Expanding HOPE Liver Transplantation: Understanding Opportunistic Infection and Cancer Risk

Early studies of liver transplantation (LT) from donors with HIV to recipients with HIV (HIV D+/R+) under the HIV Organ Policy Equity (HOPE) Act have shown acceptable transplant outcomes, supporting safety and feasibility, and prompting the Secretary of Health and Human Services to publish a federal rule to expand this practice from research-only into clinical care; however, critical knowledge gaps remain regarding some negative findings. One-year survival in D+/R+ LT was significantly lower (83%) compared to LT from donors without HIV (D-/R+) (100%). There was also a higher incidence of opportunistic infections (OIs) (cytomegalovirus [CMV], candida, aspergillus) and viral-associated cancers (Kaposi-Sarcoma associated herpesvirus [KSHV], human papillomavirus, hepatitis B and C). These early studies were relatively small, and more data and follow-up time are needed to better understand these risks and measure long-term outcomes. There are potential virologic and immunologic explanations for higher OI and cancer rates. D+ livers harbor HIV and HIV D+ are more likely to harbor other viruses as well. Reactivation of these viruses may directly lead to OIs and cancer; in addition, the viruses may trigger immune activation and inflammation, that impair immune responses to infections. A better understanding of these pathways can identify interventions to improve outcomes, such as optimal HIV D+ selection, targeted monitoring, and prophylaxis. We propose a renewal of our initial HOPE in Action HIV D+/R+ LT U01 grant, entitled Expanding HOPE Liver, a multicenter study where we will perform 40 HIV D+/R+ LT and 40 D-/R+ LT at 20 transplant centers, measuring the incidence of OI and cancer. We will combine this new cohort with earlier cohorts (Pilot N=45, initial U01 N=80), to provide sufficient statistical power for precision and to measure outcomes beyond 5 years. Within this study, we will perform mechanistic assays to examine virologic and immunologic pathways underlying OI and cancer. We will characterize prior and active viral infections in donors and recipients with phage display and immunoprecipitation sequencing, plasma virome molecular studies, and KSHV surveillance. We will measure immune activation with a multiplexed electrochemiluminescence detection assay for cytokines and chemokines. We will measure immune responses to CMV and other infections with intracellular cytokine staining and flow cytometry, and we will use CITE-seq to measure the functional state of immune cells. Our HOPE in Action Multicenter Consortium has an established track record of conducting multicenter transplantation trials, including HIV D+/R+ LT. We will expand our existing transplant center network and leverage existing infrastructure to oversee operations, data management, analysis, and safety monitoring. In summary, the proposed research will determine the impact of HIV D+ livers on opportunistic infection and cancer, will quantify long term outcomes, and elucidate mechanisms underlying these complications. This knowledge can provide a pathway to safely expand HIV D+/R+ LT while improving outcomes.