S.B. Willemse

Sofosbuvir plus simeprevir for the treatment of HCV genotype 4 patients with advanced fibrosis or compensated cirrhosis is highly efficacious in real life

Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease and liver‐related death. Recently, multiple regimens of different direct‐acting antiviral agents (DAAs) have been registered. Although treatment with sofosbuvir (SOF) and simeprevir (SMV) is registered for the treatment of genotype 4 patients in some countries, data on efficacy of this combination are lacking. We aimed to assess the efficacy of SOF and SMV with or without RBV during 12 weeks in a real‐life cohort of genotype 4 HCV patients. A retrospective multicentre observational study was conducted in 4 hospitals in Amsterdam, the Netherlands, including patients with advanced liver fibrosis or liver cirrhosis treated with SOF plus SMV with or without RBV during 12 weeks for a genotype 4 chronic HCV infection from 1 January 2015 to 1 August 2015. Sustained viral response (SVR) was established at week 12 after end of treatment. A total of 53 patients with genotype 4 HCV infection, treatment naïve and experienced, were included. SVR was achieved in 49 of 53 patients (92%). The four failures all had a virological relapse and did not receive ribavirin. Three were nonresponder to earlier interferon‐based treatment, and one was treatment naive. In this real‐life cohort of patients with HCV genotype 4 infection and advanced liver fibrosis/cirrhosis, we show that treatment with SOF and SMV is effective. The addition of RBV could be considered in treatment‐experienced patients as recommended in guidelines.

Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands

Background People who inject drugs (PWID) are disproportionally affected by the hepatitis C virus (HCV) infection. The efficacy of HCV treatment has significantly improved in recent years with the introduction of direct-acting antivirals (DAAs). However, DAAs are more costly than pegylated-interferon and ribavirin (PegIFN/RBV). We aimed to assess the cost-effectiveness of four HCV treatment strategies among PWID and treatment scale-up. Methods An individual-based model was used describing HIV and HCV transmission and disease progression among PWID. We considered two epidemiological situations. A declining epidemic, based on the situation in Amsterdam, the Netherlands, and a stable HCV epidemic, as observed in other settings. Data on HCV incidence, prevalence, treatment setting and uptake were derived from observed data among PWID in Amsterdam. We assessed the incremental cost-effectiveness ratio (ICER, costs in €/quality-adjusted life year (QALY)) of four treatment strategies: 1) PegIFN/RBV; 2) sofosbuvir/RBV for genotype 2–3 and dual DAA for genotype 1–4; 3) Dual DAA for all genotypes; 4) Dual DAA with 3x treatment uptake. Results In both types of epidemic, dual DAA therapy was most cost-effective strategy. In the declining epidemic, dual DAA yielded an ICER of 344 €/QALY while in the stable epidemic dual DAA led to cost-savings. Scaling-up treatment was also highly cost-effective. Our results were robust over a range of sensitivity analyses. Conclusion HCV treatment with DAA-containing regimens is a highly cost-effective intervention among PWID. Based on the economic and population benefits of scaling-up treatment, stronger efforts are needed to achieve higher uptake rates among PWID.

LO7 : A single subcutaneous dose of 2mg/kg or 4mg/kg of RG-101, a GalNAc-conjugated oligonucleotide with antagonist activity against MIR-122, results in significant viral load reductions in chronic hepatitis C patients

GWAS hits were validated in independent cohorts from Germany (529 cases vs. 761 controls) and Belgium (619 cases vs. 161 controls) and the results of the joint analyses combined. Genotyping was undertaken using Illumina BeadChips (Illumina Inc., San Diego, CA, USA); SNP replication was undertaken using Taqman chemistry (Applied Biosystems, Foster City, Ca, USA) on an automated platform. Results: The strongest association signal in the initial metaanalysis was observed between the rs738409 variant in PNPLA3 (Pmeta =1.17×10−28, OR=2.38 [2.08–2.69]); 102 separate variants at the PNPLA3 locus associated with genome-wide significance (Pthreshold <5×10−8). In addition, nine other independent loci provided borderline association signals (Pthreshold ≤1.1×10−5). Validation genotyping for rs738409 in PNPLA3 and lead markers for the top 10 associated regions confirmed disease association for rs738409 in PNPLA3, and for (MBOAT7: rs641738 Preplication = 1.35×10−4; Pcombined = 9.25×10−10; OR=1.63 [1.46–1.80] and TM6SF2: rs10401969 Preplication = 3.29×10−5; Pcombined = 1.73×10−8; OR=1.35 [1.25–1.44]).

Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti‐MicroRNA‐122, RG‐101

MicroRNA‐122 is an important host factor for the hepatitis C virus (HCV). Treatment with RG‐101, an N‐acetylgalactosamine‐conjugated anti‐microRNA‐122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic HCV infection. Here, we analyzed the effects of RG‐101 therapy on antiviral immunity. Thirty‐two chronic HCV patients infected with HCV genotypes 1, 3, and 4 received a single subcutaneous administration of RG‐101 at 2 mg/kg (n = 14) or 4 mg/kg (n = 14) or received a placebo (n = 2/dosing group). Plasma and peripheral blood mononuclear cells were collected at multiple time points, and comprehensive immunological analyses were performed. Following RG‐101 administration, HCV RNA declined in all patients (mean decline at week 2, 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma interferon‐γ‐induced protein 10 (IP‐10) levels declined significantly upon dosing with RG‐101. Furthermore, the frequency of natural killer (NK) cells increased, the proportion of NK cells expressing activating receptors normalized, and NK cell interferon‐γ production decreased after RG‐101 dosing. Functional HCV‐specific interferon‐γ T‐cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post–RG‐101 injection. No increase in the magnitude of HCV‐specific T‐cell responses was observed at later time points, including 3 patients who were HCV RNA–negative 76 weeks postdosing. Conclusion: Dosing with RG‐101 is associated with a restoration of NK‐cell proportions and a decrease of NK cells expressing activation receptors; however, the magnitude and functionality of ex vivo HCV‐specific T‐cell responses did not increase following RG‐101 injection, suggesting that NK cells, but not HCV adaptive immunity, may contribute to HCV viral control following RG‐101 therapy. (Hepatology 2017;66:57–68).

Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial

BACKGROUND Antiviral treatment is currently not recommended for patients with chronic hepatitis B with a low viral load. However, they might benefit from acquiring a functional cure (hepatitis B surface antigen [HBsAg] loss with or without formation of antibodies against hepatitis B surface antigen [anti-HBs]). We assessed HBsAg loss during peg-interferon-alfa-2a (peg-IFN) and nucleotide analogue combination therapy in patients with chronic hepatitis B with a low viral load. METHODS In this randomised controlled, open-label trial, patients were enrolled from the Academic Medical Center (AMC), Amsterdam, Netherlands. Eligible patients were HBsAg positive and hepatitis B e antigen (HBeAg) negative for more than 6 months, could be treatment naive or treatment experienced, and had alanine aminotransferase (ALT) concentrations less than 5 × upper limit of normal (ULN). Participants were randomly assigned (1:1:1) by a computerised randomisation programme (ALEA Randomisation Service) to receive peg-IFN 180 μg/week plus adefovir 10 mg/day, peg-IFN 180 μg/week plus tenofovir disoproxil fumarate 245 mg/day, or no treatment for 48 weeks. The primary endpoint was the proportion of patients with serum HBsAg loss among those who received at least one dose of study drug or had at least one study visit (modified intention-to-treat population [mITT]). All patients have finished the initial study of 72 weeks and will be observed for up to 5 years of follow-up. This study is registered with ClinicalTrials.gov, number NCT00973219. FINDINGS Between Aug 4, 2009, and Oct 17, 2013, 167 patients were screened for enrolment, of whom 151 were randomly assigned (52 to peg-IFN plus adefovir, 51 to peg-IFN plus tenofovir, and 48 to no treatment). 46 participants in the peg-IFN plus adefovir group, 45 in the peg-IFN plus tenofovir group, and 43 in the no treatment group began treatment or observation and were included in the mITT population. At week 72, two (4%) patients in the peg-IFN plus adefovir group and two (4%) patients in the peg-IFN plus tenofovir group had achieved HBsAg loss, compared with none of the patients in the no treatment group (p=0·377). The most frequent adverse events (>30%) were fatigue, headache, fever, and myalgia, which were attributed to peg-IFN dosing. Two (4%) serious adverse events were reported in the peg-IFN plus adefovir group (admission to hospital for alcohol-related pancreatitis [week 6; n=1] and pregnancy, which was electively aborted [week 9; n=1]), three (7%) in the peg-IFN plus tenofovir group (admission to hospital after a suicide attempt during a severe depression [week 23; n=1], admission to hospital for abdominal pain [week 2; n=1], and an elective laminectomy [week 40; n=1]), and three (7%) in the no treatment group (admission to hospital for septic arthritis [week 72; n=1], endocarditis [week 5; n=1], and hyperthyroidism [week 20; n=1]). INTERPRETATION In patients with chronic hepatitis B with a low viral load, combination treatment (peg-IFN plus adefovir and peg-IFN plus tenofovir) did not result in significant HBsAg loss compared with no treatment, which does not support the use of combination treatment in this population of patients. FUNDING Roche, Fonds NutsOhra.

Limited Generalizability of Registration Trials in Hepatitis C: A Nationwide Cohort Study

Background Approval of drugs in chronic hepatitis C is supported by registration trials. These trials might have limited generalizability through use of strict eligibility criteria. We compared effectiveness and safety of real world hepatitis C patients eligible and ineligible for registration trials. Methods We performed a nationwide, multicenter, retrospective cohort study of chronic hepatitis C patients treated in the real world. We applied a combined set of inclusion and exclusion criteria of registration trials to our cohort to determine eligibility. We compared effectiveness and safety in eligible vs. ineligible patients, and performed sensitivity analyses with strict criteria. Further, we used log binomial regression to assess relative risks of criteria on outcomes. Results In this cohort (n = 467) 47% of patients would have been ineligible for registration trials. Main exclusion criteria were related to hepatic decompensation and co-morbidity (cardiac disease, anemia, malignancy and neutropenia), and were associated with an increased risk for serious adverse events (RR 1.45–2.31). Ineligible patients developed significantly more serious adverse events than eligible patients (27% vs. 11%, p< 0.001). Effectiveness was decreased if strict criteria were used. Conclusions Nearly half of real world hepatitis C patients would have been excluded from registration trials, and these patients are at increased risk to develop serious adverse events. Hepatic decompensation and co-morbidity were important exclusion criteria, and were related to toxicity. Therefore, new drugs should also be studied in these patients, to genuinely assess benefits and risk of therapy in the real world population.

Immune responses in DAA treated chronic hepatitis C patients with and without prior RG-101 dosing

Background&aims: With the introduction of DAAs, the majority of treated chronic hepatitis C patients (CHC) achieve a viral cure. The exact mechanisms by which the virus is cleared after successful therapy, is still unknown. The aim was to assess the role of the immune system and miRNA levels in acquiring a sustained virological response after DAA treatment in CHC patients with and without prior RG‐101 (anti‐miR‐122) dosing. Methods: In this multicenter, investigator‐initiated study, 29 patients with hepatitis C virus (HCV) genotype 1 (n = 11), 3 (n = 17), or 4 (n = 1) infection were treated with sofosbuvir and daclatasvir ± ribavirin. 18 patients were previously treated with RG‐101. IP‐10 levels were measured by ELISA. Ex vivo HCV‐specific T cell responses were quantified in IFN‐&ggr;‐ELISpot assays. Plasma levels of miR‐122 were measured by qPCR. Results: All patients had an SVR12. IP‐10 levels rapidly declined during treatment, but were still elevated 24 weeks after treatment as compared to healthy controls (median 53.82 and 39.4 pg/mL, p = 0.02). Functional IFN‐&ggr; HCV‐specific T cell responses did not change by week 12 of follow‐up (77.5 versus 125 SFU/106 PBMC, p = 0.46). At follow‐up week 12, there was no difference in plasma miR‐122 levels between healthy controls and patients with and without prior RG‐101 dosing. Conclusions: Our data shows that successful treatment of CHC patients with and without prior RG‐101 dosing results in reduction of broad immune activation, and normalisation of miR‐122 levels (EudraCT: 2014‐002808‐25). Trial registration: EudraCT: 2014‐002808‐25. HighlightsDAA treatment is highly effective in chronic hepatitis C patients with and without prior anti‐miR‐122 treatment.Successful treatment of chronic hepatitis C patients results in reduction of broad immune activation.There is no restoration of HCV adaptive immunity after SVR in chronic hepatitis C patients.Plasma miR‐122 levels normalise after successful treatment of chronic hepatitis C virus infection.

Dynamics of the Immune Response in Acute Hepatitis B Infection

Abstract Background Acute hepatitis B virus infection in adults is generally self-limiting but may lead to chronicity in a minority of patients. Methods We included 9 patients with acute hepatitis B virus (HBV) infection and collected longitudinal follow-up samples. Natural killer (NK) cell characteristics were analyzed by flowcytometry. HBV-specific T-cell function was analyzed by in vitro stimulation with HBV peptide pools and intracellular cytokine staining. Results Median baseline HBV DNA load was 5.12 log IU/mL, and median ALT was 2652 U/mL. Of 9 patients, 8 cleared HBsAg within 6 months whereas 1 patient became chronically infected. Early time points after infection showed increased CD56bright NK cells and an increased proportion of cells expressing activation markers. Most of these had normalized at week 24, while the proportion of TRAIL-positive CD56bright NK cells remained high in the chronically infected patient. In patients who cleared HBV, functional HBV-specific CD8+ and CD4+ responses could be observed, whereas in the patient who developed chronic infection, only low HBV-specific T-cell responses were observed. Conclusions NK cells are activated early in the course of acute HBV infection. Broad and multispecific T-cell responses are observed in patients who clear acute HBV infection, but not in a patient who became chronically infected.