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HBV-Related Liver Cancer and the Role of Aspirin

Aspirin may be chemopreventive against the development of hepatocellular carcinoma (HCC) in chronic hepatitis B (HBV), according to a large Taiwanese cohort study in JAMA Internal Medicine.

Compared with no use, daily aspirin therapy significantly lowered cumulative HCC incidence over 5 years: 5.20% (95% confidence interval 4.11-6.29) versus 7.87% (95% CI 7.15-8.60, P<0.001).

“Our findings may be of help in future efforts to further improve the chemoprevention of HBV-related HCC, and a proof-of-concept study is thus warranted,” wrote a group led by Chun-Ying Wu, MD, PhD, of Taipei Veterans General Hospital.

The study looked at 204,507 chronic hepatitis B patients in Taiwan’s National Health Insurance Research Database during the period of January 1, 1997 to December 31, 2012. Excluding those with confounding conditions, the team identified 2,123 patients who had continuously received daily aspirin for 90 or more days; they were randomly matched in a one-to-four ratio with 8,492 patients who had never received antiplatelet therapy, by propensity scores consisting of the follow-up index date, baseline characteristics, and potentially chemopreventive drug use over follow-up. Data were analyzed from August 1 to November 30, 2018.

Of the 10,615 patients included in the analysis, 7,690 (72.4%) were men, mean age was 58.8 (standard deviation, 11.8 years), and median duration of aspirin therapy was 3.1 years. More than 80% in the treated group were taking aspirin because of cardiovascular risk factors such as diabetes, hyperlipidemia, and hypertension, followed by about 40% each for coronary artery and cerebral vascular disease.

Multivariable analysis adjusted for age, male sex, liver cirrhosis, diabetes, hyperlipidemia, hypertension, statin use, metformin use, and nucleoside/nucleotide analogue (NA) use.

Independently associated with increased HCC risk were the following variables:

  • Older age: HR 1.01 per year (95% CI 1.00-1.02, P=0.001)
  • Male sex: HR 1.75 (95% CI 1.43-2.14, P<0.001)
  • Liver cirrhosis: HR 2.89 (95% CI 2.45-3.40, P<0.001)

Correlating with reduced HCC risk were:

  • NA use: HR 0.54 (95% CI 0.41-0.71, P<0.001)
  • Statin use: HR 0.62 (95% CI 0.42-0.90, P=0.01)

Aspirin use also decreased HCC risk in patients not receiving NA therapy, echoing a recent study that also reported that aspirin reduced HCC risk even after effective NA therapy.

The authors noted that platelets are instrumental in the pathogenesis of HBV-related liver disease by sustaining inflammation, while aspirin blocks thromboxane A2 production and inhibits platelet activation.

Last year, MedPage Today reported that 325 mg of aspirin twice a week over at least 5 years reduced HCC risk by 49%. But this drug is also well known to correlate with a greater risk of gastrointestinal bleeding and hemorrhagic stroke. The Taiwanese group, however, found no significant increase in the 5-year cumulative incidence of peptic ulcer bleeding in the aspirin-treated versus the untreated group: 6.13% (95% CI 5.05-7.21) and 5.52% (95% CI 4.99-6.0, P =0.09), respectively. Nor was peptic ulcer bleeding risk in treated patients significantly higher in those with cirrhosis than without: 7.49% (95% CI 4.65-10.32) versus 5.85% (95% CI 4.68-7.01, P=0.41).

“However, patients selected in the treated group could tolerate aspirin therapy for at least 90 days; therefore, their [peptic ulcer bleeding] risk might be underestimated,” the authors acknowledged.

In a related commentary, Rena K. Fox, MD, of the University of California, San Francisco, and colleagues, called the positive findings promising, especially for HBV patients not receiving NA therapy, and called for well-designed studies to confirm the chemopreventive effect of aspirin in NA users, especially for the subgroup with cirrhosis.

“The potential role for aspirin to be used as chemoprevention for HCC would be relevant to patients worldwide and would bring a change in practice for primary care clinicians and specialists, including gastroenterology, hepatology, infectious diseases, and oncology,” Fox et al. wrote, citing aspirin’s ease of use and affordability, which could potentially benefit hundreds of millions of patients globally.

“There is optimism in the current research, but a recommendation for widespread use of aspirin across the HBV population is premature, as important questions remain, including duration of therapy, age at initiation, degree of benefit for patients taking NAs, and risk for gastroduodenal toxic effects,” the editorial cautioned.

Fox and colleagues recommended that the World Health Organization consider further investigation. “In the meantime, physicians can individually counsel patients who have an indication for aspirin about the potential for HCC risk reduction, especially if they are not candidates for NA therapy,” the editorial stated.

Study limitations, Wu and co-authors said, included its observational design, which could not determine causality and could have introduced selection and other biases, despite consideration of all potential confounders. In addition, because most patients were middle-age or older, the results may not be generalizable to younger populations. Another limitation was the unavailability of detailed laboratory data, such as HBV viral load, that indicate disease severity. Furthermore, some patients discontinued aspirin therapy during the study period, which could have impacted results. In addition, the information in the health insurance database was limited by reliance on insurance claims. Finally, although data on medications were detailed, the accuracy may have been limited by patient adherence to prescribed therapy, the researchers said.

The study was supported in part by the Ministry of Science and Technology, the National Health Research Institutes, and Taichung Veterans General Hospital, Taiwan.

One co-author reported financial relationships with Gilead and Bristol-Myers Squibb outside of the study.

Fox and associates reported having no competing interests.