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Antiviral Therapy for Hepatitis C, Especially with Sustained Response, Lowers Liver Cancer Risk

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Interferon-based antiviral therapy lowers the likelihood that people with liver fibrosis or cirrhosis due to chronic hepatitis C will develop hepatocellular carcinoma (HCC), with the greatest risk reduction seen among those who achieve virological response, according to a study described in the October 22, 2012, edition of open-access online journal BMJ Open.

Over years or decades chronic hepatitis C virus (HCV) infection can lead to serious liver disease including fibrosis, cirrhosis (scarring), and HCC, a form of primary liver cancer. Interferon-based treatment suppresses HCV viral load and in some cases gets rid of the virus, but studies of the impact of therapy on long-term clinical outcomes have yielded conflicting data.

Nina Kimer and colleagues from Copenhagen University Hospital performed a systematic review and meta-analysis to determine whether antiviral therapy reduces the risk of developing HCC among chronic hepatitis C patients.

The researchers conducted electronic database and manual searches to find prospective cohort studies in which participants were treated with pegylated or conventional interferon, with or without ribavirin. These studies were conducted prior to the advent of direct-acting antiviral agents.

From an initial pool of 1171 potentially relevant studies, they excluded duplicates and studies that did not report the desired outcomes, leaving 8 randomized controlled trials that compared antiviral therapy versus placebo or no intervention to be included in the analysis. Some observational studies were also analyzed.

The studies were conducted in France, Italy, Spain, Japan, and the U.S., and all were published in English. Of the randomized trials, 2 included patients with cirrhosis or fibrosis, while the rest included only those with cirrhosis; 2 trials assessed pegylated interferon and 1 assessed conventional interferon plus ribavirin, while the remainder looked at interferon monotherapy. All control groups received no treatment.

Treatment duration ranged from 1 to 5 years and duration of follow-up ranged from 2.0 to 8.7 years (some studies looked at long-term interferon maintenance therapy). The included observational studies compared interferon versus no intervention for patients with cirrhosis; here duration of therapy ranged from 0.5 to 1.5 years and duration of follow-up from 5 to 7 years.

Results

  • A total of 81 out of 1156 patients assigned to receive antiviral therapy in randomized trial developed HCC, compared with 129 out of 1074 untreated control patients.
  • A random effects meta-analysis showed that antiviral therapy significantly reduced the likelihood of developing HCC, with a risk ratio (RR) of 0.53, or about half the risk.
  • The number needed to treat to prevent a single case of HCC over 5 years was 8 patients.
  • Similar results were seen when looking only at trials of patients with fibrosis (RR 0.51).
  • Antiviral therapy had a greater protective effect for patients with virological response, or undetectable HCV viral load, compared with non-responders (RR 0.15 vs 0.57, respectively).
  • Observational studies also found that antiviral treatment reduced the risk of developing HCC (RR 0.29)

"Antiviral therapy may reduce the risk of HCC in hepatitis C-related fibrosis and cirrhosis," the study authors concluded. "The effect may be seen irrespective of the virological response, but is more pronounced among virological responders compared with non-responders."

"Our subgroup analyses suggest that the antiviral therapy may have beneficial effects on the risk of developing HCC that are unrelated to the virological response," they elaborated in their discussion. "Although the intervention was more beneficial among sustained virological responders than non-responders, there was a clear effect in both patient groups."

"Chronic inflammation of the liver is critical to the development of HCC. Hepatitis C patients with cirrhosis or fibrosis are likely to have a higher degree of chronic inflammation than patients without these histological changes," they continued. "It is therefore likely that patients without fibrosis or cirrhosis have a smaller benefit of antiviral therapy than the patient population included in our analyses."

Importantly, only 2 of the included trials evaluated pegylated interferon, most did not include ribavirin, and none looked at direct-acting agents such as the recently approved HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek). Therefore, the benefits of treatment in preventing HCC would likely be even greater using modern state-of-the-art therapy.

10/30/12

Reference

N Kimer, EK Dahl, LL Gluud, and A Krag. Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C: systematic review and meta-analysis of randomised controlled trials. BMJ Open 2(5): e001313. October 22, 2012.