A single-tablet
regimen containing the hepatitis C virus (HCV) nucleotide polymerase
inhibitor sofosbuvir and
the NS5A inhibitor ledipasvir – the combination in Gilead Science's
recently approved Harvoni pill – was well-tolerated and cured 97% of
patients with HCV genotype 1 in the Phase 3 ION trials, researchers
reported at the IDWeek 2014 meeting earlier this month in
Philadelphia, United States.
The
advent of direct-acting antiviral agents has revolutionised treatment for
chronic hepatitis C, especially with the long-awaited arrival of all-oral
regimens that dispense with interferon and its difficult side-effects.
Mark
Sulkowski from Johns Hopkins University Medical School and colleagues presented
pooled findings from a trio of pivotal Phase 3 studies that supported the
approval of the sofosbuvir/ledipasvir co-formulation. Results from these studies
were previously presented
in full at the
EASL (European Association for the Study of the Liver) International Liver Congress this past April:
Glossary
- compensated cirrhosis
The earlier stage of
cirrhosis, during which the liver is damaged but still able to perform most of
its functions. See also ‘cirrhosis’ and ‘decompensated cirrhosis’.
- IL28B
An inherited gene which all individuals have. There are three genotypes of IL28B; these influence response to hepatitis C and its treatment. People with CC genotype are more likely to spontaneously clear acute infection or (during chronic infection) respond well to interferon-based treatment. The other two genotypes are known as CT and TT.
- ION-1: (n = 865) previously untreated
HCV genotype 1 (16% with cirrhosis) – 12 vs 24 weeks with or without
ribavirin;
- ION-2: (n = 440) prior non-responders
HCV genotype 1 (20% with cirrhosis) – 12 vs 24 weeks with or without
ribavirin;
- ION-3: (n = 647) previously untreated
HCV genotype 1 (without cirrhosis only) – 12 weeks without ribavirin, or 8
weeks with or without ribavirin.
Taken
together, the ION trials included 1952 randomised and treated patients. A
majority (60%) were men, most were white, 16% were black, and the median age
was 53 years. Looking at factors associated with poorer response, 74% had
harder-to-treat HCV subtype 1a (vs 1b), 23% were treatment-experienced
(including 12% who had previously tried triple therapy with the
first-generation HCV protease inhibitors boceprevir [Victrelis] or telaprevir
[Incivek]), 12% had compensated liver cirrhosis, 26% had a body mass index >30,
75% had an unfavourable IL28B gene pattern, and most (82%) had high HCV viral
load >800,000 IU/ml.
The
primary endpoint in all the trials was sustained virological response, or
continued undetectable HCV RNA viral load, at 12 weeks after completion of
treatment (SVR12).
Results
- Overall, 97% of all patients
achieved SVR12:
o ION-1: 97% to 99%;
o ION-2: 94% to 99%;
o ION-3: 93% to 95%.
- Among the 3% of participants
who did not achieve SVR12:
o 1.8% relapsed after completing
therapy;
o 0.1% experienced viral breakthrough
while still on treatment;
o 1.3% were lost to follow-up or
withdrew consent.
Overall,
there was no significant difference in response rates between patients treated
for 12 or 24 weeks.
In ION-3,
relapse was more common in the 8-week arm compared with the 12-week arm (5 vs
1%), mostly occurring in people with high baseline HCV viral load. A cut-off of
6 million IU/ml was found to be the threshold for poorer response with 8 weeks
of treatment in an ad hoc analysis.
People
with cirrhosis had somewhat poorer response in the 12-week compared with
24-week treatment arms – confirming that people with cirrhosis should not be
treated for only 8 weeks.
There was
no significant difference in response rates between people who did or did not
receive ribavirin.
Sofosbuvir/ledipasvir
was generally safe and well-tolerated. Serious adverse events were uncommon (2%
with and 3% without ribavirin), as were treatment discontinuations due to
adverse events (1% with or without ribavirin). The most common side-effects
were fatigue, headache, nausea, and insomnia. A majority of adverse events –
including decreased haemoglobin – occurred more often among people who received
ribavirin.
"All-oral,
interferon-free therapy with ledipasvir/sofosbuvir for 8, 12, or 24 weeks
resulted in high SVR in genotype 1 HCV," the researchers concluded.
"Addition of ribavirin did not increase rate of SVR and resulted in more
frequent adverse events and laboratory abnormalities."