This study represents a quantitative assessment of published data on the role of chronic HBV and HCV infections in causing HCC in China. The studies included differed widely in their OR estimates for each infective marker. Even after grouping the studies by geographical area and type of controls, we found significant differences within subgroups. However, in almost all studies, we found a strong association between HCC and positivity for both HBsAg and anti-HCV/HCV RNA, with summary OR 14.1 for HBsAg positivity and 4.6 for anti-HCV/HCV RNA positivity. In 1994, Zhao et al (1994)
reported a summary OR for HBsAg positivity in HCC in China of 13.43, rather similar to our finding, indicating that the strength of the association in China has not altered much in the last decade. In 1998, Donato et al
reported a summary OR for HBsAg positivity in HCC worldwide of 13.7, little different from that in western countries.
In 1997, Ge et al (1997)
reported a summary OR for anti-HCV positivity in HCC in China of 6.7 and other workers reported a summary OR worldwide of 11.5 (Donato et al, 1998
), while the summary OR in the present analysis of 4.6 was significantly lower than these. This is mainly due to the fact that the ORs for anti-HCV/HCV RNA positivity in HCC of most studies after 1997 were not high, especially in the larger of the studies (Yu et al, 1997
; Gao et al, 1998
; Li et al, 1999
; Ding et al, 2004
). The studies performed before 1997 mainly used the first or second generation anti-HCV test with low sensitivity and specificity, while since then third generation anti-HCV test and RT–PCR have been widely used with improved sensitivity and specificity. The OR for HBsAg positivity and for anti-HCV/HCV RNA positivity using hospital controls in this analysis were 10.5 and 4.4, both lower than the corresponding estimates using community controls (18.0 and 4.7), probably because chronic infections by HBV and HCV were more prevalent in hospital patients than those in the general population (Donato et al, 1998
The above studies did not evaluate the dual infection by HBV and HCV as in our analysis. The OR for HBsAg positivity anti-HCV/HCV RNA negativity and for HBsAg negativity anti-HCV/HCV RNA positivity in this analysis were 15.6 and 8.0, respectively. Although these indicate a strong association between each infection alone and HCC in China, the corresponding ORs worldwide of 22.5 and 17.3 were significantly higher, especially for HCV, showing that the risk is higher in western countries. In fact, the proportion of HCC patients for anti-HCV/HCV RNA positivity was 19.13% among HBsAg positive patients and 28.01% among HBsAg negative patients, and the corresponding proportions worldwide were 19.3 and 35.8% (Donato et al, 1998
), which also supported the results. All the above results indicate that chronic infection by HBV and HCV alone were independent high risk factors for HCC.
The proportion showing positivity for both HBsAg and anti-HCV/HCV RNA in HCC patients was 13.78% in the studies overall, 12.13% in studies using hospital controls and 15.88% in studies using community controls, while the proportion in controls overall was only 1.37% (Donato et al, 1998
). The proportion of positivity for both HBsAg and anti-HCV/HCV RNA has been reported as 6.29% in HCC patients and 0.20% in controls, and showed that the dual infection rate by HBV and HCV in China was higher than that in western countries both in cases and controls. As China is a hyperepidemic area for HBV, HCV and HCC, the above results suggested a close relation between HCC and the dual infection by HBV and HCV. Our OR for positivity for both HBsAg and anti-HCV/HCV RNA was 35.7 in the studies overall, 44.9 in studies using hospital controls and 39.5 using community controls. Donato et al (1998)
reported a corresponding overall OR of 135, 34.6 for hospital controls and 420 using community controls, which differ appreciably from our results. The low sensitivity and specificity of anti-HCV testing in early years and low dual infection rate by HBV and HCV in western countries might account for the differences. Donato et al (1998)
reported only 14 persons positive for both HBsAg and anti-HCV/HCV RNA in 6988 controls, whereas there were 55 ones in 4005 controls in this analysis, showing that the dual infection rate by HBV and HCV in general population in China was significantly higher than that in western countries (1.37 vs
In this analysis, the OR for positivity for both HBsAg and anti-HCV/HCV RNA was higher than the sum of the OR for HBsAg positivity anti-HCV/HCV RNA negativity and for HBsAg negativity anti-HCV/HCV RNA positivity, 35.7 vs 23.7 in total studies, 44.9 vs 17.8 in studies using hospital controls and 39.5 vs 31.0 in studies using community controls. All the results mentioned above indicate that the concurrent infection by HBV and HCV was associated with a much higher risk of HCC than each infection alone in China, pointing to a synergism between HBV and HCV in HCC. We did not find significant differences between the results in higher and lower incidence areas, probably owing to the diversity of risk factors for HCC in China, such as aflatoxin intake, drinking pond water, eating pickle, etc.
The different mechanisms that have been hypothesised as being associated with development of HBV- or HCV-related cancer suggest that both viruses could play an active role at different steps of the carcinogenic process when they are present together in hepatocytes. Most evidence suggests that HBV is capable of initiating the neoplastic process, while HCV could act as a promoter, and that they may be synergistic in causing HCC (Donato et al, 1998
As meta-analyses are based on published studies, bias and confounding factors may be present (Egger and Smith, 1998
). The interaction of other risk factors with HBV and HCV infections was not studied in this analysis. Bias and potential confounding factors may not be well controlled due to the limited details in the literature, and may therefore slightly affect the results. For more accurate results, further studies are required.