Prevention of hepatitis B virus-related liver cancer (Hepatocellular carcinoma)

The most effective means of preventing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) is to prevent HBV infection via global vaccination of infants. Universal vaccination of newborns has been shown to significantly reduce the incidence of HCC among Taiwanese children. Among HBV carriers, the incidence of HCC was significantly higher in those who were hepatitis B e antigen positive, suggesting that antiviral therapy that results in viral clearance or sustained suppression of HBV replication should reduce the incidence of HCC. Review of data from >1000 chronic hepatitis B patients who received interferon treatment found that interferon has no minimal overall effect on preventing HCC, but a beneficial effect may be attained in responders. The negative results are in part related to the small number of patient, short duration of follow-up and low response rate to interferon therapy. Only one prospective randomized controlled trial of antiviral therapy with incidence of HCC as an endpoint has been reported. In this trial, 651 Asian patients with compensated HBV-related cirrhosis were randomized to receive lamivudine or placebo. After a median follow-up of 32 months, HCC was diagnosed in 3.9 percent lamivudine-treated patients and in 7.4 percent placebo controls (P=0.047). Further studies using antiviral agents with lower risk of drug-resistance are needed to confirm these results. In addition, questions on who to treat and how long treatment should be administered must be addressed before recommendations on the use of antiviral therapy to prevent HBV-related HCC can be made.

There is strong evidence for an etiological association between chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). HBV along with cigarette smoking are considered the most potent environmental carcinogens. In a landmark study by Beasley et al., 22,707 Taiwanese men, of whom 3454 tested positive for hepatitis B surface antigen (HBsAg), were followed for a mean of 8.9 years; the relative risk of HCC among HBaAG carriers was found to be 98. Worldwide, chronic HBV infection is the most common cause of HCC. Therefore, the most effective means of preventing HCC is to prevent HBV infection via vaccination. The exact mechanisms by which HBV infection causes HCC are unclear. Two pathways have been proposed. One involves chronic necroinflammation of hepatocytes, cellular injury, mitosis, and hepatocyte regeneration. The other pathway evokes direct oncogenic potential of HBV through chromosomal integration (cisactivation) or transactivation of cellular genes. It is likely that both pathways contribute to HBV-related hepatic carcinogenesis. Thus, treatment that is effective in eradicating HBV or in sustained suppression of HBV replication and the accompanying necroinflammation may reduce the risk of HCC among persons who are infected with HBV.

Prevention of HBV-related HCC via HBV Vaccination

HBV vaccine is the first vaccine that has been shown to prevent cancer. A study of Taiwanese children found that the average annual incidence of liver cancer in children 6-14 years of age declined from 0.70 per 100,000 between 1981 and 1986 to 0.57 between 1986 and 1990 and to 0.36 between 1990 and 1994 (P<0.01). The decrease in incidence of HCC coincided with the implementation of a nationwide hepatitis B vaccination program for newborns and children in July 1984 and an ensuing decline in HBsAG carrier rate from 9.8 percent in 1984 to 1.3 percent in 1994 and 0.7 percent in 1999 among persons younger than 15 years of age. It is anticipated that the implementation of global vaccination of all newborns will ultimately lead to a worldwide reduction in incidence of HBV-related HCC, although it may take a few decades for the impact to be observed among adults and in countries with low or intermediate carrier rates. Using sensitive amplification assays, many studies have shown that HBV DNA persists at every low levels among persons who have serological recovery from transient HBV infection. In most instances, these low levels of HBV are not associated with liver injury, but mild hepatitis and fibrosis have been reported in some subjects more than 10 years after recovery from an acute HBV infection, and HCC has been reported in person with serological markers of recovered HBV infection. In the latter situation, it is not clear if HCC developed in individuals who recovered from acute HBV infection or in carriers who spontaneously cleared HBsAg after many decades of chronic HBV infection.

Whatever the situation may be, the risk of HCC is substantially lower in persons who are immune to HBV. Thus, in the study by Beasley et al., the incidence of HCC is substantially lower in persons compared with carriers, five versus 495 per 100,000 per year. Similarly, studies in woodchucks found that HCC developed in 100 percent of woodchucks with chronic woodchuck hepatitis virus infection but in only 17 percent of woodchucks with recovered woodchuck hepatitis virus infection and none of the noninfected woodchucks. These data indicate that robust immune response that prevents progression from acute to chronic HBV infection is associated with significantly lower risk of HCC. Because the risk of progression from acute to chronic HBV infection is highest among infants, universal immunization of infants is the most effective way of preventing chronic HBV infection and HCC.

Efficacy Of Antiviral Therapy In Preventing HBV-related HCC

Based on the foregoing discussions, antiviral therapy that results in viral clearance or sustained suppression of HBV replication and associated hepatic necroinflammation should reduce the incidence of HCC. Data in support of this hypothesis may be obtained through long-term follow-up of previously treated patients or prospective study with incidence of HCC at the end-point. Reports based on the former approach have focused on the effects of interferon therapy because the other approved treatments, lamivudine and adefovir dipivoxil, have only been available in recent years. Individual studies have in general failed to show an effect of interferon on reducing the incidence of HCC.

However, the negative results may be related to the small number of patients in each study, the low rate of antiviral response, the short duration of follow-up, the ethical and logistical difficulties in withholding treatment from controls during the course of follow-up, and the slow rate of HCC development even in untreated patients. The ultimate proof that antiviral therapy can prevent HCC in patients with chronic HBV infection relies on data from prospective randomized controlled clinical trials. Such trials will need to enroll a large number of patients with high risk of HCC followed for an adequate duration.

Conclusions

In summary, prevention of HBV-related HCC is best accomplished by preventing HBV infection via HBV vaccination. Concerted efforts among the scientific community, public health officials, and philanthropists are needed to ensure implementation of global childhood HBV vaccination. For persons who are already chronically infected, development of more effective antiviral therapies that can result in sustained suppression of HBV replication and reduction of necroinflammatory liver damage in a high proportion of patients with chronic hepatitis B will likely lead to reduction in incidence of HCC. These treatments must be safe and affordable with low risk of drug resistance. For patients who fail to achieve sustained response after a course of therapy and for patients who have advanced liver disease, there may be a role for maintenance anti-viral therapy in preventing HCC. Such treatment must have established long-term safety, be affordable, and have a low risk of drug resistance. In addition, questions on who to treat and how long treatment should be administered must be addressed before recommendation on the use of antiviral therapy to prevent HBV-related HCC can be made.