Factors Associated with Development of Hepatocellular Carcinoma in Chronic Hepatitis B Patients

By Liz Highleyman

Over years or decades, people with chronic hepatitis B virus (HBV) infection may progress to advanced liver disease including cirrhosis and hepatocellular carcinoma (HCC).

HCC has a high mortality rate, in part because it is often diagnosed at an advanced stage. Knowing which hepatitis B patients are at greatest risk could allow for more targeted liver cancer screening. Pre-existing cirrhosis and a specific HBV mutation increase the risk for HCC, according to 2 studies presented at the recent 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) in Copenhagen.

HCC in Younger Patients

Since liver disease progression typically takes many years, people with HCC are usually older than 40 years of age. In the first study, C.J. Chen and colleagues evaluated the risk of HCC among participants in the REVEAL-HBV cohort who were younger than 40 at the time of enrollment into the cohort.

The analysis included 1216 patients. The median age was 35 years and a majority (62%) were men. Within this group, 280 (23%) were hepatitis B "e" antigen (HBeAg) positive and 12 (1%) had cirrhosis. 60% had serum ALT < 15 IU/L, 33% had 15-44 IU/L, and 6% had > 45 IU/L. About one-fifth (22%) had undetectable HBV DNA (< 300 copies/mL), 31% had 300-9999 copies/mL; 16% had 10,000-99,999 copies/mL, 9% had 100,000-999,999 copies/mL, and 22% had > 1,000,000.

Results

Over a median 12 years of follow-up (reflecting 14,393 person-years [PY]), 16 patients -- all men -- developed HCC.

This represented an incidence rate of 111 per 100,000 PY of follow-up.

Elevated serum ALT and liver cirrhosis were independent predictors of HCC.

Compared with a serum ALT < 15 IU/L, patients with baseline ALT 15-44 were 3 times more likely to develop HCC (adjusted hazard ratio [HR] 3.0), while those with ALT > 45 were about 8 times more likely (adjusted HR 8.3).

Liver cirrhosis at baseline was also associated with an increased risk of HCC (adjusted HR 12.5).

Alcohol consumption, older age, higher serum HBV DNA, and HBeAg positive status were all associated with a trend towards higher HCC risk, but these did not reach statistical significance.

"The overall risk of developing HCC in subjects below age 40 over a 12 year follow up was very low in this cohort," the investigators concluded. "The strongest risk predictor is the presence of cirrhosis, already present in a small number of these young subjects."

Genomics Research Center, Academia Sinica, Taipei, Taiwan; Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan; Research and Development, Bristol-Myers Squibb Company, Wallingford, CT.

Pre-S Deletion

A.P. Yeung and colleagues looked at the role of pre-S deletions in the HBV genome and HBeAg status in the development of HCC. Recent case-control studies have suggested that HBV pre-S/S mutations are associated with HCC, the researchers noted as background, but these patients were not matched for age, sex, and HBeAg status.

In the present analysis, the researchers investigated the association between pre-S deletions and HCC using both a matched case-control approach and a longitudinal approach. In addition, they also looked at the association between pre-S deletions and HBeAg seroconversion.

The study included 117 chronic hepatitis B patients with HCC and 117 without HCC, matched with regard to age, sex, and HBeAg status. Serum samples collected 1 to 7 years before development of HCC were assessed in 16 HCC patients with pre-S deletions.

HBV pre-S deletions were also determined in 76 chronic hepatitis B patients without HCC 1 to 8 months (median about 6 months) before HBeAg seroconversion and 2 to 8 months (median about 6 months) after seroconversion.

Results

Pre-S deletions were detected in 33 out of 117 patients with HCC (28%).

Nucleotide sequence analysis of 78 HCC/non-HCC matched pairs showed that 26 patients with HCC (33%) and 15 (19%) without HCC acquired pre-S deletions.

In the longitudinal study, pre-S deletions were absent in 4 case patients (25%) before they developed of HCC.

In the second analysis, 7 of 76 patients (9%) had newly emergent pre-S deletions after HBeAg seroconversion, while 5 (7%) had pre-S deletions before HBeAg seroconversion.

In conclusion, the investigators stated, "These findings suggested that pre-S deletions were associated with HCC development.

"25% of HCC patients had developed pre-S deletions within 1 year before the occurrence of HCC," they continued. "However its association with HBeAg seroconversion was not clear."

The researchers are currently conducting further research to validate these findings in a larger number of patients.

Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong S.A.R., China

6/2/09

References

CJ Chen, HI Yang, J Su, and others. Risk and Predictors of HCC in People Less than 40 Years of Age: Update from the REVEAL HBV Study. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

AP Yeung, DKH Wong, J Fung, and others. Association of Hepatitis B Virus Pre-S Deletions with the Risk of Development of Hepatocellular Carcinoma. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

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15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
Coverage by HIV and Hepatitis.com - February 8 - 11, 2009, Montreal
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