Sofosbuvir/velpatasvir for hepatitis C virus infection

A new direct-acting antiviral (DAA) for chronic hepatitis C virus (HCV) infection is available in Australia. With the approval of this agent there are now interferon (IFN)-free treatments available for all six HCV genotypes.^1,2

Sofosbuvir/velpatasvir (400 mg/100 mg) fixed dose combination (FDC) (Epclusa) is a pan-genotypic DAA. Sofosbuvir is an inhibitor of HCV NS5B nucleotide polymerase, essential for viral replication. Velpatasvir is an inhibitor of NS5A, essential for both RNA replication and the assembly of HCV virions.³

PBS listing

The listing is Authority Required, General Schedule and Section 100, for the treatment of chronic HCV infection in patients with HCV genotypes 1–6.^1,4

For patients with decompensated cirrhosis requiring chronic HCV treatment, sofosbuvir/velpatasvir should be used in combination with ribavirin.¹

For patients with genotype 3 infection with compensated cirrhosis, the listing also recommends considering the addition of ribavirin if prescribing sofosbuvir/velpatasvir.¹

Although sofosbuvir/velpatasvir is an effective treatment against all six HCV genotypes, the PBS listing still requires genotyping for all patients with HCV infection.¹

Genotyping provides important clinical information, particularly regarding the management of HCV genotype 3, which consistently demonstrates lower rates of sustained virological response (SVR) when treated with DAAs, compared with other HCV genotypes.^5,6

For example in ASTRAL-1, a Phase III, double-blind clinical trial involving patients with chronic HCV genotype 1, 2, 4, 5 or 6 infection, treatment with sofosbuvir/velpatasvir over 12 weeks showed rates of SVR of 99% (95% confidence interval [CI] 98 to > 99).⁷

High rates of SVR were observed in all patient subgroups, including those with compensated cirrhosis (99%), and those with previous treatment experience (> 99%).⁷

For patients with genotype 3 HCV the ASTRAL-3 trial, a Phase III open-label study of sofosbuvir/velpatasvir over 12 weeks, had an overall SVR of 95%.⁸

However, subgroup analysis showed that patients with compensated cirrhosis or who were treatment-experienced had a lower SVR of 89% to 93%.^7,8

Neither the ASTRAL-1 nor ASTRAL-3 trials included patients with decompensated cirrhosis.^7,8

However, in the ASTRAL-4 trial, patients with HCV genotype 3 and decompensated cirrhosis achieved 85% SVR with sofosbuvir/velpatasvir and ribavirin, compared with 50% in the non-ribavirin groups.⁹

People with HCV 3 genotype infection also have increased rates of steatosis, fibrosis and hepatocellular carcinoma, compared to those infected with other HCV genotypes.^5,6

The patient must be treated by a medical practitioner or an authorised nurse practitioner experienced in the treatment of chronic hepatitis C infection; or in consultation with a gastroenterologist, hepatologist or infectious diseases physician experienced in the treatment of chronic hepatitis C infection.¹

The patient must meet the criteria set out in the General Statement for Drugs for the Treatment of Hepatitis C, and:²

• the patient must be taking this drug as part of a regimen set out in the matrix in the General Statement for Drugs for the Treatment of Hepatitis C, based on the hepatitis C virus genotype, patient treatment history and cirrhotic status, and
  
• the treatment must be limited to a maximum duration of 12 weeks.
  

Perform a PCR assay for HCV RNA

Patients with genotype 1 infection with no previous treatment, no cirrhosis and an HCV RNA level < 6 × 106 IU/mL are eligible for an 8-week treatment duration of ledipasvir/sofosbuvir. This may be preferred, as sofosbuvir/velpatasvir has a 12-week regimen.¹⁰

The goal of treatment is SVR, or undetectable plasma HCV RNA at least 12 weeks after treatment is complete, with routine on-treatment and end-of-treatment HCV RNA assessments not required.¹⁰

Check for cirrhosis

Evaluating the patient for cirrhosis is required when seeking PBS authority. This determines the need for the addition of ribavirin for genotype 3 or patients with decompensated cirrhosis.^1,10

Patients with cirrhosis should undergo screening for liver cancer prior to initiation of DAA treatment, and require long-term follow-up and surveillance for liver cancer even if SVR is achieved.¹⁰

Check renal function

Sofosbuvir is renally excreted and is not recommended in patients with an estimated glomerular filtration rate < 30 mL/min/1.73 m².¹⁰

Are there potential drug interactions?

Sofosbuvir/velpatasvir is not recommended for patients taking amiodarone, as sofosbuvir may cause severe symptomatic bradycardia when coadministered with amiodarone and another HCV DAA.³

Velpatasvir requires an acidic environment for absorption. Therefore PPIs may have an effect on velpatasvir. The Product Information suggests doses of PPI comparable with omeprazole 20 mg can be administered when sofosbuvir/velpatasvir is administered with food. Also PPIs should be taken concurrently but not before sofosbuvir/velpatasvir.³

Drugs that are potent inducers of P-glycoprotein and/or moderate-to-potent inducers of some cytochrome P450 (CYP) enzymes are not recommended.³

Interactions of all concurrent prescription, over-the-counter and complementary and alternative medicines should be assessed using a drug interaction checker, such as the University of Liverpool HEP Drug Interaction Checker.

If your patient is at risk of a potential drug interaction, modify the treatment for the 12 weeks of DAA treatment, eg, stop PPI or reduce dose or use an H2-antagonist.

Sofosbuvir/velpatasvir is a once-daily single-tablet regimen effective against all six HCV genotypes. This is currently unique in the regimens approved in the General Statement for Drugs for the Treatment of Hepatitis C.^4,11

A pan-genotypic therapy may be beneficial for patients with mixed and recombinant infections, which present challenges to treatment.¹²

Before this listing the only option for patients with genotypes 5 and 6 was an IFN-containing regimen,¹ which is an S100 highly specialised drug requiring referral to a specialist.^13,14

IFN is also known for its toxicity,¹⁵ and the introduction of IFN-free regimens improved health-related quality of life compared with interferon regimens.¹⁶ IFN-free regimens are also more effective than IFN-containing treatments.¹⁷

The once-daily single-tablet regimen can enhance compliance, especially for patients in institutional settings (eg, drug and alcohol rehabilitation) where medication may be administered from a Webster pack.

This may also be beneficial for patients receiving opioid substitution treatment (OST) at the local pharmacy where DAA treatment could be integrated with the OST pickup regimen.

The option of an IFN-free regimen, for patients with genotypes 5 and 6, reduces the side effects experienced from IFN and the need for injections.

Limitations for sofosbuvir/velpatasvir would be use for patients with poor renal function, potential drug interactions and in cases where ribavirin is necessary. 

The PBS listing recommends sofosbuvir/velpatasvir combined with ribavirin for all patients with HCV infection and decompensated cirrhosis.^1,10 However, these patients require management by a gastroenterology specialist.

The ASTRAL-4 study showed that when ribavirin was added to a 12-week sofosbuvir/velpatasvir regimen in patients with decompensated cirrhosis, classified as Child–Turcotte–Pugh (CTP) class B,⁹ 94% of patients achieved SVR for all genotypes except genotype 5, compared with 83% for 12 weeks of sofosbuvir/ velpatasvir alone. There was also a treatment arm of sofosbuvir/velpatasvir for 24 weeks.⁹

Limitations to the study include small numbers of patients with HCV genotype 2, 4 or 6.¹⁸ Also, ASTRAL-4 only enrolled adult HCV patients with moderate liver decompensation.¹⁸ 

The most common adverse events in clinical trials were headache, fatigue, nausea, and nasopharyngitis. Rates were not significantly different from placebo.^10,11