How DAAs have changed the therapeutic landscape for hepatitis C

The hepatitis C virus (HCV) is a member of the flavivirus family of RNA viruses and initiates an immune response in the liver which can cause chronic liver disease including cirrhosis, decompensated liver disease, liver cancer and death. HCV is a blood-borne virus, with 80% of prevalent cases and 90% of new cases in Australia acquired via injecting drug use. There is a low risk (~5%) of vertical and sexual transmission of HCV. Additional risks of transmission arise from unsafe needles used for tattooing, piercings or vaccinations and receiving contaminated blood from blood transfusions that took place overseas or in Australia before 1990.

There are 6 genotypes of HCV and numerous subtypes but in Australia over 90% of cases are caused by HCV 1a and 1b (54% prevalence) and HCV 3a (37% prevalence). Approximately ~230,470 people are living with chronic hepatitis C in Australia and it is estimated that ~23,000 of those are living in WA. HCV infection has significant morbidity and mortality however prior to the availability of DAAs less than 2% of affected Australians were receiving treatment.

Treating Hepatitis C
Previously, interferon (IFN)-based therapies were the standard care however numerous problems including toxicity, a prolonged treatment course (24-48 weeks) and a low cure rate are believed to have contributed to the low rate of treatment uptake. However, over the last 10-15 years the therapeutic landscape has changed and nowadays direct acting antivirals (DAAs) are the treatment of choice for HCV infection. These new generation DAAs are more effective (>90% cure rate), are orally administrated tablets so easier to take, have a shorter treatment duration time (8-12 weeks in most cases) and are better tolerated with few or usually minimal side effects.

DAAs target various non-structural (NS) viral proteins that are involved in the HCV lifecycle to disrupt viral replication and infection. These proteins and are categorised into four classes depending on their mechanism of action and therapeutic target:

  • Non-structural proteins 3/4A (NS3/4A) protease inhibitors
  • NS5B nucleoside polymerase inhibitors (NPIs)
  • NS5B non-nucleoside polymerase inhibitors (NNPIs)
  • NS5A inhibitors

From March 2016 the Australian government started funding DAA treatment for anyone with hepatitis C regardless of liver disease stage and since January 2017 a number of DAAs are available on the Pharmaceutical Benefits Scheme (PBS) including:

  • Daklinza® (daclatasvir)
  • Harvoni® (sofosbuvir + ledipasvir)
  • Ibavyr® (ribavirin)
  • Sovaldi® (sofosbuvir)
  • Viekira Pak® (paritaprevir + ritonavir + ombitasvir + dasabuvir)
  • Viekira Pak RBV® (paritaprevir + ritonavir + ombitasvir + dasabuvir + ribavirin)
  • Zepatier (grazoprevir + elbasvir)

Following clinical assessment, these medications are used either independently or in combination and generally means IFN-free treatment for most people. The combination of DAAs required depends on the individual and includes factors such as HCV genotype, prior treatment, whether they have developed liver cirrhosis, medications and co-morbidities.

DAA treatment may reduce liver transplants
Hepatitis C has been a leading indication for liver transplantation in both Europe and the US over recent years. Early evidence presented at the 2016 AASLD Liver Meeting suggests that DAA treatment for hepatitis C is reducing the need for liver transplants by slowing or halting liver disease progression. One study of the impact of DAA treatment on liver transplant waiting lists showed a statistically significant decrease of 32% in the rate of liver transplant wait-listing for HCV complicated by decompensated cirrhosis in the era of DAA therapy compared to the interferon era.

New safety issues for Hep C antivirals
The Institute for Safe Medication Practices (ISMP) reviewed MedWatch reports from the Food and Drug Administration (FDA) and examined the emerging risks DAAs for triggering liver failure. The ISMP reviewed the most recent 12 months' FDA adverse event reporting system (FAERS) data and found that although HCV was suppressed to undetectable levels in most patients, globally there were 524 reported cases of liver failure associated with DAAs, 1,058 reports of severe liver injury and a further 761 cases where the adverse event was antiviral failure against the targeted virus. The FDA also identified 24 cases of hepatitis B reactivation, with three of the patients experiencing liver failure. This finding prompted the FDA to announce that they were adding a warning to the DAA packaging.

Other useful resources
Kirby Institute Annual Surveillance Report

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