Effect of ASV and DCV Therapy on the Quality of Immune Status in Chronic HCV Patients (ImmunoDual)

Rationale: Chronic HCV infection is characterised by a weak HCV specific CD8+ T cell response, due to continuous pressure of high viral load. Treatment of chronic HCV patients with ASV and DCV will result in a significant drop in HCV viral load. At present, no information is available on the immunological effects of treatment with ASV and DCV, nor on the early effects of viral load reduction caused by a compound that is thought not to possess direct immunomodulatory effects. This information will be crucial for a better understanding of the mechanisms that may limit the effectiveness of treatment, occurrence of viral rebound or relapses during, at the end of treatment or during the follow up period.

Objective: To evaluate in detail the functionality of immune cells in blood in chronic HCV patients before, during and after treatment with ASV and DCV, in an IFN-free regimen.

Study design: This is an investigator-initiated single center open label study with one arm of 12 patients.

Study population: Adult chronic HCV patients with genotype 1b, who are previous non-responders to the treatment.

Intervention (if applicable): All patients will be treated with twice daily a 200 mg oASV and once daily a 60 mg DCV for 24 weeks.

Main study parameters/endpoints:

1. Phenotype and function of blood leukocytes during treatment; frequency of HCV-specific T cells, NK cells and monocytes
2. Gene expression levels of leukocyte populations before, during and after treatment
3. Gene expression levels of the type I IFN signaling pathway on whole blood samples
4. Serum cytokines levels using multiplex platforms

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis C
• Intervention / Treatment: Drug: Daclatasvir; Drug: asunaprevir

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Rotterdam, Netherlands, 3015 CE
    • Erasmus Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients between 18 and 70 years of age, with a chronic hepatitis C - genotype 1b infection
• Patients are non-responders to previous treatment with peginterferon or conventional interferon plus ribavirin combination therapy
• High viral load (>400,000 IU/ml)
• Indication for antiviral therapy of hepatitis C according to current clinical guidelines
• Written informed consent

Exclusion Criteria:

• Decompensated cirrhosis (Child-Pugh Grade B or C)
• Hepatic imaging (ultrasound, CT or MRI) with the evidence of hepatocellular carcinoma within the last 3 months.
• Females who are pregnant or breast-feeding
• History or other evidence of severe illness, malignancy or any other condition which would make the patient, in the opinion of the investigators, unsuitable for the study
• Co-infections with human immunodeficiency virus (HIV) or Hepatitis B virus (HBV)
• Presence of contra-indications for antiviral therapy with ASV and DCV:
• Interfering substance abuse, such as high alcohol intake (indicator: 28 drinks/ week)
• Any exposure to NS3 protease inhibitors or NS5A polymerase inhibitors
• Treatment with peginterferon/ ribavirin within 6 months before start of therapy
• Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating and completing in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Daclatasvir and asunaprevir; daclatasvir 60 mg once daily asunaprevir 100 mg BID	Drug: Daclatasvir; 60 mg once daily; Drug: asunaprevir; 100 mg BID

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
HCV-specific T cell phenotype and function (a composite measure of (I) HCV-specific T-cell frequency and (II) phenotypic expression of memory markers and (III) inhibitory receptor markers	1 year
NK cell phenotype and function (a composite measure of (I) NK cell frequency and (II) expression of activation and inhibitory markers (III) IFN-y production upon IL-12/IL-18 stimulation and (IV) Perforin granzyme production	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Gene expression levels of the type I IFN signaling pathway on whole blood samples measured by multiplex	1 year
Gene expression levels of leukocyte populations before, during and after treatment measured by microarray	2 years
Serum cytokines levels using multiplex platforms LUMINEX -100	1 year

Collaborators and Investigators

• Sponsor: Foundation for Liver Research
• Investigators: Principal Investigator: Rob de Knegt, M.D., Erasmus MC

Publications and helpful links

General Publications

• Spaan M, van Oord G, Kreefft K, Hou J, Hansen BE, Janssen HL, de Knegt RJ, Boonstra A. Immunological Analysis During Interferon-Free Therapy for Chronic Hepatitis C Virus Infection Reveals Modulation of the Natural Killer Cell Compartment. J Infect Dis. 2016 Jan 15;213(2):216-23. doi: 10.1093/infdis/jiv391. Epub 2015 Jul 28.

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: October 23, 2014
• First Submitted That Met QC Criteria: November 3, 2014
• First Posted (Estimate): November 4, 2014

Study Record Updates

• Last Update Posted (Estimate): October 19, 2015
• Last Update Submitted That Met QC Criteria: October 16, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Immunity
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Hepatitis C; Hepatitis C, Chronic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Asunaprevir
• Other Study ID Numbers: Foundation_LiverR