Short Duration Therapy of Acute Hepatitis C Genotypes 1 or 4 (SAHIV)

Short Duration Therapy of Acute Hepatitis C Genotypes 1 or 4: Efficacy and Tolerability of Grazoprevir 100mg/Elbasvir 50mg During 8 Weeks

The purpose of this study is to assess the rate of sustained virological response (SVR) 12 weeks after 8-week oral treatment with grazoprevir 100mg/elbasvir 50mg (MRK-combo) in patients with acute hepatitis C genotype1 or 4.

Study Overview

• Status: Completed
• Conditions: HIV; Acute Hepatitis C
• Intervention / Treatment: Drug: Grazoprevir/Elbasvir

Detailed Description

Increasing rates of acquisition of HCV in men who have sex with men (MSM) have been reported since 2001 in Western European countries and particularly in France. Observational studies have recently reported that HIV-infected gay and bisexual men with sexually transmitted hepatitis C have shown unexpectedly rapid liver disease progression in a relatively short period of time.

It is therefore admitted that, in the absence of a spontaneous HCV clearance within 3 months of acute HCV infection, treatment should be initiated. Pegylated interferon in combination with weight-adapted ribavirin is still recommended as the treatment of choice for all HCV genotypes in an acute setting. For patients developing a rapid virologic response, treatment duration of 24 weeks is recommended. If antiviral therapy was initiated within 24 weeks after diagnosis, sustained virologic response rates of 60 to 80% have been observed at the price of a high side effects burden.

However, short course therapies with new direct acting antivirals are likely to be safer and more efficient. But their efficacy in acute hepatitis C has still to be established. To date, US- and Europe- based trials are ongoing in this setting with the association of sofosbuvir and ribavirine, sofosbuvir / ledipasvir or sofosbuvir / simeprevir, for a duration of 4, 6, 8 or 12 weeks. Preliminary results are very diverse, with SVR12 ranging from 56% to 95%. MSD has been evaluating the efficacy and safety of a double drug combination (grazoprevir + elbasvir) in HIV-infected patients which exhibits paramount efficacy and excellent tolerance in a diverse range of genotypes, including 1 and 4 HCV strains, which are those mainly encountered in the French acute HCV epidemics in MSM. This association has the potential to be used for short treatment duration especially with regards to the fact that patients will have no fibrosis at the time of treatment initiation. This MRK-combo would therefore be an ideal candidate for treating acute hep C due to GT1 or 4 in a "test and treat" approach in high-risk population such as MSM.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Lyon, France, 69317
    • CHU de Lyon
  • Nice, France, 06200
    • Chu de Nice
  • Paris, France, 75012
    • Hôpital Saint-Antoine
  • Paris, France, 75020
    • Hôpital Tenon
  • Paris, France, 75013
    • Hôpital La Pitié-Salpêtrière
  • Paris, France, 75018
    • Hôpital Bichat

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Adult ≥18 years.
2. A recent acute HCV infection [defined by (i) detectable HCV RNA within 6 months after a negative HCV RNA or HCV serology test OR (ii) detectable HCV RNA and acute clinical hepatitis within 5 months prior to screening visit (ALT ≥250 IU/L with normal ALT within the preceding 8 months OR ALT ≥500 IU/L with either no measured ALT or with abnormal ALT within the preceding 8 months)] or reinfection [defined by documented de novo infection after prior clearance post-treatment (defined by one negative HCV RNA ≥6 months after end of treatment) or spontaneously (defined by two negative HCV RNA a minimum of 6 months apart OR documented infection with a new viral strain, confirmed by phylogenetic or genotypic analysis)] within 5 months prior screening OR (iii) patients having reported a risk factor for HCV contamination (traumatic sexual intercourse, intranasal, rectal or intravenous drug use) ≥6 months AND presenting a negative HCV RNA or HCV serology test within 12 months.
3. Infection with HCV genotype 1 or 4 (confirmed at screening visit or by using a previous biological test performed 1 to 4 weeks before week 0).
4. Plasma HCV-RNA ≥ 1000 IU/mL (confirmed at screening visit or by using a previous biological test performed 1 to 4 weeks before week 0).
5. Confirmed HIV infection (only for HIV co-infected patients).
6. Without HIV treatment or with an authorized stable HIV treatment for at least two weeks (only for HIV co-infected patients).
7. Body weight ≥40 kg and ≤125 kg.
8. Female patients with child-bearing potential and their heterosexual partners must use adequate contraception from the date of screening until 30 days after administration of the last dose of study drug. Male participants must agree to consistently and correctly use a condom, while their female partner must use adequate contraception from the date of screening until 30 days after administration of the last dose of study drug.
9. Informed and signed consent.
10. Patients with Health insurance (Sécurité Sociale or Couverture Médicale Universelle).

Exclusion Criteria:

1. Opportunistic infections (stage C), active or occurred within 6 months prior to baseline.
2. Primary HIV infection.
3. Co-infection with Hepatitis B virus (HBsAg-positive) without appropriate treatment (TDF or TAF) for at least 2 weeks.
4. Confirmed cirrhosis (before acute HCV diagnosis).
5. Any other causes of acute hepatitis.
6. Pregnant or breast-feeding women.
7. Liver transplant recipients.
8. Evolutive malignancy.
9. Patients with a history of non-adherence, who will be at risk of being unable to respect the study follow-up timetable.
10. Patients participating in another clinical trial (with an experimental treatment) or within an exclusion period of a previous clinical trial at screening.
11. Patients under legal gardianship or incarcerated.
12. Hemaglobulin <10 g/dL (female) or <11g/dL (male).
13. Platelet count <50,000/mm3.
14. Neutrophil count < 750/mm3.
15. Other antiretroviral drugs than those allowed in the study.
16. Contra-indications to grazoprevir and/or elbasvir or to any of the excipients listed in the summary of the product characteristics.
17. Contra-indicated treatment likely to interfere with the study drugs as listed in the summary of the product characteristics.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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: Grazoprevir/Elbasvir; Once-daily, oral grazoprevir/elbasvir combination therapy at fixed-dose (100mg/50mg) for 8 weeks	Drug: Grazoprevir/Elbasvir; Once-daily, oral grazoprevir/elbasvir combination therapy at fixed-dose (100mg/50mg) for 8 weeks; Other Names: Zepatier

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sustained Virological Response 12 Weeks Post-treatment (SVR12)	Undetectable plasma HCV RNA (<12 IU/mL) 12 weeks post-treatment.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Virological Failure	Number of patients harboring HCV (NS5A and NS3/4) resistance mutations 12 weeks post treatment	12 weeks
Treatment Adherence	Number of patients missing study drug within the last four days during treatment	8 weeks
Number of Participants With Undetectable HIV RNA	Number of participants with undetectable HIV RNA at 12 weeks post treatment (in HIV-positive co-infected patients)	12 weeks
CD4 Cell Count	CD4+ T cell count at 12 weeks post treatment (in HIV-positive co-infected patients)	12 weeks
Incidence of HCV Re-infection	Number of patients with positive HCV RNA 48-weeks post treatment.	48 weeks

Collaborators and Investigators

• Sponsor: Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba
• Collaborators: Merck Sharp & Dohme LLC; Institut National de la Santé Et de la Recherche Médicale, France
• Investigators: Principal Investigator: Karine Lacombe, MD, PhD, Hôpital Saint-Antoine, Service des maladies infectieuses et tropicales

Publications and helpful links

General Publications

• Gambotti L, Batisse D, Colin-de-Verdiere N, Delaroque-Astagneau E, Desenclos JC, Dominguez S, Dupont C, Duval X, Gervais A, Ghosn J, Larsen C, Pol S, Serpaggi J, Simon A, Valantin MA, Velter A; Acute hepatitis C collaborating group. Acute hepatitis C infection in HIV positive men who have sex with men in Paris, France, 2001-2004. Euro Surveill. 2005 May;10(5):115-7.
• Fierer DS, Dieterich DT, Fiel MI, Branch AD, Marks KM, Fusco DN, Hsu R, Smith DM, Fierer J. Rapid progression to decompensated cirrhosis, liver transplant, and death in HIV-infected men after primary hepatitis C virus infection. Clin Infect Dis. 2013 Apr;56(7):1038-43. doi: 10.1093/cid/cis1206. Epub 2012 Dec 21.
• European AIDS Treatment Network (NEAT) Acute Hepatitis C Infection Consensus Panel. Acute hepatitis C in HIV-infected individuals: recommendations from the European AIDS Treatment Network (NEAT) consensus conference. AIDS. 2011 Feb 20;25(4):399-409. doi: 10.1097/QAD.0b013e328343443b. No abstract available.
• Rockstroh JK, Nelson M, Katlama C, Lalezari J, Mallolas J, Bloch M, Matthews GV, Saag MS, Zamor PJ, Orkin C, Gress J, Klopfer S, Shaughnessy M, Wahl J, Nguyen BY, Barr E, Platt HL, Robertson MN, Sulkowski M. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. Lancet HIV. 2015 Aug;2(8):e319-27. doi: 10.1016/S2352-3018(15)00114-9. Epub 2015 Jul 9. Erratum In: Lancet HIV. 2015 Aug;2(8):e316. Lancet HIV. 2015 Oct;2(10):e416.

Study record dates

Study Major Dates

• Study Start (Actual): May 31, 2017
• Primary Completion (Actual): December 31, 2018
• Study Completion (Actual): September 16, 2019

Study Registration Dates

• First Submitted: August 29, 2016
• First Submitted That Met QC Criteria: August 29, 2016
• First Posted (Estimate): September 1, 2016

Study Record Updates

• Last Update Posted (Actual): January 29, 2020
• Last Update Submitted That Met QC Criteria: January 20, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• 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; Enterovirus Infections; Picornaviridae Infections; Hepatitis; Hepatitis A; Hepatitis C; Anti-Infective Agents; Antiviral Agents; Grazoprevir; Elbasvir-grazoprevir drug combination
• Other Study ID Numbers: IMEA 50

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All data are available as IPD. An official request must be made to the Principal Investigator. The request will be reviewed by the Scientific Committee. If approved, data will be exchanged according to European Union General Data Protection Regulation.
• IPD Sharing Time Frame: Data are available as of January 1, 2020 and will be available for request until December 31, 2025.
• IPD Sharing Access Criteria: Please contact the Principal Investigator for further details.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No