Managing hepatitis C in the age of new antivirals
Published in Health News and Evidence
Date published: About this date
Background | Initial assessment for HCV | Monitoring chronic HCV infection | Managing chronic HCV infection | Cleared HCV infection | Novel DAAs set to revolutionise HCV therapy | What makes DAAs different? | Information to support decisions about treatment | References
- A primary care role in the management of chronic viral hepatitis involves providing information, support and referral as well as initial and ongoing clinical assessment and monitoring.
- Interferon-based therapies have been the standard of care for chronic hepatitis C virus (HCV) infection in Australia over the last 15 years, but with the arrival of new direct-acting antivirals, the therapeutic landscape for hepatitis C is changing.
- Boceprevir and telaprevir are direct-acting antivirals that increase the sustained virological response and shorten the treatment duration in both treatment-naïve and treatment-experienced patients with chronic HCV genotype 1 infection.
- From 1 April 2013 boceprevir (Victrelis) and telaprevir (Incivo) can be prescribed on the Pharmaceutical Benefits Scheme for treatment of chronic HCV (genotype-1) infection in patients who meet specific criteria and are managed by an accredited treatment centre.
Primary care physicians have an important role in providing patients with up-to-date advice on the risk, prognosis and management of HCV infection.1 This includes initial and ongoing clinical assessment, monitoring, support and referral.2 While most treatment is based in hospitals, there is an important trend towards treatment in the community, with GPs taking on a greater role in the support and monitoring of patients being treated for HCV infection.3 With the arrival of direct-acting antiviral (DAA) therapy in Australia a major increase in uptake of treatment of HCV infection is anticipated, 4 and GPs hold the key to expanding access to treatment.1
Initial assessment for HCV
In the initial assessment of a patient with possible HCV:
- address whether the patient has active or inactive disease or has cleared infection
- establish the likelihood of the patient having significant fibrosis by considering contributing factors such as history of significant alcohol consumption, obesity or diabetes
- evaluate the patient for ongoing risks such as injecting drug use and ongoing, excessive alcohol consumption.2
Virological markers (Table 1) and liver function tests form the basis of the initial assessment for HCV.2,3
Table 1. Virological markers in HCV infection
|HCV antibodies (anti-HCV)||A positive test shows evidence of previous exposure to the virus|
|HCV RNA||A positive test indicates active infection and viral load|
|Alanine aminotransferase (ALT)||Elevated levels with anti-HCV-positive indicates degree of liver disease from HCV virus|
Monitor liver enzymes every 1–2 months for several months to establish whether enzymes are persistently normal, abnormal or fluctuating — while patients with persistent elevation of ALT are at higher risk of significant liver damage and disease progression, patients with normal liver enzyme levels may be at risk of progressive disease.2
Monitoring chronic HCV infection
Most people with active infection progress to chronic infection, defined as a positive test for HCV RNA in serum 6 months after the estimated date of infection.3
In patients with chronic infection, assess and document risk for the development of serious liver damage and factors that influence the severity of disease and/or response to treatment, including:
- a quantitative polymerase chain recation (PCR) test for HCV RNA load before treatment starts is a prognostic indicator of long-term response to treatment and used to monitor response while on therapy5
- liver function tests such as liver enzymes ALT or aspartate aminotransferase (AST) to ALT ratio (>1.0) every 6–12 months to assess the degree of hepatic inflammation, fibrosis or cirrhosis — or a more definitive liver biopsy2
- full blood count and prothrombin time or international normalised ratio, which may be useful indicators for the presence of cirrhosis2
Managing chronic HCV infection
- Educate patients against behaviours that risk reinfection and transmission to others; offer vaccination for hepatitis A and B to all patients with chronic HCV.3
- Identify and address modifiable risk factors (e.g. excessive alcohol consumption).3
- Educate patients about treatment and assess the patient's desire for treatment.3
- Determine each patient's individual need for support services.3
- Evaluate and recommend shared-care responsibilities.3
Cleared HCV infection
Only 25% of people with acute HCV infection spontaneously clear the infection within 6 months without treatment.6 All anti-HCV reactive (positive) results must be subjected to a minimum of one alternative immunoassay to confirm the result, followed by a qualitative HCV RNA test to establish current infection5. A patient can be considered to have cleared HCV infection if they return two negative PCR tests carried out 3 months apart.3 The HCV RNA test is subsidised on the MBS for this indication.
Reassure patients with persistently normal ALT levels who are found to be HCV RNA-negative that, while they have probably been exposed to the virus, they have cleared the infection.2 Repeat PCR testing annually to detect HCV reinfection — antibody testing will NOT reveal new infection in this group of patients, as their existing antibody will remain positive.2,3 If HCV RNA remains negative with persistently normal ALT levels, no further follow-up is necessary.2
Novel DAAs set to revolutionise HCV therapy
Interferon(IFN)-based therapies have been the standard of care for chronic HCV in Australia over the last 15 years7, but with the arrival of DAAs, the therapeutic landscape for hepatitis C is changing.4 Boceprevir (Victrelis) and telaprevir (Incivo) are the first in this class to be approved in Australia8,9 and will be listed for subsidy on the Pharmaceutical Benefits Scheme (PBS) from 1 April 2013.10
These first-generation DAAs offer a significant advance, especially in treatment for people with genotype 1 infection, which reflects most Australian and worldwide infections11,12 and is associated with a lower likelihood of success with current IFN-based treatment.13 Although the listing for these drugs requires treatment managed by an accredited treatment centre, GPs will continue to have a role in providing information, support and referral as well as initial and ongoing clinical assessment in primary care.2
Despite the availability of effective treatment, uptake among Australians remains low (<2% treated per year)7 and advanced hepatitis C accounts for 25% of liver transplants.14 Some of the barriers to treatment uptake include toxicity of IFN-based therapy, prolonged course of treatment (24–48 weeks), and lack of awareness of the curative potential of treatment.4 The availability of DAA therapy is expected to be accompanied by a major increase in treatment uptake.4 GPs play an important role in presenting patients with specific treatment options and potential side effects to help with treatment decisions, especially in relation to recent advances in treatment for hepatitis C.
What makes DAAs different?
Unlike the non-specific antiviral activity of existing IFN and ribavirin (RBV) therapies, DAAs are designed to inhibit viral proteins involved in the HCV life cycle.15 Telaprevir and boceprevir act through formation of a reversible enzyme-inhibitor complex that targets a protease involved in replication of genotype 1 HCV.16
Selection of patients for referral for DAA therapy
- Appropriate selection of patients for therapy with new DAAs is crucial4 and should be based on a consideration of risks and benefits for each patient.17
- Telaprevir and boceprevir have limited potency against non-genotype 1 HCV infections; in these patients, pegylated IFN + ribavirin (peg-IFN/RBV) remains the standard of care.17
- Treatment efficacy of telaprevir is reduced in patients who have failed to respond previously to peg-IFN/RBV; fewer than one-third of peg-IFN/RBV null responders achieved sustained viral response (SVR) with telaprevir.18 Comparable data are not available for boceprevir.
- Consider previous treatment response and fibrosis stage — triple therapy with telaprevir or boceprevir is recommended for patients with significant fibrosis (i.e. periportal or septal fibrosis or cirrhosis), especially in patients with prior peg-IFN/RBV post-treatment relapse.4
- Both telaprevir and boceprevir are potent inhibitors of the CYP3A4 metabolic pathway and may lead to drug interactions.8,9
- Consider predictive factors that support treatment selection. Genetic polymorphisms in the interleukin 28B (IL28B) region are associated with peg-IFN/RBV response in chronic HCV genotype 1 infection.19
- Side effects are common and GPs treating patients referred for DAA therapy should consult with specialists about side effects.
The DAA drug development pipeline is currently addressing several other potential targets, with a view to advancing to IFN-free HCV therapy.4,15Triple therapy with peg-IFN/RBV/DAA (boceprevir or telaprevir) is expected to be the standard of care for patients with chronic HCV genotype 1 infection for the next 2–3 years, with IFN-free combination DAA therapy anticipated within 3–5 years.4
Information to support decisions about treatment
- HCV is treated to prevent the development of cirrhosis, which is associated with hepatocellular failure and hepatocellular cancer;2 the aim is to achieve viral eradication or SVR.3
- Encourage people at highest risk of progression of liver disease to consider therapy as soon as practicable.3
- For other people, consider their social situation, living arrangements and availability of support, their mental health and current income/work situation and current drug use in deciding whether to initiate treatment.3
- Advise people with chronic HCV infection, who are at risk of liver disease progression, of the potential benefits of antiviral therapy — Table 2 summarises some key points about available treatments.
- Treatment is contraindicated in patients with decompensated liver disease, those with severe depression or other major psychiatric conditions, autoimmune disease, significant cardiac disease and during pregnancy.3
- In Australia treatment is available under Section 100 of the PBS for any patient 18 years or older who is treatment naïve or has one prior failed treatment, is HCV-antibody positive and HCV-RNA negative, has compensated liver disease and agrees to effective contraception.3
- Advise patients that side effects are common but do not usually require discontinuation of treatment — most patients who start a full course of treatment for HCV complete it, and GPs can support and encourage patients to persist with treatment.3
Table 2. Available treatment options for chronic HCV in Australia
|Therapy||Virological response and side effects|
A combination of once-weekly subcutaneously injected peg-IFN plus twice-daily oral RBV.
This is the current standard of care for chronic HCV. The dose and duration of therapy depends on HCV genotype20
Influenza-like symptoms and psychiatric side effects (e.g. depression) are common.21
Dose adjustment may be needed to manage common adverse effect such as anaemia (associated with RBV) and neutropenia (associated with peg-IFN)20
Triple therapy of peg-IFN/RBV with telaprevir or boceprevir.
This regimen has been adopted in the US as the new standard of care for most patients with genotype 1 HCV infection17,23
Enhanced SVR in treatment naïve patients (67% for boceprevir;24 75% for telaprevir25) and treatment-experienced patients (66% for boceprevir;26 64% for telaprevir18) compared with standard peg-IFN/RBV alone in clinical trials. Enhanced SVR was also achieved in patients with a prior relapse or partial response.18,26
Nearly half the treatment-naïve patients receiving triple therapy with telaprevir or boceprevir achieved SVR with a shortened treatment duration of 24 and 28 weeks, respectively, compared with the 48 weeks required for standard peg-IFN/RBV therapy.17,18
On-treatment response (e.g. development of a rapid virological response or extended virological response early during treatment) appears to be the strongest predictor of patients who could benefit from shorter treatment with no loss in SVR.23
Adverse events occurred more frequently in patients treated with telaprevir or boceprevir than in those treated with peg-IFN/RBV alone.24,25 The most common adverse events observed in the telaprevir trials included rash (61%), pruritus (50%), nausea (43%), anaemia (37%) and diarrhoea (32%),25 whereas for boceprevir anaemia (49%), nausea (48%) and dysgeusia (43%) were most common24
- Hellard ME, Wang YH. The role of general practitioners in managing and treating hepatitis C. Med J Aust 2009;191:523–4. [PubMed]
- Feller R SS, Ward J, Deakin G. Primary care management of chronic viral hepatitis. In: Bradford D, Hoy J, Matthews G (eds). HIV, viral hepatitis and STIs – a guide for primary care. Australasian Society for HIV Medicine, 2008; 111–9. http://www.ashm.org.au/images/publications/monographs/HIV_viral_hepatitis_and_STIs_a_guide_for_primary_care/hiv_viral_hepatitis_and_stis_whole.pdf (accessed 26 February 2013).
- Australian Society for HIV Medicine Inc. General Practitioners and Hepatitis C. 2008. http://www.ashm.org.au/images/publications/booklets/gp_august2008-web.pdf (accessed 28 February 2013).
- Dore GJ. The changing therapeutic landscape for hepatitis C. Med J Aust 2012;196:629–32. [PubMed]
- National HCV Testing Policy Expert Reference Committee. National hepatitis C testing policy 2012. Commonwealth of Australia Department of Health and Ageing, 2012. http://www.ashm.org.au/images/HCV_Testing_portal/HepC_TESTING_POLICY_FORMATTED_V10.pdf (accessed 28 February 2013).
- Micallef JM, Kaldor JM, Dore GJ. Spontaneous viral clearance following acute hepatitis C infection: a systematic review of longitudinal studies. J Viral Hepat 2006;13:34–41. [PubMed]
- Gidding HF, Topp L, Middleton M, et al. The epidemiology of hepatitis C in Australia: notifications, treatment uptake and liver transplantations, 1997–2006. J Gastroenterol Hepatol 2009;24:1648–54. [PubMed]
- Janssen-Cilag Pty Ltd. Incivo product information. 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-01385-3 (accessed 26 February 2013).
- Merck Sharp & Dohme pty Ltd. Victrelis product information. 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2012-PI-01200-3 (accessed 27 February 2013).
- Australian Government Department of Health and Ageing. Subsidy for groundbreaking virus treatments. PBS News Updates 2013. http://www.pbs.gov.au/info/news/2013/02/subsidy-for-groundbreaking-virus-treatments (accessed 27 February 2013).
- Sievert W, Altraif I, Razavi HA, et al. A systematic review of hepatitis C virus epidemiology in Asia, Australia and Egypt. Liver Int 2011;31[Suppl.]2:61–80. [PubMed]
- Dusheiko G, Schmilovitz-Weiss H, Brown D, et al. Hepatitis C virus genotypes: an investigation of type-specific differences in geographic origin and disease. Hepatology 1994;19:13–8. [PubMed]
- Gidding HF, Law MG, Amin J, et al. Hepatitis C treatment outcomes in Australian clinics. Med J Aust 2012;196:633–7. [PubMed]
- The Kirby Institute. HIV, viral hepatitis and sexually transmissible infections in Australia Annual Surveillance Report 2012. The Kirby Institute, the University of New South Wales, 2012. http://www.kirby.unsw.edu.au/sites/hiv.cms.med.unsw.edu.au/files/hiv/resources/2012AnnualSurvReport.pdf (accessed 25 February 2013).
- Naggie S. Management of hepatitis C virus infection: the basics. Top Antivir Med 2012;20:154–61. [PubMed]
- Pan Q, Peppelenbosch MP, Janssen HL, et al. Telaprevir/boceprevir era: from bench to bed and back. World J Gastroenterol 2012;18:6183–8. [PubMed]
- Jacobson IM, Pawlotsky JM, Afdhal NH, et al. A practical guide for the use of boceprevir and telaprevir for the treatment of hepatitis C. J Viral Hepat 2012;19[Suppl.2]:1–26. [PubMed]
- Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011;364:2417–28. [PubMed]
- Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 2009;41:1100–4. [PubMed]
- Therapeutic Guidelines Limited. eTG Complete. Treatment of chronic hepatitis c 2012. http://etg.hcn.com.au/ (accessed 25 February 2013).
- Fried MW, Hadziyannis SJ. Treatment of chronic hepatitis C infection with peginterferons plus ribavirin. Semin Liver Dis 2004;24[Suppl.2]:47–54. [PubMed]
- Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002;122:1303–13. [PubMed]
- Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:1433–44. [PubMed]
- Poordad F, McCone J, Jr., Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1195–206. [PubMed]
- Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011;364:2405–16. [PubMed]
- Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011;364:1207–17. [PubMed]