Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844.

Long non-coding RNAs (lncRNAs) play critical roles in diverse cellular processes; however, their involvement in many critical aspects of the immune response including the interferon (IFN) response remains poorly understood. To address this gap, we compared the global gene expression pattern of primary human hepatocytes before and at three time points after treatment with IFN-α. Among ∼200 IFN-induced lncRNAs, one transcript showed ∼100-fold induction. This RNA, which we named lncRNA-CMPK2, was a spliced, polyadenylated nuclear transcript that was induced by IFN in diverse cell types from human and mouse. Similar to protein-coding IFN-stimulated genes (ISGs), its induction was dependent on JAK-STAT signaling. Intriguingly, knockdown of lncRNA-CMPK2 resulted in a marked reduction in HCV replication in IFN-stimulated hepatocytes, suggesting that it could affect the antiviral role of IFN. We could show that lncRNA-CMPK2 knockdown resulted in upregulation of several protein-coding antiviral ISGs. The observed upregulation was caused by an increase in both basal and IFN-stimulated transcription, consistent with loss of transcriptional inhibition in knockdown cells. These results indicate that the IFN response involves a lncRNA-mediated negative regulatory mechanism. lncRNA-CMPK2 was strongly upregulated in a subset of HCV-infected human livers, suggesting a role in modulation of the IFN response in vivo.

Although experimental evidence has indicated that ischemia-reperfusion (I/R) injury of the liver stimulates growth of micrometastases and adhesion of tumor cells, the clinical impact of I/R injury on recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) has not been fully investigated. To study this issue, we conducted a retrospective review of the medical records of 391 patients from two transplant centers who underwent LT for HCC. Ischemia times along with other tumor/recipient variables were analyzed as risk factors for recurrence of HCC. Subgroup analysis focused on patients with HCC who had pathologically proven vascular invasion (VI) because of the associated increased risk of micrometastasis. Recurrence occurred in 60 patients (15.3%) with median time to recurrence of 0.9 years (range, 40 days-4.6 years). Cumulative recurrence curves according to cold ischemia time (CIT) at 2-hour intervals and warm ischemia time (WIT) at 10-minute intervals showed that CIT >10 hours and WIT >50 minutes were associated with significantly increased recurrence (P 5 0.015 and 0.036, respectively). Multivariate Cox's regression analysis identified prolonged cold (>10 hours; P 5 0.03; hazard ratio [HR] 5 1.9) and warm (>50 minutes; P 5 0.003; HR 5 2.84) ischemia times as independent risk factors for HCC recurrence, along with tumor factors, including poor differentiation, micro-and macrovacular invasion, exceeding Milan criteria, and alphafetoprotein >200 ng/mL. Prolonged CIT (P 5 0.04; HR 5 2.24) and WIT (P 5 0.001; HR 5 5.1) were also significantly associated with early (within 1 year) recurrence. In the subgroup analysis, prolonged CIT (P 5 0.01; HR 5 2.6) and WIT (P 5 0.01; HR 5 3.23) were independent risk factors for recurrence in patients with VI, whereas there was no association between ischemia times and HCC recurrence in patients with no VI. Conclusion: Reducing ischemia time may be a useful strategy to decrease HCC recurrence after LT, especially in those with other risk factors. (HEPATOLOGY 2015;61:895-904)

Liver allocation based on MELD-Na score successfully improved waitlist outcomes and provided significant benefit to hyponatremic patients. Given the discrepancy in transplantation survival benefit, the current rules for liver allocation might require revision.

Mycophenolate mofetil (MMF) and sirolimus (SRL) have been used for calcineurin inhibitor (CNI) minimization to reduce nephrotoxicity following liver transplantation. In this prospective, open‐label, multicenter study, patients undergoing transplantation from July 2005 to June 2007 who were maintained on MMF/CNI were randomized 4 to 12 weeks after transplantation to receive MMF/SRL (n = 148) or continue MMF/CNI (n = 145) and included in the intent‐to‐treat population. The primary efficacy endpoints were the mean percentage change in the calculated glomerular filtration rate (GFR) and a composite of biopsy‐proven acute rejection (BPAR), graft lost, death, and lost to follow‐up 12 months after transplantation. Patients were followed for a median of 519 days after randomization. MMF/SRL was associated with a significantly greater renal function improvement from baseline with a mean percentage change in GFR of 19.7 ± 40.6 (versus 1.2 ± 39.9 for MMF/CNI, P = 0.0012). The composite endpoint demonstrated the noninferiority of MMF/SRL versus MMF/CNI (16.4% versus 15.4%, 90% confidence interval = −7.1% to 9.0%). The incidence of BPAR was significantly greater with MMF/SRL (12.2%) versus MMF/CNI (4.1%, P = 0.02). Graft loss (including death) occurred in 3.4% of the MMF/SRL‐treated patients and in 8.3% of the MMF/CNI‐treated patients (P = 0.04). Malignancy‐related deaths were less frequent with MMF/SRL. Adverse events caused withdrawal for 34.2% of the MMF/SRL‐treated patients and for 24.1% of the MMF/CNI‐treated patients (P = 0.06). The use of MMF/SRL is an option for liver transplant recipients who can benefit from improved renal function but is associated with an increased risk of rejection (but not graft loss). Liver Transpl 19:675–689, 2013.. © 2013 AASLD.