The first interferon-free, oral antiviral treatment option for chronic genotype 4 HCV infection

Key points

  • The first interferon-free treatment option for patients with chronic genotype 4 hepatitis C virus (HCV) infection
    Grazoprevir with elbasvir (Zepatier) fixed-dose combination is an all-oral antiviral regimen that can be used for 12–16 weeks (with or without ribavirin) to achieve high rates (> 95%) of sustained viral response at 12 weeks post-treatment (SVR12) in treatment-naïve and treatment-experienced patients.1,2
  • An additional interferon-free treatment option for patients with chronic genotype 1 HCV infection
    Both treatment-naïve and treatment-experienced patients with genotype 1 infection can achieve high rates of SVR12 (> 90%) with 12–16 weeks of grazoprevir/elbasvir (with or without ribavirin).
  • High response rates achieved in patients with or without cirrhosis
    Similar rates of SVR12 were achieved in patients with genotype 1 or 4 infection with or without cirrhosis.
  • A salvage therapy in patients for whom triple therapy with an earlier-generation protease inhibitor has failed
    Patients with genotype 1 infection who had previously not attained SVR12 with peginterferon and ribavirin plus boceprevir, telaprevir or simeprevir were shown to achieve high rates of SVR12 (> 96%) with grazoprevir/elbasvir and ribavirin.
  • Can be used in patients with advanced chronic kidney disease
    Grazoprevir/elbasvir is not renally cleared and can therefore be used in patients with advanced chronic kidney disease (stage 4 or 5), including those on haemodialysis and peritoneal dialysis.
  • Contraindicated in patients with moderate and severe hepatic impairment (decompensated cirrhosis, Child–Pugh grade B or C)
    Grazoprevir/elbasvir is contraindicated in patients with moderate hepatic impairment due to a lack of clinical safety and efficacy experience, and in those with severe hepatic impairment due to significant increase in grazoprevir exposure.

Crosshairs

Evidence Snapshot

What is known about this drug combination?

Grazoprevir with elbasvir fixed-dose combination can achieve high rates of response in treatment-naïve or treatment-experienced patients with chronic genotype 1 or 4 hepatitis C virus (HCV) infection, with or without cirrhosis. It is used with or without ribavirin, depending on treatment history and HCV genotype.

It can be used for treating patients:

  • for whom triple therapy with a first-generation protease inhibitor (boceprevir, telaprevir or simeprevir) has failed
  • with chronic kidney disease (stage 4 or 5) without ribavirin
  • with HIV/HCV co-infection. See details in the How does it compare? section for more information on these studies.

Grazoprevir/elbasvir was well tolerated by patients in key clinical trials. Common adverse events included headache, fatigue, asthenia and nausea.

Liver function testing is recommended for patients receiving this regimen due to the increased risk of liver aminotransferase elevations.

Areas of uncertainty

There are limited data on comparative safety and efficacy of grazoprevir/elbasvir with other interferon-free treatment regimens for HCV. Grazoprevir/elbasvir was compared with peginterferon, ribavirin and sofosbuvir for genotype 1 or 4 HCV infection in the C-EDGE HEAD-2-HEAD study.3

What does NPS MedicineWise say?

Grazoprevir/elbasvir adds to the interferon-free treatment options currently available for treatment of chronic genotype 1 HCV. It is also the first interferon-free treatment option for patients with chronic genotype 4 HCV infection.

Advantages of grazoprevir/elbasvir include its fixed-dose formulation and the ability to achieve high rates of SVR12 in patient populations that tend to be harder to treat and cure.

PBS listing

Authority required

Grazoprevir with elbasvir (Zepatier) is listed on the PBS General Schedule (Section 85) and Section 100 Highly Specialised Drugs (S100 HSD) for treatment-naïve and treatment-experienced patients with chronic genotype 1 or 4 HCV infection.4

What is it?

Grazoprevir with elbasvir is a fixed-dose combination (FDC) containing two direct-acting antivirals (DAAs), grazoprevir and elbasvir, effective against the hepatitis C virus.5

Grazoprevir is an inhibitor of hepatitis C NS3/4A protease, which is necessary for proteolytic cleavage of the hepatitis C-encoded polyprotein, and is essential for viral replication.5

Elbasvir inhibits NS5A, a non-structural protein essential for hepatitis C viral RNA replication and virion assembly.5,6

Used together these agents have non-overlapping resistance profiles and target multiple steps in the hepatitis C virus lifecycle.5

Who is it for?

Grazoprevir with elbasvir FDC is approved by the Therapeutic Goods Administration for treatment of chronic genotype 1 or 4 HCV infection in adults.7

This FDC is PBS listed for use, with or without ribavirin, in treatment-naïve and treatment-experienced patients with genotype 1 or 4 infection.4

To be eligible for PBS-subsidised grazoprevir/elbasvir:4,8,9

What sets this regimen apart from other oral interferon-free DAA regimens?

Grazoprevir/elbasvir is the first all-oral treatment regimen to be approved for patients with genotype 4 HCV infection.8

Grazoprevir/elbasvir also allows for shorter treatment duration (12–16 weeks) in treatment-experienced patients with genotype 1 infection and cirrhosis, compared with the 24 weeks of treatment required for ledipasvir with sofosbuvir, or daclatasvir with sofosbuvir.8,10

Grazoprevir/elbasvir is also an effective treatment option for patient populations that are more difficult to treat. This includes:

  • people with advanced chronic kidney disease
  • those on haemodialysis or peritoneal dialysis5
  • those for whom triple therapy with peginterferon, ribavirin and a first-generation protease inhibitor (boceprevir, simeprevir or telaprevir) has previously failed.

As a second-generation protease inhibitor, grazoprevir/elbasvir appears to have an increased barrier to resistance compared with these first-generation protease inhibitors.11,12

Note that grazoprevir/elbasvir is an example of a DAA that does not interact with acid-reducing agents (proton pump inhibitors, histamine-2 blockers, antacids).5

Where does it fit?

Grazoprevir with elbasvir (GRZ/EBR) is the first-interferon-free treatment option available for use in patients with genotype 4 infection, and is an additional interferon-free treatment option for patients with chronic genotype 1 HCV infection.8,9

An additional interferon-free treatment option for chronic genotype 1 HCV infection

The recommended regimen and treatment duration of GRZ/EBR for patients with chronic genotype 1 HCV infection depends on treatment history and HCV subtypea:5,8,9,12

  • treatment duration of 12 weeks is recommended (irrespective of cirrhotic status) for patients with genotype 1a infection who are treatment-naïve (or who have relapsed12) and for those with genotype 1b infection who are treatment-naïve or treatment-experienceda
  • for those with genotype 1a infection who are treatment-experienced (with or without cirrhosis) and have experienced on-treatment virologic failurea, 16 weeks of GRZ/EBR and ribavirin is recommended.

Other interferon-free, DAA treatment options available on the PBS for patients with genotype 1 chronic hepatitis C infection include:8

For patients with chronic genotype 1 HCV, all these interferon-free treatment regimens are highly effective, achieving high rates (≥ 95%) of SVR12b.12 They can be used in treatment-naïve or treatment-experienced patients, with or without cirrhosis (in some cases patients with cirrhosis also require ribavirin).8,12

The first interferon-free treatment option for genotype 4 HCV infection

The recommended treatment regimen and duration for patients with chronic genotype 4 HCV infection is:

  • 12 weeks of GRZ/EBR for treatment-naïve patients, or treatment-experienceda patients who have relapseda (with or without cirrhosis)12
  • 16 weeks of GRZ/EBR with ribavirin for treatment-experienceda patients who have experienced on-treatment virologic failure at week 12a.12

  1. Treatment experience generally refers to peginterferon alpha plus ribavirin, with or without first-generation protease inhibitors. Relapsed patients refers to those who failed to achieve SVR12 despite achieving an end-of-treatment response. On-treatment virologic failure refers to patients who have had a null response, partial response, virologic breakthrough or rebound, or intolerance to prior treatment.12
  1. Sustained viral response (SVR) is the goal of treatment for chronic hepatitis C, and is used as a marker to indicate successful viral clearance. It is defined as undetectable plasma HCV RNA at least 12 weeks after treatment has ceased.12 Achieving SVR is associated with clinical benefits such as improved quality of life, loss of infectivity, regression of liver fibrosis and cirrhosis, reduction in the risk of liver failure and hepatocellular carcinoma, and reduction in the risk of liver-related and all-cause mortality.12

Choosing a treatment regimen for patients with chronic HCV infection

When deciding between treatment regimens, considerations include:12

  • HCV genotype and subtype
  • the presence or absence of cirrhosis
  • the presence or absence of liver decompensation
  • prior treatment history
  • potential for interactions with concurrent medicines
  • comorbidities.

An online tool for determining potential medicine interactions with hepatitis C treatment regimens is available from the University of Liverpool.

How does it compare?

Multiple phase II and III studies have demonstrated efficacy and safety of GRZ/EBR in patients with chronic genotype 1 or 4 HCV infection.

There is also evidence for use of GRZ/EBR in specific populations, including patients:

  • with advanced chronic kidney disease
  • who have failed triple therapy with a first-generation protease inhibitor
  • with HIV/HCV co-infection
  • who are receiving opioid-agonist therapy.

Treatment-naïve patients with genotype 1 HCV infection achieve high response rates with 12 weeks of GRZ/EBR

Phase II and III studies have shown that 12 weeks of treatment with GRZ/EBR is sufficient to achieve high rates of SVR12 (≥ 90%) in treatment-naïve patients with genotype 1 HCV infection.1,3,13 High response rates were observed for patients with and without cirrhosis.1,3 

Adding ribavirin to this treatment regimen did not substantially improve response rates in treatment-naïve patients with genotype 1 infection.13 Subgroup analysis of the 12- and 18-week treatment group combined showed that SVR12 was achieved in 95.0% (57/60) and 93.7% (59/63) of patients in the absence and presence of ribavirin, respectively.13

Treatment-experienced patients with genotype 1 infection: duration and regimen influenced by HCV subtype

For treatment-experienced patients, rates of response in those with genotype 1a infection were generally lower than those achieved in patients with genotype 1b infection.2

After 12 weeks of GRZ/EBR treatment, SVR12 rates of treatment-experienced patients with genotype 1b infection were 100% (34/34).2

By comparison, SVR12 rates using the same regimen in treatment-experienced patients with genotype 1a infection were 93.2% (55/59), and 91.8% (45/49) in previous non-responders to peginterferon and ribavirin.2

By adding ribavirin to GRZ/EBR and extending the duration of treatment to 16 weeks, SVR12 rates were 100% (20/20) for all treatment-experienced patients, including those with genotype 1a infection and prior non-responders.2

Incidence of virologic failure was also more common in treatment-experienced patients with genotype 1a infection compared with those with genotype 1b infection who received 12 weeks of GRZ/EBR (6.8% vs 0%, respectively).2

Extending treatment duration to 16 weeks and adding ribavirin reduced the incidence of virologic failure in patients with genotype 1a infection to zero.2

High rates of SVR12 in treatment-naïve and treatment-experienced patients with genotype 4 infection

For treatment-naïve patients with genotype 4 infection, 12 weeks of GRZ/EBR was sufficient to achieve high rates of SVR12 (100%, 18/18) in the C-EDGE TN study.1 No virologic failure or relapse was observed in this group.1

However, for patients with genotype 4 infection for whom previous treatment with peginterferon and ribavirin had failed, lower rates of SVR12 were achieved after 12 weeks of treatment with GRZ/EBR (88.9%, 32/36), and 12.5% experienced virologic failure.2

By adding ribavirin and extending treatment duration to 16 weeks, an SVR rate of 100% (8/8) was achieved, with no virologic failure.2

Although only a small number of patients with genotype 4 infection (n = 37, 9%) were included in this study, the results suggest that 16 weeks of GRZ/EBR treatment with ribavirin is necessary to achieve higher response rates in treatment-experienced patients.2

Equivalent or higher SVR12 rates compared with those for sofosbuvir with peginterferon and ribavirin

The phase III C-EDGE Head-2-Head study reported higher overall rates of SVR12 in patients with genotype 1 or 4 infections treated with GRZ/EBR for 12 weeks (99.2%, 128/129) compared with sofosbuvir with peginterferon and ribavirin (SOF/PR; 90.5%, 114/126).3

About 75% of patients in this trial were treatment-naïve and 25% had shown prior treatment failure with peginterferon and ribavirin. Patients with and without cirrhosis were included in the trial.3

For patients with genotype 1a infection, SVR12 rates were equivalent between the GRZ/EBR and SOF/PR groups (100% for both); however, for those with genotype 1b or 4 infection, higher rates of SVR12 were achieved with GRZ/EBR compared with SOF/PR (99.0% vs 90.4%, and 100% vs 60%, respectively).3

When considered overall, rates of virologic failure were lower in the GRZ/EBR-treated group compared with those treated with SOF/PR (0/129 vs 11/126).3

GRZ/EBR in specific patient populations

Patients with HCV genotype 1 infection and chronic kidney disease (stage 4 or 5)

SVR12 was achieved in 99.1% (115/116) of patients with genotype 1 infection and stage 4 or 5 chronic kidney disease who received GRZ/EBR for 12 weeks, according to a modified-analysis data setc.14

Subgroup analysis demonstrated that high response rates were achieved after 12 weeks of GRZ/EBR both in patients on haemodialysis (98.9%; 86/87) and those not on haemodialysis (100%; 29/29).14

The frequency of adverse events and serious adverse events occurred at similar rates between the immediate- and deferred-treatment (placebo) groups (76% and 84%; 14% and 15%, respectively).14


  1. This data set included patients assigned to the immediate-treatment group or assigned to the intensive pharmacokinetic group, and excluded patients who failed to receive one or more doses of the study drug, died or discontinued early for reasons unrelated to hepatitis C treatment.14

Patients with HCV genotype 1 infection for whom previous triple therapy with boceprevir, telaprevir or simeprevir had failed

In the C-SALVAGE study, 12 weeks of GRZ/EBR with ribavirin was effective for treatment of patients with genotype 1 infection for whom previous treatment with peginterferon and ribavirin plus boceprevir, telaprevir or simeprevir had failed.15

The overall SVR12 rate was 96.2% (76/79), and high rates of SVR12 were achieved in patients with or without cirrhosis (94.1% (32/34) and 97.8% (44/45), respectively).15

Patients with resistance-associated substitutions (RASs)

Resistance-associated substitutions (RASs) are heterogeneous regions in the HCV genetic sequences associated with resistance to antiviral agents.16 They arise spontaneously during replication due to the error-prone HCV RNA polymerase.12

RASs present before antiviral therapy starts are termed baseline RASs, while those first detected during antiviral therapy are considered treatment-emergent.12

Multiple studies have investigated the association between resistance-associated substitutions (RASs) in relevant HCV target sequences and response to GRZ/EBR treatment, with or without ribavirin.1,2,15

In these studies the RASs of interest were in the HCV sequences that interact with grazoprevir and elbasvir – in the NS3 protease and NS5A protein, respectively.2,5,15

Lower rates of SVR12 were observed in patients with genotype 1 infection treated with GRZ/EBR who had NS5A RASs present at baseline. These RASs confer more than a fivefold reduction in elbasvir antiviral activity in vitro (with or without NS3 RASs) compared with those without these RASs at baseline.15

These patients had previously not attained SVR after ≥ 4 weeks of treatment with peginterferon, ribavirin and an earlier-generation protease inhibitor.15

Baseline NS5A RASs have also been associated with virologic failure in patients with genotype 1a infection treated with GRZ/EBR for shorter duration (12 weeks) without ribavirin.1,2 However, with longer duration of treatment (16 weeks) and addition of ribavirin, no instances of virologic treatment failure were observed.2

Currently there is no clinical role for baseline HCV resistance testing in treatment-naïve people with chronic HCV infection, or prior non-responders to either peginterferon treatment, or protease inhibitor-based triple therapy.12

Current guidelines note that resistance testing for NS3, NS5B and NS5A RASs should be considered after failed combination DAA treatment to guide salvage therapy. These patients should be managed in specialist centres.12

Patients with HCV/HIV co-infection

High SVR12 rates achieved in patients with HCV/HIV co-infection

For patients with HCV/HIV co-infection, 12 weeks of treatment with GRZ/EBR resulted in high rates of SVR12 against HCV (87% to 98%) in the presence or absence of ribavirin.17,18 These high response rates were demonstrated in patients with or without cirrhosis.17,18

Patients included in these studies were either naïve to antiretroviral therapy or stable for at least 8 weeks on:

  • raltegravir plus two nucleoside or nucleotide reverse transcriptase inhibitors,18 or
  • with tenofovir or abacavir, and either emtricitabine or lamivudine plus raltegravir, dolutegravir or rilpivirine.17

The safety profiles and rates of adverse events with GRZ/EBR treatment, with or without ribavirin, were similar between the mono-infected and co-infected patients.18

The treatment regimen was well tolerated by patients with or without cirrhosis.17

Precautions and contraindications for patients with HCV/HIV co-infection

The efficacy and safety studies of GRZ/EBR with anti-retrovirals have been restricted to tenofovir or abacavir and either emtricitabine or lamivudine plus raltegravir, dolutegravir or rilpivirine because of potential for medicine interactions.17

The following HIV medicines are contraindicated for use with GRZ/EBR:5

  • efavirenz
  • atazanavir
  • darunavir
  • lopinavir
  • saquinavir
  • tipranavir.

Other HIV medicines not recommended for co-administration with GRZ/EBR because they may reduce the therapeutic effect of GRZ/EBR are:5

  • etravirine
  • elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate or alagenamide (fixed-dose combination).

Patients receiving opioid-agonist therapy

People who inject drugs comprise a major population of patients affected by hepatitis C infection that is rarely included in studies of DAAs.19 The C-EDGE CO-STAR study evaluated the safety and efficacy of grazoprevir with elbasvir in this population.

The study enrolled 301 treatment-naïve patients with chronic HCV genotype 1, 4 or 6 infection who were stable on opioid-agonist therapy (with methadone, buprenorphine, or buprenorphine/naloxone) for at least 3 months before enrolment and at least 80% adherent to opioid-agonist therapy appointments. Patients who were actively using drugs of potential abuse while receiving opioid-agonist therapy were not excluded from the study.19

SVR12 was achieved by 91.5% (95% confidence interval [CI], 86.8 to 95.0) of patients in the immediate-treatment group, who received GRZ/EBR in a blinded fashion for 12 weeks.

In the deferred-treatment group, patients were given placebo for 12 weeks, followed by 4 weeks of follow-up, then 12 weeks of open-label treatment with GRZ/EBR. In these patients, SVR12 was achieved in 89.5% (95% CI 81.5–94.8) in the active phase.19

Although SVR12 was similar in patients with genotype 1a, 1b or 4 infection, it was lower in the few patients with genotype 6 infection.19

Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy.19

GRZ/EBR treatment was well tolerated, and the safety profile of GRZ/EBR in the immediate-treatment group was similar to that of placebo in the deferred-treatment group.19

Based on these results, the authors of the study concluded that drug use should not be a barrier to interferon-free treatment for patients receiving opioid-agonist therapy.19

Safety issues

GRZ/EBR, with or without ribavirin, was generally well tolerated by patients in clinical trials. Overall, very common adverse events (> 10% frequency) in the GRZ/EBR treatment groups (with or without ribavirin) were headache, fatigue, asthenia and nausea, and most were of mild to moderate intensity.1,2,13,15

A higher frequency of drug-related adverse events was observed in ribavirin-containing GRZ/EBR treatment groups compared with those not treated with ribavirin.2,13,18 Adverse events such as fatigue, nausea, accidental overdose, anaemia and pruritus were reported to be more common in the groups receiving ribavirin-containing treatment than in those without ribavirin.2

There was a low incidence of serious adverse events across studies, occurring at similar rates between patients receiving the ribavirin-containing and ribavirin-free regimens (1% to 3.1%).1,2,13,18 Few patients discontinued treatment due to adverse events (1% to 1.7%).1,2,13,18

For information about reporting adverse reactions to the TGA, or to report suspected adverse reactions online, see the TGA website.

Increased risk of ALT elevations

Late elevations in liver aminotransferase measurements (more than five times the upper limit of normal) were observed in a small number of patients treated with GRZ/EBR, in the presence or absence of ribavirin (≤ 1%).1,13,17

In most cases these elevations resolved without discontinuation of treatment.17 However, in one study two patients discontinued treatment due to this adverse event, as per the study protocol.1

These aminotransferase elevations were transient and reversible1 and resolved after treatment stopped and SVR12 was achieved.1,13

Due to the increased risk of alanine aminotransferase (ALT) elevations in patients receiving GRZ/EBR, liver function testing is recommended for all patients receiving GRZ/EBR (with or without ribavirin):5

  • before starting treatment
  • at treatment week 8
  • at treatment week 12 (if patient is receiving 16 weeks of treatment)
  • as clinically indicated.

If ALT elevations are observed in patients receiving GRZ/EBR, discuss the findings with a specialist who has experience in treatment of chronic hepatitis C.

Instruct patients to consult their healthcare professional without delay if they experience fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discoloured faeces.5

Contraindicated in patients with moderate or severe hepatic impairment

After administration, GRZ/EBR is highly protein bound and becomes distributed in most tissues (elbasvir), and predominantly in the liver (grazoprevir).5

For those with moderate hepatic impairment (Child–Pugh grade B), GRZ/EBR is contraindicated due to a lack of clinical safety and efficacy experience in this population, and the expected fivefold increase in grazoprevir exposure.5

GRZ/EBR is also contraindicated in patients with severe hepatic impairment (Child–Pugh grade C) based on an approximate 12-fold expected significant increase in grazoprevir exposure.5

If GRZ/EBR is administered with ribavirin, the contraindications to ribavirin also apply to this combination regimen. Refer to the ribavirin Product Information for a list of contraindications to ribavirin.

Medicines contraindicated for use with GRZ/EBR

Strong cytochrome P450 3A inducers

Grazoprevir and elbasvir are predominantly metabolised by the cytochrome P450 3A4 system.20 Strong cytochrome P450 3A (CYP 3A) inducers can decrease plasma concentrations of elbasvir and grazoprevir, reducing their therapeutic effects – possibly leading to a loss of virologic response.5 Therefore, strong CYP 3A4 inducers such as rifampicin, phenytoin, carbamazepine and St John’s wort are contraindicated for co-administration with GRZ/EBR.5

Some medicines for HIV

See section Patients with HIV/HCV co-infection for more information.

OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations

Grazoprevir is a substrate of organic anion-transporting polypeptides 1B1/3 (OATP1B1/3), and co-administration with inhibitors of OATP1B transport may result in a clinically relevant increase in grazoprevir plasma concentration.5 This can increase the risk of ALT elevations.5

GRZ/EBR is contraindicated with OATP1B1/3 inhibitors that are known or expected to significantly increase grazoprevir plasma concentrations, including:5

  • rifampicin
  • atazanavir, darunavir, lopinavir, saquinavir and tipranavir
  • ciclosporin.

Precautions

Caution should be used when co-administering GRZ/EBR with:5

  • strong cytochrome P450 3A4 inhibitors (eg, ketoconazole and ritonavir), which may lead to increased concentrations of elbasvir and grazoprevir.
  • HMG-CoA reductase inhibitors (atorvastatin, rosuvastatin, fluvastatin, lovastatin or simvastatin). If co-administration is required, the lowest dose of HMG-CoA reductase inhibitor possible should be used (maximum dose: atorvastatin 20 mg; rosuvastatin 10 mg) Note that dose reduction of pravastatin is not required for patients receiving GRZ/EBR.

Concomitant administration with moderate CYP3A inducers not recommended

Concomitant administration is not recommended with moderate CYP 3A inducers such as nafcillin, bosentan or modafinil because they may lead to decreased concentrations of grazoprevir and elbasvir and therefore may decrease its therapeutic efficacy.5

Monitoring required if co-administered with tacrolimus

Co-administration of GRZ/EBR with systemic tacrolimus can increase concentrations of tacrolimus. If co-administration is required, frequently monitor tacrolimus whole blood concentrations, changes to renal function and adverse events associated with tacrolimus.5

See the Zepatier Product Information for a full list of medicine interactions, contraindications and precautions.

Pregnancy category B1

There are no adequate or well-controlled studies of GRZ/EBR in pregnant women. GRZ/EBR should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus.5

There is also a lack of information on whether GRZ/EBR is excreted in human breast milk, which requires careful consideration of benefits and risks.5

Reason for PBS listing

The PBAC recommended the Authority required listing of grazoprevir with elbasvir for the treatment of chronic hepatitis C virus infection for treatment-naïve and treatment-experienced patients with genotype 1 or 4 infections.7,9

The PBAC considered that there were insufficient data to recommend GRZ/EBR for listing for genotype 3.9

Dosing issues

Treatment durations and regimens are outlined in the General Statement for Drugs for the Treatment of Hepatitis C, based on the patient’s HCV genotype, treatment history and cirrhotic status.

One tablet, taken orally, once daily (with or without food)

GRZ/EBR is a fixed-dose combination product containing 100 mg of grazoprevir and 50 mg of elbasvir in a single tablet. The recommended dosage is one tablet, once daily, with or without food.5

Dosage adjustment required for most statins (HMG-CoA reductase inhibitors) if administered concurrently with GRZ/ELB

Dosage adjustments are required for concurrent administration of the following statins with GRZ/EBR:5

  • atorvastatin – dosage of atorvastatin should not exceed 20 mg daily when co-administered with GRZ/ELB
  • rosuvastatin – dosage of rosuvastatin should not exceed 10 mg daily when co-administered with GRZ/ELB
  • fluvastatin, lovastatin, simvastatin – dosage of these medicines should not exceed 20 mg daily when co-administered with GRZ/ELB.

If dosage adjustments of concomitant medicines are made due to treatment with GRZ/EBR, dosages should be readjusted after administration of GRZ/EBR is completed.5

Note that no dosage adjustment is required for pravastatin if co-administered with GRZ/ELB.5

No dosage adjustment required for patients with renal impairment or mild hepatic impairment

No dosage adjustment is recommended for patients with mild, moderate or severe renal impairment or those who are on dialysis (including haemodialysis or peritoneal dialysis).5

Note that GRZ/EBR should be administered without ribavirin in patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2) or with end-stage renal disease, including patients on dialysis.5

No dosage adjustment is required for patients with mild hepatic impairment (Child–Pugh grade A).5

Information for patients

Advise patients taking grazoprevir with elbasvir as follows.21

  • Grazoprevir with elbasvir must always be taken as directed by your health professional, with or without food.
  • Other medicines can interact with grazoprevir/elbasvir, and this can lead to more serious side effects. Tell your health professional about all medicines you are taking, including other prescription and non-prescription medicines, vitamins and herbal supplements.
  • In particular, tell your health professional if you are taking medicines such as carbamazepine or phenytoin for epilepsy and seizures, ciclosporin to stop organ transplant rejection, efavirenz, atazanavir, darunavir, lopinavir, saquinavir or tipranavir for HIV, rifampicin for tuberculosis, St. John’s wort (Hypericum perforatum, a herbal medicine) for depression or other problems.
  • Talk to your health professional before starting or discontinuing your medicines.
  • Ask your health professional for advice before taking this medicine if you are pregnant, planning to become pregnant, breastfeeding or planning to breastfeed.21

Discuss the Zepatier Consumer Medicine Information (CMI) leaflet with the patient.

References

  1. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir–elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: a randomized trial. Ann Intern Med 2015;163:1-13.
  2. Kwo P, Gane E, Peng C-Y, et al. Effectiveness of Elbasvir and Grazoprevir Combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection. Gastroenterology 2016.
  3. Sperl J, Horvath G, Halota W, et al. Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: A phase III randomized controlled trial. J Hepatol 2016.
  4. Australian Government Department of Health, Pharmaceutical Benefits Scheme. Grazoprevir + elbasvir. 2017 (accessed 4 January 2017).
  5. Merck Sharp and Dohme (Australia) Pty Limited. Product Information: Elbasvir/grazoprevir tablets (Zepatier). 2016 (accessed 2 November 2016).
  6. Asselah T, Boyer N, Saadoun D, et al. Direct‐acting antivirals for the treatment of hepatitis C virus infection: optimizing current IFN‐free treatment and future perspectives. Liver Int 2016;36:47-57.
  7. Therapeutic Goods Administration. ZEPATIER elbasvir/grazoprevir 50 mg/100 mg tablet blister pack. Public Summary. TGA, 2016 (accessed 4 November 2016).
  8. Australian Government Department of Health, Pharmaceutical Benefits Scheme. General statement for drugs for the treatment of hepatitis C. 2017. (accessed 4 January 2017).
  9. Australian Government Department of Health, Pharmaceutical Benefits Advisory Committee. Grazoprevir 100 mg/ Elbasvir 50 mg, fixed dose combination tablet (Zepatier). Public Summary Document - July 2016 PBAC Meeting. 2016 (accessed 2 November 2016).
  10. Landaverde C, Wells J, Hamner R, et al. Dual therapy of grazoprevir and elbasvir for the treatment of hepatitis C infection. Expert Rev Gastroenterol Hepatol 2016;10:419-29.
  11. Buti M, Gordon SC, Zuckerman E, et al. Grazoprevir, elbasvir, and ribavirin for chronic hepatitis C virus genotype 1 infection after failure of pegylated interferon and ribavirin with an earlier-generation protease inhibitor: final 24-week results from C-SALVAGE. Clin Infect Dis 2016;62:32-6.
  12. Hepatitis C Virus Infection Consensus Statement Working Group. Australian recommendations for the management of hepatitis C virus infection: a consensus statement 2016. Gastroenterological Society of Australia, 2016 (updated), (Accessed December 2016.)
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