First published 3 January 2017

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer’s approved product information, a drug information centre or some other appropriate source.

Approved indication: hepatitis C
Zepatier (MSD)
tablets containing elbasvir 50 mg and grazoprevir 100 mg
Australian Medicines Handbook section 5.5

The management of chronic hepatitis C is rapidly changing, with newer regimens containing directacting antivirals without interferon.1 This product is a fixed-dose combination tablet of elbasvir and grazoprevir indicated for people with hepatitis C genotypes 1 or 4.

Elbasvir inhibits the NS5A protein involved in the production and assembly of virus particles, and grazoprevir inhibits the NS3/4A protease involved in viral replication. After oral administration, peak plasma concentrations are reached within 2–3 hours. Steady-state concentrations are reached after six days of once-daily dosing. Almost all of the dose is excreted in the faeces as metabolites.

The approval of this combination is based on several trials in treatment-naïve and treatment-experienced patients infected with genotypes 1, 4 and 6. Studies included people co-infected with HIV, those with chronic kidney disease and people receiving opioid substitution therapy (see Table).2-7 To be enrolled, patients had to have at least 104 IU/mL of hepatitis C viral RNA in their blood at baseline. Liver cirrhosis was allowed but those with decompensated liver disease were excluded from the trials.

Table - Efficacy of elbasvir/grazoprevir with or without ribavirin in chronic hepatitis C

Trial

Patient characteristics

Genotype

Treatment arm (duration)*

Efficacy – patients with SVR12

C-EDGE2
(double-blind)

Treatment-naïve patients

1, 4, 6

elbasvir/grazoprevir 
(12 weeks)

94.6% (299/316)

C-EDGE CO-INFECTION3
(open-label)

Treatment-naïve patients co-infected with HIV

1, 4, 6

elbasvir/grazoprevir 
(12 weeks)

96.3% (210/218)

C-EDGE TE4
(open-label)

Previous treatment
failure with
peginterferon/ribavirin, with or without HIV co-infection

1, 4, 6

elbasvir/grazoprevir 
(12 weeks)

92.4% (97/105)

elbasvir/grazoprevir+
ribavirin (12 weeks)

94.2% (98/104)

elbasvir/grazoprevir 
(16 weeks)

92.4% (97/105)

elbasvir/grazoprevir+
ribavirin (16 weeks)

98.1% (104/106)

C-SALVAGE5
(open-label)

Previous treatment
failure with
peginterferon/ribavirin in combination with boceprevir, telaprevir or simeprevir

1

elbasvir/grazoprevir+
ribavirin (12 weeks)

96.2% (76/79)

C-SURFER6
(double-blind)

Stage 4 or 5 chronic kidney disease, treatment-naïve or experienced (previous treatment failure with peginterferon with or without ribavirin)

1

elbasvir/grazoprevir
(12 weeks)

94.3% (115/122)

C-EDGE CO-STAR7
(double-blind)

Treatment-naïve patients with or without cirrhosis receiving opioid substitution therapy

1, 4, 6

elbasvir/grazoprevir
(12 weeks)

91.5% (184/201)


* elbasvir 50 mg and grazoprevir 100 mg given once-daily and ribavirin given twice-daily

SVR12 sustained virologic response 12 weeks after the end of treatment


The primary measure of effectiveness in the trials was the proportion of patients who achieved a sustained virologic response. This was defined as undetectable viral RNA in a blood test 12 weeks after the end of treatment (SVR12).

In the C-EDGE trial, which enrolled people who had not received previous treatment for hepatitis C, almost 95% of participants had a sustained virologic response to 12 weeks of treatment with elbasvir/grazoprevir.2 Response rates were 92% (144/157) with genotype 1a, 99% (129/131) with genotype 1b, 100% (18/18) with genotype 4 and 80% (8/10) with genotype 6. Similarly high response rates were seen in treatment-naïve patients co-infected with HIV (C-EDGE CO-INFECTION).3 In both trials, cirrhosis and high viral load at baseline did not seem to affect response rates.

Response rates to elbasvir/grazoprevir were high in patients who had failed on previous therapy with peginterferon/ribavirin (C-EDGE TE). Extending therapy to 16 weeks and adding ribavirin increased the response rate from 92% to 98%.4

Adding ribavirin to elbasvir/grazoprevir was also very effective in those who had failed previous therapy with peginterferon/ribavirin combined with boceprevir, telaprevir or simeprevir (C-SALVAGE).5

Another trial enrolled patients with stage 4 or 5 chronic kidney disease (C-SURFER) – 76% of participants were dependent on haemodialysis and 81% had stage 5 chronic kidney disease. After 12 weeks of treatment with elbasvir/grazoprevir, 94% had a sustained virologic response.6

In a trial of patients receiving opioid substitution therapy (C-EDGE CO-STAR), 92% had a sustained virologic response following a 12-week course of elbasvir/grazoprevir.7

Resistance to elbasvir/grazoprevir was observed in the trials. This was associated with single amino acid substitutions in the NS5A and NS3/4A proteins.

Fatigue, headache and nausea were the most common adverse effects in people taking elbasvir/grazoprevir,2 including those co-infected with HIV3 and those with advanced chronic kidney disease.6 In patients who received the combination with ribavirin, anaemia was also common (14.8% of patients).4

Alanine aminotransferase elevations greater than five times the upper limit of normal occurred in 0.77% of patients given elbasvir/grazoprevir with or without ribavirin. Onset was generally eight weeks after starting treatment and usually resolved with ongoing therapy. Elevated bilirubin was also observed, often in those given ribavirin (6% of patients). Elbasvir/grazoprevir is contraindicated in moderate and severe hepatic impairment.

Both elbasvir and grazoprevir are partially metabolised by oxidation, primarily by cytochrome P450 (CYP) 3A, so there are numerous potential drug interactions. Strong inducers of CYP3A, such as the HIV drug efavirenz, phenytoin, carbamazepine and St John’s wort, are contraindicated as they can reduce the concentrations of elbasvir and grazoprevir. Grazoprevir is also a substrate of OATP1B and co-administration with drugs that inhibit this transporter, such as cyclosporin and HIV drugs atazanavir, darunavir, lopinavir, saquinavir and tipranavir, may cause alanine aminotransferase elevations due to the increase in grazoprevir exposure. Interactions with other drugs may require dose changes and the product information should be consulted. For example, elbasvir/grazoprevir increases exposure to co-administered atorvastatin so the daily statin dose should not exceed 20 mg.

The recommended elbasvir/grazoprevir dose for previously untreated patients or those who have relapsed since finishing a previous course is one tablet a day for 12 weeks. In patients who have had a null or partial response, or viral breakthrough during previous treatment, ribavirin should be added. This treatment should be given for 12 weeks in those with genotype 1b infection and for 16 weeks in those with 1a or 4 infection. Patients with severe renal impairment or end-stage renal disease should not be given ribavirin.

There have been no studies of the elbasvir/grazoprevir combination in pregnant women. Studies of high doses in rats and rabbits found no adverse effects on fetal development. It is not known if elbasvir and grazoprevir are excreted in human milk, however, in preclinical studies both drugs were excreted in lactating rats. No adverse effects were seen on nursing pups.

If ribavirin is added to elbasvir/grazoprevir, female patients and female partners of male patients must use contraception during and for six months after the end of treatment. 

This fixed-dose combination of elbasvir and grazoprevir was very effective and generally well tolerated in people with chronic hepatitis C genotype 1 or 4. It seems to be suitable for people with HIV infection or advanced kidney disease. However, similar to paritaprevir/ritonavir/ombitasvir plus dasabuvir,8 it is contraindicated in people with moderate to severe hepatic impairment. Other regimens such as ledipasvir with sofosbuvir9 may be more suitable for these patients. The elbasvir/grazoprevir combination has numerous potential drug interactions, particularly with HIV medicines.

Read about The Transparency Score  manufacturer provided additional useful information


The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA, European Medicines Agency and the Therapeutic Goods Administration.

References

  1. Thompson AJ, Holmes JA. Treating hepatitis C - what’s new? Aust Prescr 2015;38:191-7.
  2. Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ben Ari Z, Zhao Y, et al. Grazoprevir-elbasvir combination therapy for treatmentnaïve cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4 or 6 infection. Ann Intern Med 2015;163:1-13.
  3. Rockstroh JK, Nelson M, Katlama C, Lalezari J, Mallolas J, Bloch M, et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a nonrandomised, open-label trial. Lancet HIV 2015;2:e319-27.
  4. Kwo P, Gane E, Peng CY, Pearlman B, Vierling JM, Serfaty L, et al. Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection. Gastroenterology 2016 Oct 5:S0016-5085(16)35170-8. Epub ahead of print.
  5. Forns X, Gordon SC, Zuckerman E, Lawitz E, Calleja JL, Hofer H, et al. Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent. J Hepatol 2015;63:564-72.
  6. Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour H Jr, et al. Grazoprevir plus elbasvir in treatmentnaïve and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet 2015;386:1537-45.
  7. Dore GJ, Altice F, Litwin AH, Dalgard O, Gane EJ, Shibolet O, et al.; C-EDGE CO-STAR Study Group. Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy: a randomized trial. Ann Intern Med 2016;165:625-34.
  8. Paritaprevir/ritonavir/ombitasvir plus dasabuvir/with ribavirin for chronic hepatitis C. Aust Prescr 2016;39:141-3.
  9. Ledipasvir with sofosbuvir. Aust Prescr 2015;38:219-21.