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.
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.
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:
- 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’.
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
- ION-2: (n = 440) prior non-responders
HCV genotype 1 (20% with cirrhosis) – 12 vs 24 weeks with or without
- ION-3: (n = 647) previously untreated
HCV genotype 1 (without cirrhosis only) – 12 weeks without ribavirin, or 8
weeks with or without ribavirin.
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.
primary endpoint in all the trials was sustained virological response, or
continued undetectable HCV RNA viral load, at 12 weeks after completion of
- Overall, 97% of all patients
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
o 0.1% experienced viral breakthrough
while still on treatment;
o 1.3% were lost to follow-up or
there was no significant difference in response rates between patients treated
for 12 or 24 weeks.
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.
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.
no significant difference in response rates between people who did or did not
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
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."