Sofosbuvir treatment combinations for chronic hepatitis C

• Sofosbuvir inhibits replication of hepatitis C virus (HCV)
  It is a nucleotide analogue inhibitor of HCV-specific NS5B RNA polymerase, which is essential for HCV replication.
• Multiple sofosbuvir-based treatment regimens now available on the PBS
  Most sofosbuvir combinations are oral and interferon-free, and patients are eligible for PBS subsidy irrespective of treatment experience and cirrhotic status; however, these factors influence treatment regimen and duration.
• High rates of sustained virological response (SVR) for patients with chronic HCV infection
  Sofosbuvir treatment regimens are highly effective in patients with chronic HCV across multiple genotypes, irrespective of treatment experience or cirrhotic status.
• 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.

Authority required

Sofosbuvir (Sovaldi) is listed on the General Schedule (S85) and PBS Section 100 Highly Specialised Drugs (S100 HSD) program for treatment-naïve or treatment-experienced patients, with or without cirrhosis, as part of an interferon-free, oral treatment regimen with:¹³

• ribavirin, for genotype 2 or 3 HCV infection
• ledipasvir, as part of a fixed-dose combination product, for patients with genotype 1 HCV infection (see the separate NPS RADAR review Ledipasvir with sofosbuvir fixed-dose combination for chronic hepatitis C)
• daclatasvir, with or without ribavirin, for genotype 1 or 3 HCV infection (see separate review Daclatasvir with sofosbuvir, with or without ribavirin, for chronic hepatitis C)

Specific treatment combinations and treatment duration depend on the HCV genotype, whether the patient has received previous treatment for hepatitis C, and the patient’s cirrhotic status. Treatment regimens are outlined in a prescribing matrix General Statement for Drugs for Treatment of Hepatitis C on the PBS website.

When applying for authority to prescribe, the hepatitis C virus genotype and the patient’s cirrhotic status (non-cirrhotic or cirrhotic) must be provided.

In addition, evidence of chronic hepatitis C infection (repeatedly testing positive for antibody to hepatitis C virus [anti-HCV] and hepatitis C virus ribonucleic acid [HCV RNA]) and the hepatitis C virus genotype must be documented in the patient’s medical records.

PBS patient and prescriber eligibility is the same whether the medicine is prescribed under the PBS General Schedule or the HSD program.¹⁵

May be prescribed by specialists or GPs

Gastroenterologists, hepatologists or infectious-disease physicians experienced in the treatment of chronic hepatitis C infection can prescribe sofosbuvir on the PBS. Other health professionals, including GPs, can also prescribe sofosbuvir under the PBS, provided that it is done in consultation with one of these specialists.¹⁵

Community pharmacists can only dispense under the General Schedule

Sofosbuvir 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. 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.¹⁵

Sofosbuvir is a nucleotide analogue inhibitor of HCV-specific NS5B RNA polymerase, which prevents replication of HCV.¹⁴ As a pro-drug, sofosbuvir is extensively metabolised in the liver to an active uridine analogue triphosphate, and has selective in vitro activity against all six HCV genotypes (1a and b, 2a, 3a, 4a, 5a and 6a).^{1, 2,16}

Sofosbuvir is an oral tablet used as a component of a combination HCV antiviral regimen for treatment of chronic HCV infection.¹⁴

This article focuses predominantly on data concerning the combination of sofosbuvir with ribavirin. See:

• the ribavirin wrap-up for details on the separate PBS listing of ribavirin
• the full NPS RADAR review Ledipasvir with sofosbuvir fixed-dose combination for chronic hepatitis C for details on the fixed-dose combination with ledipasvir
• the full RADAR review Daclatasvir with sofosbuvir, with or without ribavirin, for chronic hepatitis C for combination with daclatasvir
• the interferon wrap-up for combination with ribavirin and peginterferon.

Sofosbuvir is a Therapeutic Goods Administration – approved treatment option for adults (18 years or older) with chronic HCV, as a component of a combination antiviral treatment regimen.¹⁷ Note that use of sofosbuvir as a monotherapy is not recommended and is not PBS listed.¹⁴

Sofosbuvir combination treatment regimens are PBS listed for patients with chronic HCV infection with or without cirrhosis, including those who are treatment-naïve or treatment-experienced.¹³ Here, the combination of sofosbuvir with ribavirin is discussed in detail.

Interferon-free, dual oral treatment options for genotype 2 and 3 infection

Sofosbuvir and ribavirin are PBS listed for patients with chronic genotype 2 or 3 HCV infection with or without cirrhosis, who are treatment-naïve or treatment-experienced.¹³

Uncertain safety and efficacy in patients with decompensated cirrhosis

The safety and efficacy of sofosbuvir has not been established in patients with decompensated cirrhosis; however, these patients are not excluded from receiving the PBS subsidy.¹³ No dose adjustment of sofosbuvir is required for patients with mild, moderate or severe hepatic impairment.¹⁴

Use in pregnancy

There have been no adequate or well-controlled clinical studies of sofosbuvir in pregnant women (pregnancy category B1), and it must not be used as a monotherapy in this population. Avoid breastfeeding while taking sofosbuvir.¹⁴ Note that ribavirin is contraindicated for patients who are pregnant or breastfeeding.²

When using sofosbuvir in combination with ribavirin, extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients, for approximately 6 months after completion of therapy.¹⁴

Use in patients co-infected with hepatitis B or HIV

The safety and efficacy of sofosbuvir has not been established in patients co-infected with hepatitis B virus, and there are limited data on safety and efficacy in patients co-infected with HIV.¹⁴

Note that the precautions and contraindications of other direct-acting antivirals, ribavirin or peginterferon alfa also apply when sofosbuvir is used in combination with any of these agents.¹⁴ See the Product Information under precautions and contraindications.

Consensus recommendations list the following interferon-free sofosbuvir combination treatment regimens as first-line treatment options:¹¹

• sofosbuvir and ledipasvir, or sofosbuvir and daclatasvir (with or without ribavirin) for patients with genotype 1 HCV infection
• sofosbuvir and ribavirin for patients with genotype 2 HCV infection
• sofosbuvir and daclatasvir, or sofosbuvir and ribavirin for patients with genotype 3 HCV infection.¹¹

In addition, an interferon-containing treatment regimen of sofosbuvir, ribavirin and peginterferon is the first-line treatment for patients with genotype 4, 5 or 6 infection.¹¹ Although this treatment regimen is also PBS listed for genotypes 1 and 3,^{13, 18} it is less well-tolerated and likely to be considered a second-line option for patients who are intolerant of,¹² or fail to respond to,¹¹ first-line treatment with interferon-free regimens.

Dual treatment with sofosbuvir and ribavirin has been evaluated for safety and efficacy in five key phase 3 trials in patients with chronic hepatitis C.^7-9 Across these studies, the primary clinical outcome was the proportion of patients achieving SVR.

Dual combination treatment with sofosbuvir and ribavirin at least as effective as standard of care for treatment-naïve genotype 2 or 3

The efficacy of a 12-week, interferon-free, dual combination treatment regimen consisting of sofosbuvir and ribavirin (n = 256) was compared with standard-of-care treatment with 24 weeks of peginterferon alfa-2a and ribavirin (n = 243) in a randomised non-inferiority study (FISSION) of treatment-naïve patients with genotype 2 or 3 infection.⁸

In this patient population, 12 weeks of sofosbuvir and ribavirin (SOF + RBV) was at least as effective as 24 weeks of peginterferon alfa-2a and ribavirin (PEG + RBV) treatment for achieving SVR 12 weeks after treatment (p < 0.001), with nearly identical overall SVR rates (67%) for both groups.⁸

Superior efficacy of with sofosbuvir and ribavirin compared with no treatment for treatment-experienced patients

An interferon-free regimen of SOF + RBV was studied in two key phase 3 trials (POSITRON and FUSION) in patients with genotype 2 or 3 infection.⁷

In patients for whom interferon was not an option (due to absolute or relative contraindications; POSITRON, randomised), treatment with SOF + RBV (n = 207) for 12 weeks produced SVR rates of 78% (95% CI 72 to 83) 12 weeks after treatment, compared with 0% (p < 0.001) for placebo (n = 71).⁷ None of the patients with SVR 12 weeks after treatment with SOF + RBV showed virological relapse for up to 24 weeks after treatment.⁷

The second study (FUSION) focussed on patients with genotype 2 or 3 infection who had either not responded to prior interferon therapy, or displayed virological breakthrough during the prior interferon treatment or virological relapse afterward.

Patients were randomised to either 12 weeks of SOF + RBV followed by 4 weeks of matching placebo (n = 103), or 16 weeks of SOF + RBV (n = 98). Overall, longer duration of treatment with SOF + RBV was associated with higher rates of SVR 12 weeks after treatment (72.6% vs 50% for 16 and 12 weeks, respectively).⁷

Longer treatment duration necessary for genotype 3

Patients with chronic HCV genotype 3 consistently showed lower rates of response to SOF + RBV in the POSITRON, FUSION and FISSION studies, compared with those with genotype 2 infection.^{7, 8}

Of patients treated with SOF + RBV in the FISSION study, lower rates of SVR were observed in those with genotype 3 infection (56% [95% CI 48.2 to 63.1]) compared with those with genotype 2 infection (97% [95% CI 90 to 100).⁸

Similarly, the POSITRON study also reported lower rates of SVR in patients with genotype 3 infection who were treated with SOF + RBV (61.2% [95% CI 51 to 71]), compared with genotype 2 (92.7% [95% CI 86 to 97]).⁷

Extending the duration of SOF + RBV treatment was shown to improve SVR rates for patients with genotype 3 infection. The FUSION study demonstrated that extending treatment from 12 to 16 weeks improved SVR rates, particularly for patients with genotype 3 infection, with response rates rising from 30% (95% CI 19 to 42) to 62% (95% CI 49 to 74).⁷

When treatment duration was extended from 12 to 24 weeks in the VALENCE study, the SVR rates for patients with genotype 3 infection increased from 27% (95% CI 6 to 61) to 85% (95% CI 80 to 89).⁹

Low rate of virological breakthrough during treatment but relapse varies

In the POSITRON and FUSION studies, no patient receiving sofosbuvir had virological breakthrough during treatment.^{7, 8}

A low rate of virological breakthrough was observed during 12 weeks of SOF + RBV treatment for patients with genotype 2 or 3 infection in the FISSION trial (< 1%), compared with 7% in patients treated with PEG + RBV for 24 weeks.⁸

One case of virological breakthrough was reported in the 24-week SOF + RBV treatment group in the VALENCE study; however, this was likely due to non-adherence, as no drug was detected in that patients’ blood during weeks 12–24 of treatment.⁹

Relapse, however, occurred in all four studies at varying rates. For treatment-naïve patients with genotype 1, 4, 5 or 6 infection receiving sofosbuvir in combination with ribavirin and peginterferon, relapse occurred at a rate of 8%.⁸ For patients with genotype 2 or 3 infection, relapse rates after 12 weeks of treatment with SOF + RBV were 29%, 20% and 46% (FISSION, POSITRON, FUSION, respectively).^{7, 8}

The higher relapse rates observed in the last of these studies were obtained in a patient group that had not responded to previous interferon treatment, and extending treatment duration to 16 weeks improved rates of relapse to 27% ⁷

For details on the interferon-containing sofosbuvir-based regimen that has been PBS listed for patients with chronic genotype 1, 3, 4, 5 or 6 HCV infection, see the wrap-up article on interferon-containing sofosbuvir combination treatment.

Safety data for the interferon-free, dual oral treatment regimen containing SOF + RBV for chronic hepatitis C infection comes mainly from key clinical trials.^7-9 The long-term safety profile for sofosbuvir beyond 24 weeks is not yet known.¹⁴

More favourable safety profile of interferon-free treatment compared with interferon-based treatment

An interferon-free, dual combination treatment regimen consisting of SOF + RBV over 12, 16 or 24 weeks was associated with common adverse effects (> 10%) which typically related to:^{7, 8}

• fatigue
• headache
• nausea
• insomnia
• anaemia.

Influenza-like symptoms and fever, which occur frequently in people receiving interferon treatment,²⁰ only occurred in 1–4% of patients taking SOF + RBV.⁸

Extending duration of SOF + RBV treatment to 16 or 24 weeks resulted in a similar frequency of most adverse events compared with the 12-week group,^{7, 9} although diarrhoea and irritability were more common in those receiving 24 weeks of treatment.⁹

Treatment discontinuation rates due to adverse events were low in patients receiving dual therapy for 12–24 weeks (ranging from 1–2% across studies).^7-9 By comparison, standard of care treatment with PEG + RBV for 24 weeks resulted in a discontinuation rate of 11% due to adverse events.⁸

Rates of serious adverse events during treatment for patients receiving SOF + RBV for 12, 16 or 24 weeks were generally low (0–5%).^7-9 These included anaemia (0.4%),⁸ cellulitis (0.4–0.5%),^{7, 8} chest pain (0.4–0.5%)^{7, 8} and arrhythmia (0.4%).⁹

For treatment-experienced patients who did not respond to previous interferon treatment, serious adverse event rates were 5% and 3% after receiving SOF + RBV for 12 and 16 weeks, respectively.⁷

The serious adverse event rate for patients receiving treatment for 24 weeks was higher than that observed in the 12-week and placebo groups (4% vs 0% vs 2%, respectively).⁹ However, no single serious adverse event occurred in more than 1% of patients taking SOF + RBV during 24 weeks of treatment.⁹

Available for use in patients co-infected with hepatitis B or HIV

The safety and efficacy of sofosbuvir has not been established in patients co-infected with hepatitis B virus, and there are limited data for patients co-infected with HIV.¹⁴ However, treatment regimens for chronic HCV infection in these populations should be the same as those used for HCV mono-infection.¹¹

Avoid combination with potent P-glycoprotein inducers

Potent P-glycoprotein inducers of the intestine (eg, rifampicin, tipranavir, or St John’s wort) should not be used with sofosbuvir, as they may significantly decrease sofosbuvir plasma concentration, leading to reduced therapeutic effect of sofosbuvir.¹⁴

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

The Pharmaceutical Benefits Advisory Committee recommended the listing of sofosbuvir in combination with ribavirin for the treatment of genotype 2 chronic hepatitis C (12 weeks) and genotype 3 chronic hepatitis C (24 weeks) on the basis of cost-effectiveness of the treatment over ‘no treatment’.¹

The PBAC 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.¹

The recommended dose of sofosbuvir in dual combination with ribavirin is 400 mg taken once daily, orally with or without food.¹⁴

No dose adjustment required for mild or moderate renal impairment

No dosage adjustment of sofosbuvir is required in patients with mild or moderate renal impairment, based on results of pharmacokinetic studies. However, the safety of sofosbuvir has not been assessed in patients with severe renal impairment (eGFR < 30 mL/min/1.73m²) or end-stage renal disease.¹⁴ Sofosbuvir is currently not recommended in patients with severe renal impairment.¹¹

No dose adjustment required for mild, moderate and severe hepatic impairment

Sofosbuvir is extensively metabolised in the liver; however, no dosage adjustment of sofosbuvir is required for patients with mild, moderate or severe hepatic impairment.¹

Avoid use of combination treatment if pregnant or breastfeeding

There are no adequate and well-controlled clinical studies of sofosbuvir in pregnant women (pregnancy category B1), and it is not known whether sofosbuvir and its metabolites are excreted in human breast milk.¹⁴

Due to the significant teratogenic and/or embryocidal effects of ribavirin, patients should not undergo dual therapy with sofosbuvir and ribavirin if pregnant. Women of childbearing potential and their male partners must use effective contraception during treatment with ribavirin and for approximately 6 months after the treatment has concluded.¹⁴

Use in children and the elderly

The safety and effectiveness of sofosbuvir has not been established in children under the age of 18 years.¹⁴

No dose adjustment is required for sofosbuvir in elderly patients. However, exercise caution when prescribing sofosbuvir combination treatment to elderly patients due to greater frequency of anaemia, potential for impaired renal, hepatic and cardiac function, and concurrent medicines.¹⁴

Advise patients taking sofosbuvir as follows:²²

• sofosbuvir must always be taken together with other hepatitis C medicines, as it will not work on its own
• ask your health professional for advice before taking this medicine if you are pregnant, think you may be pregnant or are planning to have a baby, or if you are breastfeeding, or planning to breastfeed
• tell your health professional if you are taking rifampicin, St John’s Wort, amiodarone, anti-epileptic medicines, or any other medicines, herbal supplements or vitamins
• talk to your health professional if you have liver problems (other than hepatitis C), hepatitis B, HIV infection, severe kidney problems, you are on haemodialysis, or have any other medical condition.

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