Glecaprevir with pibrentasvir (Maviret) – the second pan-genotypic DAA regimen available on PBS for chronic hepatitis C

• Glecaprevir with pibrentasvir is an effective treatment option for patients with genotype 1-6 chronic hepatitis C infection
  It can be used to treat patients with chronic hepatitis C who are treatment-naïve or treatment-experienced, with or without compensated cirrhosis.
• Duration of treatment may be 8, 12 or 16 weeks, based on treatment experience, cirrhosis status and genotype
  While 8 weeks of treatment is sufficient for all treatment-naïve patients without cirrhosis, longer treatment durations (12 or 16 weeks) are recommended for those with compensated cirrhosis and/or who are treatment-experienced.
• Can be used in patients with previous NS3/4A protease inhibitor or NS5A inhibitor experience
  For genotype 1, treatment duration is 12 weeks for those who have whose previous treatment with an NS3/4A protease inhibitor has been unsuccessful, and 16 weeks for those whose treatment with an NS5A inhibitor has been unsuccessful’. Treatment-experienced genotype 3 patients also require 16 weeks.
• Not for use in patients with moderate or severe hepatic impairment (Child-Pugh B or C)
  Glecaprevir with pibrentasvir is not recommended for patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated for patients with severe hepatic impairment (Child-Pugh C). 

While chronic hepatitis C (CHC) was previously a condition primarily managed by specialists, the role of GPs in managing uncomplicated CHC has expanded in recent years.¹

A range of direct-acting antivirals (DAAs) are available for prescribing in primary care through the Pharmaceutical Benefits Scheme (PBS), supported by Australian recommendations for the management of hepatitis C virus (HCV) infection.¹

On 1 August 2018, the fixed-dose combination glecaprevir with pibrentasvir became the second pan-genotypic DAA treatment regimen for CHC to be listed on the PBS.^2-6

With so many CHC treatment options now listed on the PBS, you may be wondering how glecaprevir with pibrentasvir fits into management of CHC. Here, we provide some practical guidance on the place of this treatment option in the management of CHC.

What is glecaprevir with pibrentasvir?

It is a fixed dose combination oral tablet containing 100 mg glecaprevir and 40 mg pibrentasvir.⁷ The recommended dose is 3 tablets once daily.⁷ Glecaprevir inhibits a protease (NS3/4A) that is necessary to make essential proteins required for viral replication, and pibrentasvir inhibits a key protein (NS5A) that is essential for viral RNA replication and virion assembly.⁷

Which patients are eligible for this treatment option?

Glecaprevir with pibrentasvir is available on the PBS for:^3,6

• patients with CHC infection of any genotype (1-6), and
  
• patients with or without a history of previous CHC treatment (including NS5A inhibitors), and
  
• patients with or without compensated cirrhosis.
  

Glecaprevir with pibrentasvir has an Authority Required listing on the PBS General Schedule (Section 85) and Section 100 Highly Specialised Drugs (S100 HSD).³

Recommended treatment duration – based on treatment history, cirrhosis status and genotype

A brief summary is provided in Table 1 on recommended duration of glecaprevir with pibrentasvir treatment, according to previous treatment experience and cirrhosis status.^6,7

Note that glecaprevir with pibrentasvir is suitable for treatment of patients with compensated cirrhosis/mild hepatic impairment (Child-Pugh A), however it is not recommended for patients with moderate hepatic impairment (Child-Pugh B) and is contraindicated in those with severe hepatic impairment (Child-Pugh C).⁷ These patients should be managed in specialist centres.¹

^a Compensated cirrhosis (Child Pugh A).⁷

^b Treatment for 8 weeks for treatment-experienced patients with genotype 1 who have failed regimens containing peginterferon, ribavirin and/or sofosbuvir but no prior treatment experience with an HCV NS3/4A PI or NS5A inhibitor. Treatment for 12 weeks for treatment-experienced patients with genotype 1 who have failed regimens containing an NS3/4A PI. Treatment for 16 weeks for treatment-experienced patients with genotype 1 who have failed regimens containing an NS5A inhibitor.⁶

^c Treatment for 12 weeks for treatment- experienced patients with genotype 1 who have failed regimens containing an NS3/4A PI. Treatment for 16 weeks for treatment-experienced patients with genotype 1 who have failed regimens containing an NS5A inhibitor.⁶

For more information, see the General Statement for Drugs for the Treatment of Hepatitis C.

How effective is glecaprevir with pibrentasvir?

The effectiveness of medicines for CHC treatment is indicated by sustained viral response (SVR), a marker for successful viral clearance.¹

SVR is defined as undetectable plasma HCV RNA at least 12 weeks after treatment has ceased (SVR12).¹ After SVR is achieved, patients remain anti-HCV positive, however this does not represent active infection, and does not confer immunity to reinfection.¹

High rates of SVR achieved with 8 weeks of treatment in treatment-naïve and some treatment-experienced patients without cirrhosis

Genotype 1: After 8 weeks of glecaprevir with pibrentasvir treatment, SVR12 was achieved in 99% of genotype 1-infected patients without cirrhosis who were either treatment-naïve or had previously been treated with either interferon/peginterferon ± ribavirin, or sofosbuvir plus ribavirin ± peginterferon.⁸

Genotype 2: For non-cirrhotic patients with genotype 2 infection, 8 weeks of glecaprevir with pibrentasvir treatment resulted in SVR12 for 98% of patients who were either treatment naïve or had failed previous treatment with interferon/peginterferon ± ribavirin or sofosbuvir plus ribavirin ± peginterferon.⁹

Genotype 3: For treatment-naïve patients with genotype 3 infection and no cirrhosis, 95% achieved SVR12 after 8 weeks of glecaprevir with pibrentasvir treatment.⁸

Genotypes 4, 5 and 6: After 8 weeks of glecaprevir with pibrentasvir treatment, SVR12 was achieved in 93% (43/46) of genotype 4-, 100% (2/2) of genotype 5- and 90% (9/10) of genotype 6-infected patients who were either treatment-naïve patients or had previously failed regimens containing interferon or peginterferon ± ribavirin.⁹

Treatment-experienced patients with genotype 3 infection

For patients with genotype 3 infection and previous treatment, a longer treatment duration is required to achieve an SVR12 of ≥ 95%.^10,11

SVR12 was achieved in 91% of patients without cirrhosis with previous peginterferon, ribavirin ± sofosbuvir treatment experience after 12 weeks of treatment with glecaprevir with pibrentasvir, and this increased to 95% after 16 weeks of treatment.¹¹

A 12- or 16-week treatment duration for patients with compensated cirrhosis

SVR12 was achieved in 99-100% of treatment-naïve or peginterferon/ ribavirin/sofosbuvir experienced patients with compensated cirrhosis and genotype 1, 2, 4, 5 or 6 infection after 12 weeks of treatment with glecaprevir with pibrentasvir.¹²

For treatment-naïve patients with genotype 3 infection and compensated cirrhosis, 98% (95% CI 87 to 99) achieved SVR12 after 12 weeks of glecaprevir with pibrentasvir treatment. Those with prior treatment experience achieved an SVR12 of 96% (95% CI 86 to 99) after 16 weeks of treatment.¹¹

Longer treatment duration required for those who have not responded to treatment with other DAAs

Another clinical trial assessed response to glecaprevir with pibrentasvir in patients who had failed prior treatment with NS3/4A protein inhibitors and/or NS5A inhibitors.¹³ In this cohort of patients, almost 30% (27/91) had compensated cirrhosis, the majority had genotype 1 infection (87 of 91 patients) and the remainder (4 patients) had genotype 4 infection.¹³

For those with past experience of treatment with NS3/4A protein inhibitors, 100% achieved SVR12 with 12 or 16 weeks of glecaprevir with pibrentasvir treatment.¹³

For patients with previous experience of NS5A inhibitor treatment only, SVR12 rates were 88% (95% CI 64 to 97) after 12 weeks, and 94% (95% CI 74 to 99) after 16 weeks of glecaprevir with pibrentasvir treatment.¹³

In comparison, those that had past experience with both classes of inhibitors (NS3/4A and NS5A) achieved SVR12 rates of 79% (95% CI 52 to 92) after 12 weeks of treatment, and 81% (95% CI 57 to 93) after 16 weeks of treatment.¹³

Safety of glecaprevir with pibrentasvir

When pooled across clinical trials, the most frequently reported adverse effects for patients taking glecaprevir with pibrentasvir were fatigue (15.0%), headache (16.9%) and diarrhoea (10.3%).²

Adverse effects were typically mild (grade 1 in 80% of cases), and these reactions occurred at a similar frequency in patients taking placebo.⁷ Adverse reactions occurred at a similar frequency to those for sofosbuvir and daclatasvir in the ENDURANCE-3 trial.⁷

The overall safety of glecaprevir with pibrentasvir was similar for patients receiving the treatment for 8, 12 or 16 weeks, and the type and severity of adverse reactions for patients with compensated cirrhosis was comparable to that seen in patients without cirrhosis.⁷

Overall in clinical trials, very few patients (0.1%) permanently discontinued treatment because of adverse reactions.⁷

With so many CHC treatment options now listed on the PBS, you may be wondering how glecaprevir with pibrentasvir fits into management of CHC.

Here, we ask clinical expert Associate Professor Simone Strasser to answer some key questions.

Where does glecaprevir with pibrentasvir fit into treatment of CHC, considering the wide range of other direct-acting antivirals listed on the PBS?

In Australia, it is estimated that over 90% of the patients with HCV who are so far untreated do not have advanced liver disease.

Once cirrhosis is excluded, the new fixed dose combination of glecaprevir with pibrentasvir is an excellent 8-week regimen that has a high chance of cure regardless of the HCV genotype.

That means this regimen is appropriate for almost all our previously untreated, non-cirrhotic patients.

Many of the older drugs and drug combinations that were listed in 2016 are becoming less relevant in the era of pan-genotypic regimens.

Moving forward, the majority of patients can be treated with a highly effective fixed-dose pan-genotypic regimen for either 8 or 12 weeks.

Which patients with CHC is glecaprevir with pibrentasvir particularly suitable for?

The 8-week regimen of glecaprevir with pibrentasvir is potentially suitable for anyone without cirrhosis who has not been previously treated. This is the majority of the untreated population in Australia.

An 8-week treatment is also suitable for patients without cirrhosis who were previously treated with pegylated interferon, except if they have HCV genotype 3 when 16 weeks treatment is recommended.

Now that pan-genotypic DAA regimens are available, is hepatitis C genotype testing still required?

Currently the PBS still requires HCV genotyping prior to access to HCV antiviral treatment. There are still some treatment regimens available that are genotype-specific yet are highly effective and easy to take. Furthermore, it will always be essential to document that a patient is viraemic (has detectable HCV RNA) before treatment.

Spontaneous resolution of acute HCV occurs in up to 25% of people within 6 months of infection, and with increasing numbers of people having successful HCV treatment, we are all going to see more and more people who are HCV antibody (anti-HCV) positive but HCV RNA negative.

Clearly these people do not require antiviral treatment. In the future, it is likely that point-of-care tests for HCV RNA will become available. Such tests that require just a finger-prick blood sample will be of significant benefit in the diagnosis, post-treatment assessment and ongoing monitoring of patients with poor venous access, or who have limited access to medical services.

Is a fibrosis assessment required before starting treatment?

It is essential that all patients are assessed for fibrosis severity before starting HCV antiviral treatment. Cirrhosis can be confidently excluded in patients with an APRI score (AST to platelet ratio index) of less than 1, or transient elastography (Fibroscan) score of < 12.5 kPa.

Patients who may have cirrhosis should have further specialist evaluation, will require at least a 12-week duration of glecaprevir with pibrentasvir and will require long-term surveillance for liver cancer with 6-monthly liver ultrasound examinations.

What are some key points to keep in mind when prescribing (or dispensing) glecaprevir with pibrentasvir?

It is important to remind patients to take 3 pills once a day (with food) for the duration of treatment, and then be checked 12 weeks after finishing treatment with an HCV RNA blood test to ensure the treatment was successful.

Are there any particular medicine interactions to be aware of?

Glecaprevir with pibrentasvir should not be coprescribed with ethinyloestradiol-containing preparations such as oral contraceptives. This is because ALT elevations have been reported in this situation.

Glecaprevir with pibrentasvir can be used by patients requiring proton-pump inhibitors for gastro-oesophageal reflux and is safe for patients with severe kidney disease. The ability to use glecaprevir with pibrentasvir for patients with severe renal impairment differentiates this fixed-dose combination from sofosbuvir-based treatments.

There are important drug-drug interactions with some statins and with some HIV antivirals.

Potential drug-drug interactions should always be checked before prescribing, using such tools as the Interaction-Checker.

What monitoring is required for patients taking glecaprevir with pibrentasvir?

No special monitoring is required during treatment apart from ensuring that patients are adhering to their treatment course and have a follow-up HCV RNA test 12 weeks after completion.

In particular situations, such as some patients on daily opiate-substitution therapy, it might be beneficial to treat patients with directly observed therapy with daily or weekly dispensing, rather than relying on them adhering to longer periods of unsupervised treatment. 

Disclosures: Associate Professor Simone Strasser has received honoraria for speaker fees for advisory board participation from: AbbVie, Gilead, Merck Sharp and Dohme, Bristol Myers-Squibb, Novartis, Astellas, Norgine, Bayer, Sirtex, Eisai, Pfizer, Ipsen. 

For more detailed information about management of CHC , see the recommendations from the Gastroenterological Society of Australia.

For more details on available DAA treatments on the PBS, see the General Statement for Drugs for the Treatment of Hepatitis C (updated version released 1 September 2018) .

To assist you with decisions about which CHC medicines are most suitable for your patients, see the HCV Treatments Quick Reference Tool developed by the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicines.

For patients taking glecaprevir with pibrentasvir, advise the following:¹⁴

• Treatment is 3 tablets ONCE daily with food
  
• It is important to take the medicine every day for the full treatment duration.
  
• Patients need to keep their health professional (GP, nurse, pharmacist, specialist) informed of any new medicines (prescription or non-prescription) that they will be taking while being treated with glecaprevir with pibrentasvir. Interactions can occur with numerous medicines including: rifampicin, statins, carbamazepine, ciclosporin, medicines to treat HIV infection, digoxin, St John’s wort, oral contraceptives containing ethinyloestradiol, or warfarin or dabigatran.
  
• Treatment of hepatitis C infection with any direct-acting antiviral (including glecaprevir with pibrentasvir) is not recommended while a woman is pregnant or breastfeeding. Women requiring treatment for chronic hepatitis C infection should speak with their health professionals if they are pregnant, planning to become pregnant, breastfeeding or planning to breastfeed, before starting this medicine.
  

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