An initiative to increase HBV awareness and treatment was commenced by the WHO and other health agencies in 2016, with the aim of eliminating viral hepatitis by 2030 [58]. High-impact interventions were planned, followed by studies that modeled the hepatitis epidemiology and covered aspects such as increasing sanitation, newborn mass vaccination against HBV, screening, and linkage to care of the infected populations. In patients with an untreated HBV infection, the incidence of HCC increases with the increase in the serum HBV DNA level. The advised first-line regimen for chronic hepatitis B is INF-α and tenofovir (TDF) and entecavir (ETV), which reduces hepatic inflammation via viral suppression [56]. Randomized controlled trials and meta-analyses have demonstrated that administering IFN for a finite duration reduces the risk of HCC in treated compared to untreated patients [59,60,61,62]. In most patients, the continued administration of either NA has caused attenuation, but unfortunately not the eradication, of the HCC risk. The persistence of the HCC risk results from NA failing to eradicate cccDNA and the integrated sequences of the HBV DNA. This leads to the limited rates of serum HBsAg clearance in NA-treated patients, whereas the persistence of residual HCC risk has been recognized even in patients who do not show serum HBsAg following anti-viral therapy, specifically in those patients with HBsAg seroclearance occurring after 50 years of age [56]. As per a joint report of the American and European Societies of the Study of the Liver, the pragmatic goal of NA therapy is to achieve a functional HBV cure, defined as permanent HBsAg clearance with or without HBsAg seroconversion after treatment completion [63]. In real-world practice, however, durable suppression of serum HBV DNA coexisting with detectable HBsAg is the expected outcome of most patients treated with NA [11,55,64].

Several large-scale epidemiological studies identify high levels of HBV DNA in the serum as a critical risk factor for HCC development in chronic HBV cases [65,66]. The REVEAL-HBV study, which followed more than 3600 HBsAg carriers for an average of 11 years, revealed an independent dose-dependent relationship between a serum HBV DNA level above 2000 IU/mL and HCC development [39]. Other HBV-related factors associated with an increased risk for HCC include specific variations in the HBV DNA sequence, the HBV genotype, mutations in the basal core promoter, and levels of quantitative HBsAg [67,68,69]. Given the close relationship between these viral characteristics and the risk for HCC, HBV replication is a logical target for preventing HCC in this setting.

The first evidence for preventing HCC with anti-viral therapy in patients with chronic HBV comes from studies with older NAs, such as lamivudine and adefovir. Liaw et al. reported that lamivudine (with a mean treatment duration of 3 years) significantly reduced the HCC risk compared to a placebo (HCC incidence 3.9% vs. 7.4%; hazard ratio (HR): 0.49; p = 0.047) [70]. A meta-analysis, including more than 6800 patients, reported similar 4-year HCC rates in lamivudine-treated and control patients [71]. However, these first-generation NAs are no longer used, mainly due to suboptimal virological responses associated with HBV resistance, which is referred to as a low genetic resistance barrier. Currently, the treatment guidelines for HBV unanimously recommend the use of ETV or TDF [56,72]. These agents are well-tolerated and have a much higher genetic resistance barrier. Their long-term use induces sustained virological suppression in the vast majority of patients (>95%), along with histological improvements and regression of fibrosis and cirrhosis [73,74]. Furthermore, cohort and population studies carried out all across the world demonstrate that long-term use (>5 years) of either ETV or TDF prevents the development of HCC in the majority of patients [11,75,76,77]. A cohort study from Hong Kong including 1225 chronic HBV patients who were treated with ETV between 2002 and 2015 compared the HCC incidence among ETV-treated patients to the expected HCC incidence calculated with well-established HCC risk scores for a patient with chronic HBV [76]. The reduction in HCC risk achieved with ETV was significant starting from year six of treatment with a standardized incidence ratio of 0.68 (95% CI: 0.535–0.866). Notably, the HCC-preventing effect of ETV was seen in both cirrhotic and non-cirrhotic patients [76].

Like HBV, active HCV infection is central to the hepatocarcinogenic process. Thus, viral elimination is the goal for the secondary prevention of HCC. In this respect, studies from the IFN era convincingly demonstrated that an SVR following IFN-based therapy reduced the risk for HCC to 0.5–1% per year (vs. 2–8% per year in untreated chronic HCV patients with cirrhosis) [12,103]. Unfortunately, an SVR to IFN-based therapy was only achieved in half of the patients. Furthermore, IFN toxicity limits its use in patients with cirrhosis.

During the last decade, IFN-free DAA drugs have revolutionized the HCV treatment landscape. An SVR is obtained with these agents in >95% of patients, and most show improvements in liver fibrosis and liver function and a reduction in portal hypertension [104]. Moreover, these agents have an excellent safety profile and minimum adverse effects and can be used in patients with decompensated liver disease. Achieving SVR is proven to be beneficial at all stages of fibrosis, including in patients with decompensated cirrhosis; however, the elimination of risk in HCC in patients with decompensated cirrhosis cannot be achieved; therefore, surveillance for HCC is extremely important for patients with advanced fibrosis or cirrhosis after achieving SVR. [105]. Bruno et al. discuss the ‘point of no return’, since disturbances to the liver architecture in decompensated cirrhosis tend to have a poor prognosis that leads to the development of HCC [106]. Box 1 provides the summary of treatment options for viral hepatitis that are under consideration or development aimed towards HCC prevention.