Date Published: December 8, 2017
Publisher: Public Library of Science
Author(s): Karine Dubé, Laurie Sylla, Lynda Dee, Jeff Taylor, David Evans, Carl Dean Bruton, Adam Gilberston, Lisa Gralinski, Brandon Brown, Asheley Skinner, Bryan J. Weiner, Sandra B. Greene, Amy Corneli, Adaora A. Adimora, Joseph D. Tucker, Stuart Rennie
Abstract: In an essay, Karine Dubé and coauthors discuss the ethics of preclinical and clinical studies relevant to achieving an HIV cure.
Partial Text: Khoury and colleagues developed a classification framework for translational research that is divided into 4 categories: T0, preclinical research; T1, translation of discoveries to humans; T2, translation of findings to evidence-based practice; T3, translation of interventions to clinical practice; and T4, transition of interventions to improve population health . The T0–T4 translational research continuum provides a unifying framework bridging the range of HIV cure scientific discoveries, human application, advancement into clinical practice, and work towards global HIV cure. We apply this continuum for our analysis of the ethical and implementation issues related to translational HIV cure research. Kagarise and Sheldon are credited with proposing the concept of “translational ethics,” which aims to help stakeholders “navigate the ethical ramifications of technological and scientific advances .” Translational HIV cure research will require not only the transfer of discoveries into interventions to improve the lives of PLWHIV but also the effective and responsible translation of interventions into clinical practice and public health .
Most current HIV cure experiments occur in the preclinical (T0) research stage and involve genes, mechanistic pathways, cell lines, and animal models . Significant advancements in HIV treatment, together with increased understanding of animal models for HIV research, have enabled the development of animal models to study HIV persistence and how HIV remains latent inside cells . Nonhuman primates, including rhesus and pigtail macaques, and humanized mice that mimic human immune functions provide useful models to answer scientific questions that inform HIV cure research . Animal models can also allow for control of key variables such as virus dose, route of infection, and host genetics, all of which contribute to infection outcomes. The design of animal model experiments should be scientifically sound to augment the chance that they will be able to predict intervention effectiveness in human studies . This includes ensuring proper sample sizes, applying randomization and blinding, and defining inclusion/exclusion criteria with animal models . There also need to be basic evidentiary thresholds for animal models before interventions are applied to humans . HIV cure scientists must further pay attention to animal research ethics issues, in the context of animals’ intrinsic value and moral rights and independent of their utility in preclinical HIV cure research . The basic tenet of ethical research using animals involves 3 Rs: “reduce the number of animals used to the minimum necessary for meaningful results, refine procedures to minimize pain and other burdens, and replace whole-animal experiments with in vitro models or experiments with less sentient organisms whenever possible .”
The T1 level of translation involves transferring preclinical discoveries to first-in-human (FIH) studies involving Investigational New Drug (IND) applications . These include new investigational approaches to curing HIV (such as gene therapy or stem cell transplants), as well as repurposed drugs (e.g., compounds borrowed from oncology) or novel drugs and biologics advanced from animal models. HIV cure studies face many of the ethical dilemmas surrounding other early-phase research, such as oncology . One key difference, however, is that most HIV cure experiments occur in volunteers who are “otherwise healthy” . HIV cure research is usually conducted among individuals on highly effective and safe antiretroviral therapy, many of whom enjoy an almost normal life expectancy . One of the major ethical issues relates specifically to the high risk of investigational interventions and the corresponding low prospect of direct clinical benefit . HIV cure researchers must make all efforts possible to minimize risks while maximizing the social value of cure studies.
The T2 level of translation refers to late-phase clinical trials, observational studies, and guideline development . There are few Phase II and III HIV cure clinical trials at present . Further, there are limited validated biomarkers to predict the effects of HIV cure research interventions. The field of HIV cure research could benefit from better harmonization of HIV reservoir assessments and biomarkers and endpoints, within and across types of HIV cure research strategies. The field could also benefit from clear criteria warranting ATIs and benchmarks to define remission success following ATIs . Virologic rebound cannot be predicted during ATIs . Thus, studies involving ATIs must include proper informed consent and frequent virological monitoring. Third-party risks, such as secondary transmissions due to unpredictable relapses of viremia, should be minimized. Adequate standard of prevention packages for the sexual partners of study participants, including information on preexposure prophylaxis (PrEP) or other effective preventive methods , should be offered, and sufficient privacy protections should be in place.
The T3 level of translation refers to the transfer of effective interventions to clinical practice. T3 also includes implementation research and phase IV clinical trials . At the T3 stage of translation, opinion leader approval is paramount. In the HIV cure research field, there remains a dearth of robust social sciences research around perceptions of HIV care providers . If HIV clinicians are not on board with HIV cure interventions, it is unlikely that patients will receive them. For example, HIV care provider buy-in is one of the facilitators for PrEP uptake in some populations, along with cost and other access issues, as well as considerations about effectiveness and side effects . Further, issues of availability (physical access) and affordability (financial access) of the intervention become prominent at this stage. The HIV cure research field should address the economics of equitable distribution of a cure for HIV. The high costs initially associated with hepatitis C cure inform us of the importance of integrating access factors early in HIV cure development. It would be unethical to deny PLWHIV in the United States and abroad access to a future approved HIV cure because of pricing constraints. Legislators, policy makers, insurance companies, and HIV activists should partner in efforts to ensure that any future HIV cure approaches are accessible to PLWHIV without pricing constraints, especially with regards to low- and middle-income countries .
The T4 level of translation refers to the application of effective interventions to improve population health . If an HIV cure strategy proves successful, a comprehensive rollout strategy that accounts for the ability to scale-up the interventions will be necessary. The scalability of an HIV cure is a key topic in translational ethics, as it refers to the absorptive capacity of healthcare settings to adopt the intervention into existing systems . Scalability must be a key factor in assessing the social value of specific HIV cure research strategies. Efforts are underway to make some HIV cure research approaches more scalable, such as “gene therapy in a box” . To ensure implementation feasibility of an HIV cure around the world, challenges of healthcare worker shortages, limited laboratory capacity and access, financing, quality monitoring, public reluctance to accept new technologies, and priority setting for high-cost interventions will also need to be surmounted .
Tremendous human, financial, and social capital is being invested in the discovery of an HIV cure. For an HIV cure regimen to prove valuable, it should be effective, safe, simple, affordable, and scalable . It should also be translatable to human study participants, evidence-based practice, clinical care, and diverse populations. Appreciating the inherent translational ethics issues across the entire research continuum is essential, as HIV cure discoveries must eventually translate to real-world implementation. In this paper, we reviewed some of the considerations at each step of the HIV cure translation and implementation continuum; the issues described are not comprehensive. We asserted that an ethics of translation should begin early in the HIV cure discovery effort, before the availability of efficacious interventions. Logistical, social, cultural, and economic issues will affect the implementation of HIV cure research and interventions at the individual, institutional, national, and global levels. Ongoing community and stakeholder engagement efforts will be crucial to foresee, negotiate, and resolve potential ethical and implementation challenges. Innovative translational and implementation research paradigms utilized at all phases of the HIV cure research continuum will permit us to address critical issues that will ultimately help leverage cutting-edge HIV cure research discoveries to benefit PLWHIV around the globe.