Can Research at the End-of-life be a Useful Tool to Advance HIV Cure?

Abstract

Despite extensive investigations, we still do not fully understand the dynamics of the total body HIV reservoir and how sub-reservoirs in various compartments relate to one another. Studies using macaque models are enlightening but eradication strategies will still need to be tested in humans. To take the next steps in understanding and eradicating HIV reservoirs throughout the body, we propose to develop a “peri-mortem translational research model” of HIV-infected individuals (called ‘The Last Gift’), which is similar to existing models in cancer research. In this model, altruistic, motivated HIV-infected individuals with advanced non-AIDS related diseases and with six months or less to live will participate in HIV cure research and donate their full body after they die. Engaging this population provides a unique opportunity to compare the HIV reservoir before and after death across multiple anatomic compartments in relation to antiretroviral therapy use and other relevant clinical factors. Furthermore, people living with HIV/AIDS at the end of their lives may be willing to participate to cure interventions and accept greater risks for research participation. A broad, frank, and pragmatic discussion about performing HIV cure research near the end of life is necessary.

OPINION PIECE

Modern antiretroviral therapy (ART) has saved millions of years of life [1], but it cannot eradicate latently infected cells [2, 3]. The replication competent provirus that remains during ART represents the major barrier to curing HIV [4]. Most of this latent reservoir resides in solid tissues and not in circulating blood, and we have yet to fully define the sanctuary sites of HIV persistence [5]. Timothy Ray Brown (known by many as the ‘Berlin Patient’) may be the closest to an HIV cure after being treated with an allogeneic hematopoietic stem cell transplant from a donor who was homozygous for the CCR5Δ32 deletion [6]. Unfortunately, this remarkable success has not been reproduced, and robust viral replication resumes almost universally following treatment interruption [7–9]. Even if strategies currently in development succeed in purging HIV from circulating CD4⁺ T cells, residual virus can remain in the central nervous system (CNS), gut-associated lymphoid tissue (GALT), genital tract, adipose tissue and others [9–12].

Thus, cure efforts must tackle the eradication of HIV reservoirs in anatomic compartments and sanctuaries throughout the body.

The earliest stages of HIV infection are characterized by high levels of viral replication and little immune response [13, 14]. This window of uncontrolled replication allows the virus to seed reservoirs throughout the body, as early as within 2 weeks of HIV infection [15], which persist indefinitely throughout the lifespan of HIV-infected individuals [10]. These proviral reservoirs continue to expand and diversify until viral replication is successfully suppressed with ART. Despite extensive investigations, we still do not fully understand the dynamics of the total body HIV reservoir and how sub-reservoirs in various compartments relate to one another. For example, it remains unclear what factors govern the size and the activity of replication competent HIV DNA in the CNS compared to the genital tract and blood. Most studies that have explored non-blood reservoirs among persons living with HIV infection have been limited to small samples of cerebrospinal fluid (CSF), genital secretion, gut, and shallow lymph nodes [10, 16]. Studies using macaque models with Simian Immunodeficiency Viruses (SIV) have been enlightening for reservoirs in different tissues [17–23], but while SIV shares a high degree of structural and sequence identity to HIV, studies of SIV will not suffice to test eradication strategies in humans. For example, the Merck adenovirus type 5 (Ad5) trivalent HIV-1 vaccine trial (STEP trial) did not show efficacy in preventing HIV infection or slowing disease progression [24], despite promising results in various macaques’ trials [25–27].

As the field tackles the ambitious goal of eradicating HIV from the human body, we will need to test the effectiveness of cure interventions in living persons. Consequently, we will need to measure changes in HIV reservoirs in circulating blood, and limited sampling in accessible compartments, like CSF, genital secretions, gut, etc. Unfortunately, we do not know how these measures relate to reservoirs in harder to reach places, like the brain, spleen, prostate, etc. Cure strategies based on reducing HIV populations in circulating blood cells, may have no impact whatsoever on deeper non-circulating HIV reservoirs. Such ‘hard-to-reach’ reservoirs can subsequently repopulate the systemic HIV RNA pool, similar to the viral rebounds observed in persons who were thought to have been eradicated, such as ‘Mississippi baby’ and the ‘Boston patients’ [28, 29].

Most of our understanding of deep HIV reservoirs has come from autopsy studies, but these previous studies had variable ART intake and limited ante-mortem characterization that can be compared to post-mortem measures [12, 30, 31]. Also, there is typically a significant delay in time from ante-mortem visits until death (for example the average time between the last clinical assessment and death is 262.6 days (Standard deviation: 402.7 days) and is rarely < 6 months in the California NeuroAIDS Tissue Network [32]). The inability to collect information during the last months of life about the use of ART and other drugs and HIV measures in blood- limits our ability to interpret reservoir data in post-mortem samples. To better understand how accessible HIV reservoirs relate to deeper reservoirs, we will need evaluations that span the peri-mortem timeframe. In our ‘Last Gift’ model, we propose that some HIV-infected individuals with a non-AIDS related advanced illness would be willing to participate in such research. Examples of non-AIDS related diseases relevant for a Last Gift cohort include solid cancers, cardiovascular disease, and neurodegenerative diseases [33, 34]. Participants would be eligible for our Last Gift cohort when they are certified as being terminally ill by a physician and having a prognosis of 6 months. From these volunteers, limited blood samples can be collected while they are alive, and some participants might be willing to also donate genital secretions, stool, cerebrospinal fluid samples, or even limited rectal and lymph node biopsies. Importantly, participants could be extensively characterized closely prior to death in terms of ART intake and other drugs, neurocognitive and daily functioning, all illnesses, etc. and this information could be very helpful with the interpretation of data generated on post-mortem tissue.

In fact, we hypothesize that some individuals would welcome the opportunity to give back to their community, even if it will provide them no tangible benefit whatsoever. This is analogous to the early days of HIV where hundreds and thousands of gay men and other affected communities enrolled into research at enormous self-sacrifice, with many knowing they personally were unlikely to benefit [35]. We propose that such innate human altruism can be tapped with open and honest discussions with very sick HIV-infected persons about research participation at the end of their lives.

Ultimately, an HIV cure will need to be at least as safe and well tolerated as current ART [36]. However, the first generation of cure interventions will likely come with significant toxicities and other burdens. Also, like the first generations of ART, their effectiveness will likely be suboptimal. Thus, first-generation cure efforts will require significant sacrifice and risk for research participants. We understand that HIV cure efforts are important for the whole HIV community and many altruistic individuals will be motivated to participate if provided opportunities to advance the cure field. We propose that HIV-infected people at the end of their lives may be willing to accept greater risks for research participation. For example, volunteers may be more willing to participate in trials of potentially toxic immunomodulatory agents, neutralizing antibodies or highly experimental ‘kick and kill’ strategies, thus offering a unique opportunity to evaluate the mechanisms of clinical cure interventions and their effect across various tissues, which are not accessible in living participants.

The proposed research model has been useful for cancer research [33]. In particular, cancer research has greatly benefited from rapid autopsy programs by allowing a better understanding of cancer disease mechanisms and how various therapies have impacted these mechanisms [33, 37]. Characterization of these mechanisms has involved samples collected from rapid autopsies and state-of-the-art laboratory techniques like proteomics, genomics, metabolomics, etc. Similarly, HIV cure research can benefit from this peri-mortem research model by allowing deep tissue to be sampled quickly after death (ideally within 6 hours) thus allowing lab-based techniques to clarify how HIV can persist in deep tissues during ART. The End of Life Option law that went into effect in California June 9, 2016 might be a way to optimize timing for autopsy and organ specimen collection in a way that that could maximize their usefulness to HIV cure research. This could be comforting or gratifying to those able to make this research contribution and their families. Of course, this raises several ethical concerns, which would need to be addressed further.

Interestingly, one recent study found that HIV-infected people who perceive themselves as ‘not very healthy/not at all healthy’ were significantly more likely to participate to HIV cure research compared to otherwise healthy chronically HIV-infected individuals [38]. In this study, a prominent recurring theme that emerged, especially from long-term survivors approaching end of life, was the frustration that they had been excluded from most HIV research, especially cure research, because of accumulated ART drug resistance and HIV comorbidities. Similarly, we interviewed 12 HIV-infected individuals receiving hospice services, who were referred by their primary providers at the UCSD primary HIV care clinic (i.e., the Owen Clinic) or the San Diego Veterans Affairs HIV care clinic. These individuals were receiving palliative care services for a variety of illnesses (heart failure; pancreatic, liver, or lung cancer, etc.). During an unstructured interview, all of these individuals expressed a desire to be able to ‘give back’ in some way, especially at this time near the end of his or her life. Each of these 12 individuals expressed a strong interest in participating in research aimed at curing HIV, often citing such participation as a ‘gift’ to their friends still living with HIV. A few important quotes include: “I feel like these last few weeks are wasted.” “I hate my cancer but I hate HIV more.” “I wish I could do something else to help.” “At least I could be doing something.” An important theme expressed by these individuals was that they did not like the idea that they would be excluded from research “just because I am dying.” See Figure 1. The proposed ‘Last Gift’ study represents an opportunity for these individuals to be involved in HIV cure research. In particular older HIV-infected individuals are typically excluded from most cure research because of their age, length of chronic infection, or possibly confounding co-morbidities, and many could appreciate the opportunity to still make a contribution to cure research, especially at the end of life. To specifically address HIV cure research questions, it might be most helpful to study volunteers who remain on ART and die with suppressed HIV RNA. These individuals are now more prevalent than a few decades ago, when most HIV-infected patients were dying from HIV-related conditions and had underlying uncontrolled infection. Such willing participants could be identified through oncology or cardiovascular hospice services, rather than AIDS-specific hospices.

Figure 1.

This type of research will likely encounter various barriers, which can be actively addressed by understanding the desires and needs of this special population. These achievements will require considerable participatory research efforts including engagement to educate community members, but more importantly to listen to the community members and to allow time for two-way discussion and contemplation. We believe that providing individuals who suffer from advanced diseases the opportunity to participate in clinical research could revolutionize translational HIV research by offering a large supply of well-informed, eager and appropriately consented human volunteers. The samples collected and stored and the procedures developed for the appropriate engagement and enrollment of altruistic individuals into peri-mortem studies, will lay the groundwork for future studies that can tackle a wide variety of open questions concerning how HIV populates tissues throughout the body.

Currently, there are few opportunities for terminally ill individuals to participate in HIV research, likely due to various cultural taboos and ethical concerns, such as exploitation, vulnerability and coercion. While unreasonable expectations related to cure research outcomes might create greater vulnerability in this population, with appropriate education and ethical review, we feel that it would be unethical to withhold cure research opportunities from those who have the capability to provide informed consent. The proposed model should be developed following the strictest ethical guidelines and in complete accordance with the Declaration of Helsinki. Individuals with advanced disease that qualifies them for hospice support are routinely ineligible for HIV research trials, yet such an opportunity may offer considerable meaning to- the individual, his or her community, and the world.