Improved Survival With Higher-risk Donor Grafts in Liver Transplant With Acute-on-chronic Liver Failure

Use of higher-risk grafts in liver transplantation for patients with acute-on-chronic liver failure (ACLF) has been associated with poor outcomes. This study analyzes trends in liver transplantation outcomes for ACLF over time based on the donor risk index (DRI). Methods: Using the Organ Procurement and Transplantation Network and the United Network for Organ Sharing registry, 17 300 ACLF patients who underwent liver transplantation between 2002 and 2019 were evaluated. Based on DRI, adjusted hazard ratios for 1-y patient death were analyzed in 3 eras: Era 1 (2002-2007, n = 4032), Era 2 (2008-2013, n = 6130), and Era 3 (2014-2019, n = 7138). DRI groups were defined by DRI2.0. Results: ACLF patients had significantly lower risks of patient death within 1 y in Era 2 (adjusted hazard ratio, 0.69; 95% confidence interval, 0.61-0.78; P \u3c 0.001) and Era 3 (adjusted hazard ratio, 0.48; 95% confidence interval, 0.42-0.55; P \u3c 0.001) than in Era 1. All DRI groups showed lower hazards in Era 3 than in Era 1. Improvement of posttransplant outcomes were found both in ACLF-1/2 and ACLF-3 patients. In ACLF-1/2, DRI 1.2 to 1.6 and \u3e2.0 had lower adjusted risk in Era 3 than in Era 1. In ACLF-3, DRI 1.2 to 2.0 had lower risk in Era 3. In the overall ACLF cohort, the 2 categories with DRI \u3e1.6 had significantly higher adjusted risks of 1-y patient death than DRI \u3c1.2. When analyzing hazards in each era, DRI \u3e 2.0 carried significantly higher adjusted risks in Eras 1 and 3\u27 whereas DRI 1.2 to 2.0 had similar adjusted risks throughout eras. Similar tendency was found in ACLF-1/2. In the non-ACLF cohort, steady improvement of posttransplant outcomes was obtained in all DRI categories. Similar results were obtained when only hepatitis C virus-uninfected ACLF patients were evaluated. Conclusions: In ACLF patients, posttransplant outcomes have significantly improved, and outcomes with higher-risk organs have improved in all ACLF grades. These results might encourage the use of higher-risk donors in ACLF patients and provide improved access to transplant

MicroRNA-214 enriched exosomes from human cerebral endothelial cells (hCEC) sensitize hepatocellular carcinoma to anti-cancer drugs

Hepatocellular carcinoma (HCC) is the most common primary liver tumor worldwide. Current medical therapy for HCC has limited efficacy. The present study tests the hypothesis that human cerebral endothelial cell-derived exosomes carrying elevated miR-214 (hCEC-Exo-214) can amplify the efficacy of anti-cancer drugs on HCC cells. Treatment of HepG2 and Hep3B cells with hCEC-Exo-214 in combination with anti-cancer agents, oxaliplatin or sorafenib, significantly reduced cancer cell viability and invasion compared with monotherapy with either drug. Additionally, the therapeutic effect of the combination therapy was detected in primary tumor cells derived from patients with HCC. The ability of hCEC-Exo-214 in sensitizing HCC cells to anti-cancer drugs was specific, in that combination therapy did not affect the viability and invasion of human liver epithelial cells and non-cancer primary cells. Furthermore, compared to monotherapy with oxaliplatin and sorafenib, hCEC-Exo-214 in combination with either drug substantially reduced protein levels of P-glycoprotein (P-gp) and splicing factor 3B subunit 3 (SF3B3) in HCC cells. P-gp and SF3B3 are among miR-214 target genes and are known to mediate drug resistance and cancer cell proliferation, respectively. In conclusion, the present in vitro study provides evidence that hCEC-Exo-214 significantly enhances the anti-tumor efficacy of oxaliplatin and sorafenib on HCC cells

Improvements in liver transplant outcomes in patients with HCV/HIV coinfection after the introduction of direct-acting antiviral therapies

BACKGROUND: In recipients with HCV/HIV coinfection, the impact that the wider use of direct-acting antivirals (DAAs) has had on post-liver transplant (LT) outcomes has not been evaluated. We investigated the impact of DAAs introduction on post-LT outcome in patients with HCV/HIV coinfection. METHODS: Using Organ Procurement and Transplant Network/United Network for Organ Sharing data, we compared post-LT outcomes in patients with HCV and/or HIV pre- and post-DAAs introduction. We categorized these patients into two eras: pre-DAA (2008-2012 [pre-DAA era]) and post-DAA (2014-2019 [post-DAA era]). To study the impact of DAAs introduction, inverse probability of treatment weighting was used to adjust patient characteristics. RESULTS: A total of 17 215 LT recipients were eligible for this study (HCV/HIV [n = 160]; HIV mono-infection [n = 188]; HCV mono-infection [n = 16 867]). HCV/HIV coinfection and HCV mono-infection had a significantly lower hazard of 1- and 3-year graft loss post-DAA, compared pre-DAA (1-year: adjusted hazard ratio [aHR] 0.29, 95% confidence interval (CI) 0.16-0.53 in HIV/HCV, aHR 0.58, 95% CI 0.54-0.63, respectively; 3-year: aHR 0.30, 95% CI 0.14-0.61, aHR 0.64, 95% CI 0.58-0.70, respectively). The hazards of 1- and 3-year graft loss post-DAA in HIV mono-infection were comparable to those in pre-DAA. HCV/HIV coinfection had significantly lower patient mortality post-DAA, compared to pre-DAA (1-year: aHR 0.30, 95% CI 0.17-0.55; 3-year: aHR 0.31, 95% CI 0.15-0.63). CONCLUSIONS: Post-LT outcomes in patients with coinfection significantly improved and became comparable to those with HCV mono-infection after introducing DAA therapy. The introduction of DAAs supports the use of LT in the setting of HCV/HIV coinfection

Sofosbuvir and Ribavirin Prevent Recurrence of HCV Infection After Liver Transplantation: An Open-Label Study

Background & AimsPatients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward.MethodsIn a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child–Turcotte–Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation.ResultsSixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%).ConclusionsAdministration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844

Drug Hepatotoxicity: Causality Assessment

Drug induced liver injury is a diagnosis that relies on the patterns of injury associated with specific medications and toxins. The process by which a clinician determines which agent is the likely culprit of the liver injury is called causality assessment. The Roussel Uclaf Causality Assessment Method (RUCAM) and additional causality assessment methods have been developed with the goal of providing a more standardized, less subjective approach to causality assessment. RUCAM remains the most used standardized method, however many physicians continue to rely on their experience for causality assessment

Antiviral Chemotherapy for Viral Hepatitis

Chronic hepatitis B viral infection remains one of the major medical problems in the world and is a leading cause of morbidity and mortality. Advances in the treatment and prevention of hepatitis B virus (HBV) infection represent among the most dramatic achievements of modern medicine and have resulted from fully exploiting discoveries in molecular immunology and virology as well as rational drug design. The first major breakthrough in the therapy of HBV was the development of regimens of interferon-alfa that give 30–40% long term remission rates in chronically infected patients. Despite this advance, the glass has also remained half empty. The more recent development of nucleoside analog agents with potent antiviral activity have now provided additional armamentarium in the care of HBV infected patients. The initial part of this chapter will address, in a practical manner, the therapy of appropriate patients with interferon and the anticipated effects and benefits of this therapy. The chapter will then discuss the evolving role of nucleoside analogs and even more experimental agents in the management of patients who are either refractory to or are poor candidates for interferon-alfa therapy

Outcomes of TIPS for ascites as a function of baseline renal function.

BACKGROUND Transjugular intrahepatic portosystemic shunts (TIPS) are used to treat ascites secondary to cirrhosis. There is limited data on the safety and efficacy of this modality in patients with significant renal insufficiency (RI). In this study, we evaluate patient outcomes with TIPS with an emphasis on baseline renal function. METHODS 88 patients who underwent TIPS for ascites and/or hepatic hydrothorax were analyzed retrospectively. Patients were divided into 3 groups based on calculated GFR (MDRD); \u3c45 mL/min (Group 1), 45‐60 (Group 2), and \u3e60 (Group 3). Outcomes measured include change in renal function, number of paracentesis/thoracentesis, hepatic encephalopathy (HE) and mortality. RESULTS There were 24, 24, and 40 patients in Groups 1, 2 and 3, respectively. The mean ages for Group 1, 2 and 3 were 59, 58 2 and 55 7 years, mean MELD‐Na at baseline were 18.29, 16.62, 15.1, mean creatinine were 1.99, 1.36, and 0.9 mg/dl and mean GFR were 35.15, 53.49, and 84.6 ml/min. Mean number of para/thora performed in the 90 days prior to TIPS were 7.71, 8.01, and 9.9.90 and 180‐day mortality was 4% and 17%, 11% and 8%, and 7.5% and 10% in Groups 1, 2 and 3, respectively. 33.3%, 14.2% and 23.5% of patients were transplanted at 180 days post‐TIPS. The mean number of para/thora required in the 90 days after TIPS declined to 1.14, 3.77, and 2.83 for the 3 groups. Length of stay (LOS) following TIPS increased for those with hydrothorax vs without: 5.47 vs 3 days (P=0.012). Those in Group 1 experienced an average increase in GFR of 12.01 mL/min at 30 days (P= 0.002) and 9.76 at 90 days (P=0.007). Those in Group 2 had an increase in GFR of 4.34 at 30 days and 10.01 at 90 days (NS). Those in Group 3 had an average increase in GFR of 8.61 at 30 days and a decrease of 7.31 at 90 days (NS). Post‐TIPS, the proportion of patients with hepatic encephalopathy was 67%, 54%, and 48% for Group 1, 2 and 3. For those in Group 1 and 2 only, there was a greater increase in HE if the change in portosystemic gradient after TIPS was \u3e10 vs \u3c10 mmHg (78% vs 33% for Group 1 and 44% vs 28% for those in Group 2) CONCLUSION Our results illustrate that TIPS is reasonably safe and effective in patients with ascites/hydrothorax with significant renal dysfunction. This group experienced a significant increase in GFR after the procedure and had comparable mortality compared to those with preserved renal function. All groups had a significant decline in the need for paracentesis. Patients with RI had more HE and this was especially marked in patients with a change in portosystemic gradient \u3e 10 mmHg. Those with hepatic hydrothorax had longer hospital stays following TIPS

Fulminant hepatitis B following rituximab therapy in a patient with Evans syndrome and large B-cell lymphoma

No abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50653/1/20540_ftp.pd