A pilot trial of recombinant interleukin-12 in patients with chronic hepatitis C who previously failed treatment with interferon-α

OBJECTIVE: Interleukin-12 is a cytokine with a multitude of immunomodulatory actions. Currently, interferon-α (IFN-α) monotherapy and combination treatment with IFN and ribavirin are the only therapies with proven efficacy against chronic hepatitis C infection. The purpose of this study was to assess the safety and antiviral activity of recombinant interleukin-12 (rhIL-12) in adults with chronic hepatitis C who did not achieve a sustained response to previous IFN-α therapy. METHODS: This was a randomized, placebo-controlled, double-blind trial. We randomized 24 patients to one of three dose groups: 30 ng/kg, 100 ng/kg, and 300 ng/kg. Within each group, six patients received rhIL-12, and two patients received placebo administered s.c. twice a week for 12 wk. RESULTS: Three of six patients treated with rhIL-12 at a dose of 300 ng/kg had loss of detectable hepatitis C RNA by reverse transcription-polymerase chain reaction compared with the placebo group ( p = 0.05). All patients relapsed at the end of the 3-month treatment period. No other dose group demonstrated a loss of detectable hepatitis C RNA. CONCLUSIONS: RhIL-12 at 300 ng/kg can suppress hepatitis C RNA to undetectable levels by reverse transcription-polymerase chain reaction, although relapse occurred when treatment was stopped. RhIL-12 was well tolerated with the most common side effects being flu-like symptoms and headaches

Effects of immunosuppression regimens on occurrence of graft versus host disease in liver transplantation. an analysis of UNOS registry

Background: Graft-versus-host disease (GVHD) after liver transplant is a rare complication. This study aimed to analyze the UNOS registry to identify risk factors for fatal GVHD, focusing on effects of immunosuppression regimens. Methods: We used the UNOS registry. All liver transplant and liver-kidney transplant patients between 2002 and 2018 were analyzed. An endpoint was set as mortality due to GVHD. Patients who died within 30 days after transplant were excluded. We analyzed associations between GVHD and immunosuppression regimens, including induction and maintenance, along with other recipient and donor characteristics. Multivariate Cox regression model was used. Results: A total of 85033 patients were eligible. There were 128 patients (0.2%) who died of GVHD. Rabbit-antithymocyte globulin (rATG), Basiliximab, and Rituximab were used as induction in 8406 (9.9%), 13173 (15.5%), and 1802 (2 .1%), and Mycophenolate and Azathioprine were used as maintenance in 56360 (66.2%) and 1443 (1.7%), respectively. When comparing between groups with and without induction on multivariate analysis, the induction group showed a significantly higher risk for GVHD (hazard ratio [HR], 1.60; P=0.02). When immunosuppression regimens were separately included in a multivariate model, Basiliximab (HR, 1.93; P=0.003) remained as independent risk factors, along with recipient-donor age discrepancy (HR, 1.03 [per year]; P\u3c0.001). Mycophenolate maintenance showed a protective effect (HR, 0.56; P=0.002) and rATG was not associated with GVHD (HR, 0.95; P=0.88). Conclusions: Avoiding Basiliximab induction and adding Mycophenolate to maintenance may be favorable to decrease a risk of GVHD

Rapid deterioration of pre-transplant kidney function requiring dialysis is a prognostic factor in liver transplant alone.

Aim: Etiologies of acute kidney injury before liver transplant extend beyond hepatorenal syndrome (ie infection, gastrointestinal bleeding) and therefore, may not be resolved by liver transplantation. We hypothesized that rapid deterioration of kidney function immediately before transplant would impact outcome significantly. The aim of this study was to review the safety of liver transplant alone (LTA) in cases of rapid deterioration of kidney function requiring dialysis by comparing outcomes in liver transplant alone (LTA) and simultaneous liver-kidney transplant (SLK). Methods: We retrospectively reviewed of 532 primary deceased donor LT patients from 2009 to 2015. SLK patients (n=44) were compared to patients who required pre-transplant dialysis. The latter group was categorized according to the duration of low GFR (Group 1: GFR\u3c30mL/min for 3 weeks or less [rapid deterioration group, n=24], Group 2: GFR\u3c30mL/min over 3 weeks [sustained injury group, n=16]). Results: Median durations of low GFR (\u3c60mL/min and \u3c30mL/min) and pretransplant dialysis were shorter in Group 1 than Group 2 (23, 13, and 7 days vs. 51, 33, and 18 days). Group 1 showed significantly worse one-year survival than the SLK group (66% vs. 93%, P=0.01), whereas it was comparable between the Group 2 and SLK group (88% vs. 93%, P=0.52). Post-transplant dialysis was required in 100% and 87% of patients in Groups 1 and 2, respectively. Seven patients in Group 1 died in the first year, five of whom remained on dialysis until their deaths. In Group 2, one patient who recovered kidney function died of PTLD on POD 220. While GFR at 12 months after transplant was significant better in the SLK group, it was comparable between Groups 1 and 2, (63, 47, and 45mL/min in the SLK, Groups 1, and 2, respectively, P=0.03). Graft survival after one year was similar among these 3 groups (P=1.0). Conclusion: Rapid deterioration of kidney function before LTA, rather than sustained kidney injury, is more likely lead to persistent renal failure and increase one-year mortality. In patients with rapid renal dysfunction; deferring LTA until etiology of renal dysfunction can be clarified may be warranted. Further investigation is needed determine if SLK improves early outcomes of this population

Molecular analysis of rejection and injury in liver transplant biopsies: The INTERLIVER STUDY

Background. Distinguishing T cell-mediated rejection (TCMR) from other sources of inflammation in liver transplant biopsies by histology has been challenging. Recent progress in molecular assessment of kidney, heart, and lung transplants suggests that microarray biopsy phenotyping would provide novel insights for liver transplantation. Method. We prospectively studied 102 liver transplant biopsies (90% for indications) from USA, Canada, Europe, and Australia with gene expression microarrays (INTERLIVER ClinicalTrials.gov NCT03193151). We used 453 kidney-derived rejection-associated transcripts (RATs) in unsupervised archetypal (AA) and principal component analyses (PCA). Results. Every liver biopsy yielded abundant high quality RNA for microarray analysis. In PCA, principal component 1 correlated with transcripts associated with inflammation (e.g. PTPRC/CD45), TCMR (e.g. Granzyme A) and interferon-gamma effects (e.g. GBP5), and with histologic portal triaditis; PC2 correlated with injury-induced transcripts (e.g. SERPINB8). AA identified 3 archetypes (A1, A2, and A3) and scored every biopsy for similarity to each: S1normal, S2TCMR, and S3injury (Figure 1, with biopsies colored by highest score). Biopsy groups were studied for expression of previously annotated transcript sets (Table 1). S1normal biopsies lacked rejection, inflammation, and injury. S2TCMR biopsies had high expression of rejection- and IFNG-inducible transcripts. S3injury biopsies had increased transcripts reflecting injury and cellular damage (e.g. DAMPs), and were early post-transplant i.e. had donation-implantation injury. Additional 5-archetype analyses suggested a small subclass of late biopsies with plasma cells and mast cell transcripts, which in other organs are associated with fibrosis. No biopsies manifested molecular changes suggesting ABMR. Conclusion. Molecular phenotyping classifies liver transplant biopsies as normal, TCMR, and early injury. The incidence of biopsies with TCMR-like changes (25%) was higher than in other organ transplants which raises the possibility that immunoregulatory mechanisms such as T cell exhaustion may be operating