Strategies to Reduce Serious Infections in High-Risk Solid Organ Transplant Recipients

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

Strategies to Reduce Serious Infections in High-Risk Solid Organ Transplant Recipients

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

Early steroid withdrawal in HIV-infected kidney transplant recipients: Utilization and outcomes.

Kidney transplant (KT) outcomes for HIV-infected (HIV+) persons are excellent, yet acute rejection (AR) is common and optimal immunosuppressive regimens remain unclear. Early steroid withdrawal (ESW) is associated with AR in other populations, but its utilization and impact are unknown in HIV+ KT. Using SRTR, we identified 1225 HIV+ KT recipients between January 1, 2000, and December 31, 2017, without AR, graft failure, or mortality during KT admission, and compared those with ESW with those with steroid continuation (SC). We quantified associations between ESW and AR using multivariable logistic regression and interval-censored survival analysis, as well as with graft failure and mortality using Cox regression, adjusting for donor, recipient, and immunologic factors. ESW utilization was 20.4%, with more zero HLA mismatch (8% vs 4%), living donors (26% vs 20%), and lymphodepleting induction (64% vs 46%) compared to the SC group. ESW utilization varied widely across 129 centers, with less use at high- versus moderate-volume centers (6% vs 21%, P < .001). AR was more common with ESW by 1 year (18.4% vs 12.3%; aOR: 1.08 1.612.41 , P = .04) and over the study period (aHR: 1.02 1.391.90 , P = .03), without difference in death-censored graft failure (aHR 0.60 0.911.36 , P = .33) or mortality (aHR: 0.75 1.151.77 , P = .45). To reduce AR after HIV+ KT, tailoring of ESW utilization is reasonable

Early national and center-level changes to kidney transplantation in the United States during the COVID-19 epidemic.

In March 2020, coronavirus disease 2019 (COVID-19) spread rapidly nationally, causing widespread emergent changes to the health system. Our goal was to understand the impact of the epidemic on kidney transplantation (KT), at both the national and center levels, accounting statistically for waitlist composition. Using Scientific Registry of Transplant Recipients data, we compared data on observed waitlist registrations, waitlist mortality, and living-donor and deceased-donor kidney transplants (LDKT/DDKT) March 15-April 30, 2020 to expected events calculated from preepidemic data January 2016-February 2020. There were few changes before March 15, at which point the number of new listings/DDKT/LDKT dropped to 18%/24%/87% below the expected value (all P < .001). Only 12 centers performed LDKT March 15-31; by April 30, 40 centers had resumed LDKT. The decline in new listings and DDKT was greater among states with higher per capita confirmed COVID-19 cases. The number of waitlist deaths was 2.2-fold higher than expected in the 5 states with highest COVID-19 burden (P < .001). DCD DDKT and regional/national imports declined nationwide but most steeply in states with the highest COVID-19 burden. The COVID-19 epidemic has resulted in substantial changes to KT; we must adapt and learn rapidly to continue to provide safe access to transplantation and limit the growing indirect toll of an already deadly disease