Original article
Pancreas, biliary tract, and liver
Effect of Nucleos(t)ide Analogue Therapy on Risk of Intrahepatic Cholangiocarcinoma in Patients With Chronic Hepatitis B

https://doi.org/10.1016/j.cgh.2017.09.031Get rights and content

Background & Aims

Chronic infection with hepatitis B virus (HBV) increases risk of intrahepatic cholangiocarcinoma (ICC), but it is not clear whether antiviral therapy reduces risk. We investigated the association between nucleos(t)ide analogue therapy and ICC risk.

Methods

We performed a nationwide long-term cohort study using Taiwan’s National Health Insurance Research Database to obtain data on 185,843 patients with chronic HBV infection from October 1, 2003 through December 31, 2012. We excluded patients with confounding disorders such as infection with hepatitis C virus, HIV, or other hepatitis-associated viruses; liver flukes; biliary stone diseases; cholangitis; congenital biliary anomalies; biliary tract surgeries; or cancer. We identified 10,062 patients who received nucleos(t)ide analogue therapy (the treated group), and used propensity scores to match them (1:1) with patients who received hepatoprotectants (the untreated group). Cumulative incidences of and hazard ratios (HRs) for ICC development were analyzed.

Results

The cumulative incidence of ICC was significantly lower in the treated group after 3 years of therapy (1.28%; 95% CI, 0.56–2.01) than in the untreated group (3.14%; 95% CI, 2.02–4.27) and after 5 years of therapy (1.53%; 95% CI, 0.73–2.33 vs 4.32% in untreated group; 95% CI, 2.96–5.6869). In multivariable regression analysis, nucleos(t)ide analogue therapy was independently associated with a reduced risk of ICC (HR, 0.44; 95% CI, 0.25–0.78; P = .005). Older age (HR 1.05 per year; 95% CI, 1.03–1.07) and cirrhosis (HR, 2.80; 95% CI, 1.52–5.1415) were independently associated with an increased risk of ICC. Sensitivity analyses verified the association between nucleos(t)ide analogue therapy and a reduced ICC risk.

Conclusion

A nationwide long-term cohort study in Taiwan showed that nucleos(t)ide analogue therapy for chronic HBV infection is significantly associated with a reduced ICC risk.

Section snippets

Study Design

In this retrospective nationwide cohort study, we retrieved medical records from Taiwan’s National Health Insurance Research Database (NHIRD) between October 1, 2003 and December 31, 2012. The NHIRD contains healthcare data from more than 99% of Taiwan’s entire population of 23.38 million.20 As outlined in our previous studies,19, 21, 22 the NHIRD database comprises comprehensive medical data, and diseases are defined according to the International Classification of Diseases, 9th Revision

Study Subjects

As presented in Figure 1, we screened 185,843 patients who had been diagnosed with chronic hepatitis B between October 1, 2003 and December 31, 2012, and 80,641 patients who used NAs or hepatoprotectants for at least 90 days were identified. After excluding patients with potential confounding factors, 51,707 patients were selected. Furthermore, patients in the NA-treated cohort were matched with patients in the untreated cohort, and a total of 10,062 patients in the treated group and 10,062 in

Discussion

Although HBV infection has been shown to be a major risk factor for ICC development,16, 17 the protective effect of NA therapy via directly inhibiting HBV replication is poorly understood. This large cohort study demonstrated that ICC development rates were significantly lower in the NA-treated group compared with rates in the untreated group, and NA therapy was an independent risk factor associated with reduced risk of ICC development. This study reports a positive effect of NA therapy on the

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      Another retrospective study using Taiwan's National Health Insurance Research Database compared 10,062 patients with HBV who received treatment to 10,062 propensity-matched controls who did not receive treatment for their HBV. The cumulative incidence of IHCC was significantly higher in patients with untreated HBV than those who received treatment (4.32%, 95%CI 2.96-5.68 vs 1.53%, 95%CI 0.73-2.33; P = 0.005), suggesting that uncontrolled HBV infection may contribute to the development of IHCC.24 Infection with the liver flukes Clonorchis sinensis and Opisthorchis viverrini, foodborne trematode parasites that chronically infect the bile ducts, is a significant risk factor for the development of IHCC.22

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    This article has an accompanying continuing medical education activity, also eligible for MOC credit, on page e71. Learning Objective–Upon completion of this activity, successful learners will be able to identify the high-risk patients for antiviral therapy to prevent hepatitis B virus-related liver cancer.

    Conflicts of interest The authors disclose no conflicts.

    Funding Supported in part by the National Health Research Institutes (CA-106-PP-37) and the Taichung Veterans General Hospital (106DHA0500150), Taiwan.

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