Ethical considerations for HIV remission clinical research involving participants diagnosed during acute HIV infection
BMC Medical Ethics volume 22, Article number: 169 (2021)
HIV remission clinical researchers are increasingly seeking study participants who are diagnosed and treated during acute HIV infection—the brief period between infection and the point when the body creates detectable HIV antibodies. This earliest stage of infection is often marked by flu-like illness and may be an especially tumultuous period of confusion, guilt, anger, and uncertainty. Such experiences may present added ethical challenges for HIV research recruitment, participation, and retention. The purpose of this paper is to identify potential ethical challenges associated with involving acutely diagnosed people living with HIV in remission research and considerations for how to mitigate them. We identify three domains of potential ethical concern for clinicians, researchers, and ethics committee members to consider: 1) Recruitment and informed consent; (2) Transmission risks and partner protection; and (3) Ancillary and continuing care. We discuss each of these domains with the aim of inspiring further work to advance the ethical conduct of HIV remission research. For example, experiences of confusion and uncertainty regarding illness and diagnosis during acute HIV infection may complicate informed consent procedures in studies that seek to recruit directly after diagnosis. To address this, it may be appropriate to use staged re-consent procedures or comprehension assessment. Responsible conduct of research requires a broad understanding of acute HIV infection that encompasses its biomedical, psychological, social, and behavioral dimensions. We argue that the lived experience of acute HIV infection may introduce ethical concerns that researchers and reviewers should address during study design and ethical approval.
While exact definitions vary , acute HIV infection (AHI) generally refers to the brief period (circa 25 days; designated Fiebig stages 1 and 2) between initial infection and detectable HIV-specific antibodies, i.e., seroconversion [1,2,3]. It is during this time that individuals are most infectious [4,5,6], yet their HIV infections are undetectable using HIV antibody assays . As a result, many people are unaware that they are living with HIV [8,9,10]. During early AHI, reservoirs of replication-competent viral DNA become established within the body [11,12,13]. These latent reservoirs comprised of memory CD4 + T [14,15,16] and other cells [17, 18] largely account for HIV’s current incurability, despite the effectiveness of combination antiretroviral therapies (cART) [11, 19,20,21,22]. However, initiation of cART during the earliest stages of infection may limit reservoir size [11, 23, 24]. Moreover, people diagnosed and treated with cART during AHI (referred to here as “AHI people”) tend to have better long-term prognoses than those diagnosed and treated at later stages . AHI people are known to have less severe inflammatory responses [26, 27], less genetically diverse infections , and fewer comorbidities associated with chronic HIV infection (CHI) . Additionally, research suggests that they may have faster immunological recovery , decreased immune activation and exhaustion and better preservation of HIV-specific immunity , greater potential for post-treatment HIV control, and less opportunity for viral immune escape [32, 33].
For these reasons, AHI people have long been of special interest for HIV prevention and treatment research [12, 34]. In recent years, AHI people have also increasingly become important for research aimed at achieving HIV remission [11, 19, 35, 36]. By HIV remission, we mean long-term cART-free control of viremia at undetectable levels without complete viral elimination, which is more feasible than viral eradication . There is good reason to believe that limiting the establishment of HIV latent reservoirs in the body may be an initial, yet crucial step in the development of therapies that can consistently achieve HIV remission [39, 40]. If this proves to be the case, AHI people [41,42,43] may be among the first to achieve long-term, post treatment control of HIV .
However, AHI’s short duration,  combined with HIV diagnostic limitations for detecting HIV prior to antibody production, [1, 7, 45] make AHI people relatively difficult and more costly to identify and recruit for research [45,46,47]. Despite these challenges, several HIV remission studies involving AHI participants are in progress or completed,  more are planned,  and numerous AHI research cohorts already exist [50,51,52,53,54,55,56,57].
While these efforts have already led to a better understanding of HIV pathogenesis [35, 58], potential ethical issues associated with the inclusion of AHI people in clinical research have received comparatively less attention , although empirical reports are starting to emerge . This gap is concerning because studies involving potentially more vulnerable participants (i.e., those more susceptible to incurring wrong via research participation) [61,62,63] generally require increased ethical scrutiny [64, 65]. Existing research suggests that certain social [8,9,10, 66,67,68,69,70,71,72], psychological [73, 74], and illness [23, 75] experiences associated with AHI may make some participants uniquely susceptible  to adverse outcomes. Yet, one question that remains is to what extent the lived experiences and needs of AHI participants vary significantly from those of people newly diagnosed or already living with CHI.
HIV remission studies involving people living with HIV are scaling up globally. The potential risks posed to participants by these studies cover a wide range, from very low (e.g., observational studies and low-risk procedures such as leukapheresis and brain MRI) to higher risk (e.g., longer-term analytical treatment interruption, experimental and/or potentially toxic interventions, invasive study procedures such as lumbar puncture, lymph node and colon biopsy, etc.). In this paper, we consider how lived experiences might differ between AHI and CHI people and identify potential ethical issues that may warrant greater scrutiny during research proposal design and review, especially for higher risk studies. Our aim is to identify points to consider for clinicians, researchers, and ethics committee members regarding the recruitment, retention, and monitoring/care of adult AHI people. Our hope is to encourage dialogue between researchers, ethicists, and other stakeholders, to inform the design and conduct of future studies, and to suggest needed avenues for further research.
The social, behavioral, and psychological dimensions of acute HIV infection
Regardless of one’s stage of infection, receiving an HIV diagnosis is a difficult, life-changing, uncertainty-fraught experience . This potentially tumultuous process may involve the formation of new HIV-positive identities  and negotiating what infection means to patients, their partners, and families. For those diagnosed during AHI, evidence suggests that this time is “often a marker of chaotic events in patients’ lives”  and, similar to HIV diagnoses generally, AHI diagnoses have been linked to distress, anxiety, depression , anger, confusion , and guilt . Previous research on AHI has considered its social, emotional, and sexual hallmarks [56, 66,67,68,69,70,71, 78,79,80]. The National Institute of Mental Health Multisite Acute HIV Infection study [81, 82] found that AHI people reduced their numbers of sexual partners and serosorted, but continued to practice condomless sex . This study also found AHI people to have a substantial burden of psychiatric morbidities, including alcohol/substance abuse disorders (though for most people, these conditions existed prior to AHI diagnosis and may therefore not be attributable to AHI ). The authors also noted limited awareness among people about the meaning and public health importance (i.e., increased infectiousness) of AHI .
Although AHI people and those diagnosed during CHI seem to have similar experiences at diagnosis, including shock, hopelessness, and detachment , evidence suggests that AHI post-diagnosis experiences may be somewhat different. Such differences, briefly noted below, may warrant special ethical attention during the recruitment procedures for HIV remission clinical studies.
First, during the AHI period a person has not yet begun to produce detectable levels of HIV antibodies, and it may be difficult to diagnose them accurately and definitively , especially in contexts lacking access to the latest diagnostic technologies . During AHI up to two-thirds of people experience symptoms of infection known as acute retroviral syndrome (ARS) , with symptoms that include fever, rash, anorexia, body aches, fatigue, and/or headache [46, 85, 86]. These flu-like symptoms are ambiguous and easy to misattribute to other conditions [12, 46]. This, combined with the finding that many care providers are unfamiliar with AHI [8, 81], compounds known challenges in AHI diagnosis . Preliminary test results interpreted as “false positive” or indeterminate may add to patient confusion [8,9,10] and potentially foster mistrust toward the medical system, including biomedical research. Recognition of the difficulties in diagnosing AHI has led others to call for primary and emergency care providers to have a low threshold of clinical suspicion for AHI in many settings [7, 8, 10, 82].
Second, due to the shorter duration between infection and diagnosis, AHI people may have a much better understanding of the risk behaviors or sex partners that led to their infections [8, 9, 74, 78] compared to CHI counterparts. Therefore, AHI people may have more guilt and/or clearly directed resentment toward their partners [74, 78], depending on the circumstances of the suspected route of transmission. Conversely, in the age of cART and its widely understood benefits, AHI people who perceive themselves as at higher risk for infection may feel grateful to have prompt detection of HIV infection and the opportunity to begin cART early .
Third, following HIV diagnoses, almost all people receive new and potentially overwhelming information concerning HIV, their health, and the healthcare system. Soon after diagnosis, individuals must make important decisions regarding their HIV care. Examples of these decisions include where to receive care, HIV status disclosure, how to protect sex/drug use partners, whether and when to begin lifelong treatment, and whether to participate in research (if offered the opportunity). In Kenya, researchers found that people’s decisions to begin cART on the same day as their diagnosis were linked to an understanding of their advantaged status as AHI people [72, 88, 89]. For those diagnosed during AHI, these decisions may be perceived as especially urgent and anxiety-ridden, given their heightened infectiousness and the long-term benefits offered by immediate uptake of cART [90, 91]. Furthermore, studies seeking to enroll AHI people often try to do so soon (if not immediately) after diagnosis. Enrollment immediately or soon after diagnosis is less often necessary within studies involving (even newly diagnosed) CHI people.
Potential ethical issues in research involving AHI participants
Previous research has highlighted people’s experiences during AHI [8,9,10, 66, 68, 73, 74, 81, 92], the ethics of HIV treatment [93,94,95] and prevention [96,97,98,99,100,101], and the ethics of clinical research generally [102,103,104]. Additionally, much work has been dedicated to clinical research ethics for studies involving adults living with HIV [36, 59, 105,106,107,108,109,110], including issues related to informed consent [111,112,113,114,115,116], analytical treatment interruption (ATI) [60, 87, 109, 117,118,119], and risks versus benefits [120,121,122,123,124,125,126,127,128]. Following these efforts, we suggest three primary domains of potential ethical concern for HIV remission clinical studies involving AHI participants. These are: (1) Recruitment and informed consent; (2) Transmission risks and partner protection; and (3) Ancillary and continuing care.
(1) Recruitment and informed consent
Depending on the intervention, trial phase, research hypothesis and other factors, some HIV remission studies currently recruit AHI participants immediately after diagnosis, while others require that AHI participants have a history of successful suppressive therapy before they are eligible to participate . Given the immunological advantages of diagnosing HIV early, and as HIV remission research progresses and more promising interventions are found, it seems likely that future studies will increasingly recruit AHI people as early as possible. If this becomes common practice, one key ethical challenge might be how best to provide assistance, counseling, and support to recently diagnosed patients, who may be experiencing symptoms such as ARS, to increase their likelihood of making autonomous decisions to join or decline participation in remission studies.
Available research suggests that receiving informed consent from AHI study candidates at diagnosis may be especially challenging. For instance, studies have found that some AHI participants recalled not having understood the meaning of “acute” HIV during diagnosis, as well as difficulty absorbing information during post-diagnosis counselling [8, 72]. Describing their experiences in one study, a participant explained that, “emotionally, I wasn’t able to probably hear.” Another participant in the same study offered that, “my mind was elsewhere” when explaining why he could not remember discussing the significance of AHI . Other research has shown that although participants suffering from depression can understand informed consent information, they tend to be less capable of recognizing its significance to their situations, especially concerning treatment options [129, 130].
While it remains unclear whether there should always be heightened concern about the quality of informed consent among AHI participants, researchers should at least consider the possibility that unique life experiences associated with AHI might color perceptions and/or unduly bias individuals to accept or decline research opportunities. Therefore, even when individuals have provided informed consent to participate close to diagnosis and appear to comprehend the nature of a study, this understanding may be, in some cases, suboptimal or fleeting [8, 72]. However, knowing about the mental health challenges that some AHI patients face should not lead to the assumption that mental health interventions are always needed or wanted, or that an AHI participant’s decisional capacity is necessarily compromised to an extent that justifies non-inclusion. Instead, capacity to provide valid informed consent should be assumed unless the participant (or their behavior) suggests otherwise. If researchers recognize these issues from the outset, they can plan to provide more interactive and much longer than usual sessions for informed consent  and/or incorporate tests of understanding and informed consent comprehension enhancement strategies [131,132,133,134,135,136]. If concerns around psychosocial issues arise, referral mechanisms for mental health services  should be included in a protocol's design and budget.
To ensure patients do not feel rushed to make decisions about participation, and to help mitigate the aforementioned issues related to informed consent, researchers can schedule recruitment and consent procedures for a time well after diagnosis. When this is not possible, or when doing so would undermine research quality or preclude conducting the research entirely, it may be advisable to employ staged informed consent, re-consent, or process consent procedures as alternative strategies. Staged informed consent refers to procedures involving more than one meeting, allowing participants additional time to think, discuss, and/or seek further advice prior to enrollment . Re-consent means providing participants with multiple opportunities to review consent materials after enrollment and to decide whether or not to continue with participation . Doing so allows participants to review at a later, calmer time their earlier decisions made at or around the time of diagnosis. As a result, participants may be able to make more informed choices concerning their continued participation in research. Process consent consists of learning more about the person before the consent process begins, assessing legal capacity, obtaining initial consent, providing opportunities for ongoing consent (e.g., frequent re-consent), and obtaining feedback and providing the participant with additional support . While process consent has been championed as a more appropriate means of obtaining consent from individuals living with dementia , other cognitive impairments, or within the context of palliative care , the “person-centered” nature of this approach could offer useful insights for researchers who work with other participants whose inclusion in research may raise similar ethical concerns.
Other challenges related to informed consent may arise if AHI people’s own healthcare providers offer them opportunities to participate in research. Primary care providers are among those more likely to identify individuals in the acute phase of HIV [1, 82] and are important gatekeepers linking people to research opportunities. A familiar worry among ethicists is that people might agree to participate in research out of deference to medical authority , fear of losing medical benefits, or feelings of indebtedness for access to the latest experimental interventions that are unavailable to the public . Unlike participants in most oncology studies, people living with HIV have access to highly effective treatment on which most can fare well for the rest of their lives . As such, joining research out of deference to medical authority or fear of losing medical benefits (even if unfounded), or in order to gain access to the latest experimental interventions, could be morally worse in the case of HIV remission research involving ATI, given the effectiveness of continued cART as the standard of care. Based on concerns similar to those outlined here, the Declaration of Helsinki suggests that researchers use non-clinical personnel to recruit patients in all clinical trials . To avoid conflating medical care with clinical research, individuals providing diagnoses should be different (when possible) from those offering research participation, even if some patients may prefer to be recruited by their already known and trusted care providers.
Early HIV diagnosis may inspire optimism among people about their disease progression [8, 144]. Such positive outlooks may be communicated or reinforced to people during the informed consent process , depending on whether and how participants are informed about why AHI is particularly important for HIV remission studies. For example, research from Thailand suggests that AHI people may come to see themselves as having bodies that are “special” to science [60, 87]. Evidence-based optimism about the long-term benefits of early-initiated cART could spill over into non-evidence based optimism (i.e., therapeutic misconception or misestimation) about the likelihood of achieving remission in early-phase trials that will not provide this benefit [105, 146, 147]. To counter this, researchers should strive to make clear to every potential participant the risks and the lack of direct medical benefit from study interventions (as appropriate), and spend more time and effort on this aim  than would be called for in other types of studies.
(2) Transmission risks and partner protections
Analytical treatment interruption (ATI) is currently a necessary component within the protocols of certain HIV remission clinical studies [49, 148,149,150]. Analytical treatment interruption involves the temporary suspension of cART in order to assess participants’ times to viral rebound or altered viral set point, proxy measures for the efficacy of a given intervention . Unfortunately, there may be multiple biological risks associated with longer duration ATI beyond any potential toxicities related to experimental interventions. These include flu-like illness (ARS), increased inflammatory immunological responses, reduced CD4 + count, reseeding of the HIV reservoir, viral drug resistance, cardiovascular, central nervous system, liver, and kidney damage, loss of the long-term immunological advantages of early cART, and decreased responsiveness to future remission interventions [109, 110, 128, 152,153,154,155,156]. Importantly, recent evidence suggests that short-term ATI does not result in permanent immune system damage, drug resistance, or expansion of the HIV reservoir . Additionally, some participants may look forward to ATI and to “feeling normal” and taking a “break” from daily cART adherence .
However, longer-term ATI does introduce the risk of HIV seroconversion for participants who would have otherwise remained antibody negative due to early treatment initiation prior to seroconversion and continued cART . The presence of HIV antibodies—and a positive HIV antibody test—could result in stigmatization and other social harm events. In certain countries such as Thailand, employment prospects, health insurance, and mortgage applications can be negatively affected . These concerns are similar to those voiced by participants living without HIV in HIV studies involving antibody-inducing vaccines who, though they remain HIV free, may test positive via antibody-based tests [158, 159]. Participant circumstances and local contexts should therefore be considered when determining the inclusion and exclusion criteria for HIV remission study protocols involving AHI participants . Such considerations have prompted suggestions to exclude AHI participants who remain antibody negative from HIV remission studies involving ATI .
There is no risk of sexual transmission of HIV while a person is undetectable for HIV under suppressive cART [161, 162]. However, participants who undergo ATI for research purposes (especially for extended periods) may increase the risk of HIV transmission to their partner(s) [107, 109, 110, 119, 128, 163, 164]. For participants, ATI may also introduce the potential for HIV superinfection (coinfection with a second strain of HIV) [151, 165, 166]. These transmission risks to participants and their partners should not be underestimated given the persistent high-risk social/sexual networks and evidence for continued post-diagnosis condomless sex found among some AHI people . Additional social and financial risks associated with stigmatization, discrimination, and/or loss of employment may be incurred , as well as legal risks for participants who live within jurisdictions that have criminalized the act of knowingly transmitting or exposing others to the risk of HIV transmission .
From an ethics or regulatory perspective, research participants’ partners do not fit the definition of “research subjects” . Despite this, researchers utilizing ATIs may have ethical and/or legal responsibilities toward third-party non-participants if doing so puts them at increased risk of HIV acquisition (if they are not already living with HIV) [169, 170]. Some ethicists have suggested that researchers should avoid conducting studies that pose serious harm to non-participants . There are at least three possible positions to consider concerning the protection of participants’ partners, distinguished by the degrees of researcher intervention.
The first, and least interventionist, places the burden of responsibility to protect partners solely on research participants: researchers are under no obligation because only participants are responsible for protecting their partners. The second also places the central responsibility on research participants, while acknowledging that they may be in need of some resources and support to do so. Here, researchers could be seen as obligated to assist participants to determine their obligations to protect their partners. A third approach would shift considerable responsibility to researchers, and impose the expectation that they act directly to protect their participants’ partners, regardless of how participants’ obligations to protect are perceived. For instance, researchers could make efforts to inform their participants’ partners of potential risks, provide these partners with preventive measures, and/or obtain partners’ informed consent.
However, the latter, more interventionist approach might present additional risks such as the introduction of conflict into participants’ relationships if research personnel seek out and interact with their partners. As was learned during the vaginal microbicide trials that considered involving the male partners of female participants, policies that force researchers to inform participants’ partners about research risks are prone to deterring individuals from participating or remaining in research studies . This is to say nothing of the potential complexities involved if participants have multiple partners, participants do not name some or all of their partners, partners are anonymous , or if a partner (or participant) does not want the relationship known to others. Would researchers need to compensate partners for the harm done to them if they acquired HIV from an ATI study participant ? Fortunately, a recent study suggests that participants in a trial involving ATI took seriously the increased risk of transmission and made behavioral changes to protect their partners .
While HIV remission researchers who utilize ATIs within their protocols should take the protection of their participants’ partners seriously, going as far as to seek them out for consent is probably too difficult and fraught, given the hypothetical situations mentioned above. That said, at the very least researchers can inform participants during consent processes about potential risks to their partners [151, 173] and provide them with condoms and/or their partners with pre-exposure prophylaxis (PrEP) [109, 110, 175] and/or referrals for regular testing, as appropriate per the context of the study and its participants . Additionally, researchers who ask their participants to suspend cART should take into consideration the potential for relationship-related harms (e.g., conflict or abuse) and social, legal, and economic harms to non-participant partners such as stigmatization, privacy violations, and employment discrimination . Depending on the circumstances, couples could be provided with counselling sessions to discuss and help process any risks versus benefits of participation, and/or partners could be invited to attend informational sessions to learn more about the study.
In the US, federal guidelines do not address research-related risks to non-participants [171, 173, 177, 178]. The burden to protect these non-participants (to the extent that it exists), and to consider whether to include discussions of these risks during informed consent processes, therefore falls on researchers, ethical reviewers, institutional funding bodies, and other stakeholders. Although others have previously made proposals for how the process of considering these risks and practices to mitigate them [179, 180] might be standardized [169, 173, 177], more research is needed to determine the most practical and efficient way forward.
(3) Ancillary and continuing care
Although clinical research does not normally involve patient care in the traditional sense, HIV remission studies with AHI participants may encounter ethical challenges regarding responsibilities for ancillary care given the known associations between AHI and mental health issues [10, 73, 74], substance abuse problems , and other comorbidities [10, 85]. Ancillary care is care that is not required to make a study scientifically valid, to ensure a trial's safety, or to redress research injuries . Ethicists (in particular, Richardson ) have developed theories to explain why researchers may have ancillary care responsibility towards research participants, and have identified factors determining to what extent ancillary care responsibilities are present. These include cases where participants have no alternative means to access care, care is relatively inexpensive, participants would otherwise suffer, participants and researchers have longstanding or deep personal relationships, and/or researchers owe research populations debts of gratitude. Given the relative scarcity of AHI people willing and eligible to participate in HIV remission research, and their important scientific contributions via risky studies with little potential for personal benefit, researchers may have a significant debt of gratitude toward this population.
Similarly, continuing care, or the responsibility to provide health benefits associated with study interventions after study completion,  is also a likely consideration in HIV remission research involving AHI participants. For instance, research interventions could eventually have relative health benefits, such as sustained viral suppression for years without treatment . If AHI participants experience prolonged viral suppression following cART interruption, only to later experience viral recrudescence (and ARS), are researchers responsible to ensure participants’ access to care, even if the need for care “outlives” the study?
While this and similar questions are speculative, what remains clear is that attention and resources must be dedicated to AHI participants’ physical and mental health issues. Not only will this contribute to minimizing research risks and balancing these risks against the scientific benefits, doing so may as well contribute toward a broader ethics of care with this particular study population.
Researchers are more likely to encounter ancillary and continuing care issues in cohort-based and longitudinal studies, as well as within research that is conducted in low or middle-income countries with weaker health care infrastructures . While much of this research currently takes place in wealthier countries, remission research is advancing quickly . As new interventions move through trial phases, these efforts may increasingly be located in the resource-constrained countries most affected by HIV in sub-Saharan Africa and elsewhere. Thus, preparation for ancillary and continuing care may become increasingly crucial. Attention to these ethical and implementation issues ahead of proposal submissions will allow researchers to adequately plan and budget for ancillary and continuing needs for AHI participants . While neither ancillary nor continuing care considerations are unique to HIV remission clinical research involving AHI people, the lessons learned by addressing questions concerning responsibilities for care will be useful to informing similar challenges in other types of clinical research.
Table 1 provides an overview of the ethical themes, potential concerns, and possible ways to mitigate risks identified above. These ethical themes and potential routes of mitigation offer a primer for meaningful ethical dialogue concerning best practices for HIV remission clinical research involving AHI participants. While some of the issues raised here may be specific to AHI participants, others may apply to all HIV remission study participants living with HIV, especially recently diagnosed CHI people. However, it is important to remember one clear distinction between studies involving AHI and newly diagnosed CHI people: the urgency with which people may be recruited into research. AHI people are often asked to enroll in studies very soon after diagnosis. In HIV remission studies involving CHI people, there is not usually the same imperative to enroll immediately. Additionally, we recognize that not all remission studies carry the same risks for participants; if and how researchers and ethics committee members should respond to these potential concerns will depend on the relative balance of risks and benefits within a given study. We also acknowledge that this list is not comprehensive and further concerns may arise. For instance, the issue of whether and when to use randomized-controlled and placebo-controlled trials will become increasingly important as interventions begin showing greater signs of potential efficacy [151, 185].
As the number of HIV remission studies around the world increases, it is important to consider further the ethical concerns raised here via empirical work and ethical analyses. Significant gaps exist concerning how lived experiences during AHI might influence research participation, as well as participant wellbeing. While these gaps clearly necessitate further research, evidence suggests that research involving AHI participants, or certain subcategories thereof, may introduce distinctive ethical concerns, or amplify those already familiar to researchers and ethicists, during research design and ethical approval processes.
Availability of data and materials
Acute HIV infection
Acute retroviral syndrome
Combination antiretroviral therapy
Chronic HIV infection
Cohen MS, Gay CL, Busch MP, Hecht FM. The detection of acute HIV infection. J Infect Dis. 2010;202(Supplement 2):S270–7.
Fiebig EW, Wright DJ, Rawal BD, Garrett PE, Schumacher RT, Peddada L, et al. Dynamics of HIV viremia and antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection. AIDS. 2003;17(13):1871–9.
Hare CB, Kahn JO. Primary HIV infection. Current Infect Dis Rep. 2004;6(1):65–71.
Wawer MJGR, Sewankambo NK. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J Infect Dis. 2005;191:1403–9.
Pilcher CD, Tien HC, Eron JJ, Vernazza PL, Leu S-Y, Stewart PW, et al. Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis. 2004;189(10):1785–92.
Selik RM, Linley L. Viral loads within 6 weeks after diagnosis of HIV infection in early and later stages: observational study using national surveillance data. JMIR Public Health Surveill. 2018;4(4):e10770.
Branson BM, Stekler JD. Detection of acute HIV infection: we can’t close the window. J Infect Dis. 2012;205(4):521–4.
Grace D, Steinberg M, Kwag M, Chown SA, Doupe G, Trussler T, et al. Diagnostic technologies in practice: gay men’s narratives of acute or recent HIV infection diagnosis. Qual Health Res. 2014;25(2):205–17.
Wolpaw BJ, Mathews C, Mtshizana Y, Chopra M, Hardie D, Lurie MN, et al. Patient experiences following acute HIV infection diagnosis and counseling in South Africa. PLoS ONE. 2014;9(8):e105459.
Zetola N, Pilcher C. Diagnosis and management of acute HIV infection. Infect Dis Clin N Am. 2007;21:19–48.
Ananworanich J, Dube K, Chomont N. How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs? Curr Opin HIV AIDS. 2015;10(1):18–28.
Cohen MS, Shaw GM, McMichael AJ, Haynes BF. Acute HIV-1 infection. N Engl J Med. 2011;364(20):1943–54.
Sedaghat AR, Siliciano RF, Wilke CO. Low-level HIV-1 replication and the dynamics of the resting CD4+ T cell reservoir for HIV-1 in the setting of HAART. BMC Infect Dis. 2008;8:2.
Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA. 1997;94(24):13193–7.
Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997;278(5341):1295–300.
Chun TW, Engel D, Berrey MM, Shea T, Corey L, As F. Early establishment of a pool of latently infected, resting CD4 T cells during primary HIV-1 infection. Proc Natl Acad Sci USA. 1998;95:8869–73.
Kulpa DA, Chomont N. HIV persistence in the setting of antiretroviral therapy: when, where and how does HIV hide? J Virus Erad. 2015;1(2):59–66.
Hellmuth J, Valcour V, Spudich S. CNS reservoirs for HIV: implications for eradication. J Virus Erad. 2015;1(2):67–71.
Archin NM, Sung JM, Garrido C, Soriano-Sarabia N, Margolis DM. Eradicating HIV-1 infection: seeking to clear a persistent pathogen. Nat Rev Microbiol. 2014;12(11):750–64.
Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, et al. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999;5(5):512–7.
Blankson JN, Persaud D, Siliciano RF. The challenge of viral reservoirs in HIV-1 infection. Annu Rev Med. 2002;53:557–93.
Blankson JN, Siliciano JD, Siliciano RF. Finding a cure for human immunodeficiency virus-1 infection. Infect Dis Clin N Am. 2014;28(4):633–50.
Strain MC, Little SJ, Daar ES, Havlir DV, Günthard HF, Lam RY, et al. Effect of treatment, during primary infection, on establishment and clearance of cellular reservoirs of HIV-1. J Infect Dis. 2005;191(9):1410–8.
Rutstein SE, Ananworanich J, Fidler S, Johnson C, Sanders EJ, Sued O, et al. Clinical and public health implications of acute and early HIV detection and treatment: a scoping review. J Int AIDS Soc. 2017;20(1):21579–81.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the USE of antiretroviral agents in adults and adolescents living with HIV. Washington, DC: Department of Health and Human Services; 2018.
Mogensen TH, Melchjorsen J, Larsen CS, Paludan SR. Innate immune recognition and activation during HIV infection. Retrovirology. 2010. https://doi.org/10.1186/1742-4690-7-54.
Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000;407:523.
Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, et al. Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci USA. 2008;105(21):7552–7.
Deeks SG, Lewin SR, Havlir DV. The end of AIDS: HIV infection as a chronic disease. Lancet. 2013;382(9903):1525–33.
Le T, Wright EJ, Smith DM, He W, Catano G, Okulicz JF, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1 antiretroviral therapy. N Engl J Med. 2013;368(3):218–30.
Takata H, Buranapraditkun S, Kessing C, Fletcher JLK, Muir R, Tardif V, et al. Delayed differentiation of potent effector CD8+ T cells reducing viremia and reservoir seeding in acute HIV infection. Sci Transl Med. 2017;9(377):eaag1809.
Hiener B, Horsburgh BA, Eden JS, Barton K, Schlub TE, Lee E, et al. Identification of genetically intact HIV-1 proviruses in specific CD4(+) T cells from effectively treated participants. Cell Rep. 2017;21(3):813–22.
Lee GQ, Reddy K, Einkauf KB, Gounder K, Chevalier JM, Dong KL, et al. HIV-1 DNA sequence diversity and evolution during acute subtype C infection. Nat Commun. 2019;10(1):2737.
Padian NS, McCoy SI, Karim SSA, Hasen N, Kim J, Bartos M, et al. HIV prevention transformed: the new prevention research agenda. Lancet. 2011;378(9787):269–78.
Ananworanich J, Schuetz A, Vandergeeten C, Sereti I, de Souza M, Rerknimitr R, et al. Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection. PLoS ONE. 2012;7(3):e33948.
Grossman CI, Ross AL, Auerbach JD, Ananworanich J, Dubé K, Tucker JD, et al. Towards multi-disciplinary HIV cure research: integrating social science with biomedical research. Trends Microbiol. 2016;24(1):5–11.
Ho DD, Toward HIV. Eradication or remission: the tasks ahead. Science. 1998;280(5371):1866–7.
Pino M, Paiardini M, Marconi VC. Progress in achieving long-term HIV remission. Curr Opin HIV AIDS. 2018;13(5):435–45.
Bowman MC, Archin NM, Margolis DM. Pharmaceutical approaches to eradication of persistent HIV infection. Expert Rev Mol Med. 2009;11:e6.
Robb ML, Ananworanich J. Lessons from acute HIV infection. Curr Opin HIV AIDS. 2016;11(6):555–60.
Walker BD, Hirsch MS. Antiretroviral therapy in early HIV infection. N Engl J Med. 2013;368(3):279–81.
Chéret A, Bacchus-Souffan C, Avettand-Fenoël V, et al. Combined ART started during acute HIV infection protects central memory CD4+ T cells and can induce remission. J Antimicrob Chemother. 2015;70(7):2108–20.
Krebs SJ, Ananworanich J. Immune activation during acute HIV infection and the impact of early antiretroviral therapy. Curr Opin HIV AIDS. 2016;11(2):163–72.
Namazi G, Fajnzylber JM, Aga E, Bosch RJ, Acosta EP, Sharaf R, et al. The control of HIV after antiretroviral medication pause (CHAMP) study: posttreatment controllers identified from 14 clinical studies. J Infect Dis. 2018;218(12):1954–63.
Pilcher CD, Fiscus SA, Nguyen TQ, Foust E, Wolf L, Williams D, et al. Detection of acute infections during HIV testing in North Carolina. N Engl J Med. 2005;352(18):1873–83.
Daar ES, Little S, Pitt J, Santangelo J, Ho P, Harawa N, et al. Diagnosis of primary HIV-1 infection. Ann Intern Med. 2001;134:25–9.
Phanuphak P, Phanuphak N. Socioeconomic empowerment in an acute HIV cohort. Lancet HIV. 2018;5(1):e5–6.
Muccini C, Crowell TA, Kroon E, Sacdalan C, Ramautarsing R, Seekaew P, et al. Leveraging early HIV diagnosis and treatment in Thailand to conduct HIV cure research. AIDS Res Ther. 2019;16(1):25.
Treatment Action Group. Research toward a cure trials 2020 [cited 2020 24 March]. 17 March 2020. http://www.treatmentactiongroup.org/cure/trials.
Micallef J, Kaldor J. Catalogue of clinical trials and cohort studies to identify biological specimens of relevance to the development of assays for recent HIV infection: Final report. Geneva: University of New South Wales and Family Health International; 2010.
van Loggerenberg F, Mlisana K, Williamson C, Auld SC, Morris L, Gray CM, et al. Establishing a cohort at high risk of HIV infection in South Africa: challenges and experiences of the CAPRISA 002 Acute Infection Study. PLoS ONE. 2008;3(4):e1954.
Dong KL, Moodley A, Kwon DS, Ghebremichael MS, Dong M, Ismail N, et al. Detection and treatment of Fiebig stage I HIV-1 infection in young at-risk women in South Africa: a prospective cohort study. Lancet HIV. 2018;5(1):e35–44.
Robb ML, Eller LA, Kibuuka H, Rono K, Maganga L, Nitayaphan S, et al. Prospective study of acute HIV-1 infection in adults in East Africa and Thailand. N Engl J Med. 2016;374(22):2120–30.
McKellar MS, Cope AB, Gay CL, McGee KS, Kuruc JD, Kerkau MG, et al. Acute HIV-1 infection in the Southeastern United States: a cohort study. AIDS Res Hum Retroviruses. 2013;29(1):121–8.
Dijkstra M, de Bree GJ, Stolte IG, Davidovich U, Sanders EJ, Prins M, et al. Development and validation of a risk score to assist screening for acute HIV-1 infection among men who have sex with men. BMC Infect Dis. 2017;17(1):425.
Gorbach PM, Javanbakht M, Bolan RK. Behavior change following HIV diagnosis: findings from a Cohort of Los Angeles MSM. AIDS Care. 2018;30(3):300–4.
Lama JR, Brezak A, Dobbins JG, Sanchez H, Cabello R, Rios J, et al. Design strategy of the Sabes study: diagnosis and treatment of early HIV infection among men who have sex with men and transgender women in Lima, Peru, 2013–2017. Am J Epidemiol. 2018;187(8):1577–85.
Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog. 2013;9(3):e1003211.
Tucker JD, Rennie S, the Social Ethical Working Group on HIV Cure. Social and ethical implications of HIV cure research. AIDS. 2014;28(9):1247–50.
Henderson GE, Waltz M, Meagher K, Cadigan RJ, Jupimai T, Isaacson S, et al. Going off ART in a closely monitored HIV “cure” trial: longitudinal assessments of acutely-diagnosed trial participants and decliners. J Int AIDS Soc. 2019;22:e25260.
Hurst SA. Vulnerability in research and health care; describing the elephant in the room? Bioethics. 2008;22(4):191–202.
Martin AK, Tavaglione N, Hurst S. Resolving the conflict: clarifying’ vulnerability’ in health care ethics. Kennedy Inst Ethics J. 2014;24(1):51–72.
Tavaglione N, Martin AK, Mezger N, Durieux-Paillard S, François A, Jackson Y, et al. Fleshing out vulnerability. Bioethics. 2015;29(2):98–107.
Mann H. Ethics of research involving vulnerable populations. Lancet. 2003;362(9398):1857.
Sutton LB, Erlen JA, Glad JM, Siminoff LA. Recruiting vulnerable populations for research: revisiting the ethical issues. J Prof Nurs. 2003;19(2):106–12.
Steward WT, Remien RH, Higgins JA, Dubrow R, Pinkerton SD, Sikkema KJ, et al. Behavior change following diagnosis with acute/early HIV infection-a move to serosorting with other HIV-infected individuals. The NIMH multisite acute HIV infection study: III. AIDS Behav. 2009;13(6):1054–60.
Fox J, White PJ, Macdonald N, Weber J, McClure M, Fidler S, et al. Reductions in HIV transmission risk behaviour following diagnosis of primary HIV infection: a cohort of high-risk men who have sex with men. HIV Med. 2009;10(7):432–8.
Colfax GN, Buchbinder SP, Cornelisse PGA, Vittinghoff E, Mayer K, Celum C. Sexual risk behaviors and implications for secondary HIV transmission during and after HIV seroconversion. AIDS. 2002;16(11):1529–35.
Pettifor A, MacPhail C, Corneli A, Sibeko J, Kamanga G, Rosenberg N, et al. Continued high risk sexual behavior following diagnosis with acute HIV infection in South Africa and Malawi: implications for prevention. AIDS Behav. 2011;15(6):1243–50.
Gorbach PM, Drumright LN, Daar ES, Little SJ. Transmission behaviors of recently HIV-infected men who have sex with men. J Acquir Immune Defic Syndr. 2006;42(1):80–5.
Vallabhaneni S, McConnell JJ, Loeb L, Hartogensis W, Hecht FM, Grant RM, et al. Changes in seroadaptive practices from before to after diagnosis of recent HIV infection among men who have sex with men. PLoS ONE. 2013;8(2):e55397.
Van Der Elst EM, Kombo B, Mugo P, Thiong’o A, Kanungi J, Wahome E, et al. Adjustment to acute or early HIV-1 infection diagnosis to prompt linkage to care and ART initiation: qualitative insights from coastal Kenya. Psychol Health Med. 2018;24:631–41.
Atkinson JH, Higgins JA, Vigil O, Dubrow R, Remien RH, Steward WT, et al. Psychiatric context of acute/early HIV infection. The NIMH Multisite Acute HIV Infection Study: IV. AIDS Behav. 2009;13(6):1061–7.
Fox J, Weber J, Fidler S. Primary HIV. Sexual Transm Infect. 2006;82:267–8.
Weitz R. Uncertainty and the lives of persons with AIDS. J Health Soc Behav. 1989;30(3):270–81.
Schrems BM. Informed consent, vulnerability and the risks of group-specific attribution. Nurs Ethics. 2014;21(7):829–43.
Baumgartner LM, David KN. Accepting being Poz: the incorporation of the HIV identity into the self. Qual Health Res. 2009;19(12):1730–43.
Hino S, Grodensky C, Rutstein SE, Golin C, Smith MK, Christmas L, et al. HIV status disclosure during acute HIV infection in Malawi. PLoS ONE. 2018;13(7):e0201265.
Grace D, Chown SA, Kwag M, Steinberg M, Lim E, Gilbert M. Becoming, “Undetectable”: longitudinal narratives of gay men’s sex lives after a recent HIV diagnosis. AIDS Educ Prev. 2015;27(4):333–49.
Gilbert M, Taylor D, Michelow W, Grace D, Balshaw R, Kwag M, et al. Sustained reduction in sexual behavior that may pose a Risk of HIV transmission following diagnosis during early HIV infection among gay men in Vancouver, British Columbia. AIDS Behav. 2018;22(7):2068–78.
Kelly JA, Morin SF, Remien RH, Steward WT, Higgins JA, Seal DW, et al. Lessons learned about behavioral science and acute/early HIV infection. The NIMH Multisite Acute HIV Infection Study: V. AIDS Behav. 2009;13(6):1068–74.
Kerndt PR, Dubrow R, Aynalem G, Mayer KH, Beckwith C, Remien RH, et al. Strategies used in the detection of acute/early HIV infections. The NIMH Multisite Acute HIV Infection Study: I. AIDS Behav. 2009;13(6):1037–45.
Remien RH, Rabkin JG. Psychological aspects of living with HIV disease. West J Med. 2001;175:332–5.
Granich R, Gupta S, Hall I, Aberle-Grasse J, Hader S, Mermin J. Status and methodology of publicly available national HIV care continua and 90–90–90 targets: a systematic review. PLoS Med. 2017;14(4):e1002253.
Braun DL, Kouyos RD, Balmer B, Grube C, Weber R, Günthard HF. Frequency and spectrum of unexpected clinical manifestations of primary HIV-1 infection. Clin Infect Dis. 2015;61(6):1013–21.
Wood E, Kerr T, Rowell G, Montaner JS, Phillips P, Korthuis PT, et al. Does this adult patient have early HIV infection? The rational clinical examination systematic review. JAMA. 2014;312(3):278–85.
Henderson GE, Peay HL, Kroon E, Cadigan RJ, Meagher K, Jupimai T, et al. Ethics of treatment interruption trials in HIV cure research: addressing the conundrum of risk/benefit assessment. J Med Ethics. 2018;44(4):270–6.
Ndhlovu ZM, Kazer SW, Nkosi T, Ogunshola F, Muema DM, Anmole G, et al. Augmentation of HIV-specific T cell function by immediate treatment of hyperacute HIV-1 infection. Sci Transl Med. 2019. https://doi.org/10.1126/scitranslmed.aau0528.
Ndung’u T, Dong KL, Kwon DS, Walker BD. A FRESH approach: Combining basic science and social good. Sci Immunol. 2018. https://doi.org/10.1126/sciimmunol.aau2798.
Kassutto S, Maghsoudi K, Johnston MN, Robbins GK, Burgett NC, Sax PE, et al. Longitudinal analysis of clinical markers following antiretroviral therapy initiated during acute or early HIV type 1 infection. Clin Infect Dis. 2006;42(7):1024–31.
INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795–807.
Remien RH, Higgins JA, Correale J, Bauermeister J, Dubrow R, Bradley M, et al. Lack of understanding of acute HIV infection among newly-infected persons-implications for prevention and public health: The NIMH Multisite Acute HIV Infection Study: II. AIDS Behav. 2009;13(6):1046–53.
World Health Organization. Guidance on ethics and equitable access to HIV treatment and care. 2004. https://www.who.int/ethics/Guidance%20on%20Ethics%20and%20HIV.pdf.
Rennie S, Behets F. AIDS care and treatment in Sub-Saharan Africa: implementation ethics. Hast Cent Rep. 2006;36(3):23–31.
Rintamaki LS, Davis TC, Skripkauskas S, Bennett CL, Wolf MS. Social stigma concerns and HIV medication adherence. AIDS Patient Care STDS. 2006;20(5):359–68.
Rennie S, Sugarman J. Developing ethics guidance for HIV prevention research: the HIV Prevention Trials Network approach. J Med Ethics. 2010;36(12):810–5.
MacQueen K, Shapiro K, Karim Q, Sugarman J. Ethical challenges in international HIV prevention research. Account Res Polic Qual Assur. 2004;11(1):49–61.
Haire B, Folayan MO, Hankins C, Sugarman J, McCormack S, Ramjee G, et al. Ethical considerations in determining standard of prevention packages for HIV prevention trials: examining P r EP. Dev World Bioeth. 2013;13(2):87–94.
Sugarman J, Mayer KH. Ethics and pre-exposure prophylaxis for HIV-infection. J Acquir Immune Defic Syndromes (1999). 2013;63(2):S135.
Rennie S, Sugarman J. HPTN ethics guidance for research. Bethesda: National Institutes of Health; 2009.
Jay JS, Gostin LO. Ethical challenges of preexposure prophylaxis for HIV. JAMA. 2012;308(9):867–8.
Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA. 2000;283(20):2701–11.
Emanuel EJ, Grady CC, Crouch RA, Lie RK, Miller FG, Wendler DD. The Oxford textbook of clinical research ethics. Oxford: Oxford University Press; 2008.
Lo B. Ethical issues in clinical research: a practical guide. Philadelphia: Lippincott Williams & Wilkins; 2012.
Lo B, Grady C, Working Group on Ethics of the International Aids Society. Ethical considerations in HIV cure research: points to consider. Curr Opin HIV AIDS. 2013;8(3):243–9.
Sugarman J. Ethics of Curing HIV: roundtable discussion talk. In: 7th IAS conference on HIV pathogenesis, treatment, and prevention; Kuala Lumpur 2013.
Sugarman J. HIV cure research: expanding the ethical considerations. Ann Intern Med. 2013;159(7):490–1.
Eyal N, Kuritzkes DR. Challenges in clinical trial design for HIV-1 cure research. Lancet. 2013;382(9903):1464–5.
Garner SA, Rennie S, Ananworanich J, Dube K, Margolis DM, Sugarman J, et al. Interrupting antiretroviral treatment in HIV cure research: scientific and ethical considerations. J Virus Erad. 2017;3(2):82–4.
Eyal N, Holtzman LG, Deeks SG. Ethical issues in HIV remission trials. Curr Opin HIV AIDS. 2018;13(5):422–7.
Henderson GE. The ethics of HIV “cure” research: what can we learn from consent forms? AIDS Res Hum Retroviruses. 2015;31(1):56–63.
Henderson G, Peay H. What motivates participation in HIV cure trials? A call for real-time assessment to improve informed consent. J Virus Erad. 2015;1:51–3.
Staunton C. Informed consent for HIV cure research in South Africa: issues to consider. Med Ethics. 2015;16(3):1–7.
Annas GJ. Cure research and consent: the Mississippi Baby, Barney Clark, Baby Fae and Martin Delaney. J Med Ethics. 2016;43:104–7.
Bromwich D, Millum JR. Informed consent to HIV cure research. J Med Ethics. 2017;43:108–13.
Moodley K, Staunton C, Rossouw T, de Roubaix M, Duby Z, Skinner D. The psychology of “cure” - unique challenges to consent processes in HIV cure research in South Africa. BMC Med Ethics. 2019;20(1):9.
Arnold M, Evans D, Vergel N. Recruitment and ethical considerations in HIV cure trials requiring treatment interruption. J Virus Erad. 2015;1:43–8.
Sugarman J, Lewin SR, Henrich TJ, Rasmussen TA. Ethics of ART interruption after stem-cell transplantation. Lancet HIV. 2016;3(1):e8–10.
Eyal N, Deeks SG. Risk to nonparticipants in HIV remission studies with treatment interruption: a symposium. J Infect Dis. 2019;220(Supplement_1):S1–4.
Eyal N. The benefit/risk ratio challenge in clinical research, and the case of HIV cure: an introduction. J Med Ethics. 2016;43:65–6.
Largent E. For love and money: the need to rethink benefits in HIV cure studies. J Med Eth. 2016;43:96–9.
Dresser R. First-in-human HIV-remission studies: reducing and justifying risk. J Med Ethics. 2016;43:78–81.
Gilbertson A, Kelly EP, Rennie S, Henderson G, Kuruc J, Tucker JD. Indirect benefits in HIV cure clinical research: a qualitative analysis. AIDS Res Hum Retroviruses. 2019;35(1):100–7.
Dubé K, Taylor J, Sylla L, Evans D, Dee L, Burton A, et al. “Well, it’s the risk of the unknown… right?” A qualitative study of perceived risks and benefits of HIV cure research in the United States. PLoS ONE. 2017;12(1):e0170112.
Eyal N. How to keep high-risk studies ethical: classifying candidate solutions. J Med Ethics. 2017;43:74.
Hare C. Risk and radical uncertainty in HIV research. J Med Ethics. 2016;43:87–9.
Kumar R. Contractualist reasoning, HIV cure clinical trials, and the moral (ir)revelance of the risk/benefit ratio. J Med Ethics. 2017;43:4.
Kuritzkes DR. Why cure, why now? J Med Ethics. 2016;43:67–70.
Grisso T, Appelbaum P. Assessing competence to consent to treatment: a guide for physicians and other health professionals. New York: Oxford University Press; 1998.
Hindmarch T, Hotopf M, Owen GS. Depression and decision-making capacity for treatment or research: a systematic review. BMC Med Ethics. 2013;14(54):1–10.
Corneli AL, Sorenson JR, Bentley ME, Henderson GE, Bowling JM, Nkhoma J, et al. Improving participant understanding of informed consent in an HIV-prevention clinical trial: a comparison of methods. AIDS Behav. 2012;16(2):412–21.
Woodsong C, Karim QA. A model designed to enhance informed consent: experiences from the HIV prevention trials network. Am J Public Health. 2005;95(3):412–9.
Nishimura A, Carey J, Erwin PJ, Tilburt JC, Murad MH, McCormick JB. Improving understanding in the research informed consent process: a systematic review of 54 interventions tested in randomized control trials. BMC Med Ethics. 2013;14(1):28.
Flory J, Emanuel E. Interventions to improve research participants’ understanding in informed consent for research: a systematic review. JAMA. 2004;292(13):1593–601.
Sudore RL, Landefeld CS, Williams BA, Barnes DE, Lindquist K, Schillinger D. Use of a modified informed consent process among vulnerable patients: a descriptive study. J Gen Intern Med. 2006;21(8):867–73.
Kadam RA. Informed consent process: a step further towards making it meaningful! Perspect Clin Res. 2017;8(3):107–12.
Grady C. Ethics of vaccine research. Nat Immunol. 2004;5(5):465–8.
Resnik DB. Re-consenting human subjects: ethical, legal and practical issues. J Med Ethics. 2009;35(11):656–7.
Dewing J. Participatory research: a method for process consent with persons who have dementia. Dementia. 2007;6(1):11–25.
Haraldsdottir E, Lloyd A, Dewing J. Relational ethics in palliative care research: including a person-centred approach. Palliat Care Soc Pract. 2019;13:2632352419885384.
Kipnis K. Vulnerability in research subjects: A bioethical taxonomy. In: Ethical and Policy Issues in Research Involving Human Participants. Volume II: Commissioned Papers. National Bioethics Advisory Commission; 2001. https://aapcho.org/wp/wp-content/uploads/2012/02/Kipnis-VulnerabilityinResearchSubjects.pdf.
Miller FG. Recruiting research participants. In: Emanuel E, Grady C, Crouch R, Lie R, Miller F, Wendler D, editors. The Oxford textbook of clinical research ethics. Oxford: Oxford University Press; 2011. p. 397–403.
World Medical Association. WMA Declaration of Helsinki—ethical principles for medical research involving human subjects. Fortaleza: World Medical Association; 2013.
INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373(9):795–807.
Rennie S, Siedner M, Tucker JD, Moodley K. The ethics of talking about “HIV cure.” BMC Med Ethics. 2015;16:1–8.
Henderson GE, Churchill LR, Davis AM, Easter MM, Grady C, Joffe S, et al. Clinical trials and medical care: defining the therapeutic misconception. PLoS Med. 2007;4(11):e324.
Peay HL, Henderson GE. What motivates participation in HIV cure trials? A call for real-time assessment to improve informed consent. J Virus Erad. 2015;1(2):51–3.
Li J, Davey S, Mellors J. The critical roles of treatment interruption studies and biomarker identification in the search for an HIV cure. AIDS. 2015;29(12):1575–7.
Sgaier SK, Baer J, Rutz DC, Njeuhmeli E, Seifert-Ahanda K, Basinga P, et al. Toward a systematic approach to generating demand for voluntary medical male circumcision: insights and results from field studies. Global Health Sci Pract. 2015;3(2):209–29.
Margolis DM, Deeks SG. How unavoidable are analytical treatment interruptions in HIV cure-related studies? J Infect Dis. 2019;220(Supplement_1):S24–6.
Julg B, Dee L, Ananworanich J, Barouch DH, Bar K, Caskey M, et al. Recommendations for analytical antiretroviral treatment interruptions in HIV research trials—report of a consensus meeting. The Lancet HIV. 2019;6:e259–68.
Cooper DA, Emery S, Cordery DV. Disease progression and fatal outcomes in HIV-infected patients during interruption of antiretroviral treatment. J Infect Dis. 2008;197(5):775 (author reply -6).
Worthington MG, Ross JJ. Aseptic meningitis and acute HIV syndrome after interruption of antiretroviral therapy: implications for structured treatment interruptions. AIDS. 2003;17(14):2145–6.
Paton NI. Treatment interruption strategies: how great are the risks? Curr Opin Infect Dis. 2008;21(1):25–30.
Dubé K, Evans D, Dee L, Sylla L, Taylor J, Skinner A, 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. AIDS Res Hum Retroviruses. 2018;34(1):67–79.
Colby DJ, Trautmann L, Pinyakorn S, Leyre L, Pagliuzza A, Kroon E, et al. Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection. Nat Med. 2018;24(7):923–6.
Clarridge KE, Blazkova J, Einkauf K, Petrone M, Refsland EW, Justement JS, et al. Effect of analytical treatment interruption and reinitiation of antiretroviral therapy on HIV reservoirs and immunologic parameters in infected individuals. PLoS Pathog. 2018;14(1):e1006792.
Voronin Y, Zinszner H, Karg C, Brooks K, Coombs R, Hural J, et al. HIV vaccine-induced sero-reactivity: a challenge for trial participants, researchers, and physicians. Vaccine. 2015;33(10):1243–9.
VISR Working Group of Global HIV Vaccine Enterprise, Voronin Y, Zinszner H, Karg C, Brooks K, Coombs R, et al. HIV vaccine-induced sero-reactivity: a challenge for trial participants, researchers, and physicians. Vaccine. 2015;33(10):1243–9.
Kroon E. Early intervention therapies in humans: art, antibodies, and vaccines. In: Conference on retroviruses and opportunistic infections; 4–7 March. 2020 CROI Foundation/IAS-USA, Boston; 2018.
Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 2011;365(6):493–505.
Rodger AJ, Cambiano V, Bruun T, Vernazza P, Collins S, Degen O, et al. Risk of HIV transmission through condomless sex in serodifferent gay couples with the HIV-positive partner taking suppressive antiretroviral therapy (PARTNER): final results of a multicentre, prospective, observational study. Lancet. 2019;393(10189):2428–38.
Lawrence D, Kuo L, Church E, Poon B, Smiley S, Sanders-Beer B, et al. Highlights from the third biennial strategies for an HIV cure meeting: 14–16 November 2016, Bethesda, MD, USA. J Virus Erad. 2017;3(1):69.
Lelièvre J-D, Hocqueloux L. Unintended HIV-1 transmission to a sex partner in a study of a therapeutic vaccine candidate. J Infect Dis. 2019;220(Supplement_1):S5–6.
Redd AD, Quinn TC, Tobian AAR. Frequency and implications of HIV superinfection. Lancet Infect Dis. 2013;13(7):622–8.
Hecht FM, Acute HIV. Infection: recent issues in treatment, progression, and superinfection. New York: Physician’s Research Network; 2005.
Burris S, Cameron E. The case against criminalization of HIV transmission. JAMA. 2008;300(5):578–81.
Office for Human Research Protections. Protection of Human Subjects 45 C.F.R. 46. Department of Health and Human Services, Washington, DC; 2009.
Eyal N, Lipsitch M, Bärnighausen T, Wikler D. Opinion: Risk to study nonparticipants: a procedural approach. Proc Natl Acad Sci USA. 2018;115(32):8051–3.
Dawson L. Human immunodeficiency virus transmission risk in analytical treatment interruption studies: relational factors and moral responsibility. J Infect Dis. 2019;220(Supplement_1):S12–5.
Resnik DB, Sharp RR. Protecting third parties in human subjects research. IRB. 2006;28(4):1–7.
Woodsong C, Macqueen K, Namey E, Sashay S, Morar N, Mehendale S. Women’s autonomy and informed consent in microbicides clinical trials. J Empir Res Hum Res Ethics. 2006;1(3):11–26.
Shah SK, Kimmelman J, Lyerly AD, Lynch HF, Miller FG, Palacios R, et al. Bystander risk, social value, and ethics of human research. Science. 2018;360(6385):158–9.
De Scheerder M-A, van Bilsen WPH, Dullaers M, Martinez-Picado J, Davidovich U, Vandekerckhove L. Motivations, barriers and experiences of participants in an HIV reservoir trial. J Virus Erad. 2021;7(1):100029.
Lelièvre J-D. Preexposure prophylaxis for mitigating risk of HIV transmission during HIV cure–related clinical trials with a treatment interruption. J Infect Dis. 2019;220(Supplement_1):S16–8.
Peluso MJ, Dee L, Campbell D, Taylor J, Hoh R, Rutishauser RL, et al. A collaborative, multidisciplinary approach to HIV transmission risk mitigation during analytic treatment interruption. J Virus Erad. 2020;6(1):34–7.
Hausman DM. Third-party risks in research: should IRBs address them? IRB. 2007;29(3):1–5.
Eyal N. Removing One Barrier to Protecting Sex Partners in HIV Remission Studies With a Treatment Interruption. J Infect Dis. 2019;220(Supplement_1):S22–3.
Eyal N. How to address the risk of HIV transmission in remission studies with treatment interruption: the low-hanging fruit approach. J Infect Dis. 2019;220(Supplement 1):S7–11.
Eyal N, Magalhaes M. Is it ethical to isolate study participants to prevent HIV transmission during trials with an analytical treatment interruption? J Infect Dis. 2019;220(Supplement_1):S19–21.
Belsky L, Richardson HS. Medical researchers’ ancillary clinical care responsibilities. BMJ. 2004;328(7454):1494–6.
Richardson HS. Moral entanglements: the ancillary-care obligations of medical researchers. Oxford: Oxford University Press; 2012.
Grady C. The challenge of assuring continued post-trial access to beneficial treatment. Yale J Health Policy Law Ethics. 2005;5(1):425.
Participants in the Georgetown University Workshop on the Ancillary-Care Obligations of Medical Researchers Working in Developing C. The ancillary-care obligations of medical researchers working in developing countries. PLoS Med. 2008;5(5):e90–1.
Sugarman J. Ethics of HIV and hepatitis B cure research. Curr Opin HIV AIDS. 2020;15(3):180–4.
We owe special thanks to Liz Kelly and Meredith Blumberg for their production assistance. The authors would also like to acknowledge the support of the UNC Center for Bioethics, UNC’s Department of Social Medicine, and the Pacific Institute for Research and Evaluation Chapel Hill Center.
This research was funded by the US National Institutes of Health 1R21AI120549-01A1, R01A108366-01, and UNC CFAR (P30 AI050410 18). Funders had no role in this research.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Gilbertson, A., Tucker, J.D., Dubé, K. et al. Ethical considerations for HIV remission clinical research involving participants diagnosed during acute HIV infection. BMC Med Ethics 22, 169 (2021). https://doi.org/10.1186/s12910-021-00716-1
- Acute HIV
- Primary HIV
- Early HIV
- HIV remission
- HIV cure
- Medical ethics
- Clinical trials