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Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma.In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509.Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related.First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

ZusammenfassungRheumatologische und hepatologische Erkrankungen haben einige Überschneidungen, die für Behandler aus beiden Disziplinen relevant sind. In dieser Übersicht wird ein Schlaglicht auf 2 Erkrankungen geworfen, die sich an der Schnittstelle befinden: Arthropathie bei Hämochromatose und Systemische Sklerose bei Primär Biliärer Cholangitis. Daneben werden hepatologische Fragestellungen bei rheumatologischer Therapie beleuchtet.

Background & aims Acute hepatitis B virus (HBV) infections may clear spontaneously or become chronic and run through different phases. The single nucleotide polymorphisms (SNPs) rs3077, rs9277535 and rs9277534 within the human leucocyte antigen (HLA)-DP gene have been found to be associated with HBV susceptibility and persistence in Asians. However, evidence for the influence of these variants in Caucasians has been limited so far. The aim of our study was to investigate the impact of these polymorphisms on the outcome of HBV infections in a large Caucasian population. Methods In this case-control study, we retrospectively analysed 1111 Caucasian individuals, including 618 with chronic HBV infections (CHB), 239 with spontaneous HBsAg seroclearance (SC) and 254 healthy controls (HC). The rs3077, rs9277535 and rs9277534 SNPs were genotyped by a polymerase chain reaction from blood samples and melting curve analysis. Results A significant difference in the allele distributions was observed only for the rs3077 SNP between the HC and the CHB group as well as between the SC and CHB groups. The rs3077-C allele was associated with a lower probability for spontaneous HBsAg seroclearance in comparison with the rs3077-T allele (OR 0.704, 95% CI 0.509-0.974; P = 0.033). No association of the three SNPs with the stages of chronic HBV infection was found. Conclusion This is the first study demonstrating an association of the rs3077-T allele with spontaneous HBsAg seroclearance in Caucasians. Further studies are needed to elucidate the role of HLA-DP variants in disease pathogenesis and their potential role for individualized disease management.

Background and Aims. Systemic treatment with sorafenib has been the standard of care (SOC) in patients with advanced Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) for more than a decade. TACE has been reported to allow better local tumor control in selected patients with BCLC stage C HCC. Methods. A retrospective analysis of patients with BCLC stage C HCC that were treated with sorafenib and TACE was conducted, they were compared to BCLC stage C patients treated either with TACE or sorafenib in the same period of time outside a clinical trial. Results. A total of 201 patients with BCLC stage C were identified, who were treated with either sorafenib and TACE (group A, n = 54), sorafenib (group B, n = 82) or TACE (group C, n = 65). No significant difference in baseline characteristics was observed. Time to progression was 7.0 months (95% CI: 4.3–9.7), 4.1 months (95% CI: 3.6–4.7) and 5.0 months (95% CI: 2.9–7.1) in groups A, B and C, respectively, and overall survival was 16.5 months (95% CI: 15.0–18.1), 8.4 months (95% CI: 6.0–10.8) and 10.5 months (95% CI: 7.5–13.6), respectively (group A vs. group B: p &lt, 0.001, group A vs. group C: p = 0.0023). Adverse events of grade 3/4 occurred in 34% of patients in group A. Conclusions. Although sorafenib is a SOC in patients with BCLC stage C HCC, TACE is frequently used as an additional locoregional treatment in selected patients. This combined approach resulted in a significant overall survival benefit in selected patients, although randomized trials have not yet proven this benefit.

BACKGROUND & AIMS: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the efficacy and safety of a combination of sorafenib and selective internal radiation therapy (SIRT) - with yttrium-90 (90Y) resin microspheres - to sorafenib alone in patients with advanced HCC. METHODS: SORAMIC is a randomised controlled trial comprising diagnostic, local ablation and palliative cohorts. Based on diagnostic study results, patients were assigned to local ablation or palliative cohorts. In the palliative cohort, patients not eligible for TACE were randomised 11:10 to SIRT plus sorafenib (SIRT + sorafenib) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat (ITT) population. RESULTS: In the ITT cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months in the SIRT + sorafenib arm, and 11.4 months in the sorafenib arm (hazard ratio [HR] 1.01; 95% CI 0.81-1.25; p = 0.9529). Median OS in the per protocol population was 14.0 months in the SIRT + sorafenib arm (n = 114), and 11.1 months in the sorafenib arm (n = 174; HR 0.86; p = 0.2515). Subgroup analyses of the per protocol population indicated a survival benefit of SIRT + sorafenib for patients without cirrhosis (HR 0.46; 0.25-0.86; p = 0.02); cirrhosis of non-alcoholic aetiology (HR 0.63; p = 0.012); or patients ≤65 years old (HR 0.65; p = 0.05). Adverse events (AEs) of Common Terminology Criteria for AE Grades 3-4 were reported in 103/159 (64.8%) patients who received SIRT + sorafenib, 106/197 (53.8%) patients who received sorafenib alone (p = 0.04), and 8/24 (33.3%) patients who only received SIRT. CONCLUSION: Addition of SIRT to sorafenib did not result in a significant improvement in OS compared with sorafenib alone. Subgroup analyses led to hypothesis-generating results that will support the design of future studies. LAY SUMMARY: Sorafenib given orally is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). In selective internal radiation therapy (SIRT), also known as radioembolisation, microscopic, radioactive resin or glass spheres are introduced into the blood vessels that feed the tumours in the liver. This study found that the addition of SIRT with 90yttrium-loaded resin microspheres to sorafenib treatment in people with advanced HCC did not significantly improve overall survival compared with sorafenib treatment alone. However, the results give an indication of how future studies using this combination therapy in people with advanced HCC could be designed. STUDY REGISTRATION: EudraCT 2009-012576-27, NCT0112 6645. ispartof: JOURNAL OF HEPATOLOGY vol:71 issue:6 pages:1164-1174 ispartof: location:Netherlands status: published

BACKGROUND AND AIMS There is limited real-world information on the effectiveness of antiviral treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAA) in people on opioid substitution therapy (OST). This study compared sustained virological response (SVR) rates and proportion of lost to follow-up (LTFU) between OST and non-OST patients in the German Hepatitis C-Registry (DHC-R). DESIGN National multi-centre prospective real-world registry (German Hepatitis C-Registry, DHC-R). Non-OST patients comprised patients with former/current drug use (non-OST/DU) and patients never consuming drugs (non-OST/NDU). SETTING A total of 254 medical centres in Germany, including 123 centres providing OST. PARTICIPANTS A total of 7747 chronic HCV patients started DAA therapy (739 OST and 7008 non-OST; 1500 non-OST/DU; 5508 non-OST/NDU) patients. Five hundred and twenty-eight OST and 5582 non-OST patients had completed antiviral therapy and at least one follow-up documentation [intention-to-treat (ITT) population]. MEASUREMENTS Study outcomes were SVR, proportion of LTFU and safety of treatment. FINDINGS SVR (ITT) was documented in 85% (450 of 528) OST patients versus 86% (969 of 1126) in non-OST/DU (P = 0.651) and 92% (4113 of 4456) non-OST/NDU (P 90 × 109/l (aOR = 1.51, CI = 1.14-2.01), cirrhosis (aOR = 0.77; CI = 0.62-0.96) and patient group (OST/DI (aOR = 0.58; CI = 0.42-0.78); non-OST/DU (OR: 0.63; CI = 0.50-0.78). In per-protocol analysis (PP), SVR rates were ≥ 94% in all patient groups. In OST the proportion of LTFU was higher (10.2%) than in non-OST/DU (8.5%) and non-OST/NDU (3.2%, P

Background & Aims There is currently no virological cure for chronic hepatitis B but successful nucleos(t)ide analogue (NA) therapy can suppress hepatitis B virus (HBV) DNA replication and, in some cases, result in HBsAg loss. Stopping NA therapy often leads to viral relapse and therefore life-long therapy is usually required. This study investigated the potential to discontinue tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. Methods Non-cirrhotic HBeAg-negative patients who had received TDF for ≥4years, with suppressed HBV DNA for ≥3.5years, were randomly assigned to either stop (n=21) or continue (n=21) TDF monotherapy. Standard laboratory tests including HBV DNA viral load, HBsAg and alanine aminotransferase (ALT) measurements, and adverse event reporting were carried out during treatment and post-treatment follow-up for 144weeks. Results Of the patients who stopped TDF therapy, 62% (n=13) remained off-therapy to Week 144. Median HBsAg change in this group was −0.59log 10 IU/ml (range −4.49 to 0.02log 10 IU/ml) vs. 0.21log 10 IU/ml in patients who continued TDF therapy. Four patients (19%) achieved HBsAg loss. Patients stopping therapy had initial fluctuations in viral load and ALT; however, at Week 144, 43% (n=9) had either achieved HBsAg loss or had HBV DNA Conclusions This controlled study demonstrated the potential for HBsAg loss and/or sustained virological response in non-cirrhotic HBeAg-negative patients stopping long-term TDF therapy. Lay summary: Nucleos(t)ide analogue (NA) is usually a life-long therapy for HBV patients. This randomised controlled study investigated the discontinuation of tenofovir disoproxil fumarate (TDF) therapy in HBeAg-negative patients. Of the patients who stopped TDF therapy, 62% remained off-therapy to Week 144, of which 43% of patients had achieved either HBsAg loss or HBV DNA Clinical trial number: NCT01320943.

Background and aim Hepatic encephalopathy (HE) is a frequent complication of cirrhosis, characterized by cognitive deficits that negatively impact patients' quality of life. The mild, minimal hepatic encephalopathy (mHE) can only be detected by psychometric tests and early mHE detection can prevent more severe complications or even survival times. Here, we aimed to investigate the feasibility and validity of the novel-developed electronic number connection test (eNCT), which is designed as a fast and easy-to-perform mHE patient self-test. Methods The eNCT design was inspired by the paper-pencil number connection test version A, showing 25 numbers on the screen (1-25), in a random order. The time required to tap on all digits in the correct order was measured. A total of 238 individuals (112 patients with liver cirrhosis) were enrolled in this study and eNCT times were compared with well-established paper-pencil tests. The Psychometric Hepatic Encephalopathy Score test battery was used to detect mHE and cut-off values for mHE detection by the eNCT were defined. Results Overall, cirrhotic patients showed significantly slower test completion times compared with control participants. The eNCT performance was inversely correlated with Psychometric Hepatic Encephalopathy Score test performance in cirrhotic patients, independent of the HE status. Thirty cirrhotic patients fulfilled the mHE criteria and receiver operating characteristic curve analysis showed high sensitivity (>82%) and specificity (>85%) for mHE detection. Finally, the eNCT showed excellent test-retest reliability (intraclass correlation coefficient=0.94). Conclusion The novel eNCT is a reliable HE self-test to monitor cognitive function and detect cognitive impairment in cirrhotic patients.

Patients with hepatocellular carcinoma (HCC) in cirrhosis have an increased risk for postoperative complications including liver failure. However, there is some evidence that the use of laparoscopy markedly decreases this risk. Patients Between 2010 – 2015, a total of 21 laparoscopic liver resections were performed for HCC in Child-A cirrhosis at our center. Mean MELD score was 9 (6 – 12), and the mean LiMAx was 261 µg/h/kg (101 – 489). All resections were performed by conventional laparoscopy using 4 – 6 trocars. Liver parenchyma was transected using ultrasonic shears. Hilar occlusion was used on demand. In the earlier years, laparoscopic resections were performed occasionally and mainly if tumors were easily accessible. With increasing experience, currently most HCC in cirrhosis are resected laparoscopically. Likewise, 12 out of the 21 resections were performed within the last 12 months, including 2 anatomic left hemihepatectomies. Results Conversion rate, postoperative mortality, and operative revision rate were all 0 %. Four patients (19 %) developed mild complications Clavien-Dindo grade 1 or 2 (ascites, transfusion, pneumonia, renal impairment). One patient (4.8 %) developed a grade 3 event (bile leak, percutaneous drainage). All but 1 early patient underwent R0 resection (95 %). The mean duration of hospital stay was 10.5 days (5 – 21), and the mean duration of ICU stay was 1.8 days (1 – 7). No case of decompensation of liver cirrhosis was observed. In 1 case, a prolonged production of ascites evolved. Conclusion Even in patients with severely impaired liver function, no severe complications and especially no decompensation of cirrhosis was observed. Therefore, in accordance with other single center experiences, liver resection for HCC in cirrhosis should be performed preferentially by laparoscopy.

Background/aim The use of lamivudine for the treatment of chronic hepatitis B (CHB) is limited by high rates of lamivudine resistance. However, it is still in use in many regions. Factors associated with lamivudine resistance development have been studied in only a few European cohorts. The aim of our study was to assess the rate and risk factors for lamivudine resistance in a large real-life European cohort. Patients and methods We retrospectively analyzed patients with CHB treated in three German University centers over up to 12 years. Lamivudine resistance was defined as virologic breakthrough and presence of genotypic lamivudine resistance. The probability of resistance was estimated by Kaplan-Meier analysis and resistance predictors by Cox regression. Results A total of 227 patients were included into the analysis (hepatitis B envelope antigen positive or negative). Rates of lamivudine resistance by years 1-7 were 7, 26, 35, 41, 46, 53, and 55%, respectively. Interestingly, two hepatitis B envelope antigen-negative patients developed resistance during the year 12 of treatment. Independent risk factors for resistance development were hepatitis B virus DNA levels of at least 10 copies/ml before and detectable hepatitis B virus DNA by month 6 of treatment. Conclusion Even after long-term response to lamivudine more than 10 years, resistance may still develop. Our findings further discourage the use of lamivudine for the treatment of CHB.

Background The new directly acting antivirals (DAAs) enable all-oral interferon-free treatment of chronic hepatitis C virus (HCV) infection. We here investigated the effect of DAAs on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C. Methods Twenty-one patients with elevated liver enzymes or advanced fibrosis/compensated cirrhosis caused by recurrent HCV were treated with sofosbuvir either in combination with simeprevir, or in combination with ribavirin or daclatasvir with or without ribavirin for 12 weeks. Biochemical parameters, tacrolimus trough levels, and the maximal liver function capacity (LiMAx) were measured monthly during the treatment and 12 weeks after the end of treatment. Results All patients achieved sustained virological response 12 weeks after the end of the treatment. The transaminases and cholestasis parameters normalized until week 8 of treatment. The mean LiMAx (normal ranges >315 μg/kg/h) increased from 344±142 μg/kg/h before treatment to 458±170 μg/kg/h (P

Hepatocellular carcinoma (HCC) is a leading cause of cancer death. The multikinase inhibitor sorafenib is widely used for systemic therapy in advanced HCC. Sorafenib might affect epoxyeicosanoids, as it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of epoxides derived from long-chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding diols. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) showed that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this pilot study, we assessed the effect of sorafenib treatment on the presence of lipid mediators, such as EETs, in blood of the patients with HCC using the lipidomics technology. We found a significant increase in 11,12-EET and 14,15-EET levels in HCC patients treated with sorafenib. Furthermore, while not significant in this small sample set, the data presented indicate that sorafenib can also increase the level of omega-3 DHA-derived 19,20-EDP. While the effect on EETs might hamper the anti-tumor effect of sorafenib, we hypothesize that supplementation of DHA in sorafenib-treated HCC patients could increase the level of 19,20-EDP and thereby enhance its anti-tumor effect.

Innate immunity can induce spontaneous hepatitis B surface antigen (HBsAg) seroclearance (SC) of hepatitis B virus (HBV) infection or transition towards an inactive carrier state. Toll-like receptor (TLR) 3 signalling has been linked to these processes. Alterations in the TLR3 gene might impair immune responses against HBV. In our study, we analysed the impact of the TLR3 polymorphisms rs3775291 and rs5743305 on the natural course of HBV infection. In this retrospective study, a Caucasian cohort of 621 patients with chronic HBV infection (CHB), 239 individuals with spontaneous HBsAg SC, and 254 healthy controls were enrolled. In the CHB group, 49% of patients were inactive carriers, and 17% were HBeAg-positive. The TLR3 rs3775291 A allele was associated with a reduced likelihood of spontaneous HBsAg SC and HBeAg SC, and an increased risk of developing chronic hepatitis B. In haplotype analysis, the haplotype including both risk variants rs3775291A and rs5743305A had the lowest likelihood of HBsAg SC. Further research in larger cohorts and functional analyses are needed to shed light on the impact of TLR3 signalling.

Background SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to prolong survival and improve tolerability. This phase III study compared clinical efficacy and safety of NIVO with SOR as 1L therapy in pts with aHCC. Methods Systemic therapy–naive pts aged ≥18 years with aHCC were randomized 1:1 to NIVO (240mg IV Q2W) or SOR (400mg oral BID). Primary endpoint was overall survival (OS). Additional endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review per RECIST v1.1, efficacy by tumor programmed death ligand 1 (PD-L1) expression, and safety. Results 743 pts with aHCC were randomized to NIVO (n=371) or SOR (n=372) with minimum follow-up of 22.8 months at data cutoff. OS did not meet the predefined threshold of statistical significance (HR 0.84, P=0.0419). Median OS (mOS) was 16.4mo for NIVO and 14.7mo for SOR (HR 0.85 [95% CI: 0.72–1.02]; P=0.0752). Clinical benefit was observed across predefined subgroups, including hepatitis infection status, presence of vascular invasion and/or extrahepatic spread, and region (Asia vs non-Asia). ORR was 15% for NIVO (14 pts with complete response [CR]) and 7% for SOR (5 pts with CR; Table). Grade 3/4 treatment-related adverse events were reported in 81 pts (22%) in the NIVO arm and 179 pts (49%) in the SOR arm and led to discontinuation in 16 (4%) and 29 (8%) pts, respectively. No new safety signals were observed with NIVO. 140 pts (38%) in the NIVO arm and 170 pts (46%) in the SOR arm received subsequent therapy. Additional OS analyses and patient-reported outcomes will be presented to support the benefit of NIVO.Table: LBA38_PREfficacy resultsTable: LBA38_PRNIVOSORn=371n=372Median OS (95% CI), mo16.4 (13.9–18.4)14.7 (11.9–17.2)12-mo OS rate, % (95% CI)59.7 (54.4–64.6)55.1 (49.8–60.1)24-mo OS rate, % (95% CI)36.8 (31.8–41.8)33.1 (28.3–38.0)Median PFS, mo (95% CI)3.7 (3.1–3.9)3.8 (3.7–4.5)ORR, n (%)57 (15)26 (7)BOR, n (%)Complete response14 (4)5 (1)Partial response43 (12)21 (6)ORR by baseline tumor PD-L1 expression, n/n (%)PD-L1 ≥1%20/71 (28)6/64 (9)PD-L1 Conclusions Though the primary endpoint of OS did not achieve statistical significance vs SOR, NIVO showed clinically meaningful improvements in OS, ORR, and CR rate as 1L treatment for aHCC. NIVO demonstrated a favorable safety profile consistent with previous reports. Clinical trial identification NCT02576509. Editorial acknowledgement Writing and editorial assistance was provided by Andrea L. Hammons of Parexel International (Waltham, MA, USA) and funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure T. Yau: Honoraria (institution), Advisory / Consultancy: Bristol-Myers Squibb. R.S. Finn: Honoraria (self), Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eisai; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli-Lilly; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Honoraria (self), Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Pfizer; Honoraria (self), Speaker Bureau / Expert testimony: Roche/ Genentech. A. 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Harding: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Speaker Bureau / Expert testimony: Exelexis; Honoraria (self), Speaker Bureau / Expert testimony: Elly Lilly ; Honoraria (self), Speaker Bureau / Expert testimony: CytomX; Honoraria (self), Speaker Bureau / Expert testimony: QED. P. Merle: Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution): IPSEN; Advisory / Consultancy: Eisai; Advisory / Consultancy: Lilly; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Merck; Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: AstraZeneca. O. Rosmorduc: Honoraria (self): Bayer; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: Sirtex; Honoraria (self): Eisai. L. 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Kelley: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Honoraria (self), Speaker Bureau / Expert testimony, IDMC membership: Genentech/Roche; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): AstraZeneca. D. Begic: Full / Part-time employment: Bristol-Myers Squibb. J. Neely: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. J. Anderson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. B. Sangro: Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: BTG; Advisory / Consultancy: H3 Biomedicine; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: Onxeo; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sirtex Medical; Advisory / Consultancy: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Terumo. All other authors have declared no conflicts of interest.

The objective of this study was to investigate the correlation between hepatic venous pressure gradient (HVPG) and in vivo viscoelasticity of the liver and spleen before and after transjugular intrahepatic portosystemic shunt (TIPS) implantation.Ten patients with portal hypertension were examined twice by 3-dimensional multifrequency magnetic resonance elastography as well as prior and subsequent TIPS intervention; HVPG was also measured during TIPS placement. Five harmonic vibrations (25-60 Hz) were transferred to the abdominal region and recorded for the reconstruction of 2 viscoelastic constants, |G*| and φ, corresponding to the magnitude and the phase angle of the complex shear modulus G* of the liver and spleen.All patients had cirrhosis, yielding high |G*| values in the liver (8.34 ± 2.18 kPa) and spleen (8.44 ± 1.36 kPa). In both organs, a decrease of |G*| after TIPS placement was observed (liver: 8.34 ± 2.18 kPa vs 7.02 ± 1.46 kPa, P = 0.01; spleen: 8.44 ± 1.36 kPa vs 7.06 ± 1.32 kPa, P = 0.01), whereas φ was insensitive to TIPS. Relative changes in |G*| of the spleen were correlated with the relative change of HVPG (R² = 0.659, P = 0.013).The observed linear correlation between spleen viscoelasticity HVPG raises the prospect of an image-based noninvasive assessment of portal pressure by magnetic resonance elastography in the follow-up of TIPS placements.

Historically, hepatitis C virus genotype 3 infection has not been as hard to treat as genotype 1 using interferon-based therapy. Now, genotype 3 infection can be treated using interferon-free regimes such as the combination of sofosbuvir and daclatasvir, which is a highly successful and reliable therapeutic option before liver transplant. However, real world data are rather limited regarding the use of antivirals (sofosbuvir/daclatasvir) for hepatitis C virus genotype 3 recurrence after liver transplant. Here, we present the results of antiviral treatment with sofosbuvir and daclatasvir in patients with genotype 3 recurrence after liver transplant and also viewed published data, to finally close the chapter on genotype 3 elimination.We analyzed 11 patients who received liver transplants due to hepatitis C virus genotype 3-associated cirrhosis at our center. Two patients were nadve for any antiviral therapy. All patients received antiviral treatment with sofosbuvir/daclatasvir for 12 weeks after liver transplant, with 1 patient also having ribavirin. The endpoint was hepatitis C virus RNA-free survival after 12 weeks of therapy. Secondary endpoints were preservation of renal and liver function and incidence of adverse events.All patients were free of hepatitis C virus RNA by at least 8 weeks after therapy initiation. Elevated transaminases and gamma-glutamyltransferase at the beginning of therapy normalized quickly during treatment. Synthesis and excretion were stable at all dates. Patients displayed no severe adverse effects, especially regarding renal function and blood counts. Sustained virologic response rates at week 12 were achieved in all 11 patients.Hepatitis C virus could be eliminated in all patients after liver transplant with 12-week sofosbuvir/daclatasvir therapy. Sofosbuvir combined with daclatasvir is safe and reliable for recurrent hepatitis C virus genotype 3 infection. Our results have closed the chapter on genotype 3 recurrence after liver transplant in our outpatient clinic.

Background Spontaneous reports of acute liver injuries (ALI) in patients taking dronedarone triggered an EMA alert in 2011. This study aimed to assess the risk of ALI for class III antiarrhythmic drugs controlling for the use of other potential ALI-inducing drugs. Methods Between 2010 and 2014, consecutive ALI cases (≥50 years-old) were identified across Germany. ALI was defined as a new increase in at least one of the transaminases ≥3 times the upper limit of normal (ULN) or ≥2 ULN if alkaline phosphatase, with (“definite” case) or without (“biochemical” case) suggestive signs/symptoms of ALI, excluding other liver diseases. Recruited community controls were matched to cases on gender, age and inclusion date. Exposure to antiarrhythmic drugs and co-medication up to 2 years before ALI onset was informed by patients and confirmed by physicians' prescriptions. Adjusted Odds Ratios (aOR) were obtained from conditional multivariable logistic regressions, adjusted for a multivariate disease risk score and co-medication. Results 252 cases and 1081 matched controls were included (59.1% females; mean age: 64 years). Exposure to class III antiarrhythmic drugs was 4.0% in cases and 1.5% in controls, aOR = 3.6 (95% CI: 1.6–8.4). Associations with exposure to dronedarone and amiodarone were respectively 3.1 (95% CI: 0.7–14. 8) and 5.90 (1.7–20.0). Restricting the analysis to definite or severe ALI cases did not change these results. Conclusions Class III antiarrhythmic drugs were associated with ALI, amiodarone displaying the highest risk, and results were robust to case definitions. Continued vigilance is needed for patients taking these drugs.