Hepatitis C virus (HCV) was discovered in 1989. Genotype 1 is still the most common of the six genotypes of the virus that have been identified to date.

The majority of people who contract HCV are asymptomatic. However in some individuals chronic infection can eventually lead to cirrhosis and subsequent life threatening conditions including liver failure, oesophageal varices and hepatocellular carcinoma.8,10 Acute infection in adults leads to chronic infection in around 80% of cases. Approximately 120-130 million individuals are chronically infected with HCV worldwide.

In 2010 an estimated 297,000 people living in Australia had been infected with HCV.11 In this group, an estimated 48,000 people had chronic HCV and moderate liver disease and 6,100 were living with HCV related cirrhosis.11 Chronic HCV infection was the underlying cause of liver disease in 25% of patients requiring liver transplants in 2010.11

Infection amongst those admitted to correctional facilities is higher than the general population. In 2006, 34% of new prisoners and 56% of injecting drug users admitted to prisons in Australia had hepatitis C.1 Transmission appears to occur predominantly among those with a recent history of injecting drug use.10

The aim of treatment is to achieve a sustained virological response (SVR), that is undetectable HCV-RNA 24 weeks after the end of treament.5,9

Interferon and ribavirin

Treatment for HCV is currently based on a combination of a pegylated form of interferon (peginterferon) and ribavirin. Interferon is an immunostimulant. Ribavirin interferes with RNA and DNA synthesis and hence viral replication.

This combination is not successful in all patients. Cure rates are much higher in those infected with genotypes 2 or 3 (80%) but only 50% in patients infected with genotypes 1 or 4.5 Patients should be tested for genotype before treatment to determine dose and duration therapy.

For patients with genotypes 1, 4, 5 and 6, current treatment recommendations are for 48 weeks of treatment with peginterferon and ribavirin. Patients with genotypes 2 and 3 usually undergo a 24-week course of treatment, but this can be extended to 48 weeks if necessary.3,4,5

There are serious potential side effects with this treatment. Full blood count and liver biochemistry should be monitored every 4 weeks, more frequently for those with advanced liver disease or low pre-treatment haemoglobin.

Ribavirin can lead to significant haemolytic anaemia in up to 30% of patients. However a haemoglobin drop of more than 30g/L has been associated with improved SVR rates. If the patient’s anaemia is symptomatic then the dose of ribavirin can be reduced but the dose should be increased again, if possible, once it improves as the success of treatment appears to be dependent on cumulative ribavirin exposure.5

Peginterferon commonly causes neutropenia and also thrombocytopenia. Therapeutic Guidelines5 suggest that neutrophil count as low as 0.5×109/L (normal 1.5-7.5×109/L) is tolerable as long as the patient remains well and the count is monitored closely. Patients with conditions that predispose them to infection should also be monitored closely. Platelet counts are commonly allowed to drop as low as 30×109/L (normal 120-400 x109/L), as long as the patient is asymptomatic and has no other risk factors for bleeding.3,4,5

Other common side effects of this medication regime include anorexia and gastrointestinal upset, skin irritations, sinusitis, dyspnoea, myalgia, dry mouth, insomnia, sweating and rigors.9

Drug interactions with ribavirin can occur up to 2 months after ceasing due to its long half-life.9

Protease inhibitors

Two newer medications, telaprevir and boceprevir, are protease inhibitors and work by binding to the non-structural 3 protease which is essential for viral replication. Rather than replacing current treatments, they are added to the standard peginterferon and ribavirin treatment for patients with HCV genotype 1.

These drugs demonstrate SVR increases above 25%, in patients with HCV genotype 1 when given in combination with peginterferon and ribavirin in both previously treated and untreated patients.6,7,8 They should never be given alone as there are concerns that resistance is more likely to develop in the absence of peginterferon and ribavirin.

Both medications are metabolised by cytochrome P450. This means there is potential for many drug interactions. Co-administration with medications that have a narrow therapeutic window and are substrates of cytochrome P3A should be avoided. These include amiodarone, cisapride, pimozide, quinidine, terfenadine, ergot derivatives, simvastatin, atorvastatin, oral midazolam and sildenafil. Also class 1a and class 111 antiarrhythmics should not be given with these medications.3,4 Medications which may reduce the effect of boceprevir and telaprevir, through reducing plasma concentrations, include rifampicin, St John’s Wort, carbamazepine, phenytoin and phenobarbitone.3,4,9

Caution should also be taken when these medications are given with other medications that prolong the QT interval in the heart, for example methadone, or in patients with a past history of QT prolongation.3,4,9

Telaprevir (INCIVO) comes as a 375mg film coated tablet. Dosage is 750mg eight-hourly with food for 12 weeks. The drug should be commenced when commencing peginterferon and ribavirin. HCV-RNA is tested at week 4 and 12. If there is insufficient response to treatment, all three medications are ceased. In patients responding to treatment, telaprevir is continued until week 12. Peginterferon and ribavirin are then continued alone for an additional 12 to 36 weeks.

This medication should not be used in patients coinfected with hepatitis B. Telaprevir is not recommended in patients with moderate or severe hepatic impairment, or those with decompensated liver disease.3

Common adverse reactions include anaemia, pruritus, rash, nausea and diarrhoea. Stevens-Johnson syndrome has been reported in patients taking telaprevir. The addition of telaprevir increases the incidence of anaemia compared to standard treatment alone. If this occurs it is suggested that the dose of ribavirin is reduced, rather than that of telaprevir. Hyperbilirubinaemia, hyperuricaemia, hypokaleamia, decreased lymphocyte and platelet counts and increased LDL and total cholesterol are also more common when telaprevir is added to standard treatment. However all appear to normalise by the end of treatment.7

Boceprevir (VICTRELIS) is available in a 200mg capsule. The recommended dose is 800mg three times a day, with food. Unlike telaprevir, boceprevir should not be initiated until week five of peginterferon and ribavirin therapy.

Response is tested at week 8. For patients with undetectable HCV-RNA treatment is continued with all three drugs until week 28. Those patients with detectable HCV-RNA at week 8, treatment is continued until week 24, and then retested. If there is still detectable HCV-RNA all three medications are discontinued. Patients with no detectable HCV-RNA continue all three drugs until week 28, then peginterferon and ribavirin alone until week 48.4

Common adverse reactions include fatigue, anaemia, nausea, headache and taste disturbances. Almost half of the patients given boceprevir develop anaemia compared to about a third of those given peginterferon alpha and ribavirin alone.6 This is commonly treated with erythropoietin. Patients with galactose intolerance disorders should not take boceprevir.

These two medications offer exciting potential in the treatment of HCV resistant to standard treatment. Boceprevir and telaprevir appear comparable in terms of sustained virologic response, relapse, or discontinuation of therapy for patients treated with both standard-dose therapy durations and response-guided therapy durations.2 Both telaprevir and boceprevir have been approved by the Therapeutic Goods Administration for the treatment of genotype 1 HCV, becoming the first new treatments in more than a decade. Both medications were recommended for PBS listing as Section 100, Highly Specialised Drugs at the July
meeting of the Pharmaceutical Benefits Advisory Committee.

References:

  1. Australian Federation of AIDS Organisations Inc. Briefing Paper: HIV and Hepatitis C in prisons. Newtown: AFAO; 2007.
  2. Cooper CL, Druyts E, Thorlund K, Nachega JB, El Khoury AC, O’Regan C, et al. Boceprevir and telaprevir for the treatment of chronic hepatitis C genotype 1 infection: an indirect comparison meta-analysis. Ther Clin Risk Manag. 2012; 8: 105–30.
  3. INCIVO (teleprevir) Australian approved product information. Macquarie Park: Janssen-Cilag. Approved 6 March 2012, amended 23 May 2012.
  4. VICTRELIS (boceprevir) Australian approved product information. South Granville: Merck Sharp & Dohme (Australia). Approved 22 December 2011, amended 26 March 2012.
  5. Hepatitis C [revised 2011 Feb]. In: eTG complete [CD-ROM]. Melbourne: Therapeutic Guidelines Limited; 2012 Mar.
  6. National Prescribing Service. New Drugs: Boceprevir. Aust Prescr 2012; 35: 102–103.
  7. National Prescribing Service. New Drugs: Telaprevir. Aust Prescr 2012; 35: 128–35.
  8. Pawlotsky J. New Antiviral Agents for Hepatitis C. F1000 Biol Rep 2012; 4: 5.
  9. Rossi S (Ed). Australian Medicines Handbook 2011. Adelaide: Australian Medicines Handbook Pty Ltd; 2011.
  10. Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002; Nov; 36 (5 Suppl 1): S35–46.
  11. McDonald A (Ed). HIV, viral hepatitis and sexually transmissible infections in Australia Annual Surveillance Report 2011. The Kirby Institute, the University of New South Wales, Sydney, NSW.

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