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.
Edward Gane
from Auckland Clinical Studies presented the latest data
from the ELECTRON trial, sponsored by Gilead Sciences.
Glossary
- 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.
"Adding ledipasvir increased the efficacy of
sofosbuvir plus ribavirin".
ELECTRON investigators
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
tolerated.
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.