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BACKGROUND Switzerland has made strides towards hepatitis C virus elimination, but as of 2019, elimination was not guaranteed. However, political interest in viral hepatitis has been increasing. We sought to develop a better understanding of Switzerland's progress towards HCV elimination and the profile of remaining HCV-RNA-positive patients. METHODS A previously described Markov model was updated with recent diagnosis and treatment data and run to generate new forecasts for HCV disease burden. Two scenarios were developed to evaluate HCV morbidity and mortality under the status quo and a scenario that achieves the Swiss Hepatitis Strategy Elimination targets. Next, an analysis was conducted to identify population segments bearing a high burden of disease, where future elimination efforts could be directed. RESULTS At the beginning of 2020, an estimated 32��100 viremic infections remained in Switzerland (0.37% viremic prevalence). Adult (���18��years of age) permanent residents born abroad represented the largest subpopulation, accounting for 56% of HCV infections. Thirteen countries accounted for ���60% of viremic infections amongst permanent residents born abroad, with most people currently residing in Zurich, Vaud, Geneva, Bern, Aargau and Ticino. Amongst Swiss-born HCV-RNA-positive persons, two-thirds had a history of IDU, corresponding to 33% of total infections. CONCLUSIONS In Switzerland, extra efforts for diagnosis and linkage to care are warranted in foreign-born populations and people with a history of drug use. Population-level measures (eg increasing the number of providers, increase screening) can identify patients who may have otherwise fallen through the gaps or avoided care because of stigma.

Background Heterozygous ABCB4 variants are not routinely tested in adults with cholestasis because of their supposed rarity and high costs. Methods Nineteen adult patients presenting with unexplained cholestasis, and/or recurrent gallstones were included; genotyping was not done in five due to lack of health insurance approval. Results heterozygous ABCB4 variants were identified in seven patients, followed by cascade testing of 12 family members: one patient underwent liver transplantation at age 40 for end-stage liver disease; one had compensated cirrhosis; all symptomatic adults had gallstones, including four with low phospholipid-associated cholelithiasis; four had intrahepatic cholestasis of pregnancy; all children and one 54-year old female were asymptomatic. Genotype: Families A and C: c.2211G>A (p.Ala737=) combined with c.959C>T (p.Ser320Phe) in one subject; Family B: c.1130T>C (p.Ile377Thr); Family D: large deletion removing ABCB4 exons 1-4 plus ABCB1, RUNDC3B, SLC25A40, DBF4, ADAM22 exons 1-3; Family E: c.1565T>C (p.Phe522Ser) ; Family F: c.1356+2T>C combined with c.217C>G (p.Leu73Val). All patients responded to ursodeoxycholic acid. Conclusions We found ABCB4 variants in half of the adults with unexplained cholestasis and/or recurrent gallstones presenting at our center, suggesting that this condition is underdiagnosed and undertreated, with serious consequences not only for the patients and their families, but also in terms of healthcare costs.

After an acute hepatitis E (HEV) outbreak in Southern Switzerland, in January 2017 the local public health authorities started an active program of food chain control and public education. In this retrospective study, we analysed all laboratory-confirmed acute cases of HEV infection diagnosed between 2014 and 2020. In the period before the public health intervention, the number of cases increased steadily from 2014 (4 of 40 tests, 10%) reaching a peak in the last quarter of 2016 (42 of 285 tests, 14.7 %). Afterwards, the number of positive cases decreased steadily, reaching its lowest value (0.3%) in the second quarter of 2019. There was a statistically significant difference between the frequency of positive cases and period of testing, i.e., before and after the introduction of the public health interventions. Our study shows that active public health measures to control sausages containing raw pork liver can reduce the prevalence of HEV infection.

Background Autochthonous hepatitis E is increasingly recognized as zoonotic infection in western countries. Serologic assays have varying sensitivity and specificity. Methods We implemented molecular testing to identify and characterize acute hepatitis E acquired in Switzerland. Results Ninety-three cases of mostly symptomatic acute hepatitis E acquired in Switzerland were documented by PCR between November 2011 and December 2016. Median HEV RNA was 7.5 x 104 IU/ml (range, 5.3 to 4.7 x 107 IU/ml). HEV genotyping was successful in 78 patients, revealing genotype 3 in 75 and genotype 4 in 3 patients. Phylogenetic analyses revealed a few limited geographial and temporal clusters. Of the 91 patients with available anti-HEV IgM serology, 4 were negative; three of these were also IgG-negative, likely as a result of immunosuppression, and one was IgG positive, a constellation compatible with HEV reinfection. Median age of the patients was 58 years (range, 20-80 years); 71 (76.3%) were men and 49 of these (69.0%) were ≥ 50 years old. The clinical course was particularly severe in patients with underlying chronic liver disease, with fatal outcome in two patients. Six patients (6.5%) presented with neuralgic amyotrophy. Conclusions Nucleic acid-based diagnosis reveals HEV as a relevant cause of acute hepatitis in Switzerland. Middle-aged and elderly men constitute the majority of symptomatic patients. Testing for HEV should be included early in the diagnostic workup of acute hepatitis and of neuralgic amyotrophy, a typical extrahepatic manifestation of HEV genotype 3 infection. This article is protected by copyright. All rights reserved.

Introduction: In the last years, nonalcoholic steatohepatitis (NASH) has become a leading indication for liver transplant (LT). After transplant, both recurrent and de novo nonalcoholic fatty liver disease (NAFLD) can be commonly diagnosed. However, dedicated surveillance programs for patients with pre- or post-transplant NAFLD are not available. Areas covered: Patients waiting for LT for NASH show specific peculiarities and would deserve targeted stratification of mortality risk. Obesity, hyperlipidemia, and diabetes mellitus can be often found after transplant. These conditions, together with immunosuppressive regimen, make LT recipients a high-risk population for both recurrent and de novo NAFLD. Development of fatty liver disease after LT has a relevant impact on both morbidity and mortality. Expert commentary: A targeted stratification of neoplastic and cardiovascular risk for patients with NASH waiting for LT would be mandatory. In both pre- and post-transplant period, NAFLD should be considered not only a liver disease but also a cardiovascular risk factor. Patients within Transplant Program, especially those with known metabolic risk factors, should be followed with personalized diagnostic and life-style interventions before and after LT.

ObjectiveTo assess the prevalence and clinical features of neurologic involvement in patients with acute hepatitis E virus (HEV) infection in Southern Switzerland.MethodsAmong 1,940 consecutive patients investigated for acute hepatitis E, we identified 141 cases of acute of HEV infection (anti-HEV immunoglobulin M and immunoglobulin G both reactive and/or HEV RNA positive) between June 2014 and September 2017. Neurologic cases were followed up for 6 months. We compared patients with and without neurologic symptoms.ResultsNeurologic symptoms occurred in 43 acute HEV cases (30.4%) and consisted of neuralgic amyotrophy (NA, n = 15, 10.6%) and myalgia (n = 28, 19.8%). All NA cases were immunocompetent. Men had higher odds (OR = 5.2, CI 1.12–24.0, p = 0.03) of developing NA after infection with HEV, and in 3 couples simultaneously infected with HEV, only men developed NA. Bilateral involvement of NA was predominant (2:1) and occurred only in men. Seven NA cases were viremic (all genotype 3), but HEV was undetectable in their CSF. In the acute phase of NA, 9 patients were treated with intravenous immunoglobulin and 4 with prednisone, reporting no side effects and improvement in pain and strength. Myalgia occurred both without (n = 16) or with (n = 12) concomitant elevated serum creatinine kinase. Seven cases with myalgia in the shoulder girdle did not have muscle weakness (“forme fruste” of NA).ConclusionsNeurologic symptoms occurred in one-third of acute HEV infections and consisted of NA and myalgia. NA seems to occur more frequently in men infected by HEV and has a predominant (but not exclusive) bilateral involvement.

The etiology of autoimmune hepatitis (AIH) is unknown, though hepatotropic viruses may be potential triggers. Hepatitis E virus (HEV) infection, an increasingly recognized cause of acute hepatitis, has been misdiagnosed as AIH due to the occurrence of autoantibodies during its acute phase. It has also been suggested that HEV infection may lead to or unmask AIH. The HEV seroprevalence has been ascertained in patients with AIH, but the prevalence of AIH-related autoantibodies in patients with HEV infection has not been systematically tested. We aimed to investigate whether acute HEV infection is associated with the presence of AIH-relevant autoantibodies, following the liver autoimmune serology guidelines of the International AIH Group. We tested 48 patients with acute HEV infection. Half of them had at least one autoantibody, 17% two autoantibodies. Anti-nuclear antibody (ANA) were detected in 16 (33%), anti-smooth muscle antibody (SMA) in 10 (21%), and anti-neutrophil cytoplasmic antibody (ANCA) in 7 (14.6%). Of note, two patients showed SMA with VG or VGT patterns and five had ANA with homogeneous appearance, both being typical of AIH type 1. Other AIH-specific autoantibodies were negative. Atypical anti-mitochondrial antibody, without evidence of primary biliary cholangitis, was positive in one patient, disappearing at follow-up. Follow-up (median 12 months) serum was available from seven autoantibody positive patients: two became negative, while five remained positive, although no patient developed AIH to date. In conclusion, autoantibodies are frequently present during acute HEV infection, indicating that HEV should always be excluded before diagnosing AIH. Importantly, a minority of patients with acute hepatitis E develops AIH-specific autoantibodies, and, though they did not progress to autoimmune liver disease in the short-term, they warrant long-term monitoring.

No data on primary biliary cholangitis (PBC) are available in Switzerland. We established a national patient cohort to obtain information on PBC phenotypes and disease course in Switzerland. Local databases in all university hospitals and in two large secondary centers were searched for case finding. In addition, all primary care physicians, gastroenterologists, rheumatologists, and dermatologists were invited to contribute patients from their own medical records. PBC diagnosis was centrally reviewed. Five hundred one PBC patients were identified, 474 were included in data analysis, and 449 of them were enrolled by tertiary centers. The catchment area accounts for approximately one third of the Swiss population or approximately 2.8 million inhabitants. The median age at diagnosis was 53 years, 84% were women, and 86% were anti-mitochondrial antibody positive. The median follow-up was 5.4 years, 12.6% experienced a liver-related endpoint. Splenomegaly was present at diagnosis in one quarter of patients and in half of male patients. Approximately one third were non-responders to ursodeoxycholic acid (UDCA). The median transplant-free survival at 10 years was 85%. The following variables were independently associated with poor outcome: low platelet count at baseline (HR = 0.99, p

Catalyzed by the concerns over the growing public health and economic burden of Hepatitis C virus (HCV) in Switzerland, a diverse group of experts and patient representatives came together in 2014 to develop the Swiss Hepatitis Strategy, setting targets for the elimination of viral hepatitis in Switzerland by 2030. Previous studies have reported the estimated number of chronic HCV infections and forecasted burden of disease given different intervention strategies. However, given new prevalence data by the Swiss Federal Office of Public Health, which decreased total infections by about half, an updated analysis is warranted. We aimed to provide an updated viremic prevalence estimate for Switzerland and evaluate the impact on forecasted liver related morbidity and mortality of an 'inaction' scenario and intervention scenarios to achieve the Global Health Sector Strategy for Viral Hepatitis and Swiss Hepatitis Strategy goals by 2030. A Markov disease-progression model was used to calculate the present and future burden of HCV infection by disease stage according to these different strategies. In 2017, there were an estimated 36,800 (95% UI: 26,900-39,200) viremic infections in Switzerland. Given the current standard of care, total viremic infections are expected to decline by 45%, while cases of decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths will decrease by 20%. If treatment and diagnosis efforts were to cease in 2018, late stage HCV-related morbidity and mortality would increase by 90-100% by 2030. Increasing treatment and diagnosis to achieve the Global Health Sector Strategy or Swiss Hepatitis Strategy goals by 2030, will reduce the number of chronic infections to less than 13,000 and 4,000, respectively. Although the HCV epidemic is declining in Switzerland, efforts to expand diagnosis and treatment are needed to achieve elimination by 2030.

During the last 20 years, relevant diagnostic procedures and advanced treatments have been progressively introduced in the management of hepatocellular carcinoma (HCC). The aim of the present study was to assess up-to-date survival trends for HCC in southern Switzerland, a region with one of the highest incidence rates in the country.HCCs diagnosed in 1996-2009 were selected by the Ticino Cancer Registry. Cancer-specific survival (CSS) analysis was performed using the Kaplan-Meier method by calendar period: 1996-2000, 2001-2005 and 2006-2009. The log-rank test was used to detect differences in survival curves. Simultaneous assessment of prognostic factors was performed by a multivariate analysis using the Cox proportional-hazards regression model.619 HCCs were analysed. There was a significant increase of patients undergoing transarterial chemoembolisation (TACE), whereas patients undergoing curative or palliative supportive treatments remained unchanged (p0.0001). No shift to earlier stages was detected. Significant differences in CCS were observed by age-group (p0.0001), diagnosis period (p0.0001), diagnosis technique (p = 0.0035), Barcelona-Clinic liver cancer stage (p0.0001), treatment (p0.0001). Multivariate analysis confirmed the independent impact on CSS of factors above mentioned, not including the diagnosis technique. Death risk was higher for patients diagnosed in 1996-2000 (HR: 1.32; 95% CI: 1.03; 1.68) and 2001-2005 (HR: 1.33; 95% CI: 1.05; 1.67) in comparison with 2006-2009 (reference group).The current population-based report describes a major increase in HCC survival. Simultaneously an increased use of TACE has been detected, probable cofactor of the observed survival increase. Possibly additional efforts could be made to decrease the HCC stage at diagnosis through active surveillance of cirrhotic patients to allow an increase in curative treatments. For sure efforts should be made to comply with a standardised staging system for HCC, particularly for comparative population-based issues.

Acute cholecystitis is a common disease and a frequent cause of emergency admission to surgical wards. Evidence regarding antibiotic administration in urgent procedures is limited and remains a contentious issue. According to the Tokyo guidelines, the antibiotic administration should be guided by the severity of cholecystitis, but internationally accepted guidelines are lacking. In particular, the need to perform antibiotic therapy after laparoscopic cholecystectomy is controversial for mild and moderate acute calculous cholecystitis (Tokio I and II). We performed a comprehensive computer literature search of PubMed and MEDLINE databases in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. We selected patients treated with cholecystectomy for mild or moderate acute calculous cholecystitis (Tokio I or II), only randomized controlled trials, (post-operative antibiotic administration versus placebo or untreated), data about local or systemic infection rate in the next 30 days after surgery. Three hundred and fifty-nine articles were identified, and three articles were considered eligible for the meta-analysis, including 676 patients. Overall surgical site infections were documented in 18 (5.49%) of 328 patients treated with post-operative antibiotics versus 25 (7.18%) of 348 patients treated without post-operative antibiotics. Overall results and the subgroup analysis (superficial and deep incisional infection and organ/space infection) showed no statistically significant reduction of surgical site infections rate under antibiotic therapy. Our meta-analysis shows no significant benefit of extended antibiotic therapy in reducing SSI after cholecystectomy for mild and moderate acute cholecystitis (Tokio I and II). Further RCTs with adequate statistical power and involving a higher number of patients with subgroups are needed to better evaluate the benefit of post-operative antibiotic treatment in reducing the rate of organ/space surgical site infections.

Hepatitis E virus (HEV) infection is gaining global attention, not only because of the increasing burden of the disease in low endemicity countries, in terms of morbidity and mortality rates, but also due to recent advances in the molecular virology and epidemiology of this emerging pathogen. HEV infection spread can be described as the evolution of a zoonosis towards an established human infection. As known from other viruses, such as the human immunodeficiency virus or the influenza viruses, crossing the species barriers from animals to humans is a recurrent phenomenon. Albeit slow at the beginning, once the virus has adapted to humans, the person-to-person spread can proceed very quickly. Although an optimal cell culture system for HEV is not yet available, outstanding progress has been made with the in vitro expression of HEV-like particles. These new tools have fostered new research to understand the molecular, structural and immunological aspects of human HEV infection. Although some promising data from Phase II vaccine trials are available, recent discoveries will certainly open new avenues for HEV-specific prophylaxis and therapy.

WOS: 000426979400014, PubMed ID: 28404132, Background The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of-and expansion on-the 2014 analysis, which reported 80 million (95% CI 64-103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1.0% (95% uncertainty interval 0.8-1.1) in 2015, corresponding to 71.1 million (62.5-79.4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections., John C Martin Foundation, John C Martin Foundation.

Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.

Die Betreuung von Patienten mit Leberzirrhose ist komplex, da die Leber mit ihren multiplen physiologischen Funktionen eine Vielzahl von homöostatischen Systemen beeinflusst. In der vorliegenden Übersicht haben wir versucht, die im klinischen Alltag wichtigsten Aspekte zu diskutieren und praktisch anwendbare Informationen zu vermitteln. Die Unterscheidung in kompensierte und dekompensierte Zirrhose ist klinisch hilfreich, um das Risiko von Komplikationen und damit die Art und Intensität der klinischen Kontrollen zu bestimmen. Patienten mit Leberzirrhose und ihre Angehörigen müssen über mögliche Komplikationen informiert sein, um Alarmsymptome zu erkennen und rasch ärztliche Hilfe ersuchen zu können.

Kaposi's sarcoma-associated herpesvirus (KSHV) specific T cell responses and KSHV viremia were analyzed in seven HIV-infected patients with active Kaposi's sarcoma lesions who initiated highly active antiretroviral therapy, and were compared between patients with improved Kaposi's sarcoma and those with progressive Kaposi's sarcoma requiring further systemic chemotherapy. Patients with controlled Kaposi's sarcoma disease demonstrated undetectable Kaposi's sarcoma viremia together with KSHV-specific CD8 T cells secreting interferon-gamma and tumor necrosis factor-alpha, whereas progressors showed increasing viremia with weak or no T-cell responses. These data point toward a potential role of KSHV-specific immunity in the control of AIDS-associated Kaposi's sarcoma.

Background/Aims Orthotopic liver transplantation (OLT) is an important therapeutic option for HBV-related end-stage-liver disease, yet it is often hampered by a scarcity of organ availability. One option to increase organ availability is the use of virologically compromised organs from HBV-infected donors. Transplantation of anti-HBcore positive grafts has been associated with a low risk of HBV recurrence if adequately treated with nucleoside analogs, irrespective of concomitant HBV-specific immunoglobulin therapy. Experience using HBsAg positive grafts is, however, very limited. Methods Here, the analysis of the cellular and humoral HBV-specific immunity of a subject with past HBV infection (anti-HBs and anti-HBc positive) receiving an HBsAg positive liver graft is reported. Results Nine months post-OLT, the patient experienced a spontaneous anti-HBs re-seroconversion allowing the discontinuation of HBIG. The data show a concurrent increase in the cellular and humoral immunity at times of reduced viral antigenemia, demonstrating effective immune control of HBV post-OLT. Conclusions These data support the use of marginal organs in this setting, providing a potential strategy to further alleviate organ shortage.

Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in1% of the viral quasispecies may still allow1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo.Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.

Promiscuous binding of T helper epitopes to MHC class II molecules has been well established, but few examples of promiscuous class I-restricted epitopes exist. To address the extent of promiscuity of HLA class I peptides, responses to 242 well-defined viral epitopes were tested in 100 subjects regardless of the individuals' HLA type. Surprisingly, half of all detected responses were seen in the absence of the originally reported restricting HLA class I allele, and only 3% of epitopes were recognized exclusively in the presence of their original allele. Functional assays confirmed the frequent recognition of HLA class I-restricted T cell epitopes on several alternative alleles across HLA class I supertypes and encoded on different class I loci. These data have significant implications for the understanding of MHC class I-restricted antigen presentation and vaccine development.

Kaposi's sarcoma-associated herpesvirus (KSHV) is endemic in South Africa and the clinical manifestation of AIDS-associated Kaposi's sarcoma (KS) represents a significant clinical problem. Whereas the positive effects of HAART on the regression of KS have been well established, less is known about the role of herpesvirus-specific cellular immunity in disease improvement.Thirty-three treatment-naive HIV clade C-infected individuals with KS were randomly assigned into two treatment arms (HAART plus systemic chemotherapy versus HAART alone). KSHV-specific cellular immune responses, viral loads and clinical outcome were evaluated.KSHV, Epstein-Barr virus and HIV-specific cellular immunity was measured using an IFN-gamma enzyme-linked immunospot assay in samples obtained at baseline and up to 11 months after treatment initiation. Cell-associated KSHV viremia was determined by real-time polymerase chain reaction.Robust increases in CD4 cell counts and suppressed HIV viral loads were seen in parallel with significant increases in the KSHV-specific cellular immune responses over time. Although slowly increasing after 5 months, KSHV-specific T-cell responses were significantly elevated only after 11 months, with both lytic and latent antigens being more frequently targeted. A trend towards better clinical outcome with HAART plus chemotherapy treatment was observed compared with HAART alone, and was accompanied by a significant reduction in cellular KSHV viral load in the HAART plus chemotherapy-treated subjects but not those treated with HAART alone after 11 months of treatment.The data show a temporal association between the clinical improvement of KS and the re-appearance of KSHV-specific cellular immunity, and demonstrate an effective suppression of KSHV viral replication using combination therapy.

The cellular immunity against Kaposi's sarcoma-associated herpesvirus (KSHV) is poorly characterized and has not been compared to T-cell responses against other human herpesviruses. Here, novel and dominant targets of KSHV-specific cellular immunity are identified and compared to T cells specific for lytic and latent antigens in a second human gammaherpesvirus, Epstein-Barr virus. The data identify a novel HLA-B57- and HLA-B58-restricted epitope in the Orf57 protein and show consistently close parallels in immune phenotypes and functional response patterns between cells targeting lytic or latent KSHV- and EBV-encoded antigens, suggesting common mechanisms in the induction of these responses.

BACKGROUND: Hepatitis B virus (HBV) genotypes can influence treatment outcome in HBV-monoinfected and human immunodeficiency virus (HIV)/HBV-coinfected patients. Tenofovir disoproxil fumarate (TDF) plays a pivotal role in antiretroviral therapy (ART) of HIV/HBV-coinfected patients. The influence of HBV genotypes on the response to antiviral drugs, particularly TDF, is poorly understood. METHODS: HIV/HBV-co-infected participants with detectable HBV DNA prior to TDF therapy were selected from the Swiss HIV Cohort Study. HBV genotypes were identified and resistance testing was performed prior to antiviral therapy, and in patients with delayed treatment response (>6 months). The efficacy of TDF to suppress HBV (HBV DNA

BackgroundChronic hepatitis C virus infection is a major cause of liver disease in Switzerland and carries a significant cost burden. Currently, only conservative strategies are in place to mitigate the burden of hepatitis C in Switzerland. This study expands on previously described modeling efforts to explore the impact of: no treatment, and treatment to reduce HCC and mortality. Furthermore, the costs associated with untreated HCV were modeled.MethodsHepatitis C disease progression and mortality were modeled. Baseline historical assumptions were collected from the literature and expert interviews and strategies were developed to show the impact of different levels of intervention (improved drug cure rates, treatment and diagnosis) until 2030.ResultsUnder the historical standard of care, the number of advanced stage cases was projected to increase until 2030, at which point the annual economic burden of untreated viremic infections was projected to reach €96.8 (95% Uncertainty Interval: €36 - €232) million. Scenarios to reduce HCV liver-related mortality by 90% by 2030 required treatment of 4,190 ≥F2 or 3,200 ≥F3 patients annually by 2018 using antivirals with a 95% efficacy rate. Delaying the implementation of these scenarios by 2 or 5 years reduced the impact on mortality to 75% and 57%, respectively.ConclusionsWith today's treatment efficacy and uptake rates, hepatitis C disease burden is expected to increase through 2030. A substantial reduction in disease burden can be achieved by means of both higher efficacy drugs and increased treatment uptake. However, these efforts cannot be undertaken without a simultaneous effort to diagnose more infections.

In Switzerland, fewer than 40% of hepatitis C virus (HCV) infected individuals have been diagnosed. The aim of this project was to analyse the distribution of HCV cases in order to develop better detection strategies.Historical data on the HCV-infected population in Switzerland were obtained from published literature, unpublished data and government reports. A disease progression model was used to age the infected population to 2015. The HCV distribution was then used to identify 5-year age cohorts with the highest HCV prevalence. The estimated number of cases needed to screen within an age cohort was calculated using the estimated viraemic prevalence, removing the percent previously diagnosed.In 2015, the median age of the viraemic HCV infected population was 49 years, with 75% of the population born between 1951 and 1985. Random screening of the general population could identify one new viraemic HCV case per 159 persons screened, compared with targeted birth cohort screening, which could identify one new viraemic HCV case per 90-99 persons screened.Considering only the direct cost of screening and treatment informing tests, targeted screening by birth cohort is more effective and cost effective than random screening in the general population.

Viral hepatitis B and C, structurally two completely different viruses, commonly infect human hepatocytes and cause similar clinical manifestations. Since their discovery, IFN has been a pillar in the treatment. However, because of the different natures of the viruses, therapeutic approaches diverge and new treatment targets are tailored specifically for each virus. Herein, the authors analyse therapeutic approaches for hepatitis B virus (HBV) and hepatitis C virus (HCV) and focus on emerging concepts that are under clinical evaluation. In particular, promising viral inhibitors for HBV and HCV are reviewed and the current status of research for gene therapy for HCV is described. Immune therapy is a fast-moving field with fascinating results which include therapeutic vaccines and toll-like receptor agonists that could improve tomorrow's treatment approaches.

Macrophage activating syndrome (MAS) is a rare hematological disorder associated with uncontrolled systemic T-cell activation. Persistent fever, fatigue and hepatosplenomegaly are frequent clinical manifestations, whereas hyperferritinemia, elevated serum lactate dehydrogenase levels and cytopenia are key criteria for the diagnosis of MAS. The nature of liver pathology in MAS has been partially elucidated but destructive biliary lesions have been rarely described. This report illustrates four cases of MAS developing marked cholestasis, leading to one case of biliary cirrhosis necessitating liver transplantation. Histologically, liver involvement was characterized in all cases by acute lobular hepatitis, marked hepatocyte apoptosis and small bile duct injury similar to the vanishing bile duct syndrome. Immuno-histological studies showed that the inflammatory changes and bile duct lesions were dominated by the presence of activated macrophages and T-cells, in particular CD8+ lymphocytes, and in part NK-cells. These findings suggest that in MAS, various T-cell triggers such as infection, autoimmune disease and malignancy might result in the release of cytokines, which in turn activate macrophages to trigger a systemic acute phase response and local tissue damage. This communication suggests that a macrophage, T- and NK-cell network is operational in the pathogenesis of the cholangiocyte, hepatocyte and sinus endothelial cell damage in MAS.

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) play an important role in HIV infection. Given the viral genetic diversity, the selection of suitable antigens and epitope variants will be important in the design of an effective vaccine. We have previously shown that combinatorial libraries are useful tools to identify epitope mimics as well as potentially cross-reactive natural sequences in protein databases. We have applied this approach to the HIV Gag p17-derived epitope SL9 (SLYNTVATL) to identify broadly recognized SL9 mimics and to assess the cross-recognition of naturally occurring SL9 variants. Nine nonapeptides were identified that were up to one order of magnitude more effective than SL9 in stimulating CTL responses in PBMC from HIV-infected subjects. Using transgenic mice, we demonstrate that a number of these epitope mimics were able to generate de novo T cell responses that cross-reacted with the original SL9 sequence. Particularly, mimics with changes at the relatively conserved F-pocket anchor residue were frequently cross-recognized. This approach may lead to vaccine candidates with higher in vivo immunogenicity and increased potential for cross-recognition of naturally occurring SL9 variants.

Hemolysis is a frequent adverse effect of ribavirin (RBV). It has been suggested that oxidative stress plays a role, but mechanisms and predictive risk factors for severe forms remain unknown. Markers of redox status were determined in erythrocytes of 34 patients with hepatitis C-four of them with glucose-6-phosphate-dehydrogenase (G6PD) deficiency-before and during treatment with RBV and interferon (IFN) and were compared with 10 healthy control subjects. In addition, erythrocytes were incubated with RBV, and the effects of dipyridamole (DPD), diethylmaleate (DEM), and glutathione ester (GSHE) were studied in vitro. Of the 30 patients without G6PD deficiency who were treated with RBV and IFN-alpha, five developed major hemolysis (Delta hemoglobin > 6 g/dL) and 25 developed minor hemolysis (Delta hemoglobin < 2.5 g/dL). Patients with major hemolysis had lower median pretreatment values of membrane protein sulfhydrils than patients with minor hemolysis (28.4 vs. 36.7 nmol/mg, P

Gilead Sciences The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. the largest reduction in HCV-related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3-5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical. Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-30625 Hannover, Germany German Liver Fdn, Hannover, Germany Orebro Univ Hosp, Dept Infect Dis, Orebro, Sweden Univ Orebro, Sch Hlth & Med Sci, SE-70182 Orebro, Sweden Hosp Valle de Hebron, CIBERehd, Barcelona, Spain UCL, Div Med, UCL Inst Liver & Digest Hlth, London, England Inst Clin & Expt Med, Dept Hepatogastroenterol, Prague, Czech Republic Cairo Univ, Cairo, Egypt Ankara Univ, TR-06100 Ankara, Turkey Ghent Univ Hosp, Ghent, Belgium Wilhelminenspital Stadt Wien, Dept Internal Med 4, Vienna, Austria Ege Univ, Izmir, Turkey Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden Karolinska Univ Hosp, Dept Gastroenterol & Hepatol Infect Dis, Stockholm, Sweden Univ Leipzig, D-04109 Leipzig, Germany Osped Cantonale, Dept Gastroenterol, Bellinzona, Switzerland Univ Montreal, Dept Med, Liver Unit, Montreal, PQ H3C 3J7, Canada Adv Tech Hlth Serv Res TAISS, Madrid, Spain Fed Univ State Rio de Janeiro, Dept Gastroenterol, Rio de Janeiro, Brazil Arud Ctr Addict Med, Zurich, Switzerland Hosp Santo Antonio Capuchos, Ctr Hosp Lisboa Cent, Dept Gastroenterol, Lisbon, Portugal Hosp Puerta Hierro, Madrid, Spain Univ Fed Rio Grande do Sul, Hosp Clin, Porto Alegre, RS, Brazil Odense Univ Hosp, Dept Infect Dis, DK-5000 Odense, Denmark Region Hosp Hovedstaden, Region Hovedstaden, Denmark Univ Fed Rio de Janeiro, Dept Clin Med, Rio de Janeiro, Brazil Univ Plymouth, Peninsula Sch Med & Dent, Plymouth PL4 8AA, Devon, England Univ New S Wales, Kirby Inst, Sydney, NSW, Australia Ain Shams Univ, Cairo, Egypt Dokuz Eylul Univ, Izmir, Turkey Ctr Dis Anal CDA, Louisville, CO USA Karolinska Inst, Dept Med Huddinge, Karolinska Univ Hosp, Infect Dis Unit, Stockholm, Sweden Exigo Consultores, Alhos Vedros, Portugal Universidade Federal de São Paulo, Div Gastroenterol, São Paulo, Brazil Universidade Federal de São Paulo, Div Infect Dis, São Paulo, Brazil Hosp Carlos III, CIBERehd, Madrid, Spain Univ Copenhagen, Copenhagen, Denmark Direccao Geral Saude, Lisbon, Portugal Univ Estadual Campinas, Fac Ciencias Med, Disciplina Doencas Infecciosas, Grp Estudo Hepatites,Dept Clin Med, São Paulo, Brazil Univ São Paulo, Sch Med, Div Gastroenterol & Hepatol, São Paulo, Brazil Hop Henri Mondor, Serv Hepatogastroenterol, F-94010 Creteil, France Med Univ Vienna, Div Gastroenterol & Hepatol, Dept Internal Med 3, Vienna, Austria Masaryk Univ, Clin Infect Dis, Univ Hosp Brno, Brno, Czech Republic Ankara Univ, Dept Gastroenterol, Sch Med, TR-06100 Ankara, Turkey Univ Manitoba, Dept Internal Med, Sect Hepatol, Winnipeg, MB, Canada Hlth Sci Ctr, Viral Hepatitis Invest Unit, Winnipeg, MB, Canada European Liver Patients Assoc, St Truiden, Belgium Istanbul Univ, Istanbul, Turkey Univ British Columbia, British Columbia Ctr Dis Control, Vancouver, BC V5Z 1M9, Canada Aalborg Univ Hosp, Dept Med Gastroenterol, Aalborg, Denmark Aalborg Univ Hosp, Sect Mol Diagnost, Aalborg, Denmark Katholieke Univ Leuven, Univ Hosp Leuven, Louvain, Belgium Univ Western Ontario, Div Gastroenterol, London, ON, Canada Univ Dusseldorf, Dusseldorf, Germany Univ São Paulo, Sch Med, São Paulo, Brazil Univ Libre Brussels, Erasme Univ Hosp, Brussels, Belgium Univ Zurich Hosp, Swiss HPB Hepatopancreatobiliary Ctr, CH-8091 Zurich, Switzerland Univ Zurich Hosp, Dept Gastroenterol & Hepatol, CH-8091 Zurich, Switzerland Univ Calgary, Div Gastroenterol & Hepatol, Liver Unit, Calgary, AB, Canada Natl Inst Publ Hlth, Natl Reference Lab Hepatitis, Prague, Czech Republic Univ Southhampton, Southampton, England Dalhousie Univ & Hepatol Serv, Queen Elizabeth II Hlth Sci Ctr, Capital Dist Hlth Author, Dept Med, Halifax, NS, Canada Dalhousie Univ & Hepatol Serv, Queen Elizabeth II Hlth Sci Ctr, Capital Dist Hlth Author, Dept Surg, Halifax, NS, Canada Univ British Columbia, Dept Gastroenterol, Vancouver, BC V5Z 1M9, Canada Assembleia Republ, Lisbon, Portugal Alfred Hosp, Melbourne, Vic, Australia Monash Univ, Melbourne, Vic 3004, Australia Hop Henri Mondor, Dept Sante Publ, F-94010 Creteil, France Nottingham Univ Hosp NHS Trust, Nottingham, England Biomed Res Unit, Nottingham, England Ctr Hosp Porto, Dept Infect Dis, Oporto, Portugal JW Goethe Univ Hosp, Frankfurt, Germany Cantonal Hosp St Gallen, Div Gastroenterol & Hepatol, St Gallen, Switzerland Univ Toronto, Toronto Gen Hosp, Univ Hlth Network, Toronto, ON M5G 1L7, Canada Egyptian Liver Res Inst & Hosp ELRIAH, Dakahliah, Egypt Catholic Univ Louvain, Clin Univ St Luc, Brussels, Belgium Med Univ Graz, Div Gastroenterol & Hepatol, Dept Internal Med, Graz, Austria St Vincents Hosp, Dept Gastroenterol, Melbourne, Vic, Australia Univ Melbourne, Melbourne, Vic, Australia Charles Univ Prague, Dept Internal Med, Fac Med 1, Prague, Czech Republic Cent Mil Hosp, Prague, Czech Republic Univ Antwerp, B-2020 Antwerp, Belgium Deutsch Leberhilfe eV, Cologne, Germany Univ Ghent, Dept Hlth Econ & Patient Safety, B-9000 Ghent, Belgium Hasselt Univ, Diepenbeek, Belgium Med Univ Innsbruck, A-6020 Innsbruck, Austria Natl Liver Inst, Menoufia, Egypt Copenhagen Univ Hosp, Hvidovre, Denmark Univ New S Wales, St George Hosp Clin Sch Med, Sydney, NSW, Australia Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia Univ Hosp, Div Gastroenterol & Hepatol, Geneva, Switzerland Univ Hosp, Div Clin Pathol, Geneva, Switzerland Monash Hlth, Melbourne, Vic, Australia Division of Gastroenterology, Federal University of São Paulo, São Paulo, Brazil Division of Infectious Disease, Federal University of São Paulo, São Paulo, Brazil Web of Science

Gilead Sciences Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. for some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. the largest viremic populations were in Egypt, with 6358000 cases in 2008 and Brazil with 2106000 cases in 2007. the age distribution of cases differed between countries. in most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV-infected populations are critical for addressing HCV-related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level. Arud Ctr Addict Med, CH-8005 Zurich, Switzerland Univ Leipzig, D-04109 Leipzig, Germany Odense Univ Hosp, Dept Infect Dis, DK-5000 Odense, Denmark Univ Libre Brussels, Erasme Univ Hosp, Brussels, Belgium Univ Fed Rio de Janeiro, Dept Gastroenterol, Rio de Janeiro, Brazil Hop Henri Mondor, Dept Sante Publ, F-94010 Creteil, France Hosp Santa Maria, Ctr Hosp Lisboa Norte, Dept Gastroenterol, Lisbon, Portugal Univ Toronto, Toronto Gen Hosp, Univ Hlth Network, Toronto, ON M5G 1L7, Canada Nottingham Univ Hosp NHS Trust, Nottingham, England Biomed Res Unit, Nottingham, England Inst Clin & Expt Med, Dept Hepatogastroenterol, Prague, Czech Republic Ege Univ, Izmir, Turkey Ankara Univ, TR-06100 Ankara, Turkey Osped Cantonale, Dept Gastroenterol, Bellinzona, Switzerland Univ Montreal, Dept Med, Liver Unit, Montreal, PQ H3C 3J7, Canada Adv Tech Hlth Serv Res TAISS, Madrid, Spain Hosp Valle de Hebron, CIBERehd, Barcelona, Spain Hosp Santo Antonio Capuchos, Dept Gastroenterol, Ctr Hosp Lisboa Cent, Lisbon, Portugal Hosp Puerta Hierro, Madrid, Spain Univ Fed Rio Grande do Sul, Hosp Clin, Porto Alegre, RS, Brazil Region Hosp Hovedstaden, Region Hovedstaden, Denmark Univ Fed Rio de Janeiro, Dept Clin Med, Rio de Janeiro, Brazil Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany German Liver Fdn, Hannover, Germany Univ Plymouth, Peninsula Schools Med & Dent, Plymouth PL4 8AA, Devon, England Univ New S Wales, Kirby Inst, Sydney, NSW, Australia Cairo Univ, Cairo, Egypt Orebro Univ Hosp, Dept Infect Dis, Orebro, Sweden Univ Orebro, Sch Hlth & Med Sci, SE-70182 Orebro, Sweden Ain Shams Univ, Cairo, Egypt Dokuz Eylul Univ, Izmir, Turkey Ctr Dis Anal CDA, Louisville, CO USA Karolinska Inst, Infect Dis Unit, Dept Med Huddinge, Stockholm, Sweden Exigo Consultores, Alhos Vedros, Portugal Universidade Federal de São Paulo, Div Gastroenterol, São Paulo, Brazil Universidade Federal de São Paulo, Div Infect Dis, São Paulo, Brazil Hosp Carlos III, CIBERehd, Madrid, Spain Univ Copenhagen, Copenhagen, Denmark Direccao Geral Saude, Lisbon, Portugal Univ Estadual Campinas, Fac Ciencias Med, UNICAMP,Dept Clin Med, Grp Estudo Hepatites,Disciplina Doencas Infeccios, São Paulo, Brazil Wilhelminenspital Stadt Wien, Dept Internal Med 4, Vienna, Austria Univ São Paulo, Sch Med, Div Gastroenterol & Hepatol, São Paulo, Brazil Hop Henri Mondor, Serv Hepatogastroenterol, F-94010 Creteil, France Med Univ Vienna, Dept Internal Med 3, Div Gastroenterol & Hepatol, Vienna, Austria Masaryk Univ, Univ Hosp Brno, Clin Infect Dis, Brno, Czech Republic Ankara Univ, Dept Gastroenterol, Sch Med, TR-06100 Ankara, Turkey Univ Manitoba, Dept Internal Med, Sect Hepatol, Winnipeg, MB, Canada Hlth Sci Ctr, Viral Hepatitis Invest Unit, Winnipeg, MB, Canada European Liver Patients Assoc, St Truiden, Belgium Istanbul Univ, Istanbul, Turkey Univ British Columbia, British Columbia Ctr Dis Control, Vancouver, BC V5Z 1M9, Canada Aalborg Univ Hosp, Dept Med Gastroenterol, Aalborg, Denmark Aalborg Univ Hosp, Sect Mol Diagnost, Aalborg, Denmark Katholieke Univ Leuven, Univ Hosp Leuven, Louvain, Belgium Univ Western Ontario, Div Gastroenterol, London, ON, Canada Univ Dusseldorf, Dusseldorf, Germany Univ São Paulo, Sch Med, São Paulo, Brazil Univ Zurich Hosp, Swiss HPB Hepatopancreatobiliary Ctr, CH-8091 Zurich, Switzerland Univ Zurich Hosp, Dept Gastroenterol & Hepatol, CH-8091 Zurich, Switzerland Univ Calgary, Liver Unit, Div Gastroenterol & Hepatol, Calgary, AB, Canada Univ Hosp, Div Gastroenterol & Hepatol, Geneva, Switzerland Univ Hosp, Div Clin Pathol, Geneva, Switzerland Natl Inst Publ Hlth, Natl Reference Lab Hepatitis, Prague, Czech Republic Univ Southhampton, Southampton, England Dalhousie Univ, Dept Med, Halifax, NS, Canada Dalhousie Univ, Dept Surg, Halifax, NS B3H 4H2, Canada Capital Dist Hlth Author, Serv Hepatol, Queen Elizabeth II Hlth Sci Ctr, Halifax, NS, Canada Univ British Columbia, Dept Gastroenterol, Vancouver, BC V5Z 1M9, Canada Assembleia Republ, Lisbon, Portugal Alfred Hosp, Melbourne, Vic, Australia Monash Univ, Melbourne, Vic 3004, Australia UCL, UCL Inst Liver & Digest Hlth, Div Med, London, England Ctr Hosp Porto, Dept Infect Dis, Oporto, Portugal JW Goethe Univ Hosp, Frankfurt, Germany Cantonal Hosp St Gallen, Div Gastroenterol & Hepatol, St Gallen, Switzerland Egyptian Liver Res Inst & Hosp ELRIAH, Dakahliah, Egypt Monash Hlth, Melbourne, Vic, Australia Catholic Univ Louvain, Clin Univ St Luc, Brussels, Belgium Med Univ Graz, Dept Internal Med, Div Gastroenterol & Hepatol, Graz, Austria St Vincents Hosp, Dept Gastroenterol, Melbourne, Vic, Australia Univ Melbourne, Melbourne, Vic, Australia Charles Univ Prague, Dept Internal Med, Fac Med 1, Prague, Czech Republic Cent Mil Hosp, Prague, Czech Republic Deutsch Leberhilfe eV, Cologne, Germany Ghent Univ Hosp, Ghent, Belgium Univ Ghent, B-9000 Ghent, Belgium Hasselt Univ, Dept Hlth Econ & Patient Safety, Diepenbeek, Belgium Med Univ Innsbruck, A-6020 Innsbruck, Austria Natl Liver Inst, Menoufia, Egypt Copenhagen Univ Hosp, Hvidovre, Denmark Univ New S Wales, St George Hosp Clin Sch Med, Sydney, NSW, Australia Univ New S Wales, Sch Med Sci, Sydney, NSW, Australia Univ Antwerp, B-2020 Antwerp, Belgium Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden Karolinska Univ Hosp, Dept Gastroenterol & Hepatol Infect Dis, Stockholm, Sweden Universidade Federal de São Paulo, Div Gastroenterol, São Paulo, Brazil Universidade Federal de São Paulo, Div Infect Dis, São Paulo, Brazil Web of Science

Hepatitis B virus (HBV) is a major cause of acute and chronic liver inflammation worldwide. The immune response against the virus represents a key factor in determining infection outcome, in terms of both viral clearance and the perpetuation of liver damage. Significant advances have recently been achieved regarding the functions of antiviral CD8+ T cells, leading to a better understanding of their abnormalities during chronic infection as well as the pathways to be manipulated to reverse the immune impairment of chronic infection. In this review, we aimed to analyse the patterns of adaptive immunity that develop during acute infection and the profiles in chronic infection. In addition to CD8+ T cells, which are the best-described subset to date, we reviewed and commented on the direct and indirect roles of CD4+ T cells and B cells.

Background & Aims: The immune impairment characterizing chronic hepatitis B (cHBV) infection is thought to be the consequence of persistent exposure to viral antigens. However, the immune correlates of different clinical stages of cHBV and their relation with different levels of HBsAg have not been investigated. The aim of the present study was to evaluate the relationship between HBV-specific T cells response and the degree of in vivo HBV control and HBsAg serum levels in HBeAg-HBeAb+ cHBV. Methods: Peripheral blood mononuclear cells from 42 patients with different clinical profiles (treatment-suppressed, inactive carriers and active hepatitis) of cHBV, 6 patients with resolved HBV infection and 10 HBV-uninfected individuals were tested with overlapping peptides spanning the entire HBV proteome. The frequency and magnitude of HBV-specific T cell responses was assessed by IFNc ELISPOT assay. Serum HBsAg was quantified with a chemiluminescent immunoassay. Results: The total breadth and magnitude of HBV-specific T cell responses did not differ significantly between the four groups. However, inactive carriers targeted preferentially the core region. In untreated patients, the breadth of the anti-core specific T cell response was inversely correlated with serum HBsAg concentrations as well as HBV-DNA and ALT levels and was significantly different in patients with HBsAg levels either above or below 1000 IU/mL. The same inverse association between anti-core T cell response and HBsAg levels was found in treated patients. Conclusions: Different clinical outcomes of cHBV infection are associated with the magnitude, breadth and specificity of the HBV-specific T cell response. Especially, robust anti-core T cell responses were found in the presence of reduced HBsAg serum levels, suggesting that core-specific T cell responses can mediate a protective effect on HBV control.

Background & Aims: A better understanding of the immunomodulatory effects of PegIFNa therapy could allow more rational optimisation of future therapeutic approaches in chronic HBV infection. In this study, we evaluated dynamic changes in the innate and adaptive arms of the immune system induced by PegIFNa. Methods: PBMC were obtained from a cohort of patients with eAg-negative CHB before, during and after PegIFNa treatment. The number, phenotype and function of global and virus-specific T cells and NK cells were analyzed by flow cytometry and serum cytokines by ELISA or CBA. Results: The absolute number of CD8 T cells was strikingly reduced on PegIFNa therapy (p

Background & Aims The main limitation of orthotopic liver transplantation (OLT) is the scarcity of available donor organs. A possibility to increase the organ pool is to use grafts from hepatitis B virus surface antigen (HBsAg) positive donors, but few data are currently available in this setting. We assessed the clinical, serovirological, and immunological outcomes of liver transplant from HBsAg positive donors in a single centre study. Methods From 2005 to 2009 10 patients underwent OLT from HBsAg positive donors, for HBV-related disease (n=6) or HBV-unrelated disease (n=4). The median follow-up was 42months (range 12–60). All recipients were HBcAb positive and were given antiviral prophylaxis. Results Patients transplanted for HBV-related disease never cleared HBsAg. Two HBsAg negative patients never tested positive for HBsAg, whereas the others experienced an HBsAg appearance, followed by spontaneous production of anti-HBs, allowing HBsAg clearance. No patient ever had any sign of HBV hepatitis. HBV replication was effectively controlled by antiviral therapy. The immunologic sub-study showed that a most robust anti-HBV specific T cell response was associated with the control of HBV infection. Conclusions OLT from HBsAg positive donors seems to be a safe procedure in the era of highly effective antiviral therapy.

The medical care of patients with liver cirrhosis is complex, since the liver is involved in a large number of physiological processes. Here, we provide a concise overview on clinical aspects relevant to daily medical practice. We find the distinction between compensated and decompensated liver disease clinically useful to stratify patients according to the risk of complications. This assessment determines the type and intensity of medical controls. Patients and their families have to be instructed about the types of complications they risk to encounter and they have to be able to recognize alarming symptoms in order to seek medical attention in a timely manner.

Since the arrival of several new antivirals and due to the growing molecular and clinical knowledge of hepatitis B virus (HBV) infection, therapy of hepatitis B has become complex. Clinical guidelines aim at streamlining medical attitudes: in this respect, the European Association for the Study of the Liver (EASL) recently issued clinical practice guidelines for the management of chronic hepatitis B. Guidelines made by international experts need however to be adapted to local health care systems. Here, we summarise the EASL guidelines with some minor modifications in order to be compatible with the particular Swiss situation, while discussing in more detail some aspects. Chronic hepatitis B is a complex disease with several phases where host and viral factors interact: the features of this continuous interplay need to be evaluated when choosing the most appropriate treatment. The EASL guidelines recommend, as first-line agents, using the most potent antivirals available with the optimal resistance profile, in order to abate HBV DNA as rapidly and as sustainably as possible. Once therapy has been started, the infection evolves and resistant viral strains may emerge. Rescue therapy needs to be started early with more potent agents lacking cross-resistance.

Background Hepatitis B immune globulins (HBIG) in combination with nucleos(t)ide analogues (NA) are effectively used for the prevention of hepatitis B virus (HBV) recurrence after liver transplantation (LT). However, associated treatment costs for HBIG are exceedingly high. Methods Fresh frozen plasma obtained from blood donors with high anti-HBs levels (hyperimmune plasma, HIP) containing at least 4,500 IU anti-HBs was used as alternative treatment for HBV recurrence prophylaxis post-LT. Results Twenty-one HBV-related LT recipients received HIP starting at transplantation, followed by long-term combination treatment with NA. Mean follow-up time was 4.5 years (range 0.5-12.6) and each patient received on average 8.2 HIP per year (range 5.8-11.4). Anti-HBs terminal elimination kinetic after HIP administration was 20.6 days (range 13.8-30.9), which is comparable to values reported for commercial HBIG products. All 21 patients remained free of HBV recurrence during follow-up and no transfusion-transmitted infection or other serious complication was observed. Seven patients developed reversible mild transfusion reactions. The cost for one HIP unit was US$140; average yearly HBIG treatment cost was US$1,148 per patient, as compared to US$25,000-100,000 for treatment with commercial HBIG. Conclusion The results of this study suggest that the use of HIP may be a useful and economical approach for the prevention of HBV recurrence post-LT if used in combination with NA. Additional prospective controlled studies in larger populations are needed to confirm these results.

Antiretroviral-therapy has dramatically changed the course of HIV infection and HIV-infected (HIV(+)) individuals are becoming more frequently eligible for solid-organ transplantation. However, only scarce data are available on how immunosuppressive (IS) strategies relate to transplantation outcome and immune function. We determined the impact of transplantation and immune-depleting treatment on CD4+ T-cell counts, HIV-, EBV-, and Cytomegalovirus (CMV)-viral loads and virus-specific T-cell immunity in a 1-year prospective cohort of 27 HIV(+) kidney transplant recipients. While the results show an increasing breadth and magnitude of the herpesvirus-specific cytotoxic T-cell (CTL) response over-time, they also revealed a significant depletion of polyfunctional virus-specific CTL in individuals receiving thymoglobulin as a lymphocyte-depleting treatment. The disappearance of polyfunctional CTL was accompanied by virologic EBV-reactivation events, directly linking the absence of specific polyfunctional CTL to viral reactivation. The data provide first insights into the immune-reserve in HIV+ infected transplant recipients and highlight new immunological effects of thymoglobulin treatment. Long-term studies will be needed to assess the clinical risk associated with thymoglobulin treatment, in particular with regards to EBV-associated lymphoproliferative diseases.

Chronic hepatitis E virus infection in liver transplant recipients. Haagsma EB, van den Berg AP, Porte RJ, Benne CA, Vennema H, Reimerink JH, Koopmans MP. Hepatitis E virus (HEV) infection is known to run a self-limiting course. Sporadic cases of acute hepatitis due to infection with HEV genotype 3, present in pig populations, are increasingly recognized. Zoonotic transmission seems infrequent. The entity of unexplained chronic hepatitis after liver transplantation has been recognized. Detection of HEV in 2 liver transplant recipients triggered a review of these cases. Freeze-stored sera were available for retrospective analysis. HEV antibodies were determined. For virus detection and identification, a fragment of the gene encoding the major capsid protein (open reading frame 2) was amplified by reverse-transcription polymerase chain reaction and sequenced to identify the genotype. Two months after liver transplantation, case A developed unexplained chronic hepatitis, which developed into cirrhosis. Retransplantation followed 7 years later, after which chronic hepatitis recurred. In retrospect, HEV RNA was present in serum 3 weeks after the first transplantation and remained present afterwards. HEV RNA was also present in retransplant liver tissue. HEV antibodies appeared late after retransplantation. Case B developed unexplained chronic hepatitis 7 years after transplantation. Retransplantation was needed 5 years later, after which no signs of hepatitis recurred. In retrospect, the period of chronic hepatitis up to the retransplantation coincided with HEV RNA in serum. In case B, antibodies developed, the viral load was much lower than in case A, and the virus seemed to be cleared after retransplantation. Genotyping in both cases revealed 2 unique strains of genotype 3. In conclusion, chronic HEV infection may develop in immunosuppressed patients, who may then serve as long-term carriers of the virus. We hypothesize that HEV may be the cause of chronic hepatitis in liver transplant recipients. (c) 2008 AASLD. [Abstract reproduced by permission of Liver Transpl 2008;14:547–553]. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. Kamar N, Selves J, Mansuy JM, Ouezzani L, Peron JM, Guitard J, Cointault O, Esposito L, Abravanel F, Danjoux M, Durand D, Vinel JP, Izopet J, Rostaing L. Hepatitis E virus (HEV) is considered an agent responsible for acute hepatitis that does not progress to chronic hepatitis. We identified 14 cases of acute HEV infection in three patients receiving liver transplants, nine receiving kidney transplants, and two receiving kidney and pancreas transplants. All patients were positive for serum HEV RNA. Chronic hepatitis developed in eight patients, as confirmed by persistently elevated aminotransferase levels, serum HEV RNA, and histologic features of chronic hepatitis. The time from transplantation to diagnosis was significantly shorter and the total counts of lymphocytes and of CD2, CD3, and CD4 T cells were significantly lower in patients in whom chronic disease developed. [Abstract reproduced by permission of N Engl J Med 2008;358:811–817].

The hepatitis E virus (HEV), known for being the cause of major outbreaks of waterborne hepatitis in Asia and Africa, is an emerging pathogen in industrialized countries. Virologic analyses of sporadic cases in Europe, Japan and the United States have shown that the origin of the infection was through autochthonous viral strains suggesting that the virus is present locally. In addition, transmission is not only enterically through contaminated water but also through ingestion of undercooked infected meat (swine or wild animals) or through infected blood products. Recently, a persistent HEV infection with chronic hepatitis and cirrhosis has been reported in patients with reduced immune surveillance as induced by chemotherapy or post-transplant immunesuppression.