Table 3 Summary of ethical and practical considerations for designing and implementing combination HIV cure trials

Considerations for combining interventions towards an HIV cure

• Ethical considerations for designing combination HIV cure research regimens—as for other types of trials—include a strong scientific rationale, social value through prioritization and optimization, balancing efficacy and safety, risk minimization and mitigation, and robust informed consent

• Trial design considerations include striking a balance between pursuing novel scientific paradigms and repurposing already existing products, ensuring careful statistical design for signal detection, maximizing potential efficacy while minimizing safety concerns, carefully selecting trial participants through clear inclusion/exclusion criteria, minimizing participant burdens such as the number of study visits/procedures, and planning for long-term follow-up of participants

• Considerations for ensuring an acceptable benefit/risk balance for combination HIV cure regimens include having robust pre-clinical safety data about single interventions, minimizing risks for otherwise healthy volunteers, maximizing the likelihood of scientific benefits, and ensuring consensus in the scientific community that a combination is worth testing

• Regulatory considerations for combination HIV cure trials include consulting existing FDA Combination Products Guidance Documents (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/combination-products-guidance-documents), collaborative regulatory reviews and case-by-case analyses, relying on the pre-IND consultation process, higher scrutiny for combination trials compared with monotherapies, evidence for intended proximal biological effect, clear endpoints, hearing the patient voice and meeting unmet medical needs

• From a regulatory and safety standpoint, it is important to know the effect of each intervention before testing them in combination. Knowing whether interventions have additive versus synergistic efficacy may be less important than excluding for antagonism or synergistic toxicity

• Focused attention should be given to prioritizing combination HIV cure strategies given limited resources and eligible trial participants. Considerations for prioritizing combination HIV cure research approaches included ensuring the “greatest positive results with least danger,” complementary mechanisms of action, future clinical viability, and patient friendliness

• The optimal number of interventions to include in combination HIV cure trials will depend on the interventions being tested. The number of interventions ultimately affects toxicity, complexity, interpretability, practicality, and scalability

• Decisions whether to administer interventions together or sequentially depend on the agents being tested, as well as their mechanisms of action, routes of administration, and side effects. Sequential administration may be warranted to measure the effect of each intervention and to prevent overreactions. Concurrent administration may be required if agents are targeting different issues or preventing resistance. The simpler the sequence, the higher the likelihood of future uptake and adherence in the real-world. The optimal timing of interventions will also depend on the mechanism of action. Biomedical researchers should rely on robust PK/PD and modeling data to determine optimal timing or dosing windows. The cancer field may provide a precedent and guidance

Considerations for specific combination HIV cure regimens

• bNAbs are viable candidates for combination HIV cure regimens, either with each other or with other HIV cure research modalities, due to their high safety profile, good characterization, and the fact that they are human-derived. However, bNAbs do carry some clinical risks (e.g., immune complexes, allergies) that should be monitored. Considerations should also be given to bNAb costs, scalability and accessibility. Safeguards should be in place to reduce resistance development, caused, for instance, by similar decay profiles that will result in functional monotherapy

• Combining cell and gene modification approaches warrants caution because of the potential for immediate and future irreversible conditions and serious and life-threatening adverse events. Possible safeguards include close FDA and Institutional Biosafety Committee oversight, following stepwise approaches, testing for off-target effects, staggering interventions and trial participants, clear stopping rules in case of intolerable toxicity of futility, and long-term follow-up of trial participants

• There may be a strong scientific rationale for combining LRAs and immune-based agents. Safeguards should include ART maintenance during LRA-only studies, long-term follow-up of trial participants, and community involvement in designing combinations

• Several types of novel combination regimens may emerge in the future. We will need to continue ensuring these strategies remain within acceptable benefit/risk parameters for otherwise healthy PLWH

Additional considerations

• To ensure combination HIV cure regimens represent improvements for PLWH, there needs to be a clear definition of the projected clinical benefits. This may require significant input from PLWH. Issues of accessibility, affordability, and stigma also need to be considered

• Designing and implementing combination HIV cure regimens may present additional challenges, such as IP issues and pharmaceutical company cross-collaborations. Incentives should be provided and public–private partnerships created to promote company collaborations. Researchers should continue working on assays and biomarkers that can identify and predict viral rebound

• Community and societal aspects of combination HIV cure research should also be carefully considered, such as managing expectations and building research literacy. Combination HIV cure regimens should also be designed with the end product in mind for eventual equitable real-world implementation