Table 3 Preliminary ethical and practical considerations for cell and gene therapy towards an HIV cure

1. Perceptions of CGT and benefit/risk considerations

1.1 Perceived benefits of CGT towards an HIV cure

Research teams should maximize the possible clinical and scientific benefits of CGT approaches towards an HIV cure. Perceived benefits included the prospect of developing “single-shot” regimens that could be less burdensome (although CGT may not prevent against re-infection), as well as scientific advancements that could lead to curative innovations for other molecular genetic diseases

1.2 Perceived risks of CGT towards an HIV cure

Research teams should minimize the possible clinical and non-clinical risks of CGT approaches towards an HIV cure. The possibility of unknown clinical risks will require careful and sustained pharmacovigilance. The risks of unintentional HIV transmission to sexual partners, therapeutic or curative misconceptions, and financial burdens of CGT should be minimized as well. Research teams should attempt to minimize social and economic risks of CGT trials

1.3 Ensuring acceptable benefit/risk balance

To ensure acceptable benefit/risk parameters, research teams should use an incremental scientific approach, ensure adequate regulatory review, minimize risks as much as possible, be transparent about potential risks, collect as much safety and efficacy data as possible, and maximize possible long-term benefits to humanity (knowledge/risk calculus) [97]

1.4 CGT strategies perceived to be unacceptable for human testing

There appears to be convergence on the unethicality of editing the germline and conducting allogeneic stem cell transplants in otherwise healthy PLWH. Research teams should remain attuned to unacceptable risk thresholds for individual study participants

1.5 Additional ethical considerations for CGT approaches towards an HIV cure

Additional ethical considerations for developing CGT HIV cure research approaches—although not unique to the field of CGT—include strong scientific rationale, fair participant selection, robust informed consent, distributive justice, and equity issues. Research teams should carefully inform trial participants about what adverse events to look for following a CGT intervention. CGT researchers should try to maximize long-term benefits for the HIV community

1.6 Considerations for first-in-humans CGT HIV cure trials

Considerations for implementing FIH CGT HIV cure trials—although not specific to this field—include a compelling scientific rationale for moving into human testing, robust pre-clinical data despite limitations of current animal models, close observance of the regulatory process, and involvement of PLWH in trial design. For a comprehensive FDA summary regarding Preclinical Assessment of Investigational Cellular and Gene Therapy Products, see https://www.fda.gov/media/87564/download

2. Safeguards and risk mitigation strategies

2.1 General safeguards for developing CGT approaches towards an HIV cure

Safeguards to developing and implementing CGT approaches towards an HIV cure may include, but are not limited to, clinical trial design considerations for example, narrow inclusion and exclusion criteria, low initial trial enrollment, dose escalation and de-escalation rules, staggering trial participants, careful monitoring for potential side effects that include long-term side effects, and clear stopping rules in the event of intolerable toxicity. CGT product specificity, manufacturing and transport safeguards (e.g., to ensure identity, purity, sterility, stability, and potency), robust research staff training, accumulating a scientific body of evidence over time, and monitoring for potential conflicts of interest of investigators are also of paramount importance

2.2 Safeguards for combining CGT approaches

Possible safeguards for combining CGT approaches may include but are not limited to, ensuring individual components are safe, determining potential harmful combinatorial or synergistic effects, combining existing safeguards, continued investment in pre-clinical work, ensuring favorable benefit/risk profiles, transparency about risks, and community involvement. See FDA Combination Products Guidance Documents, available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/combination-products-guidance-documents

2.3 Mitigating off-target effects of CGT interventions

Possible risk mitigation strategies for off-target effects may include but are not limited to, improved targeting during engineering, extensive testing for off-target effects, such as location of off-targeting, risks of off-targeting, and frequency of off-targeting, careful monitoring in the entire body, including both blood and tissue sampling, ensuring that trial participants clearly understand possible long-term risks so they know what to look for over time, and long-term participant follow-up. The risk of double stranded breaks should be minimized as much as possible. See FDA Guidance on Long-Term Follow-Up After Administration of Human Gene Therapy Products, available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/long-term-follow-after-administration-human-gene-therapy-products

2.4 Mitigating risks associated with long-term duration of CGT interventions and immune over-reactions

Possible risk mitigation strategies to control the long-term duration of CGT interventions depend on the strategies being investigated, for example, gene editing may warrant transient approaches while immune-based approaches may warrant more frequent monitoring and control. Carefully designed strategies to control the durability of a CGT investigational product, such as genetic manipulation, safety switches or ART restart should be implemented

Possible risk mitigation strategies for immune overreactions, also called cytokine release syndrome, a risk factor associated with some CGT interventions (such as CAR-T cells) include active monitoring, using the ASBMT consensus grading system and established pharmacological protocols to reduce inflammation, like cortical steroids. Possible risks of neurotoxicity should also be monitored and carefully mitigated