Short summary

Randomized clinical open label multicenter trial in 2 phases comparing 4 weeks of Glecaprevir/Pibrentasvir (co-formulated) and Ribavirin against 4 weeks of Glecaprevir/Pibrentasvir (co-formulated)  for patients with Chronic Hepatitis C and no liver impairment.

Main endpoint is sustained virological response  12 weeks post treatment (SVR-12)

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Rationale

Hepatitis C infection affects an estimated 20000 persons in Denmark. The infection can cause severe liver fibrosis or cirrhosis if untreated for decades and may lead to liver failure or liver cancer. Furthermore it has become clear that hepatitis C is a systemic disease that can cause a wide range of symptoms from fatigue to autoimmune manifestations such as glomerulonephritis or vasculitis and can contribute to the development of diabetes. Being spread mainly by blood the majority of new cases are in persons with injecting drug use that get infected by sharing drug use paraphernalia.  

The WHO published in 2016 at strategy endorsed by Denmark that commits us to reduce the prevalence of viral hepatitis by 90% in 2030. Universal treatment has been recommended by both international and Danish guidelines it is to be expected that all patients will be offered treatment in the coming years.  This transition from treating a liver disease to treating an infection has a number of implications.

Treating the approximately 5000 hepatitis C infected patients we have in care at the Danish hospitals still waiting for treatment would cost about 1.25 billion DKR with the current treatment regimens and prices. Standard of care is 12 weeks of DAA with or with-out ribavirin (ribavirin being added for "hard to treat" cases). However there are several indications that a 12 weeks course is more than enough in most patients and 8 weeks have been licensed for several easy to treat groups . We have recently shown that 4 weeks of DAA in combination with weight based ribavirin gave a cure rates of 92% (comparable results to 12 weeks) in young and easy to treat patients with no effect of adding interferon ((The 4WIDUC trial n=32) .This is to our knowledge the only trial in the world so far to use this combination for 4 weeks. The inclusion criteria for the trial were aimed at "easy to treat" patients who were treatment naïve, with a liver stiffness measurement (LSM) less than 8 kPa and age below 50 years. The trial was conducted with the DAA combination of ledipasvir/sofosbuvir and ribavirin. This drug combination was later shown to be inferior to the velpatasvir/sofosbuvir(licensed 2016) and glecaprevir/pibrentasvir(licensed in August 2017) combination (for genotype 2 and 3 especially) Three other trials of similar size with 4 weeks DAA combination (3-4 DAA's) without ribavirin have been conducted- and have all had disappointing cure rates around 30% The trials also had 6 week treatment arms with somewhat conflicting results with cure rates from 57% to 100%. The population treated in these trials were on average 15 years older than in the 4WIDUC trial and included patients with more advanced liver disease. Furthermore they included drugs now known to be less optimal than glecaprevir/pibrentasvir.  In these trials patients who failed cure with 4 weeks of therapy were retreated with a 12 week regiment and all achieved cure.

The combination of a potent NS3A and NS5A inhibitor with a high barrier to resistance will according to modeling of viral kinetics give the fastest decline in viral load and is hence optimal for short duration treatment. Ribavirin is cheap and has in many populations been shown to enhance the efficacy of the DAA treatment although the mechanism is not clear. Ribavirin has dose dependent side effects such as anemia and fatigue and is therefore often no longer included in clinical trials from the pharmaceutical industry in "easy to treat" patients but only in difficult to cure populations where DAA' alone might be insufficient (decompensated cirrhotics and patients failing prior DAA therapy).

We   hypothesize that patients under the age of 50  with mild disease could be cured receiving only four weeks of glecaprevir/pibrentasvir and aim to investigate whether ribavirin is necessary in this population. This question is of considerable public health importance as these easy to treat patients correspond to half of the Danish HCV infected population.

If 4 weeks of treatment could be a used in  large proportion of  hepatitis C infected patients it will be much more feasible to implement treatment of HCV infected drug users where compliance is a major concern. In addition this would more than half the monetary and human resources needed to control hepatitis C in the population as WHO requests.

To our knowledge there is no clinical trial planned or ongoing of 4 weeks using ribavirin as an enhancer of the efficacy of DAA therapy.

As an additional scientific gain the biological material (serum and blood cells) collected for future research as part of the trial might illuminate the changes in the immune system that can predict response to treatment success or failure. 

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Description of the cohort

Study are enrolling patients followed for chronic hepatitis C at out-patient clinics in Denmark.

Eligible subjects must have chronic hepatitis C infection,  to be under 50, with no or mild liver fibrosis and naïve to Hepatitis c treatment

Data and biological material

Data collected at baseline:

• Demographics, information on hepatitis c virus and liver affection, co-morbidities, concurrent medication.

Data collected during study:

• Study treatment received, adverse events, outcome of treatment, viral load.

Questionnaires:

• Fatigue severity scale, insomnia severity index and SF-36v2 at baseline treatment week 2,4 and post treatment week 12, 24, and 48

Biobank:

• 10 ml of EDTA blood taken at baseline, treatment week 2,4 and post treatment week 12, 24, and 48

White blood cells on patients enrolled in phase 1 ( 40 patients) collected at baseline, treatment week 2, end of treatment and 4,12 and 24 weeks post treatment.

Collaborating researchers and departments

Department of infectious Diseases, Odense University Hospital

• Professor Peer Brehm Christensen
• Lone Wulff Madsen MD 

Clinic for Infectious Diseases, Rigshospitalet

•  Professor Jan Gerstoft

Department of infectious Diseases, Copenhagen University Hospital

• Associate Professor Nina Weis

Unit for Infectious Diseases, Department of Medicine, Zeeland University Hospital

• Associate Professor Toke Barfod

Department of Infectious Diseases, Aarhus University Hospital

• Associate Professor Alex Lund Laursen

Department of Medical Gastroenterology, Aalborg University Hospital

• Associate Professor Henrik Bygum Krarup