An interferon-free regimen of sofosbuvir and
ledipasvir (Harvoni) produced
sustained virological response rates of 93% for people with HCV genotype 4 and
95% for those with genotype 5, according to a French study presented at the
European Association for the Study of the Liver (EASL) 50th
International Liver Congress last month in Vienna, Austria.
The advent of direct-acting antiviral agents (DAAs) that
can be used in interferon-free combinations has revolutionised treatment for
people with hepatitis C virus (HCV) genotypes 1 and 2. Better treatment options
are still needed for HCV genotype 3, while limited information is available
about treatment for genotypes 4, 5 and 6.
HCV genotype 1 is the most common type worldwide, including
in Europe and the US. Genotype 2 is a minority variant everywhere. Genotype 3
is common in the UK, some European countries, Russia and South Asia. Genotypes 4,
5 and 6 are less widely distributed and are mainly found in countries that are
poorer or have less medical research infrastructure. Genotype 4 is prevalent in
the Middle East and parts of Africa (accounting for most cases in Egypt), genotype
5 is mostly found in South Africa, and genotype 6 is mostly seen in China and
Southeast Asia.
Armand Abergel of Université d'Auvergne in France and colleagues evaluated the
safety and efficacy of sofosbuvir/ledipasvir in people with chronic hepatitis C genotypes 4 or 5. Estimates suggest that these two
genotypes together account for about 14% of all hepatitis C infections
worldwide, he noted.
Sofosbuvir/ledipasvir produces cure rates above 90% for people with HCV genotype 1, but
ledipasvir is not very active against genotype 3; sofosbuvir plus ribavirin
alone is highly effective for genotype 2. Laboratory studies have shown that
both sofosbuvir (a nucleotide NS5B polymerase inhibitor) and ledipasvir (an
NS5A inhibitor) are active against genotypes 4 and 5 in vitro. Genotype 4 has been studied along with genotype 1 in
several clinical trials, but has usually accounted for only a small number of
patients.
This phase 2 study enrolled 44 participants with
genotype 4 and 41 patients with genotype 5 at five sites in France. In the
genotype 4 group, about two-thirds were men and the mean age was 51 years. In
the genotype 5 group, about half were men and the mean age was older at 63
years. In both groups, half were treatment-experienced, nearly one-quarter had
liver cirrhosis and most had high baseline HCV viral load. All genotype 5
patients had subtype 5a. A majority of genotype 4 patients had subtype 4a, but
several other subtypes were represented (4b, 4d, 4f, 4m, 4o and 4r).
All
participants in this open-label study received sofosbuvir/ledipasvir in a
once-daily fixed-dose coformulation (90/400mg) for 12 weeks.
After
12 weeks of therapy plus 12 weeks of post-treatment follow-up, 93% of genotype
4 patients and 95% of genotype 5 patients achieved sustained virological
response (SVR12), or continued undetectable HCV RNA.
In
the genotype 4 group, 96% of treatment-naive and 91% of treatment experienced
patients achieved SVR12, while there was no difference according to prior
treatment status in the genotype 5 group (both 95%). Ninety-one per cent of people without cirrhosis and
100% of people with cirrhosis with genotype 4, and 97% of people without cirrhosis and 98% of
people with cirrhosis and genotype 5, were cured.
All
five treatment failures (three genotype 4 and two genotype 5) were due to
relapse after completing therapy. Abergel noted that two of the three patients
with subtype 4r relapsed. Presence of NS5A resistance-associated variants
(RAVs) at baseline did not affect SVR12 rates (there were no pre-existing NS5B
RAVs). Two relapsers had evidence of new NS5B resistance mutations.
Sofosbuvir/ledipasvir
was generally safe and well-tolerated, with no notable side-effects not seen in
previous genotype 1 studies. The most common adverse events were fatigue/weakness
(46%) and headache (26%). Most side-effects were mild or moderate and there
were no grade 3/4 laboratory abnormalities. One person experienced a serious
adverse event (worsening depression, not considered drug-related) but there
were no discontinuations due to adverse events.
"[Sofosbuvir/ledipasvir]
for 12 weeks represents a safe and effective all-oral treatment for patients
with genotype 4 and genotype 5 HCV," the researchers concluded.
New EASL hepatitis C treatment guidelines
released at the conference recommend sofosbuvir/ledipasvir for genotypes 4 and
5. Sofosbuvir plus simeprevir (Olysio)
and paritaprevir/ritonavir/ombitasvir (Viekirax)
are also recommended for genotype 4, while sofosbuvir plus daclatasvir (Daklinza) is an option for all
genotypes. In the US, Harvoni is approved
only for genotype 1. The latest AASLD guidelines
recommend sofosbuvir/ledipasvir, paritaprevir/ritonavir/ombitasvir with
ribavirin, or sofosbuvir with ribavirin alone for genotype 4, but only sofosbuvir
plus pegylated interferon/ribavirin is recommended for genotype 5.