that they had nothing to gain from a cure because they were happy with their current situation in life and their current medication regimen: “I would just have to compare [a cure] to the situation that I have right now . … I have no risk of dying from the medication at this point, and I have no risk of getting reinfected” (Interviewee 13, <1% risk). Another explained, “I would not do it because I am good the way that I am” (Interviewee 15, 0% risk).

Others stated that the effects of a cure were uncertain and worried about potential side effects of the treatment. One respondent stated, “We can very easily simplify the image of a drug trial, for example, and just take a pill and swallow it and walk away. But frequently, it’s a lot more than that. … If it’s a very complicated kind of therapy, and then the treatment can go wrong in a very bad way” (Interviewee 5, <1% risk).

General unwillingness to risk death.

Several respondents expressed a general unwillingness to risk death. As one put it, “If I am going to die, let me die. A cure would be wonderful, but going through it … and then I might croak. … I cannot risk that” (Interviewee 15, 0% risk). Another said, “I think a 1% risk of death is probably too high. I would want to let others figure it out first and then maybe decide later” (Interviewee 13, <1% risk).

Uncertainty about risk taking.

Some respondents expressed contradictory reasons for their risk answers. These respondents tended to fall more in the middle of the risk-of-death spectrum of responses. Their conflict came from wanting to take a high risk for others, but acknowledging that they may not follow through. As one respondent explained, “I’d be scared. And most likely, I probably wouldn’t. But I would like to say that I would. But I most likely wouldn’t. Because I still [have] my life ahead of me” (Interviewee 8, 60% risk). As another respondent expressed it, “Right now I would say yes. But actually, going to do it that day, I would probably back out” (Interviewee 3, 30% risk).

DISCUSSION

Many people living with HIV can expect a normal life expectancy and control their infection with a single pill a day.¹⁶ Yet some nevertheless express a willingness to incur significant risks to find a cure for HIV. In 22 semistructured interviews, we not only explored the risk of death from enrolling in HIV cure studies that people who were stable in their disease felt they would accept for a potential cure but also their reasons for thinking they would take on such a risk. We found that several respondents expressed a willingness to incur a moderate to high risk of death and were able to offer multifaceted and complex reasons for this expressed willingness.

One way to interpret these findings is that many responses about willingness to take moderate to high risks (e.g., 50% to 100% chance of death) demonstrate respondents’ misunderstanding about either the hypothetical scenario or the nature of risk. For example, as we reported, interviewee 19 expressed a willingness to accept a 100% chance of death for a cure but also said he or she would want to go on the news and let everyone know he or she was finally cured. Similarly, as we report in table S2, three respondents provided contradictory responses to the question of the maximum risk of death they would be willing to take. Furthermore, one might argue that study participants’ responses about how much risk they are willing to take and why are merely hypothetical—who knows if they would actually be willing to take that risk for those reasons if presented with the decision to enroll in a risky trial or take a risky treatment to be cured of HIV.

Thus, we do not interpret these findings as providing evidence that people living with HIV are (or are not) willing to take such and such risk for a cure for such and such reason—or that they are necessarily fully rational and have a clear understanding about the risks involved. Rather, we view the findings (and the point of this study) as providing a realistic flavor of the potential reasons people living with HIV might have for being willing to assume risk (even quite high risk) for the sake of an HIV cure even when their disease is stable and well managed. We found that the reasons people gave and the benefits people expected they would receive strongly tended toward altruistic motivations (e.g., the duty to pay it forward, a drive to advance the science and treatment of HIV, and feelings of human compassion and love) as well as feelings of community and identity. The expression of altruism as a reason to take some sort of risk for an HIV cure is consistent with findings from prior studies that examine people’s motivation for participation in cure trials.¹⁷

The central normative question presented by these findings is, what ought we to make of these potential reasons that people living with HIV have to assume substantial risk for a cure?

Although researchers and ethicists may be prone to think primarily about the health risk-benefit ratio of clinical trial participation¹⁸ and to view people living with HIV as “healthy volunteers,”¹⁹ the themes that arose in these interviews tapped into perceived benefits and values much deeper than health. One theme reflects a broader conception of benefits in risk-benefit assessment; and the other, considerations about risk taking, reasonableness, and altruism.

HIV is a disease that has become incorporated into people’s lives—community, relationships, work, and sense of self—and this has an impact beyond their health status. This is consistent with previous literature showing that people’s HIV-positive identities influence their willingness to take risk for participating in HIV cure trials.²⁰ In fact, when asked to explain their sense of willingness to take risk, few of the respondents in our study mentioned personal benefit, as many felt their lives were currently good. Thus, researchers and ethicists ought to embrace a broader conception of benefits.

When asked to explain their sense of willingness to take risk in HIV cure research, few respondents mentioned personal benefit. The reasons they gave strongly tended toward altruistic motivations and feelings of community and identity.

There is widespread agreement that an “acceptable risk-benefit profile” is an ethical requirement for biomedical research. As Rid and Wendler point out, this has been embraced by the International Conference of Harmonization, the Council for International Organizations of Medical Sciences, and the U.S. federal regulations governing research with humans.²¹ But as Rid and Wendler also point out, there has been little guidance in interpreting and implementing this requirement of an “acceptable” ratio. Thus, Rid and Wendler set out to develop the first comprehensive framework for risk-benefit assessment in biomedical research. Their framework requires, among other things, that the “potential clinical benefits” be identified and evaluated—and weighed against the risks (to determine net benefits or risks). This weighing is supposed to be done using a “normative” “informed clinician test” whereby the central question is “whether a fully informed clinician who is committed solely to promoting participants’ clinical interests would recommend that they undergo the intervention in question.”²²

The problem with this framework, especially in light of our findings, is the narrow focus on “clinical” benefits and interests. More things matter to patients than potential health-related gains. Rid and Wendler do allow for the possibility that a trial that poses net risks could be justified by “the study’s social value.” However, they put a limit on the weight that social value should have in cases where the risks “clearly exceed the general limits of acceptable research risk,”²³ but admit that “exactly what defines these upper risk limits remains an open question.”²⁴ To help with this difficult question, they propose the “ideal social arbiter test” whereby the central question is “whether a fully informed and impartial social arbiter would recommend the study in question.” Our findings give voice not to the impartial social arbiter, but to the partial social arbiter actually living with HIV.

Aside from broadening our conceptual understanding of “benefits,” these findings pose an additional important normative question: even with a broadened understanding of benefits, is it rational to be willing to take such a substantial risk for an HIV cure, and is it ethical to allow people to do so? Importantly, our empirical data do not provide a clear answer to the question about permissibility of risky trials. Key stakeholders in the debate have maintained that some risks are too great to be acceptable, and others have argued that it is difficult to place a limit on acceptable risk because of the complexity of weighing risk-benefit ratios in HIV research.²⁵ Still others point to the great potential for social good generated from allowing some to take substantial risks.²⁶

One way to answer the question about whether it is “rational” to be willing to take substantial risk for a cure is to consider our findings in the context of the “reasonableness” framework developed by philosopher Joel Feinberg. In his landmark book, Harm to Self,²⁷ Feinberg argues that while “prudence” may dictate that we take the less risky option when faced with a choice, prudence is not always reasonable. Sometimes it is reasonable to assume a great risk to assume a great gain. There is no simple mathematical formula for judging decisions as reasonable or unreasonable, and such judgments may defy objective assessment because of value judgments (e.g., how important it is to a person that she climb to the top of Mount Everest). There are, however, according to Feinberg, some considerations that can inform the reasonableness question. These include the degree of probability that harm to oneself will result, the seriousness of the harm, the degree of probability that the goal inclining one to shoulder the risk will in fact result, the value or importance to the person of achieving that goal, and the necessity of that risk to get to the desired goal.²⁸

In the case of a high chance of death for an HIV cure, the harm is serious, and the probability of harm is high. There were two categories of “goals” articulated by risk takers: personal and other oriented (societal). Personal benefits such as recognition, redemption, and freedom from stigma are goals that are important, but it is likely not necessary that participants enroll in a risky trial to meet these goals. There may be other avenues. Thus, one could argue that, according to Feinberg’s framework, taking substantial risk for these reasons is not reasonable. The goal of helping others (current or future HIV patients), however, is very important, and trials may be the only way to achieve that goal. Thus, we see that it is plausible that taking such a risk would be reasonable.

Even if one were to conclude that taking such a substantial risk is unreasonable, Feinberg argues that unreasonableness alone does not justify paternalistic intervention to prevent someone from taking a risk.²⁹ Rather, in order to justify paternalistic intervention, the risk-taking person must be acting involuntarily. The conditions for a voluntary choice are that the person is competent (e.g., not an animal, insane, or severely cognitively impaired), not choosing under coercion or duress, not choosing because of ignorance or mistaken belief, and not choosing in circumstances that are temporarily distorting.³⁰

One could argue that the respondents in our study who expressed willingness to take very high levels of risk for an HIV cure were most likely choosing because of ignorance or mistaken belief or were choosing in temporarily distorting circumstances. Regarding the first point, while we cannot rule this out, our data did not show large-scale misunderstandings or mistaken beliefs on the part of participants—and qualitative interviews allow for probing and assessment of this more than other approaches such as surveys do. Perhaps the most we can say is that one should not, and cannot, assume that persons willing to risk death for an HIV cure are acting involuntarily due to mistaken beliefs.

One might argue that respondents’ extreme emotion of love or compassion or desire to help was temporarily distorting their judgment, making their expression of willingness to obtain a risky treatment for an HIV cure an involuntary one. We believe that this view may reflect what others have identified as a deep skepticism toward and bias against extreme altruism. In the book Strangers Drowning, Larissa MacFarquar describes public skepticism toward people who commit themselves to doing good beyond what seems reasonable.³¹ She describes cases of people who adopted twenty children in distress, founded a leprosy colony in the wilderness in India where they exposed themselves not only to leprosy but also to being eaten by panthers, and donated so much of their income to the poor that they barely had enough money to take care of themselves. She writes, “We honor such high ideals, but also have skepticism, hostility, think they are crazy, and it makes us uneasy.”³² As she points out, underlying all these judgments is a normative view about how one ought to live.

We are not arguing that we can never come to normative judgments about how one ought to live or about when people are taking reasonable risks, or that all people living with HIV who are willing to participate in risky cure trials are acting with full comprehension and are reasonable. Nor are we arguing that we must permit people to enroll in research trials that have substantial risk. Rather, we challenge the view that it is inherently unethical to provide a treatment or experimental therapy with what might seem like an unjustifiably high mortality rate.³³ We also challenge the view that willingness to accept such extreme risks necessarily means that people do not understand the risks or are not providing well-thought-out answers. And we also challenge the view that accepting an extreme risk is necessarily a “bad gamble.”

We may, in the end, decide that we cannot permit people to take such risks. As some have argued, the mere fact that people value a cure does not by itself mean that risky trials should continue on.³⁴ But if we are to prohibit risky trials, then it must be because of some reasoning about the principles, ends, and limits of research as an enterprise or because of consequentialist-based arguments that the research enterprise would suffer and people would not enroll in trials if we allowed people to take such high risks. It cannot, however, be because we assume that potential participants are irrational for being willing to accept such risks. And if we make claims about “bad gambles,” we must be nuanced in our analysis—because to some people, based on their personal values, they are not bad gambles.

We do, however, have an ethical obligation to thoroughly check comprehension and reasoning for willingness to take substantial risk for a cure. Our research provides one model for this—a qualitative approach that allows for in-depth assessment and follow-up questions (“triple checks”) for the assessment of potential research participants’ reasoning and motivations. Just as researchers and ethicists should not assume misunderstanding or irrationality, they should not assume that an individual is agreeing to participate voluntarily and with sufficient comprehension and rationale. Investigators should seek to find individuals who meet the criteria of voluntariness and sufficient comprehension.

It is worth noting that, although several study respondents claimed a willingness to risk death for a cure (with some feeling that they would be willing to take even a very high risk—even certain death), others expressed hesitance to take any risk of death and cited reasons such as prior negative experiences with the health care system, having nothing to gain from a cure, uncertain effects of a cure, and a general unwillingness to risk death. These are equally reasonable judgments and have been reflected in other research on concerns about HIV cure trials.³⁵

STUDY LIMITATIONS

Our study has several limitations. First, the interview population consisted of a convenience sample of HIV-positive individuals who are engaged in the HIV community and willing to volunteer for an interview study. The population we interviewed had a large number of people who had been HIV positive for greater than 10 years, which may give them a unique perspective on the disease’s progression. Participants were also from two limited geographic areas. Second, the standard gamble method of preference elicitation uses probabilities of events, which are often not well understood and can be difficult for people to respond to. We addressed this limitation by using icon arrays to indicate risk so that subjects would have a better sense of what, for example, a 20-out-of-100 chance of risk means and by conducting follow-up questioning to ensure people’s answers reflected an accurate understanding of the risk attitudes they were espousing.³⁶

Third, participants’ responses may have been influenced by social desirability bias.³⁷ Some might argue that the mere fact that some individuals said they were willing to take a 99% to 100% risk of death is near proof that a social desirability bias was at play or that they did not fully understand the question or situation. We cannot rule out social desirability, but the interviewer was a research assistant not involved in patient care, and participants were encouraged to speak freely and reassured that there were no right or wrong answers. We also note that qualitative methodology allows the interviewer to sense if an interviewee does not understand the question and to reexplain it in a way that the participant better understands. It is true, however, that we did not conduct an in-depth assessment of participant understanding of the science behind HIV cure research. Fourth, the scenarios presented were all hypothetical; no participants had already participated in HIV cure research; their responses could change if they are faced with a real cure scenario, rather than a hypothetical one. However, findings similar to ours have emerged from studies during and after participation in research.³⁸

CONCLUSION

In this interview study, we found that many people considered themselves willing to take substantial risk (even to risk death) for an HIV cure, and their reasons for doing so went far beyond how a cure would improve their health. The driving reason was altruism, or, more specifically, a desire to do good for their community of HIV-positive persons, past and present. A nontrivial number of participants expressed a willingness to take significant risks of death for an HIV cure.

There is a tendency to assume that people willing to take such risks don’t understand the nature, purpose, or outcome of HIV cure trials. Our study challenges this tendency. We found that many participants who expressed willingness to take a 99% to 100% risk of death had thoughtful reasons for doing so. Part of the reasoning for this was the hope for personal benefit—both the health benefits of not having HIV and the psychosocial benefits, such as reduced stigma and positive impact on emotional and sexual relationships. But most of the reasoning came from a strong desire to be altruistic.

Finally, it is important to stress that if we do permit people living with HIV (particularly those who have a reasonable explanation for their willingness to take risk) to enroll in risky HIV cure trials, there need to be additional important ethical safeguards. As Lo, Grady, and the Working Group on Ethics of the International AIDS Society outline, we must consider collaborative partnership and ensure that the trials have social value, scientific validity, fair selection of participants, favorable risk-benefit balances, independent review, informed consent, and respect for enrolled participants and communities.³⁹ Sugarman has also stressed the importance of rigorous consent processes and advocated for trial oversight that includes relevant expertise and the use of empirical data to inform trial design and consent.⁴⁰ Attention to informed consent processes is particularly important given that some studies have found that consent forms for HIV cure research can be misleading.⁴¹

We do not take a stand regarding what level of risk is acceptable to allow patients to take in the context of either treatments or trials. Rather, we contend that, in the ethical debate surrounding the “bad gamble” of HIV cure trials, potential participants’ expressed willingness to risk death should not be dismissed as irrational, and a more nuanced conception of benefits is needed. This does not mean that we should allow people to participate in research that is sure to kill them, but understanding that patient preferences play a strong and reasonable role in research participation may allow increased comfort if an HIV cure trial entails risk of modest harm.♦