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Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL ) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants., Competing Interests: The authors declare no conflict of interest.

Objectives: The objectives of this study were to describe the clinical findings, treatment and outcomes of six dogs with presumed idiopathic chronic hepatitis treated with mycophenolate mofetil (MMF)., Materials and Methods: Medical records were retrospectively searched to identify dogs in which idiopathic chronic hepatitis was diagnosed on histopathology between January 2010 and June 2022 that were treated with MMF for at least two weeks with >2 follow-up examinations. Data recorded from each dog included signalment, clinical signs, diagnostic test results and treatment., Results: Six dogs were treated with MMF at a median initial dosage of 9.6 mg/kg PO q 12 h. Reported adverse effects from MMF included decreased appetite, vomiting and diarrhoea. In all six dogs, MMF was used successfully long term for the treatment of idiopathic chronic hepatitis as determined by 46% or greater improvement of alanine aminotransferase (ALT) between 4 and 18 weeks of starting MMF. Three dogs were also temporarily treated for 4-6 months on a tapering dose of prednisone. In two dogs, ALT remained within the reference interval, and in one dog, it was very mildly elevated when on MMF alone. In all six dogs, owners reported that the medication was well tolerated., Clinical Significance: To the authors' knowledge, this is the first report describing the use of MMF with and without a tapering dose of prednisone for the treatment of idiopathic chronic hepatitis in six dogs. Based on the outcomes of the dogs in this report, MMF can be effective for the long-term treatment of idiopathic chronic hepatitis as measured by reduction in ALT and improvement of clinical signs., (© 2023 The Authors. Veterinary Medicine and Science published by John Wiley & Sons Ltd.)

Background & Aims: Bulevirtide (BLV) is a HDV/HBV entry inhibitor that is associated with virologic response (responders, HDV-RNA undetectable or ≥2 log 10 IU/ml decrease from baseline) in >50% of patients after a 24-week treatment. However, some patients only achieve a <1 log 10 IU/ml decline in HDV-RNA after the 24-week treatment (non-responders). Here, we report a viral resistance analysis in participants receiving BLV monotherapy who were non-responders or experienced virologic breakthrough (VB, i.e., two consecutive increases in HDV-RNA of ≥1 log 10 IU/ml from nadir or two consecutive HDV-RNA detectable results if previously undetectable) from the phase II MYR202 and phase III MYR301 study., Methods: Deep-sequencing of the BLV-corresponding region in HBV PreS1 and of the HDV HDAg gene, as well as in vitro phenotypic testing, were performed for the participant with VB (n = 1) and non-responders (n = 20) at baseline (BL) and Week 24 (WK24)., Results: No amino acid exchanges associated with reduced susceptibility to BLV within the BLV-corresponding region or within HDAg were identified in isolates from any of the 21 participants at BL or at WK24. Although variants (HBV n = 1; HDV n = 13) were detected at BL in some non-responders or in the participant with VB, none were associated with reduced sensitivity to BLV in vitro. Furthermore, the same variant was detected in virologic responders. A comprehensive phenotypic analysis demonstrated that the BLV EC 50 values from 116 BL samples were similar across non-responders, partial responders (HDV RNA decline ≥1 but <2 log 10 IU/ml), and responders regardless of the presence of HBV and/or HDV polymorphisms., Conclusions: No amino acid substitutions associated with reduced sensitivity to BLV monotherapy were detected at BL or WK24 in non-responders or the participant with VB after 24-week BLV treatment., Impact and Implications: This is the first study investigating the development of resistance in patients treated with BLV. Excluding resistance to BLV as an explanation for an insufficient decrease in HDV-RNA levels during BLV therapy is an important finding for patients, clinicians, and researchers. It demonstrates that BLV has a high barrier to resistance, indicating it is safe and suitable for long-term treatment, although long-term surveillance for resistance should be performed. Our results hint at other still unknown mechanisms as an explanation for the persistence of serum HDV-RNA during inhibition of viral entry., Clinical Trial Numbers: NCT03546621 and NCT03852719., Competing Interests: Conflicts of interest JH reports no conflict of interest. YL, SX, SC, RM, SM, TA, BH, TY, LM, DH, AS, JF, DM, VS, CR, RM, EM, TC, and HM are employees and stockholders of Gilead Sciences. TA, PL, HW, and SO are consultants for Gilead Sciences. SU is co-applicant and co-inventor on patents protecting Hepcludex (Bulevirtide/Hepcludex) and consultant for Gilead Sciences. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Hepatitis type E virus (HEV) is one of the main causes of acute hepatitis globally and has thus gained attention as a public health issue. The diverse clinical manifestations of hepatitis type E are typically acute and self-limiting with mild symptoms, but populations with underlying liver disease or immunocompromised patients can have severe and chronic symptoms. Severity and chronicity can arise and manifest as fulminant hepatitis, chronic hepatitis, or even hepatic failure. HEV infection-induced hepatic failure (acute-on-chronic liver failure), based on the different backgrounds of chronic liver disease, is a clinical phenotype of severe HEV infection that requires attention. In addition, HEV infection can exhibit extrahepatic clinical manifestations of multi-system and organ involvement like neurological diseases (Guillain-Barré syndrome), renal diseases (membranous/membranous proliferative glomerulonephritis, cryoglobulinemia), and blood diseases (thrombocytopenia). At home or abroad, there are no antiviral drugs approved, particularly for HE treatment. Since most acute HE can resolve spontaneously, no special treatment is required clinically. However, in patients with severe or chronic HE, ribavirin (RBV) monotherapy and/or pegylated interferon-combination therapy have achieved certain antiviral effects. Combined small-molecule drugs and RBV have been attempted to treat HEV, but high-level evidence-based treatment is still lacking. Thus, new, highly effective anti-HEV drugs are clinical priorities to address these concerns. Severe and chronic HEV infections' clinical phenotype, early detection, mechanism, intervention, and outcome need additional study.

Chronic hepatitis Delta (CHD) is a rare and severe form of chronic viral hepatitis. Until recently, the only therapeutic approach has been the off-label use of a 48 weeks course of PegInterferon alpha (PegIFNα), that was characterized by suboptimal efficacy and burdened by significant side effects that limited treatment applicability in patients with advanced liver disease. In July 2020, European Medicines Agency (EMA) conditionally approved the entry inhibitor Bulevirtde (BLV) at the dose of 2 mg/day for the treatment of adult patients with compensated CHD. Efficacy and safety of BLV in CHD have been evaluated in clinical trials either as monotherapy or in combination with PegIFNα. These results were confirmed by real-life studies, which also evaluated long-term BLV monotherapy in patients with advanced compensated cirrhosis. Notwithstanding these promising results there are still several issues to be addressed, such as the optimal duration of the treatment, the rates of off-therapy responses, as well as the long-term clinical benefits. This review summarizes updated and current literature data about clinical trials and real-life studies with BLV monotherapy and/or in combination with PegIFNα., (© 2023 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Hepatitis E virus (HEV) is the most prevalent hepatitis virus worldwide. Genotypes 3 (HEV3) and 4 (HEV4) as well as rat HEV can lead to chronic hepatitis E and cirrhosis in immunosuppressed patients. Within the last decade, several options for treating chronic hepatitis have been developed and have achieved a sustained virological response. However, there are still unmet needs such as optimizing immunosuppression to allow HEV clearance with or without ribavirin, as well as alternative therapies to ribavirin that are discussed in this paper.

Background: Currently, there is little evidence about the outcome of two-stage exchange arthroplasty for the treatment of knee periprosthetic joint infection (PJI) in patients with chronic viral hepatitis. To evaluate it, we set the primary outcome as infection recurrence, and the secondary outcome as the difference between patients diagnosed with hepatitis B virus or hepatitis C virus., Patients and Methods: Between June, 2010 and December, 2016, 172 patients with knee PJIs were treated with two-stage exchange arthroplasty at our institute. Treatment success was defined using Delphi-based consensus. These patients were further divided into groups with or without chronic hepatitis. Variables were analyzed, including age, sex, comorbidities, microbiology, and operative methods. Minimum follow-up was 12 months (mean, 35 months; range, 12-85 months)., Results: Of the 172 knee PJI patients, 25 were identified with chronic hepatitis. The infection recurrence rate in the hepatitis group (28%, 7 in 25) was significantly higher than that in the non-hepatitis group (9.5%, 14 in 147), p = 0.017. However, there was no significant difference in the infection recurrence rates between patients with HBV (24%, 4 in 16) and HCV (33.3%, 3 in 9). Regarding the outcomes of patients with infection recurrence, 4 of the non-hepatitis patients were treated with the debridement, antibiotic treatment, irrigation, and retention of prosthesis (DAIR) procedure, with a success rate of 75%. The other 17 patients (7 with hepatitis and 10 without) were treated with repeated two-stage exchange arthroplasty with 100% infection elimination rate until the final follow-up., Conclusions: Knee PJI patients with chronic hepatitis have higher infection recurrence rate after two-stage exchange arthroplasty (28%).

The management of viral hepatitis in the setting of pregnancy requires special consideration. There are five liver-specific viruses (hepatitis A, B, C, D, E), each with unique epidemiology, tendency to chronicity, risk of liver complications and response to antiviral therapies. In the setting of pregnancy, the liver health of the mother, the influence of pregnancy on the clinical course of the viral infection and the effect of the virus or liver disease on the developing infant must be considered. Although all hepatitis viruses can harm the mother and the child, the greatest risk to maternal health and subsequently the fetus is seen with acute hepatitis A virus or hepatitis E virus infection during pregnancy. By contrast, the primary risks for hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus are related to the severity of the underlying liver disease in the mother and the risk of mother-to-child transmission (MTCT) for HBV and HCV. The prevention of MTCT is key to reducing the global burden of chronic viral hepatitis, and prevention strategies must take into consideration local health-care and socioeconomic challenges. This Review presents the epidemiology of acute and chronic viral hepatitis infection in pregnancy, the effect of pregnancy on the course of viral infection and, conversely, the influence of the viral infection on maternal and infant outcomes, including MTCT.

The Nobel Prize for Physiology or Medicine, in the year 2020, has been awarded to three scientists, Harvey Alter, Michael Houghton, and Charles Rice, for jointly discovering the hepatitis C virus (HCV). This remarkable achievement is a huge breakthrough in the fight against hepatitis C. Most importantly, their pioneering works have successfully saved millions of lives by acting as the foundation for sensitive blood tests and effective antivirals. Inspired by the 2020 Nobel Prize winners, this review article honors their great efforts and discusses several unmet needs in the path toward HCV elimination. In Taiwan, we adopted a micro-elimination approach plus patient-centric outreach program to tackle the obstacles that stand in the way of HCV elimination. With its significant results, HCV elimination could be achieved in the near future., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG-interferon alpha-2a (PEG-IFNα-2a) is the only effective treatment but its long-term clinical impact is unclear. The aim of this study was to investigate the long-term outcome after 48 weeks of pegylated interferon alpha-2a therapy. We performed a retrospective follow-up study of the Hep-Net-International-Delta-Hepatitis-Intervention-Study 1 (HIDIT-I trial). Patients had received 48 weeks of treatment with either PEG-IFNα-2a plus adefovir dipivoxil (ADV) (Group I), PEG-IFNα-2a alone (Group II) or adefovir dipivoxil alone (Group III). Liver-related complications were defined as liver-related death, liver transplantation, liver cancer and hepatic decompensation defined as development of Child-Pugh scores B or C or an increase in Model for End-stage Liver Disease (MELD) scores of five or more points in relation to baseline values. Patients were considered for further analysis when they were retreated with PEG-IFNα-2a. Follow-up data (at least 1 visit beyond post-treatment week 24) were available for 60 patients [Group I, (n = 19), Group II (n = 20), Group III (n = 21)]. Mean time of follow-up was 8.9 (1.6 - 13.4) years. 19 patients were retreated with IFN-based therapy: 42% (n = 8) in PEG-IFNα-2a arms and 58% (n = 11) in the adefovir only arm. Clinical complications on long-term follow-up occurred in 17 patients and were associated with nonresponse to therapy and baseline cirrhosis. The annual event-free survival rate in patients with cirrhosis vs noncirrhotic patients at year 5 and 10 was 70% vs 91% and 35% vs 76%. Long-term follow-up of a large randomized clinical trial suggests that off-treatment HDV RNA response to PEG-IFNα-2a treatment leads to improved clinical long-term outcome., (© 2020 John Wiley & Sons Ltd.)

The hepatitis E virus (HEV) is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s. Globally, it is one of the most frequent causes of acute viral hepatitis. The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus. Among the eight different genotypes identified to date, HEV genotype 1 (HEV1), HEV2, HEV3, and HEV4 are the most frequent genotypes causing infections in humans. HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies. They are also responsible for severe hepatitis in pregnant patients and infants. In contrast, HEV3 and HEV4 are zoonotic, and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals. Their main reservoir is the pig, and they are mostly encountered in developed countries. The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women, infants, older people, immunocompromised individuals, patients with underlying chronic liver diseases, and workers that come into close contact with HEV-infected animals. In the clinical perspective, HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis, acute-on-chronic liver disease, chronic hepatitis, cirrhosis, and liver failure. Although HEV mainly results in acute self-limiting infection, chronic HEV infection may occur among immunocompromised patients ( e.g ., solid-organ transplant recipients). Additionally, HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade, although the causal link for many of them still needs to be proven. Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success. However, ribavirin is contraindicated in pregnant patients, and interferon-alpha cannot be used in most transplant recipients. Therefore, there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirin-resistant HEV. In this review article, a literature search using PubMed and MEDLINE databases was performed, up to March 2020. Only the articles published in English were reviewed., Competing Interests: Conflict-of-interest statement: All authors have no conflicts of interest to be stated., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

The SARS-CoV-2 pandemic has proven to be a serious challenge for the Spanish healthcare system. The impact of the virus on the liver is not well known, but in patients with chronic liver disease, mostly in advanced stages, it can critically compromise survival and trigger decompensation. Treatment in this subpopulation is complex due to the potential hepatotoxicity of some of the medicinal products used. Moreover, the pandemic has also negatively impacted patients with liver disease who have not contracted COVID-19, since the reallocation of human and material resources to the care of patients with the virus has resulted in a decrease in the treatment, diagnosis and follow-up of patients with liver disease, which will surely have negative consequences in the near future. Efficient reorganization of hepatology units is a priority to minimise the impact of the pandemic on a population as vulnerable as liver disease patients., (Copyright © 2020 Elsevier España, S.L.U. All rights reserved.)

Background: Hepatitis E virus (HEV) may be resistant to immunosuppression reduction and ribavirin treatment in kidney transplant recipients because of mutant strains and severe side effects of ribavirin which conduct to dose reduction. Sofosbuvir efficacy is controversial. Peg-interferon 2 alpha (PEG-IFN) is currently contraindicated due to a high risk of acute humoral and cellular rejection. The present study assessed, for the first time, the effect of PEG-IFN in a kidney transplant recipient infected with HEV., Case Presentation: The patient had chronic active HEV that was resistant to immunosuppression reduction and optimal ribavirin treatment. He developed significant liver fibrosis. PEG-IFN was administered for 10 months, and it was well tolerated and did not induce rejection. A sustained virological response was obtained., Conclusions: We conclude that prolonged treatment with PEG-IFN in kidney transplant recipients infected with HEV could be considered as a salvage option.

Background: English springer spaniels (ESS) show an increased risk of chronic hepatitis (CH). In a previous study of 68 ESS with CH, in which only one dog received corticosteroids, a median survival time of 189 days was noted. Some ESS with CH appear to improve with prednisolone treatment; therefore, we aimed to investigate the response to prednisolone in this breed., Participants: ESS with histologically confirmed idiopathic CH were treated with prednisolone 1-2 mg/kg/day. Nine female and three male ESS were enrolled (median age at diagnosis of five years). Patients were monitored clinically and had biochemistry samples taken to assess markers of hepatocellular damage and function., Results: The mean starting dose of prednisolone was 1.1 mg/kg/day. All symptomatic patients showed an initial clinical improvement. Two cases were euthanased while receiving prednisolone. The median time since diagnosis is 1715 days (range: 672-2105 days) and the remaining patients are clinically well, with seven patients still receiving a mean dose of 0.4 mg/kg prednisolone every other day. Statistical analysis demonstrated significant (P<0.05) reductions in serum alkaline phosphatase, alanine aminotransferase and bilirubin following 2-4 weeks of prednisolone treatment., Conclusion: This study demonstrates improved clinical and biochemical parameters when some ESS with CH are managed with prednisolone and standard supportive treatments., Competing Interests: Competing interests: None declared., (© British Veterinary Association 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Hepatitis C virus (HCV) infection is associated with increased cardiovascular risk. We evaluated effects of direct-acting antiviral agents (DAAs) on flow-mediated dilation (FMD), a recognized marker of cardiovascular risk. We evaluated FMD and post-ischemic hyperemia (PIH) in consecutive HCV out-patients before starting DAAs, at the end of treatment (T eot ) and 12 weeks thereafter. In 22 HCV subjects (age 64.0 years), baseline FMD was 4.52% ± 1.90 and PIH of 5814.4 (IQR 3786.9-7861.9). At (T eot ), all patients showed undetectable levels of HCV-RNA and FMD changed from 4.52% ± 1.90 to 9.39% ± 4.06 (p < 0.001), with a direct correlation between changes in FMD and baseline HCV-RNA levels (r = 0.494, p = 0.020). In parallel, PIH increased from 5814.4 (IQR 3786.9-7861.9) to 7277.6 (IQR 4579.8-10388.8) (p = 0.019). Twelve weeks after T eot , all patients had persistently negative HCV-RNA, FMD was 10.9% ± 4.65 and PIH was 10930.3 (IQR 6254.6-18248.2) suggesting a further significant improvement in these parameters. Results remained significant regardless of the presence of cardiovascular risk factors, whereas FMD changes were not statistically significant in subjects with cirrhosis. A persistent and significant improvement in endothelial function is observed in HCV patients obtaining viral eradication with DAAs treatment. This might suggest a beneficial effect of DAAs treatment on cardiovascular risk profile of HCV patients.

Hepatitis E virus (HEV) infection is an emerging disease in industrialized countries which is usually characterized by a self-limited course. However, there is an increased risk of HEV persistence in immunocompromised risk populations, comprising patients following solid organ transplantation or hematological malignancies. Recently, chronic HEV infection following rituximab-containing treatment regimens has been described. Here we report five patients with chronic hepatitis E after prior rituximab therapy for various indications. We determined the immunological characteristics of these patients and analyzed the development of ribavirin (RBV) treatment failure-associated mutations in the HEV genome. One patient became chronically HEV-infected 110 months after administration of rituximab (RTX). Immunological characterization revealed that all patients exhibited significant hypogammaglobulinemia and CD4+ T cell lymphopenia. One patient permanently cleared HEV following weight-based ribavirin treatment while three patients failed to reach a sustained virological response. In depth mutational analysis confirmed the presence of specific mutations associated with RBV treatment failure in these patients. Our cases indicate that rituximab-containing treatment regimens might imply a relevant risk for persistent HEV infection even years after the last rituximab application. Moreover, we provide further evidence to prior observations suggesting that chronically HEV infected patients following RTX-containing treatment regimens might be difficult to treat.

A 69-year-old man was referred to our department with acute hepatitis. He had been newly treated with benidipine hydrochloride for two months. His blood test results were as follows: aspartate aminotransferase, 1,614 IU/L; alanine aminotransferase, 1,091 IU/L and anti-smooth muscle antibody, ×80. Needle liver biopsy specimen showed interface hepatitis with mainly lymphocytic infiltration and bridging fibrosis in the periportal area. Immunohistochemistry revealed lymphocytic infiltration positive for IgG4. We diagnosed him with IgG4-related AIH with an etiology that was suspected of being drug-induced. Oral prednisolone was started and then tapered after achieving biochemical remission. Hepatitis recurred after the cessation of steroids; however, remission was achieved with ursodeoxycholic acid.

Background: The etiology of idiopathic chronic hepatitis (ICH) in dogs is poorly understood, but evidence supports an immune-mediated pathogenesis in some dogs., Objectives: To describe a case series of dogs with presumed ICH treated with cyclosporine (CsA) with or without concurrent medications and to document the incidence of biochemical remission and factors associated with failure to attain remission., Animals: Forty-eight client-owned dogs diagnosed with presumed ICH, treatment of which included CsA., Methods: Two-institution, retrospective case series of dogs between 2010 and 2017. All dogs were treated with CsA with or without concurrent medications for ≥2 weeks. Data were collected from medical records., Results: Biochemical remission (<1.1 times the upper limit of normal for alanine aminotransferase activity) was attained in 79% of dogs (38/48). Median dose of CsA at remission was 7.9 mg/kg/d (range, 2.5-12.7 mg/kg/d) and median time to remission was 2.5 months (range, 0.75-18 months). Concurrent hepatoprotectant treatment was not associated with likelihood of remission. Clinical score, ascites, hypoalbuminemia, hyperbilirubinemia, prolonged coagulation times, dose, and duration of treatment were not associated with the probability of remission or time to remission. Common adverse effects of CsA were gastrointestinal signs in 38% (18/48) and gingival hyperplasia in 25% (12/48) of treated dogs., Conclusion and Clinical Importance: A treatment regimen including CsA and frequent hepatoprotectant use resulted in biochemical remission of ICH in most dogs. None of the evaluated factors, including hepatoprotectant use, were significantly associated with likelihood of remission. Future prospective studies are indicated to evaluate CsA monotherapy in ICH dogs., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: Hepatitis E virus (HEV) infection is now recognized as a major cause of acute hepatitis worldwide. HEV specific antibodies develop shortly after infection and are thought to confer protection., Case Presentation: We report an immunocompromised patient who developed chronic HEV infection despite the presence of high level antibodies. HEV infection was detected using RT-PCR upon diagnostic evaluation due to increased liver enzymes. Upon retrospective analysis of stored serum samples we found that the patient was HEV RNA positive since 7 months. Chronic HEV infection was successfully treated with ribavirin., Conclusions: In conclusion, the patient suffered from a chronic course of HEV infection, which was successfully treated with ribavirin. Our case underlines the importance of RT-PCR for HEV diagnostics in immunosuppressed patients and supports the notion that HEV antibodies do not confer universal protection. Counseling patients at risk for chronic HEV infection seems advisable. The role of the humoral and T-cell mediated immune response in cases of HEV reinfection deserves further study.

Hepatitis E virus (HEV) infection causes chronic hepatitis in solid organ transplant (SOT) recipients. Antiviral therapy consists of three months of ribavirin, although response rates are not optimal. We characterized plasma HEV kinetic patterns in 41 SOT patients during ribavirin therapy. After a median pharmacological delay of three (range: 0-21) days, plasma HEV declined from a median baseline level of 6.12 (3.53-7.45) log copies/mL in four viral kinetic patterns: (i) monophasic ( n = 18), (ii) biphasic ( n = 13), (iii) triphasic ( n = 8), and (iv) flat-partial response ( n = 2). The mean plasma HEV half-life was estimated to be 2.0 ± 0.96 days. Twenty-five patients (61%) had a sustained virological response (SVR) 24 weeks after completion of therapy. Viral kinetic patterns (i)-(iii) were not associated with baseline characteristics or outcome of therapy. A flat-partial response was associated with treatment failure. All patients with a log concentration decrease of plasma HEV at day seven of >15% from baseline achieved SVR. In conclusion, viral kinetic modeling of plasma HEV under ribavirin therapy showed, for the first time, four distinct kinetic profiles, a median pharmacologic delay of three days, and an estimated HEV half-life of two days. Viral kinetic patterns were not associated with response to therapy, with the exception of a flat-partial response.

Background: Copper-associated hepatopathy (CAH) is a common cause of liver disease in dogs. Although d-penicillamine can be an effective treatment, some dogs fail treatment or develop adverse effects. Ammonium tetrathiomolybdate (TTM) has been used to treat pathologic copper accumulation in other species, but its therapeutic potential for CAH is unknown., Objectives: To investigate short-term safety and efficacy of TTM for treatment of CAH., Animals: Ten dogs with CAH., Methods: Prospective study. All dogs were treated with TTM PO for 6 weeks, and hepatic biopsies were performed after the treatment course. Dog experiencing initial decreases in hepatic copper concentrations ([Cu] H ) received 6 additional weeks of TTM treatment and underwent 1 additional biopsy. Physical and laboratory examinations were performed every 2 weeks for study duration., Results: Eight of 10 dogs had decreases in [Cu] H . Compared to baseline (median, 1606 μg/g; range, 572-5158 μg/g), [Cu] H were decreased at 6 weeks (1033 μg/g, 450-2975 μg/g; P = .04) and 12 weeks (931 μg/g, 218-1677 μg/g; P = .02). Hepatic molybdenum concentrations increased >50-fold (P < 0.001). Changes in histologic scores and hematologic and biochemical test results were variable and not significantly different from baseline. One dog developed presumed immune-mediated anemia and thrombocytopenia, but it was unclear if this was related to TTM administration., Conclusions and Clinical Importance: Results suggest that TTM can effectively decrease [Cu] H in some dogs with CAH. Larger studies are needed to determine the overall safety and efficacy of TTM for treating CAH and how it compares with current treatments., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Glycyrrhizin is used to treat chronic hepatitis, but it also plays an important role in pseudoaldosteronism. Multidrug resistance-associated protein 2 is important for glycyrrhizin excretion. Dysfunction of this transporter increases the serum levels of direct bilirubin, glycyrrhizin and its metabolites. Hence, elevated direct-bilirubin levels could predict the risk of pseudoaldosteronism. This study aimed to evaluate the relationship between elevated direct-bilirubin levels and hypokalaemia, which is the most sensitive marker of pseudoaldosteronism. This retrospective cohort study was conducted in a Japanese university hospital. The occurrence of hypokalaemia is defined as a serum potassium level of ≤3.5 mEq/L after the administration of a glycyrrhizin-containing medication, and a further decline of ≥0.5 mEq/L or an increase of ≥0.5 mEq/L after discontinuing the glycyrrhizin-containing medication was examined in patients with chronic hepatitis between January 2009 and December 2015. This analysis involved 1392 patients, including 596 women. Hepatitis C virus infections were the most common cause of chronic hepatitis in this study. Seventy-nine patients received glycyrrhizin (exposed group; mean age: 60.5 ± 14.2) and 1313 did not receive glycyrrhizin (control group; mean age: 58.3 ± 15.8 years). Synergistic effects of glycyrrhizin-containing medications and elevated direct-bilirubin levels were associated with hypokalaemia. Elevated direct-bilirubin levels and hypoalbuminaemia were associated with hypokalaemia in the exposed group. Older age, female sex, high daily glycyrrhizin dosage, longer duration of glycyrrhizin intake, and potassium-lowering medications were not associated with hypokalaemia after the model adjustment. Elevated direct-bilirubin levels and hypoalbuminaemia may predict pseudoaldosteronism caused by glycyrrhizin., (© 2018 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Hepatitis E virus (HEV) has traditionally been associated with an acute, self-limiting hepatitis and is not known to have any chronic sequelae. HEV genotypes 1 and 2, which are human pathogens, have been associated with this self-limiting presentation, in both sporadic and epidemic settings. HEV genotype 3, which is zoonotically transmitted, is increasingly being reported as a cause of chronic infection in immunocompromised patients. These include patients with solid organ transplants, patients receiving chemotherapy for haematologic malignancies and patients infected with HIV. Chronic infection is associated with rapidly progressing liver disease and extrahepatic manifestations including neurologic disorders. We review the clinical manifestations of chronic HEV infection and discuss factors determining persistence and chronicity of HEV., (© 2019 John Wiley & Sons Ltd.)

This study aimed to evaluate medication adherence and associated factors among patients with chronic viral hepatitis. A cross-sectional questionnaire survey was conducted in 171 outpatients receiving antiviral treatment of chronic viral hepatitis at 6 national/regional liver disease treatment centers in Japan. Medication adherence was calculated as the subject-reported number of antiviral tablets taken in the past 2 weeks compared with the prescribed number of tablets. Subjects were divided according to 100% adherence or nonadherence. The impact of items pertaining to everyday experiences and perceptions regarding medication adherence were examined. Factors associated with medication adherence were identified via multiple logistic regression. The mean medication adherence rate was 95.8% ± 9.5% (range = 0%-100%), although a smaller proportion (95 subjects; 55.6%) was 100% adherent. Multiple logistic regression indicated a greater "lack of understanding of need for medication" (1 point: odds ratio (OR) = 1.51, 95% confidence interval (CI) [1.30, 1.76], p ≤ .01) and greater "restriction in life due to medication" (1 point: OR = 1.26, 95% CI [1.03, 1.54], p = 0.03) as associated with nonadherence. In conclusion, to improve medication adherence, healthcare professionals should improve patients' understanding of the need for medication and minimization of life restrictions.

Objectives: Hepatitis E virus (HEV) infection is a pandemic with regional outbreaks, including in industrialized countries. HEV infection is usually self-limiting but can progress to chronic hepatitis E in transplant recipients and HIV-infected patients. Whether other immunocompromised hosts, including rheumatology and internal medicine patients, are at risk of developing chronic HEV infection is unclear. Methods: We conducted a retrospective European multicenter cohort study involving 21 rheumatology and internal medicine patients with HEV infection between April 2014 and April 2016. The underlying diseases included rheumatoid arthritis ( n = 5), psoriatic arthritis ( n = 4), other variants of chronic arthritis ( n = 4), primary immunodeficiency ( n = 3), systemic granulomatosis ( n = 2), lupus erythematosus ( n = 1), Erdheim⁻Chester disease ( n = 1), and retroperitoneal fibrosis ( n = 1). Results: HEV infection lasting longer than 3 months was observed in seven (33%) patients, including two (40%) patients with rheumatoid arthritis, three (100%) patients with primary immunodeficiency, one (100%) patient with retroperitoneal fibrosis and one (100%) patient with systemic granulomatosis. Patients with HEV infection lasting longer than 3 months were treated with methotrexate without corticosteroids ( n = 2), mycophenolate mofetil/prednisone ( n = 1), and sirolimus/prednisone ( n = 1). Overall, 8/21 (38%) and 11/21 (52%) patients cleared HEV with and without ribavirin treatment, respectively. One patient experienced an HEV relapse after initially successful ribavirin therapy. One patient (5%) was lost to follow-up, and no patients died from hepatic complications. Conclusion: Rheumatology and internal medicine patients, including patients treated with methotrexate without corticosteroids, are at risk of developing chronic HEV infection. Rheumatology and internal medicine patients with abnormal liver tests should be screened for HEV infection.

Hepatitis E virus (HEV) can cause chronic infections in immunosuppressed patients with adverse clinical outcomes. Intervention strategies are limited with ribavirin (RBV) being the only main therapeutic option as off-label drug. Recent reports on RBV monotherapy failures show a coherence with the presence of certain single nucleotide variants (SNVs) and in-frame insertions in the hypervariable region of open reading frame 1 in the HEV genome. Importantly, some of the alterations were present in the viral population as minor variant before RBV administration. Individualized infection medicine by early detection of emerging viral variants in patients could improve treatment outcome and prognosis., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Dengue fever is the commonest mosquito-borne illness in the tropics and subtropics. Renal transplantation is one of the ever expanding modes of treatment of end-stage renal disease. Hepatitis B is a common infection in South and East Asia, but rare in Sri Lanka. Here we describe a recipient of a renal transplant with a stable graft, on antiviral treatment for hepatitis B infection, developing dengue superinfection and entering a complex clinical course. To the best of our knowledge this is the first report of such a case., Case Presentation: A 59-year-old Sri Lankan woman developed acute renal failure and needed dialysis support; she had upper gastrointestinal bleeding that needed transfusions, pancytopenia, and a prolonged phase of thrombocytopenia. She eventually recovered from illness, and her renal functions returned to baseline levels. The differences in presentation, signs, symptoms, and mortality of renal transplant recipients infected with dengue fever from the general population are discussed, with possible reasons for altered presentation., Conclusions: Dengue superinfection in transplant recipients with hepatitis B infection can lead to management difficulties. The recovery can be slow as seen from this case, with prolonged thrombocytopenia.

Chronic hepatitis is a general designation class of diseases, which results in different degrees of liver necrosis and inflammatory reaction, followed by liver fibrosis, may eventually develop into cirrhosis. However, the molecular pathogenesis of chronic hepatitis is too complex to elucidate. Herbal medicines, featured with multiple targets and compounds, have long displayed therapeutic effect in treating chronic hepatitis, though their molecular mechanisms of contribution remain indistinct. This research utilized the network pharmacology to confirm the molecular pathogenesis of chronic hepatitis through providing a comprehensive analysis of active chemicals, drug targets and pathways' interaction of Sinisan formula for treating chronic hepatitis. The outcomes showed that 80 active ingredients of Sinisan formula interacting with 91 therapeutic proteins were authenticated. Sinisan formula potentially participates in immune modulation, anti-inflammatory and antiviral activities, even has regulating effects on lipid metabolism. These mechanisms directly or indirectly are involved in curing chronic hepatitis by an interaction way. The network pharmacology based analysis demonstrated that Sinisan has multi-scale curative activity in regulating chronic hepatitis related biological processes, which provides a new potential way for modern medicine in the treatment of chronic diseases., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

We present a 38-year-old white British man who was taking long-term immunosuppressive medication following kidney transplantation. On routine review, he was noted to have an isolated and asymptomatic rise in alanine aminotransferase. After thorough investigation, he was found to have positive IgM and IgG serology to hepatitis E virus-and given the duration of his transaminitis, he was determined to have chronic hepatitis E infection. Treatment options were complicated by the presence of his kidney transplant, by chronic anaemia and by his wish for concomitant fertility treatment. Ribavirin therapy was instituted with a dramatic and immediate drop in serum viral load, although stool viraemia persisted. No clear protocols guide duration of treatment in chronic hepatitis E infection, but protracted faecal virus shedding predicts viral recrudescence, and treatment should continue at least until the stool is clear of virus., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Hepatitis E virus (HEV) infection can lead to acute and chronic hepatitis as well as to extrahepatic manifestations such as neurological and renal disease; it is the most common cause of acute viral hepatitis worldwide. Four genotypes are responsible for most infection in humans, of which HEV genotypes 1 and 2 are obligate human pathogens and HEV genotypes 3 and 4 are mostly zoonotic. Until quite recently, HEV was considered to be mainly responsible for epidemics of acute hepatitis in developing regions owing to contamination of drinking water supplies with human faeces. However, HEV is increasingly being recognized as endemic in some developed regions. In this setting, infections occur through zoonotic transmission or contaminated blood products and can cause chronic hepatitis in immunocompromised individuals. HEV infections can be diagnosed by measuring anti-HEV antibodies, HEV RNA or viral capsid antigen in blood or stool. Although an effective HEV vaccine exists, it is only licensed for use in China. Acute hepatitis E is usually self-limiting and does not require specific treatment. Management of immunocompromised individuals involves lowering the dose of immunosuppressive drugs and/or treatment with the antiviral agent ribavirin.

Background: Decompensated liver disease due to portal hypertension leads to significant morbidity and mortality. Statins can modulate intrahepatic vascular tone, but the clinical significance remains uncertain., Aim: To determine the effects of statin use on the risk of liver decompensation and death among patients with chronic viral hepatitis., Methods: We conducted a population wide cohort study using a hospital based database from the Hong Kong Hospital Authority. Adults with chronic viral hepatitis without prior liver decompensation were identified from 2000 to 2012 by International Classification of Diseases, Ninth Revision, Clinical Modification, diagnostic codes. Statin use was defined as a cumulative defined daily dose of >28. Landmark analysis was used to overcome immortal time bias. Propensity score weighting was further performed to minimise baseline confounders. Primary outcome was a composite of portal hypertension related liver decompensation events, with adjustment for death as a competing risk., Results: A total of 69 184 patients with chronic viral hepatitis (2053 statin users and 67 131 statin non-users) were identified for the 2-year landmark analysis. After propensity score weighting of 23 baseline covariates, statin use was associated with a significant reduction in composite liver decompensation events (HR: 0.55; 95% CI: 0.36-0.83; P = .005), ascites (HR: 0.57; 95% CI: 0.36-0.92; P = .02), and a dose-dependent decrease in death (HR: 0.87; 95% CI: 0.76-0.99; P = .035) relative to no statin use., Conclusions: Patients with chronic viral hepatitis who used statins have a reduced risk of liver decompensation and death compared to non-users in this propensity score weighted landmark analysis., (© 2017 John Wiley & Sons Ltd.)

Rationale: Acute hepatitis E virus (HEV) infections are usually self-limiting in immunocompetent patients. HEV persistence has been described only in immunosuppressed patients such as solid-organ transplant recipients, patients with hematological diseases, or patients with human immunodeficiency virus (HIV) infection., Patient Concerns: A 61-year-old patient was admitted in hospital for jaundice and asthenia., Diagnoses: The patient had underlying cirrhosis and developed a chronic HEV infection., Intervention: Ribavirin therapy was initiated., Outcomes: Ribavirin therapy for 12 months allowed the clearance of the virus and HEV viral load remained undetectable thereafter. This patient had taken no immunosuppressive drugs, was not suffering from any autoimmune disease and was not infected with HIV. We studied the patient's anti-HEV immune response months after the viral clearance. His peripheral blood mononuclear cells (PBMC) were stimulated in vitro by HEV peptides. The patient had a mild T lymphopenia, but polyclonal stimulation of PBMC showed a robust T cell response. The response of his anti-HEV specific interferon-γ producing T cells was low., Lessons: Other studies are now needed to identify the population with a chronic evolution of HEV infection despite no apparent immunodepression.

Statins have proven effects in the primary and secondary prevention of coronary disease. Besides lowering LDL-cholesterol beneficial pleiotropic consequences of statin therapy are increasingly discussed. Retrospective analyses of large cohort studies have shown favorable effects on the sequels of chronic viral induced liver disease and of non alcoholic fatty liver disease. These findings are substantiated by experimental work showing that statins reduce inflammation, fibrosis and proliferation in the diseased liver. Prospective controlled trials are necessary to elucidate whether, when and where statins have a role in the therapeutic armamentarium for liver disease., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (© Georg Thieme Verlag KG Stuttgart · New York.)

Hepatitis E virus (HEV) infection is increasingly being reported in immunocompromised patients and particularly organ transplant recipients. In this context, HEV infection frequently evolves to chronic infection with a rapid progression of fibrosis to cirrhosis. Ribavirin monotherapy and a minimization of immunosuppression represent the treatment of choice, with a good response rate. However, no data are available on whether treatment can achieve a regression of liver fibrosis in chronic HEV patients. A 57-year-old male patient received a liver transplant for alcoholic cirrhosis and, 6 years later, developed biopsy-proven chronic HEV infection. The patient received different antiviral therapy regimens (pegylated interferon alpha 2b and ribavirin different dosages, and long-term treatment with ribavirin monotherapy still ongoing) but without achieving a sustained virological response. Liver function parameters normalized after 1 month of treatment but without the clearance of HEV. Hepatitis E virus RNA levels also remained detectable in the serum and stools throughout ribavirin monotherapy. No serious adverse events were reported. A gradual regression of liver fibrosis was reported (Metavir A0/F1 in 2015 versus A3/F4 in 2008). Long-term treatment with ribavirin is safe in liver transplant recipients, without achieving HEV sustained virological response, and may induce a biopsy-proven regression of liver fibrosis in a liver transplant recipient with cirrhosis after chronic HEV infection.

Background: A nationwide survey of autoimmune hepatitis (AIH) patients was performed in Japan in 2015. The aims of this study were to elucidate the trends and characteristics of AIH in Japan, in addition to identifying differences in AIH between acute hepatitis and chronic hepatitis., Methods: Questionnaires about patients with AIH diagnosed from 2009 to 2013 were sent to 437 hospitals or clinics with hepatology specialists., Results: A total of 1682 patients were enrolled. The mean age at diagnosis was 60.0 years, and 87.1 % of patients were female. Serum immunoglobulin G levels were high, peaking at 1.5-2.0 g/dL. Histological diagnoses of chronic hepatitis, acute hepatitis, and cirrhosis were seen in 79.6, 11.7, and 6.7 % of patients respectively. In addition to elevation of aminotransferase levels, the frequencies of emperipolesis and human leukocyte antigen (HLA)-DR2 positivity were higher in patients with acute hepatitis than in those with chronic hepatitis. Approximately 80 % of patients were treated with corticosteroids, and in 97.7 % of them, their condition improved. Steroid pulse therapy was more frequently given to patients with acute hepatitis than to those with chronic hepatitis., Conclusions: In the present nationwide survey of AIH patients in Japan, patients with acute hepatitis had clinical features different from those of patients with chronic hepatitis.

Ethnopharmacological Relevance: There is a decided lack of in-depth studies to evaluate the effectiveness of Chinese Herbal Medicine (CHM) as an adjuvant therapy on the incidence of chronic hepatitis in patients with colon cancer., Aim of the Study: The aim of this study is to assess whether CHM treatment decreased the incidence of chronic hepatitis in colon cancer patients who received conventional Western medical treatment., Materials and Methods: A Taiwanese nationwide population-based study of colon cancer patients receiving Western medicine treatment in conjunction with CHM treatment, using data provided by the National Health Insurance (NHI) Research Database, was conducted. A total of 61676 patients were diagnosed with colon cancer in Taiwan within the defined study period, from 1997 to 2010. After randomly equal matching for age, sex, excluding patients younger than 18 years of age, chronic hepatitis before colon cancer diagnosis date, receiving acupuncture and/or moxibustion and taking CHM for less than 30 days, data from 155 patients were analyzed. Hazard ratios of incidence rate of chronic hepatitis were used to determine the influence of CHM and the therapeutic potential of herbal products in treating patients with colon cancer., Results: CHM used for patients with colon cancer exhibited significantly decreased incidence rates of chronic hepatitis [hazard ratio (HR)=0.53; 95% confidence interval (CI):0.38-0.74], with multivariate adjustment, compared to those without CHM use. The protective effect of CHM treatment with statistical significance across the stratification of age, gender, co-morbidity and treatment modality was noted. The cumulative incidence of chronic hepatitis was also reduced in patients with colon cancer receiving CHM treatment during a five-year period. In this study, we provide the ten most used single herbs and herbal formulas that were prescribed for patients with colon cancer; moreover, we identify the eight single herbs and five formulas used in CHM treatment which significantly decreased incidence of chronic hepatitis among colon cancer patients., Conclusions: This nationwide retrospective cohort study determined that therapy using CHM as an adjuvant modality may have a significant impact on liver protection in patients with colon cancer., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Chronic hepatitis in immunosuppressed patients because of infection with hepatitis E virus is increasingly recognized, but there is a paucity of knowledge about hepatitis E virus infection in solid-organ transplant recipients. Herein, we reported the first confirmatory case of hepatitis E virus genotype 4 infection in a 47-year-old woman who underwent a liver transplant recipient in Taiwan. The patient presented with unexplained hepatitis and severe jaundice. Hepatitis E virus RNA was present in serum and identified as the genotype 4 by reverse transcription polymerase chain reaction. Pathological findings revealed that prominent zone 3 canalicular and hepatocellular cholestasis with a few acidophilic bodies and giant cell transformation, which was typical of hepatitis E virus hepatitis. Even undergoing ribavirin treatment, she had worse cholestasis and recurrent urinary tract infections. She died from encephalopathy and sepsis 6 months after the initial presentation. So far, compared with genotype 3 hepatitis E virus hepatitis, genotype 4 hepatitis E virus infection in solid-organ transplant recipients has been reported less frequently in the literature, and that warrants further accumulation of experiences.