Interferon-free treatment using a single once-daily combination pill
containing sofosbuvir plus ledipasvir demonstrated potent activity against
hepatitis C virus (HCV) and was generally well tolerated in a primarily
African-American inner city population with HCV genotype 1a, researchers
reported at The
Liver Meeting 2013, the 64th annual meeting of the American
Association for the Study of Liver Diseases (AASLD) held this month in Washington, DC.
Adding a third drug resulted in high early post-treatment sustained response
rates with shorter treatment.
Combining direct-acting antiviral agents (DAAs) that target different
steps of the hepatitis C virus lifecycle allows for effective treatment without
the prolonged duration and side-effects associated with the former standard of
care, pegylated interferon plus ribavirin.
Most clinical trials of next-generation hepatitis C drugs have been
sponsored by pharmaceutical companies. In parallel, the US National Institute
of Allergy and Infectious Diseases (NIAID) has conducted studies in underserved
populations with the aim of finding simple, brief and well tolerated treatment
for people prone to difficulties with poor adherence and side-effects.
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.
In the previous
SPARE study, Anu Osinusi and colleagues tested a simple two-drug regimen consisting
of Gilead Science's nucleotide HCV polymerase inhibitor sofosbuvir (formerly
GS-7977) plus either standard weight-based or low-dose ribavirin in primarily
African-American, treatment-naive, genotype 1 hepatitis C patients in
inner-city neighbourhoods of Washington, DC. Because ribavirin can cause anaemia,
especially in black patients, they assessed whether starting with a lower dose
could reduce side-effects without compromising effectiveness.
As previously reported, treatment was generally safe
and well-tolerated, with 24-week post-treatment sustained
virological response (SVR24) rates of 68% for the weight-based ribavirin arm,
falling to 48% for the low-dose arm. These rates compare favourably to
pegylated interferon/ribavirin for difficult-to-treat patients. However, numerous
studies have since shown that even better response rates are possible with DAA
combination regimens.
In the NIAID SYNERGY study, described in a poster at
the Liver Meeting, Osinusi, Anita Kohli and colleagues evaluated ribavirin-free oral DAA
regimens using a fixed-dose co-formulation containing sofosbuvir and the NS5A
inhibitor ledipasvir (GS-5885).
This phase 2 study included 60 people with previously untreated
genotype 1 chronic hepatitis C. Most (88%) were African-American, 72%
were men, 70% had harder-to-treat HCV subtype 1a, 80% had unfavourable non-CC
IL28B gene patterns, 23% had advanced liver fibrosis (stage F3) and three
people had cirrhosis (stage F4); people with hepatitis B or HIV co-infection
were excluded.
People of African descent were traditionally regarded
as poor responders to interferon-based therapy, but it is now known that this
is largely attributable to a low frequency of the favourable IL28B CC variant
associated with good interferon responsiveness.
Participants were consecutively enrolled into three
arms. People in arm A received the once-daily sofosbuvir/ledipasvir coformulation (400/90mg)
alone for 12 weeks; people in arm B received sofosbuvir/ledipasvir plus the
non-nucleoside polymerase inhibitor GS-9669 (500mg/day) for six weeks; and people in arm
C received sofosbuvir/ledipasvir plus the HCV protease inhibitor GS-9451 (80mg/day)
for six weeks.
HCV viral load declined rapidly
in all three arms soon after starting treatment. People in arm C, who used drugs that interfered with three distinct targets of HCV replication, saw the
greatest decline in viral load by day seven of treatment. One hundred per cent of participants in
all arms achieved viral suppression by the end of treatment.
In arm A, 100% of patients who
received sofosbuvir/ledipasvir alone achieved 12-week post-treatment sustained
virological response (SVR12). In arm B – using two types of HCV polymerase inhibitor – 90% maintained viral suppression through 4 weeks post-treatment (SVR4). In
arm C, 100% achieved SVR4.
One person in arm B relapsed two weeks after stopping therapy, and one
who achieved SVR at two weeks post-treatment missed the next visit to determine
SVR4.
All three sofosbuvir/ledipasvir
regimens were generally well-tolerated, with no serious adverse events related
to study drugs or discontinuations due to adverse events. The most common side-effect was diarrhoea, reported by 8 people. Alanine aminotransferase normalisation
occurred within a median of seven days in all arms.
"Subjects with poor prognostic factors for
traditional interferon-based therapy can be effectively treated with
interferon- and ribavirin-free DAA-only regimens," the researchers
concluded.
"The single combination pill of
[sofosbuvir/ledipasvir fixed-dose combination] for 12 weeks is an effective
regimen to treat HCV in this population," they continued. This study
provided "proof of concept that multiple DAAs targeting various stages of
the HCV lifecycle in combination can effectively reduce HCV treatment durations,"
though these findings will need to be confirmed with longer follow-up (SVR12)
and in larger clinical trials.