Solid organ transplant (SOT) recipients endure frequent serious infections owing to multifactorial immunosuppression. This population, however, contains subgroups with distinctive immunodeficiencies including persons with HIV (PWH) and those with poor vaccine responses for whom infection risks may differ. This dissertation focuses on identifying high-risk phenotypes and strategies to reduce infections including immunosuppressive optimization and targeted prophylaxis.
The first work analyzes data from the HOPE in Action trials of HIV-donor-to-HIV-recipient SOT (Chapter 2) to elaborate the profile of donors with HIV. Certain coinfections (hepatitis B, syphilis, cytomegalovirus) were more prevalent among donors with HIV. Most donors were taking effective antiretroviral therapy (ART); 20% showed severe immunosuppression. Although HIV drug resistance mutations were frequent, resistance that might evade standard recipient ART was rare (2%). Overall, a minority of donors appeared high-risk for opportunistic infection transmission, though prophylaxis can be optimized.
The second work analyzes a national registry of 1225 PWH undergoing kidney transplant (HIV+ KT) (Chapter 3) evaluating the relationship between corticosteroid maintenance and organ rejection, treatment of which predisposes to infection. Early steroid withdrawal (ESW) varied widely among centers (0-90%), and was associated with increased rejection (18.4% vs 12.3% at one year; aHR:1.02.1.39.1.90, p=0.03); graft failure and mortality were not increased. Tailoring ESW to lower alloimmune risk PWH may mitigate the HIV+ KT infection-rejection cycle.
The final work (Chapter 4) is a clinical trial evaluating immunoprotection phenotypes following third SARS-CoV-2 mRNA vaccination in high-risk KT recipients. Preceding negative SARS-CoV-2-spike antibody (anti-RBD) after two-dose vaccination was strongly associated with poor responses to third doses; 45% remained seronegative, none showed Omicron variant neutralization. Immunogenicity varied considerably; 9% showed negative global (anti-RBD/T cell) responses, associated with high-dose mycophenolate use, while 40% showed global positive response; SARS-CoV-2-spike-specific CD4+ T cell expansion appeared necessary, but not sufficient for anti-RBD response. Breakthrough infections occurred in 16%, concentrated among poor anti-RBD responders, emphasizing need for alternative vaccine strategies to improve post-transplant COVID-19 immunoprotection.
These findings reinforce complementary roles of observational and trials datasets in understanding infection risks in SOT subpopulations. The COVID-19 pandemic highlights needed rigor for evaluating immunodeficiencies in generating personalized strategies to prevent serious post-transplant outcomes
