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AASLD 2012: Nucleoside Analogs Reduce Hepatitis B Liver Cancer Risk, Cirrhosis Remains a Concern


Treatment of chronic hepatitis B with nucleoside/nucleotide analogs including lamivudine (Epivir-HBV) and entecavir (Baraclude) can reduce the risk of developing hepatocellular carcinoma, including cancer recurrence after successful resection, according to studies presented at the recent American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) and published in the Journal of the American Medical Association.

Over years or decades, chronic hepatitis B virus (HBV) 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 can trigger abnormal cell growth.

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

As described at an oral session on liver cancer at the AASLD meeting and in the November 14, 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 HBV-related liver cancer who underwent curative resection. More than 80% were men and the mean age was about 55 years. Patients with hepatitis C coinfection and those who had undergone previous HCC treatment or liver transplantation were excluded. Data on HBV viral load and liver function were not available, but the researchers noted that Taiwan's national health program only reimburses nucleoside analogs for people considered to be at high risk for liver disease progression.

Wu's team compared therisk of tumor recurrence between people taking nucleoside analogs and those not taking antiviral drugs. In the treated cohort, 487 patients received just 1 nucleoside analog, including 159 who took lamivudine, 292 who took entecavir, and 36 who took telbivudine (Tyzeka); the rest received more than 1 nucleoside drug. Treated participants used antiviral therapy for a mean duration of 1.5 years.


  • People treated with nucleoside analogshad a significantly lower risk of HCC recurrence and death than untreated patients, despite a higher prevalence of liver cirrhosis:

o   Liver cirrhosis: 48.6% treated vs 38.7% untreated;

o   HCC recurrence: 20.5% vs 43.6%, respectively;

o   Overall mortality: 10.6% vs 28.3%, respectively.

  • After adjusting for competing causes of mortality, treated patients had a significantly lower 6-year HCC recurrence rate (45.6% vs 54.6%, respectively).
  • 6-year overall mortality rates were 29.0% for treated patients compared with 42.4% for untreated individuals.
  • The primary identifiable causes of death for both nucleoside-treated and untreated patients 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 included:

o   Nucleoside analog use: hazard ratio (HR) 0.67, or 33% risk reduction;

o   Statin use (drugs typically used to manage elevated blood lipid): HR 0.68, or 32% risk reduction;

o   Non-steroidal anti-inflammatory drug (NSAID) or aspirin use: HR 0.80, or 20% risk reduction.

  • A stratified analysis showed that these associations were seen in all patient sub-groups, including those without liver cirrhosis.

Based on these findings, the researchers concluded, "Nucleoside analog 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 NSAIDs or aspirin.

In an accompanying editorial, Anna Lok from the University of Michigan at Ann Arbornoted that surgical resection is the treatment of choice for HCC patients with solitary tumors and no evidence of cirrhosis. While only 5% of HCC cases in western countries exhibit this pattern, it reaches 40% in Asia, where HBV is endemic and is the primary cause of liver cancer.

HCC recurrence after resection is common, occurring in 50% to 70% of patients within 5 years. Early recurrence is usually due to metastasis from the original primary tumor, Lok explained, while late recurrence is often due to newly developed primary tumors in people with ongoing active HBV infection or cirrhosis.

"Given the long interval between cell damage, malignant transformation, and tumor development, it is unrealistic to expect that administration of antiviral therapy for 1 to 2 years can prevent HCC recurrence, particularly because early recurrence is likely due to previously undiscovered metastasis from the primary tumor," Lok wrote.

"However, nucleoside/nucleotide analogs 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 analogs may prevent de novo primary tumors and further progression of liver disease, thereby decreasing late HCC recurrence and long-term mortality."

Risk Factors for HCC

At the Liver Meeting, Tetsuya Hosakafrom Toranomon Hospital in Tokyo and colleagues presented findings showing that long-term treatment with entecavir reduces HCC incidence in chronic hepatitis B patients. This retrospective cohort study included 472 formerly treatment-naive hepatitis B patients who received entecavir and 1568 untreated patients.

About 3% of participants in the entecavir group developed liver cancer over a mean follow-up period of about 3 years, compared with about 14% of untreated patients over about 10 years of follow-up. Cumulative 5-year HCC rates were about 4% and about 12%, respectively. In a multivariate analysis, entecavir use significantly reduced the risk of HCC (HR 0.40. or 60% risk reduction).

"Long-term entecavir treatment reduces the incidence of HCC in chronic hepatitis B patients," the researchers concluded. "The treatment effect was greater in patients with higher risks."

However, other studies presented at the meeting found that antiviral treatment does not always do the trick.

Liu-Qing Yang from the Third Affiliated Hospital of Sun Yat-Sen University in Guangzhou, China, and colleagues conducted a retrospective/prospective cohort study of more than 500 chronic hepatitis B patients treated with nucleoside/nucleotide analogs who were followed from 2007 through March 2012.

A total of 22 cases of HCC were diagnosed, most presenting with small single tumors. All patients who developed HCC had cirrhosis, and a multivariate analysis showed that baseline cirrhosis before starting antiviral therapy was the only independent risk factor for HBV-related HCC in this study. Antiviral treatment for 1-2 years did not significantly reduce the risk of HCC, even for patients with good virological and biochemical (ALT normalization) response.

Finally, Adriano Pellicelli and fellow investigators with the Italian CLEO Group (Gruppo Epatologi Ospedalieri) studied the effect of liver fibrosis on development of HCC in hepatitis B "e" antigen (HBeAg) negative patients receiving nucleoside/nucleotide analog treatment.

This retrospective/prospective analysis looked at HCC incidence among people with HBV genotype D -- the predominant type in Southern and Eastern Europe and the Middle East -- treated with nucleoside/nucleotide analogs for at least 18 months, with a median of about 60 months.

During follow-up, 2 people without cirrhosis developed HCC, for an incidence rate of 0.36 per 100 person/years, compared with 20 cases among patients with compensated cirrhosis, an incidence rate of 4.80 per 100 person/years.

In a multivariate analysis, only age > 60 years (HR 4.85, or about 5-fold higher risk) and liver cirrhosis were independent predictors of developing HCC, with cirrhosis increasing the risk by about 13-fold (HR 13.3). Lack of virological response and resistance to nucleoside/nucleotide analogs upped HCC risk somewhat, but the difference did not reach statistical significance.

"Long-term therapy with [nucleoside/nucleotide analogs] does not eliminate HCC risk in HBeAg negative genotype D patients with liver cirrhosis," the researchers concluded.

Taken together, these studies indicate that although HCC can occur in the absence of advanced fibrosis, cirrhosis is a key risk factor. Short-term treatment with nucleoside/nucleotide analogs may not be enough to diminish HCC risk, but long-term therapy can reduce the likelihood of both initial liver cancer and HCC recurrence after resection. Early antiviral therapy that prevents advanced fibrosis or cirrhosis from developing in the first place may have an even greater beneficial effect.



C-Y Wu, Y-J Chen, HJ Ho, et al. Association Between Nucleoside Analogues and Risk of Hepatitis B Virus-Related Hepatocellular Carcinoma Recurrence Following Liver Resection. Journal of the American Medical Association 308(18):1906-1913. November 14, 2012.

C-Y Wu, Y-C Hsu, and J-T  Lin. Effect of lamivudine on hepatitis B virus-related hepatocellular carcinoma following liver resection: a nationwide experience in Taiwan. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 166.

AS Lok. Does Antiviral Therapy Prevent Recurrence of Hepatitis B Virus-Related Hepatocellular Carcinoma After Curative Liver Resection?(Editorial) Journal of the American Medical Association 308(18):1922-1924. November 14, 2012.

T Hosaka, F Suzuki, M Kobayashi, et al.Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with chronic hepatitis B. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 357.

L-Q Yang, X-Y Li, Y Wu, and Y Chong. Risk Factor Analysis of HCC for Chronic Hepatitis B Patients with Nucleos(t)ide Analogues Therapy. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 344.

A Pellicelli, P Vignally, E Mazzoni, et al. Impact of liver fibrosis in development of hepatocellular carcinoma in HBeAg negative genotype D patients with chronic hepatitis B treated with nucleos(t)ide analogues. 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 21.

Other Source

JAMA. Patients With HBV-Related Liver Cancer Who Receive Antiviral Therapy Have Lower Risk of Tumor Recurrence. Media advisory. November 12, 2012.