Six main themes emerged from the data. The key discussion focused on the way in which HIV cure research differed from other clinical trials, and the risks that this may expose research participants to. The discussion is framed around the construct that researchers are obliged to protect participants from dangers that may not be realised or that are difficult to conceptualise.
The emergent themes are discussed in detail below:
HIV exceptionalism and consent
In any clinical trial, provision of informed consent prior to enrolment is a pre-requisite to participation. The standard procedure is well outlined in Good Clinical Practice (ICH-GCP) guidelines for clinical trials and in various other research ethics guidelines. A central theme throughout the interviews was that these guidelines should direct HIV cure trial research and that some special additional considerations need to be applied to ensure complete understanding. There was also concern that HIV has, at times, been treated as “different”.
All clinical studies should be done exactly the same. (L = REC member)
I am not too sure why people see it [HIV] as (different); or what people foresee as an ethical difficulty. I mean as long as the agent follows the normal process of what clinical trials do, and the safety considerations of clinical trials. As long as it follows the normal processes; I am not quite sure what the ethical dilemmas even are. (G = public health administrator)
Having said that, the dominant narrative identified areas within the current requirements that do need particular attention in the case of HIV cure given the desperation and vulnerability of many HIV-infected participants in the South African context:
I think there needs to be a lot more dialogue than normally would happen. I mean because of all the attention around the illness. (A= private health funder)
Well, consent is basic …and I think that it is problematic - to really make sure that people are well informed … as people may sort of grab at the last straw to say “Well let’s try it” just out of being desperate and not really being well informed. (M = religious leader)
Improving understanding through science translation
Respondents expressed concern over scientifically complex patient information leaflets and consent documents:
The lengthier and the more detailed the informed consent process is, the more likely the patients are to switch off. So it's easier for them to understand one page than it is to understand – I mean some of the pharmaceutical trial informed consent documents are like mini-theses; and you get tired just looking at them and they tend to be very repetitive, not easy to read and all sorts of clauses which are more designed to protect the researchers and the sponsor, than... are really of benefit to patients. (B = academic)
Likewise, many of the constructs used in the explanation of cure are difficult to understand. For example, remission has been suggested as a suitable alternative to the word “cure”. However, it can be difficult to communicate; metaphors such as talking about remission in cancer are not necessarily accurate and carry loaded meanings depending on the person’s experience and awareness. Very few people, even in research and clinical settings, fully understand the meaning of the words remission, functional cure or reservoirs, amongst others. These are all words that cure research uses extensively and will require accurate, yet simple, explanation.
I've got a PhD and I work in health research; I don't really know what remission means… and I'm English speaking; but I still think in our context we have to deal with many, many issues in clinical trials that people struggle to understand… but we’ve got to keep trying. So… who understands randomization; who understands prophylaxis? (aa = social scientist)
The level of explanation required did vary across the sample that we interviewed, with some respondents feeling that the standard GCP requirements were sufficient with a good assessment of knowledge. Others argued that a far more detailed profile and assessment of the readiness of potential participants was necessary.
It would have to be quite an extensive psychological evaluation on these potential candidates … where it’s fully explained to them… what the risks are and then somebody – a psychologist or somebody would have to determine ″Okay, this patient is fully aware of everything and he’s in a position – a stable position where he would happily make this decision, and he can cope with the consequences. (FGB2 = medical student)
The informed consent is sort of providing the support framework, so it is the same as when you do any of the psychological studies that you have built in; that there is recourse to support. And this – if it’s built in from the beginning that there are regular check-ups to assess mental state and understanding. (D = REC member)
A key point raised was that the processes by which people construct meaning based on what they are told are poorly understood. As with any other new or different construct people may encounter, they tend to reconstruct it in terms that they understand. This background knowledge used to construct meaning cannot always be known by the research team, so achieving informed consent may require an active process to explain the study, to engage and work with the potential participant until an adequate level of understanding has been achieved. The potential for confusion and misunderstanding of the implications of participation is immense. Participants may be getting different messages and information from other healthcare providers during the trial, as well as from non-medical sources such as friends, traditional and alternative healers, family members and the media.
We know that memory isn't recall, it's a reconstruction; so all of this is going to get reconstructed and changed and reconfigured. (aa = social scientist)
Communicating risks and benefits accurately
A strong consistent recommendation from respondents was to refrain from calling these studies “cure” research, as this creates artificial expectations and may lead to people consenting without clear understanding. The role of the trial should be explained as being part of the overall development of research on HIV and potential treatment and cures. The actual naming of the trial and its impact on the virus and the participants’ potential well-being will differ from trial to trial, but the naming of the research as the testing of a “cure” has to be avoided until a much higher level of scientific confidence exists.
I don’t think you could tell anybody you’re going to give them an HIV cure. You’re going to say what you’re looking at is trying to reduce the amount of HIV in their body; and that you’re working towards a cure. You certainly can’t put people on the study and tell them that you’re going to cure them; unless you know for sure that you’re going to cure them. (F = HIV researcher)
People are going to have to understand what you mean by cure. How does that define my life? If I have to take the drugs plus this other drug, how do I do it? When do I know about it? When will it be determined that I’m cured? What do I have to do afterwards? (1 = HIV activist)
The inherent risks involved in participation must be understood and highlighted in the information provided. This includes both the risk that the cure may fail and, even if it appears to work initially, that the risk of relapse exists.
Through a good informed consent process…they would acknowledge that this was a risk and that they were willing, they went in with their eyes wide open. (12 = academic)
Present to the patient the fact that there’ve been “X” number of people that have been treated and 1, 2 or 9 patients…have actually experienced this problem. The informed consent form will change so patients will know that there's a good chance of relapse. (6 = HIV researcher)
Desperation and its impact on risk assessment
Among the respondents drawn from a patient, community or activist base, the desperation for a cure was a consistent theme. Even amongst those who had controlled the virus with HAART, there is a desire to be cured and to end dependence on medication. Desperation for a cure could influence consent processes considerably.
So the ethical concern is will the patients really understand that; and there's always a risk that the patients might be so desperate and be willing to try anything ... even if it’s not in their best interest. (I = social scientist)
I think for any person if you’re going through something as life threatening as HIV there’s always that hope of “I would wake up one day and it’s gone.” So the mere fact that this might be a cure - that in itself is hope and that “I could be cured, I could go back to having a normal life.” (B = academic)
Other respondents, mainly the laboratory researchers, those working on HIV treatment trials and some of the treating physicians, felt that potential respondents would take a considered decision. These respondents felt especially that those who had controlled the virus using HAART and were consistently adherent may not be willing to risk their current diagnostic status and protection to participate in a trial. Although, even in this group, there was an acknowledgement of the desire to be cured.
People will assess their risks and assess what they want to do. It’s going to have to be communicated very well though. (1 = HIV activist)
I suppose there might be a group of patients who would say, well, you know “I'm living happily on my ARVs, you know, why rock the boat?” (B = academic)
Options for improving information sharing
A number of ideas on methods of improving information sharing and encouraging understanding were shared. There was general agreement for the need to have a strong community education programme in addition to individual consent. Options discussed included the use of pictures and diagrams, or educational videos to aid problems of literacy and to offer a combined verbal and visual display.
You would want your two-page summary, but at the same time it probably isn’t just giving out a brochure. It would be things like having interactive seminars; like what they’ve had in terms of producing a video …and importantly checking understanding, because that’s often lacking in the consent process, …seeing how they understand the risk rather than anything else. So yes, you will probably spend more time on it than you would on any normal study. (D = REC member)
I think more use should be made possibly of pictures rather than words. (B = academic)
Videos would be another way of conveying information. You know, people – I suppose it might be, even more so in the current electronic era; that people's skills with the written word are not that great. And they're more used to pictures, videos, and interactive programmes. (B = academic)
Respondents also suggested that behavioural scientists should make a stronger input into trials so research could be more easily understandable.
The minute it got medicalised we jumped on and then we learnt very quickly that actually doing the medical without the behavioural was folly anyway. (3 = HIV researcher)
Some respondents from a community advisory board suggested training people from the community to act as counsellors and consultants that potential participants could go and talk to. These community informants would be fully informed about the study, and could talk to potential study participants in terms that make sense to them and reflect community issues. These discussions could also happen in a less stressful environment than a research setting.
But people from the community; people whom they trust…like a social worker…I think – because I mean she’s – you can, anybody can explain it to her in English; and she will be able to communicate that to people. (M = religious leader)
It would also be useful to conduct a separate, probably qualitative study, before going into the field to find out what different people need to know, what current beliefs exist about HIV and cure and how these may affect consent, and the capacity of community members to participate in the study if complicated follow-up demands are made.
Then you have a community discussion and really see what people’s thoughts are. If I were you, I would also do a survey with the community; what do you think about this research? (N = REC member)
It is also important to improve assessment of how well participants understood the material. According to respondents, this assessment should also include a component for assessing expectations, especially given the emotions around and desperation for a cure. This would go beyond the usual test of understanding of the consent form that is currently conducted in some HIV studies.
The idea of some sort of questionnaire; be it even a visual one, to assess patients’ expectations if they were to be enrolled into a trial; and to validate any score that might be used as a criterion for entry. (B = academic)
Psychologically I guess you can do some screening, … what the patient’s motivations are; and see if they really understand the risks... And to prepare them for an adverse outcome. (I = social scientist)
A further option raised was to look at consent as a counselling process, where the potential participants are taken through the information in a supportive manner with the research team acting as facilitators to work with the potential participant to make an informed decision.
This kind of informed consent is just not a process of informing and educating the person. It’s about ...it’s actually taking the person through a counselling process. You really need to be taken through the issues like why is it important for you to be part of this research. (1 = HIV activist)
Consent over a longer time period
Respondents spoke about the implications of having to obtain consent for the extended period of the study, which may be up to 10 or 15 years, to assess if the intervention is a sterilizing or functional cure. Maintaining this relationship over a long trial does have implications. If conditions change years down the trial or the participant realises implications of consent, this has to be taken into account.
You are a participant; you are told things; you haven't done informed consent in the last five minutes, you've done informed consent back at some point a few years ago. You are now three years down in your relationship with this person and you get told stuff. (C = social scientist)
Information provision on HIV, the treatment and the study trial also has to continue over the long-term. As new information emerges about the treatment or about HIV, this has to be communicated to participants, especially if it has to do with their health or risk of a negative outcome.
Willingness to participate based on trust
Due to the trust participants may place in doctors and other health professionals and in the scientific process, they may be willing to place their trust in the trial without really appreciating the consequences. This trust must not be abused, so all communication must be honest and accurate. Consent in this context does imply a greater dependence on altruism from participants in making their decisions about whether to participate. As stated earlier, a cure is not guaranteed and many early trials are likely to fail. This must be communicated, so that participants understand that their participation is unlikely to bring them an early benefit. Psychological support should also be provided willingly and upfront.
They have trust in the system… and I think we need to be very careful not to abuse that trust. (W = private health funder)
My experience and my work with people is a question of trust …That trust is sort of …on a personal level …they will really open up and they will be willing also to share their experiences if they feel that they can trust. (M= religious leader)
This trust has to be maintained throughout long studies, potentially spanning many years. Therefore, retraining and reinvesting in the relationship will also have to occur regularly.
The challenge with informed consent is that it’s an ongoing process you know so there has always got to be that rapport so they can keep asking questions. (T = HIV researcher)