An interferon-free regimen containing
sofosbuvir (formerly GS-7997), ledipasvir (formerly GS-5885) and ribavirin
produced a 12-week post-treatment sustained virological response (SVR12) rate
of 100% for both treatment-naive hepatitis C patients and prior interferon non-responders,
according to data presented yesterday at the 20th Conference
on Retroviruses and Opportunistic Infections (CROI
2013) in Atlanta.
Direct-acting antiviral agents that target different
steps of the hepatitis C virus lifecycle have ushered in a new era of
treatment, but many patients and clinicians are awaiting all-oral therapy that
avoids interferon and its difficult side-effects.
from Auckland Clinical Studies presented the latest data
from the ELECTRON trial, sponsored by Gilead Sciences.
"Adding ledipasvir increased the efficacy of
sofosbuvir plus ribavirin".
initially tested a simple 12-week regimen of the
once-daily nucleotide analogue HCV polymerase inhibitor sofosbuvir plus
1000-1200mg weight-based ribavirin for previously untreated people with
easier-to-treat HCV genotypes 2 or 3. As reported at the 2011 AASLD Liver
Meeting, that regimen cured 100% of these patients.
The ELECTRON researchers then looked at genotype 1
patients, both treatment-naive and null responders to previous interferon-based
therapy. As Gane reported at CROI last year, sofosbuvir/ribavirin alone was not adequate for this harder-to-treat
population. While participants saw a rapid decline in HCV RNA and had
undetectable viral load at the end of therapy, some treatment-naive patients
and almost all prior null responders relapsed, resulting in cure rates of 84%
and 10%, respectively.
The investigators then asked whether adding a second
direct-acting agent – the NS5A replication complex inhibitor ledipasvir – could increase cure rates for people with HCV genotype
1. Studies to date have shown that drugs in this class are highly potent and well
The analysis included
25 treatment-naive participants and nine prior null responders. Two-thirds of
the naive participants were women, whilst 78% of the experienced patients were
men. Overall, about 90% were white and the average age was 48 years. Most had
unfavourable IL28B gene patterns (only one-third of the treatment-naive and
none of the experienced patients had the favourable CC pattern associated with
good interferon response). More than 80% had the more difficult-to-treat HCV
subtype 1a and baseline HCV RNA levels were high.
After four weeks on treatment, all
treatment-naive patients and all but one null responder had rapid virological response and
reached undetectable HCV RNA. By the end of the 12-week course of therapy, the
remaining null responder also achieved viral suppression, yielding
end-of-treatment response rates of 100% for both groups. At both 4 and 12 weeks
post-treatment, all participants in both groups maintained undetectable HCV viral
load and achieved SVR12, considered a cure.
The triple combination regimen was
generally safe and well-tolerated. Two people (8%) experienced serious adverse
events and one person (4%) stopped treatment for this reason. The most common side-effects
were anaemia (20%), depression (8%) and headache (4%). About 44% experienced
grade 3 laboratory abnormalities including anaemia.
Based on these findings the ELECTRON
researchers concluded, "Adding ledipasvir increased the efficacy of
sofosbuvir plus ribavirin".
Gilead is currently testing a
fixed-dose coformulation containing sofosbuvir and ledipasvir in a phase III
trial. Investigators will also look at a dual combination of sofosbuvir plus
ledipasvir without ribavirin, as adding ledipasvir lowers the risk of relapse
and may make ribavirin unnecessary for some or all patients.