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.
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.
Blocking two steps in the lifecycle of the virus stops it from
reproducing and clears the virus from the body rapidly.
The aim of treatment is to achieve a sustained virologic response 12
weeks after completing treatment. If the hepatitis C virus remains undetectable
at this point, it means the virus has been cleared from the body and a person
is cured of hepatitis C.
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.
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 |
Zepatier
|
12 weeks
|
|
Genotype
1a with NS5A
polymorphisms and/or HCV RNA above 800,000 IU/ml |
Zepatier
+ ribavirin
|
16 weeks
|
|
Genotype
1b
Previously
untreated
|
Zepatier
|
12 weeks
|
|
Genotype
4
Previously
untreated
|
Zepatier
|
12 weeks
|
Genotype 4 with NS5A
polymorphisms and/or HCV RNA above 800,000 IU/ml |
Zepatier +
ribavirin
|
16 weeks
|
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?
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 cured using
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, affecting at least one in a
hundred people were loss of appetite, insomnia, anxiety, depression, dizziness,
nausea, diarrhoea, constipation, abdominal pain, dry mouth, vomiting, itching,
hair loss, muscle pain, joint pain, weakness and irritability. One in ten
people reported fatigue or headache.
Fewer than one in a hundred 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, anticonvulsants, 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. Ask your doctor or
liver specialist if Zepatier may be a good option for you.
Factsheet reviewed April 2022.