Zepatier
is a new medication used to treat hepatitis C. It is a combination pill
containing grazoprevir plus elbasvir. It was approved in Europe in July 2016 for
treatment of adults with genotype 1 or 4 chronic hepatitis C.
Zepatier offers
a new interferon-free option for many people with hepatitis C. Some people with
harder-to-treat disease may do better if they take Zepatier with ribavirin. Successful treatment reduces the risk of
long-term complications of hepatitis C such as cirrhosis, liver cancer or
needing a liver transplant.
How does Zepatier work?
Zepatier
contains two direct-acting antiviral drugs that target different steps of the
hepatitis C virus (HCV) lifecycle. Grazoprevir is an HCV protease inhibitor,
meaning it interferes with the protease enzyme which the virus needs to
reproduce. Elbasvir is an HCV NS5A replication complex inhibitor that
interferes with another protein HCV uses to reproduce. Targeting two different
steps of the HCV lifecycle makes it harder for the virus to develop drug
resistance.
Who can
use Zepatier?
Zepatier is
approved for use by adults with chronic hepatitis C, meaning infection lasting
more than six months. It is approved for people with HCV genotypes 1 or 4.
Genotype 1 is the most common type in Europe. People with genotype 1a should
receive a test for virus mutations that can cause drug resistance before
starting Zepatier.
Zepatier can be
used by people being treated for hepatitis C for the first time and for
retreatment of people who were not cured with previous interferon-based therapy
(known as ‘treatment-experienced’).
Zepatier has
been tested in people with HIV and HCV co-infection. Response rates and
side-effects were similar to those seen in HIV-negative people, but Zepatier should not be used with certain
HIV medications. People with HIV and HCV co-infection who want to take Zepatier should do so under the care of
a doctor who has experience treating both infections.
Zepatier can be
used by people with compensated cirrhosis who still have relatively good liver
function. It is not recommended for people with moderate or severe liver
impairment or decompensated cirrhosis (Child-Pugh class B or C). It has not yet
been tested for people who are awaiting or have received a liver transplant.
Zepatier can be
used by people with chronic kidney disease and those undergoing kidney dialysis.
How is Zepatier taken?
Zepatier
is taken as a single pill once daily with or without food. Some people
will also need to take ribavirin pills twice daily, with doses based on body
weight. The length of treatment and whether Zepatier
should be taken with ribavirin depends on HCV genotype and prior treatment
history.
Most people who have not taken HCV treatment before
and who have HCV genotype 1 or 4, with or without liver cirrhosis, will be able
to take Zepatier without ribavirin
for 12 weeks.
People with HCV genotype 1a, which is harder to treat
than 1b, should first receive a test for HCV NS5A mutations – also known as polymorphisms
or resistance-associated variants (RAVs) – that can cause resistance to
elbasvir and make Zepatier less
effective. People with these mutations should add ribavirin and extend
treatment to 16 weeks.
People with genotype 1a without these mutations and
those with genotype 1b who were previously unsuccessfully treated with
pegylated interferon and ribavirin (abbreviated as ‘IFN/RBV’ in the table
below) can take Zepatier alone for 12
weeks.
People with genotype 1a or 1b who were treated with
pegylated interferon and ribavirin plus the older HCV protease inhibitors
boceprevir (Victrelis), telaprevir (Incivo) or simeprevir (Olysio) should add ribavirin. Previously
treated people with genotype 4 should both add ribavirin and extend treatment
to 16 weeks.
| |
Treatment
regimen
|
Length
of treatment
|
|
Genotype
1a
Previously
untreated or
IFN/RBV-experienced
without NS5A polymorphisms
|
Zepatier
|
12 weeks
|
|
Genotype
1a
Previously
untreated or
IFN/RBV-experienced
with NS5A polymorphisms
|
Zepatier
+ ribavirin
|
16 weeks
|
|
Genotype
1b
Previously
untreated or
IFN/RBV
experienced
|
Zepatier
|
12 weeks
|
|
Genotype
1a or 1b
Prior
IFN/RBV and
protease
inhibitor treatment
|
Zepatier
+ ribavirin
|
12 weeks
|
|
Genotype
4
Previously
untreated
|
Zepatier
|
12 weeks
|
|
Genotype
4
IFN/RBV-experienced
|
Zepatier +
ribavirin
|
16 weeks
|
Recommended Zepatier
uses for people with HIV and HCV co-infection are the same as those for HIV-negative
people. However, it should not be used with antiretroviral medications that can
interact with Zepatier, including HIV
protease inhibitors, efavirenz (Sustiva)
or regimens that contain ritonavir or cobicistat as ‘boosters’.
Zepatier is not
approved for people with HCV genotypes 2, 3, 5 or 6.
How
effective is Zepatier?
Zepatier works
better for some people than for others.
People with higher HCV viral load, or HCV NS5A
mutations – also known as polymorphisms or resistance-associated variants
(RAVs) – that can cause resistance to elbasvir, have a lower chance of cure. This
may be overcome by longer treatment or by adding ribavirin, which helps prevent
viral relapse.
Unlike some other direct-acting antivirals, having
more advanced liver disease, including early cirrhosis, does not appear to have
much effect on response to Zepatier.
However, Zepatier is not suitable for
use in advanced cirrhosis (Child-Pugh B or C).
Other factors that traditionally predict poor response
to interferon-based therapy do not make as much difference with interferon-free
treatment.
Zepatier treatment
response
People with sustained virological response, who still
have undetectable HCV viral load 12 weeks after finishing treatment (known as ‘SVR12’),
are considered cured.
The safety and effectiveness of Zepatier were tested in nearly 1400 people with chronic hepatitis C
in several clinical trials. Overall, 90 to 100% of study participants with HCV
genotype 1 or 4 were curedusing Zepatier with or without ribavirin.
Zepatier alone
for 12 weeks cured 95% of previously untreated people with HCV genotype 1, with or without
cirrhosis, in the phase 3 C-EDGE treatment-naive study, and cured HCV
for 96% of people with genotype 1 HCV and HIV co-infection in the C-EDGE
co-infection trial.
In
the C-EDGE treatment-experienced study, 92% of genotype 1 prior non-responders to pegylated
interferon and ribavirin were cured using Zepatier alone for 12 weeks, rising to 97% using Zepatier plus ribavirin for 16 weeks.
This study included people with and without cirrhosis and both HIV-negative and
HIV-positive people.
The
C-SALVAGE study showed that Zepatier
plus ribavirin for 12 weeks cured 96% of people with or without cirrhosis who
had previously been unsuccessfully treated with interferon and ribavirin plus older
HCV protease inhibitors.
In the
C-SURFER trial, 94% of hepatitis C patients with severe kidney impairment using
Zepatier alone for 12 weeks were
cured. The study included both previously untreated and treatment-experienced
people.
For
previously untreated people with HCV genotype 4, the combined cure rate using Zepatier alone for 12 weeks was 97% in three
studies, again including patients with cirrhosis and HIV-positive participants.
The response rate was 100% for the small number of people with genotype 4 HCV
who used Zepatier plus
ribavirin for 16 weeks in the C-EDGE treatment-experienced trial.
In the C-EDGE CO-STAR study, Zepatier
alone for 12 weeks cured HCV for 92% of people who inject drugs who were
using opioid substitution therapy such as methadone.
The effectiveness of Zepatier in ‘real world’ use may be somewhat lower than cure rates
seen in clinical trials, in part because patients may be sicker or have other
conditions that make treatment more complicated. It is currently unknown how
effective Zepatier is in patients who
have previously taken treatment with newer direct-acting antivirals.
What are
the side-effects of Zepatier?
The drugs in Zepatier
are generally safe and well tolerated. The most common side-effects seen in
clinical trials were fatigue, headache and nausea. A small number of study participants
developed elevated levels of the liver enzyme ALT because of grazoprevir. If
there are high ALT elevations and/or other signs of possible liver toxicity
such as nausea, yellow eyes or skin, patients should urgently consult with
their doctors. Ribavirin can cause other side-effects including
anaemia (low haemoglobin level).
Zepatier has not yet been
tested in pregnant or breastfeeding women. Ribavirin can cause birth defects,
so it should not be used by pregnant women or their male partners.
Does Zepatier interact with other drugs?
The drugs in Zepatier
can interact with other drugs that are processed by the same enzymes in the
liver or intestines. This can lead to low drug levels that are less effective
or high levels that can cause worse side-effects.
Drugs that can interact with Zepatier include some antiretroviral drugs (such as HIV protease
inhibitors and efavirenz), antibiotics, TB medications, statins and herbal
products containing St John’s wort. Sometimes drug doses can be adjusted to
overcome these interactions, but some medications should not be used together
with Zepatier. Information about
specific drug interactions is available online at www.hep-druginteractions.org.
How can
I get Zepatier?
Zepatier is
available by prescription in European Union countries to treat people with
hepatitis C genotypes 1 or 4, subject to national funding arrangements. When to
start treatment will depend on a number of factors including severity of liver
damage (as determined by FibroScan or
a liver biopsy). Ask your doctor or liver specialist if Zepatier may be a good option for you.