How can researchers reduce risks to sexual partners in studies involving treatment interruptions?

As studies working towards a functional cure or HIV eradication are creating risks not only for the HIV-positive people who take part, but also their sexual partners, researchers need to reconsider their ethical obligations and the support they offer to non-participants, leading cure researchers and ethicists argue in a supplement to the August 1 Journal of Infectious Diseases.

These studies may require that HIV-positive volunteers interrupt their antiretroviral therapy (ART) and be closely monitored: an approach referred to as an ‘analytical treatment interruption’, or ATI. While this may advance the science, the potential risks for the participant include the development of a resistant virus, an acute retroviral syndrome (signs of HIV infection, reminiscent of the primary stages of the infection), thrombocytopaenia (low platelet counts), AIDS-defining events and HIV-related events.

There are also risks for the participant’s sexual partner or partners. As we reported earlier this year, an HIV-positive man transmitted HIV to his female sexual partner after an analytical treatment interruption in a therapeutic vaccine study in France. That case report takes central stage in the journal’s supplement and raises a series of ethical questions.

The risk was, in part, created by the research study. The man had been previously virally suppressed but was requested to interrupt his treatment, inevitably leading to viral rebound and infectiousness. While the man was informed of the risk of sexual transmission and advised to use condoms, this was apparently not sufficient to prevent any harm occurring in this case.

His partner had come with him to study appointments and so knew what was involved. But there usually aren’t formal procedures in trials for sexual partners to be informed of the risk of sexual acquisition and on how to reduce this risk. Partners are not always offered pre-exposure prophylaxis (PrEP) or regularly tested for HIV. They may receive no advice or support should infection occur. And if a participant has several casual partners, the risk to others is multiplied.

Different studies, different risks

The potential for sexual transmission occurring during an ATI depends in part on how studies are organised, says Professor Steven Deeks of the University of California.

For studies that seek to dramatically reduce or eliminate the HIV reservoir, viral load monitoring is likely to be intensive (perhaps weekly), with ART resumed as soon as virus has been detected and it is clear that HIV has not been eradicated. In this case, it is theoretically possible to resume therapy before viral load peaks to a level that poses a substantial risk to a sexual partner.

Treatment interruptions are often longer in studies working towards durable control of the latent reservoir without ART (remission or functional cure). In these studies, the researchers may need to wait until the patient’s viral load reaches a steady-state set point. Following interruption of ART, viral load will usually increase sharply to a peak, before the immune system is able to respond and bring it down to a lower level, referred to as the set point.

“Plasma HIV RNA levels might need to remain well over 10 000 copies RNA/mL for a few weeks before control is gradually achieved,” says Deeks. “The risk of such studies is much greater than those in which ART is resumed once a rebound is detected.”

Involving partners?

While there are clear ethical guidelines and regulations to protect people who volunteer to directly participate in research studies, no such framework exists to protect non-participants. Dr Liza Dawson, an ethicist at the US National Institute of Allergy and Infectious Diseases, says that bioethics tends to uniquely focus on the individual. She would prefer a ‘relational’ approach which considers the social relationships and networks that matter to a study participant.

As many participants express strong concern about not transmitting HIV to their sexual partners, it is reasonable for researchers to help participants to prevent this occurring, she says. Researchers doing so could be framed as part of their primary obligation to the participants themselves. She points out that in routine care (rather than in research studies), a clinician’s primary commitment may be to the patient, but they often try to limit risks to others. For example, clinicians give advice to people with sexually transmitted infections about avoiding onward transmission and encourage them to engage with contact tracing.

Should researchers go further and make contact with a study participant’s sexual partner or partners? They could then be fully informed about the nature of the study and/or offered preventative services.

However, this could be complex. Many people do not have steady partners and over the course of a study, their relationships may change. The partners won’t necessarily want to be identified or to engage with the researchers.

There are particular concerns about confidentiality. Study participants may not want their HIV status or involvement in the study revealed to their sexual partners. They may not wish to discuss their sexual behaviour with the researchers and clinicians. A recent set of guidelines on running ATIs specifically excluded making any contact with sexual partners, in order to respect confidentiality.

But ethicist Dr Nir Eyal of Rutgers University says that individuals whose partners are not aware of their HIV status or study participation should be excluded from studies in any case ­- because there is a greater potential for harm to partners. (There’s more on exclusion criteria later in this article). As a result, this confidentiality concern is unlikely to arise in practice. Eyal says that stable partners should be contacted, but the practical difficulties and confidentiality concerns of reaching out to casual partners are likely to be too great.

He also suggests the novel approach of asking stable partners for their consent to their partner taking part in the study. Offering this veto would make the risk of HIV transmission “ethically more justifiable” he says, as the person exposed to the risk had consented to it.

The partner could consider the balance of risks and benefits for themselves. For both the person actually taking part and for their sexual partner, the direct benefits are minimal or non-existent (so far, no HIV remission studies have been clinically beneficial). For both, the main benefit is altruistic - the knowledge that they are contributing to scientific research. However the participant and the partner are exposed to different risks.

Researchers could be obliged to offer counselling and information on the treatment interruption, condom use and PrEP to stable partners. A further step would be for the researchers to actually provide PrEP to those partners who would like to use it.

However, Professor Jean-Daniel Lelièvre of the Université Paris Est Créteil argues that PrEP won’t be a solution to all problems. It is not certain that PrEP will eliminate risk to sexual partners, given that there are no data on its effectiveness in the context of the very high and sustained viral rebounds that could occur in an ATI. Moreover, in communities where PrEP is not generally available, is it ethical to selectively provide PrEP when others at high risk of HIV are denied it?

One reason those running clinical trials might not want to get further involved with participants’ sexual partners is that it would create a direct relationship with them. Pharmaceutical companies and other trial sponsors may be worried that this would imply that they would be legally (or morally) responsible should a partner come to any harm.

Eyal argues that this stems from a misunderstanding of the legal framework in which studies are conducted. There is no legal requirement for study participants - never mind their sexual partners - to be compensated if they come to harm. Moreover, he believes that taking care of sexual partners is essential to preserving public trust in medical research generally and in HIV-cure research specifically. Regardless of the formal position that sexual partners are not study participants, “there is no guarantee that in the court of public opinion, injury to a sexual partner would be judged any more leniently than injury to a participant”.

The choice of participants

Other ways to reduce the risk of HIV transmission focus on the person taking part in the study and don’t necessarily require their partner to be contacted. The informed consent process should be thorough and fully explore the ways in which partners can be protected. Throughout the trial, regular counselling on safer sex and contraception is necessary.

Also, a study’s exclusion criteria can be used to prevent the participation of individuals judged at greater risk of onward transmission, just as the criteria are already used to exclude individuals whose medical history suggests they are more likely to be harmed by a viral rebound.

“Inclusion criteria should be used to select for individuals who may be better able to navigate safe sex practices,” says Liza Dawson. This might exclude: individuals reporting sex without any form of protection, people who say their partners would not want to use condoms or PrEP, people who have had recurrent sexually transmitted infections, and those struggling with substance use.

Potential participants reporting casual partners could also be excluded. “Reported multiplicity of partners would usually increase both the probability of and the risk from infection, both cumulatively and for each partner, for example, by making counseling of all on safe sex and on ART adherence more difficult,” says Nir Eyal.

This might appear to be an unfair restriction on who can take part in these studies. But Dawson says that this concern is misplaced - exclusion from research is an ethical issue when taking part might offer a direct clinical benefit, which is highly unlikely in this case.

Conclusion

The authors also consider - and reject - several other possible measures. These including seeking ‘community consent’ for the risks to unknown persons, enrolling partners as study participants, and geographically isolating study participants during an ATI.

But what is remarkable, say Eyal and Deeks, is how few of the recommendations made by the contributors to the supplement have been implemented in HIV remission studies to date.