In 2015, it was estimated that over 230,000 people in Australia were living with chronic hepatitis C. Hepatitis C is transmitted via blood-to-blood contact, with the majority of cases being caused by the unsafe use of injectable drugs. Other sources of infection include tattooing and body piercing with contaminated instruments, and needlestick injuries.

The hepatitis C virus (HCV) is a ribonucleic acid (RNA) virus. The HCV can be divided into six main genotypes; some with numerous subtypes. The virus utilises the host’s liver cells to reproduce, resulting in an immune response which can lead to inflammation and cell death. After 20 years of infection, it is estimated that between 5% and 20% of chronic hepatitis C sufferers will develop cirrhosis, which may progress to liver failure or hepatocellular carcinoma. Listed below are some risk factors for disease progression:

  • Age over 50 years
  • Male
  • Longer duration of infection
  • Co-infection with hepatitis B, HIV, or schistosomiasis
  • Higher degree of inflammation on liver biopsy
  • High alanine aminotransferase (ALT) levels
  • Alcohol consumption
  • Daily cannabis use
  • Obesity
  • Type 2 diabetes.

Approximately 25% of people with acute hepatitis C infection will go on to clear the infection spontaneously. These people will still test positive for hepatitis C antibodies, however this does not confer immunity. Risk factors should be addressed in order to prevent reinfection. The other 75% of people will go on to have a chronic hepatitis C infection. Chronic sufferers show hepatitis C antibodies and detectable HCV RNA in their blood.

Once diagnosed, patients must have a HCV genotype test to determine the most appropriate treatment plan. A liver biopsy can provide useful information relating to the extent of hepatic fibrosis, inflammation, or necrosis. However, this procedure is not routinely performed due to the risks involved and the diagnostic accuracy of serum HCV RNA tests.

There are several lifestyle measures that will help to prevent disease progression in hepatitis C. Alcohol consumption should be discouraged, and avoided altogether in patients with severe fibrosis or cirrhosis. Cannabis use should also be avoided and overweight patients should be encouraged to lose weight. To prevent co-infection, patients who are serologically negative for hepatitis A and B should be vaccinated.

Drug therapy for hepatitis C is aimed at reducing HCV RNA to a level undetectable by polymerase chain reaction 24 weeks after treatment completion. This is termed a sustained virological response (SVR) and is the most commonly used efficacy endpoint in hepatitis C studies. Until recently, hepatitis C was treated with weekly subcutaneous injections of peginterferon, combined with oral ribavirin taken twice daily. The dose and duration of the course of therapy is determined by the HCV genotype and the patient’s response. Detailed treatment plans are available in the Therapeutic Guidelines.

Response rates to peginterferon/ribavirin therapy are variable, and are influenced by a number of factors. The most influential of these is the HCV genotype. SVR is achieved in approximately 80% of patients with genotype 2 and 3, however in only 50% of patients with genotype 1. Other predictors of a good response are a low initial viral load (under 800,000IU/mL), female gender, age under 40 years, body weight under 75kg, non-diabetic, an ALT level more than three times the upper limit of normal, absence of bridging fibrosis or cirrhosis, and a favourable genotype in the interleukin-28B (IL28B) gene. Regardless of HCV genotype or stage of fibrosis, patients who respond early to treatment have a higher probability of SVR and lower probability of relapse.

Unfortunately, peginterferon/ribavirin regimens are associated with significant and frequent adverse effects. These include fatigue, flu-like symptoms (headache, muscle ache, fever), anxiety, depression, rash, and gastrointestinal effects (diarrhoea and nausea). There are now many more treatment options available which are often better tolerated.

As of 1 March 2016, new treatments for hepatitis C have been included on the Pharmaceutical Benefits Scheme (PBS). These medications are extremely expensive and are estimated to cost the PBS more than $1 billion over five years. The new drug listings comprise Daklinza® (daclatasvir), Harvoni® (ledipasvir with sofosbuvir), Sovaldi® (sofosbuvir) and Ibavyr® (ribavirin). Viekira Pak (paritaprevir, ritonavir, ombitasvir, and dasabuvir) and Viekira Pak-RBV(with ribavirin) were later added to the PBS in May.

  • Daclatasvir is a nucleotide polymerase inhibitor, which inhibits the non-structural 5A (NS5A) protein involved in viral replication. Potential drug interactions exist as daclatasvir is metabolised by CP3A4.
  • Ledipasvir also targets protein NS5A in the hepatitis C virus. Its solubility, and therefore absorption, is pH-dependent and can be reduced by antacids, proton pump inhibitors, and H2-receptor antagonists.
  • Sofosbuvir is a pro-drug converted to its active form in hepatocytes. This active form inhibits RNA synthesis and viral replication by binding to RNA polymerase. Sofosbuvir is a substrate for p-glycoprotein and should not be used in combination with P-glycoprotein inducers such as rifampicin and St John’s wort at the risk of reducing sofosbuvir efficacy. Other drugs that may reduce the effect of Sofosbuvir include modafinil, carbamazepine, phenytoin, phenobarbitone, and combined tipranavir/ritonavir.
  • Ribavirin is a nucleoside analogue that inhibits protein synthesis and viral replication. It is not effective as monotherapy and must be combined with other agents.

The availability of these new oral antiviral drugs is a significant step forward in the treatment of hepatitis C, with cure rates of over 90%. Other advantages include a shorter and simpler treatment course, along with more favourable side effect profiles. There are a number of treatment regimens currently recommended, with selection based on the patient’s hepatitis C genotype, cirrhotic status, and treatment history. Table 1 outlines PBS eligibility for non-cirrhotic treatment naïve patients and those who have not achieved an SVR with previous therapies.

Table 1: Hepatitis C – Non-cirrhotic patients

Treatment naïve

Treatment experienced

Genotype 1

LEDIPASVIR + SOFOSBUVIR
[8 or 12 weeks] 1

OR
DACLATASVIR and SOFOSBUVIR
[12 weeks]

OR
SOFOSBUVIR and PEG-IFN
(&) RBV
[12 weeks]

OR
PARITAPREVIR + RITONAVIR +
OMBITASVIR (&) DASABUVIR
[12 weeks] 2

OR
PARITAPREVIR + RITONAVIR +
OMBITASVIR (&) DASABUVIR (&) RBV
[12 weeks]3

LEDIPASVIR + SOFOSBUVIR
[12 weeks] 4

OR
DACLATASVIR and SOFOSBUVIR
[12 or 24 weeks] 5

OR
SOFOSBUVIR and PEG-IFN (&) RBV

[12 weeks]

OR

PARITAPREVIR + RITONAVIR + OMBITASVIR (&)
DASABUVIR
[12 weeks]2

OR

PARITAPREVIR + RITONAVIR + OMBITASVIR (&)
DASABUVIR (&) RBV
[12 weeks]3

Genotype 2

SOFOSBUVIR and RBV
[12 weeks]

SOFOSBUVIR and RBV
[12 weeks]

Genotype 3

DACLATASVIR and SOFOSBUVIR
[12 weeks]

OR
SOFOSBUVIR and RBV
[24 weeks]

OR
SOFOSBUVIR and PEG-IFN (&) RBV
[12 weeks]

DACLATASVIR and SOFOSBUVIR
[12 weeks]6

OR
SOFOSBUVIR and RBV
[24 weeks]

OR

SOFOSBUVIR and PEG-IFN (&) RBV
[12 weeks]

Genotype 4,5,6

SOFOSBUVIR and PEG-IFN (&) RBV
[12 weeks]

SOFOSBUVIR and PEG-IFN (&) RBV
[12 weeks]

Reproduced with permission from Australian Government Department of Health. Canberra.

KEY
PEG-IFN (&) RBV- peginterferon alfa-2a (&) ribavirin
RBV- ribavirin

1 [LEDIPASVIR + SOFOSBUVIR] for treatment-naïve, non-cirrhotic patients:
– consider treatment for 8 weeks where pre-treatment HCV RNA is less than 6 million IU/mL;
– otherwise treatment for 12 weeks where pre-treatment HCV RNA is 6 million IU/mL or greater.
2 [PARITAPREVIR + RITONAVIR + OMBITASVIR (&) DASABUVIR] for treatment-naïve and treatment experienced, non-cirrhotic patients, treatment for 12 weeks in patients with genotype 1b HCV.
3 [PARITAPREVIR + RITONAVIR + OMBITASVIR (&) DASABUVIR (&) RBV] for treatment-naïve and treatment experienced, non-cirrhotic patients, treatment for 12 weeks in patients with genotype 1a HCV.
4 A 12 weeks treatment regimen for [LEDIPASVIR + SOFOSBUVIR] for treatment-experienced, non-cirrhotic patients who have failed prior treatment with either:

– PEG-IFN alfa (&) RBV; or
– a HCV protease inhibitor + PEG-IFN alfa (&) RBV.
5 [DACLATASVIR and SOFOSBUVIR] for treatment-experienced, non-cirrhotic patients:
– consider treatment for 12 weeks in patients who have failed PEG-IFN alfa (&) RBV; or
– consider treatment for 24 weeks in patients who have failed a protease inhibitor + PEG-IFN (&) RBV.
6 [DACLATASVIR and SOFOSBUVIR] for treatment-experienced, non-cirrhotic patients, treatment for 12 weeks in patients:

– who have failed SOFOSBUVIR and RBV; or
– who have failed PEG IFN alfa (&) RBV.

 

The new medications require either a written or phone PBS authority prior to prescribing and are not available on streamlined authority. Prescribers who are eligible to prescribe these medications are gastroenterologists, hepatologists, or infectious disease physicians experienced in the treatment of chronic hepatitis C infection. Additionally, to meet the objectives of the Fourth National Hepatitis C Strategy 2014-2017 in enabling primary carers a greater role in hepatitis C management, general practitioners may also prescribe these medications. This is subject to state and territory requirements, and one of the specialists listed above must be consulted.

To be eligible for a PBS prescription for the new medications, patients must be over 18. At the time of application, hepatitis C virus genotype and the patient’s cirrhotic status must be provided. Evidence of hepatitis C infection (anti-HCV positive and HCV RNA positive), as well as the hepatitis C virus genotype, must be documented in the patient’s notes. All adult patients with chronic hepatitis C infection are eligible, including patients who are currently inmates in prison facilities.

The Pharmaceutical Benefits Advisory Committee (PBAC) has sought to ensure the broadest possible access to these new medicines by making them available through both the PBS general schedule (Section 85) and the Highly Specialised Drugs Program (Section 100). Pharmacy eligibility to dispense prescriptions is dictated by the prescriber setting and subsequent prescription type, as shown in Table 2.

 

Table 2. PBS requirements for prescription and supply of hepatitis C therapies.

Patient Type

Prescriber Setting

PBS Authority
Prescription Type

HSD Prefix Required

Eligible PBS Approved
Dispensing Locations

Private Patient

Community

Section 85

N/A

Community Pharmacies

Private Hospital

Community or Private Hospital Pharmacies

Public Hospital non-admitted
(excluding patients in NSW and ACT)*

Section 85

N/A

Community Pharmacies

Section 100

HSD PTE

Community or Private Hospital Pharmacies

HSD PUB

Public Hospital Pharmacies

Public Patient

Public Hospital non-admitted
(excluding patients in NSW and ACT)*

Section 85

N/A

Community or Public Hospital Pharmacies

Section 100

HSD PUB

Public Hospital
Pharmacies

Public Hospital non-admitted
(NSW and ACT)

Section 100

HSD PUB

Custodial Setting

Public Hospital / prison outpatient service

Section 100

HSD PUB

Public hospital / community pharmacy (subject to state/territory agreements)

 

*NSW and ACT do not participate in the Pharmaceutical Reforms.

There is a high burden of disease associated with chronic hepatitis C infection. Many people infected with chronic hepatitis C remain untreated. This may be either due to a contraindication or unwillingness to use an interferon-based regimen because of its prohibitive adverse effects. It is estimated that the accessibility of new oral direct acting antivirals will improve both treatment and SVR rates and reduce the number of people with chronic hepatitis C by 60% by 2030. The availability of new treatments on the PBS is a positive step forward in the control and potential elimination of this virus.

References:

  1. Australian Government Department of Health. Hepatitis C medicines fact sheet for consumers. Canberra: Pharmaceutical Benefits Scheme; 2016.
  2. Australian Government Department of Health. New hepatitis C medicines – Frequently Asked Questions. Canberra: Pharmaceutical Benefits Scheme; 2016.
  3. eTG complete [internet]. Melbourne: Therapeutic Guidelines Limited; 2011. Accessed 15 March 2016.
  4. NPS MedicineWise. New drugs – daclatasvir. Aust Prescr. 2015; 38(6): 217-9.
  5. NPS MedicineWise. New drugs – ledipasvir with sofosbuvir. Aust Prescr. 2015; 38(6): 219-21.
  6. NPS MedicineWise. New drugs – sofosbuvir. Aust Prescr. 2014; 37(5): 177-9.
  7. Pharmaceutical Benefits Advisory Committee. Public summary document: March 2016 PBAC meeting LEDIPASVIR 90 MG / SOFOSBUVIR. Canberra: Australian Government Department of Health and Ageing; 2015.

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