A six-week regimen of sofosbuvir (Sovaldi)
plus two experimental direct-acting antivirals being developed by Gilead
Sciences cured more than 90% of previously untreated people with genotype 1
hepatitis C virus and no liver cirrhosis, according to a poster presentation at
the European Association for the Study of the Liver (EASL) 50th
International Liver Congress last month in Vienna, Austria. A four-week regimen was not
effective for any group, however, and six weeks appears inadequate for
harder-to-treat patients. Other studies showed that the new drugs, GS-5816 (velpatasvir) and GS-9857, are also active
against other HCV genotypes.
Now that interferon-free direct-acting antiviral (DAA) regimens taken
for 12 weeks can cure most people with HCV genotype 1, researchers are working
to develop new drugs that work against multiple HCV genotypes (known as
'pan-genotypic') and that can produce sustained viral suppression with a
shorter duration of treatment, which would be more convenient for patients and
could potentially lower costs.
Edward Gane of Auckland Clinical Studies in New Zealand and
colleagues tested a three-drug regimen consisting of Gilead's nucleotide HCV NS5B
polymerase inhibitor sofosbuvir, the pan-genotypic NS5A inhibitor GS-5816 and
the pan-genotypic NS3/4A HCV protease inhibitor GS-9857 taken for four or six weeks.
Combining drugs that attack HCV at three different steps of its lifecycle may
enable shorter treatment, the researchers hypothesised.
Glossary
- direct-acting antiviral (DAA)
A drug which prevents hepatitis C from reproducing by blocking certain steps in its lifecycle.
- 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 preclinical and early clinical research presented in posters at the
International Liver Congress (abstracts
P0861, P0899, P0901), GS-9857 demonstrated potent antiviral activity
against HCV genotypes 1-6, an improved resistance profile compared to older HCV
protease inhibitors, and good pharmacokinetics and oral bioavailability.
Further along in the pipeline, a coformulation of sofosbuvir and GS-5816 has shown
promising efficacy in patients with all HCV genotypes and is now being
evaluated in the phase 3 ASTRAL trials.
This open-label phase 2 study enrolled 75 participants with HCV genotype
1, stratified according to prior treatment experience and presence or absence
of liver cirrhosis. A majority were men, 79% had harder to treat HCV subtype 1a
and 68% had unfavourable IL28B gene variants.
Previously untreated participants without cirrhosis were randomly
assigned to receive sofosbuvir/GS-5816 plus GS-9857 for four or six weeks.
Treatment-naive patients with cirrhosis, and treatment-experienced patients (including
17% with cirrhosis) who were not previously cured with interferon-free regimens
containing at least two DAAs, all received the triple regimen for 6 weeks.
Looking first at the 6-week regimen, 93% of treatment-naive participants
without cirrhosis achieved sustained virological response, or continued
undetectable HCV RNA at 12 weeks after completing therapy (SVR12).
The SVR12 rate was 87% for treatment-naive patients with cirrhosis, but
fell to 67% for treatment-experienced participants. Within the
treatment-experienced group, cure rates were 68% for people without cirrhosis
and 60% for people with cirrhosis, but the latter subgroup included only five people.
The four-week treatment duration did not perform as well. Among the 15
treatment-naive people without cirrhosis assigned to this regimen, the SVR12 rate
was only 27%.
In all cases, failure to achieve SVR12 was due to relapse after the end
of treatment. Recent
mathematical modelling research has suggested that four weeks of therapy does not
lower viral load enough to achieve sustained response even when combining three
classes of direct-acting antivirals.
Younger age and
lower HCV viral load at baseline were the only factors that predicted SVR12 in
a univariate analysis of the treatment-experienced patients. A pharmacokinetic
substudy found that GS-5816 and GS-9857 drugs levels in the body were similar
in people who did and did not achieve sustained response.
The cure rate was
somewhat higher for people who did not have pre-existing HCV NS3 or NS5A
resistance-associated variants (RAVs) at baseline, compared to people who had
these mutations (approximately 60% vs 40%); only one person had evidence of
NS5B resistance. RAVs were rarely observed at the time of relapse and no one
showed resistance to multiple DAA classes.
Treatment with the triple
regimen was generally safe and well-tolerated. All study participants completed
treatment. There were no serious adverse events or drug discontinuations for
this reason. The most common side-effects were nausea (25%), headache (24%) and
fatigue (16%). Four people (5%) experienced transient, asymptomatic lipase
elevations.
Treatment with sofosbuvir/GS-5816
plus GS-9857 for six weeks "was
highly effective in treatment-naive genotype 1 patients without cirrhosis,"
but "shortening treatment duration to 4 weeks was associated with a higher
relapse rate," the
researchers concluded. Treatment-experienced patients and those with cirrhosis "may
benefit from treatment for [longer than] 6 weeks."
Ongoing phase 2
studies are now testing sofosbuvir/GS-5816 plus GS-9857 for treatment durations
of six, eight and twelve weeks in treatment-naive and treatment-experienced people with and without cirrhosis, with HCV genotypes 1 through 6 – including
hardest-to-treat genotype 3.