Effect of Current and Novel Antivirals on the Prevention of Hepatocellular Carcinoma: Beyond Viral Suppression

Hepatitis B virus (HBV) has substantial oncogenic potential promoting carcinogenesis through multifactorial and multi-route processes, which involve insertional mutagenesis following HBV DNA integration into host genome, increased genomic instability caused by HBV DNA integration and direct effects of viral proteins. HBV related oncogenic activity is enhanced in patients with long-term active necro-inflammatory activity and particularly in those with established cirrhosis, but it exists even in patients with inactive chronic HBV infection, since HBV DNA integration into the host genome occurs early in the phase of chronic HBV infection. Thus, it is easily understood why even non-cirrhotic chronic hepatitis B (CHB) patients carry some risk of hepatocellular carcinoma (HCC) development, which has considerable implications for their long-term monitoring. Current treatment options can inhibit HBV replication and prevent the progression of chronic liver injury and even achieve regression of cirrhosis in most of compliant treated patients with CHB. However, since HBV cannot be eradicated, HCC may still develop after several years of effective therapy. Therefore, HCC remains the major complication of treated CHB patients, particularly those with cirrhosis. Given that persistent high HBV replication increases the risk of HCC, antiviral therapy should reasonably prevent or reduce the risk of HCC in patients with chronic HBV infection. Today, treatment of patients with chronic HBV infection is mostly based on therapy with an oral nucleos(t) ide analogue (NA), although interferon-alpha (IFNa), almost exclusively pegylated IFNa, may be also used in a minority of cases. Treatment with any NA is usually given for long, perhaps for life, aiming to maintain on-therapy virological remission. Several studies and meta-analyses including initially patients treated with lamivudine and/or adefovir (the first two licensed oral anti-HBV agents) showed that long-term NA therapy significantly reduces but does not completely eliminate the risk of HCC, particularly in patients with pre-existing cirrhosis.5,6 Subsequent studies with the current first-line high-genetic barrier NAs, entecavir and tenofovir, reported rather variable annual incidence rates of HCC making comparisons with historical untreated controls and therefore conclusions rather complex. However, in all studies including appropriately matched untreated chronic hepatitis B patients, treatment with entecavir or tenofovir was also found to reduce but not to eliminate the risk of HCC. The benefit of antiviral therapy is particularly evident in patients with cirrhosis which are at increased risk for HCC, but there may be a preventive effect on the HCC incidence in non-cirrhotic patients as well. Prolongation of therapy with entecavir or tenofovir and particularly effective therapy for more than 5-7 years seems to further reduce the risk of HCC, especially in patients with pretreatment cirrhosis. Recently, there have been some data suggesting that the HCC risk may be lower in patients treated with tenofovir than entecavir, but contradictory studies have been also reported and hidden confounding factors could not be definitely excluded leaving the issue controversial. In clinical practice, patients with chronic HBV infection who are at increased risk for HCC should be advised to remain under HCC surveillance for ever, even if they achieve complete virological remission after antiviral therapy. In particular, all patients with cirrhosis should undergo HCC surveillance for life, although there are some emerging data suggesting that perhaps patients with pretreatment cirrhosis who achieve elastographic reversion of cirrhosis before the age of 40 years have minimal HCC risk and may discontinue HCC surveillance. On the other hand, treated non-cirrhotic CHB patients have a low baseline HCC risk which may be further reduced under NA therapy and therefore there is a lot of interest for the accurate prediction of the HCC risk and for the identification of such patients who require HCC surveillance. Recently, several risk scores have been reported for accurate prediction of HCC risk in treated CHB patients, one from a European Caucasian cohort (PAGE-B) and several from East Asian cohorts (South Korea: mPAGE-B, HCC-Rescue, AASL; Taiwan and Hong-Kong: APA-B, CAMD). All these scores include similar parameters, like age, gender and a variable expressing liver fibrosis severity (combined with one more variable in some of these scores) and appear to offer similarly good HCC predictability in Asian and Caucasian patients. The most important characteristic of all these HCC risk scores is their excellent negative predictive value, which offers identification of patient subgroups with no or negligible HCC risk (<0.2% per year) and thus no need for HCC surveillance. Whether novel treatment options that are currently under investigation can achieve greater reduction in the HCC risk of CHB patients is unknown. Given that all experimental treatment options aim to achieve greater rates of functional cure defined as HBsAg seroclearance, which is an endpoint that has been associated with lower HCC risk, we can only hope that the potential new treatment options will further reduce the HCC risk in this setting, particularly if they are used at an early phase of chronic HBV infection.