Regression of Liver Fibrosis After Daclatasvir and Asunaprevir Treatment

Overview

A study on regression of liver fibrosis assessed by transient elastography after Daclatasvir and Asunaprevir combined treatment in advanced fibrotic/cirrhotic patients with chronic hepatitis C genotype 1b Infection

Full Title of Study: “Regression of Liver Fibrosis Assessed by Transient Elastography After Daclatasvir and Asunaprevir Combined Treatment in Advanced Fibrotic/Cirrhotic Patients With Chronic Hepatitis C Genotype 1b Infection”

Study Type

  • Study Type: Observational [Patient Registry]
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: December 2018

Detailed Description

The measurement of liver stiffness by transient elastography (TE) has been shown to correlate with the hepatic fibrosis stage and to have considerable accuracy for the diagnosis of cirrhosis in patients with chronic hepatitis C. Previous studied reported that liver stiffness is significantly reduced in SVR patients with pegylated interferon (IFN) and ribavirin treatment. Once a patient achieve sustained virological response (SVR), and resultingly lower liver stiffness score than baseline value, it is believed that he will have a better long-term outcome due to the improvement of liver fibrosis. Daclatasvir(DCV) and Asunaprevir(ASV) combined treatment showed a greater SVR rate in CHC compared to IFN based therapy. The investigators hypothesize that DCV and ASV combined treatment may achieve the improvement of liver stiffness measured by TE and a more favorable clinical outcomes in patients with advanced liver fibrosis. The investigators will also compare the change of fibrosis stage assessed by TE between this study subjects and those treated with other DAA agents during same observational period.

Interventions

  • Drug: Daclatasvir and Asunaprevir
    • Daclatasvir and Asunaprevir combined treatment will not be assigned to the enrolled patients, but the patients who are treated with Daclatasvir and Asunaprevir will be included in this observational study.

Arms, Groups and Cohorts

  • Daclatasvir plus Asunaprevir treatment
    • Among patients taking Daclatasvir and Asunaprevir combined treatment and having advanced liver fibrosis assessed by transient elastography

Clinical Trial Outcome Measures

Primary Measures

  • The change of liver fibrosis stage at 48 weeks assessed by transient elastography in patients treated with Daclatasvir and Asunaprevir
    • Time Frame: baseline to 48weeks
    • To compare the change of liver fibrosis stage (defined as F3, ≥8; F4, ≥12) assessed by transient elastography between baseline and 48 weeks in advanced fibrotic/cirrhotic Chronic Hepatitis C patients who achieved sustained virological response with Daclatasvir and Asunaprevir combined treatment

Secondary Measures

  • Proportion of patients who were treated with Daclatasvir and Asunaprevir achieved SVR12 assessed by HCV RNA
    • Time Frame: baseline to 36 weeks
  • Proportion of patients who maintained sustained virologic response at SVR24, SVR72, SVR120, SVR168, and SVR216.
    • Time Frame: baseline to 48weeks, 96weeks, 144weeks, 192weeks, 240weeks
  • The change of liver fibrosis stage assessed by transient elastography at 96weeks, 144weeks, 192weeks, 240weeks in patients treated with Daclatasvir and Asunaprevir
    • Time Frame: baseline to 96weeks, 144weeks, 192weeks, 240weeks
  • The change of AST to Platelet Ratio Index
    • Time Frame: baseline to 48weeks, 96weeks, 144weeks, 192weeks, 240weeks
    • APRI = [(AST/upper limit of normal)/platelet count]x100
  • The change of Fibrosis 4 (Fib-4) index
    • Time Frame: baseline to 48weeks, 96weeks, 144weeks, 192weeks, 240weeks
    • FIB-4 = age (years) × AST [IU/L] / [platelet count × sqr(ALT [IU/L])]
  • Comparison of change of liver fibrosis stage assessed by transient elastography between Daclatasvir and Asunaprevir combined treatment versus other DAA treatment
    • Time Frame: baseline to 48weeks, 96weeks, 144weeks, 192weeks, 240weeks
    • Comparison of change of liver fibrosis stage assessed by transient elastography at 48weeks, 96weeks, 144weeks, 192weeks, 240weeks between Daclatasvir and Asunaprevir combined treatment versus other DAA treatment during same observational period
  • Comparison of the incidence of hepatocellular carcinoma or liver cirrhosis complications between Daclatasvir and Asunaprevir combined treatment versus other DAA treatment
    • Time Frame: baseline to 48weeks, 96weeks, 144weeks, 192weeks, 240weeks
    • Compare the incidence of hepatocellular carcinoma or liver cirrhosis complications at 48weeks, 96weeks, 144weeks, 192weeks, 240weeks between Daclatasvir and Asunaprevir combined treatment versus other Direct antiviral agents during same observational period
  • The change of Fibrometer score
    • Time Frame: baseline to 48weeks, 96weeks, 144weeks, 192weeks, 240weeks
    • alpha2 macroglobulin, GGT, AST, ALT, prothrombin index, urea, platelet count

Participating in This Clinical Trial

Inclusion Criteria

  • Chronically infected with Hepatitis C virus genotype 1b – HCV RNA ≥ 10^4 IU/mL (10,000 IU/mL) – Chronic Hepatitis C with advanced fibrosis or cirrhosis (defined as ≥F3, ≥8 kilopascals) – Treatment-naïve or those who previously failed to treatment with peg-interferon alfa and ribavirin – Women of childbearing potential (WOCBP) and men, who use effective methods of birth control Exclusion Criteria:

  • Patients with baseline key NS5A RAVs (Y93 and/or L31) – Estimated GFR < 30mL/min without hemodialysis – Alanine aminotransferase (ALT) > 100 IU/L – Coinfection with other hepatitis virus or human immunodeficiency virus – A daily alcohol intake >30 g – Decompensated liver disease or hepatocellular carcinoma, liver or any other organ transplantation

Gender Eligibility: All

Minimum Age: 19 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Sang Gyune Kim
  • Collaborator
    • Seoul National University Boramae Hospital
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Sang Gyune Kim, Professor – Soonchunhyang University Hospital
  • Overall Official(s)
    • Sang Gyune Kim, Professor, Principal Investigator, Soonchunhyang University Hospital
  • Overall Contact(s)
    • Sang Gyune Kim, Professor, 82-32-621-5071, mcnulty@schmc.ac.kr

References

Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, de Lédinghen V, Marcellin P, Dhumeaux D, Trinchet JC, Beaugrand M. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005 Jan;41(1):48-54.

Hézode C, Castéra L, Roudot-Thoraval F, Bouvier-Alias M, Rosa I, Roulot D, Leroy V, Mallat A, Pawlotsky JM. Liver stiffness diminishes with antiviral response in chronic hepatitis C. Aliment Pharmacol Ther. 2011 Sep;34(6):656-63. doi: 10.1111/j.1365-2036.2011.04765.x. Epub 2011 Jul 13.

Arima Y, Kawabe N, Hashimoto S, Harata M, Nitta Y, Murao M, Nakano T, Shimazaki H, Kobayashi K, Ichino N, Osakabe K, Nishikawa T, Okumura A, Ishikawa T, Yoshioka K. Reduction of liver stiffness by interferon treatment in the patients with chronic hepatitis C. Hepatol Res. 2010 Apr;40(4):383-92. doi: 10.1111/j.1872-034X.2009.00618.x. Epub 2010 Mar 4.

Wang JH, Changchien CS, Hung CH, Tung WC, Kee KM, Chen CH, Hu TH, Lee CM, Lu SN. Liver stiffness decrease after effective antiviral therapy in patients with chronic hepatitis C: Longitudinal study using FibroScan. J Gastroenterol Hepatol. 2010 May;25(5):964-9. doi: 10.1111/j.1440-1746.2009.06194.x.

Crisan D, Radu C, Grigorescu MD, Lupsor M, Feier D, Grigorescu M. Prospective non-invasive follow-up of liver fibrosis in patients with chronic hepatitis C. J Gastrointestin Liver Dis. 2012 Dec;21(4):375-82.

Bourliere, Marc, et al.

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