Two patients treated with simeprevir plus pegylated-interferon and ribavirin triple therapy for recurrent hepatitis C after living donor liver transplantation: case report.

We previously reported our data on telaprevir (TVR) used in combination with pegylated-interferon and ribavirin (PEG-IFN/RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). TVR substantially increases the blood levels of immunosuppressive agents such as cyclosporine and tacrolimus for drug-drug interactions. On the other hand, the effect of simeprevir (SMV) on the blood levels of these immunosuppressive agents is unclear. We report 2 patients who achieved viral responses with little effect on the blood levels of cyclosporine and tacrolimus using SMV plus PEG-IFN/RBV treatment. The first was a 71-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. She was treated with 40 mg/d of cyclosporine, and received SMV plus PEG-IFN/RBV treatment. The second was a 65-year-old man with HCV-related liver cirrhosis who failed to respond to PEG-IFN/RBV after living donor LT. He was treated with 3 mg/d of tacrolimus, and received SMV plus PEG-IFN/RBV treatment. Serum HCV RNA became undetectable using TaqMan polymerase chain reaction (PCR) test after 4 weeks of treatment in both patients, and no remarkable fluctuation in blood concentration was observed either in cyclosporine or tacrolimus during the 12 weeks of SMV treatment. Completion of 12-week SMV triple therapy was followed by PEG-IFNα2b plus RBV, and both patients achieved sustained virological response 12 weeks after the end of treatment. SMV plus PEG-IFNRBV treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.

Emergence of resistant variants detected by ultra-deep sequencing after asunaprevir and daclatasvir combination therapy in patients infected with hepatitis C virus genotype 1.

Daclatasvir (DCV) and asunaprevir (ASV) are NS5A and NS3 protease-targeted antivirals respectively, currently under development for the treatment of chronic hepatitis C virus (HCV) infection. We analysed the relationship between pre-existing drug-resistant variants and clinical outcome of the combination treatment with DCV and ASV. Ten patients with HCV genotype 1b were orally treated with a combination of ASV and DCV for 24 weeks. The frequencies of amino acid (aa) variants at NS3 aa positions 155, 156 and 168 and at NS5A aa31 and 93 before and after treatment were analysed by ultra-deep sequencing. We established a minimum variant frequency threshold of 0.3% based on plasmid sequencing. Sustained virological response (SVR) was achieved in 8 out of 10 patients (80%), and relapse of HCV RNA after cessation of the treatment and viral breakthrough occurred in the other two patients. Pre-existing DCV-resistant variants (L31V/M and/or Y93H; 0.9-99.4%) were detected in three out of eight patients who achieved SVR. Pre-existing DCV-resistant variants were detected in a relapsed patient (L31M, Y93H) and in a patient with viral breakthrough (Y93H); however, no ASV-resistant variants were detected. In these patients, HCV RNA rebounded with ASV- and DCV- double resistant variants (NS3 D168A/V plus NS5A L31M and Y93H). While pre-existing DCV-resistant variants might contribute to viral breakthrough in DCV and ASV combination therapy, the effectiveness of prediction of the outcome of therapy based on ultra-deep sequence analysis of pre-existing resistant variants appears limited.

Stress analysis in human temporomandibular joint affected by anterior disc displacement during prolonged clenching.

Parafunctional habits, such as prolonged clenching and bruxism, have been associated with dysfunctional overloading in the temporomandibular joint (TMJ). In this study, stress distributions in the TMJ were analysed during prolonged clenching, using three-dimensional finite element (FE) models of the TMJ with and without disc displacement. The aim of this study was to investigate stress distribution of the cartilaginous tissues in the TMJ with and without disc displacement. Finite element models were developed on the basis of magnetic resonance images from two subjects with and without anterior disc displacement. Condylar movements recorded during a 5-min clenching were used as the loading condition for stress analysis. In the asymptomatic model, the highest von Mises stresses were located in the lateral area (4·91 MPa) of the disc surfaces, and after 5-min clenching, the higher stresses were still located at the lateral area (3·65 MPa). In all the cartilaginous tissues, 30-50% of stress reduction occurred during 5-min clenching. In contrast, the von Mises stress in the cartilaginous tissues of the symptomatic model with disc displacement was markedly lower, compared with the asymptomatic model. However, in the condylar cartilage, stress relaxation during clenching was not recognised. Furthermore, relatively high stresses were observed in the retrodiscal tissues throughout clenching. The present results indicate that disc position could be involved in the stress distribution of the TMJ components during prolonged clenching.

IL28B polymorphism may guide pegylated interferon plus ribavirin therapy even after curative treatment for hepatitis C virus-related hepatocellular carcinoma.

The present study was designed to determine the predictive factors for the viral response to pegylated interferon-alpha plus ribavirin combination therapy (PEGIFN/RBV) administered after curative treatment for hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). The study group was 78 patients treated between January 2005 and January 2009. The sustained viral response (SVR) rate was 25.8% (15/58) in patients infected with HCV-genotype 1 and 55.0% (11/20) in those with genotype 2. Among the 78 patients, 32 (41.0%) could not complete the treatment protocol, and this was because of HCC recurrence in 17 (53%) of them. Multivariate analysis identified partial early viral response (pEVR) as the only independent determinant of SVR [odds ratio (OR) 14.73, P = 0.013] for patients with genotype 1. Multivariate analysis identified male gender (OR 8.72, P = 0.001) and interleukin-28B (IL-28B) genotype (rs8099917) TT (OR 7.93, P = 0.007) as independent predictors of pEVR. Multivariate analysis also identified IL-28B genotype GG+TG (OR 14.1, P = 0.021) and α-fetoprotein >30 (OR 5.4, P = 0.031) as independent predictors of null response. Patients with SVR showed a better survival rate than those without SVR (P = 0.034). The second HCC recurrence rate tended to be lower in patients with SVR than in those without SVR (P = 0.054). With regard to the prognosis of patients with SVR, it is desirable to achieve SVR with interferon therapy even when administered after HCC treatment. IL-28B genotype is a potentially useful marker for the response to PEGIFN/RBV therapy administered after curative treatment of HCV-related HCC.

Effects of the time interval between clamping and linear stapling for resection of porcine small intestine.

BACKGROUND: Although a wait of several seconds after clamping is recommended when an automatic stapler is used to achieve adequate hemostasis, this wait has not been experimentally clarified. METHODS: To determine whether waiting is necessary between clamping and firing of a linear stapler, this study evaluated the number of staple line bleeding points and histologic changes in stapling sites of porcine small intestine (n = 46). It also assessed the ratio of dry to wet tissue weight (DW ratio) (n = 20) of porcine small intestine clamped between the prongs of a linear stapler. The sites were studied separately as follows: no wait with a four-row device (n = 12), no wait with a six-row device (n = 11), wait with a four-row device (n = 12), and wait with a six-row device (n = 11). The linear stapler was fired immediately after clamping in the no wait group and 1 min after clamping in the wait group. RESULTS: The mean number of staple line bleeding points in 2 to 5 min with the six-row device and in 3 to 5 min with the four-row device after firing were significantly less in the wait group than in the no wait group using the same device (p < 0.05). Cross sections of staple lines showed a higher frequency of mucosal cutting in the no wait group than in the wait group for both the four-row and the six-row devices (both significant at p < 0.01). Although the mean wet tissue weights of anastomotic sites did not change in either group, the mean DW ratio was significantly less in the wait group than in the no wait group (p < 0.01). CONCLUSIONS: A 1-min interval after clamping decreases the amount of clamped tissue. Waiting may thus be necessary to reduce bleeding from stapling sites, which may be related to a decrease in mucosal cutting.