We think it’s unlikely that there’s a direct carcinogenic effect associated with hepatitis C, and certainly there’s no viral integration. It’s much more likely that the mechanisms of hepatocarcinogenesis are indirect, through inflammation, fibrosis, and cirrhosis.— Adrian M. Di Bisceglie, MD
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Chronic viral hepatitis is a major causative factor for hepatocellular carcinoma, but antiviral therapy might reduce the incidence of hepatocellular carcinoma by preventing or eliminating chronic hepatitis infections, according to Adrian M. Di Bisceglie, MD, Professor of Internal Medicine at Saint Louis University Liver Center in St. Louis, Missouri.1
Worldwide, chronic viral hepatitis accounts for nearly 75% of all cases of hepatocellular carcinoma. About 55% of cases are associated with hepatitis B infection, 30% are associated with hepatitis C infection, and 14% are related to metabolic liver disease. Despite popular belief, alcohol use is not a major contributor to hepatocellular carcinoma, accounting for only about 0.8% of cases, he noted.
“Hepatocellular carcinoma is interesting to me because in almost every case, you can point to the direct etiology,” said Dr. Di Bisceglie at the 2017 American Association for Cancer Research (AACR) International Conference on New Frontiers in Cancer Research, held recently in Cape Town, South Africa.
Global Burden of Hepatitis B
About 400 million people worldwide are chronically infected with hepatitis B, resulting in about a half-million deaths each year. “In the United States, hepatitis B prevalence is only about 0.4%, but the Centers for Disease Control and Prevention has pointed out that our cases of chronic hepatitis B are, essentially, imported,” he explained. Chronic infection of individuals who acquire hepatitis B in the United States is essentially disappearing, but the number of cases coming to the country is growing substantially, mostly from parts of Asia and Africa.
According to Dr. Di Bisceglie, the mechanisms of hepatocarcinogenesis associated with hepatitis B are not well known, despite several decades of study, but are thought to be either direct (by transactivation or viral integration) or indirect (via inflammation, fibrosis, or cirrhosis). In the REVEAL study of a cohort of individuals infected with hepatitis B,2 high viral load was shown to be associated with an increased incidence of hepatocellular carcinoma, which led to the question: “If you lower the viral load with antiviral therapy, does it reduce your risk of cancer?”
Antiviral therapy against hepatitis B has largely evolved away from using interferon alfa. The nucleoside analog lamivudine and antiviral agents entecavir and tenofovir are now widely used to control hepatitis B. In the only large, prospective, randomized, placebo-controlled trial of antiviral therapy for patients with hepatitis B and advanced liver disease, 3.9% of patients receiving lamivudine developed hepatocellular carcinoma compared to 7.4% on placebo (P = .047).3 Data supporting the use of entecavir and tenofovir for the prevention of hepatocellular carcinoma are controversial, but both agents appear to be highly effective in controlling hepatitis B infection, he noted.
Chronic Hepatitis C Infection
Hepatitis C is now the single largest cause of infectious disease death in the United States, recently surpassing infection with the human immunodeficiency virus. About 2,700,000 people in the United States have chronic hepatitis C infection, and about 17,000 new cases per year are seen, resulting in about 10,000 deaths annually.
“We think it’s unlikely that there’s a direct carcinogenic effect associated with hepatitis C, and certainly there’s no viral integration,” he said. “It’s much more likely that the mechanisms of hepatocarcinogenesis are indirect, through inflammation, fibrosis, and cirrhosis. And it’s these patients with cirrhosis who go on to get hepatocellular carcinoma and die from their disease.”
Chronic hepatitis C infection is associated with about 30% of hepatocellular carcinoma cases worldwide, but in some regions, including Europe and the United States, it is the leading underlying cause of the disease. Substantial evidence suggests that effective treatment of hepatitis C can reduce the risk of hepatocellular carcinoma.
The HALT-C trial enrolled more than 1,000 patients with hepatitis C and advanced fibrosis to receive either long-term maintenance therapy with low-dose peginterferon alfa or no treatment at all for a period of 4 years.4 An analysis of liver-related outcomes after 7 to 8 years of follow-up among patients who did not respond to therapy showed that patients who achieved viral cure had significantly lower rates of hepatic decompensation and hepatocellular carcinoma than those who did not respond to interferon.5 This suggests that in patients with chronic hepatitis C infection, viral clearance through the use of interferon-based therapies may reduce the risk of not only progression in liver disease, but also hepatocellular carcinoma.
“One hypothesis to explain this is that viral clearance is associated with the sudden loss of an inflammatory response that allows new tumors to develop and grow. The virus is gone, so there’s no need for an inflammatory response,” he said. “Or, we are now treating patients with much more advanced liver disease and therefore a higher likelihood of developing hepatocellular carcinoma.”
He explained that hepatitis C virus therapies have evolved away from the use of interferon-based treatment to direct-acting antiviral agents. Recently, concern has been raised about what may be an increased rate of hepatocellular carcinoma after viral clearance with direct-acting antivirals compared to what had previously been seen with interferon-based therapies.
According to Dr. Di Bisceglie, antiviral treatment for viral hepatitis appears to have benefits in decreasing the risk of hepatocellular carcinoma in chronically infected patients. The benefit is most pronounced in patients with chronic hepatitis C and more marginal in patients with chronic hepatitis B, for which antiviral therapy usually results in viral suppression rather than elimination. Additionally, patients with hepatitis C and cirrhosis should be continuously monitored, even after they are cured of their hepatitis C infection, he said. ■
Disclosure: Dr. Di Bisceglie has served as a consultant to AbbVie, Bristol-Myers Squibb, and Gilead; and his institution has received research funding from these same companies, which market drugs to treat hepatitis C and hepatitis B.
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