Prevention of Hepatocellular Carcinoma in Interferon-Treated Viral Hepatitis Patients

ABSTRACT & COMMENTARY

Synopsis: In this analysis, patients with hepatitis B or C with associated Child's A cirrhosis were matched for prognostic factors for cancer development, and the incidence of liver tumor development was compared for those that received interferon treatment and those that didn't. Patients with hepatitis-C that were treated had less hepatocellular cancer than those that were not treated. This treatment effect was not observed in patients with hepatitis-B.

Source: International Interferon-a Hepatocellular Carcinoma Study Group. Lancet 1998;351:1535-1539.

There remains a controversy as to whether interferon treatment prevents hepatocellular cancer in patients with chronic hepatitis B or C infections. The current paper investigated this issue by a retrospective analysis of 913 patients from 21 centers in Italy and Argentina. All patients had chronic hepatitis (either B, C, or both) and Child's A cirrhosis, were positive for HbsAg or hepatitis-C-virus antibodies (anti-HCV), and had been screened yearly for at least three years by ultrasonography and a-1-fetoprotein testing. Prognostic risk factors for hepatocellular carcinoma, defined by Cox regression analysis, were used for group matching and conditional logistic regression analysis of the independent interferon-a treatment effect.

This analysis led to the conclusion that age, male sex, and portal hypertension were significant risk factors for hepatocellular carcinoma. There was a trend for hepatic inflammation and iron storage to each be risk factors, but these did not reach a level of significance for the group as a whole.

When examined with respect to interferon treatment, it was found that 66 (19%) of the untreated patients developed hepatocellular carcinoma, compared to 29 (10%) of the 281 treated patients (relative risk for no treatment, 1.99; 95% confidence interval 1.09-3.64). The corresponding proportions for anti-HCV-positive patients were 48 (18.5%) of 259 vs. 21 (9.1%) of 232 (3.14 [1.46-6.80]) and those for hepatitis B (HBV) patients were 18 (19%) of 97 patients and eight (16%) of 49 (0.98 [0.33-2.92]) patients. When examining those individuals who had serologic evidence for hepatitis-C alone (i.e., excluding hepatitis-C patients who also had hepatitis B), 29 (20%) of 129 untreated and six (5%) of 116 treated patients developed hepatocellular carcinoma (relative risk for no treatment, 6.28 [1.65-23.8]).

Thus, interferon treatment lowered the rate of progression to hepatocellular carcinoma two-fold and the risk reduction was greatest for those patients with hepatitis-C. Although interferon is effective at preventing hepatitis B-related cirrhosis and decreased hepatic function, no evidence for a preventive effect on hepatocellular carcinoma induced by hepatitis B was found.

COMMENTARY

Both hepatitis B and C can result in cirrhosis and lead to hepatocellular carcinoma. The mechanism of the hepatocarcinogenesis is unknown but probably is different for the two viruses. Hepatitis B may be directly carcinogenic because it can integrate into the genome and is known to activate genes that regulate cell proliferation.1 Hepatitis-C is an RNA virus that does not integrate into the genome, but HCV proteins can transactivate cell genes.2 Furthermore, both viruses could indirectly result in carcinoma development through liver inflammation, necrosis, and regeneration. Interferon-a therapy has resulted in clinical improvement in about one-third of hepatitis-C patients, and it has been speculated that those who respond to interferon are less likely to develop hepatic cancer.3 There are, however, several unanswered questions regarding interferon treatment, including which are the patients most likely to benefit and does immediate clinical response (e.g., reduction in hepatic enzymes, improved histology) correlate with reduced cancer development?

In this retrospective analysis of a relatively large series of patients, there are clues to the answers to some of these questions. All of the evaluated patients had serological evidence for chronic hepatitis and histologic evidence for cirrhosis. Those with abnormal blood counts were excluded, primarily because they were not considered candidates for interferon treatment. Treated and untreated patients were matched with regard to other risk factors and then evaluated for the development of progression to hepatocellular malignancy. The group as a whole had a two-fold reduction in tumor development. However, there did not seem to be a benefit in this regard for those with hepatitis-B. In contrast, those with hepatitis-C (either alone or with hepatitis-B) had less tumor development and the treatment was associated with a six-fold reduction in hepatic cancer risk for those with hepatitis-C alone.

Another finding of interest was that for hepatitis-C patients, a sustained response to therapy does not appear necessary for benefit from interferon treatment. Transient responses were most common in all groups, including those with hepatitis-C alone, and this may relate to the antiproliferative effects of interferon. This notion is supported by the finding that in those interferon-treated hepatitis-C patients that developed tumor, the mean diameter of the tumor at diagnosis was 2 cm as compared to 3 cm for non-treated patients.

Thus, it appears from this retrospective study that interferon treatment of patients with chronic hepatitis-C (but not hepatitis-B) associated with cirrhosis results in less hepatocellular carcinoma. Additional work in this area needs to confirm this finding and determine the necessary length of treatment and the effect on overall survival. Furthermore, the work highlights the need for other anti-viral approaches for chronic hepatitis-B infected patients.

References

    1. Wang J, et al. Nature 1990;343:555-557.

    2. Ray RB, et al. Virus Res 1995;37:209-220.

    3. NIH Consensus Development Conference. Hepatology 1997;26:83-108.