Few opportunities currently exist for terminally ill people to participate in HIV research as a result of various cultural taboos and ethical concerns, such as exploitation, vulnerability, and coercion.1 However, when faced with their approaching death, some individuals may be willing to participate in research that offers no hope for their condition to leave a final gift to their community.
In the first of a 3-part series, Sara Gianella Weibel, MD, on behalf of Infectious Disease Advisor, talks with Davey Smith, MD, professor of medicine and head of the Division of Infectious Disease at the University of California, San Diego, about ethical concerns and practical barriers in end-of-life research and how this type of research could be an important tool to advance the field of HIV cure.
Infectious Disease Advisor: Dr Smith, why is HIV cure research important?
Davey Smith, MD: That is a good question. People often ask me why we need to go after a cure, as we have medications that work so well and let people live long and healthy lives even though they are infected with HIV.
An HIV cure is important, both scientifically and culturally. Scientifically, the pursuit of an HIV cure will open up more understanding of human biology, as HIV research has done for the last 30 years. These discoveries will likely push beyond HIV, as it has in the past. For example, the new treatments for hepatitis C are directly related to previous HIV research. HIV cure will be important for the world as a great human achievement and would eliminate a lot of the stigma and the discrimination that accompanies HIV. That will help humanity be a little more human.
Infectious Disease Advisor: In your opinion, what are the main barriers to curing HIV?
Dr Smith: HIV can live in a quiet, latent state in all tissues of the human body, such as the brain, fat, lungs, kidney, and others. So even though HIV therapy works well, once the virus is dormant in these tissues, it cannot be awoken and eradicated. That is the most significant barrier to curing HIV.
Infectious Disease Advisor: What do you think will be the next step or steps on the path to successfully eradicating HIV?
Dr Smith: We have many things we need to do before we can successfully eradicate HIV. First of all, we still do not know how to awaken the virus when it is in its latent state, and we also do not know how to train the immune system to attack the cells that are infected and clear them from the entire body. We also need to make sure the treatment is not as toxic as the disease itself. We must develop therapies that will clear the reservoir safely and test them in human volunteers. First-generation cure efforts will require significant sacrifice and risk for research participants. Because HIV cure efforts are important for the whole HIV community, we think many altruistic individuals will be motivated to participate if provided with an opportunity to advance the cure field. We think HIV-infected people at the end of their lives may be willing to accept greater risks for the opportunity to participate in research. For example, terminally sick volunteers may be willing to take part in trials of potentially toxic immunomodulatory agents, neutralizing antibodies, or highly experimental “kick and kill’ strategies, offering a unique opportunity to evaluate the mechanisms of clinical cure interventions and their effect in various tissues, which would not be accessible in living participants.
Infectious Disease Advisor: Following up on this idea, you and your team are proposing a new model to study HIV persistence, which may help identify the next step toward a cure. What exactly are you proposing with this new model, which is called the “Last Gift,” and why do you think it is important?
Dr Smith: The Last Gift study is for people who are HIV infected, who have a terminal illness such as cancer or advanced heart disease, and who have a prognosis of living less than 6 months. We ask those terminally sick people whether they want to participate in HIV cure studies to look at how HIV persists and lies dormant in various tissues throughout the body. We monitor those individuals and collect blood and detailed clinical information while they are alive, and they donate their full bodies to the study on their death. This allows us to look at how the data we obtained during life correlate with data obtained from the brain, genital tract, and lymph nodes after death.
Infectious Disease Advisor: Other similar autopsy studies exist, such as the National NeuroAIDS Tissues Consortium; what makes the Last Gift study so special?
Dr Smith: Important autopsy studies have been performed in HIV/AIDS research for a long time that have allowed us to learn how the virus populates virtually every part of the body. As the next step, we need to do autopsies quickly (ideally within 6 hours of death) to save proteins and nucleic acids to study the physiology in those tissues. Without that rapid autopsy, the virus and cells degrade and the physiology changes, so we might lose some of the insights into how the virus persists. Cancer research has greatly benefited from rapid autopsy programs by allowing a better understanding of cancer disease mechanisms and the effect various therapies have had on these mechanisms.2,3 Most previous autopsy studies in the HIV field did not have the capability to perform rapid autopsies; this will be a significant advantage of our Last Gift study.
Another advantage is that we will follow each participant closely until the time of death by performing home or hospice visits several times a week. Therefore, participants will be extensively characterized in terms of antiretroviral therapy intake and other drugs, neurocognitive and daily functioning, any other illnesses, and so on, and this information could be helpful with the interpretation of data generated from postmortem tissue.