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Background & Aims There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients. Methods Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients. Results Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12. Conclusions VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients. Lay summary The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%).

Introduction The risk of hepatocellular carcinoma persists in some patients despite achieving sustained virologic response with current interferon‐free direct‐acting antiviral therapy for hepatitis C. The subject of an even higher carcinoma risk in this context has been reported and is currently being debated. The quest for understanding this paradox relative to the dynamics of inflammatory biomarkers in cirrhosis patients receiving antiviral therapy thus remains a subject of importance. Objective Here, we aimed at evaluating the effects of direct‐acting antiviral therapy‐induced hepatitis C cure on plasmatic markers of systemic inflammation measured before, during and after treatment. Specifically, soluble immune mediator phenotype associations that impact the odds of hepatocellular carcinoma development and the related changes that arise upon direct‐acting antiviral‐mediated hepatitis C clearance in cirrhosis patients was investigated. Methods Employing multiplex technology that measured up to 91 circulating biomarker proteins, we profiled the plasma soluble immune mediator concentrations of cirrhosis patients who developed posttreatment hepatocellular carcinoma and their respective negative controls, before and after direct‐acting antiviral treatment. Results Elevated pretherapy concentrations of specific soluble immune mediators including MCP‐3, GDNF, CDCP1, IL‐17C, IL‐17A, signalling lymphocytic activation family 1, CCL11, FGF‐5, LIF‐R, interleukin 10 (IL‐10), IL‐10RA, IL‐15RA, beta NGF, CCL28, CCL25 and NT‐3 distinguished patients who developed posttreatment hepatocellular carcinoma relative to those that did not. Particularly, GDNF, FGF‐5 and IL‐15RA displayed independent predictive biomarker attributes for delineating carcinoma emergence regardless of de novo or recurrence groupings. Upon successful therapy, the elevated pretherapy soluble immune mediator establishment of the patients who eventually developed hepatocellular carcinoma stayed largely unperturbed whereas a panel of some 38 soluble immune mediators in the posttherapy carcinoma‐free patients experienced significant ameliorations. Conclusions These results have considerable implications for delineating potential hepatocellular carcinoma emergence before initiating direct‐acting antiviral therapy for hepatitis C in cirrhosis patients. They provide preliminary contribution to unravelling cases where the benefit of direct‐acting antiviral therapies would be superior to the risk of developing carcinoma., Key Summary Established knowledge on this subject Current interferon (IFN)‐free direct‐acting antivirals (DAAs) are effective at eliminating hepatitis C virus (HCV), but risks of residual liver disease and development of hepatocellular carcinoma persists.The hepatic inflammation that occurs during chronic hepatitis C causes systemic changes in blood soluble immune mediators (SIMs) that impact carcinogenetic processes involved in the growth, invasion and metastasis of hepatocellular carcinoma (HCC).DAA‐induced HCV cure does not lead to a complete immunological restitution of the altered soluble inflammatory compartment in chronic hepatitis C. Significant and/or new findings of this study An elevated pre‐therapy plasma profile of an extended repertoire of SIMs in cirrhosis was associated with HCC development post‐DAA therapy.Successful DAA therapy did not alter the baseline elevated plasma SIM profile of cirrhosis patients that developed post‐therapy HCC contrary to its effect in those that remained HCC‐free.

Unconventional T cells (UTCs) are a heterogenous group of T cells that typically exhibit rapid responses towards specific antigens from pathogens. Chronic hepatitis C virus (HCV) infection causes dysfunction of several subsets of UTCs. This altered phenotype and function of UTCs can persist over time even after direct acting antiviral (DAA) mediated clearance of chronic HCV. However, it is less clear if and how UTCs respond in acute, symptomatic HCV infection, a rare clinical condition, and if rapid DAA treatment of such patients reverses the caused perturbations within UTCs. Here, we comprehensively analyzed the phenotype and reinvigoration capacity of three major UTC populations, mucosal associated invariant T (MAIT) cells, γδ T cells, and CD4 and CD8 double-negative αβ T cells (DNT cells) before, during, and after DAA-mediated clearance of acute symptomatic HCV infection. Furthermore, MAIT cell functionality was systematically studied. We observed a reduced frequency of MAIT cells. However, remaining cells presented with a near-to-normal phenotype in acute infection, which contrasted with a significant dysfunction upon stimulation that was not restored after viral clearance. Notably, DNT and γδ T cells displayed a strong activation ex-vivo in acute HCV infection, which subsequently normalized during the course of treatment. In addition, DNT cell activation was specifically associated with liver inflammation and inflammatory cytokines. Altogether, these data provide evidence that UTCs respond in a cell type-specific manner during symptomatic HCV infection. However, even if early treatment is initiated, long-lasting imprints within UTCs remain over time. This article is protected by copyright. All rights reserved.

Background Treatment with direct-acting antivirals (DAAs) in patients with chronic hepatitis C infection leads to partial restoration of soluble inflammatory mediators (SIMs). In contrast, we hypothesized that early DAA treatment of acute hepatitis C virus (HCV) with DAAs may normalize most SIMs. Methods In this study, we made use of a unique cohort of acute symptomatic hepatitis C patients who cleared HCV with a 6-week course of ledipasvir/sofosbuvir. Plasma samples were used for proximity extension assay measuring 92 proteins. Results Profound SIM alterations were observed in acute HCV patients, with marked upregulation of interleukin (IL)-6 and CXCL-10, whereas certain mediators were downregulated (eg, monocyte chemoattractant protein-4, IL-7). During treatment and follow-up, the majority of SIMs decreased but not all normalized (eg, CDCP1, IL-18). Of note, SIMs that were downregulated before DAA treatment remained suppressed, whereas others that were initially unchanged declined to lower values during treatment and follow-up (eg, CD244). Conclusions Acute hepatitis C was associated with marked changes in the soluble inflammatory milieu compared with both chronic hepatitis patients and healthy controls. Whereas early DAA treatment partly normalized this altered signature, long-lasting imprints of HCV remained.

Bulevirtide is a first-in-class peptidic entry inhibitor for hepatitis B virus (HBV) and hepatitis D virus infection. In July, 2020, bulevirtide 2 mg received conditional marketing authorisation by the European Medical Agency for treatment of chronic hepatitis D virus infection. We investigated the antiviral activity of bulevirtide in patients chronically infected with HBV and hepatitis D virus.MYR202 (ClinicalTrials.gov, NCT03546621; EudraCT, 2016-000395-13) was a multicentre, parallel-group, randomised, open-label, phase 2 trial. Adults (aged 18-65 years) with chronic hepatitis D virus infection, including patients with cirrhosis and patients who had contraindications to PegIFNα treatment or for whom treatment did not work, were eligible and were enrolled from four hospitals in Germany and 12 hospitals in Russia. Patients were randomly assigned (1:1:1:1) to receive 2 mg (n=28), 5 mg (n=32), or 10 mg (n=30) subcutaneous bulevirtide once per day with tenofovir disoproxil fumarate (TDF; 245 mg once per day orally) or TDF alone (245 mg once per day orally; n=30) for 24 weeks. Randomisation was done using a digital block scheme with stratification, consisting of 480 randomisation numbers separated into 30 blocks. The primary endpoint was undetectable hepatitis D virus RNA or 2 logBetween Feb 16, 2016, and Dec 8, 2016, 171 patients with chronic hepatitis D virus infection were screened; 51 were ineligible based on the exclusion criteria and 120 patients (59 with cirrhosis) were enrolled. At week 24, 15 (54%, 95% CI 34-73) of 28 patients achieved undetectable hepatitis D virus RNA or a 2 logBulevirtide induced a significant decline in hepatitis D virus RNA over 24 weeks. After cessation of bulevirtide, hepatitis D virus RNA concentrations rebounded. Longer treatment durations and combination therapies should be investigated.Hepatera LLC, MYR GmbH, and the German Centre for Infection Research, TTU Hepatitis.

Recurrence or de novo infection of hepatitis C virus (HCV) after liver transplantation (LT) has been associated with progressive graft hepatitis that can be improved by treatment with novel direct-acting antivirals. Cases of rejection episodes have been described during and after HCV treatment. The evolution of innate and adaptive immune response during and after cure of HCV LT is unknown. We studied 74 protein biomarkers in the plasma of LT patients receiving antiviral therapy. In addition, deep immune phenotyping of both the myeloid and lymphoid immune cell subsets in peripheral blood mononuclear cells was performed. We found that LT patients with active HCV infection displayed distinct alterations of inflammatory protein biomarkers, such as C-X-Cmotif chemokine 10 (CXCL10), caspase 8, C-C motif chemokine 20 (CCL20), CCL19, interferon γ, CUB domain-containing protein 1 (CDCP1), interleukin (IL)-18R1, CXCL11, CCL3, IL8, IL12B, tumor necrosis factor-beta, CXCL6, osteoprotegerin, IL10, fms-related tyrosine kinase 3 ligand, hepatocyte growth factor, urokinase-type plasminogen activator, neurotrophin-3, CCL4, IL6, tumornecrosis factor receptor superfamily member 9, programmed death ligand 1, IL18, and monocyte chemotactic protein 1, and enrichment of peripheral immune cell subsets unlike patients without HCV infection who received transplants. Interestingly, patients who cleared HCV after LT did not normalize the altered inflammatory milieu nor did the peripheral immune cell subsets normalize to what would be seen in the absence of HCV recurrence. Overall, these data indicate that HCV-specific imprints on inflammatory analytes and immune cell subsets after LT are not completely normalized by therapy-induced HCV elimination. This is in line with the clinical observation that cure of HCV after LT did not trigger rejection episodes in many patients.

Background With the introduction of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection, drug–drug interactions (DDIs) emerged as significant challenge. Since then, HCV therapy and the infected population have rapidly changed. So far, very limited data are available regarding the clinical relevance of DDIs when using most modern DAA regimens. We aimed to assess how the importance of DDIs has evolved over time. Methods From January 2014 to July 2018, 668 consecutive HCV patients were evaluated for their outpatient medication and assessed for DDIs with DAAs. Different time periods were defined based on market approval of key DAAs: A (01/2014–11/2014), B (11/2014–08/2016), and C (08/2016–07/2018). Results The frequency of patients with real-world DDIs was highest in period B (A: 37.1%, B: 49.6%, C: 38.8%). The recently approved DAAs (period C) theoretically showed a lower DDI risk profile. However, real-world DDIs were still comparable to period A, as HCV patients’ characteristics changed (eg, age ≥75 years: A: 3.1%, B: 9.8%, C: 5.6%; polypharmacy/patients with ≥8 drugs: A: 11.1%, B: 15.2%, C: 17.2%). Furthermore, although DDIs via CYP 3A4 became less important for some modern regimens, other mechanisms like an altered pH value in the stomach, causing reduced bioavailability, evolved. Relevant DDIs most frequently occurred with proton pump inhibitors, metamizole, statins, and carvedilol. Conclusions DDIs during antiviral treatment still affect about 40% of HCV patients. The lower DDI potential of modern DAA regimens is partly counteracted by changing patient characteristics. Therefore, DDIs should not be underestimated.

BACKGROUND & AIMS Ribavirin (RBV) is commonly used for the treatment of hepatitis C virus (HCV) infection. However, RBV is associated with a reduced quality of life (QOL). We aim to assess the impact of RBV on QOL in a real-world setting. METHODS In a prospective study, QOL was measured by a SF-36 questionnaire in 174 patients. In all, 85 patients were treated with RBV and 89 patients without RBV. QOL was assessed at baseline, week 12 of treatment and 24 weeks after treatment. RESULTS Patients treated with RBV were more likely to have HCV genotype 2 and 3 infection and cirrhosis (all P

Background and aim The advent of direct-acting antivirals has revolutionized treatment of chronic hepatitis C with very high cure rates and excellent tolerability compared to interferon-based hepatitis C virus (HCV) treatment. However, long-term effects of interferon-free cure of HCV infection on the metabolic condition of patients have not been investigated so far. Methods We investigated weight development during and after antiviral treatment of hepatitis C. In a prospective single-center cohort study, interferon-free antiviral treatment was initiated in 284 patients. Each patient’s weight was monitored 1 year before the start of treatment, at baseline (BL), end of treatment (EOT), follow-up week 24 (FU24), and follow-up week 48 (FU48). Results Weight gain after HCV cure was observed in 20 %, 33 %, and 44 % of patients at EOT, FU24, and FU48, respectively. The mean overall weight change at FU48 compared to baseline was 1.45 kg (95 % CI 0.44; 2.46, p = 0.02, compared to the pretreatment period). Multivariate regression revealed age as the only factor predicting weight change at FU48 (B − 0.107, 95 % CI, − 0.202 to − 0.011, p = 0.03), while gender, cirrhosis, diabetes mellitus, ribavirin, and body mass index had no influence. In the subgroup of patients younger than 60 years, mean weight gain at FU48 compared to baseline was 2.8 kg (95 % CI, 1.23 – 4.4). In contrast, patients 60 years and older had a mean weight change of − 0.04 kg (95 % CI, − 1.12 to 1.03, p = 0.005). Conclusions Cure of HCV by interferon-free antiviral treatment was associated with weight gain in up to 44 % of patients during long-term follow-up. Weight gain occurred predominantly in patients younger than 60 years. The precise mechanism of weight gain remains to be elucidated.

Refractory ascites has a poor prognosis. Recurrent large-volume paracentesis is the current standard of care; however, it results in circulatory dysfunction and renal dysfunction, and hospitalization is commonly required. Transjugular intrahepatic portosystemic shunt placement is not an option in a substantial number of patients because of contraindications. The placement of a tunneled peritoneal drainage catheter has been shown to be effective in patients with malignant ascites. However, data in patients with nonmalignant refractory ascites are rare.We followed 24 consecutive patients in whom tunneled peritoneal drainage catheters were placed in the Endoscopy Unit at Hannover Medical School between June 2013 and December 2014.Catheters were placed in 24 patients with refractory ascites in end-stage liver disease and with a contraindication to transjugular intrahepatic portosystemic shunt placement. Placement was technically successful in all patients. The dosage of diuretics could be reduced significantly. The number of paracentesis decreased from 2.2±1 to 0 per week, although the volume of daily ascites removal remained stable (2 l). Despite frequent drainage of ascites, kidney function, serum sodium, and serum albumin remained stable. Seven adverse events occurred in six (25%) patients. Five patients listed for liver transplantation underwent successful transplantation without a negative impact.The tunneled peritoneal drainage catheter placement is a viable and effective treatment alternative in patients with refractory ascites because of end-stage liver disease, reducing diuretic intake and the need for paracentesis. The procedure avoids hyponatremia, worsening kidney function, and albumin infusions without an increased risk of spontaneous bacterial peritonitis.

Summary Background Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25–30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown. We aimed to explore whether prolonged treatment of HDV with 96 weeks of peginterferon would increase HDV RNA response rates and reduces post-treatment relapses. Methods We did two parallel, investigator-initiated, multicentre, double-blind randomised, controlled trials at 14 study sites in Germany, Greece, Romania, and Turkey. Patients with chronic HDV infection and compensated liver disease who were aged 18 years or older were eligible for inclusion. All patients were HBsAg positive for at least 7 months, anti-HDV positive for at least 3 months, and HDV-RNA positive at the local laboratory at the screening visit. Patients were ineligible if alanine aminotransferase levels were higher than ten times above the upper limit of normal and if platelet counts were lower than 90 000 per μL, or if they had received interferon therapy or treatment with a nucleoside and nucleotide analogue within the preceding 6 months. Patients were randomly assigned by blinded stratified block randomisation (1:1) to receive 180 μg of peginterferon alfa-2a weekly plus either TDF (300 mg once daily) or placebo for 96 weeks. The primary endpoint was the percentage of patients with undetectable HDV RNA at the end of treatment assessed by intention to treat. The trials are registered as NCT00932971 and NCT01088659 . Findings Between June 24, 2009, and Feb 28, 2011, we randomly assigned 59 HDV RNA-positive patients to receive peginterferon alfa-2a plus TDF and 61 to receive peginterferon alfa-2a plus placebo, including 48 (40%) patients with cirrhosis to the two treatment groups (23 in the peginterferon alfa-2a plus TDF group and 25 in the peginterferon alfa-2a plus placebo group). The primary endpoint was achieved in 28 (48%) of 59 patients in the peginterferon alfa-2a plus TDF group and in 20 (33%) of 61 patients in the peginterferon alfa-2a plus placebo group (odds ratio 1·84, 95% CI 0·86–3·91, p=0·12). We recorded 944 adverse events (459 in the peginterferon alfa-2a plus TDF group and 485 in the peginterferon alfa-2a plus placebo group). The most common adverse events were haematological, behavioural (eg, fatigue), musculoskeletal, influenza-like syndromes, and psychiatric complaints. Interpretation Addition of TDF resulted in no significant improvement in HDV RNA response rates at the end of treatment. These findings highlight that alternative treatment options are needed for hepatitis D. Funding The HepNet Study-House (a project of the German Liver Foundation founded by the German Liver Foundation, the German Ministry for Education and Research, and the German Center for Infectious Disease Research), Hoffmann-La Roche, and Gilead Sciences.

BACKGROUND: Hepatitis delta is the most severe form of viral hepatitis. Pegylated interferon alfa (PEG- IFNα) is effective in only 25-30% of patients and is associated with frequent side effects. The aim of this study was to analyze the clinical long-term outcome of hepatitis delta in relation to different antiviral treatment strategies. METHODS: We studied 136 anti-HDV-positive patients who were followed for at least 6 months in a retrospective single-center cohort (mean time of follow up 5.2 years; range 0.6 -18.8 years). Liver cirrhosis was already present in 62 patients at first presentation. 29% of patients did not receive any antiviral treatment, 38% were treated with interferon alfa-based therapies, and 33% received nucleos(t)ide analogues (NA) only. RESULTS: Clinical endpoints defined as hepatic decompensation (ascites, encephalopathy, variceal bleeding), hepatocellular carcinoma, liver transplantation and liver-related death developed in 55 patients (40%). Patients who received IFNα-based therapies developed clinical endpoints less frequently than patients treated with NA (p=0.02, HR: 4.0) or untreated patients (p=0.05, HR: 2.2) (17%, 64% and 44%) respectively, which was significant in both chi-square and Kaplan-Meier analysis. In addition, considering various clinical and virological parameters, IFNα therapy was independently associated with a more benign clinical long-term outcome in multivariate logistic regression analysis (p=0.04, OR: 0.25, 95% CI: 0.07 – 0.9). Loss of HDV RNA during follow-up was more frequent in IFNα-treated patients and strongly linked with a lower likelihood to experience liver-related complications. CONCLUSIONS: IFNα-based antiviral therapy of hepatitis delta was independently associated with a lower likelihood for clinical disease progression. Durable undetectability of HDV RNA is a valid surrogate endpoint in the treatment of hepatitis delta. This article is protected by copyright. All rights reserved.

This prospective study investigated viral and host markers after stopping long-term therapy with nucleos(t)ide analogues in noncirrhotic patients with hepatitis B e antigen-negative chronic hepatitis B. After stopping therapy, 13 of 15 patients experienced a virological relapse. Rebound of hepatitis B virus DNA and hepatitis B core-related antigen was associated with induction of plasma tumor necrosis factor, interleukin (IL) 10 , IL-12p70, CXCL10 and subsequent decline in hepatitis B surface antigen (HBsAg), with 20% HBsAg loss after long-term follow-up. The peak levels of hepatitis B virus DNA and hepatitis B core-related antigen after cessation of therapy were positively correlated with the level of HBsAg decline at week 48. Thus, stopping or interrupting NA treatment should be further investigated as a strategy to accelerate HBsAg loss.

Background Hepatitis C virus (HCV) clearance with IFN-based therapies reduces the incidence of hepatocellular carcinoma (HCC). There has been some debate if IFN-free therapy with direct-acting antivirals alters the risk for HCC. Aim To investigate the HCC incidence in cirrhotic HCV patients who cleared HCV with direct-acting antivirals vs untreated controls. Methods We prospectively monitored 373 patients with chronic hepatitis C who received IFN-free therapies with direct-acting antiviral after January 2014. A retrospective control cohort of untreated cirrhotic patients was recruited out of 3715 HCV patients who were followed at our centre between 2007 and 2013, with similar HCC screening protocols. Results 158 direct-acting antiviral-treated and 184 control patients with liver cirrhosis were included in this analysis. The groups did not differ in gender and genotype distribution, severity of liver disease and prevalence of diabetes mellitus. Patients were followed up for a median of 440 (range 91-908) and 592 (range 90-1000) days. HCCs developed in 6 and 14 patients during follow-up, resulting in an incidence of 2.90 vs 4.48 HCCs per 100 person-years. In the direct-acting antiviral-treated group, there was no new case of HCC later than 450 days after treatment initiation. In multivariate analysis, higher MELD-Scores and AFP-levels were independently associated with HCC development. Transplant-free patient survival was similar in both groups. Conclusions IFN-free direct-acting antiviral therapy of chronic hepatitis C does not alter the short-term risk for HCC in patients with liver cirrhosis. A reduced HCC incidence may become evident after more than 1.5 years of follow-up.

SummaryBackground Successful antiviral treatment of decompensated hepatitis B with HBV polymerase inhibitors is associated with improvement of liver function. To what extent liver function also improves in cirrhotic patients with chronic hepatitis C receiving novel interferon-free (IFN-free) therapies is unknown. Aim To study liver function in cirrhotic HCV patients receiving IFN-free therapies. Methods We here studied 80 consecutive patients with advanced HCV associated liver cirrhosis including 34 patients (43%) with Child B/C cirrhosis and 42 patients (53%) with platelet counts of

Objective Although hepatitis delta is considered an immune-mediated disease, adaptive immune responses to hepatitis delta virus (HDV) are hardly detectable. Thus, the role of other immune responses, including those mediated by natural killer (NK) cells, must be considered in HDV pathogenesis and in treatments with immune-stimulating agents such as interferon (IFN)α. However, the phenotype and function of NK cells in chronic HDV infection, or in HDV-infected individuals undergoing IFNα treatment, have not been extensively studied. Design We performed an extensive analysis of NK cells in chronically HDV-infected patients before and during treatment with IFNα, and compared the results with those for patients with HBV mono-infection as well as healthy controls. Results In untreated HDV-infected patients, a higher than normal frequency of NK cells was observed in peripheral blood with unaltered phenotypic NK cell differentiation status. In contrast, long-term IFNα treatment of HDV-infected patients caused a significant change in NK cell differentiation status, with selective loss of terminally differentiated NK cells and, in parallel, a relative enrichment in immature NK cell subsets. Treatment was associated with marked functional impairment of the NK cells, which was independent of the changes in NK cell differentiation status. Furthermore, treatment polarised NK cell IFN signalling from STAT4 towards STAT1 dependency. Strikingly, a high frequency of CD56 dim NK cells at baseline was positively associated with IFNα treatment outcome in the patients. Conclusions We describe in detail how HDV infection, and IFNα treatment of this infection, affects the NK cell compartment and what consequences this has for the functional capacity of NK cells.

Summary Background Drug–drug interactions (DDIs) in the treatment of chronic hepatitis C infection became a potential challenge with the introduction of direct-acting anti-virals (DAAs). Both currently approved DAAs, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), are substrates and inhibitors of P-glycoprotein and the cytochrome P450 3A4, which are regularly involved in DDIs. Aim To analyse the risk for DDIs in patients with chronic HCV genotype 1 infection considered for PI treatment at a tertiary referral centre. Methods The first 115 consecutive patients selected for a PI therapy at Hannover Medical School were included. All changes to co-medication before and during PI treatment were documented. Drugs were checked for DDIs with TVR and BOC using DDI websites and the respective prescribing information. Results Out-patient medication contained 116 different drugs. Median number of drugs/patient was 2 (range 0–11). The risk for DDIs was substantial for 38% of the drugs affecting 49% of patients. Only 4% of the drugs were strictly contraindicated. DDIs between a PI and drugs newly prescribed during anti-viral therapy were considerable in 42% of the patients. Suspected DDIs were managed by dose adjustments and discontinuation of co-medication in 7% and 21% of the patients respectively. Conclusions Many patients with chronic HCV genotype 1 infection are affected by potential DDIs if treated with a protease inhibitor, but only in a minority of cases co-medication is strictly incompatible. Overall, the challenge of DDIs is time-consuming, but well manageable by a careful review of the patient's drug chart and monitoring during treatment.

Background With the approval of direct-acting antivirals (DAAs), the management of drug-drug interactions (DDIs) has become an important challenge while treating individuals with hepatitis C. To date, the potential of causing DDIs for the recently approved DAAs has not been systematically investigated. We aimed to assess the clinical significance of DDI between the regular outpatient medications and DAA therapies in a large real-world cohort. Methods Overall, 261 hepatitis C virus monoinfected patients who were selected for DAA therapy at 2 intervals between 2011 and 2014 were asked about their regular outpatient medications. The potential for DDIs between all these drugs and sofosbuvir/ribavirin, ledipasvir/sofosbuvir, sofosbuvir/daclatasvir, sofosbuvir/simeprevir, ombitasvir/paritaprevir/ritonavir ± dasabuvir as well as boceprevir and telaprevir triple therapy was assessed using www.hep-druginteractions.org and the relevant prescribing information. Results The 261 patients took a median number of 2 drugs (range 0-15); 20% of patients did not take any medication. Sofosbuvir/ribavirin had the lowest risk to cause a potentially significant DDI (9.6%). In contrast, for ombitasvir/paritaprevir/ritonavir ± dasabuvir potentially significant DDIs could be expected in 66.3% of the patients. Significant DDIs for sofosbuvir/simeprevir would be expected in 31.4%, for sofosbuvir/daclatasvir in 36.8%, and for sofosbuvir/ledipasvir in 40.2%. Proton pump inhibitors, thyroid hormones, and dihydropyridine derivatives were frequently used and presented a risk of interacting with the antiviral regimen. Conclusions A significant number of patients are at risk for DDIs if treated with the recently approved DAA regimens. A careful evaluation of potential DDI is essential to prevent adverse effects or unnecessary risk of treatment failure.

Background: Effective suppression of HBV DNA with nucleoside or nucleotide analogues (NA) has shown to delay disease progression in patients with chronic hepatitis B. However, HBsAg loss during NA treatment is a rare event. Thus, treatment duration with NA is not finite and stopping rules before HBsAg loss are not clearly defined, especially in HBeAg negative patients. Methods: We prospectively stopped NA treatment in patients with HBeAg negative chronic hepatitis B. Inclusion criteria were ongoing antiviral treatment with NA and suppressed HBV DNA 2000 IU/ml. Quantitative HBsAg levels one year before and after treatment cessation were compared to assess differences in HBsAg levels. Results: Data are available for 13 patients with one year follow-up. Virological relapse after treatment cessation was detected in 4 patients (31%) at week 4, in 7 patients (54%) at week 8 and in 1 patient at week 24. No virological relapse occurred in 1 patient. Two patients developed an ALT flare > 5 ULN. No patient experienced signs of liver failure or significant increase of bilirubin. In 11/12 patients with virological relapse treatment was re-initiated with either entecavir or tenofovir and HBV-DNA was successfully suppressed at week 48 follow-up. HBsAg levels showed no significant decline in the year before cessation of NA treatment (1206 ± 1123 IU/ml vs 1232 ± 999 IU/ml, p = 0.86). However, treatment cessation resulted in a significant decline in mean HBsAg levels from baseline to 48 week follow-up (1232 ± 999 IU/ml vs 760 ± 709 IU/ml, p = 0.0012). Interestingly, both patients with ALT flares > 5 ULN showed a decline of HBsAg levels > 2 log from baseline to week 48 follow-up. Conclusion: Treatment cessation in HBeAg negative chronic hepatitis B is safe but leads to virological relapse in > 90% of patients until week 24. However, treatment cessation led to a significant decline in HBsAg levels with the strongest decline observed in patients with ALT flare > 5 ULN. Thus interrupting NA treatment and inducing ALT flares should be further investigated as an option to facilitate HBsAg loss. Corresponding author: Honer zu Siederdissen, Christoph E-Mail:HoenerzuSiederdissen.Christoph@mh-hannover.de

Background: Recently, it has been shown that considerable drug-drug interactions (DDI) between a first wave protease inhibitor (PI, boceprevir or telaprevir) and the regular outpatient medication affect up to 50% of hepatitis C virus (HCV) infected patients. The lately approved second wave direct-acting antiviral agents (DAA) sofosbuvir (SOF) and simeprevir (SMV) are supposed to be involved in less DDI. However, so far, no data is available regarding the potential benefit in the real-world. We here aimed to evaluate the risk for DDI with the regular outpatient medication during therapy with SOF and SMV in comparison to first wave PIs. Methods: A cohort of 115 patients has been assessed for their concomitant outpatient medication, which importantly also included over-the-counter medicine and herbals. DDI with SMV and SOF have been assessed using different DDI websites and the prescribing information of all analyzed drugs. DDI were assigned to 4 different categories (0 = Classification not possible due to lack of information, 1 = no clinically significant interactions expected, 2 = interaction possible, may need dose adjustment/monitoring, 3 = co-administration not recommended). DDI were also compared to DDI with first-wave PI, which have been previously described in the same cohort (Maasoumy et al. AP&T, 2013). Results: 115 patients took 116 different drugs with mean 2.7 drugs per patient (range 0 – 11). Importantly, category 3 DDI did not occur in any of the patients with either SOF or SMV. This is in contrast to the first wave of PIs, in which 10% of these patients were affected by category 3 DDI (p < 0.0001 for both, SOF and SMV). 3% of the drugs had category 2 DDI with SOF, affecting 3% of the patients. On the contrary, 21% of the drugs had category 2 DDI with SMV, affecting 39% of patients. In comparison, SOF had significantly lower category 2 DDI than first wave PIs and SMV (p < 0.0001). SMV showed a trend to a lower rate of DDIs in comparison to first wave PIs (p = 0,13). In both, SOF and SMV, DDIs could not be assessed for 4% of the concomitant drugs due to lack of information in all of the above mentioned databases, affecting 7% of patients (category 0). This was caused by certain supplements and herbal medications. Conclusion: Treatment with SOF and SMV is associated with a lower potential for DDI in comparison with first-wave PI, especially for category 3 DDI. However, the risk for DDI must not be neglected, as it still affects a significant number of patients, in particular, if SMV is used as part of the therapeutic regimen. Corresponding author: Honer zu Siederdissen, Christoph E-Mail:hoenerzusiederdissen.christoph@mh-hannover.de

Background & Aims Several real world data demonstrated that eligibility for and tolerability of triple therapy against hepatitis C virus (HCV) infection with a first-wave protease inhibitor is limited. With the approval of sofosbuvir (SOF) effective treatment with and without pegylated interferon (PEG-IFN) has become available for most genotypes. However, no data are available regarding the added benefit of an interferon-free treatment concerning eligibility and tolerability in a real-world scenario. We aimed to assess the eligibility and safety of SOF based therapies in patients with primarily advanced cirrhosis, including decompensated cirrhosis, in a real-world setting. Results In total, 207 patients were evaluated for a SOF based treatment with and without PEG-IFN. Twenty-six patients did not receive treatment because of safety reasons. Common causes were severe concomitant cardiac disease and advanced renal disease. Autoimmune disease, thrombopaenia, anaemia or hepatic dysfunction did not preclude treatment. Eighty-four patients started treatment, 15 with decompensated cirrhosis. During the first 12 weeks hospitalization occurred in 11 patients most frequently because of typical complications of advanced liver disease. Risk factors for hospitalization were low platelet count and deteriorated liver function. Overall, 982 of 1008 planned treatment weeks (97%) were successfully completed within the first 12 weeks of therapy. Conclusion With the better safety profile of interferon-free therapies, eligibility for HCV treatment will expand broadly, including patients with decompensated cirrhosis. Current limitations are renal failure and concomitant cardiac disease. Patients with advanced cirrhosis still have a high risk for hospitalization even with interferon-free therapies, but can continue HCV treatment in most cases.

Background & Aim Mechanisms of non-responsiveness to peginterferon alfa-2a are not completely understood. Inadequate plasma levels may contribute to reduced response. The aim of this prospective, multicentre, crossover, Phase 1 study was to evaluate the pharmacokinetics and viral kinetics of intravenous vs. subcutaneous peginterferon alfa-2a in patients with genotype 1 chronic hepatitis C infection who showed null response to previous peginterferon/ribavirin. Methods Patients were randomized in four treatment arms to subcutaneous or intravenous peginterferon alfa-2a 180 μg, once or twice weekly for 2 weeks. After a washout phase of 6 weeks, patients first receiving intravenous administration switched to subcutaneous or vice versa for additional 2 weeks. Results Intravenous administration of pegylated interferon resulted in a stronger and faster decline in HCV RNA than subcutaneous administration with a maximum decline of 1.17 log10 vs. 0.41 log10 or 1.32 log10 vs. 0.54 log10 after a once or twice weekly application, respectively. Pharmacokinetic studies revealed significantly higher maximum concentration (Cmax)0–12 h and Cmax 0–7 d following intravenous administration, irrespective of dosing frequency A rapid rebound in HCV RNA was observed in all treatment arms. Adverse events occurred more frequently following intravenous administration. Conclusion Intravenous administration of peginterferon alfa-2a results in considerably higher plasma concentration and a stronger decline in HCV RNA and offers an interesting approach in order to overcome interferon non-responsive state in patients with full null response to previous peginterferon/ribavirin combination therapy.

Triple therapy with pegylated-interferon-α, ribavirin, and a protease inhibitor (PI), boceprevir or telaprevir, is the standard of care for the treatment of chronic hepatitis C genotype 1 in several countries. Pivotal studies showed reasonable results for safety and efficacy. However, it remains uncertain to what extent this can be transferred to the real world.Here, we aimed to analyze the effectiveness and safety of pegylated-interferon-α/ribavirin/PI triple therapy in a real-world cohort of a tertiary referral center.Between June 2011 and November 2011, a total of 208 consecutive patients with chronic hepatitis C genotype 1 were evaluated for the initiation of a triple-therapy regimen and included in this study. Eighty-six patients (86% F3/F4) started a triple-therapy regimen and were followed until 12 weeks after the end of treatment.Overall, 36 out of the 86 treated patients (42%) achieved a sustained virological response. However, only 17% of the initially screened 208 patients were cured with triple therapy at our center. A high rate of serious adverse events (28%) was documented during treatment. The risk/benefit ratio was poor for patients with signs of advanced liver cirrhosis (n=33, 38%), indicated by increased bilirubin, low albumin, and/or low platelet count at baseline.The effectiveness and safety of PI-based triple therapy can be limited in real-world cohorts including large numbers of patients with advanced liver disease. Future therapies can only overcome these limitations if interferon-free regimens are established.