Screening

Current evidence does not support population screening programs for liver cancer (see principles of screening). 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 liver cancer occur after the age of 40 years^[1], 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 high prevalence countries, and low uptake of hepatitis treatment, mean liver cancer prevalence in Australia is expected to increase in coming years.

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.

The risk of progression to liver cancer 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 people being treated for chronic hepatitis B^[2][3][4] and cure can be achieved in over 95% of people treated for chronic HCV^[5][6][7]. There is moderately strong evidence that treatment of hepatitis B^[8] substantially reduces, but does not eliminate, the risk of liver cancer. Similarly, achievement of sustained virologic response in patients with chronic HCV reduces the risk of liver cancer but does not eliminate cancer risk, particularly in those already living with cirrhosis^[9].

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 ^[10]. Hepatitis testing enables early referral to treatment, reduces transmission to others, and is a cost-effective strategy to reduce liver cancer.

Testing for hepatitis

Health professionals and policy makers have identified sub-optimal diagnosis as one of the main challenges in reducing the burden of chronic hepatitis^[11]. Identifying people with chronic hepatitis involves two steps: risk factor screening and serological testing. Effective prevention of hepatitis-related cancer relies on targeted risk factor screening and serological testing to identify people with chronic HBV and/or HCV infection such that they can be referred for treatment and/or monitoring. Testing for hepatitis is an important strategy to reduce liver cancer burden as it identifies people most at risk of developing cancer.

It is estimated that about 39% of people with chronic HBV, and 20% with chronic HCV, remain undiagnosed and unaware that they are infected. Most HCV patients are also not diagnosed properly using HCV RNA testing.^[12]

There is growing evidence of the benefits and cost-effectiveness of testing people at highest risk for chronic hepatitis infection.^[13] 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. Targeted education of primary and community healthcare providers, to increase awareness about the natural history of HBV and HCV and potential for progression to liver cancer, and of the importance of testing and treatment of high-risk groups is required. The potential to follow up notifications of chronic viral hepatitis by health departments and assist with linkage to treatment and care has been recommended in Australia’s National Hepatitis B and C Strategies and other policy recommendations and should be prioritised as an opportunity. Public health coordination to link people diagnosed with care should be explored as a key liver cancer prevention intervention.

In addition to earlier referral to treatment, early identification of individuals with viral hepatitis enables opportunities to reduce transmission to others through education, controlling infectivity, reducing risk behaviours and offering HBV vaccination to at-risk contacts.

Treating chronic hepatitis

The introduction of new direct acting antivirals regimens and the listing of these drugs on the Pharmaceutical Benefits Scheme (PBS) in March 2016 has revolutionised the treatment of HCV in Australia. Newer antivirals are more effective, have a shorter duration of treatment and better tolerability than previous treatment methods. New models of care and improving awareness of the benefits of treatment are essential to increasing uptake of treatment ^[14].

In order to realise the full benefit of advances in treatment in reducing the future burden of liver cancer, early diagnosis, proper referral and adherence to treatment as well as ongoing monitoring of people with chronic viral hepatitis is required.

Treating chronic hepatitis B infection

Currently approved treatments for chronic HBV in Australia, subsidised through the PBS, include injected immunomodulating drugs (interferon-α and pegylated interferon), and five oral antiviral agents: lamivudine, telbivudine, entecavir (nucleoside analogues), adefovir and tenofovir (nucleotide analogues) ^[15]. In 2017, only 8% of people living with chronic HBV were estimated to be receiving antiviral therapy.^[12]

The aim of chronic HBV treatment is to achieve sustained viral suppression, normalisation of alanine transaminase levels and prevention of cirrhosis and liver cancer.^[16][17]There is strong evidence that timely treatment with antivirals suppresses viral replication^[18] and reduces the risk of liver related complications including progression to cirrhosis and liver cancer^[17]. However, complete viral clearance is rarely achieved from antiviral therapy and treatment benefits are limited to patients with active disease who have persistently high alanine transaminase levels or substantial liver disease.^[16] Antiviral therapy is generally not offered to patients with chronic HBV who are in the immune tolerance or immune control phases as there is no strong evidence of benefit^[19].

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^[20][21][22]. More than 90% of cases of liver cancer complicating HCV develop in the cirrhotic liver, thus the aim of therapy is to prevent cirrhosis by successful elimination of HCV infection. In 2017, 12% of all people estimated to be living with HCV initiated antiviral therapy.^[12]

Research in this area is progressing rapidly. Direct-acting antivirals (DAA) provide vastly improved outcomes for people infected with HCV genotype 1 (the predominant type in Asia) ^[23][24][25]. Multiple second-generation direct acting antivirals have been introduced^[14][26] and are highly effective treatment options^[27]. Currently, pan-genotypic antivirals (combination drug variants) are available through the PBS, which are used to treat all 6 HCV genotypes. This includes glecaprevir/pibrentasvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.^[28] Pan-genotypic drugs simplify antiviral therapy, are well tolerated, and have high rates of sustained virologic response (SVR).^[29]

Reduced incidence of liver cancer has also been observed in HCV patients, and HCV patients with cirrhosis who both achieve sustained virologic response from antiviral therapy ^[30][31][32]. However, HCV patients with cirrhosis remain at higher risk of liver cancer.^[31] Achievement of a sustained virological response reduced – but did not eliminate – the risk of liver cancer, meaning patients with cirrhosis need continued surveillance.

Liver cancer 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. Liver cancer surveillance is the accepted standard of care internationally and in Australia for people with HBV and HCV in at-risk groups^{[33][34][35][36]}.

Early stage liver cancer is asymptomatic and can only be detected by imaging. In Australia, the implementation of a comprehensive liver cancer surveillance program supported by population-based registries and communication strategies could monitor the progression of chronic hepatitis to liver cancer and allow for early diagnosis and treatment of liver cancer. The population groups that may benefit from surveillance include all patients with cirrhosis and patients with HBV without cirrhosis but have additional risk factors (Asian men over 40 years, Asian women over 50 years, Africans over 20 years, Aboriginal and Torres Strait Islander people over 50 years and those with a family history of liver cancer)^[36]. Studies have demonstrated that diagnosis of liver cancer within a surveillance program significantly improves survival in patients with cirrhosis and early tumour detection ^[37][38]. The Australasian Society for HIV, Viral Hepatitis, and Sexual Medicine recommends using biennial ultrasounds, with or without alpha-fetoprotein, to screen all patients with cirrhosis or other high-risk patients without cirrhosis.^[36]