Chronic HBV Infections Associated With Liver Malignancies

Untreated chronic hepatitis B infections are associated with increased risks of most major extrahepatic cancer types, shows a new study conducted in South Korea.

In this study, which was published in the Journal of Clinical Oncology, researchers found that long-term treatment with nucleos(t)ide analogues (NAs) for patients with chronic hepatitis B lowered their risk of developing extrahepatic cancer types.

In addition to lowering the risk of liver cancers, treatment with nucleos(t)ide analogues, including tenofovir disoproxil fumarate, entecavir, lamivudine, telbivudine, adefovir, and clevudine, lowered the risk of developing cancer of the pancreas and prostate, but increased the risk of breast cancer.

By controlling chronic hepatitis B infections (CHB), NAs have been known to reduce the risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. About half of the 700,000 people who die each year from chronic hepatitis B infections also have an intrahepatic malignancy.

But extrahepatic cholangiocarcinoma, in which tumors grow outside of the liver in the bile ducts, is exceedingly rare, affecting only 8,000 people each year in the United States.

The study was led by Jeong-Hoon Lee, MD, PhD, Seoul National University, South Korea.

The Study Details

Researchers sought to understand whether CHB treatment with NA drugs could reduce the risk of extrahepatic cancer. The study is based on an analysis of South Korean medical insurance claims data that included 90,944 patients (6,539 treated with NAs) with a newly diagnosed chronic hepatitis B infection, and 685,436 controls. The median age of the groups ranged from 47 to 51, and the percentage of men ranged from 51.3% to 62.5%.

Over the median 47.4-month study period, 3.9% (30,413) of subjects developed cancer outside the liver. Patients with CHB who weren’t treated with NAs had a higher overall risk vs. the NA-treatment group (adjusted subdistribution hazard ratio = 1.28; 95% confidence interval, 1.12-1.45; P < .001) and vs. controls (aSHR = 1.22; 95% CI, 1.18-1.26; P < .001).

The researchers write that “the direction of the original result was maintained” even after adjustment for cancer risk factors such as smoking and alcohol consumption. “Randomized controlled trials might be warranted to explore whether NA treatment will reduce the risk of extrahepatic malignancy in patients with CHB outside the current treatment indication,” they wrote.

In an accompanying commentary, Lewis R. Roberts, MBChB, PhD, of Mayo Clinic, Rochester, Minn., said that what is perhaps “the most controversial result … one that is not the direct subject of their study, the observation that NA treatment was not associated with a decrease in risk of primary intrahepatic malignancy – hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma. The observed decrease in risk of intrahepatic malignancy was 12%, with an adjusted subdistribution hazard ratio of 0.88 (95% CI, 0.77-1.01; P = .08).”

As Roberts wrote, the authors suggested this could be related to the low prevalence of cirrhosis in the study group. “This explanation is plausible, as it has previously been shown that the major impact of NA treatment in reducing HCC incidence is in those with CHB-induced cirrhosis,” he wrote.

Roberts added that randomized trials of NA in CHB would be difficult because the drugs are so effective. “The most important implication of this study may be the observation that CHB is associated with a higher risk of a range of extrahepatic malignancies, and the opportunity to advise patients with CHB to adhere to current recommendations for screening for the major cancer types.”

The study was publicly funded, but several study authors report numerous disclosures including relationships with Yuhan Corporation, Bayer, Gilead Sciences, Bristol Myers Squibb, and others. Roberts reports numerous personal and institutional disclosures including relationships with Bayer, Gilead Sciences, Medscape, Roche, and others plus a patent and royalties.

This story originally appeared on, part of the Medscape Professional Network.

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