There are early indications that the primary prevention approaches described in the Prevention section – particularly blood screening and hepatitis B virus (HBV) immunisation – have reduced incident hepatitis rates in Australia. However, most cases of hepatocellular carcinoma occur after the age of 40 years, so the full impact of vaccination will not be observed for some time. The current (and ageing) pool of people with chronic HBV and/or hepatitis C virus (HCV) infections, continuing immigration of people from countries where infants were not immunised or immunisation programs have only recently been implemented, and low uptake of hepatitis treatment, mean hepatocellular carcinoma prevalence in Australia is expected to increase in coming years.
Effective screening and referral also requires the development and implementation of systems to support testing and follow-up. Secondary prevention of hepatitis-related liver cancers involves managing established chronic hepatitis infection through appropriate screening, diagnostic testing, treatment and follow-up of infected individuals.
Hepatocellular carcinoma risk for individuals with chronic HBV or HCV infection is greatly reduced if viral replication is controlled either spontaneously or with treatment. Advances in antiviral treatments mean viral replication now can be effectively suppressed in 95% of cases of chronic hepatitis B and up to 75% of chronic hepatitis C cases. There is moderately strong evidence that effective antiviral therapy to control HBV infection or eradicate HCV substantially reduces – but does not completely eliminate – the risk of hepatocellular carcinoma.
Many people in Australia with chronic HBV or HCV infection are unaware of their infection and remain undiagnosed and hence, untreated. Very few of those who would benefit from treatment access it. Hepatitis testing enables early referral to treatment, reduces transmission to others, and is a cost-effective strategy to reduce hepatocellular carcinoma.
Screening for hepatitis
Screening for hepatitis is an important strategy to reduce liver cancer burden, health professionals and policy makers have identified sub-optimal diagnosis as one of the main challenges in reducing the burden of chronic hepatitis. The aim of hepatitis screening is to identify people most at risk of developing hepatocellular carcinoma. Effective prevention of hepatitis-related cancer relies on effective and targeted screening and detection programs to identify people with chronic HBV and/or HCV infection such that they can be referred for treatment and/or monitoring.
It is estimated that about 40% of people with chronic hepatitis B, and 20% with chronic hepatitis C, remain undiagnosed and unaware that they are infected. Of those who are aware of their infection and eligible for treatment, it is estimated that less than 2% access specialist treatment. Similarly, it has been estimated that only 2% of all patients with chronic HCV actually receive antiviral therapy each year.
There is growing evidence of the benefits and cost-effectiveness of screening members of the population groups at highest risk. This requires targeted education of primary and community healthcare providers, to increase awareness about the natural history of hepatitis B and C and potential for progression to hepatocellular carcinoma, and of the importance of screening patients in high-risk groups and appropriate referral to treatment. Groups recommended for hepatitis screening in Australia are outlined in the Policy context section of this chapter.
Identifying infected persons involves two steps: risk factor screening and serological testing.
Risk factor screening aims to identify people in high-risk groups for HBV and HCV infection. Screening is also recommended for individuals with known risk factors and those in population groups with higher HBV and HCV prevalence. Screening of all individuals with symptoms and signs of liver disease, as well as household and sexual contacts of people diagnosed with HBV or HCV is ideal.
The second step in identifying patients most at risk of developing hepatocellular carcinoma is serological testing. Markers of HBV infection include hepatitis B e-antigen (HBeAg) and HBV DNA: HBeAg is a marker of HBV replication and infectivity; HBV DNA is a measure of viral replication and is often used as a criterion for starting antiviral therapy. Long-term epidemiological studies have established the role of positive HBeAg, high HBV DNA and viral genotypes in hepatocellular carcinoma development. It is generally accepted that baseline and serial HBV DNA levels are the best risk discriminators, given the direct correlation between HBV DNA titre and hepatocellular carcinoma risk.
The first step in diagnosing HCV infection is testing for HCV antibodies (anti-HCV) to determine past exposure. Individuals who are anti-HCV positive are then tested for current infection by either HCV RNA or HCV antigen (HCV Ag) testing. Early detection of HCV infection is an effective strategy to prevent hepatocellular carcinoma, due to the treatment options available, see below for more information.
In addition to earlier referral to treatment, early identification of infected individuals enables opportunities to reduce transmission to others through education, controlling infectivity, reducing risk behaviours and offering vaccination to at risk contacts.
Barriers to early identification of hepatitis infection include low awareness among primary and community healthcare providers of risk factors and the natural history of hepatitis, and the absence of systems to support testing and follow-up. This is further discussed in the Policy context section of this chapter.
Antiviral therapies can effectively suppress viral replication in the majority of people with chronic hepatitis B and C who successfully complete treatment. Despite the proven efficacy of these treatments, it has been estimated that only 2% of all patients with chronic HBV and 2% of those with HCV who require treatment actually receive antiviral therapy each year. While difficult to establish, it has been suggested that anywhere from five to eight times the number currently receiving hepatitis B treatment could benefit.
Sub-optimal access to treatment is largely due to under-diagnosis (see Screening for hepatitis above), but even in those who are diagnosed and referred to treatment, uptake and adherence is low. Reasons include toxicity of interferon-based therapy, duration of treatment, lack of treatment infrastructure (in settings accessible to people at highest risk such as community health, primary care, methadone clinics and prisons) and lack of awareness of the benefits of treatment.
Realising the potential of antiviral therapies to reduce the future burden of hepatocellular carcinoma requires proper diagnosis, referral to care, ensuring adherence to treatment and ongoing monitoring of people with chronic hepatitis B and/or C. A recent survey of general practitioners found support for a shared care model and the need for training programs, referral pathways and clinical guidelines to support GPs in screening, diagnosing and managing patients with hepatitis B.
Economic modelling in 2008 showed an enhanced management and treatment scenario – with a largely increased proportion of people with chronic hepatitis B receiving therapy – would be economically justified, given the reduction in HBV-related liver cancer and deaths achieved (although these analyses did not include costs of screening and detecting people infected with HBV). Similarly, modelling shows increasing uptake of HCV treatment would be highly cost-effective in terms of cost per quality adjusted life year gained.
Treating chronic hepatitis B infection
The two main and widely authorised therapies are interferons, which act by stimulating the immune system to eradicate the viral infection, and direct antiviral agents (nucleoside and nucleotide analogues), which prevent viral replication by inhibiting the function of the viral polymerase.
Currently approved treatments for chronic hepatitis B in Australia, subsidised through the Pharmaceutical Benefits Scheme, include injected immunomodulating drugs (interferon-α and pegylated interferon), and five oral antiviral agents: lamivudine, telbivudine, entecavir (nucleoside analogues), adefovir and tenofovir (nucleotide analogues).
There is strong evidence that timely treatment with antivirals suppresses viral replication. Therapy with interferon or lamivudine reduces the risk of progression to cirrhosis and hepatocellular carcinoma. Treatment of HBV infection with nucleoside/nucleotide analogue therapy has been shown to reduce the risk of hepatocellular carcinoma by 72%. Another studies has reported that, over a median four year follow-up, the risk of liver cancer in patients treated with antiviral therapy was less than half that of untreated patients.
However, complete viral clearance is rarely achieved, occurring in only 3–8% of patients receiving interferon therapy and in less than 5% of patients receiving nucleoside/nucleotide analogue therapy, and treatment benefits are limited to patients with active disease who have sustained raised alanine transaminase (ALT) – an enzyme indicative of liver injury – or substantial liver disease. As such, the aim of treatment is sustained viral suppression that results in normal ALT levels, decreased HBV DNA and prevention of cirrhosis and hepatocellular carcinoma.
Antiviral therapy is generally not offered to patients with chronic hepatitis B who are in the immune tolerance or immune control phases (see Natural history) as there is no evidence of benefit. Because infected individuals move between phases, all patients who are hepatitis B surface antigen positive should be followed-up over the long term to ensure they are regularly and properly assessed and offered antiviral therapy when needed.
Treating hepatitis C infection
In the absence of an effective vaccine against HCV, antiviral therapy remains the best strategy for prevention of liver cancer in people infected with HCV. Accumulated evidence indicates that effective antiviral therapy substantially reduces the risk of hepatocellular carcinoma. More than 90% of cases of hepatocellular carcinoma complicating hepatitis C develop in the cirrhotic liver, thus the aim of therapy is to prevent cirrhosis by successful elimination of HCV infection.
Research in this area is progressing rapidly. In February 2013, it was announced that new HCV treatments, Boceprevir and Telaprevir, would be made available in Australia through the Pharmaceutical Benefits Scheme. Further treatment options are expected to emerge in the following two to five years.
Direct Acting Antivirals such as Boceprevir or Telaprevir provide vastly improved outcomes for people infected with HCV genotype 1 (the predominant type in Asia). Treatment of HCV genotype 1 with these therapies can achieve sustained virological response in up to 75% of cases.
In Australia the current standard treatment for is peginterferon-alpha and ribavirin. This is expected to change with the availability of Boceprevir or Telaprevir, anticipated for May 2013. HCV genotypes 2 and 3 are considered easier to treat, and peginterferon-alpha/ribavirin treatment achieves higher levels of clearance of these genotypes compared with genotype 1. Sustained virological response can be achieved in 80–90% of patients with HCV genotype 2 and 3. Unfortunately, interferon is often not well tolerated and is associated with common side effects of treatment including neutropenia, anaemia and depressive or other mood changes, affecting patient adherence.
A meta-analysis of 20 studies, including nine randomised controlled trials, reported that antiviral therapy with interferon and/or ribavirin significantly reduces the risk of hepatocellular carcinoma development. Reduced incidence of hepatocellular carcinoma has also been observed in patients with HCV cirrhosis who achieve viral eradication after antiviral therapy. Achievement of a sustained virological response reduced – but did not entirely eliminate – the risk of hepatocellular carcinoma, meaning patients with cirrhosis need continued surveillance.
Hepatocellular carcinoma surveillance
For patients with chronic hepatitis infection and cirrhosis who are at highest risk of hepatocellular carcinoma, the key to improving survival is early diagnosis through surveillance. Hepatocellular carcinoma surveillance is the accepted standard of care in the US and Europe for people with hepatitis B and C in at-risk groups.
Observational studies have demonstrated a survival benefit of surveillance in at-risk populations, as surveillance detects hepatocellular carcinoma at an early stage, increasing the possibility of curative therapy. An Australian study has demonstrated that the survival of hepatocellular carcinoma patients detected through surveillance was significantly higher compared with those diagnosed by other means.
Early stage hepatocellular carcinoma is asymptomatic and can only be detected by imaging. Surveillance with six-monthly combination serum alpha-fetoprotein (AFP) measurement and abdominal ultrasound is common practice. There is evidence of a 37% reduction in mortality with this surveillance strategy. However there is disagreement regarding the cost-effectiveness of AFP determination as part of a surveillance strategy. The most recent guidelines from the American Association for the Study of Liver Diseases state that the evidence suggests that AFP measurement lacks adequate sensitivity and specificity for effective surveillance and cost-effectiveness. As such, they recommend that hepatocellular carcinoma surveillance be based on 6-monthly abdominal ultrasound in high-risk groups.
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