Nucleoside analogues reduce hepatitis B liver cancer risk

Treatment of chronic hepatitis B with nucleoside analogues including lamivudine (Epivir) and entecavir (Baraclude) can reduce the risk of developing hepatocellular carcinoma, including cancer recurrence after successful resection surgery, according to data presented at The Liver Meeting 2012, the 63^rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), and published in the Journal of the American Medical Association.

Over years or decades, chronic hepatitis B infection can lead to severe liver disease including advanced fibrosis, cirrhosis and hepatocellular carcinoma (HCC), a form of primary liver cancer. It is thought that the liver's ongoing attempt to repair itself after injury triggers abnormal cell growth.

Chun-Ying Wu from National Yang-Ming University in Taipei and colleagues looked at the effect of hepatitis B treatment on HCC recurrence following curative resection, or successful surgical removal of liver tumours. Although resection is amongst the most effective HCC treatments for people with isolated tumours, liver cancer recurs at least half the time.

As described at an oral session on liver cancer at The Liver Meeting and in the 14 November 2012 Journal of the American Medical Association, the researchers conducted a nationwide cohort study using data from the Taiwan National Health Insurance Research Database collected between October 2003 and September 2010.

Out of a total 100,938 newly diagnosed HCC patients, they identified 4569 with hepatitis B-related liver cancer who underwent curative resection. More than 80% were men and the mean age was about 55 years. Data on HBV viral load and liver function were not available, but the researchers noted that Taiwan's national health programme only reimburses nucleoside analogues for people considered to be at high risk for liver disease progression.

Wu's team compared the risk of tumour recurrence between people taking nucleoside analogues and those not taking antiviral drugs. In the treated cohort 487 patients received just one nucleoside analogue, including 159 who took lamivudine, 292 who took entecavir and 36 who took telbivudine (Sebivo or Tyzeka); the rest received more than one nucleoside drug. Treated participants used antiviral therapy for a mean duration of 1.5 years.

People treated with nucleoside analogues were found to have a significantly lower risk compared with untreated people for HCC recurrence (21 vs 44%, respectively) and death (11 vs 28%), despite having a higher prevalence of liver cirrhosis (49 vs 39%).

After adjusting for competing causes of death, nucleoside analogue-treated patients had a significantly lower six-year HCC recurrence rate compared with untreated individuals (46 vs 55%, respectively). Six-year overall mortality rates were 29% for treated patients compared with 42% for untreated people.

The primary identifiable causes of death for both nucleoside-treated and untreated people were HCC or HCC treatment-related mortality, liver cirrhosis, sepsis and pneumonia.

In a multivariate analysis, factors independently associated with reduced risk of HCC recurrence were use of nucleoside analogues (hazard ratio [HR] 0.67, or 33% risk reduction), use of statin drugs (HR 0.68) and use of non-steroidal anti-inflammatory drugs or aspirin (HR 0.80). These associations were seen in all patient sub-groups, including those without liver cirrhosis.

Based on these findings the researchers concluded, "Nucleoside analogue use was associated with a lower risk of HCC recurrence among patients with HBV-related HCC after liver resection."

In their discussion, they noted that, while prior studies had linked statin use and lower liver cancer risk, this study was the first to see such an association for non-steroidal anti-inflammatory drugs or aspirin.

In an editorial accompanying the JAMA report, Anna Lok from the University of Michigan at Ann Arbor noted that surgical resection is the treatment of choice for HCC patients with solitary tumours and no evidence of cirrhosis. HCC recurrence after resection is common, however, occurring in 50 to 70% of patients within five years. Early recurrence is usually due to metastasis from the original primary tumour, whilst late recurrence is often due to newly developed primary tumours in people with ongoing active HBV infection or cirrhosis.

"Given the long interval between cell damage, malignant transformation and tumour development, it is unrealistic to expect that administration of antiviral therapy for one to two years can prevent HCC recurrence, particularly because early recurrence is likely due to previously undiscovered metastasis from the primary tumour," Lok wrote.

"However, nucleoside/nucleotide analogues may decrease short-term mortality after liver resection, particularly among patients with underlying cirrhosis, high levels of HBV replication or active hepatic inflammation", she continued. "For patients who do not experience early HCC recurrence, continued therapy with nucleoside/nucleotide analogues may prevent de novo primary tumours and further progression of liver disease, thereby decreasing late HCC recurrence and long-term mortality."