https://orcid.org/0000-0002-6471-4200
Commentary
At a recent annual meeting of one of the Martin Delaney Collaboratories for HIV Cure Research, a Principal Investigator expressed their desire to hear from the community regarding current perceptions and acceptability of HIV cure-related research strategies as well as participants’ willingness to tolerate potential adverse events of cure research interventions. As a community member, I understood that such questions should be the focus of future research. In this commentary, I offer my personal experience and views in the hope that they are helpful in some way to the field of HIV cure-related research and to informing person/participant-centered approaches.
About me
I am a 60-year-old gay white male living in the United States with HIV for approximately the past twenty-five years. I have been on antiretroviral therapy (ART) for the past twenty years, currently take a one-pill-per-day regimen and have an undetectable viral load. While my HIV has been consistently well managed, I have over the years suffered a number of coinfections (e.g., hepatitis C (HCV), herpes simplex virus (HSV), shingles leading to Methicillin-resistant Staphylococcus aureus (MRSA)-induced osteonecrosis of the cervical spine), comorbidities (hypertension, depression) and complications of HIV (weight gain and changes in lipid levels during the past three years while on tenofovir disoproxil fumarate (TDF)/tenofovir alafenamide (TAF) regimens; post-infection syndrome after both MRSA and COVID-19). While combination ART has made HIV a manageable chronic condition for many of us with access to it, living with HIV is no walk in the park.
My clinical research experience
I have been involved with various aspects of clinical research since I worked for a biotechnology start-up company (1989 – 2003) that developed and introduced into clinical practice new technologies to diagnose and monitor cancer. I worked in business development with various roles in sales, in recruitment and support of clinician-investigators, and as co-developer of a just-in-time health information service for cancer-treating physicians and their patients. For the past decade, I have served on various advisory boards to support HIV clinical research focused on HIV prevention (e.g., HIV Prevention Trials Network (HPTN), treatment (e.g., AIDS Clinical Trials Group (ACTG), Center for AIDS Research (CFAR)) and cure research (e.g., Martin Delaney Collaboratories for HIV Cure Research (MDC)). I knew and know clinical researchers as colleagues, as clients and as personal friends.
Over the years, I have participated in perhaps two dozen HIV-related clinical studies. Some have been observational studies to assess various HIV-related aspects of my health and monitor changes over time. Others have been investigational trials to test safety and efficacy of potential treatments for HIV or its effects on the body. I participated in an analytical treatment interruption (ATI) trial from August 2019 – September 2020. The aim of the trial was to test if combination infusion of two investigational agents (monoclonal antibodies (mAbs) VRC01 and 10-1074 administered together) was safe and effective to help control HIV infection without taking daily ART. My experience in the trial was positive despite the onset of the COVID-19 pandemic during the second ATI.
I share the above details to illustrate that I am quite familiar and comfortable with clinical research and the healthcare system, perhaps more so than some others living with or affected by HIV. This of course may color my views.
My hopes for HIV cure research
I can recall as if it were yesterday the precise moment I read the first newspaper report of the strange new disease affecting gay men in San Francisco and New York City. I was still in school at the time, living with my parents and siblings in a small village of 800 on the rural North Fork of Long Island, NY. I did not yet understand fully or accept that I was gay, yet I knew with cold dread that the news article affected me personally.
To this day, if I close my eyes and call myself back to the family room of our home that Sunday morning where I sat on the floor next to Dad’s favorite chair to read each section of the newspaper as he finished with it, I can feel my heart drop upon reading that one-paragraph news blurb, my face flush, and my fear that others in the room would somehow sense and know about me, my otherness. In the many years since that day, I have lost friends to this disease. I have also had the privilege to work with fiercely intelligent and dedicated scientists, philanthropists, and advocates to end this pandemic, an end I hope to witness in this life.
While we now have dozens of effective interventions (behavioral, biomedical, and non-pharmaceutical) to prevent or treat HIV, they have to date proven insufficient. Ending the HIV epidemic will likely require also effective vaccines and cure strategies.
My perceptions of cure interventions: ‘classical’ versus ‘functional’ cure
Classical cure
My ideal would be the development of cure interventions to eliminate HIV from the body, preferably after a single, tolerable treatment intervention that could be made widely accessible to all people living with HIV (PLWH). Intervention(s) that work with high efficacy/high probability of success and for which treatment outcome (cured/not cured) could be determined promptly after treatment.
Maximizing the social value of cure research requires intentional efforts to develop effective virus eradication interventions both for PLWH who have benefited from rapid-start ART during acute infection and also for the much larger population of PLWH who live with chronic infection and may as a result have larger latent reservoirs to address.
As an interim step toward classical cure strategies, I am willing to accept functional cure (with conditions, described below).
As a volunteer research participant, I am most interested to participate in research towards a classical cure (clearing the virus completely from the body), understanding that such participation in today’s early-stage clinical trials would not benefit myself directly but would help advance the science in some meaningful way to benefit the next generation of PLWH.
Functional cure
I see tremendous value in functional cure intervention(s) that show meaningful effect to reduce or eliminate chronic immune activation, inflammation, and resulting comorbidities. Effective relief from these HIV-associated comorbidities would greatly benefit PLWH and is a worthy research objective in and of itself.
I see acceptable value in research toward functional cure (e.g., block and lock) in which the specific intervention holds promise of further development toward permanent HIV silencing – of viremia, of pro-viral replication, of chronic immune activation and inflammation – and/or toward complete HIV elimination (excision).
In my experience, taking the present generation of ART is both easy to do and effective to maintain undetectable viral load. As a result, I do not see benefit to undergo a complex, expensive cure-directed intervention to achieve a functional cure if the only net benefit is that I would no longer need to take a daily pill (ART). Such benefit is already within reach with long-acting injectable ART (LAIs) without the likely risk and expense of more-complex cure interventions.
As a volunteer research participant, I would consider participation in either of the first two functional cure scenarios but probably not for research whose net benefit would be to eliminate the need to take daily ART and nothing more.
Administration routes
I have taken (for various conditions) and find acceptable oral administration, injection, and/or infusion. All have been safe and well tolerated. Also acceptable and well tolerated are the full range of clinic visits, physical exams, lab work, and specimen collection procedures, including leukapheresis, that are integral to many cure-directed interventions.
Access and uptake
To maximize access and uptake of any effective cure intervention, special attention must be paid to the attitudes, perceptions and acceptability to the full diversity of PLWH, their partners and families, and to other community stakeholders; to psychosocial readiness, preparation and support of intervention recipients, their partners and families before, during and after interventions; to the required healthcare infrastructure and logistics, e.g., shipping and storage; to effective implementation into clinic workflow; and to the related matters of total cost of the intervention (includes all clinic visits, lab work, etc.), cost effectiveness (relative to other treatment options, to outcomes, etc.), and payment/insurance reimbursement, etc. Effective cures that remain out of reach of those who might benefit from them may not meet the high social value required to justify the risk and expense involved in their development.
Adverse events (AEs)
I find acceptable any type of mild-moderate physical AEs (fever, chills, flu-like symptoms) or psychological AEs (anxiety, uncertainty, worry) of short-term duration (several days-weeks) that can be managed effectively with standard interventions that are understood and accessible. I consider routine, and therefore acceptable, any discomfort, pain, bruising, and/or low risk of infection from venipuncture, injections, and infusion.
Unacceptable AEs include unintended onward transmission of HIV to sex partners, children, or others. To reduce such risks, we must develop now effective partner protection strategies for the diverse groups impacted by HIV. We must anticipate the likelihood that few participants would be willing to commit to abstinence expected to last for months or years during ATI or after a cure intervention. Likewise, low rates of condom use and suboptimal uptake of pre-exposure prophylaxis (PrEP) make clear the need for other/additional partner protection methods with high efficacy and greater acceptance.
Finally, we must modernize both criminal and civil laws to reflect advances made (and ongoing) in the fields of HIV prevention, treatment and cure research to reduce or eliminate any potential legal risks from failure to disclose HIV status to sex partners; exposing sex partners to HIV even in the absence of transmission; and/or unintended transmission of HIV to a sex partner after a cure intervention. What is my responsibility to disclose, if any, that I once had HIV but have since been cured? From a legal perspective, am I considered cured after testing negative once? After a confirmatory negative test? Or must I test negative on an ongoing basis to protect myself from legal risk? In this era of condoms, PrEP and post-exposure prophylaxis (PEP), what responsibility does my partner(s) share to protect themselves?
Other unacceptable AEs would include further damage to the immune system that would leave the recipient in worse condition than before the intervention or significantly increased risk of serious AEs such as heart attack, stroke, life-threatening blood clots, organ failure, etc.
Also unacceptable would be the development, testing and/or implementation into clinical practice of any biomedical cure intervention without accompanying evidence-based psychosocial supports for recipients, their partners and families. HIV is an infectious disease transmitted through intimate contact with others – through sex, through sharing of drug ‘works’, through the birth process. As a result, living with HIV affects one’s fundamental perception and understanding of oneself and their relationship to others. To be effective, to win broad uptake, and to meet the fundamental ethical requirement to avoid causing harm, cure interventions must be designed and implemented within the contexts of both whole-person and social health.
We must be able to tell people with confidence when and how it is safe for them and their partners to resume sexual activity after an ATI or cure intervention. If and how they may have children while minimizing risk of transmission, to each other and to the child. Whether and under what conditions it might be safe to donate blood or organs to others in need.
Now is the time to identify and consider such questions, to design and put into place the processes needed to answer them, over time. Failure to do so would place cure trials participants and cure recipients, their partners and communities at unacceptably high risk of unintended transmission as well as of potential harm to mental and social health. Such harm must be avoided, even if doing so would require a pause in cure research to provide time to build, test and implement the necessary safeguards. We must act now to avoid such delays.
Unacceptable social AEs to cure intervention recipients include potential loss of housing, health insurance/healthcare coverage, disability or other social safety net services without first benefitting from a formal and evidence-based assessment to determine if the cured individual is both capable and ready to return to self-sufficiency without those supports, then provided time and assistance to make that transition successfully. Tossing persons into the street, so to speak, after cure would in fact cure little.
Also unacceptable would be any health, employment, or public policy mandates or sanctions that require or coerce PLWH to undergo cure interventions involuntarily at any time for any reason. We saw panicked and politicized imposition of such mandates during the public response to the recent COVID-19 pandemic and need to plan now to avoid similar ethical failures with HIV cure strategies.
As a clinical trial participant, my decision to volunteer for a specific clinical trial is made with consideration not only of any short-term/immediate risks during an ATI but also of potential future/long-term (5+ years) risks such as increased risk of cancer, cardiovascular disease (CVD), etc., risks of which little is known today. Now is the time to begin assessment of such long-term risks together with continuous updates to the informed consent process as more is learned.
To help ensure continued community support and an adequate supply of prospective participants for scaled-up ATI trials, I strongly recommend creation of a curated online public platform highlighting the individual experiences of HIV cure research participants. In this way, those with lived experience might engage and inform the public to increase health literacy and acceptance of cure research and interventions.
I thank all those who invite community views and all those who work toward ending this epidemic.
Rockville, MD
Acknowledgements
Many thanks to Jeff Taylor and Karine Dubé for encouraging me to share my perspectives, and special thanks to Karine Dubé for her assistance in submitting this manuscript for publication.
Disclosure statement
No potential conflict of interest was reported by the authors.