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The coronavirus disease-2019 (COVID-19) is primarily a disease of the respiratory system and is manifested by an infectious pneumonia, with fever, cough and breathlessness as the most common presenting symptoms.

Background: Budd-Chiari syndrome (BCS) is a rare disease defined as hepatic venous outflow obstruction at any level from the hepatic venules up to the cavo-atrial junction. Transjugular Intrahepatic Portosystemic Shunt (TIPS) is performed as a decompressive treatment in some patients.Aim: To evaluate the potential role of Transient Elastography (TE) in assessing liver stiffness in patients with primary BCS.Methods: Twenty one BCS patients and 10 patients with liver cirrhosis with different underlying etiologies underwent abdominal ultrasound and TE.Results: Ninety-five percent of BCS patients had liver stiffness compatible with F4 with a median of 21 kPa, values which are usually obtained in patients with liver cirrhosis. Ten BCS and 10 cirrhotic patients underwent repeated TE with a median of 320 days between exams for BCS and 4.5 years for cirrhotic patients. The change of liver stiffness in BCS patients was 5.75 kPa (range − 0.4 to 26.6), compared with − 4.85 kPa (range − 15.6 to 15.0) in cirrhotic patients (p-value = 0.0029). Change in liver stiffness from baseline to follow-up in BCS patients who underwent TIPS (n = 4) was 0.2 kPa (range − 0.4 to 15.3), whereas in patients without intervention (n = 6) it was 6.75 kPa (range 1.3 to 26.6). The difference was not statistically significant.Conclusion: Liver stiffness in BCS patients is a dynamic progressive process with parameters of TE resembling liver cirrhosis. Even if TIPS seem to slow down the increment of liver stiffness, because of decreased liver congestion, it kept most patients with high score. The TE in BCS patients may be considered for monitoring for stable or upfront disease deterioration.

AIM To evaluate the diagnostic value of serial biochemical blood tests in the diagnosis of biliary colic. METHODS Files were reviewed of 1039 patients who were admitted to the Share'e Zedek Medical Center emergency department between the years 2012-2013, and received the coding of acute biliary disease. Of these, the first 100 cases were selected that met the following criteria: (1) a diagnosis of biliary colic or symptomatic cholelithiasis; (2) at least two biochemical blood tests performed; and (3) 18 years of age or older. Patients with other acute biliary diseases were excluded. The biochemical profile of the patients was analyzed as were their clinical and radiological findings. RESULTS Three-quarters of the patients were women, whose average age of 37 years was younger than the average of the men, at 50 years. According to their histories, 47% of the patients had previously known cholelithiasis. Pain in either the right upper quadrant or the epigastrium was the presenting symptom in 93% cases. The greatest change in serum biochemical results was seen during the first day of the patients' admissions. Alanine aminotransferase (ALT) showed the highest initial rise above the reference range, followed by aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin and alkaline phosphatase (ALKP) - all these increases were statistically significant (P < 0.05). AST showed the sharpest decline followed by bilirubin and ALT. GGT and ALKP did not fall. A sharp rise and fall in liver enzymes, especially during the first day, most prominently in AST and ALT, was seen in 70% percent of cases. In 65% of cases trans-abdominal sonography did not give diagnostic findings. CONCLUSION Serial serum liver enzyme measurements are helpful in the initial diagnosis of acute biliary colic.

[Background & Aims] Although off-label use of sofosbuvir-containing regimens occurs regularly in patients with hepatitis C virus (HCV) infection undergoing dialysis for severe renal impairment or end-stage renal disease (ESRD), these regimens are not licensed for this indication, and there is an absence of dosing recommendations in this population. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir in patients with HCV infection with ESRD undergoing dialysis., [Methods] In this phase II, single-arm study, 59 patients with genotype 1–6 HCV infection with ESRD undergoing hemodialysis or peritoneal dialysis received open-label sofosbuvir/velpatasvir (400 mg/100 mg) once daily for 12 weeks. Patients were HCV treatment naive or treatment experienced without cirrhosis or with compensated cirrhosis. Patients previously treated with any HCV NS5A inhibitor were not eligible. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response (SVR) 12 weeks after discontinuation of treatment (SVR12). The primary safety endpoint was the proportion of patients who discontinued study drug due to adverse events., [Results] Overall, 56 of 59 patients achieved SVR12 (95%; 95% CI 86–99%). Of the 3 patients who did not achieve SVR12, 2 patients had virologic relapse determined at post-treatment Week 4 (including 1 who prematurely discontinued study treatment), and 1 patient died from suicide after achieving SVR through post-treatment Week 4. The most common adverse events were headache (17%), fatigue (14%), nausea (14%), and vomiting (14%). Serious adverse events were reported for 11 patients (19%), and all were deemed to be unrelated to sofosbuvir/velpatasvir., [Conclusions] Treatment with sofosbuvir/velpatasvir for 12 weeks was safe and effective in patients with ESRD undergoing dialysis., [Lay summary] Sofosbuvir/velpatasvir is a combination direct-acting antiviral that is approved for treatment of patients with hepatitis C virus (HCV) infection. Despite the lack of dosing recommendations, sofosbuvir-containing regimens (including sofosbuvir/velpatasvir) are frequently used for HCV-infected patients undergoing dialysis. This study evaluated the safety and efficacy of sofosbuvir/velpatasvir for 12 weeks in patients with HCV infection who were undergoing dialysis. Treatment with sofosbuvir/velpatasvir was safe and well tolerated, resulting in a cure rate of 95% in patients with HCV infection and end-stage renal disease., Clinical Trial Number: NCT03036852.

Background Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analysed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centres in Israel. Methods Blood samples and clinical data from 49 patients who failed various DAAs were collected. RAS identified in the NS3 and NS5A regions by population (Sanger) and next-generation sequencing (NGS) were compared by treatment regimen and HCV subtypes. Results The majority (71.4%, 35/49) of patients were infected with the genotype (GT)1b strain, while 12.2% (6/49) carried GT1a and 14.3% GT3a/b (7), GT4a (1) and GT1b/GT3a. RAS were identified in 85.7% (42/49) of failures, of which 90.5% (38/42) were clinically relevant RAS (known to be associated with a specific GT and DAA in patients failing therapy or those with more than twofold change in in vitro replicon assays). The most abundant RAS were 168A/E/Q/G/N/V (32.6%, 16/49) identified in NS3, and 93H/N (61.2%, 30/49), 31I/M/V (34.7%, 17/49) and 30R/H/K (12.2%, 6/49), identified in NS5A. Significantly more clinically relevant RAS were identified in NS5A (82.2%, 37/45) than in NS3 (35.7%, 10/28; PConclusions Our findings, together with additional real-life data, will contribute to the optimization of retreatment in DAA failure, when cost-related and suboptimal regimens must be employed.

BACKGROUND & AIMS Acute hepatitis C (AHC) is not frequently identified because patients are usually asymptomatic, although may be recognized after iatrogenic exposures such as needle stick injuries, medical injection, and acupuncture. We describe an outbreak of AHC among 12 patients who received IV saline flush from a single multi-dose vial after intravenous contrast administration for a computerized tomography (CT) scan. The last patient to receive IV contrast with saline flush from a multi-dose vial at the clinic on the previous day was known to have chronic HCV genotype 1b (termed potential source, PS). Here we sought to confirm (via genetic analysis) the source of infection and to predict the minimal contaminating level of IV saline flush needed to transmit infectious virus to all patients. METHODS In order to confirm the source of infection, we sequenced the HCV E1E2 region in 7 CT patients, in PS, and in 2 control samples from unrelated patients also infected with HCV genotype 1b. A transmission probabilistic model was developed to predict the contamination volume of blood that would have been sufficient to transmit infectious virus to all patients. RESULTS Viral sequencing showed close clustering of the cases with the PS. The transmission probabilistic model predicted that contamination of the multi-dose saline vial with 0.6-8.7 microliters of blood would have been sufficient to transmit infectious virus to all patients. CONCLUSION Analysis of this unique cohort provides a new understanding of HCV transmission with respect to contaminating volumes and viral titers.

© 2019 Elsevier Ltd. All rights reserved., Background: Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods: In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH, non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2-F3, or F1 with at least one accompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpoints for the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2-F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings: Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1-F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2-F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1-F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation: Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes.

Ignác Fülöp Semmelweis was born almost 200 years ago, in 1818, to a well-to-do middle class Hungarian family. He started law school in 1837, switched to medicine a year later, and graduated in 1844.

Providing here our aims and project background, we note that intravenous silibinin (SIL) is a potent antiviral agent against hepatitis C virus (HCV) genotype-1. In this proof of concept case-study we tested: (i) whether interferon-alfa (IFN)-free treatment with SIL plus ribavirin (RBV) can achieve sustained virological response (SVR); (ii) whether SIL is safe and feasible for prolonged duration of treatment and (iii) whether mathematical modelling of early on-treatment HCV kinetics can guide duration of therapy to achieve SVR. With our method, a 44 year-old female HCV-(genotype-1)-infected patient who developed severe psychiatric adverse events to a previous course of pegIFN+RBV, initiated combination treatment with 1200 mg/day of SIL, 1200 mg/day of RBV and 6000 u/day vitamin D. Blood samples were collected frequently till week 4, thereafter every 1-12 weeks until the end of therapy. The standard biphasic mathematical model with time-varying SIL effectiveness was used to predict the duration of therapy to achieve SVR. Our results show that, based on modelling the observed viral kinetics during the first 3 weeks of treatment, SVR was predicted to be achieved within 34 weeks of therapy. Provided with this information, the patient agreed to complete 34 weeks of treatment. IFN-free treatment with SIL+RBV wasmore » feasible, safe and achieved SVR (week-33). In conclusion, we report, for the first time, the use of real-time mathematical modelling of HCV kinetics to individualize duration of IFN-free therapy and to empower a patient to participate in shared decision making regarding length of treatment. SIL-based individualized therapy provides a treatment option for patients who do not respond to or cannot receive other HCV agents and should be further validated.« less

Background Direct-acting antiviral (DAA) treatment regimens and response rates of patients with HCV genotype-1 (GT1) are currently considered subtype-dependent. Identification of clinically relevant resistance-associated substitutions (RASs) in the NS3 and NS5A proteins at baseline and in DAA failures, may also impact clinical decisions. Methods In a multicentre cohort study ( n=308), NS3 or NS5B sequencing ( n=248) was used to discriminate between GT1 subtypes. The correlation between baseline NS3 and NS5A RASs on the 12-week sustained virological response (SVR12) rates of 160 of the patients treated with second-generation DAAs was also assessed. Post-treatment resistance analysis was performed on samples from 58 patients exhibiting DAA virological failure. Results GT1a, GT1b and GT1d subtypes were identified in 23.0%, 75.4% and 1.2% of tested samples. GT1b was most prevalent (97.7%, 128/131) among patients born in the former Soviet Union. The Q80K NS3 RAS was identified in 17.5% (10/57) of the GT1a carriers, most of whom were Israeli-born. NS3 and NS5A baseline RASs showed a negligible correlation with SVR12 rates. Treatment-emergent RASs were observed among 8.9% (4/45) and 76.9% (10/13) of first- and second-generation DAA failures, respectively, with D168V/E (NS3), Y93H and L31M (NS5A) being the most prevalent mutations. Conclusions NS3 sequencing analysis can successfully discriminate between GT1 subtypes and identify NS3 amino acid substitutions. While pre-treatment NS3 and NS5A RASs marginally affect second-generation DAA SVR12 rates, post-treatment resistance analysis should be considered prior to re-therapy.

The United States Food and Drug Administration recently warned that the direct acting antiviral (DAA) combination hepatitis C virus (HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin (PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis (compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment with PODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R.

Cholangiocarcinoma is an uncommon adenocarcinoma with poor prognosis. Signet ring cell cholangiocarcinoma is an extremely rare disease, with only 11 cases reported to date. However, its incidence is increasing. Similarly, there is an increasing incidence of other SRC tumors (colon, gastric etc.) as well. Most cases have described a localized mass of signet ring cells, mostly in the common bile duct. A 69-year-old Caucasian man admitted for jaundice and abdominal pain that began 3 days prior to his hospitalization. Work up including CT, ERCP and EUS was undertaken. Biopsies were taken during EUS from the CBD disclosing signet ring cholangiocarcinoma. ERCP showed that the tumor infiltrated diffusely both left and right hepatic ducts. This is the first description of diffuse type signet ring cell cholangiocarcinoma. A rapid downhill course precluded treatment. Thus, survival was extremely short – the patient passed away three weeks from the appearance of first symptoms. As the incidence of SRC’s in general as well as the incidence of SRC cholangiocarcinoma seems to be on the rise, more cases are likely to be encountered. If our observation is confirmed, then perhaps the least invasive workup should be undertaken in patients with SRC diffuse type cholangiocarcinoma.

Summary. Treatment with pegylated interferon (Peg-IFN) and ribavirin, now the standard of care, has been shown to achieve sustained viral response (SVR) in up to 60% of patients with hepatitis C (HCV). Studies of response to this combination in HCV-infected haemophilia patients are scarce. The aim of the study was to report the results and safety of interferon/ribavirin treatment in HCV and HCV-/HIV-infected patients at the Israeli National Hemophilia Center. A retrospective observational cohort study was conducted on haemophilia patients infected with HCV or HCV/HIV. Patients received combination of Peg-IFN and ribavirin. Few were still treated with standard interferon. The primary end-point was sustained viral response (SVR). The secondary end-point was safety, with emphasis on increased bleeding episodes. Some 18/43 (42%) HCV mono-infected haemophilia patients achieved SVR. Relapse occurred in 14 (33%), while 11 patients (25%) were non-responders. SVR was achieved among 17/37 (46%) naive patients receiving Peg-IFN and ribavirin. Among patients with genotype-1, SVR was achieved in 12/36 (33%) and 11/30 (37%) in the whole group and Peg-IFN treated naive patients, respectively. In HCV/HIV co-infected patients only 1 patient achieved SVR. Severe anaemia occurred in 14/50 (28%) patients, four received erythropoietin. None maintained stable haemoglobin levels. Two patients had significant bleeding episodes. In our cohort of haemophilia patients, SVR was achieved in a lower than expected rates. A relatively high relapse rate in the HCV mono-infected patients and a very high non-response rate in the HCV/HIV co-infected patients were observed as anticipated. Anaemia was a major side effect and the use of growth factors seemed unrevealing.

Background & Aims: The second slope of viral decline induced by interferon treatment has been suggested to be influenced mainly by the hepatitis C virus (HCV)-specific T-cell response; however, this hypothesis needs to be validated by results derived from experimental studies. Methods: To address this issue, the HCV-specific T-cell response of 32 genotype-1–infected patients of the 270 patients enrolled in the dynamically individualized treatment of hepatitis C infection and correlates of viral/host dynamics phase III, open-label, randomized, multicenter trial was studied in relation to viral kinetics and treatment outcome. Results: Greater proliferative responses by HCV-specific CD8 cells were found before treatment in patients with a fast viral decline and with a sustained viral response. However, no significant improvement of HCV-specific CD8 responses was observed in the first weeks of therapy in both rapid viral responder and non–rapid viral responder patients. A mild enhancement of proliferative T-cell responses and a partial restoration of the cytotoxic T-cell potential was expressed only late during treatment, likely favored by HCV clearance. Conclusions: Early restoration of an efficient T-cell response does not seem to be an essential requirement for a rapid viral decline in the first weeks of treatment. However, patients presenting a better HCV-specific CD8 cell proliferative potential at baseline are more likely to present a rapid and sustained viral response. Therefore, future treatment protocols should consider the development of strategies aimed at improving HCV-specific T-cell responses.

Pegylated interferon alfa-2b (PEG-IFN-alfa 2b ) has been shown to provide superior efficacy to IFN-alfa 2b in patients with chronic hepatitis C (predominantly genotype 1) infection as measured by viral clearance. This study was conducted to determine the optimal dosing regimen of PEG-IFN-alfa 2b required to obtain a maximum decrease of hepatitis C viral RNA.This was a 24-week, open-label, multicenter, parallel-group, randomized, active-controlled trial in the United Kingdom, France, and Israel. Individuals (n = 61) with chronic hepatitis C infection, genotype 1, received IFN-alfa 2b 3 mIU 3 times weekly for 24 weeks, or PEG-IFN-alfa 2b 1.5 or 3.0 microg/kg/wk, as total weekly full or split doses, for 12 weeks. At week 12, serum RNA titer was measured, and all PEG-IFN-alfa 2b patients continued with 1.5 microg/kg/wk for a further 12 weeks.Mean serum hepatitis C RNA levels decreased in all groups at weeks 12 and 24. PEG-IFN-alfa 2b 1.5 microg/kg/wk was superior to IFN-alfa 2b in decreasing mean serum hepatitis C RNA ( P.05 at week 12). The efficacy of split-dose PEG-IFN-alfa 2b 1.5 or 3.0 microg/kg/wk regimens was not significantly different from full-dose PEG-IFN-alfa 2b 1.5 microg/kg/wk. However, there was a significant decrease in neutrophil count in groups receiving PEG-IFN-alfa 2b 3.0 microg/kg/wk or lower, multiple-dose per week regimens.PEG-IFN-alfa 2b 1.5 microg/kg once weekly is the optimal dosing frequency for patients with chronic hepatitis C with predominantly genotype 1 infection. More frequent dosing or increasing the dose to 3.0 microg/kg/wk did not result in improved antiviral effects, but did decrease neutrophil counts.

Background Hepatitis C decreases health related quality of life (HRQL) which is further diminished by antiviral therapy. HRQL improves after successful treatment. This trial explores the course of and factors associated with HRQL in patients given individualized or standard treatment based on early treatment response (Ditto-study). Methods The Short Form (SF)-36 Health Survey was administered at baseline (n = 192) and 24 weeks after the end of therapy (n = 128). Results At baseline HRQL was influenced by age, participating center, severity of liver disease and income. Exploring the course of HRQL (scores at follow up minus baseline), only the dimension general health increased. In this dimension patients with a relapse or sustained response differed from non-responders. Men and women differed in the dimension bodily pain. Treatment schedule did not influence the course of HRQL. Conclusions Main determinants of HRQL were severity of liver disease, age, gender, participating center and response to treatment. Our results do not exclude a more profound negative impact of individualized treatment compared to standard, possibly caused by higher doses and extended treatment duration in the individualized group. Antiviral therapy might have a more intense and more prolonged negative impact on females.

AIM: To compare histological endpoint assessment using noninvasive alternatives to biopsy during treatment in a chronic hepatitis C virus (HCV) cohort. METHODS: Patients with chronic HCV were randomized to receive interferon-based therapy for 24 (genotypes 2/3) or 48 (genotype 1) wk. FibroSURE™ (FS) was assessed at baseline and at week-12 post-treatment follow-up. Baseline biopsy for METAVIR was assessed by a single pathologist. FibroScan® transient elastography (TE) was performed during treatment in a patient subset. RESULTS: Two thousand and sixty patients (n = 253 in Asia) were classified as METAVIR F0-1 (n = 1682) or F2-4 (n = 378). For F2-4, FS (n = 2055) had sensitivity and specificity of 0.87 and 0.61, respectively, with area under the receiver-operating curve of 0.82; corresponding values for TE (n = 214) and combined FS/TE (n = 209) were 0.77, 0.88 and 0.88, and 0.93, 0.68 and 0.88. Overall FS/TE agreement for F2-4 was 71% (κ = 0.41) and higher in Asians vs non-Asians (κ = 0.86 vs 0.35; P < 0.001). Combined FS/TE had 97% accuracy in Asians (n = 33). Baseline FS (0.38 vs 0.51, P < 0.001) and TE (8.0 kPa vs 11.9 kPa, P = 0.006) scores were lower in patients with sustained virological response than in nonresponders, and were maintained through follow-up. CONCLUSION: FS and TE may reliably differentiate mild from moderate-advanced disease, with a potential for high diagnostic accuracy in Asians with chronic HCV.

BACKGROUND AND AIM: The human asialoglycoprotein receptor is a membrane heterooligomer expressed exclusively in hepatocytes. A soluble secreted form, sH2a, arises, not by shedding at the cell surface, but by intracellular cleavage of its membrane-bound precursor, which is encoded by an alternatively spliced form of the receptor H2 subunit. Here we determined and report that sH2a, present at constant levels in serum from healthy individuals is altered upon liver fibrosis, reflecting the status of hepatocyte function. METHODS: We measured sH2a levels in serum using a monoclonal antibody and an ELISA assay that we developed, comparing with routine liver function markers. We compared blindly pretreatment serum samples from a cohort of 44 hepatitis C patients, which had METAVIR-scored biopsies, with 28 healthy individuals. RESULTS: sH2a levels varied minimally for the healthy individuals (150±21 ng/ml), whereas the levels deviated from this normal range increasingly in correlation with fibrosis stage. A simple algorithm combining sH2a levels with those of alanine aminotransferase allowed prediction of fibrosis stage, with a very high area under the ROC curve of 0.86. CONCLUSIONS: sH2a has the potential to be a uniquely sensitive and specific novel marker for liver fibrosis and function.

International audience; UNLABELLED: The benefit of extending treatment duration with peginterferon (PEG-IFN) and ribavirin (RBV) from 48 weeks to 72 weeks for patients with chronic hepatitis C genotype 1 infection has not been well established. In this prospective, international, open-label, randomized, multicenter study, 1,428 treatment-naïve patients from 133 centers were treated with PEG-IFN alfa-2b (1.5 μg/kg/week) plus RBV (800-1,400 mg/day). Patients with detectable hepatitis C virus (HCV) RNA and a ≥2-log(10) drop in HCV RNA levels at week 12 (slow responders) were randomized 1:1 to receive 48 weeks (n = 86) or 72 weeks (n = 73) of treatment. Sustained virologic response (SVR) rates were 43% in slow responders treated for 48 weeks and 48% in slow responders treated for 72 weeks (P = 0.644). Relapse rates were similar in slow responders treated for 48 or 72 weeks (47% versus 33%, P = 0.169). The safety profile was similar in both treatment arms; serious adverse events leading to discontinuation of treatment were observed in 3.5% of slow responders treated for 48 weeks and 8.2% of those treated for 72 weeks. Among slow responders with a

Background & Aims There is increasing interest in identifying patients with chronic hepatitis C genotype 2 or 3 infection in whom it is possible to lower the burden of therapy while retaining high levels of efficacy. Methods Treatment-naive patients with chronic hepatitis C genotype 2/3 infection were randomized to receive peginterferon alfa-2b (1.5μg/kg/wk) for 24weeks (group A); peginterferon alfa-2b (1.0μg/kg/wk) for 24weeks (group B); or peginterferon alfa-2b (1.5μg/kg/wk) for 16weeks (group C), each in combination with weight-based ribavirin (800–1200mg/d). The study population comprised two cohorts: the Hep-Net cohort enrolled in Germany and an International cohort enrolled at study sites throughout Europe and Asia. The primary end point was sustained virological response (SVR). Results The study included 682 patients; 80.2% had genotype 3 infection. In the intent-to-treat population, SVR rates were 66.5%, 64.3%, and 56.6% in groups A, B, and C, and were similar in Asian and white patients. Treatment differences (A vs . B and A vs. C) failed to reach the predefined margin for noninferiority of -10%; and thus groups B and C failed to show noninferiority relative to group A. Among patients with undetectable HCV RNA at week 4, SVR rates were 75.3%, 75.9%, and 72.4%, respectively. Relapse rates were 17.8%, 16.3%, and 29.3%, respectively. Treatment-emergent serious adverse events were highest in group A and lowest in group C, and adverse events leading to discontinuation were similar across treatment arms. Conclusions For patients with chronic hepatitis C genotype 2/3 infection, 24weeks of peginterferon alfa-2b (1.5μg/kg/wk) plus weight-based ribavirin remains a standard-of-care therapy; however, treatment for 16weeks may be considered for patients with undetectable HCV RNA at week 4 of the treatment.

Autoimmune hepatitis (AIH) is a chronic and progressive disease. The etiology and epidemiologic characterizations of AIH are not fully understood. It has a prolonged course and can affect all age groups. Symptoms and signs may appear years before diagnosis, and may be manifested for extended periods only as minor liver enzymes abnormalities. Clinical manifestations vary from lethargy and jaundice, to extremely severe deterioration in quality of life, hepatic failure and liver transplantation or death. In most cases there is a good response to therapy, making it important to diagnose the disease early in its course. The objectives of this review are to increase the awareness to AIH, to the diagnostic methods and to the treatment modalities and to discuss updates regarding AIH.

The current standard of care for patients with chronic hepatitis C virus (HCV) genotype 1 is once-weekly pegylated interferon-α (Peg-IFNα) plus daily ribavirin for 48 weeks. We evaluated the efficacy/safety of albinterferon alfa-2b (albIFN), a novel, long-acting, genetic fusion polypeptide of albumin and IFNα-2b.In the phase 3 ACHIEVE-1 trial, 1331 patients were assigned equally to 3 open-label, 48-week treatment groups: Peg-IFNα-2a 180 μg every week, or albIFN 900 or 1200 μg every 2 weeks administered subcutaneously, with weight-based oral ribavirin 1000-1200 mg/day. During the study, the data monitoring committee recommended dose modification for all patients receiving albIFN 1200 μg to 900 μg because of increased pulmonary adverse events (AEs) in the 1200-μg arms of both ACHIEVE studies. Main outcome measure was sustained virologic response (SVR; undetectable serum HCV RNA at week 72).Intention-to-treat SVR rates were 51.0% (225/441), 48.2% (213/442), and 47.3% (208/440) with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. The primary objective of showing noninferiority of albIFN 900 μg (P.001) and 1200 μg (P = .003) vs Peg-IFNα-2a for SVR was achieved. Multivariate modeling indicated consistency of treatment effect across subgroups. Serious/severe AE rates were 23.1%, 24.0%, 28.2%; treatment discontinuation rates because of AEs were 4.1%, 10.4%, 10.0%; discontinuation rates because of respiratory AEs were 0%, 0.9%, 1.6%; with Peg-IFNα-2a, and albIFN 900 and 1200 μg, respectively. Hematologic abnormality rates were comparable across the Peg-IFNα-2a and albIFN 900-μg groups.albIFN 900 μg every 2 weeks showed comparable efficacy, with similar serious/severe AE rates, although with a higher discontinuation rate, vs Peg-IFNα-2a in patients with chronic HCV genotype 1.

Subjects with plasma cholesterol levels greater than 240 mg/dl (6.21 mmol/liter) and those with greater than 200 mg/dl (5.18 mmol/liter) who have coronary artery disease, or those with 2 risk factors for ischemic heart disease who do not respond to a hypocholesterolemic diet should all be treated. Lovastatin, which is an inhibitor of hydroxymethygluteryl coenzyme A reductase, is a new agent for treating hypercholesterolemia and is administered in a dose of 20 to 80 mg/day. A study was conducted in which only 10 mg of lovastatin was given to 28 subjects with plasma cholesterol of 200 to 240 mg/dl (5.18 to 6.21 mmol/liter). Cholesterol plasma levels decreased in 19% and low-density lipoprotein cholesterol decreased by 24% from baseline levels after 20 weeks of treatment. All 28 patients decreased their cholesterol values to less than 200 mg% (5.18 mmol/liter), and only 1 had a low-density lipoprotein level greater than 130 mg% (3.36 mmol/liter) at termination of the study. Achievement of desirable values of cholesterol with 10 mg of lovastatin was accompanied by less adverse effects and with significant financial saving. The calculated saving for lovastatin consumers in the USA could be an amount of $60,000,000. Thus, it is recommended that this drug be manufactured in 10 mg tablets.

In the past 20 years, a growing proportion of new cases of celiac disease (CD) are diagnosed in adults and in patients with extraintestinal manifestations. Our understanding of the extremely wide spectra of manifestations and the profound effects on elderly patients is improving. Nevertheless, CD is still underdiagnosed in elderly patients. In this study, we describe a case series of CD patients diagnosed after the age of 60.A retrospective chart review was preformed in cases of CD diagnosed after the age of 60. Patients were included if they had positive serology and histologic findings compatible with CD. Eligible patients were reinterviewed, and demographic, clinical, and laboratory information were recorded.During the study period, 7 patients with CD diagnosed after the age of 60 were identified. The most common presenting findings were weight loss, iron deficiency anemia, and diarrhea. Two patients suffered from severe early osteoperosis and 2 additional patients had elevated liver function tests. Neurologic manifestation was suspected in 3 cases. Two female patients presented with cognitive decline that was attributed to Alzheimer dementia but ameliorated after the initiation of gluten-free diet. The third patient had peripheral neuropathy that completely resolved after the initiation of gluten-free diet. Median lag in diagnosis was 8 years. Diet treatment led to complete resolution of symptoms in most cases and a significant weight gain (median 7.75 kg, range 5 to 11). One patient developed a fatal intestinal T-cell lymphoma.In this case series, we have described several cases of CD in patients over the age of 60 with a varied spectrum of manifestations. We have also found a significant lag in diagnosis and treatment. We believe that it is important to promote the identification of CD as a possible culprit in varied clinical conditions in the elderly population.

Background and Aims: Liver diseases are associated with significant morbidity and health– related expenditure. Although cost-effective treatments are available, the disease is often asymptomatic until late in its course. ‘‘Medex Test,’’ is the noninvasive detection of liver abnormalities by the measurement of changes in electrical impedance of dermal zones. This method is based on neuroreflexology, a branch of complementary medicine. This study addressed 2 questions: can Medex Test detect liver disease, and can it measure the severity of a known liver disease. Methods: This blinded case-control study included 2 parts. First, 113 patients with a known liver disease (hepatitis C, hepatitis B, and nonalcoholic fatty liver disease) and 85 controls with no known liver disease were evaluated by the Medex Test device. Second, necroinflammatory grading of biopsy results of 60 patients with chronic hepatitis C were compared with grade determined by Medex Test. Results: Medex Test detected with high sensitivity (85%) and specificity (94.1%) the presence of liver disorders. The high rates were similar for the different disorders and were independent of age and sex. Additionally, Medex Test matched the biopsy pathologic grading of necroinflammation in 78% of patients. Positive predictive value was not affected by age and sex and was better for higher degree of necroinflammation. Conclusions: This pilot study demonstrated that Medex Test detects with high accuracy the presence of liver disorders and the necroinflammatory grade. This noninvasive, low cost test may in the future become an important tool in the diagnosis and management of liver disorders. We believe the further study of this novel method is warranted.

Background and Aims: Acute hepatitis C virus infection in the era of universal screening of blood products has not disappeared, and is thought to be transmitted primarily via injecting drug use. A growing body of evidence supports iatrogenic transmission as an important mode of transmission. The aim of this study was to examine transmission routes and clinical characteristics in a group of patients with acute hepatitis C in Israel. Methods: A retrospective chart review was conducted in three different liver clinics in Israel, of all new hepatitis C patients. Patients identified as possible acute hepatitis C were re-interviewed and all other sources such as blood bank records and pre-employment check-ups reviewed in order to establish the diagnosis of acute hepatitis C infection and to identify the transmission route. Results: Twenty-nine patients were found to have acute hepatitis C, representing 0.75% of all new referrals for hepatitis C. The most frequent (65%) mode of transmission was iatrogenic involving several, often minimal, procedures and clinical settings. The group in which iatrogenic transmission was suspected was older and the patients more often in monogamous relationship compared with other transmission routes groups. Injecting drug use was the second most common route of infection. Spontaneous seroconversion has occurred in approximately one third of the patients. Conclusions: Acute hepatitis C in the post universal blood products screening era was found to be predominantly an iatrogenic disease in the investigated localities. This finding should direct attention and resources towards the development and implementation of preventive measures.

The evaluation and follow up of liver fibrosis and cirrhosis have been traditionally performed by liver biopsy. However, during the last 20 years, it has become evident that this “gold-standard” is imperfect; even according to its proponents, it is only “the best” among available methods. Attempts at uncovering non-invasive diagnostic tools have yielded multiple scores, formulae, and imaging modalities. All are better tolerated, safer, more acceptable to the patient, and can be repeated essentially as often as required. Most are much less expensive than liver biopsy. Consequently, their use is growing, and in some countries the number of biopsies performed, at least for routine evaluation of hepatitis B and C, has declined sharply. However, the accuracy and diagnostic value of most, if not all, of these methods remains controversial. In this review for the practicing physician, we analyze established and novel biomarkers and physical techniques. We may be witnessing in recent years the beginning of the end of the first phase for the development of non-invasive markers. Early evidence suggests that they might be at least as good as liver biopsy. Novel experimental markers and imaging techniques could produce a dramatic change in diagnosis in the near future.

We present three patients in whom there was an acute presentation of malabsorption in the puerperium and in whom the final diagnosis was celiac sprue. The reason for the dramatic increase in the symptoms after delivery, as well as the absence of symptoms before this, is unclear but may be related to immunologic changes that occur during pregnancy.

Background & Aims: Few controlled studies have addressed the issue of effective medical treatment for nonalcoholic fatty liver disease (NAFLD). We herein assessed the effect of orlistat in patients with NAFLD. Methods: We performed a randomized, double-blind, placebo-controlled study on 52 patients with NAFLD diagnosed by ultrasound (US) and confirmed by liver biopsy (40 patients). The patients were randomized to receive either orlistat (120 mg 3 times daily for 6 months) or placebo. All patients participated in an identical behavioral weight loss program. All patients underwent monthly evaluation by abdominal US; liver enzyme levels, lipid profiles, insulin levels, and anthropometric parameters were monitored, and all patients underwent nutritional follow-up evaluation. Twenty-two patients underwent a second liver biopsy examination at the end of the study. Results: Fifty-two patients were recruited and 44 (mean age, 47.7 y; mean body mass index, 33) completed the study. Serum glucose and insulin levels (P < .03) were significantly higher in the orlistat group, which also presented a higher degree of fibrosis. Body mass index was reduced significantly in each group, with a nonsignificant difference between the groups. Serum alanine transaminase (ALT) levels decreased significantly in both groups, with an almost 2-fold reduction in the orlistat group (48% vs 26.4%). There was a statistically significant reversal of fatty liver by US only in the orlistat group (P < .05). Conclusions: Orlistat improves serum ALT levels and steatosis on US in NAFLD patients, beyond its effect on weight reduction.

Objective: Previous studies have demonstrated that CYP2D6 polymorphism is associated with liver cirrhosis. The aim of the present study was to find out whether CYP2D6 n 4, the poor metabolizer allele can predict fibrosis progression rate. Methods: Seventy-five Caucasian patients with chronic hepatitis C infection were recruited. They were divided into two groups, 'fast fibrosers' and 'slow fibrosers', according to Poynard's fibrosis progression curves. Sixty-two patients underwent liver biopsy. Twenty healthy neonates were included as control population. DNA was extracted from peripheral blood and CYP2D6 n 4 was tested by polymer chain reaction using fluorescent hybridization probes in a lightCycler instrument. Results: Forty-two patients were classified as 'fast fibrosers' and 33 patients as 'slow fibrosers'. The frequency of CYP2D6 n 4 allele in the 'fast fibrosers' (34.5%) was significantly higher compared with the 'slow fibrosers' (15%) (P- value 5 0.007). There was no significant difference between the frequency of CYP2D6 n 4 in the 'slow fibrosers' (15%) compared with the controls (12.5%). Carrier state of CYP2D6 n 4 was the only covariate that was significantly positively correlated with fast progression to cirrhosis (odds ratio 5 6.5, P 5 0.01). Conclusion: This study indicates for the first time that CYP2D6 genotype might be a significant predictor of liver fibrosis progression rate in chronic hepatitis C patients.

Background & AimsWe investigated the effects of the fatty acid–bile acid conjugate 3β-arachidyl-amido, 7α-12α-dihydroxy, 5β-cholan-24-oic acid (Aramchol; Trima Israel Pharmaceutical Products Ltd, Maabarot, Israel) in a phase 2 trial of patients with nonalcoholic fatty liver disease (NAFLD).MethodsWe performed a randomized, double-blind, placebo-controlled trial of 60 patients with biopsy-confirmed NAFLD (6 with nonalcoholic steatohepatitis) at 10 centers in Israel. Patients were given Aramchol (100 or 300 mg) or placebo once daily for 3 months (n = 20/group). The main end point was the difference between groups in the change in liver fat content according to magnetic resonance spectroscopy. The secondary end points focused on the differences between groups in alterations of liver enzyme levels, levels of adiponectin, homeostasis model assessment scores, and endothelial function.ResultsNo serious or drug-related adverse events were observed in the 58 patients who completed the study. Over 3 months, liver fat content decreased by 12.57% ± 22.14% in patients given 300 mg/day Aramchol, but increased by 6.39% ± 36.27% in the placebo group (P = .02 for the difference between groups, adjusted for age, sex, and body mass index). Liver fat content decreased in the 100-mg Aramchol group, by 2.89% ± 28.22%, but this change was nonsignificant (P = .35), indicating a dose–response relationship (P for trend = .01). Groups given Aramchol had nonsignificant improvements over time in endothelial function and levels of alanine aminotransferase and adiponectin, but homeostasis model assessment scores did not change. The appropriateness of a single daily dose was confirmed by pharmacokinetic analysis.ConclusionsThree months' administration of the fatty acid–bile acid conjugate Aramchol is safe, tolerable, and significantly reduces liver fat content in patients with NAFLD. The reduction in liver fat content occurred in a dose-dependent manner and was associated with a trend of metabolic improvements, indicating that Aramchol might be used for the treatment of fatty liver disease. ClinicalTrials.gov number: NCT01094158.

Conventional hepatitis B vaccines do not elicit adequate antibody production in 5-10% vaccinees. This trial tests the ability of a third-generation vaccine, containing PreS1 and PreS2 antigens in addition to the S antigen, to elicit seroprotective titres in documented non- and low-responders, compared with those to a conventional vaccine. In the primary population of non-responders (10 IU/l anti-HBs antibodies afteror = 4 previous injections of conventional vaccine) an enhanced antibody response was seen to additional injections of the third-generation vaccine compared with a conventional vaccine (absolute difference 14.9%; P = 0.006). Enhanced antibody responses were also found in a population that included low responders.

Background/Aims The aim of this study was to increase virologic response rates by individualized treatment according to the early virologic response. Methods Serum HCV-RNA was frequently quantified in patients with chronic hepatitis C ( n =270) treated with peginterferon alfa-2a (180μg/week) and ribavirin (1000–1200mg/day). After 6 weeks patients were classified as rapid (RVR), slow (SPR), flat (FPR), or null responders (NUR) and randomized within each viral kinetic class to continue therapy either with an individualized or standard regimen. Individualized therapy comprised peginterferon monotherapy (48 weeks) or shorter combination therapy (24 weeks) for RVR, triple therapy with histamine (1mg/day) (48 weeks) or prolonged combination therapy (72 weeks) for SPR, triple therapy for FPR, and high-dose peginterferon (360μg/week) plus ribavirin for NUR patients. Results Patients were categorized as RVR ( n =171), SPR ( n =65), FPR ( n =10), or NUR ( n =22). Overall end-of-treatment and sustained virologic response rates were 77 and 60% in the individualized and 77 and 66% in the standard treatment arm, respectively. Histamine in addition to peginterferon and ribavirin and high-dose peginterferon plus ribavirin did not improve virologic response rates in patients with FPR and NUR, respectively. Conclusions An improvement in virologic efficacy was not achieved with the available individualized treatment options.

Background: Experience with lamivudine treatment of immunocompetent patients with acute hepatitis B is limited. Aim of study: To evaluate the safety and efficacy of lamivudine for the treatment of acute severe hepatitis B virus (HBV) infection in immunocompetent adults. Patients and Methods: Fifteen patients (10 men, 5 women, mean age 34.3±7.3 years) with severe acute HBV infection were treated with lamivudine 100 mg daily for 3–6 months, starting 3–12 weeks after onset of infection. Prior to treatment, 5 patients had grade 1–4 encephalopathy; all patients had severe coagulopathy (mean INR was 4.5±6.4), and all patients had evidence of severe hepatocyte lysis (mean alanine aminotransferase 3738±1659 U/L, and mean total serum bilirubin 18±6.8 mg/dl). All patients had evidence of highly replicative HBV (mean HBV DNA 13.5 × 106±11 × 106 copies/ml). Results: Thirteen patients (86.6%) responded to treatment. Encephalopathy disappeared within 3 days of treatment and coagulopathy improved within 1 week. Serum HBV DNA was undetectable (by polymerase chain reaction) within 4 weeks, and serum liver enzyme levels normalized within 8 weeks. Two patients in whom lamivudine therapy was delayed developed fulminant hepatitis and underwent urgent liver transplantation. (One died of vascular complications 1 month later). The 11 patients who were serum HBeAg-positive before treatment seroconverted, and HBeAb developed within 12 weeks in 9 of them; HBsAg was undetectable in all 11 tested patients, and protective titer of HBsAb developed within 12–16 weeks in 9 of them. Therapy was well tolerated in all cases. Conclusions: These data indicate that lamivudine induces a prompt clinical, biochemical, serological and virological response in immunocompetent patients with de novo HBV infection. Lamivudine may prevent the progression of severe acute disease to fulminant or chronic hepatitis and should be considered for use in selected patients. A large randomized controlled, double-blind prospective study is needed.