Family history of liver carcinoma is one of the main risk factors for HCC, especially in the Chinese population[20–22
]. In our study, 85/170 (50%) of cases had a family history of HBV-associated chronic liver diseases. However, only 92/276 (33.3%) of control subjects did.
In China, HBV DNA levels > 5.0 log10
copies/mL have been considered clinically significant, and are suggested by clinical practice guidelines for making a decision on antiviral therapy in chronic carriers of Hepatitis B. The guidelines are supported by the findings of a meta-analysis of 26 trials of statistical significance and consistent correlations between viral load and histological grading, and biochemical and serological response[23
]. However, the relationship between different levels, especially lower levels, of HBV DNA and risk of HCC remains uncertain.
During the past 10 years, longitudinal studies have been used to evaluate HBV DNA level as risk factors of HCC in HBV carriers. A significant biological gradient of HCC risk by serum HBV DNA level from 4.0 log10
to 7.0 log10
copies/mL was observed in our cohort. Similar to previous results[24
], the HCC risk started to increase significantly at a serum HBV DNA level of 4.0 log10
copies/mL, which is much lower than the level of 5.0 log10
copies/mL suggested by clinical practice guidelines for making decisions on antiviral therapy in carriers of chronic Hepatitis B. Viral loads < 4.0 log10
copies/mL have been thought to be characteristic of an inactive carrier state and a much lower risk of HCC. Moreover, it is important to know that compared to viral loads between 5.0 log10
and 7.0 log10
copies/mL, patients with HBV DNA levels > 7.0 log10
copies/mL were at lower risk of developing HCC. Chronic HBV carriers with mid-high viral loads (4.0 log10
to 7.0 log10
copies/mL) tended to be in the phase of immune clearance, while the majority of those with viral load levels of 7.0 log10
copies/mL were immunotolerant and at lower risk of HCC. Our findings are partly consistent with studies in different areas. In Japan, Ohata et al[25
] have investigated the risk factors for HCC in 73 patients with HBV-associated liver disease. A high viral load of HBV DNA, together with age and histological fibrosis, were found to be linked to the occurrence of HCC. Yang et al[26
] have reported that HCC risk increased with the increasing HBV viral load above 7.5 log10
copies/mL. They have also found that HCC risk is associated with Hepatitis B e antigen (HBeAg) positivity among HBsAg-positive men in Taiwan. Based on these results, the serum level of HBV DNA may be used as a prominent risk predictor for HCC, independent of age, histological fibrosis and HBeAg status.
To the best of our knowledge, there have been few studies on longitudinal stability of HBV DNA level in HBV carriers over time in mainland China. In the 276 control subjects in our study, all the HBV DNA levels in samples at the last visit were compared with those collected at study entry. 186/276 (67.4%) samples of control subjects had undetectable levels of serum HBV DNA at study entry, while 221/276 (80.1%) samples had undetectable levels of serum HBV DNA at the last visit. During a follow-up period of 10 years, the HBV DNA levels of those asymptomatic carriers tended to decrease. Forty-six case patients were selected whose serum samples were collected both at study entry and after the time of HCC diagnosis. Compared with serum HBV DNA levels at study entry, viral load after HCC onset remained at high levels. This implied that for chronic HBV carriers free of antiviral therapy, HCC was preceded by persistently high replication activity of HBV and viral levels did not decline with progression of HCC.
It is generally agreed that antiviral treatment is suitable in patients with active HBV replication (≥ 5.0 log10
copies/mL) and elevated ALT level (at least twice the upper limit of the normal range)[27
] or advanced fibrosis present upon liver biopsy. In clinical trials, among patients with chronic Hepatitis B and advanced stage fibrosis, longer term lamivudine therapy reduces the risk of HCC[28,29
]. Although individuals with low viral load (< 4.0 log10
copies/mL) are at decreased risk for HCC, continued monitoring is essential because of the fluctuating nature of chronic HBV infection. Treatment choices for patients with serum HBV DNA levels < 5.0 log10
copies/mL are still controversial. In our study, HBV carriers with HBV DNA levels > 4.0 log10
copies/mL have 2.834 times excess risk of HCC compared with HBV carriers with lower HBV DNA levels. Therefore, among patients with HBV DNA levels > 4.0 log10
copies/mL, liver tests should be carefully monitored at 3-4-mo intervals, irrespective of age and ALT levels. Antiviral treatment should be advised when hepatitis flares and/or advanced fibrosis is present upon liver biopsy.
In conclusion, serum HBV DNA levels were found to be associated with increased risk of HCC. For chronic HBV carriers without antiviral therapy, HBV DNA levels changed little with the progression of HCC. Based on these findings, it is conceivable that patients with a high viral load have a high potential for hepatocarcinogenesis, and should be subjected to closer clinical monitoring[30
] and even antiviral treatment.