“I’m prepared to die to be cured of HIV” – what did people mean when they said this?

An affordable, generally applicable cure for HIV infection is keenly awaited, even if we don’t yet know which research pathway will take us there.

But how willing are people with HIV to risk harm by participating in research trials, if the positive outcome for them or other people might be a cure?

A US survey originally published last April (Murray et al) raised eyebrows when it revealed that a sizeable minority of people said that if experts developed a promising treatment to cure HIV infection, they would still take it even if its side effects meant a substantial risk of death.

Glossary

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

qualitative

Qualitative research is used to explore and understand people’s beliefs, experiences, attitudes or behaviours. It asks questions about how and why. Qualitative research might ask questions about why people find it hard to use HIV prevention methods. It wouldn’t ask how many people use them or collect data in the form of numbers. Qualitative research methods include interviews, focus groups and participant observation.

multivariate analysis

An extension of multivariable analysis that is used to model two or more outcomes at the same time.

capacity

In discussions of consent for medical treatment, the ability of a person to make a decision for themselves and understand its implications. Young children, people who are unconscious and some people with mental health problems may lack capacity.

stigma

Social attitudes that suggest that having a particular illness or being in a particular situation is something to be ashamed of. Stigma can be questioned and challenged.

A smaller but still significant minority even said they would take it if this meant a 100% risk of death.

This on the face of it is a nonsensical answer: how can someone be happy to die to be cured?

This survey was quantitative: it simply enumerated the degree of risk people would be willing to take for an HIV cure and related the answers to participant characteristics. It could not delve further into the reasons for people’s answers.

To better understand them, some of the same researchers (Kratka et al) conducted a second, qualitative survey of a different and smaller group of interviewees to find out.

They found that in some cases people did misunderstand the survey questions. In other cases, people overestimated their risk of dying of their HIV so thought risking death for a cure was a good wager.

However, the main finding that came through was that, while the original survey was designed to elicit what people felt about the balance between being cured of HIV and being harmed by the treatment as individuals, the people who said that they would be willing to take a high or even certain risk of death were thinking altruistically, of themselves as members of a community.

The way these people interpreted the research questions was something like: “Would you be prepared to take part in a research programme that might, or even would, lead to your death, if the end result was that we’d find an effective cure for HIV?” This was not the question asked: but it was the one they heard.

The first study

In the first study, which was conducted between June 2015 and February 2016, Dr Benjamin Murray and other researchers from Duke and Harvard Universities in the USA asked 200 people in two HIV clinics in Boston, Massachusetts, about the risks they would be prepared to take for a cure for HIV. All the participants had had HIV for over six months and had an undetectable viral load; all were on antiretroviral therapy (ART) except for one person who was an ‘elite controller’.

Their average age was 52, 35% were women, and on average they had lived with HIV for 19 years and had been on ART for 15 years. They had a range of educational attainment with 25% of graduates but 17% not having finished high school. Forty-three per cent were employed, and 35% reported significant poverty.

They were asked about their estimated likelihood of dying within the next 20 years, and their expectations of experiencing cancer, a heart attack or an injury (with the latter included because it was thought less likely that people would attribute this to HIV). They were asked how likely they thought these were a) if they stayed HIV positive and b) if they were cured of HIV.

They were also asked how likely they thought it was, over a 20-year period, that a) their HIV would stop responding to medical treatment and b) that they would develop serious side effects related to HIV.

They were then asked about the following scenario which, as the wording is important, needs to be quoted in full:

“Medical experts are currently trying to develop new treatments and potential cures for HIV in the hopes of completely removing HIV from the body. If successful, individuals who are cured will no longer need to take HIV medications. Suppose 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.”

They were then asked:

  1. Whether they would take the treatment if there was a 1% chance they would die and a 99% chance they would be cured
  2. Whether they would take the treatment if there was a 99% chance they would die and a 1% chance they would be cured
  3. What was the largest chance of death they would accept in order to be cured of HIV.

Regarding the first question, 73% said they would definitely or probably take a 1% risk of death the be cured of HIV. However, for 16% of respondents, even 1% was not an acceptable risk.

More surprisingly, however, over a quarter of participants (26%) said they would take a 99% risk of death in order to be cured of HIV. In other words, they were prepared to risk near-certain death for a one-in-a-hundred shot at being cured.

Regarding the third question, and dividing respondents into quartiles:

  • 25% would not accept a higher than 1% risk of death for a cure;
  • 50% would not accept a higher than 10% risk of death; and
  • 75% would not risk a higher than 50% chance of death.

This still left, however, a quarter of participants who would be prepared to risk a more than a 50% chance of death:

  • An eighth of participants who would be prepared to risk up to a 90% chance of death;
  • And 7% of participants who said they would be prepared to risk a 100% chance of death.

As the researchers say, the latter response appears to be nonsense, as if you’re dead you can’t be cured.  They speculated that when hearing the phrase “100% risk of death” some people took more note of the “risk” than the “100%” and didn’t realise that “100% risk” meant “certain death”.

In this first study, the researchers could not look in detail at people’s motivations. But they did find out that people were more pessimistic about their health prospects with HIV than might be expected. Thirty per cent of respondents expected their ART to stop working within 20 years, and 41% thought the chances of that happening were at least 50/50. No less than half thought they’d experience serious side effects due to ART in the next 20 years.

Well over half said they’d be less likely to die, get cancer or suffer a heart attack in the next 20 years if they were cured of HIV. In contrast, only 20% thought their chances of injury would reduce, showing that they expected their HIV to raise their risk of the other health conditions and of death in general. One third also said they experienced considerable stigma due to HIV.

However, when subject to multivariate analysis, the only health-related factor that was associated with willingness to take extreme risks for a cure was a high expectation that they would suffer from serious ART-related side effects in the next 20 years (which suggests a need for some updated information on ART side effects).

The other two predictors were being employed and being better off financially.

In other words, people were not willing to risk death for a cure because they were uninformed, sick or desperate. It was the well-off and well-educated who were saying this. What was going on?

The second study

The second study took place between May and November 2016. This was a small, qualitative study using semi-structured interviews of 22 people selected from a community HIV organisation in North Carolina and an HIV clinic in Washington DC (so there was no overlap in participation in the two studies).  

They were asked the same three questions as in the previous study about whether they would accept a 1% risk of death for a cure, a 9% risk of death, and what would be the maximum they would accept.

The hypothetical scenarios presented were slightly different to the first study. The first ten interviewees were asked specifically about entering a clinical research trial thus:

“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.”

However, the remaining 12 participants were asked about a post-research scenario thus:

“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.”

The researchers comment that a number of people asked about the second scenario still seemed to assume it was within the context of a research trial.

The makeup of the group was roughly similar to the participants in the previous study, with an average age of 49, 27% female, and living with HIV for anything from six months to 27 years.

Dividing the 22 participants again roughly into quartiles, about a quarter of the interviewees were very risk-averse, only willing to accept a less than 1% risk of death for a cure. The next 25% were willing to accept between a 1 and 30% risk (individually, they all accepted different risks within this range); the next 25% were willing to accept a 50 to 60% risk; but the top quarter (six individuals) were willing to accept a 99 to 100% risk of death, with two saying 100%. As with the previous study, people were more likely to accept either a very high or a very low risk of death, with fewer accepting risks in the 20 to 80% range.

People who would accept a high risk of death

"Those who accepted a 99-100% high risk of death saw it in altruistic terms, seeing their death as part of a programme of research that led to a cure for others."

A few clearly hadn’t understood the implications, with one who said they’d accept a 100% risk of death nonetheless imagining they would still be alive to talk about it:  

“I would want just to talk all over the world, on the news, to let them know what I’d been through in my 21 years…and now I’m finally cured.”

But most of the others who accepted a 99 to 100% high risk of death saw it in altruistic terms, seeing their death as part of a programme of research that led to a cure for others:

“When it is time for me to die, I am going to die happy, because when I think of all the kids I have educated and mentored about HIV…I am just as happy.”

“I feel I have nothing to lose. I’ve got to be positive that I might die, and I would be – I’d be content with that.”

“There’s so many things you can do. I am a donor to HIV research, so I want [my] organs to be studied to help someone else.”

And one had clearly anticipated that their answer might surprise the researchers:

“You’re going to think I’m a nut. I would volunteer to be the one to die if 99 could be cured. Really…it’s human compassion.”

Some also based their answers on a belief that HIV would shorten their lives anyway, though this theme arose less often than the one of altruism:

I think HIV is going to shorten my life.”

People who would accept a lower risk of death, or none

Concern about the future health and social consequences of having HIV was also a theme among those who would only accept a lower risk of death, however. One who said they’d accept a 30% risk of death said:

“My quality of life is not what it used to be…what it I were to live 5 or 10 more years? How much more physical disability would I be living with?

And someone who’d only accept a 1% risk of death said:

“The only reason I would want to take a cure is to remove that element, to not feel in any way disadvantaged or stigmatised.”

A few people were suspicious of clinical trials anyway:

“I do not do clinical trials…I am not a guinea pig. I have studied [how] different people [went] through these trials, and things that got them killed.”

But the majority of people who were not willing to take a risk, while believing a cure would be ‘wonderful’ thought it might not be worth the risk:

“I’d be scared…and most likely I wouldn’t. Because I still have my life ahead of me.” (This person had said they would accept a 60% risk of death but had reservations about this in their interview.)

“[It might] be a very complicated kind of therapy, and then the treatment can go wrong in a very bad way.”

“If I am going to die [of HIV], let me die. A cure would be wonderful, but to go through it and then croak…I cannot risk that.”

And finally, several people said they were fine as they were:

“I have no risk of dying from the medication at this point, and no risk of getting re-infected.”

“I would not do it because I am good the way I am”.

Conclusions

Medical ethics has tended to assume that people employ what has been called the “Standard Gamble” when deciding between the risk of a procedure versus its benefit: they weigh up the possible harm against the possible reward, to themselves as individuals. Exactly how much harm they are willing to risk may vary: for instance, people may be prepared to take a much higher risk if the reward is very large.

But the Standard Gamble cannot take account of other motivations, such as moral or religious convictions or feelings of social obligation, and indeed has tended to ignore these.

"People were not imagining themselves volunteering for near-certain death on the basis of gross misinformation or due to lack of capacity."

The authors of the qualitative study paper, however, say that it is important to take such motivations into account when, for instance, designing informed consent protocols for research studies in the future.

They comment that few people willing to take a high risk for a cure mentioned personal benefit as the reason; they were just as likely to rate their quality of life as high as people who would accept a low or no risk. They were not imagining themselves volunteering for near-certain death on the basis of gross misinformation or due to lack of capacity. They had thought through the implications. But their risk calculations were different from the ones medical ethicists think people make; they included a belief that they should “give something back” to the medical establishment whose research had saved their lives, and saw a clinical trial as one of the most direct ways of doing so.

The researchers emphasise that their findings do not imply that the HIV-positive public is giving them a carte blanche to relax the ethical rules that govern scientific research.  For a start, half of the respondents in the first survey were unwilling to take more than a 10% risk of death (which would still be very high for medical research into non-terminal conditions).

They also point out that when people are asked about much more specific scenarios – such as whether they would be willing to interrupt their HIV treatment and have a detectable viral load as part of an HIV cure study – they tend to be much less willing to risk harm.

What they do say is that their two studies have uncovered that people may have a much wider range of motivations for joining research studies than has been supposed by ethicists.

They say: “We view these findings….as providing a realistic flavour of the potential reasons people with HIV might have for being willing to assume risk (even quite high risk) for the sake of a cure.”

References

Murray BR et al. What risk of death would people take to be cured of HIV and why? A survey of people living with HIV. Journal of Virus Eradication 5: 109-115, 2019 (open access). 

Kratka A et al. HIV cure research: risks patients expressed willingness to accept. Ethics and Human Research 41: 23-34, 2019.

https://doi.org/10.1002/eahr.500035