Pausing ART to Identify Biomarkers for HIV RNA Rebound: Safety and Ethical Considerations

The evaluation of new strategies to achieve an antiretroviral therapy (ART)-free remission from HIV will require demonstration of efficacy through ART interruption. There are concerns about stopping ART, including patient safety, selection of drug resistance, and increased risk for HIV transmission. Identifying biomarkers to reliably predict time to viral rebound when ART is stopped could greatly accelerate the engagement of industry sponsors and other stakeholders in HIV cure efforts. Here, we discuss a new approach, namely, intensely monitored antiretroviral pause (IMAP), to identify such biomarkers and accelerate progress toward an HIV cure.

Sara Gianella Weibel, MD, on behalf of Infectious Disease Advisor, talks with Jonathan Li, MD, assistant professor of medicine at Harvard Medical School, Boston, Massachusetts, and Karine Dubé, DrPH, assistant professor at the University of North Carolina, Gillings School of Global Public Health, Chapel Hill, about the implications of requesting study participants to pause ART as part of HIV cure-related research and clinical trials.

Infectious Disease Advisor: Is there any clinical indication to interrupt ART?

Jonathan Li, MD: If there are ART regimens that are working and tolerated by the patient, there is really no clinical indication for stopping treatment outside the research setting.

Infectious Disease Advisor: Nevertheless, we are asking participants to interrupt ART as part of clinical trials for HIV cure. Why is this important?

Dr Li: One of the main goals for the HIV field is to find treatments for an HIV “functional cure” (ART-free HIV remission). The ability to achieve HIV remission has the potential to transform this epidemic. There are millions of people across the globe without reliable or universal access to HIV therapy. A readily available, safe, and effective strategy for HIV remission could enhance the well-being of people in those settings and reduce the cost of HIV care and may help reverse the spread of HIV worldwide. In addition to the freedom of not having to take medications, HIV remission could also prevent adverse effects resulting from long-term drug exposure and could remove the burden and the reminder of daily treatment adherence. This, in turn, would likely reduce the stigma surrounding HIV, which can have debilitating effects on those living with the condition.

HIV treatment interruption studies are important to evaluate new strategies for HIV remission. Unfortunately, for the time being, there is no alternative way to definitively evaluate the efficacy of such strategies. No test exists that can predict when a viral rebound will occur after pausing HIV therapy, and it is unknown why some individuals rebound quickly but others remain suppressed for an extended period of time.

Without the knowledge of when and why a person with HIV experiences a viral rebound after pausing treatment, it is challenging to develop strategies for achieving long-term HIV remission.¹

Infectious Disease Advisor: You are conducting a clinical trial of ART interruption as part of the AIDS Clinical Trials Group (ACTG). Can you describe this study?

Dr Li: A5345 is a study from the ACTG (ClinicalTrials.gov identifier: NCT03001128), also known as the IMAPs study. Our goal is to find biomarkers that can help us predict when HIV will return to detectable levels in those pausing ART. Participants in ACTG A5345 will pause their ART under carefully controlled conditions that include very close clinical and laboratory monitoring. As soon as HIV becomes detectable above a certain level, their ART will be immediately restarted and participants will be monitored until their virus has become suppressed again in the blood.

To identify potential biomarkers, we will conduct a battery of blood tests to study both the virus and the immune system. In addition, we will evaluate the role of early ART treatment on the possibility of HIV remission and the effects of short-term ART pauses on the HIV reservoir and immune activation.

We expect that most participants will be pausing their ART for only a few weeks, but there may be rare individuals who will be able stop ART for much longer (also called “posttreatment controllers”). We anticipate that only a very small subset of participants will be able to control the virus without treatment.

The blood samples and data collected in this study will be made available to researchers from around the world who are working toward the goal of HIV remission. Our hope is that the results of this study will bring us closer to finding a strategy that could free our patients from daily HIV medications and have a profound effect on those parts of the world where access to ART remains challenging.

Infectious Disease Advisor: Is it safe to discontinue ART as part of a clinical trial? Why is this different from a “real-life” clinical setting? What are the risks?

Dr Li: The ACTG A5345 study team, under the oversight of the National Institutes of Health’s Division of AIDS, has worked closely with the laboratories and research sites to ensure that participants are pausing ART for the shortest possible time. Although there are always risks associated with ART interruption,¹ this strategy of very close monitoring and rapid ART restart has proven safe in several recent studies.^2-4

As with any clinical trial, ACTG A5345 is not for everyone. Individuals involved in the screening process and currently enrolled study participants have cited 3 main reasons for taking part in the ACTG A5345 study:

• A sense of altruism to “give back to those who came before them.”
• A desire to “take a break” from medications, but do so in the safest way possible.
• An eagerness to be “part of the team” that leads to HIV remission.

Infectious Disease Advisor: What precautions are in place to minimize risks for study participants of HIV interruption studies?

Dr Li: The ACTG A5345 study is being conducted under rigorous clinical trial safety standards with direct oversight from ACTG Network Leadership, Division of AIDS, and National Institute of Allergy and Infectious Diseases representatives. Through careful selection of participants, frequent viral load monitoring, and the requirement of a rapid restart of HIV therapy when rebound is detected, ACTG A5345 ensures that no study participant is exposed to any avoidable risks. The ACTG A5345 study is approved by each participating site’s Institutional Review Board. With strict inclusion criteria and a carefully planned study design, those who choose to take part in ACTG A5345 should feel confident that their safety is of the utmost importance to the study team.

Infectious Disease Advisor: Dr Dubé, what is your role in the ART interruption study?

Karine Dubé, DrPH: I am a social scientist assigned to assessing how ACTG A5345 study participants understand the purpose of the antiretroviral pause. I will examine how participants experience the pause of anti-HIV medications at strategic points during the study: before the pause, after the viral rebound, and at the end of the study (after viral resuppression). There will also be a separate questionnaire for posttreatment controllers.

Infectious Disease Advisor: Do you see any ethical issues in asking individuals to interrupt ART for HIV research, while this practice is strongly discouraged in clinical setting?

Dr Dubé: As Dr Li mentioned before, IMAPs go against the standard of care for HIV treatment, so they are not recommended in clinical practice. Here, IMAPs are being used in a carefully controlled research context to better understand the biomarkers that will predict viral rebound. There are several ethical and social considerations related to IMAPs. We need to ensure that study participants are truly informed about the possible risks of the IMAPs. Risks are also minimized to the fullest, which includes not only the clinical risks but also the psychosocial and financial risks. Because viral rebounds can be unpredictable, we need to ensure that participants adhere to protection methods so that they do not pass the virus to sexual partners. Study participants also need to have a back-up regimen of anti-HIV medications. There need to be clear criteria for restarting anti-HIV medications. We believe ART interruption in the setting of a clinical study can be done ethically if critical safeguards are in place. There are a couple of studies that explore the scientific and ethical considerations for interrupting ART in HIV cure research.^5,6

Infectious Disease Advisor: In your experience, are individuals living with HIV willing to undergo risks related to ART interruption for the sake of cure research, and why?

Dr Dubé: We found a lot of variability in willingness to undergo IMAPs in our social sciences studies in the United States. In a quantitative survey of 400 people living with HIV, 68% of respondents were very willing or somewhat willing to interrupt treatment as part of an HIV cure-related study.⁷ However, in our key informant interviews and focus group discussions, we noticed more reluctance to undergo IMAPs, particularly among those who have been infected with HIV for a long time and had to work hard to become virally suppressed.

The main motivations to undergo IMAPs were advancing scientific progress, contributing to HIV cure research, and altruism. We need a lot more social science research to better understand motivations to undergo IMAPs as part of actual HIV cure studies. This is what we hope to do as part of the ACTG A5345 study.

Infectious Disease Advisor: What are the most important steps to follow to engage the HIV community in cure research and ensure they are informed of risks and benefits?

Dr Dubé: HIV cure science is evolving quickly, and can be very complex. We need to ensure that we have reliable sources of information about possible risks of HIV cure-related studies. An initiative called the CUREiculum can help make HIV cure science accessible to the community.

We also need to allow dialogue to take place among biomedical HIV cure researchers, people living with HIV, bioethicists, social scientists, and community advocates. This dialogue needs to be sustained. Community members should be involved in the design of the study. In fact, community involvement is a critical safeguard in clinical research. After the study, data should be disseminated in lay terms to the community to show how the involvement of people living with HIV has helped advance HIV cure science.

Also, it is important to remember that HIV cure-related research includes various strategies. Some of the HIV cure studies are simply observational, without any intervention (such as the ACTG A5345 study). Others aim to assess how HIV persists in the body, in the so-called “reservoirs.” Only very few HIV cure-related studies involve IMAPs. Ideally, the HIV cure research community would have a mechanism or platform to engage multilevel stakeholders to discuss (clarify or derive consensus) specific controversial issues that emerge as part of HIV cure-related research on an ongoing basis. IMAP is a topic on which the field needs more consensus.

References

1. Li JZ, Smith DM, Mellors JW. The need for treatment interruption studies and biomarker identification in the search for an HIV cure. AIDS. 2015;29:1429-1432.
2. SPARTAC Trial Investigators, Fidler S, Porter K, et al. Short-course antiretroviral therapy in primary HIV infection. N Engl J Med. 2013;368:207-217.
3. Volberding P, Demeter L, Bosch RJ, et al; ACTG 371 Team. Antiretroviral therapy in acute and recent HIV infection: a prospective multicenter stratified trial of intentionally interrupted treatment. AIDS. 2009;23:1987-1995.
4. Rothenberger MK, Keele BF, Wietgrefe SW, et al. Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc Natl Acad Sci U S A. 2015;112:E1126-1134.
5. Dubé K, Evans D, Dee L, et al. “We need to deploy them very thoughtfully and carefully”: perceptions of analytical treatment interruptions in HIV cure research in the United States-a qualitative inquiry [published online July 10, 2017]. AIDS Res Hum Retroviruses. doi: 10.1089/AID.2017.0067
6. Garner SA, Rennie S, Ananworanich J, et al. Interrupting antiretroviral treatment in HIV cure research: scientific and ethical considerations. J Virus Erad. 2017;3:82-84.
7. Dubé K, Evans D, Sylla L, et al. Willingness to participate and take risks in HIV cure research: survey results from 400 people living with HIV in the US. J Virus Erad. 2017;3:40-50.