Herpes Simplex Virus in Transplant Recipients: Evaluating Serostatus, Shedding, and Breakthrough Infection

Abstract

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are common neurotropic viruses; most adults in the United States and worldwide are infected with HSV-1, and around 1 in 8 are infected with HSV-2. Solid organ transplant (SOT) and allogeneic hematopoietic cell transplant (aHCT) recipients are at higher risk of HSV reactivation post-transplant than the general population due to immunosuppression. Long-term acyclovir prophylaxis is recommended for HSV prevention in select immunosuppressed populations. While highly effective against mucocutaneous HSV infection, it does not eliminate HSV shedding or clinical disease. This dissertation explores the potential roles of HSV in transplant settings through three distinct means: through viral reactivation by evaluating clinical and subclinical HSV shedding among SOT recipients, through HSV disease by characterizing the incidence and management of HSV infections that occurred despite acyclovir prophylaxis (including resistant infections) among aHCT recipients, and through prior exposure by examining the association between pre-transplant HSV serostatus and post-transplant survival among aHCT recipients. Chapter 1 describes the frequency of subclinical and clinical oral HSV reactivation among a cohort of SOT recipients not taking daily acyclovir. In this prospective study, 15 SOT recipients (median time since transplant: 20 months [range: 10-32 months]) self-collected oral swabs for HSV three times daily for a total of six weeks. The sampling schedule was feasible for participants, as shown by the high collection percentage of expected swabs (median 96.8%, range: 85.7%–101.6%), with a median of 122 swabs (range: 108–128) collected per person. Overall, 80% of participants had at least one HSV shedding episode during the 6-week follow-up and most were asymptomatic; the median per-person oral shedding rate was 8.9% (range: 0–33.6%), and the median subclinical shedding rate was 7.5% (range: 0–33.6%). For episodes of known duration, the median duration of shedding was 21.8 hours (interquartile range [IQR]: 10.8-46.1 hours). Chapter 2 explores the predictors and outcomes of breakthrough HSV infections among aHCT recipients over a 20-year period at the Fred Hutch Cancer Center. We reviewed data from 4,357 aHCT recipients between 2002-2022 for HSV infections within the first 100 days of transplant. Among 3,749 (86%) HSV seropositive patients, 23 developed breakthrough HSV infection (cumulative incidence = 0.6%). The median time from transplant to first positive test was 46 days (IQR: 24-69.5). Resistant/refractory (R/R) HSV infections were overall uncommon but represented almost half (47.8%) of cases. Treatment duration was significantly longer for patients with R/R vs. susceptible infections (median 44 vs. 15.5 days). Cord blood recipients had a significantly higher risk of breakthrough HSV than recipients of peripheral blood stem cell or bone marrow grafts (OR = 5.2 (1.5-17.4, p <0.01)). Chapter 3 evaluates the association between pre-transplant HSV-1 and HSV-2 serostatus and post-transplant relapse and mortality within the first year of aHCT among the same cohort of patients as included in Chapter 2. We fit Cox proportional hazards models for mortality up to one year post-transplant, by HSV serostatus, as determined by Western blot. Models were adjusted for age, sex, cytomegalovirus (CMV) serostatus, conditioning regimen, disease risk, graft type and HLA matching, year of transplant and acute graft-versus host disease. HSV-1 was associated with higher hazards of all-cause mortality (aHR = 1.20 (95% CI: 1.06-1.36)), relapse (1.45 (1.23-1.70)), and relapse-related mortality (1.74 (1.39-2.18)). HSV-2 seropositivity was associated with a higher hazard of relapse (1.15 (1.02-1.30)). The age-stratified HSV-1 and HSV-2 seroprevalence were consistently higher than that of the general US population, which raises questions for future research about the possibility of passive antibody transfer during pre-transplant transfusion of blood products. The findings of this work highlight the high frequency of HSV reactivation during immunosuppression, the efficacy of long-term, high-dose acyclovir/valacyclovir prophylaxis in preventing clinical HSV infection, the challenges associated with managing breakthrough HSV disease (particularly refractory or resistant infection) in aHCT recipients, and the potential impacts of HSV infection beyond mucocutaneous disease. Further research is needed to evaluate the association between blood and plasma transfusions and HSV serostatus, understand the potential clinical significance of subclinical HSV shedding, develop novel antiviral agents and treatment strategies to better suppress viral replication and to combat R/R infections, and hopefully develop a vaccine and/or cure for HSV in the future.