Figure 3B for the same patient with K19 staining highlights CoH loss around a portal tract. K7 staining highlighted the same biliary structures as did K19 staining, but also, in some specimens (Table 1), showed very focal periportal hepatocyte Selleckchem Roxadustat positivity which is common (although usually more widespread) in typical PBC biopsy specimens. EpCAM showed identical patterns of staining to

K19, differing in subcellular localization as expected (EpCAM is membranous, K19 is cytoplasmic), whereas no EpCAM-positive hepatocytes were seen in any normal, minimal change PBC, or CHC specimens (data not shown). In current American Association for the Study of Liver Diseases; (AASLD) Practice Guidelines3 diagnosis of PBC can be made with compatible biochemical tests (esp. elevated AP), positive AMA (found in ∼95% of patients), and/or a compatible histological liver biopsy specimen. However, no standard case definition has been universally accepted.10 We have previously suggested that marked CoH loss (recognized see more by immunostaining for K19 or other cholangiocyte marker) is an earliest

change in PBC,4 a finding confirmed by others,11 although no studies have assessed clinical outcomes of patients with suspected PBC, who have minimally injured liver biopsies by routine stain, but marked CoH loss with immunostaining, a finding we term “minimal change PBC. We prospectively identified patients suspected to have PBC, but who did not meet definitive, nonbiopsy criteria for diagnosis. Five of six study patients had detectable serum autoantibodies, two of whom were AMA-positive prior 上海皓元 to treatment (becoming AMA-negative with treatment) and four of six had either antismooth muscle antibody (ASMA) or ANA, serologic findings typical for AMA-negative PBC.12 The four AMA-negative patients (67%) is a higher rate than has been previously reported, which was 1/10 (10%) in our control group, in keeping with other published reports.13, 14 The difference may relate to our small cohort size and not have meaning; however, it could indicate that PBC identifiable only by CoH loss is such

an early disease stage that perhaps AMA have not yet become detectable by standard assays. To exclude the possibility that CoH loss is a nonspecific finding, unrelated to PBC, we compared the study group to two disease control specimen sets, both of which had preserved CoH. Compared to CHC, we confirm that CoH loss is not a nonspecific reaction to a chronic, portal, and peri-portal inflammation. In order to exclude the possibility that the study patients were simply recovering from an acute injury that would have spontaneously improved even without treatment, we assessed biopsy specimens from patients with chronic elevated serum liver tests for greater than 6 months, but without clinical data to indicate inciting infections or toxins. Biopsy specimens showed clustered macrophages indicating recent hepatic activity, but ongoing hepatitis was absent.

5% saturated fat) or an appropriate control diet (CD, 5.4% fat). Mice on HFD additionally received drinking water enriched with fructose and glucose. Analyses including biomet-ric, serological, histological, Western Blot and RT-PCR testing were performed after a dietary period of 12 weeks. Results: 12 weeks of HFD feeding induced a significant selleck chemicals weight gain, which was more pronounced in Bcl-3hepar mice. Moreover HFD caused elevated levels of serum ALT, triglycerides,

total cholesterol, serum fasting glucose and insulin in parallel to an increase in the relative liver weight and hepatic steatosis on H&E stain. In Bcl-3hepar mice ALT and insulin levels were significantly higher compared to the wt. In parallel, the insulin-receptor, IRS-3 and −4 in hepatic tissue were downregulated in Bcl-3hepar mice, whereas levels of IRS-1 and −2 were comparable in both genotypes. Phosphorylation of the serine-threonine kinase Akt was unaffected. Next, key regulators of hepatic glu-coneogenesis Obeticholic Acid ic50 and lipogenesis were examined. We detected a significant down-regulation of the phosphoenolpyruvate carboxykinase (PEPCK), the fructose-1,6-bisphosphatase gene Fbp-1 and Glucose-6 phosphatase (G6P) in Bcl-3hepar mice on HFD compared to the wt. In parallel, expression of regulators of hepatic de novo fatty acid synthesis including ACC, FAS and SREBP-1 were upregulated, whereas the expression of CPT1, PPARalpha and its

regulator PGC-1alpha – all of which restrict MCE公司 hepatic beta-oxidation – were downregulated in Bcl-3hepar mice. Conclusion: The regulator of cellular survival and hepatic inflammation Bcl-3 directly influences the metabolic and injurious phenotype observed in NAFLD and

thus could be an important target in the development of novel therapies. Disclosures: Peter R. Galle – Advisory Committees or Review Panels: Bayer, BMS, Lilly, Daiichi, Jennerex; Consulting: Medimmune; Grant/Research Support: Roche, Lilly; Speaking and Teaching: Bayer, BMS Marcus A. Woerns – Advisory Committees or Review Panels: Bayer, Bayer The following people have nothing to disclose: Nadine Gehrke, Amrit Mann, Yvonne Alt, Arno Schad, Ari Waisman, Jorn M. Schattenberg Background and Aim: Nonalcoholic fatty liver disease (NAFLD) has become one of the most common liver diseases worldwide. However, the factor which promotes progression of NAFLD remains unclear. S100A8, an endogenous Toll-like receptor 4 agonist released from myeloid lineage cells, has been attracting attention because it can play a pivotal role in inflammatory diseases. The aim of this study is to investigate the involvement of S100A8 in the progression of NAFLD. Method: We utilized a lithogenic diet (LD) model of NAFLD. Six-week-old male C57/ BL6 mice were fed with the LD or normal diet (ND) for 3 weeks. We also analyzed liver tissues from the patients with NAFLD. Results: We performed S100A8 Immunohistochemical staining of liver tissues from the NAFLD patients (n=54).

7. In this study we have shown that MMP-9 transactivates EGFR in brain microvascular ECs with subsequent p38 MAPK/NFκB signaling, resulting in suppressed transcription/translation and protein expression of the TJ protein occludin. These effects were attenuated with specific inhibition of EGFR in brain ECs in vitro. Moreover, we observed EGFR activation, p38 MAPK activation, and the loss of occludin in brains of mice with experimentally induced this website ALF. Together these results suggest that EGFR plays a role in activating the pathobiology of brain injury in ALF. Brain edema in ALF is unique. It occurs in the comatose stages of encephalopathy in ALF. The onset of encephalopathy in ALF patients presages impending brain edema

and a lethal course of the disease. Once liver failure is resolved, either by liver transplantation or by spontaneous recovery of the injured liver, the brain edema is resolved. However, if the brain edema is inadequately controlled, it will ultimately lead to herniation and brain death. Even with significant brain edema, both light and electron microscopic evaluations of these brains reveal that the BBB and its TJs remain relatively intact. However, there are certain subtle changes, including fine perturbations at the endothelial cellular plasma membrane and thickening of the basal lamina.37 In the absence of obvious structural breakdown of the BBB, the prominent and consistent swelling of astrocytic foot processes has led

to the dominant theory that cytotoxic mechanisms cause brain edema in ALF.38 Although vasogenic elements have been implicated,39, 40 evidence for vasogenic edema in ALF has been lacking. Increasing evidence has suggested http://www.selleckchem.com/products/idasanutlin-rg-7388.html that even with a relatively intact BBB, subtle alterations in TJ composition can result in highly selective permeability to small molecules, such as water and ammonia. In mice that are selectively deficient in claudin-5,

a component of TJ proteins, the BBB and TJ appear intact under electron microscopic examination. However, these mice have increased permeability 上海皓元医药股份有限公司 to molecules that are less than 800 Da.8 Similarly, when occludin at the TJ is targeted with a specific peptide or is modified by proteolysis, TJ permeability is significantly increased without any obvious structural change.7, 9, 41 Collectively, these data indicate that altered permeability of the BBB can result from very subtle changes in the BBB and/or TJ composition. We recently observed that there are significant biochemical alterations in occludin, claudin-5, and ZO-1 in brains of mice with experimentally induced ALF5 and that these changes were attenuated when MMP-9 was inhibited.5, 13 We observed similar findings when murine brain EC were exposed to MMP-9 in vitro.5 However, TJs make up only a small part of the brain capillary surface area. The endothelial cellular plasmalemma interacts with MMP-9 or other inciting factors within the capillary circulation to a greater extent than the TJs.

37, 38 However, the extent to which this system plays a role in human hepatitis B, especially fulminant hepatitis, is unknown. As shown in this study (Fig. 5A), inhibition of the Fas/FasL system by anti-Fas antibody dramatically reduced the effect of human PBMC transplantation. This showed the possibility that the Fas/FasL system plays an important role in the degeneration of infected hepatocytes in FHB. Further studies should be conducted to evaluate what immunological responses play important roles in human hepatitis B. The importance of NK-cell activity suggests that MK-2206 cell line the suppression of DCs

and NK-cell activity or the Fas/FasL system might have therapeutic implications for FHB.11, 35 If DCs and NK-cell activity or Fas/FasL activity could be controlled in the early stages of severe acute or fulminant hepatitis, we might be able to control hepatitis activity and prevent subsequent liver failure. Of course, it would be necessary to monitor the development of chronic hepatitis after such treatment because DCs and NK cells contribute to early host defenses and shape subsequent adaptive immune response through complex cross-talk regulating the early phase

of the immune response.19, 24, 39, 40 We analyzed liver damage using HBV genotype C–infected mice in this study. However, HBV genotype C is associated with more severe histological liver damage than genotype B,41 and future studies should compare immunological differences between genotypes B and C. In summary, we established an animal Small Molecule Compound Library model of FHB using highly repopulated human hepatocyte chimeric mice and transplanted human PBMCs. Modifications of this model will facilitate further research into acute and CHB using human immune cells, including HBV-directed

CTL clones, suppressor and regulatory T cells, MCE as well as immunological experiments to study interactions between DCs and NK cells. Such models may be useful to develop and evaluate new therapeutic strategies against HBV infection. The authors thank Rie Akiyama and Yoko Matsumoto for their expert technical assistance. This work was carried out at the Analysis Center of Life Science, Natural Science Center for Basic Research and Development, Hiroshima University. Additional Supporting Information may be found in the online version of this article. “
“Background: Recently, long-term low dose of carvedilol has suggested an option for primary prophylaxis of bleeding in patients with high-risk esophageal varices. The aim of this study is to evaluate and compare the effect of carvediolol versus propranolol on reduction in portal pressure in patients with cirrhosis. Methods: We conducted this ongoing prospective randomized multicenter study (target sample size: 130 patients) between July 2011 and February 2013 and analyzed clinical and hemodynamic measurement data of 99 cirrhotic patients with high-risk esophageal varices and severe portal hypertension (HVPG > 12 mmHg).

5 and postnatal day 7. These time points allowed them to examine hilar IHBD formation of the ductal plate, PDS, and mature duct. All three of the mouse models in this study highlight defects at different steps of bile duct tubulogenesis. The absence of HNF6 caused a somewhat resolvable early defect in biliary cell differentiation, whereas liver-specific loss of HNF1β produced a defect in PDS maturation. A third type of defect is observed in the absence of cystin-1, where an abnormal expansion of ducts was observed even though the biliary cells differentiate normally. All three specific biliary tubulogenesis defects result in an endpoint

of DPM. Specifically, examination of differentiation in Hnf6−/− mice revealed that cells lining lumens did not express the cholangiocyte marker SOX9, but did express the hepatocyte marker HNF4 at embryonic day 17.5. These data are in agreement with earlier studies that established deficient

GDC-0068 chemical structure HNF6 generates hybrid hepatobiliary cells and indicates that HNF6 is required for differentiation of biliary cells at embryonic stages.9 Postnatally, the biliary differentiation was resolved, supported by the presence of SOX9+/HNF4− Decitabine cholangiocytes. However, normal tubulogenesis did not proceed and resulted in DPM observed in hilar IHBDs at postnatal day 7. A different result was observed for Hnf1bloxP/loxPAlfp-Cre mice. Absence of HNF1β resulted in normal embryonic SOX9+/HNF4− expression around the forming bile duct lumen on the portal side, but the parenchymal side of the bile duct lumen remained SOX9−/HNF4+ throughout the liver. This is inconsistent with the progressive nature of bile duct tubulogenesis, asserting that the bile duct structures at the hilar region should be more mature than the ductal structures at the peripheral regions. The subsequent postnatal 上海皓元 phenotype displayed differentiation of SOX9+/HNF4− cholangiocytes, but with observed DPM and dysplastic ducts. This phenotype was consistent with the patient samples analyzed that carried HNF1B (TCF2; Mendelian Inheritance in Man #137920) mutations. These results support an early

differentiation role of HNF6 and a PDS maturation role for HNF1β, providing two different defects in tubulogenesis prior to the endpoint of DPM. Deficient cystin-1 (cpk−/−) does not lead to defects in differentiation at any stage of biliary tubulogenesis, but does cause DPM as also observed in human patients with ARPKD. These data demonstrate that deficient maturation during tubulogenesis is a cause of DPM. Cholangiocyte polarity was also disrupted at varying degrees of severity in each of the three mouse models. The apical-basal polarity in cases of deficient HNF6 and HNF1β was strongly affected. Apical expression of osteopontin was absent, in addition to abnormal localization of centrioles and Golgi apparatus.

Hepatoprotective effects of IL-22 were found in a primary Plasmodium chabaudi infection model,[13] but IL-22

did not show any protective effects against liver lesions CHIR-99021 manufacturer infected by the parasite Toxoplasma gondii and Mycobacterium avium.[24] In addition, in a model of hepatitis B virus (HBV) replication in HBV transgenic mice, blocking IL-22 with a neutralizing antibody ameliorated liver damage by reducing chemokine expression on hepatocytes, and subsequently preventing hepatic recruitment of inflammatory cells, suggesting that IL-22 may contribute to the pathogenesis of HBV-mediated liver inflammation and injury.[25] The liver has great regenerative ability after injury induced by hepatotoxins, infections, or loss of tissues. Under most conditions, the liver can regain its original mass through the proliferation of mature healthy hepatocytes. However, when mature hepatocytes are unable to properly proliferate to restore damaged liver during severe or chronic liver injury, LPC-mediated liver repair

will be utilized to compensate liver functions.[26-31] The beneficial effects of IL-22 on mature hepatocyte survival and proliferation have been well documented.[10-20] Recent studies from our lab suggest that IL-22 also promotes LPC growth in patients with chronic selleck chemical viral hepatitis and in mice challenged by feeding a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet or a choline-deficient, ethionine-supplemented diet.[21] Increased IL-22 expression was observed in patients with chronic HBV or HCV infection.[19, 24, 32] IL-22 expression correlated with LPC proliferation in HBV patients, which implies that IL-22 may promote LPC growth in those patients.[21] IL-22TG mice with IL-22

overexpression in the liver were not associated with increased LPC number under a normal chow, but showed significant higher LPC proliferation rate and total LPC number compared with wild-type (WT) mice after being fed a DDC diet.[21] This suggests that IL-22 alone does not initiate LPC activation, but it can promote existing LPC proliferation in vivo in the DDC model. The LPCs that were isolated from the DDC-fed mice expressed medchemexpress high levels of IL-22R1 and IL-10R2. This is not surprising because IL-22R1 is known to be expressed on epithelial cells, and LPCs are the progenitor cells for liver epithelial cells, including hepatocytes and biliary epithelial cells. In vitro treatment with IL-22 promotes proliferation of primary LPCs from the DDC-fed mice or proliferation of the LPC cell line, BMOL (bipotential mouse oval liver) cells,[21] suggesting that IL-22 directly stimulates LPC proliferation. It has previously been well documented that STAT3 activation mediates many functions of IL-22 in hepatocytes. Recently, we have provided several lines of evidence that suggest that STAT3 also plays an important role in IL-22-mediated stimulation of LPC proliferation.

, MD (Parallel Session) Nothing to disclose Harris, Matthew S., MD (Clinical Research Workshop) Consulting: Theravance, find more Drais Pharmaceuticals, Symbiomix, Rhythm Pharmaceuticals, BioMedical Systems Stock Shareholder: Ocera Therapeutics, Avaxia Biologics

Harrison, Stephen A., MD (Meet-the-Professor Luncheon) Advisory Committees or Review Panels: Merck, Nimbus Discovery Grant/Research Support: Merck, Genentech Speaking and Teaching: Merck, Vertex Heimbach, Julie, MD (AASLD/ILTS Transplant Course, Plenary Session, Transplant Surgery Workshop) Nothing to disclose Heller, Theo, MD (Early Morning Workshops, Parallel Session) Nothing to disclose Henderson, Neil C., MBChB, BSc, PhD (Parallel Session) Nothing to disclose Heneghan, Michael A., MD, MRCP (General Hepatology Update) Nutlin-3a manufacturer Speaking and Teaching: Falk Hohmann, Elizabeth L., MD (Clinical Research Workshop) Nothing to disclose Hoofnagle, Jay H., MD (State-of-the-Art Lecture) Nothing to disclose Horne, Patrick M., MSN, APRN, FNP-BC (Hepatology Associates Course) Consulting: Vertex Pharmaceuticals, Gilead Sciences, Kadmon Pharmaceuticals Grant/Research Support: Bayer Pharmaceuticals Idle, Jeffrey, PhD (SIG Program) Nothing to disclose Israni, Ajay, MD, MS (AASLD/ILTS Transplant Course) Advisory Committees or Review Panels: Astellas Grant/Research Support: Novartis, BMS Iwakiri, Yasuko, PhD (SIG Program) Nothing to disclose Jacobson, Ira M., MD (HCV Symposium) Consulting: Abbvie, Achillion, Boehringer

Ingelheim, Bristol Myers Squibb, Gilead, Idenix, Genentech, Merck, Janssen, Vertex Grant/Research Support: Abbvie, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Novartis, Genentech, Merck, Janssen, Vertex Speaking and Teaching: Bristol Myers Squibb, Gilead, Genentech, Vertex, Janssen

Jalan, Rajiv, MD, PhD (AASLD Postgraduate Course) Consulting: Ocera Therapeutics, Conatus Grant/Research Support: Grifols, Gambro Janssen, Harry L., MD, PhD (Early Morning Workshops, Meet-the-Professor Luncheon, Parallel Session) Consulting: Abbott, Bristol Myers Squibb, MCE Debio, Gilead Sciences, Merck, Medtronic, Novartis, Roche, Santaris Grant/Research Support: Anadys, Bristol Myers Squibb, Gilead Sciences, Innogenetics, Kirin, Merck, Medtronic, Novartis, Roche, Santaris Jensen, Donald M., MD (Early Morning Workshops) Grant/Research Support: Abbvie, Boehringer, BMS, Genentech/ Roche, Janssen Kamath, Binita M., MBBChir (Early Morning Workshops, Parallel Session) Nothing to disclose Kamath, Patrick S., MD (AASLD Postgraduate Course, Emerging Trends Symposium, Meet-the-Professor Luncheon) Advisory Committees or Review Panels: Sequana Medical Kanwal, Fasiha, MD (Early Morning Workshops, Parallel Session) Nothing to disclose Kapalko, Angela, MS, PA-C (Hepatology Associates Course) Advisory Committees or Review Panels: Gilead Sciences Karlsen, Tom H., MD, PhD (SIG Program) Nothing to disclose Karp, Seth J., MD (Parallel Session) Nothing to disclose Karpen, Saul J.

These results demonstrate proof-of-principle that an appropriate monogenic liver disease can be corrected by AAV-mediated gene repair in vivo. AAV, adeno-associated virus; AST, aspartate aminotransferase; dGE, diploid genome equivalent; FAH, fumarylacetoacetate

hydrolase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; hAAT, human alpha-1 antitrypsin; HTI, hereditary tyrosinemia type I; LD-PCR, long-distance polymerase chain reaction; NTBC, 2-(2-nitro-4-trifluoro-methylbenzol)-1,3-cyclohexanedione; RT-PCR, reverse transcription polymerase chain reaction; vg, vector genome. The Fah5981SB Epigenetics Compound Library datasheet mouse25 models HTI by bearing a single N-ethyl-N-nitrosourea–induced point mutation in the final nucleotide of exon 8 within the Fah gene.26 This point mutation creates a premature downstream stop codon and exon 8 loss, ultimately leading to formation of truncated, unstable FAH protein that is degraded. Fah5981SB mice die as neonates from acute liver failure if NTBC is not continually administered in the drinking water. NTBC treatment at 4 mg/mL rescues the phenotype and prevents acute hepatocellular and renal injury. Discontinuation of NTBC provides an accurate model of HTI. Mice develop liver and renal disease

within 10 days, which progresses to full end-stage liver disease and death within 6-8 weeks.27 The mice have been backcrossed 10 generations onto a C57BL6 background. The Institutional Animal Care and Use Committee of Oregon Health and Science University AZD1208 in vivo approved all

procedures and mouse experiments. Mus musculus bacterial artificial chromosome (BAC) clone RP23-121N17 from chromosome 7 (Invitrogen) was used as a template for the 4.5-kb long-distance polymerase chain reaction (LD-PCR) amplification of sequence homologous to the region centered on the point mutation in exon 8 of murine Fah (RefSeq NM_010176, chr7:84461356-84481935). Forward primer introducing NotI: 5′-GCGGCCGCTTCCCAGGGTTTTTGTTTGTT-3′; reverse primer: 5′-AGCCCCCACTGACAGCTACAGCT-3′. The PCR resulted in a 4.5-kb product with an introduced MCE公司 5′-NotI restriction site that allowed cloning into an AAV plasmid backbone as previously described.28 DNA sequencing was performed with an ABI-Prism 3130xl Genetic Analyzer (Applied Biosystems Inc., Foster City, CA) at the Vollum Sequencing Core (Portland, OR). DNA sequences were aligned with MacVector software. For time course studies, d3 Fah5981SB neonates were injected with 1 × 1011 (AAV2-Fah) or 2 × 1011 (AAV8-Fah) vector genome (vg) in 10 μL volume by intravenous facial vein injection.29 Littermate controls were similarly injected with 1 × 1011 to 2 × 1011 vg of an irrelevant serotype-matched control vector; either AAV2-hAAT,30 or AAV8-GFP.31 All mice were maintained on NTBC throughout. Livers were harvested at 1, 2, or 4 weeks after treatment.

[19] Serum levels of HBV DNA were quantified using the COBAS TaqMan HBV Test v2.0 (Roche Diagnostics, Tokyo, Japan) that had a dynamic range of 2.1–9.0 log copies/mL. Quantitative measurement of HBsAg

was performed using an HISCL HBsAg assay based on the chemiluminescence enzyme immunoassay (CLEIA; Sysmex, Kobe, Japan) which had a quantitative range of −1.5 to 3.3 log IU/mL. End titer was determined by diluting samples with normal human serum when initial results exceeded the upper limit of the assay range. Serum HB core-related antigen (HBcrAg) levels were measured using a CLEIA-based HBcrAg assay kit with a fully automated Lumipulse System analyzer (Fujirebio, Tokyo, Japan). We expressed HBcrAg level in terms of log U/mL with a quantitative SRT1720 range set at 3.0–6.8 log U/mL. HBV genotypes were determined using commercially

available ELISA kits (HBV GENOTYPE EIA; Institute of Immunology). Serum alanine aminotransferase (ALT), aspartate aminotransferase Ruxolitinib cell line (AST) and other relevant biochemical tests were performed using standard methods.[20] A virological response (VR) was defined as a HBV DNA level that was undetectable by real-time polymerase chain reaction (<2.1 copies/mL) at 24 months. A virological breakthrough was defined as an increase in HBV DNA level by 1 log copies/mL or more above nadir while on treatment following an initial decline to 2 log copies/mL or more. Six cytokines (interleukin [IL]-2, IL-6, IL-10, IL-12p70, IL-21 and IL-22) and five chemokines (CCL2/MCP-1, CCL3/MIP-1α, CXCL9/MIG, CXCL10/IP-10 and CXCL11/I-TAC) were quantified using

Luminex Multiplex Cytokine Kits (Procarta Cytokine Assay Kit) for serum samples obtained before the start of treatment and at weeks 24, 48 and 96 as reported previously.[8, 9] These markers had been implicated in HBV pathogenesis in earlier reports.[11-16, 18] All collected samples were immediately stored at −70°C and remained in storage until testing. The Mann–Whitney U-test and Kruskal–Wallis test were used to analyze continuous variables where appropriate. The Friedman test was employed to evaluate changes in serum cytokine levels over time. Spearman’s rank correlation coefficients were adopted to evaluate the relationship between pairs of markers. The χ2-test with Yates’s correction was used for the analysis of categorical data. In cases where the number of subjects was less than five, we 上海皓元 employed Fisher’s exact test. P < 0.05 was considered statistically significant. To predict treatment outcome, cut-off points for continuous variables were decided by receiver–operator curve (ROC) analysis with Youden’s index. Factors attaining a P-value of less than 0.1 in univariate analysis were evaluated by multivariate analysis using a stepwise logistic regression model. These included age, HBe positivity, platelets, and levels of HBsAg, HBcrAg, HBV DNA and IL-22 before treatment. Statistical analyses were carried out using SPSS software version 21.0J (IBM Japan, Tokyo, Japan).

Both groups had similar rates of histologic regression between baseline and Week 240. Patients with HVL generally took selleck screening library longer to achieve HBV DNA <400 copies/mL but had caught up with the non-HVL patients by Week 96. The authors stated that no patient with baseline HVL had persistent viremia at Week 240 or amino acid substitutions associated with TDF resistance. These results are remarkable and suggest that monotherapy with a potent NUC that has a high barrier to resistance such as TDF

is sufficient in maintaining viral suppression during long-term treatment even in patients with HVL. However, the results should be interpreted with caution. Persistent viremia in this study was defined as never having HBV DNA <400 copies/mL and this endpoint was only reported on patients who remained on treatment at Week 240. Thus, patients with HBV DNA <400 copies/mL at a single timepoint and higher levels of HBV DNA subsequently would not be considered to have persistent viremia and those who were no longer on treatment at Week 240 were not counted. Of the 129 patients with baseline HVL, 46 discontinued the

study before Week 240 of whom 28 had HBV DNA <400 copies/mL at the last visit. In the remaining 83 patients, 73 had HBV DNA <400 copies/mL, three had HBV DNA ≥400 copies/mL, and HBV DNA of the other seven were unknown at Week 240. Thus, based on intention to treat analysis, only 56.6% (73/129) patients GDC-0199 cell line had HBV DNA <400 copies/mL at Week 240. If the last result was carried forward, 78.3% (101/129) patients had HBV DNA <400 copies/mL. By contrast, HBV DNA <400 copies/mL at Week 240 was achieved in 76.0% (389/512) non-HVL patients by intention to treat analysis and in 91.0% (466/512) if the last result was carried forward. Furthermore, 35 HVL patients were eligible to add FTC between Week 72 medchemexpress and 240 and 28 eligible plus one noneligible patient had FTC added. Adding FTC did not appear to affect HBV DNA outcomes, with 66% (19/29) on FTC/TDF and 86% (6/7) on TDF having HBV DNA <400 copies/mL at Week 240 or last visit. The difference was not statistically significant

but this may be related to the small number of patients. HBV DNA levels of the 11 patients with HBV DNA ≥400 copies/mL were not provided. That patients with HVL take longer to achieve virologic response had also been observed by other investigators. Yuen et al.[6] studied 222 NUC-naïve patients and found that 100% and 76.5% of patients with baseline HBV DNA < and ≥8 log10 copies/mL, respectively, had undetectable HBV DNA at Year 3 of ETV therapy. The only patient in whom ETV resistance was detected had baseline HBV DNA 8.1 log10 copies/mL. In a randomized trial comparing ETV monotherapy versus combination of ETV plus TDF in NUC naïve patients, Lok et al.[14] showed that 76.4% and 83.2% patients, respectively, achieved the primary endpoint of HBV DNA <50 IU/mL (∼300 copies/mL) at Week 96 (P = 0.088).