Now PBS listed as a first-line interferon-free treatment option for chronic HCV genotype 1

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Key points

  • Ledipasvir with sofosbuvir inhibits replication of the hepatitis C virus
    Ledipasvir selectively inhibits HCV viral replication by targeting the NS5A protein, and is used in combination with sofosbuvir, which targets the HCV NS5B RNA polymerase.1
  • PBS listed as a first-line treatment option for patients with chronic genotype 1 HCV infection
    Patients are eligible for PBS subsidy irrespective of treatment experience and cirrhotic status; however, these factors influence treatment duration.2
  • High rates of sustained viral response in patients with chronic genotype 1 HCV infection
    Ledipasvir with sofosbuvir fixed-dose combination is highly effective for treatment-naïve or treatment-experienced patients, with or without cirrhosis.3-5
  • Community pharmacists can only dispense under the General Schedule
    If the prescription is written under S100 Highly Specialised Drug arrangements, approved community pharmacists will not be able to dispense.6

Evidence snapshot

What is known about this drug?

The fixed-dose combination (FDC) product ledipasvir with sofosbuvir has been shown to produce high rates of sustained viral response (SVR) in patients with chronic genotype 1 HCV infection, with similar efficacy to that of ledipasvir/sofosbuvir FDC plus ribavirin.3-5 It was also effective for patients with genotype 1 or 4 infection who were co-infected with HIV-1 and undergoing treatment with anti-retrovirals.7

The FDC product was well tolerated across key trials; common adverse events included fatigue, headache, insomnia and nausea.3-5 The incidence of these adverse events was lower in patients treated with the FDC product alone compared with those receiving the FDC with ribavirin.3-5

Areas of uncertainty

No head-to-head trials have compared ledipasvir/sofosbuvir against other treatments for chronic genotype 1 hepatitis C infection, and in this instance the Pharmaceutical Benefits Advisory Committee considered ‘no treatment’ to be the most appropriate comparator, in view of the broader context of infected individuals whose treatment preference is interferon-free therapies.8

What does NPS say?

Ledipasvir/sofosbuvir is an oral, interferon-free first-line treatment option for patients with chronic genotype 1 hepatitis C infection,9 which is well tolerated and produces high rates of response.

PBS listing

Authority required

The FDC product ledipasvir with sofosbuvir (Harvoni) is now listed on the PBS for treatment of chronic hepatitis C, under both the General Schedule (S85) and Section 100 Highly Specialised Drugs (HSD) program for patients 18 years or older with chronic genotype 1 infection.2

Treatment duration is influenced by cirrhotic status and whether the patient has received prior treatment for hepatitis C.2

For patients without cirrhosis

The duration of treatment in treatment-naïve patients is guided by pre-treatment HCV RNA level. If less than 6 million IU/mL consider a treatment duration of 8 weeks, otherwise 12 weeks is subsidised on the PBS.2

For patients who are treatment-experienced and for whom prior treatment with peginterferon alfa/ribavirin with or without an HCV protease inhibitor has failed, a 12-week treatment duration is PBS subsidised.2

Patients with cirrhosis

Treatment-naive patients can receive PBS-subsidised treatment with ledipasvir/sofosbuvir for 12 weeks, and treatment-experienced patients for whom prior treatment with peginterferon alfa/ribavirin with or without an HCV protease inhibitor has failed are eligible for 24 weeks of treatment on the PBS.2

May be prescribed by specialists or GPs

Gastroenterologists, hepatologists or infectious-disease physicians experienced in the treatment of chronic hepatitis C infection are eligible to prescribe this medicine under S85 or S100 arrangements.6 Other health professionals, including general practitioners, are also eligible to prescribe under the general schedule of the PBS, provided that it is done in consultation with one of these specialists, via phone, mail, email or videoconference.6

Community pharmacists can only dispense under the General Schedule

Ledipasvir/sofosbuvir FDC will not be available under the new S100 HSD Community Access arrangements introduced on 1 July 2015. Approved pharmacists in the community will be able to dispense when a prescription is issued under the General Schedule.6

However, if the prescription has been written under S100 HSD arrangements in a public hospital, approved pharmacists in the community will not be able to dispense.6

What is it?

Ledipasvir is an inhibitor of the NS5A protein, which regulates replication of the hepatitis C virus (HCV), and has shown in vitro antiviral activity against genotypes 1–6.1 Sofosbuvir is an inhibitor of NS5B RNA polymerase, which is also essential for replication of the HCV virus, and has activity against all HCV genotypes.1

In combination, sofosbuvir and ledipasvir have complementary antiviral activity, particularly regarding activity against resistance-associated sequence variants.1

Who is it for?

Ledipasvir/sofosbuvir FDC is contraindicated for use in patients with a known hypersensitivity to the active ingredients or any other component of the tablets, and should not be administered concurrently with other medicines that contain the same active ingredients.1

Currently approved for use in patients with genotype 1 HCV infection only

At the time of writing, ledipasvir/sofosbuvir was approved by the Therapeutic Goods Administration and PBS listed for treatment of patients with chronic genotype 1 HCV infection only.2, 10

Clinical data to support use of ledipasvir/sofosbuvir in patients with genotype 3 infection are limited, and efficacy has not been studied in patients with genotype 2 infection.1

There are data to support effectiveness of ledipasvir/sofosbuvir (with or without ribavirin) in patients with genotype 411 or 6 infection;12 however, ledipasvir/sofosbuvir is not currently TGA approved or PBS listed for these patient populations.2, 10 Australian consensus recommendations state it is likely that these regimens will be approved in Australia for genotypes 4 and 6 in the near future.9

Caution in patients who are pregnant or breastfeeding

There have been no adequate or well-controlled studies of ledipasvir/sofosbuvir in pregnant women, and it is unknown if ledipasvir, sofosbuvir or metabolites of sofosbuvir are present in human breast milk. Carefully consider the potential benefits and risks of using ledipasvir/sofosbuvir during pregnancy or breastfeeding.1

Where does it fit?

From 1 March 2016 several new treatment options for patients with chronic genotype 1 HCV infection became available on the PBS. The place in therapy for the ledipasvir/sofosbuvir FDC product is outlined below.

A first-line treatment option for patients with chronic genotype 1 HCV

Among adult patients with chronic genotype 1 HCV infection, ledipasvir/sofosbuvir is a first-line treatment option9 and is now listed on the PBS. Depending on the patient’s cirrhotic status and whether they are treatment-naive or treatment-experienced, recommended treatment duration is 8, 12 or 24 weeks.13

Note that sofosbuvir with daclatasvir, with or without ribavirin, is another option for first-line treatment of chronic genotype 1 HCV available on the PBS.13 For information about the PBS-listed daclatasvir combination treatment regimen see the separate NPS RADAR review Daclatasvir with sofosbuvir and/or ribavirin for chronic hepatitis C

Additional treatment options for patients with chronic genotype 1 HCV

Sofosbuvir and peginterferon with ribavirin is also PBS listed for patients with genotype 1 infection; however, it is not recommended as a first-line treatment option.9, 13 For information on the sofosbuvir and peginterferon with ribavirin treatment regimen see the interferon-based treatment wrap-up.

NOTE: A third interferon-free, direct-acting antiviral regimen (paritaprevir/ritonavir/ombitasvir and dasabuvir [Viekira-Pak]) with or without ribavirin is also TGA approved for patients with chronic genotype 1 HCV infection, although it is not yet PBS listed.9, 14, 15

How does it compare?

The high level of efficacy of the ledipasvir/sofosbuvir FDC had been demonstrated in three key studies of patients with chronic genotype 1 infection, across treatment-naive and treatment-experienced patients, with and without cirrhosis.3-5

High rates of SVR in patients with chronic genotype 1 HCV infection

In the randomised open-label ION-1 trial, previously untreated patients with genotype 1 infection showed SVR rates of 99% (95% CI 96 to 100) after 12 weeks of treatment with ledipasvir/sofosbuvir (n = 214), and 98% (95% CI 95 to 99) after 24 weeks of treatment (n = 217).5

Similar SVR rates were reported in patients treated with ledipasvir/sofosbuvir and ribavirin (97% [95% CI 94 to 99; n = 217)] and 99% [95% CI 97 to 100; n = 217] after 12 and 24 weeks of treatment, respectively).5 Approximately 16% of patients in this study had cirrhosis, and 67% had genotype 1a infection.5

ION-2 was a randomised open-label study involving treatment-experienced patients who had not achieved SVR after treatment with peginterferon and ribavirin, with or without a protease inhibitor.

High rates of SVR were seen among patients treated for 12 weeks (n = 109) or 24 weeks (n = 109) with ledipasvir/sofosbuvir (94% [95% CI 87 to 97] and 99% [95 to 100], respectively).

This was similar to SVR rates for 12 (n = 111) or 24 weeks (n = 111) of treatment with ledipasvir/sofosbuvir with ribavirin (96% [95% CI 91 to 99] and 99% [95 to 100], respectively).

Collectively, 20% of these patients had cirrhosis, and 79% had HCV genotype 1a infection.4

The efficacy of a shorter treatment regimen in patients without cirrhosis was then studied in the ION-3 non-inferiority trial. In terms of SVR rates, 8 weeks of treatment with ledipasvir/sofosbuvir was found to be non-inferior to 12 weeks of treatment with ledipasvir/sofosbuvir, and 8 weeks of ledipasvir/sofosbuvir with ribavirin (94% [95% CI 90 to 97] versus 95% [92 to 98] and 93% [89 to 96], respectively).3

An additional trial, ION-4, confirmed the efficacy of ledipasvir/sofosbuvir in patients with chronic HCV infection (genotype 1 or 4) and HIV-1 co-infection, while receiving an anti-retroviral regimen. Of these patients, 55% had been previously treated for HCV, and 20% had cirrhosis. Overall, 96% of patients (95% CI 93 to 98) had an SVR after 12 weeks of treatment with ledipasvir/sofosbuvir.7

Safety issues

The safety of ledipasvir/sofosbuvir FDC has been assessed in key trials. The FDC was found to be well tolerated, with a favourable safety profile compared with that of ledipasvir/sofosbuvir with ribavirin.

Ledipasvir/sofosbuvir FDC is well tolerated

Generally ledipasvir/sofosbuvir was well tolerated across key trials. The most common adverse events were fatigue, headache, insomnia and nausea. Discontinuation rates due to adverse events were low or absent for patients taking ledipasvir/sofosbuvir for 8, 12 or 24 weeks (0–2% across studies).3-5

The rate of serious adverse events was higher among patients treated for 24 weeks (6–8%)4, 5 compared with those receiving ledipasvir/sofosbuvir treatment for 8 or 12 weeks (0–2%),3-5 and those receiving a regimen containing the FDC with ribavirin for 24 weeks (< 1% to 3%).4, 5

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

Co-administration of amiodarone not recommended

Postmarketing reports of symptomatic bradycardia, fatal cardiac arrest and cases requiring pacemaker intervention have been reported when amiodarone has been taken with ledipasvir/sofosbuvir.1

Patients are at increased risk of symptomatic bradycardia with co-administration of amiodarone if they are also taking beta blockers, have underlying cardiac comorbidities, and/or advanced liver disease.1

Avoid combination with potent P-glycoprotein inducers

Potent P-glycoprotein inducers of the intestine (eg, rifampicin, St John’s wort) should not be used with ledipasvir/sofosbuvir, as they may significantly decrease plasma concentration of ledipasvir and sofosbuvir, leading to reduced therapeutic effect of the FDC product.1

Reason for PBS listing

The PBAC recommended the listing of the ledipasvir/sofosbuvir FDC for treatment of chronic genotype 1 hepatitis C infection in treatment-naive and treatment-experienced patients with or without cirrhosis, based on cost-effectiveness over 'no treatment'.8

The PBAC considered the most appropriate comparator for the ledipasvir/sofosbuvir treatment regimen was ‘no treatment’ in view of the broader context of infected individuals whose treatment preference is interferon-free therapies. Ledipasvir/sofosbuvir was found to have superior comparative effectiveness and inferior comparative safety to 'no treatment'.8

Although many of the trials that assessed safety and efficacy of the ledipasvir/sofosbuvir FDC were single-arm and had limited sample sizes, they were regarded as the best available and sufficient evidence to support listing on the PBS.8

Dosing issues

The ledipasvir (90 mg)/sofosbuvir (400 mg) FDC is a tablet that is taken once daily, orally with or without food.1 Treatment durations are outlined in the General Statement for Drugs for the Treatment of Hepatitis C.

No dose adjustment required for elderly patients

In clinical trials including patients aged 65 years or over, the response rate for those over 65 was similar to that of younger patients. However, exercise caution when prescribing in the elderly because of greater incidence of renal, hepatic or cardiac dysfunction, concomitant diseases and use of other medicines.1

No dose adjustment required for mild, moderate or severe renal impairment

No dose adjustment is required for patients with mild or moderate renal impairment; however, there is a lack of information on dose recommendations for patients with severe renal impairment and end-stage renal disease requiring haemodialysis, who may have higher exposure of the predominant sofosbuvir metabolite.1

No dose adjustment required for hepatic impairment

No dose adjustment is required for patients with mild, moderate or severe hepatic impairment; however, the safety and efficacy of this product has not been established in patients with decompensated cirrhosis.1

Co-administration with proton pump inhibitors

Proton pump inhibitors (PPIs) may reduce absorption of ledipasvir by increasing gastric pH16 and should not be taken before ledipasvir/sofosbuvir.1 PPI doses comparable to omeprazole 20 mg can be taken with, or up to 2 hours after, ledipasvir/sofosbuvir. There are currently no data for other omeprazole doses.16

Information for patients

Advise patients taking the ledipasvir/sofosbuvir FDC product as follows.17

  • Do not take Harvoni if you are also taking any another medicine that contains sofosbuvir.
  • Before taking Harvoni, let your doctor know if you are pregnant or think you may be pregnant, or are planning to have a baby.
  • You should not breastfeed while you are taking Harvoni.
  • Tell your doctor if you are taking medicines for heart conditions, high cholesterol, HIV infection, epilepsy, heartburn, stomach ulcers or reflux, antibiotics or St John’s wort, because they may interact with Harvoni.
  • If you are taking an antacid, take it at least 4 hours before or after taking Harvoni. If proton pump inhibitor treatment is required (eg, omeprazole), it should be taken at the same time, or up to 2 hours after, taking Harvoni. Do not take proton pump inhibitors before Harvoni.
  • Let your doctor know if you have any other liver problems besides hepatitis C, if you have hepatitis B, any other medical condition, or kidney problems.

Discuss the ledipasvir/sofosbuvir (Harvoni) Consumer Medicine Information (CMI) leaflet with the patient.

References

  1. Gilead Sciences Pty Ltd. Product Information – Harvoni (ledipasvir and sofosbuvir) tablets. 2015. [TGA] (accessed 10 March 2016).
  2. Australian Government Department of Health Pharmaceutical Benefits Scheme. Ledipasvir + sofosbuvir. 2016. [PBS] (accessed 9 March 2016).
  3. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis (ION-3). N Engl J Med 2014;370:1879–88. [NEJM]
  4. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection (ION-2). N Engl J Med 2014;370:1483–93. [NEJM]
  5. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection (ION-1). N Engl J Med 2014;370:1889–98. [NEJM]
  6. Australian Government Department of Health. New hepatitis C medicines – frequently asked questions. 2016 (accessed 12 February 2016).
  7. Naggie S, Cooper C, Saag M, et al. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1 (ION-4). N Engl J Med 2015;373:705–13. [NEJM]
  8. Gilead Sciences Pty Ltd. Public summary document – March 2015 PBAC meeting: Ledipasvir 90 mg/ sofosbuvir 400 mg fixed dose combination tablet (Harvoni). 2015. [PBS] (accessed 9 March 2016).
  9. Hepatitis C virus infection consensus statement working group. Australian recommendations for the management of hepatitis C virus infection: a consensus statement 2016. Melbourne: Gastroenterological Society of Australia, 2016. [ASHM] (accessed 10 March 2016).
  10. Therapeutic Goods Administration. ARTG Public Summary: Harvoni ledipasvir/sofosbuvir 90 mg/400 mg tablet bottle. 2016. [TGA] (accessed 23 March 2016).
  11. Kohli A, Kapoor R, Sims Z, et al. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study. The Lancet Infectious Diseases 2015;15:1049–54. [Lancet]
  12. Gane EJ, Hyland RH, An D, et al. Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology 2015;149:1454–61. e1. [Gastroenterology]
  13. Australian Government Department of Health Pharmaceutical Benefits Scheme. General statement for drugs for the treatment of hepatitis C. 2016. [PBS] (accessed 9 March 2016).
  14. Therapeutic Goods Administration. ARTG public summary: Viekira Pak paritaprevir/ritonavir/ombitasvir 75 mg/50 mg/12.5 mg tablets and dasabuvir (as sodium salt) 250 mg tablets composite pack blister pack. 2015. [TGA] (accessed 23 March 2016).
  15. Australian Government Department of Health Pharmaceutical Benefits Scheme. Public summary document – July 2015 PBAC meeting: paritaprevir 75 mg, ritonavir 50 mg, ombitasvir 12.5 mg and dasabuvir 250 mg ± ribavirin 200 mg/600 mg tablets, Viekira Pak / Viekira Pak-RBV® 2015. [PBS] (accessed 23 March 2016).
  16. Australian Medicines Handbook. Ledipasvir with sofosbuvir: Drug Interactions. 2016. [AMH online] (accessed 23 March 2016).
  17. Gilead Sciences Pty Ltd. Consumer Medicines Information: Harvoni tablets (ledipasvir/sofosbuvir, 90 mg/ 400 mg). 2015. [TGA] (accessed 10 March 2016).