Dickson, Rolland C.

Introduction. Increased steatosis on preimplant liver frozen section is associated with delayed graft function and primary nonfunction. Efforts to standardize histologic assessment have proven difficult. Frozen section artifact and lipopeliosis complicate the detection of steatosis. We aimed to develop and validate an AI model to recognize large droplet fat and fat induced artifact (FIA)/lipopeliosis on preimplantation frozen section and to correlate the AI results with post-transplant clinical parameters. Methods. The model was applied to 161 consecutive liver transplant specimens with preimplant slides. Results were correlated with traditional and Banff histologic assessment and clinical parameters. Results. By traditional assessment, steatosis ranged from 0%–40%. The AI model identified a range of 0 to 15.9% steatosis. There was no difference in patient survival by any measures of steatosis. AI steatosis correlated with increased risk of early allograft dysfunction (OR = 1.63, P < .001), respiratory failure (OR = 1.21, P = .003), and more advanced fibrosis (OR = 1.18, P = .030), but was not correlated with graft or patient survival. FIA/lipopeliosis were identified in a range of 0 to 6.42%. In univariate analysis the percentage of FIA/lipopeliosis correlated with both graft and patient survival ( P = .044 and P = .009, respectively), but was not associated with increased risk of early allograft dysfunction, respiratory failure, or advanced fibrosis. Conclusions. We developed an AI model that quantitates large droplet fat and FIA/lipopeliosis on frozen section slides and found a correlation with post-transplant outcomes. Further studies on larger, multi-institutional cohorts with higher fat containing donors are necessary to determine the role this model may have in organ acceptance decisions.

Abstract Background: Starting in November 2017, 3 liver transplant centers in a single health care system tested and implemented a new protocol to begin accepting livers from hepatitis C virus–seropositive donors for seronegative liver transplant recipients. Although reports show an increase in donors after protocol implementation, there are no details regarding protocol uptake at each transplant center. Literature is limited on protocol implementation that is developed and disseminated by the same protocol producers. The purpose of this study was to evaluate the implementation of a new liver transplant protocol adopted at 3 transplant centers in the same health care system. Methods: A multimethod implementation study using interview, survey, and transplant data was conducted to develop a conceptual model of protocol implementation, identify facilitators of and barriers to implementation, and detect differences in implementation between 3 centers. Results: The conceptual model included 4 domains: rationale, development, implementation, and sustainability. Facilitators included clear, science-based rationale, input from multiple hepatologists, leadership support, and funded pilot data. Barriers included insurance coverage of posttransplant medication and donor field availability. A total of 94 physicians and staff at the 3 transplant centers completed the survey. Implementation factors were all rated moderately high to high at all 3 centers. One-way analysis of variance showed significant differences in mean implementation scores between the centers (F(2, 84)=11.65; P<.001) and between physicians at the 3 centers (F(2, 23)=4.65; P=.02); post hoc comparisons indicated that the scores for physicians differed only between the leading center and 1 participating center. Transplant numbers increased across all 3 centers from 2017 to 2021. Conclusions: Protocol implementation was successful across all 3 centers, especially at the leading transplant center where the protocol was developed. Future efforts should examine the appropriateness of the protocol for other organs (eg, heart, kidney) and additional medical outcome data (eg, mortality, morbidity, quality of life). Trial Registration: Not applicable

Albumin-interferon-α (alb-IFN) is a novel recombinant protein derived from IFN-α2b genetically fused to human albumin. The resulting single polypeptide combines in one molecule the antiviral properties of IFN-α with the long serum half-life of albumin. IFN-mediated biological responses stem from the engagement of IFN-α with its target receptor and subsequent modulation of IFN-specific gene (ISG) expression. To evaluate the pharmacodynamics of alb-IFN during the Phase I/II study conducted in patients with chronic hepatitis C (CHC) who had previously failed IFN-α-containing regimens, ISG induction was evaluated in peripheral blood and compared with antiviral response. Whole blood was obtained at day 0, day 7 and day 28 from 21 patients enrolled in the higher dose (500–900 μg) alb-IFN cohort, who received two injections on day 0 and day 14. Taqman real-time PCR was used to assess candidate ISG expression. There was sustained induction on day 7 and day 28 of the ISG's OAS1, IRF-7, IFI44 and IFI27. Although all patients showed a molecular response to alb-IFN, individual variability in pretreatment gene expression levels and fold of modulation during treatment was observed. At day 28, induction of OAS1, IFI44 and IRF7 showed pairwise correlation in individual patients ( P<0.05). Moreover, the induction of expression at day 28, and pretreatment levels of OAS1 and IFI44 correlated with hepatitis C virus RNA reduction at day 28 ( P<0.05). In conclusion, alb-IFN demonstrated robust induction of ISG that was consistent with the response associated with an IFN-α.

Albumin-interferon-α (IFN-α) is a novel 85.7–kDa recombinant protein consisting of IFN-α that is genetically fused to human serum albumin. In this Phase I/II, multicentre, open-label study, we evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics of albumin-IFN-α in IFN-α-experienced patients with chronic hepatitis C. Albumin-IFN-α was administered in 22 escalating doses (7–900 μg) in a single injection or in two injections 14 days apart. In the 119 patients studied, there were no discontinuations because of adverse events, and albumin-IFN-α had a favourable safety profile at doses up to 900 μg. The most common adverse events were headache (56%), fatigue (52%), injection site erythema (38%), arthralgias (32%) and pyrexia (27%). Reduced clearance resulted in a mean elimination half-life of 159h, which supports dosing at 2- to 4-week intervals. Induction of the IFN-specific gene OAS1 was maintained for ≥28 days following a single injection of albumin-IFN-α at doses of ≥40 μg. Dose-dependent antiviral activity was observed in this IFN-α-experienced study population. Antiviral activity of ≥1.0–log reductions in HCV RNA was observed in 47% (37/78) of patients in the 120- to 900-μg cohorts and in 59% (16/27) in the 400- to 900-μg double-injection cohorts. These results support further clinical studies of albumin-IFN-α for the treatment of patients with chronic hepatitis C.

Background: Direct-acting antivirals (DAA) are highly effective for the treatment of hepatitis C (HCV), although there are limited data on the safety and efficacy of DAA therapy in hepatitis C-positive individuals awaiting liver transplantation for hepatocellular carcinoma (HCC). Methods: We conducted a retrospective cohort study of HCV-positive patients who underwent liver transplantation for HCC at 3 liver transplant centers across the United States from 2014 to 2017 with follow-up to July 2018. Transplant recipients who received DAA before transplant were compared with those who did not (DAA naive) for posttransplant HCC recurrence rate, sustained virological response (SVR), allograft failure, and death using Kaplan-Meier analysis and Cox proportional hazard models. Results: A total of 171 HCV-HCC transplant recipients (99 pretransplant DAA; 72 DAA naive controls) were included, with a median follow-up of 24 months. The overall posttransplant HCC recurrence rate was 9% (15/171). Pretransplant DAA was not associated with HCC recurrence (5% versus 14%; P = 0.07), graft failure (7% versus 3%; P = 0.21), or death (12% versus 19%; P = 0.19) as compared with DAA naive patients. SVR rates were significantly lower (P < 0.01) with pretransplant DAA (75%, 39/52) than posttransplant DAA (97%, 59/61) therapies. Those who received pretransplant DAA and those who did not were not statistically different in age, gender, alpha fetal protein levels, model for end-stage liver disease scores, or transplant wait time. Conclusions: Pretransplant DAA for HCV was not associated with an increased risk of posttransplant HCC recurrence, though pretransplant DAA had lower efficacy than posttransplant DAA in HCV-HCC transplant recipients.

Patients coinfected with hepatitis C virus (HCV) and HIV undergoing liver transplantation (LT) are at risk of early, aggressive HCV recurrence. This study investigates the use of frequent protocol-driven biopsies to identify HCV recurrence post LT in coinfected patients. Five consecutive HIV/HCV-coinfected patients underwent LT. Liver biopsies were obtained post LT at 1 hour; days 7, 120, and 365; then annually; and as clinically indicated. Stage 2 (Ishak) or higher fibrosis occurred in 4 of the 5 patients by 60, 120, 270, and 365 days. Two patients died of HCV recurrence and liver failure at 6 and 35 months post LT. Three patients survived more than 4 years after LT, 2 having sustained virologic responses to anti-HCV treatment. Another has histologic recurrence not responding to treatment. Hepatitis C virus recurrence can be rapid and aggressive after LT in HIV-coinfected patients. Serial biopsies identify recurrence early, allowing for prompt initiation of treatment.