The present study provides a comprehensive estimation of HCC risk according to HBV and HCV mono- and coinfection, using data from a community-based prospective cohort study in an area of Korea where HCC incidence is high. HBV is by far the most important risk factor for HCC in Korea. To our knowledge, this is the first study to explore the risk of HCV and discover the synergistic effect of HBV/HCV coinfection for HCC in a prospective cohort study in the general Korean population. Furthermore, in the current study it was evident that HCV genotype 1b increased HCC risk significantly more than genotype 2.
The role of chronic infection with HBV in the etiology of HCC is well established
[1, 2]. A community-based prospective cohort study titled the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study in Taiwan has reported high serum HBV DNA level, HBV genotype C, precore G1896A mutant and basal core promoter A1762T/G1764A double mutant as predictors of HCC risk
[9, 27]. The adjusted HR (13.7) of HCC by HBsAg positivity in the present study was compatible with previous study results, including two recent meta-analyses: one that included 37 case–control and 10 cohort studies conducted worldwide
, and another that used Korean data
. In addition, the risk of HCC by HBV infection was around two-fold higher than by HCV infection in present study.
One recent meta-analysis estimated the RR of HCC to be as much as 12-fold higher in people infected with HCV
. However, in Korea, there was no report of the RR of HCV, although some case–control studies reported odds ratios for HCV
[28–30], and a meta-analysis reported a pooled odds ratio of HCC of 11.5 for anti-HCV-positive individuals
. In this respect, the present study contributes more evident data on the effect of HCV infection on HCC risk in Korea to the scientific literature by reporting RRs from a prospective cohort study, although the RR of HCC by anti-HCV positivity was lower than expected.
The synergistic effect of HBV/HCV coinfection on HCC risk (SI=4.5, 95% CI=1.3-15.5) identified in this study was another meaningful finding. Indeed, HBV/HCV coinfection is not uncommon, particularly in countries with a high prevalence of HBV or HCV, as the two viruses share with some modes of transmission
It was not clear if there is a risk difference between HCV genotype 1 and 2 regarding the previous studies in Korean, even though HCV genotype 1b and 2a are dominant. The present study suggested that the HR of HCC was significantly higher in individuals infected with HCV genotype 1 (adjusted HR=29.7, 95% CI=13.6-46.8) than genotype 2 (adjusted HR=2.2, 95% CI=0.3-16.2). This strongly supports the results from a recent meta-analysis, which suggested that subjects infected with HCV genotype 1b had almost double the HCC risk of those infected with other HCV genotypes
. Moreover, the present study showed multiplicative increase in HR of HCC in individuals who had mixed infection with HCV genotype 1 and 2 (adjusted HR=68.7, 95% CI=16.4-288.4), compared to HR of solitary genotype 1 or 2 infection. To the best of our knowledge, our study is the first to show this multiplicative relationship. HCV genotype is an important determinant of the virologic response to HCV treatment, whereas differences in disease pathogenesis among genotypes may also exist. Genotype 1 is associated with a more aggressive disease, worse response to therapy, and higher risk of cirrhosis and HCC development
. There are limited studies on HCV mixed genotype infection among high-risk individuals
[31, 32] but pathogenecity of mixed infection and its effect on disease progression and treatment have not yet been elucidated. On the other hand, HBV genotype was not evaluated in the present study as genotype C was predominant (99%) among the HBV genotypes in Koreans
[16–18]. In the REVEAL study, HBV genotype C showed higher risk of developing HCC (aRR=1.76; 95% CI=1.19-2.61) and cirrhosis compare to HBV genotype B
There is convincing evidence that alcohol drinking and tobacco smoking increase the risk of primary HCC
[34–36] and synergistic effects between hepatitis infection and tobacco smoking or alcohol drinking in the development of HCC has been recently suggested
[37–41]. Heavy alcohol drinking significantly elevated HCC risk after adjustment in this study. Tobacco smoking elevated HCC risk in the crude analysis, but was not significant after adjustment. Neither FBS level or obesity were related to HCC risk in this study, although there is growing evidence suggesting that obesity and diabetes mellitus (DM) might be independent risk factors for HCC
[20, 39, 42–45]. There was a substantial amount of missing information on FBS (27% of the study population). However, the HCC risk was not statistically significant (aHR=1.7, 95% CI=0.9-3.4) in the group of unknown FBS. In addition, the HCC risk was not elevated among subjects with DM history, as a proxy of FBS in the independent regression analysis (data not shown). Insignificant result of DM and obesity in risk of HCC development may be due to predominant role of HBV and HCV as a risk factor of HCC in this study population. Dietary ingestion of aflatoxins, one of the risk factor of HCC in developing countries, is very rare in Korea.
The present study offers comprehensive scientific evidence on the effect of HBV and HCV infection, as well as some other potential risk factors, on HCC development. Nevertheless, it has several limitations that should be considered when interpreting its data. Firstly, the size of the case population was not very large (50 HCC cases). In particular, a very small number of HCC cases were identified in each category of HCV genotype, including only 1 HCC case in the group infected with HCV genotype 2. Coinfection with HCV genotype 1 and 2 showed higher HR than genotype 1 alone, but their 95% CI were very wide and overlapping due to small number of HCC cases. However, considering the relatively lower prevalence of HCV infection in Korea, and the results of this community-based long-term prospective follow-up study are valid enough to support a causal relationship. Secondly, the risk factors were investigated at cohort enrollment, with no repeated measure. Thus there were no considerations of updated information for changes in infection status, interventions for liver diseases and/or health behaviors that took place after study recruitment. Thirdly, viral load of HBV and HCV infection was not evaluated in this study. Serum HBV DNA level is a major predictor of HCC development
. Patients with a high viral load of HCV respond poorly to interferon therapy
 and had a significantly higher HCC risk (RR, 2.35; 95% CI, 1.02-5.43) than did those with a low viral load after interferon treatment
. However the current study could not provide HCC risk by viral load of HBV and HCV.
Compared to hospital-based case–control studies in Korea (HBsAg 65.4-72.3%; anti-HCV 7.6-19.3%)
[28–30], the seroprevalence of HBsAg (39.1%) and anti-HCV (32.6%) among HCC cases in the present study was relatively low. Although the serological evidence of chronic infection with HBV and HCV remains relatively constant over time, there is a possibility that infection status can change between baseline and at diagnosis of HCC. Otherwise occult HBV or HCV infection may exist in HCC cases that are negative for markers of HBV and HCV infection. Recently there has been growing evidence of occult HBV and HCV infection. Occult HBV infection was found in 0.7% of HBsAg-negative individuals in the general adult population in Korea
. Although the mechanism and clinical implications have not yet been elucidated, occult HBV infection can also be transmitted and may contribute to the development of HBV-associated diseases such as HCC
Nevertheless, this study also has much strength. It is a prospective community-based cohort study that was able to link to a national cancer registry to evaluate the causal relationship of HBV, HCV and other behavioral risk factors with HCC development, while all previous cohort studies reporting the RRs of HCC by viral hepatitis infection have used secondary data (i.e., medical insurance claims) and included no information about HCV infection and related behavioral risk factors (e.g., blood transfusion and acupuncture)
[45, 51, 52]. In addition, the present study provides additional evidence on HCC in an HBV endemic area with comprehensive analyses of HCV infection, especially for different HCV genotypes and coinfection with HBV.