direct-acting antiviral combination of two drugs cured 97% of people with early-stage genotype 3 hepatitis C virus (HCV), the hardest genotype to treat, according to results of the ENDURANCE-3 trial presented at the International Liver Congress in Amsterdam on Friday.
The AbbVie second-generation direct-acting antiviral
combination consists of a protease inhibitor and an NS5A inhibitor. Glecaprevir
is an HCV NS3/4A protease inhibitor active against all genotypes of hepatitis C. Pibrentasvir is an NS5A inhibitor also active against all genotypes of
A pangenotypic combination should be similarly effective
against all genotypes of hepatitis C. To date, direct-acting antiviral
combinations have tended to show somewhat lower efficacy in people with genotype 3, especially the hardest to treat – those with cirrhosis and those with
previous experience of treatment.
The ENDURANCE-3 study was designed to test the combination
of glecaprevir and pibrentasvir in people with genotype 3 infection without
cirrhosis. This is the population that liver specialists can expect to see more
of in their clinics as genotype 3 patients with cirrhosis are prioritised for
treatment and cured, said Professor Graham Foster of Queen Mary University,
Genotype 3 is especially prevalent in South Asia and in
South Asian populations in the United Kingdom, but these patients tend to have
more advanced disease. Genotype 3 is also found in people who inject drugs, and
most recent infections in Europe and North America occur in people who inject
“Genotype 3 is spreading in the US among young injectors,
especially young men. For every patient that we treat and cure, that’s ten of
his friends who don’t get infected,” said Prof. Foster.
ENDURANCE-3 was an international phase 3 study. It recruited
505 previously untreated people without cirrhosis, who had genotype 3 infection. The
study excluded people with HIV or hepatitis B co-infection. The study did not
exclude people who tested positive for illicit drugs or who reported drug use, to
ensure that the study population reflected real-life clinical conditions.
Participants in the first wave of recruitment were randomly
assigned in a 2:1 ratio to receive either glecaprevir and pibrentasvir for 12
weeks (n = 233) or sofosbuvir and daclatasvir for 12 weeks (n = 115). After results
of a phase 2 trial became public, a second wave of recruitment began, to an
8-week study arm, in which 157 people were assigned to receive an 8-week
course of glecaprevir and pibrentasvir.
Study participants had mild or no fibrosis (F0/F1) in the
main, ranging from 78% in the 8-week arm to 86% in the glecaprevir/pibrentasvir
12-week arm. Approximately two thirds of participants had a history of injecting
drugs, 85-90% were white and 45-59% were male according to study arm.
Results by intent-to-treat analysis showed that the 12-week glecaprevir/pibrentasvir
regimen was non-inferior to sofosbuvir/daclatasvir (95% vs 97% achieved a
sustained virologic response). The 8-week regimen was non-inferior to the
12-week regimen (95%) but showed a slightly higher frequency of viral relapse
after treatment (five relapses versus three in the 12-week arm and one in the sofosbuvir/daclatasvir
The majority of treatment failure, however, was due to loss
to follow up or non-compliance or withdrawal for other reasons (7 in the
12-week arm, 2 in the 8-week arm and 2 in the sofosbuvir/daclatasvir arm).
Overall, 97% of patients receiving glecaprevir/pibrentasvir
were cured. Ten out of 381 experienced virologic failure of treatment, with no
clear evidence that this was related to baseline NS5A polymorphisms.
Adverse events were mild, most commonly nausea, fatigue and
headache. Four patients discontinued treatment due to adverse events and a
total of ten patients experienced serious adverse events, but none was
considered to be study drug-related.
Professor Foster stressed that treating and preventing the
spread of genotype 3 in the future would depend much more on going out and
looking for patients who are likely to be unaware of their infection and
lacking any symptoms of liver damage.