Interferon Treatment for Hepatitis C Prevents Hepatocellular Cancer
Abstract & commentary
Synopsis: In a large, retrospective series of hepatitis C patients, most of whom were treated with interferon, factors associated with hepatocellular cancer development were examined. Patients with pretreatment mild to moderated fibrosis, but without cirrhosis, had the greatest benefit from interferon treatment. Those with cirrhosis or high serum transaminase levels before treatment did not achieve significant benefit and the development of hepatocellular cancer was not different from those who were untreated.
Source: Yoshida H, et al. Ann Intern Med 1999;131:174-181.
Hepatitis c has become recognized as a major worldwide epidemic.1 One consequence of chronic hepatitis C infection is hepatocellular carcinoma, but for some, this outcome can be avoided by interferon therapy.2,3 It is not clear which patients benefit from this preventive measure. Thus, in a multi-institutional study within Japan, 2890 patients with chronic hepatitis C were analyzed retrospectively with regard to risk factors, interferon treatment, and cancer development.
Of the 2890 patients with hepatitis C and liver biopsies, 2400 were treated with interferon and 490 were untreated. The liver biopsies were all obtained before treatment and the degree of fibrosis was scored from F0 (no fibrosis) to F4 (cirrhosis). Response to interferon was determined virologically (hepatitis C virus RNA by RT-PCR) and biochemically (serum alanine aminotrasferase, ALT). Screening for development of hepatocellular carcinoma was performed periodically during an average follow-up of 4.3 years.
Hepatocellular carcinoma developed in 89 interferon-treated patients (1.1%) and in 59 (3.2%) untreated patients. Among the untreated patients, the annual incidence of hepatocellular carcinoma increased with the degree of liver fibrosis, from 0.5% among patients with stage F0 or F1 fibrosis to 7.9% among patients with F4 fibrosis (cirrhosis). The cumulative incidence in treated and untreated patients differed significantly for patients with F2 fibrosis (P = 0.0128) and for those with stage F3 fibrosis (P = 0.0011). Incidence in F4 patients was not affected by interferon treatment. In multivariate analysis, interferon therapy was associated with a reduced risk for hepatocellular carcinoma, especially among patients with sustained virological response, persistently normal ALT levels, or ALT levels less than two times the upper limit of normal.
Thus, Yoshida and associates conclude that their data demonstrate interferon significantly reduces the risk of hepatocellular carcinoma, especially among those who are shown to respond to treatment by improved viral load and biochemical markers.
Comment by Dan l. Longo, MD, FACP
This is a retrospective analysis with a few methodological concerns. Treatment and nontreatment groups were not randomly assigned. Details of the interferon treatment were not provided, except to note that a certain percentage (most) received interferon alpha, others received interferon beta, and still others received both. Treatment schedules, modifications, and toxicities were not detailed. More important, explanations for why the 490 individuals were (or chose to be) untreated were not included and this leads to the possible interpretation that other factors existed that would alter the risk for cancer development (e.g., alcohol use, etc.). Nonetheless, as Yoshida et al indicate, these days it would be difficult to do a randomized trial of interferon treatment with published clinical trials already indicating some level of efficacy.
The paper does provide useful, new information. Patients with hepatitis C and existing cirrhosis were shown to have a high incidence of hepatocellular carcinoma (annual incidence approaching 8%). These individuals did not have significant reduction in cancer development with interferon therapy, although there was a trend in that direction. Those patients with mild to moderate fibrosis were clearly benefited by treatment whereas those without evidence of fibrosis had such a low incidence of hepatocellular cancer even when untreated that it was impossible to detect a treatment benefit.
As is the case with cancer treatment in which patients responding to chemotherapy can often be shown to have a survival advantage, hepatitis C patients who respond to interferon (by reduced viral load or biochemical markers) are also the ones who appear to benefit in terms of reduced cancer development. In this regard, the series provides some useful guidelines. Treatment-induced sustained clearance of virus (> 6 months), which was achieved in about one-third of patients, is a strong indicator of protection from cancer development, at least for the shortterm (the median duration of follow-up in this report was only 4.3 years). Furthermore, serum ALT may prove as good a prognostic indicator as liver biopsy. The ALT levels correlated well with the absence or presence of persistent virus. The multivariate analysis revealed that the risk for hepatocellular cancer was reduced in patients with mildly elevated ALT levels (< 2 times the normal limit) by interferon treatment, but for those with ALT levels greater than twice the normal, there was no demonstrable benefit from interferon therapy. Accordingly, it should be noted that 70% of the interferon-treated patients in this series had high levels of ALT (> 2 normal) before treatment but this number decreased significantly (to 31%) after treatment.
Thus, data from this series add strength to prior reports that interferon treatment will prevent (or delay) the development of hepatocellular cancer in patients with hepatitis C. The patients who seem to benefit the most are those with mild to moderate fibrosis (F2 or F3) and pretreatment serum ALT levels that are less than two times the normal level. (Dr. Longo is Scientific Director, National Institute on Aging, Baltimore, MD.)
References
1. Pagliaro L, et al. Ital J Gastroenterol Hepatol 1999; 31:28-44.
2. Hoofnagle JH, et al. N Engl J Med 1986;315: 1575-1578.
3. Di Bisceglie AM, et al. N Engl J Med 1989;321: 1506-1510.
Which of the following statements about the treatment of hepatitis C with interferon to prevent hepatocellular cancer is true?
a. Treatment has been shown to be beneficial at a stage when liver biopsy reveals no evidence for fibrosis and serum ALT levels are normal.
b. Treatment has been shown to be beneficial at a stage when liver biopsy reveals mild to moderate fibrosis and the serum ALT levels are less than twice normal.
c. Treatment has been shown to be beneficial at a stage when liver biopsy reveals cirrhosis and serum ALT levels are more than twice normal.
d. Treatment is associated with reduced serum ALT levels and liver fibrosis but there has been no demonstrable effect on hepatocellular cancer development.
e. Treatment is too toxic for the majority of patients and leads to an unacceptable decline in quality of life.
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