When IRBs review HIV studies, particularly those aimed at finding a cure to the disease, there are some tricky ethical challenges that might not be seen in other types of research.
The following are some of the chief ethical issues that can arise:
• Participants on analytic treatment interruption (ATI) might miss the tipping point for post-treatment control. Another type of “cure” for HIV is called post-treatment control, which occurs when a patient can stop his or her medication regimen and still remain free of detectable HIV. Researchers have studied participants with HIV to identify and learn from this phenomenon. Investigators also are studying potential treatments that would make it more likely an HIV patient achieves post-treatment control, says Rowena Johnston, PhD, vice president and director of research of amfAR, the Foundation for AIDS Research, in New York City.
The way to see whether post-treatment control is working is to take the patient off antiretroviral therapy for some weeks. If the viral load starts to rise and then falls to undetectable levels, or if it never rises, then post-treatment control might be achieved, and the person may no longer need to take daily antiretroviral therapy (ART).
Some of the research being performed with regard to post-treatment control includes a therapeutic HIV vaccine regimen and a short course of an HIV latency-reversing agent. (http://bit.ly/2ACFNc7)
“Any number of interventions could bring post-treatment control, and they all would need to go through analytic treatment interruption,” Johnston says.
“When ART is taken away, there is a virus rebound, and it can go to a very high level. But the immune system might take over and bring it back down,” she adds. “It’s a game of chicken to wait for an opportunity for the immune system to kick in.”
The ethical dilemma with this type of research involves how to fully inform participants of the risks of taking away their antiretroviral therapy when researchers do not know what will happen to an individual patient. And the study participant could be off ART long enough to see the viral load rise to 100,000 copies, Johnston explains.
“But you may miss post-treatment control if you start the person back on ART too early,” she says.
The unanswered question is, “Where is the tipping point?”
“There’s not a whole lot of consensus on that issue right now,” Johnston says. “There have been trials where the clinician wanted to wait to see where post-treatment control would happen, but the participant got so nervous, they put themselves back on ART.”
And there are failures. One study using ATI did not work, and those participants had to return to antiretroviral therapy, she notes.
“It’s a shot in the dark,” Johnston says. “You don’t know how long they’ll be off ART or how much they can tolerate.”
• Research participants might infect others. Participants must be in cancer remission, and their HIV must be undetectable. But there still is a risk of infecting someone else with HIV if ART is stopped through ATI, Johnston says.
The reason for this is that if a patient’s stem cell transplant successfully put the cancer in remission and the patient then is taken off ART for the HIV infection, there is a possibility that the patient’s HIV could rebound and lead to the person infecting someone else with the virus.
“Say you’ve gone six months without a rebound, and the doctor thinks, ‘I’ll test you every two weeks and see if you do have a viral rebound’ — then your virus might have a chance to go high enough that there’s a risk you’ll transmit that virus to somebody else,” Johnston says.
Potential participants would learn of this complex risk from informed consent, and they would be advised to use condoms. But it raises the issue of informing participants’ partners.
• Participants might not inform partners. “Getting partners involved is an ethical issue that people wring their hands over,” Johnston says. “They might not have disclosed to partners that they have HIV or have participated in the trial.”
An ethical challenge is whether this disclosure should be required when the participant will receive analytic treatment interruption.
“How do you handle this disclosure to partners?” she asks. “And not everyone has one partner. The population living with HIV includes people who might have multiple partners, whose names and contacts they don’t know.”
One way to prevent HIV-negative partners of HIV patients from becoming infected with the virus is for them to take pre-exposure prophylaxis (PrEP), which is a daily course of HIV medication that can lower their chances of getting infected. According to an HIV government website, daily PrEP reduces the risk of contracting HIV from sex by more than 90%, and its most common risk is nausea. (http://bit.ly/2racrxp)
Researchers have wondered whether they can require participants to ask partners to take PrEP to prevent HIV infection. And should the study pay for their PrEP?
At a consensus workshop, researchers and HIV advocates voted on a proposed course of action. Most voted that PrEP should be discussed and that clinical trial participants and their partners should be made aware that PrEP was recommended, Johnston says.
“The most common thought was that the trial should pay for PrEP, but that puts a lot of burden on funders,” she adds. “It potentially adds so much to the cost and risk of a trial that it would be difficult to get as many trials done as we would like to see out there.”
• Antiretroviral therapy might not work as well when patients return to it. HIV medications are much more effective now than they were a decade or two ago, but there still is a risk that a patient who has stopped ART will develop drug resistance when returning to the treatment.
“In one trial, a participant was supposed to go back on antiretroviral therapy but was not adherent and didn’t disclose to the trial that he was not adhering to ART,” Johnston recalls. “He developed drug resistance.”
If HIV-infected patients adhere to their medication regimens, drug resistance is not an issue, she adds.
“Drug resistance happens when viral replication happens, and they don’t have viral replication in the ART period because it’s been a latent cell and it’s not producing virus that goes on to infect other cells,” she explains. “You need replication to get evolution, and evolution is what leads to resistance.”
When HIV trial participants are monitored weekly for viral rebound, typically there is minimal risk of drug resistance. This is because they will detect the viral rebound and ask the patient to return a few days later for a confirmatory test.
With only one week of potential exposure to viral replication, there is not enough time for drug resistance to develop, and the person should be able to return to the same antiretroviral therapy used previously, Johnston adds.
• Is it ethical to ask people to make these choices? Before giving research participants informed consent, the studies must be reviewed and approved because there is some public good that might be achieved with answering the research question. Few would dispute that finding a cure to HIV would be a public good. But these studies have risks that are difficult to describe and define.
Johnston says the issue is especially difficult given that HIV research participants tend to be compassionate individuals.
“We’re very dependent on altruism of participants,” Johnston says. “Those who participate in HIV cure trials are incredibly altruistic; they understand that they might not directly benefit from a trial, but they’re doing it for their community.”
HIV research participants might know that a particular trial will be part of a puzzle that builds a solution, although not necessarily in their lifetime, she adds.
It is incumbent on investigators and IRBs to ensure participants understand all of the known potential risks. One strategy is to use videos. Another is to interview participants after the informed consent process to probe their comprehension. Investigators could give them a comprehension test about the study, Johnston says.
“There’s also an idea that informed consent should not be a one-time thing,” she adds.
“These trials tend to go on a very long time, and someone might be given a series of interventions over four to six months. Researchers could check in to see if their understanding is the same as when the person started in the trial.”
One innate problem with informed consent for a study of a cure to a dangerous disease is the participant’s sense of exceptionalism.
“One thing that informed consent will never resolve — and you can tell a person until you’re blue in the face that the chances of their being cured is infinitesimally small — is the sense that ‘I might be the lucky one,’” Johnston says.
That feeling of exceptionalism will exist in every clinical trial involving a disease in search of a cure, she adds.