(O6) 4 week treatment for hepatitis C – a randomized controlled trial (4RIBC)

Författare/Medförfattare

Lone Wulff Madsen[1, 9], Anne Øvrehus [1,8,9], Jan Gerstoft [2], Nina Weis [3,4], Toke Barfod [5], Alex Lund Laursen [6], Henrik Bygum Krarup [7], Anja Ernst [7], Peer Brehm Christensen [1,9]

Affiliates

1 Department of Infectious Diseases, Odense University Hospital, Odense, Denmark 2 Clinic for Infectious Diseases, Rigshospitalet, Copenhagen, Denmark 3 Copenhagen University Hospital, Hvidovre, Denmark 4 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark 5 Zeeland University Hospital, Roskilde, Denmark 6 Aarhus University Hospital, Skejby, Denmark 7 Aalborg University Hospital, Aalborg, Denmark 8 OPEN, Open Patient data Explorative Network, Odense, Denmark 9 Institute for Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense ,

Abstrakt

Background and Aims: Since the introduction of Directing Acting Antivirals (DAA) the cure rate of chronic hepatitis C has been over 90% which even includes difficult to treat patients as cirrhotic and treatment experienced patients. Shortening treatment duration could reduce overall treatment cost and probably improve adherence. If 4 weeks of treatment could be used in a large proportion of hepatitis C virus infected patients it will be much more feasible to implement in treatment of HCV infected drug users where adherence and lost to follow up is a concern.
We have previously shown that 4 weeks of ledipasvir/sofosbuvir plus weight based ribavirin gave a cure rate of 92% in young and easy to treat patients. However Ribavirin adds to side effects but the addition might be defensible if treatment can be shortened.
We hypothesize that patients under the age of 50 with no or minimal liver fibrosis could be cured receiving only four weeks of glecaprevir/pibrentasvir and aim to investigate whether ribavirin is necessary in this population.
Methods: The study consists of two phases. Phase 1: comparing glecaprevir/pibrentasvir +/- ribavirin in a single center study and hereafter in phase 2 conduct a multicenter study with 195 patients. Here we present the results of phase 1. The trial was conducted at the outpatient clinic at infectious disease department at Odense University Hospital in Denmark.
Main inclusion criteria: Treatment naive patients with chronic hepatitis C (all genotypes), age < 50 years and liver stiffness measurement of < 8 kPa.
Patients were stratified according to genotype 3/non genotype 3. Thirty two patients were randomized 1:1 to either glecaprevir/pibrentasvir or glecaprevir/pibrentasvir + ribavirin for 4 weeks. Ribavirin was dosed 15mg/kg q.d. with an upper limit of 1400 mg.
The study was sponsored exclusively by the Danish Health Authorities.
Results: From May to August 2018, 33 patients were screened and 32 patients initiated treatment. SVR12 in the ribavirin containing arm was 73% (11/15) and in the ribavirin free arm SVR12 was 59% (10/17). All SVR12 patients also achieved SVR24 and SVR48, however 1 patient were lost to follow up at week 24 and SVR 48 and 2 more patients have pending results at week 48.
Viral recurrence was observed in 11 individuals and 91% (10/11) with viral recurrence were INFL3 non CC (not significant, p=0.12). The patient with viral recurrence and INFL3 CC had a baseline NS5A RAS (A30K/L31M) which could have influenced reduced susceptibility to pibrentasvir. One patient with viral recurrence had a NS5A treatment emergent substitution (leucine at amino acid position 28 prior to treatment and phenylalanine at recurrence) (L28F). L28F is of unknown significance and has not been associated with reduced susceptibility to pibrentasvir.
Conclusions: Treatment with glecaprevir/pibrentasvir and ribavirin was well tolerated. Phase one suggest that a subpopulation of hepatitis C can be cured by 4 weeks of DAA treatment with ribavirin but larger studies are needed in the target population for short treatment to determine safety and efficacy compared to standard of care.