A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B.

BACKGROUND & AIMS: Nucleos(t)ide analogues (NUCs) are the standard and mostly lifelong treatment for chronic HBeAg-negative hepatitis B, as functional cure (loss of HBsAg) is rarely achieved. Discontinuation of NUC treatment may lead to functional cure; however, to date, the evidence for this has been based on small or non-randomized clinical trials. The STOP-NUC trial was designed with the aim of increasing the HBsAg loss rate using a NUC treatment interruption approach. METHODS: In this multicenter, randomized-controlled trial, 166 HBeAg-negative patients with chronic hepatitis B on continuous long-term NUC treatment, with HBV DNA <172 IU/ml (1,000 copies/ml) for ≥4 years, were randomized to either stop (Arm A) or continue NUC treatment (Arm B) for a 96-week observation period. In total, 158 patients were available for final analysis, 79 per arm. The primary endpoint was sustained HBsAg loss up to week 96. RESULTS: Our study met its primary objective by demonstrating HBsAg loss in eight patients (10.1%, 95% CI 4.8%-19.5%) in Arm A and in no patient in Arm B (p = 0.006). Among patients with baseline HBsAg levels <1,000 IU/ml, seven (28%) achieved HBsAg loss. In Arm A, re-therapy was initiated in 11 (13.9%) patients, whereas 32 (40.5%) patients achieved sustained remission. A decrease of HBsAg >1 log IU/ml was observed in 16 patients (20.3%) in Arm A and in one patient (1.3%) in Arm B. No serious adverse events related to treatment cessation occurred. CONCLUSIONS: Cessation of NUC treatment was associated with a significantly higher rate of HBsAg loss than continued NUC treatment, which was largely restricted to patients with end of treatment HBsAg levels <1,000 IU/ml. IMPACT AND IMPLICATIONS: As HBeAg-negative patients with chronic hepatitis B on nucleos(t)ide analogues (NUCs) rarely achieve functional cure, treatment is almost always lifelong. The STOP-NUC trial was conducted to investigate whether discontinuing long-term NUC treatment can increase the cure rate. We found that some patients achieved functional cure after stopping NUCs, which was especially pronounced in patients with HBsAg levels <1,000 at the end of NUC treatment, and that many did not need to resume therapy. The results of the Stop-NUC trial provide evidence for the concept of stopping NUC treatment as a therapeutic option that can induce functional cure.

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

Assessment of the Effect of Sorafenib on Omega-6 and Omega-3 Epoxyeicosanoid Formation in Patients with Hepatocellular Carcinoma.

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.

Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.

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.

Patterns of Resistance-Associated Substitutions in Patients With Chronic HCV Infection Following Treatment With Direct-Acting Antivirals.

BACKGROUND & AIMS: Little is known about substitutions that mediate resistance of hepatitis C virus (HCV) to direct-acting antivirals (DAAs), due to the small number of patients with treatment failure in approval studies. It is important to identify resistance patterns to select effective salvage treatments. METHODS: We performed a comprehensive analysis for resistance-associated substitutions (RASs) in HCV genes (nonstructural protein [NS]3, NS5A, NS5B) targeted by DAAs. We compared NS3, NS5A, and NS5B sequences from 626 patients in Europe with DAA failure with sequences from 2322 DAA-naïve patients, infected with HCV genotypes 1 to 4. We considered RASs to be relevant if they were associated with DAA failure in patients or conferred a greater than twofold change in susceptibility compared with a reference strain in in vitro replicon assays. Data were collected on pretreatment status, DAA regimen, the treatment initiation date and duration, and virologic response. Patients who received at least 4 weeks of antiviral treatment were included in the analysis. RESULTS: RASs in NS3 associated with simeprevir or paritaprevir failure include R155K and D168E/V. In addition, several RASs were specifically associated with failure of simeprevir (Q80K/R in patients with genotype 1a or 4) or paritaprevir (Y56H in combination with D168V in patients with genotype 1b). Y93H in NS5A was the RAS most frequently associated with failure of daclatasvir, ledipasvir, or ombitasvir in patients with genotype 1b infection, and L31M was associated with failure of daclatasvir or ledipasvir, but not ombitasvir. RASs in NS5A were heterogeneous among patients with HCV genotype 1a or genotype 4 infections. In patients with HCV genotype 3, Y93H was associated with resistance to daclatasvir, but no RASs were associated with ledipasvir failure, pointing to a limited efficacy of ledipasvir in patients with genotype 3. Among patients failed by sofosbuvir-containing regimens, L159F was enriched in patients with genotype 1b (together with C316N) or genotype 3 infection, whereas the RAS S282T was rarely observed. CONCLUSIONS: We compared RASs in NS3, NS5A, and NS5B among patients failed by DAA therapy. Theses varied with the HCV genotype and subtype, and the different drug classes. These findings might be used to select salvage therapies.

Association of HLA-DPA1 and HLA-DPB1 polymorphisms with spontaneous HBsAg seroclearance in Caucasians.

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.

Real-world effectiveness of 8-week treatment with ledipasvir/sofosbuvir in chronic hepatitis C.

BACKGROUND & AIMS: Ledipasvir/sofosbuvir (LDV/SOF) for 8 to 24 weeks is approved for the treatment of chronic hepatitis C virus infection (HCV). In the ION-3 study, 8 weeks of LDV/SOF was non-inferior to 12 weeks in previously untreated genotype 1 (GT1) patients without cirrhosis. According to the Summary of Product Characteristics (SmPC), 8-week treatment may be considered in naïve non-cirrhotic GT1-patients. However, there are only limited data on the effectiveness of an 8-week regimen of LDV/SOF under real-world conditions. The aim of the present study was to characterise patients receiving 8 weeks of LDV/SOF compared to those receiving 12 weeks of LDV/SOF, and to describe therapeutic outcomes in routine clinical practice. METHODS: The German Hepatitis C-Registry is a large national real-world cohort that analyses effectiveness and safety of antiviral therapies in chronic HCV. This data set is based on 2,404 patients. Treatment with SOF/LDV (without RBV) for 8 or 12 weeks was initiated on or before September 30, 2015. RESULTS: Overall, 84.6% (2,034/2,404) of the safety population (intention-to-treat-1 [ITT1]) and 98.2% (2,029/2,066) of the per protocol (PP) population achieved sustained virological response at week 12 (SVR12). In the 8-week group, 85.1% (824/968) of ITT1 and 98.3% (821/835) of PP patients achieved SVR12, while in the 12-week group, 85.5% (1,210/1,415) of ITT1, and 98.1% (1,208/1,231) of PP patients achieved SVR12. When treated according to the SmPC, 98.7% (739/749) of the patients achieved SVR12 (PP). Relapse was observed in 9.5% (2/21) of cirrhotic patients treated for 8 weeks (PP). CONCLUSIONS: Under real-world conditions a high proportion of eligible patients receiving 8-week LDV/SOF treatment achieved SVR12. Relapse occurred more frequently in patients who did not meet the selection criteria according to the SmPC. LAY SUMMARY: In a large real-world cohort of patients mainly treated by physicians in private practice in Germany, shorter HCV treatment (8-week) resulted in equivalent cure rates to 12-week treatment in genotype 1 HCV-infected patients. Thus, shorter treatment can be recommended in these patients which would substantially reduce costs of therapy. Clinical Trial number: DRKS00009717 (German Clinical Trials Register, DRKS).

Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study.

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 -0.59log10IU/ml (range -4.49 to 0.02log10IU/ml) vs. 0.21log10IU/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 <2,000IU/ml. There were no unexpected safety issues identified with stopping TDF therapy. 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 <2,000IU/ml. This offers a potential for long-term HBV-suppressed patients without cirrhosis to stop NA therapy under strict surveillance. Clinical trial number: NCT01320943.

The 28-year incidence of de novo malignancies after liver transplantation: A single-center analysis of risk factors and mortality in 1616 patients.

De novo malignancies (DNMs) are one of the leading causes of late mortality after liver transplantation (LT). We analyzed 1616 consecutive patients who underwent LT between 1988 and 2006 at our institution. All patients were prospectively observed over a study period of 28 years by our own outpatient clinic. Complete follow-up data were available for 96% of patients, 3% were incomplete, and only 1% were lost to follow-up. The median follow-up of the patients was 14.1 years. Variables with possible prognostic impact on the development of DNMs were analyzed, as was the incidence of malignancies compared with the nontransplant population by using standardized incidence ratios. In total, 266 (16.5%) patients developed 322 DNMs of the following subgroups: hematological malignancies (n = 49), skin cancer (n = 83), and nonskin solid organ tumors (SOT; n = 190). The probability of developing any DNM within 10 and 25 years was 12.9% and 23.0%, respectively. The respective probability of developing SOT was 7.8% and 16.2%. Mean age at time of diagnosis of SOT was 57.4 years (range, 18.3-81.1 years). In the multivariate analysis, an increased recipient age (hazard ratio [HR], 1.03; P < 0.001) and a history of smoking (HR, 1.92; P < 0.001) were significantly associated with development of SOT. Moreover, the development of SOT was significantly increased in cyclosporine A-treated compared with tacrolimus-treated patients (HR, 1.53; P = 0.03). The present analysis shows a disproportionate increase of de novo SOT with an increasing follow-up period. Increased age and a history of smoking are confirmed as major risk factors. Moreover, the importance of immunosuppression is highlighted. Liver Transplantation 23 1404-1414 2017 AASLD.

Treatment of hepatitis C virus recurrence after transplantation with sofosbuvir/ledipasvir: The role of ribavirin.

BACKGROUND: Hepatitis C virus (HCV) recurrence after liver transplantation (LT) used to be a serious problem in the era of interferon-based treatment. Since the introduction of modern directly acting antivirals, treatment has become easier and shorter. According to published data, in the natural course of hepatitis C infection the duration of antiviral treatment with sofosbuvir (SOF) and ledipasvir (LDV) may be shortened to 12 instead of 24 weeks, using ribavirin (RBV) in addition. Furthermore, the question of whether or not RBV is really necessary, in a 12-week SOF/LDV treatment in the post-transplant setting, is still unanswered. PATIENTS AND METHODS: At our institution, 100 liver transplant patients with HCV recurrence underwent interferon-free SOF-based treatment. A total of 51 patients received SOF/LDV with or without RBV. Twenty-nine HCV genotype 1 or 4 patients with histologically proven stage 0-2 fibrosis were treated with SOF/LDV for 12 weeks; another 22 patients with advanced fibrosis (stage 3-4) either received SOF/LDV plus weight-adjusted RBV or prolonged treatment for 24 weeks. RESULTS: End of treatment response and sustained virological response (SVR) were achieved in 100% of the 51 patients, irrespective of the treatment group. Patients with prolonged treatment duration or with RBV developed significantly more adverse events (AEs) compared to the SOF/LDV group: 19 (86.4%) vs 8 (27.6%), P<.001. One of the predominant and most relevant AEs was the development of anemia in 43.1% of 10 patients receiving RBV, which was a significant result (P<.001). RBV co-medication had to be reduced in 11 (55%) patients and then stopped in 8 (40%) patients because of AEs. No significant difference was observed among the groups regarding kidney function. CONCLUSION: The SOF/LDV combination is a reliable therapy of recurrent HCV infection after LT. It is easy to administer and to achieve SVR in immunocompromised patients without interactions with immunosuppressive medications. Considering the high rate of AEs, frequent discontinuation of RBV treatment, and the 100% SVR, the use of RBV as co-medication in a 12-week SOF/LDV regimen does not seem to be justified after LT.

Evolution of laparoscopic liver surgery as standard procedure for HCC in cirrhosis?

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.

Apolipoprotein E allele frequencies in chronic and self-limited hepatitis C suggest a protective effect of APOE4 in the course of hepatitis C virus infection.

BACKGROUND & AIMS: Infectious hepatitis C virus (HCV) particles bind to host lipoproteins such as low-density lipoproteins (LDLs). Low-density lipoprotein receptors (LDLR) have been termed candidate receptors for HCV-LDL complexes. Functional host genetic single nucleotide polymorphisms (SNPs) in the apolipoprotein E (APOE) gene encoding apolipoprotein E (apoE) - a major structural LDL component and natural ligand of LDLR - likely influence the course of HCV infection. We investigated the prevalence of APOE SNPs in two large and independent cohorts of patients with chronic HCV infection compared to respective controls. METHODS: We genotyped 996 chronically HCV-infected patients; 179 patients with spontaneous HCV clearance; 283 individuals with non-HCV-associated liver disease; and 2 234 healthy controls. RESULTS: APOE genotype proportions in patients with persistent HCV infection significantly differed from healthy controls (P = 0.007) primarily because of a substantial under-representation of APOE4 alleles in chronically HCV-infected patients (10.2%) compared to 13.0% in healthy controls (P = 0.001). The distribution of APOE4 allele positive genotypes (ε2ε4, ε3ε4, ε4ε4) also significantly differed between chronically HCV-infected patients and healthy controls (1.4%, 17%, 1% vs. 2.4%, 20.5%, 1.7%; P = 0.001), suggesting a protective effect of the APOE4 allele in HCV infection. This was confirmed by a significant over-representation of the APOE4 allele in patients with spontaneous HCV clearance (17.6%; P = 0.00008). The APOE4 allele distribution in patients with non-HCV-associated liver disease (14.0%) was very similar to healthy controls and also differed from chronically HCV-infected patients (P = 0.012), suggesting HCV specificity. CONCLUSIONS: Our findings suggest that the APOE4 allele may confer a protective effect in the course of HCV infection.

The impact of directly acting antivirals on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C.

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<.0001) at the 12-week follow-up. In parallel, the tacrolimus trough level to dose ratio decreased from 4.68 down to 2.72 (P=.0004). CONCLUSION: Antiviral treatment with DAAs enabled sustained elimination of recurrent HCV in liver transplant recipients and was associated with a significant improvement of the enzymatic liver function.

CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice.

UNLABELLED: The pathogenesis of primary sclerosing cholangitis (PSC) remains poorly understood. Since PSC predominantly occurs in patients with inflammatory bowel disease, autoimmunity triggered by activated T cells migrating from the gut to the liver is a possible mechanism. We hypothesized that T cells primed in the gut-associated lymphoid tissue (GALT) by a specific antigen migrate to the liver and cause cholangitis when they recognize the same antigen on cholangiocytes. We induced ovalbumin-dependent colitis in mice that express ovalbumin in biliary epithelia (ASBT-OVA mice) and crossed ASBT-OVA mice with mice that express ovalbumin in enterocytes (iFABP-OVA mice). We analyzed T-cell activation in the GALT and crossreactivity to the same antigen in the liver as well as the effects of colitis per se on antigen-presentation and T-cell activation in the liver. Intrarectal application of ovalbumin followed by transfer of CD8 OT-I T cells led to antigen-dependent colitis. CD8 T cells primed in the GALT acquired effector function and the capability to migrate to the liver, where they caused cholangitis in a strictly antigen-dependent manner. Likewise, cholangitis developed in mice expressing ovalbumin simultaneously in biliary epithelia and enterocytes after transfer of OT-I T cells. Dextran sodium sulfate colitis led to increased levels of inflammatory cytokines in the portal venous blood, induced activation of resident liver dendritic cells, and promoted the induction of T-cell-dependent cholangitis. CONCLUSION: Our data strengthen the notion that immune-mediated cholangitis is caused by T cells primed in the GALT and provide the first link between colitis and cholangitis in an antigen-dependent mouse model.

CT-guided high-dose-rate brachytherapy of unresectable hepatocellular carcinoma.

PURPOSE: The purpose of the present study was to evaluate the clinical outcome of CT-guided high-dose-rate brachytherapy (CT-HDRBT) in patients with unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Over a 6-year period, 98 patients with 212 unresectable HCC underwent CT-HDRBT applying a (192)Ir source at our institution. Magnetic resonance imaging (MRI) follow-up was performed 6 weeks after the intervention and then every 3 months. The primary endpoint was local tumor control (LTC); secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: Patients were available for MRI evaluation for a mean follow-up of 23.1 months (range 4-64 months; median 20 months). Mean tumor diameter was 5 cm (range 1.8-12 cm). Eighteen of 212 (8.5 %) tumors showed local progression after a mean LTC of 21.1 months. In all, 67 patients (68.4 %) experienced distant tumor progression. The mean PFS was 15.2 months. Forty-six patients died during the follow-up period. Median OS was 29.2 months. Actuarial 1-, 2-, and 3-year OS rates were 80, 62, and 46 %, respectively. CONCLUSION: CT-HDRBT is an effective therapy to attain local tumor control in patients with unresectable HCC. Prospective randomized studies comparing CT-HDRBT with the standard treatments like Radiofrequency ablation (RFA) and chemoembolization (TACE) are mandatory.

Safety and toxicity of radioembolization plus Sorafenib in advanced hepatocellular carcinoma: analysis of the European multicentre trial SORAMIC.

BACKGROUND & AIMS: The benefits of combined systemic and liver-directed treatments in inoperable intermediate- or advanced-stage hepatocellular carcinoma (HCC) have yet to be defined. This article presents the planned safety analyses for the first 40 patients randomized to radioembolization with yttrium-90 ((90) Y) resin microspheres followed by sorafenib (n = 20) or sorafenib only (n = 20) in the SORAMIC study. METHODS: Patients identified for palliative treatment who were poor candidates for transarterial (chemo)embolization (including those failing TACE) with preserved liver function (Child-Pugh ≤B7) and ECOG performance status <2 were screened. Radioembolization was administered using a sequential lobar approach. On day 3 after the last radioembolization procedure, sorafenib 200 mg twice daily was initiated escalating to 400 mg twice daily 1 week later; a matching sorafenib dose schedule was initiated in the control arm. RESULTS: Patients were followed up for a median of 8.3 months. Median total implanted activity of (90) Y was 1.87 (range: 0.54-2.35) GBq. Patients received a similar intensity and duration of sorafenib in the combination-treatment arm (median daily dose 614 mg over 8.5 months) and control arm (557 mg over 9.6 months). The incidence of total (196 vs. 222) and grade ≥3 (43 vs. 47) adverse events was similar in combination-treatment arm and control arm respectively (P > 0.05). No significant differences in the number of total or grade 3/4 toxicities were recorded for: total bilirubin, albumin, liver enzymes, ascites, Child-Pugh, fatigue, hand-foot skin reaction, blood pressure or diarrhoea. CONCLUSIONS: Radioembolization followed by sorafenib appears to be as well tolerated as sorafenib alone.

CT-guided Interstitial Brachytherapy of Hepatocellular Carcinoma before Liver Transplantation: an Equivalent Alternative to Transarterial Chemoembolization?

OBJECTIVES: Transarterial chemoembolization (TACE) is established as bridging therapy of HCC listed for transplantation (LT). CT-guided brachytherapy (CTB) has not been evaluated as a bridging concept. We compared CTB and TACE for bridging before LT in HCC patients. METHODS: Twelve patients with HCC received LT after CTB (minimal tumour dose, 15-20 Gy). Patients were matched (CTB:TACE, 1:2) by sex, age, number and size of lesions, and underlying liver disease with patients who received TACE before transplantation. Study endpoints were extent of necrosis at histopathology and recurrence rate after OLT. RESULTS: There were no significant differences between the CTB and TACE groups regarding Child-Pugh category (p = 0.732), AFP (0.765), time on waiting list (p = 0.659), number (p = 0.698) and size (p = 0.853) of HCC lesions, fulfilment of Milan-criteria (p = 0.638), or previous liver-specific treatments. CTB achieved higher tumour necrosis rates than TACE (p = 0.018). The 1- and 3-year recurrence rate in the CTB group was 10 and 10 % vs. TACE, 14 and 30 % (p = 0.292). CONCLUSIONS: Our data show comparable or even better response and post-LT recurrence rates of CTB compared to TACE for treating HCC in patients prior to LT. CTB should be further evaluated as an alternative bridging modality, especially for patients not suited for TACE. KEY POINTS: • CT-guided interstitial brachytherapy (CTB) is a promising alternative to transarterial chemoembolization (TACE). • CTB instead of TACE is possible for bridging to liver transplantation in HCC patients. • HCC recurrence was not associated with CTB despite potential tumour seeding.

Prognostic value of enzymatic liver function for the estimation of short-term survival of liver transplant candidates: a prospective study with the LiMAx test.

LiMAx has been recently proposed as a new quantitative liver function test. Thus, we aimed to evaluate the diagnostic ability of LiMAx to assess short-term survival in liver transplant candidates and compare its performance to the model for end-stage liver disease (MELD) and indocyanine green plasma disappearance rate (ICG-PDR). Liver function of 167 chronic liver failure patients without hepatocellular carcinoma was prospectively investigated when they were evaluated for liver transplantation. Primary study endpoints were liver-related death within 6 months of follow-up. Within 6 months of follow-up, 18 patients died and 36 underwent liver transplantation. Median LiMAx results on evaluation day were significantly lower in patients who died (99 µg/kg/h vs. 55 µg/kg/h; P = 0.024), while median ICG-PDR results did not differ within both groups (4.4%/min vs. 3.5%/min; P = 0.159). LiMAx showed a higher negative predictive value (NPV: 0.93) as compared with ICG-PDR (NPV: 0.90) and the MELD (NPV: 0.91) in predicting risk of death within 6 months. In conclusion, LiMAx provides good prognostic information of liver transplant candidates. In particular, patients who are not at risk of death can be identified reliably by measuring actual enzymatic liver function capacity.

Trigger mechanisms of secondary sclerosing cholangitis in critically ill patients.

INTRODUCTION: In recent years the development of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) has increasingly been perceived as a separate disease entity. About possible trigger mechanisms of SSC-CIP has been speculated, systematic investigations on this issue are still lacking. The purpose of this study was to evaluate the prevalence and influence of promoting factors. METHODS: Temporality, consistency and biological plausibility are essential prerequisites for causality. In this study, we investigated the temporality and consistency of possible triggers of SSC-CIP in a large case series. Biological plausibility of the individual triggers is discussed in a scientific context. SSC-CIP cases were recruited retrospectively from 2633 patients who underwent or were scheduled for liver transplantation at the University Hospital Charité, Berlin. All patients who developed secondary sclerosing cholangitis in association with intensive care treatment were included. Possible trigger factors during the course of the initial intensive care treatment were recorded. RESULTS: Sixteen patients (68% males, mean age 45.87 ± 14.64 years) with a confirmed diagnosis of SSC-CIP were identified. Of the 19 risk factors investigated, particularly severe hypotension with a prolonged decrease in mean arterial blood pressure (MAP) to <65 mmHg and systemic inflammatory response syndrome (SIRS) were established as possible triggers of SSC-CIP. The occurrence of severe hypotension appears to be the first and most significant step in the pathogenesis. It seems that severe hypotension has a critical effect on the blood supply of bile ducts when it occurs together with additional microcirculatory disturbances. CONCLUSIONS: In critically ill patients with newly acquired cholestasis the differential diagnosis of SSC-CIP should be considered when they have had an episode of haemodynamic instability with a prolonged decrease in MAP, initial need for large amounts of blood transfusions or colloids, and early development of a SIRS.

Influence of CD8 T cell priming in liver and gut on the enterohepatic circulation.

BACKGROUND & AIMS: The enterohepatic circuit of T cells may be responsible for the development of autoimmune liver disease. We employed transgenic mice to characterize phenotype and migration patterns of CD8 T cells activated in liver and gut. METHODS: We studied the migration of antigen-specific CD8 T cells primed in liver or gut after transfer in wild-type mice or mice that express ovalbumin in liver or gut. We performed transcriptome analysis of these two distinct T cell populations and confirmed our findings by flow cytometry. RESULTS: Specific migration patterns were induced by activation of CD8 T cells in gut or liver. Gut-activated CD8 T cells expressed α4ß7 and CCR9 and migrated to the gut and to the liver. Liver-activated T cells expressed integrins α4, α6, ß1, α4ß7 as well as CD62L, Ly6C, and neuropilin-1 and retained the capability to re-circulate through lymph nodes. Presence of the antigen increased retention of both types of activated T cells in the liver, but migration of liver-activated T cells to the gut was prohibited. CONCLUSIONS: CD8 T cells primed in the liver in vivo are not capable of migrating to the gut, implying that the enterohepatic circuit of CD8 T cells is in fact a one-way road from the gut to the liver. Priming of CD8 T cells in the liver results in a distinct phenotype with attributes of central memory cells and induces a unique homing pattern. Gut-primed T cells preferentially home to the liver, in principle enabling them to induce autoimmune liver disease.