Given that canalicular bile acid pumps (Abcc2/Abcb11) were not significantly affected, this finding raises a crucial question: What is the hepatic bile acid concentration in NASH? If there is a decrease in liver bile acid content, one would expect a vicious circle aggravating NASH (Fig. 1). Bile acids are ligands AZD1208 for farnesoid x receptor (FXR), which through its regulation of small heterodimer partner inhibits the transcriptional activation of sterol regulatory element binding protein-1c (SREBP-1c). SREBP1c stimulates fatty acid synthesis.

Thus inhibition of SREBP1-c via bile-acid activation of FXR results in a reduction of fatty liver.2 Moreover, activated FXR has potent anti-inflammatory and antifibrotic actions.3 The finding of Tanaka et al. may have revealed a hitherto unrecognized vicious circle around NASH (Fig. 1), starting with diet-induced lipid accumulation and tumor necrosis factor α/transforming growth factor β inflammatory cascade, leading to a possible reduction in bile acid content of the liver. Decreased ligand BMN-673 activation of FXR leads to triglyceride accumulation, inflammation, and regeneration of the noxious

circle. Interestingly, all of the pharmacological approaches capable of interrupting this vicious circle (i.e., by increasing the bile acid pool4 or inducing the expression of CYP7A1, the rate limiting enzyme in bile acid synthesis) have been Tacrolimus (FK506) shown to be beneficial for fatty liver and for NASH,5, 6 both in rodents and in humans. In conclusion, the measurement of hepatic bile acids in NASH is important to clarify the pathogenesis of NASH and

identify new therapeutic options. Chiara Gabbi M.D., Ph.D.* †, Jan-Åke Gustafsson M.D., Ph.D* †, * Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, † Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Sweden. “
“Autoimmune hepatitis (AIH) is an uncommon cause of liver disease caused by immune-mediated destruction of hepatocytes triggered by a variety of agents, including some medications. Typically the triggering event is unknown. There is a broad spectrum of presentations from incidental elevations of liver enzymes (aspartate aminotransferase/alanine aminotransferase) to acute liver failure. AIH is most often confused with drug-induced liver disease. The disease preferentially affects young women. Fortunately most respond well to treatment with corticosteroids though half may have subsequent disease flares. Overlap syndromes exist in which features of both autoimmune hepatitis and cholestatic liver disease are present. “
“In their prospective series, Soriano et al.

Method: We conducted a cross-sectional single-centre study of CHB patients treated with tenofovir compared to untreated CHB patients. BMD was measured by dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine and expressed as a Z score (age and gender adjusted). Testosterone, oestradiol, calcium, phosphate, PTH, 25(OH)VitD and biochemical markers of bone turnover (C-telopeptide of type I collagen (CTX), N-terminal propeptide of type I collagen (P1NP)) were measured. Urine testing for phosphate, amino acid, B2-microglobulin and glucose excretion was performed. Mann Whitney U was used to compare baseline characteristics and multivariate

logistic regression to adjust for cirrhosis status, age, gender and weight. Results: 10

untreated CHB see more controls and 22 patients treated R428 in vitro with tenofovir (mean treatment duration 2.6 ± 1.4 years) were enrolled. The mean age was 44.1 ± 8.7 and 52% were female (11.8% post-menopausal) and 48% were male (6.2% hypogonadal). Cirrhosis was present in 16% (5 patients on tenofovir; no patients in the control group). BMD at the lumbar spine as measured by Z score was lower in the tenofovir treated group compared to controls in the univariate analysis (−1.14 ± 1.18 vs −0.2 ± 1.3, P = 0.02) and remained significant in the multivariate analysis (P = 0.03) after adjusting for cirrhosis, age, gender and weight. There was no significant difference in serum calcium, phosphate, P1NP, CTX, 25(OH)VitD between the tenofovir and control group. Increased duration of tenofovir use was correlated with increased urinary excretion of phosphate (r = 0.567, P = 0.034). Conclusion: Tenofovir is significantly associated with reduced BMD at the lumbar spine. Increased duration of tenofovir use is associated with for increased urine phosphate loss through which accelerated bone loss may occur. Routine monitoring of BMD with 2 yearly

DXA and and urine phosphate should be considered in CHB patients on tenofovir to screen for potential accelerated bone loss. J BENJAMIN,1 S LE,1,2 A DEV1,2 1Department of Gastroenterology and Hepatology, Monash Health, Melbourne, Australia, 2Monash University, Melbourne, Australia Background/Aims: Hepatitis B virus (HBV) is a global health concern with 450 million chronically infected worldwide. Due to migration from endemic countries, CHB significantly contributes to chronic liver disease in Australia. Transition from primary to tertiary care for the management of CHB is poorly characterised. The aim of this study is to evaluate risk factors impacting access to tertiary care for CHB patients. Methods: 204 new CHB patients were referred to Liver Clinics at Monash Health between January 2010 and 2012.

In this regard, we demonstrated that Selleck R788 miR-125a-5p and 125b function as tumor suppressors by regulating abnormal activity of SIRT7 in human HCC. Altogether, these finding define a central role for SIRT7 in HCC tumorigenesis and suggest that miRNAs, miR-125a-5p and miR-125, have potential therapeutic value for the treatment of liver cancer. Additional Supporting Information may be found in the online version of this article. “
“Background

and Aim:  After failed biliary cannulation with needle knife sphincterotomy (NKS), endoscopic retrograde cholangiopancreatography (ERCP) is sometimes repeatedly performed in clinically stable patients; however, there are few reports about the results. This study assessed the results of repeated ERCPs after failure with NKS. Methods:  After failed NKS, patients who underwent repeated ERCP for the same purpose within 3 days were retrospectively identified. Success was defined as deep placement of a catheter into the common bile duct. Results:  Sixty-nine patients underwent a second ERCP procedure and, of those, six underwent a third ERCP. Of the 69 patients, cannulation was successful in 76.8% (53/69): 46 of 58 patients without additional NKS and 7 of 11 with additional NKS. Success increased to 79.7% (55/69) after the results of the third ERCP were included. Common causes of failed NKS were biliary deep cannulation failure

(78.3%) and blocking of the endoscopic view due to bleeding (13.0%). There was a significant difference Z-VAD-FMK mouse in success rates between the one day (65.7%) and the combined 2–3 day (88.2%) cases (P = 0.027). Except for the interval between ERCPs, there were no other factors associated with success rates. Complications occurred in 8, 11, and one patient after initial, second, and third ERCP and there was no difference of complication rates between each ERCPs. Conclusions:  In cases with biliary cannulation failure with NKS, it is more worthwhile repeating ERCP 2 or 3 days after

such failure than one day after, if the patient’s condition permits delay of procedure. “
“Thyroid hormone (T3) mediates cellular growth, development, and differentiation by binding to the nuclear thyroid hormone receptor (TR). Recent studies aminophylline suggest that long-term hypothyroidism is associated with human hepatocellular carcinoma (HCC) independent from other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein, antagonizes the Wnt signal pathway. In this study, we demonstrate that T3 may play a suppressor role by inducing DKK4 expression in HCC cells at both the messenger RNA (mRNA) and protein levels. DKK4 was down-regulated in 67.5% of HCC cancerous tissues. The decrease in DKK4 levels was accompanied by a concomitant decrease in TR protein levels in the matched cancerous tissues in 31% of tissues compared by immunoblotting with the adjacent noncancerous tissues.

Among the validated targets, we chose the transcriptional repressor CUTL1 (also known as CDP [CCAAT displacement protein], Cut, or Cux-1)20 for selleck screening library further investigation. Finally, we employed a lentiviral-mediated stable expression system to confirm the role of miR-122 in regulating hepatocyte proliferation and differentiation. In combination,

we placed miR-122 both upstream and downstream of the known gene regulatory network in liver development, which provides an exciting basis for understanding the regulation of liver development. In addition, our results also shed light on the cause and contribution of the down-regulation of miR-122 in HCCs. C/EBP, CCAAT/enhancer-binding protein; CTCF, CCCTC-binding factor; e, embryonic day; HCC, hepatocellular carcinoma; HNF, hepatocyte nuclear factor; LETF, liver-enriched transcription factor; MAP3K, mitogen-activated protein kinase kinase kinase; miR-122, microRNA-122; miRNA, microRNA; mRNA, messenger RNA; qRT-PCR, quantitative reverse-transcription polymerase chain reaction; SRF, serum response factor; UTR, untranslated region. Detailed materials and methods are described in the Supporting Information. Fetal, neonatal, and adult livers were isolated from C57BL/6J mice. Cell lines used were HepG2, Huh7, Sk-hep-1, SMMC-7721, and 293FT. miR-122 and control mimics were

synthesized by GenePharma (Shanghai, China). Anti-miR inhibitors for miR-122 and negative control were obtained from Ambion. All primary antibodies used for chromatin immunoprecipitation assays and western blot analyses of target genes were obtained from Santa Cruz Biotechnology. Quantitative Vasopressin Receptor reverse-transcription https://www.selleckchem.com/products/Staurosporine.html polymerase chain reaction (qRT-PCR) data are expressed as the mean ± standard deviation (SD) and luciferase data are presented as the mean + SD.

The differences between groups were analyzed using one-way analysis of variance, with P < 0.05 considered statistically significant (two-tailed). To search for regulators that might control in vivo transcription of miR-122, we focused primarily on the transcription factors that play important roles in regulating hepatocyte differentiation during liver development. Among the six families of liver-enriched transcription factors (LETFs) that have been characterized,18 several LETFs (including C/EBPα, HNF1α, HNF3α, HNF3β, and HNF3γ, and HNF4α,) are essential for expression of the complete repertoire of proteins that define hepatocyte function.21 C/EBPα, HNF1α HNF3β, and HNF4α, were further selected because they are highly abundant in both human and mouse liver (Supporting Fig. 1). We first investigated whether LETF expression correlated with miR-122 levels in both mouse embryonic livers and human HCC cell lines. The expression of miR-122 was detected by way of northern blot analysis and qRT-PCR. As shown in Fig. 1A,B, consistent with the previous report,11 miR-122 was gradually up-regulated in the fetal liver from e12.5 to birth.

10, 19 Among the physiological alterations cancer cells undergo as they continue to grow are the increase

in cell proliferation and the loss of apoptotic mechanisms.20, 21 In this study, saffron demonstrated significant antiproliferative activity by causing pronounced cell cycle arrest in vitro (Fig. 5) and reducing the number of proliferative cells (Ki-67–positive cells18) in DEN-treated animals (Fig. 3; Supporting Fig. 3). The antiproliferative activity of saffron was also associated with the induction of apoptosis as evidenced in vitro by caspase-3 GSI-IX cost cleavage and the pre-G predominant fraction in PI-FACS analysis. The apoptotic induction must have resulted from DNA damage as reflected by the up-regulation of the double-stranded DNA breakage marker, p-H2XA, (Fig. 5D) suggesting an additional role of saffron in sensitizing cancer cells to the effects of other chemotherapeutics. Consistently, saffron treatment find more increased the number of TUNEL- and M30 CytoDeath–positive cells in vivo (Fig. 3; Supporting Figs. 4 and 5). These results are in agreement with previous in vitro studies showing apoptosis and antiproliferative effect of saffron in various tumor cell lines.4, 22 These results seem to indicate that the inhibition of neoplastic development

in rat liver was associated with a reduction of cell proliferation and an induction of apoptosis. Increased oxidative stress can induce a wide spectrum of cellular damage and cellular

signaling changes that has been associated with carcinogenesis.20, 21 Administration of saffron to DEN-treated rats in this study counteracted DEN-induced oxidative stress as shown by restoration of antioxidant levels of SOD, CAT, and GST in the liver and diminishing of important markers of oxidative stress, such as oxidized lipids (MDA) and proteins (P.Carbonyl). The antioxidant effect of saffron was also accompanied by a decrease in liver damage markers, namely, serum ALT and GGT levels, suggesting a concomitant protection against hepatic damage. The prevention of oxidative stress and hepatic toxicity by saffron might be attributed to its potent antioxidant capacity which was confirmed in this study. Saffron showed ABTS and DPPH radical scavenging activities Resminostat and exhibited significant reducing power as indicated by the FRAP assay. The Antioxidant property of saffron could be credited to its phenolic content and to its active ingredients (such as safranal, crocin, crocetin, and carotene) (Table 1), all of which have been reported to have antioxidant properties.23 The association between decreased oxidative damage and reduced nodular and GST-P positive foci formations suggest that the antioxidant efficacy exhibited by saffron may be an important factor for its anticarcinogenic property.

Such changes are consistent with anti-predator response and represent either an innate response when prey are more vulnerable or shape optimization when faced with increased drag. We conclude that phenotypic expression depends critically on patterns of temporal variability in the environment, although the actual extent of expression depends on the specific trait in question. “
“Identifying biological trends and threats to organisms that make long distance migrations are often the limiting factors in their conservation. Indeed, Laysan

albatross Phoebastria immutabilis are highly vagile seabirds, Selleck GSK3235025 foraging throughout the North Pacific Ocean. Despite mark–recapture data indicating natal philopatry, Laysan albatross recently re-colonized several anthropogenically extirpated breeding locations. At the same time, a breeding population in the north-western Hawaiian Islands was lost to erosion and it was hypothesized that the colonization events were due to displacement rather than dispersal. Nuclear and mitochondrial markers were used in a range wide survey to test whether natal philopatry corresponded Selleckchem Doxorubicin to population structure in Laysan albatross, and to determine whether recent colonization events were a result of displacement from vanishing

breeding habitat. Five microsatellite loci found little population structure (FST=0.01, P=0.001), and sequences from the mitochondrial control region revealed low population structure (πST=0.05, P<0.001). The results were consistent with male-mediated dispersal and strong, but not absolute, philopatry by females. Mixed stock analyses and banding records from the newly colonized sites indicated contributions from multiple source populations, which contradicted the displacement hypothesis of a single source

population and instead supported species-wide dispersal from all source colonies. High genetic diversity (π=0.045, h=0.989), rapid colonization, and great dispersal potential bode well for the conservation of Laysan albatross. However, it may be necessary to protect high-island nesting sites, preserve genetic diversity and maintain breeding populations in the face of projected sea level rises and persistent bycatch. “
“Colour polymorphism is a widespread phenomenon either among reptiles and is often associated with alternative physiological and behavioural strategies, including dispersal and movement patterns. To test the homing ability of Podarcis muralis and look for morph-specific responses, we conducted a translocation experiment in two areas of Northern Italy during 2009 and 2010. The first study area was a wall surrounding a city park with a linear and simplified habitat structure; the second one was an archaeological park in a natural area, including stone walls remains, grasses and woods.

Ribavirin (Rebetol; Schering Plough) was administered at 200-600 mg twice a day after breakfast and dinner (daily dose: 600-1000 mg). PEG-IFN and ribavirin were discontinued or their doses reduced, as required, upon reduction of hemoglobin level, leukocyte count, neutrophil or platelet count, or the development BGB324 of adverse events. Thus, the dose of PEG-IFN was reduced by 50%

when the leukocyte count decreased below 1500/mm3, neutrophil count below 750/mm,3 or platelet count below 80,000/mm3; PEG-IFN was discontinued when these counts decreased below 1000/mm3, 500/mm3 or 50,000/mm,3 respectively. When hemoglobin decreased to <10 g/dL, the daily dose of ribavirin was reduced from 600 to 400 mg, from 800 to 600 mg and 1000 mg to 600 mg, depending on the initial dose. Ribavirin was withdrawn when hemoglobin decreased to <8.5 g/dL. However, the dose of telaprevir (MP-424) remained the same, selleck products and its administration was stopped when the discontinuation was appropriate for the development of adverse events. In those patients who discontinued telaprevir, treatment with PEG-IFNα-2b and ribavirin was also terminated. Table 1 summarizes

the profiles and laboratory data of the 81 patients at the commencement of treatment. They included 44 males and 37 females, ages 23 to 65 years (median, 55 years). The antiviral effects of the triple therapy on HCV were assessed by measuring plasma HCV RNA levels. In this

study, HCV RNA levels during treatment were evaluated at least once every month before, during, and after therapy. HCV RNA concentrations were determined using the COBAS TaqMan HCV test (Roche Diagnostics). The linear dynamic range of the assay was 1.2-7.8 log IU/mL, and the undetectable samples were defined as negative. In the present study, aa substitutions of the core region and NS5A-ISDR (IFN-sensitivity determining region) of HCV-1b were Urocanase analyzed by direct sequencing. HCV RNA was extracted from serum samples at the start of treatment and reverse transcribed with random primer and MMLV reverse transcriptase (Takara Syuzo, Tokyo). Nucleic acids were amplified by polymerase chain reaction (PCR) using the following primers: (1) Nucleotide sequences of the core region: The first-round PCR was performed with CE1 (sense, 5′-GTC TGC GGA ACC GGT GAG TA-3′, nucleotides: 134-153) and CE2 (antisense, 5′-GAC GTG GCG TCG TAT TGT CG-3′, nucleotides: 1096-1115) primers, and the second-round PCR with CC9 (sense, 5′-ACT GCT AGC CGA GTA GTG TT-3′, nucleotides: 234-253) and CE6 (antisense, 5′-GGA GCA GTC GTT CGT GAC AT-3′, nucleotides: 934-953) primers.

CT angiography has become the

primary imaging method in many centers during the past few decades, partially because of its speed in scanning, which is especially suitable for acute subarachnoid hemorrhage patients. The main disadvantages include radiation, skull base artifacts in imaging and potential harm from iodine used in the scanning.[19, 20] In our institution, CTA is not recommended for a routine. The advent of MRA may challenge the role of traditional imaging methods. MRA, requiring no radiation or iodine, is the best method especially for screening anomalies or aneurysms of intracranial arteries. With click here MRA, especially with VR reconstruction, it is possible to evaluate the whole anterior circulation at one time, allowing more accurate differentiation of Az from other ACA anomalies, and easier identification of the associated aneurysms. Furthermore, the specificity and sensitivity of 3-D-TOF MRA in detecting intracranial aneurysm is comparable to DSA, as proved in our previous work in which the patient based specificity and sensitivity of 3-D-TOF MK-1775 nmr MRA is reported up to 94.4% and 99.2%, respectively.[21]

So, 3-D-TOF-MRA at 3.0 T may replace DSA as a contrast-free, noninvasive, and nonradiation-based modality for the diagnosis and screening of intracranial aneurysms and other vascular anomalies.[21] To our knowledge, this study has reported for the first time the use of 3-D-TOF MRA with VR in screening and diagnosing Az and associated aneurysms with high imaging quality and feasibility. However, it should be noted that image quality might be degraded by some artifacts, including equipment vibration and patient movement.[22] 3-D-TOF MRA may overestimate blood turbulence or overlook small or slow-flowing vessels.[7, 23] Therefore, it is important

for us that the thin slice of source of MRI images and MIP images must be reviewed for confirmation of the anomaly. It should take a longer O-methylated flavonoid time to scan than CT angiography and it is unsuitable for patients with metal implants or pacemakers.[7] The higher demand for MRA scanners and workstation software may be an obstacle for its application and popularization. Despite these limitations, we still strongly recommend MRA as an initial method to either screen or preoperatively evaluate ACA anomalies with or without associated aneurysms. 3-D-TOF MRA with VR has been shown to be feasible for screening and diagnosing Az and associated aneurysms with high imaging quality. This study has been supported by the National Natural Scientific Fund of China (Contract number: 30970793). “
“This study aims to investigate the regional changes in the early onset of blindness using the deformation-based morphometry (DBM) method. A total of 15 early blindness and 30 gender- and age-matched sighted control subjects were recruited for the study.

Therefore, it is tempting to speculate that ethanol may up-regulate lipin-1 through these metabolic modulators. In summary,

we have demonstrated that ethanol Tanespimycin molecular weight feeding up-regulates hepatic lipin-1 mRNA and protein and promotes lipin-1 cytoplasmic localization, which, in turn, may lead to increased lipogenesis, impaired fatty acid oxidation, and the development of steatosis in mice. Furthermore, we have identified lipin-1 as a vital downstream target of AMPK-SREBP-1 signaling in the action of ethanol in the liver. Our study sheds new light on the multifactorial pathogenesis of AFLD, and suggests that future studies to investigate the effects of nutritional or pharmacological inhibitors of SREBP-1, lipin-1, and/or activators of AMPK on its development are clearly warranted. The authors thank Dr. David N. Brindley (University of Alberta, Edmonton, Canada) and Drs. this website R. Kennedy Keller and Laura Flatow (University of South Florida, Tampa, FL) for their outstanding technical and intellectual contributions. Additional Supporting Information may be found in the online version of this article. “
“Congenital abnormalities of the biliary tract belong to a family of bile duct malformations that are mostly related to abnormal remodeling of the embryonic

ductal plate (“ductal plate malformation”). They can be inherited or not inherited, and can affect the intra- and/or the extra-hepatic second biliary tree. They are broadly divided into two categories: cystic and non-cystic. Congenital cystic diseases of the intrahepatic biliary tree include the Von Meyenburg complexes, congenital hepatic fibrosis, Caroli’s syndrome, simple cysts, and polycystic liver disease (with or without polycystic kidney disease), while choledocal cyst is a congenital

cystic disease of the extrahepatic biliary tree. Congenital non-cystic diseases of the biliary tract are probably not the result of a malformation process, but rather of gradual destruction of bile ducts during fetal life. These include paucity of interlobular bile ducts (syndromic and non-syndromic) and atresia of extrahepatic bile ducts. With the exception of polycystic liver disease, the other entities will be described in this chapter. “
“Aim:  Efficacy and safety of double filtration plasmapheresis (DFPP) for chronic hepatitis C were prospectively analyzed in Japanese clinical settings. Methods:  All patients who received DFPP in combination with interferon (IFN) therapy for chronic hepatitis C were serially recruited at 36 institutions between April 2008 and July 2009 in Japan. Results:  A total of 239 patients were analyzed for the safety of DFPP and 206 patients for the efficacy. Of the 206 patients, 181 patients were treated with DFPP in combination with pegylated interferon plus ribavirin (PEG-IFN/RBV + DFPP). Among the 181 patients, 60 patients (33.1%) were treatment-naïves, 35 (19.

283 and 0.0362 ng/mL for genotype 1a and 1b, respectively. Furthermore, BMS-790052 Cmin values exceeded the protein binding-adjusted 90% median effective concentration (EC90) values after just a single dose (day 1). BMS-790052 Cmin values were numerically greater than the 10-fold protein binding adjusted EC90 for genotype 1a (2.83 ng/mL) after administration of 10-100 mg BMS-790052 once daily. There were no deaths, serious AEs or treatment discontinuations due to AEs. Treatment-emergent AEs were reported at a similar frequency following administration of BMS-790052 (16 of 24 [66.7%]) and placebo (4 of 6 [66.7%]) and no dose-related trends were apparent following administration of BMS-790052 at doses of 1-100 mg.

One placebo recipient reported a sinus ABT-888 research buy headache of severe intensity; all other AEs were mild or moderate in intensity. The most frequent treatment-emergent AE was headache (20.8% of BMS-790052-treated patients and 33.3% of placebo-treated patients); headache did not appear to be dose-related and all events were considered by the investigator to be unrelated to study

drug. Adverse events that occurred in more than one patient are shown in Table 4. There were no clinically relevant changes in clinical laboratory values, vital signs, physical examinations, or ECGs. The results of this study indicate that BMS-790052 is a potent NS5A replication complex inhibitor that produces a substantial decline in HCV RNA in patients chronically infected with either HCV genotype 1a or genotype 1b. BMS-790052 was shown

to be generally well tolerated and had a PK profile supportive of once-daily dosing. The potent antiviral effect of BMS-790052 learn more observed in a previous study was confirmed in the present study.6 In this study, HCV-RNA levels decreased by ≈3 logs after a single dose in all BMS-790052-treated groups, other than the 1 mg group. This is consistent with single ascending dose results,6 and demonstrates that the in vitro picomolar potency of BMS-790052 translates in vivo to substantial antiviral activity. In addition, although the sample size was small, it appears that patients infected Megestrol Acetate with HCV genotype 1b virus responded better than patients infected with HCV genotype 1a virus, with a more marked and sustained viral RNA decline. This is consistent with both the difference in the intrinsic potency of BMS-790052 for genotype 1a and 1b replicons (50 pM versus 9 pM), and the higher level of resistance observed in vitro for genotype 1a variants.6 The early suppression of HCV replication with BMS-790052 monotherapy is comparable with, and in some cases exceeds, that observed for other DAA agents.7, 8 Using the standard model of HCV infection and treatment,9 treatment with BMS-790052 in a prior monotherapy study6 was associated with improved estimation of HCV RNA clearance rate, shorter delay in viral clearance, and shorter HCV RNA T1/2 as compared with PEG-IFN + RBV therapy and telaprevir therapy.