Aspirin Use and Risk of Hepatocellular Carcinoma in Hepatitis B
Invited Commentary
Aspirin Use and Risk of Hepatocellular Carcinoma
in Hepatitis B
Rena K. Fox, MD; Tamar H. Taddei, MD; David E. Kaplan, MD
Liver cancer (hepatocellular carcinoma [HCC]) incidence and
mortality rates have been increasing in most countries for sev-
eral decades. Currently, HCC is the second most common cause
of cancer-related death in the world and represents the fast-
est rising cause of cancer-
Related article
related deaths in the United
States.1 Chronic hepatitis B
virus (HBV) and hepatitis C virus are the primary underlying
causes of HCC, with contributions from alcohol, tobacco, af-
latoxin, obesity, and metabolic syndrome. In patients with
chronic hepatitis C virus, the risk of HCC can be reduced rap-
idly with short-term, direct-acting antiviral medications. In
chronic HBV, oncogenesis starts with viral DNA integration into
the genome of host hepatocytes that induces a cascade of host
responses, including cell injury, necrosis, and angiogenesis, re-
flected clinically by the levels of serum alanine aminotrans-
ferase and HBV DNA, both of which are predictors of HCC.
Antiviral treatment with nucleos(t)ide analogues (NAs) re-
duces HCC incidence, yet the benefit does not become evi-
dent until more than 5 years of therapy, likely owing to the
latency of the effects of cessation of HBV replication and im-
proved necroinflammation on cancer risk.2 Despite the poten-
tial chemopreventive effect of NA, only patients with HBV and
cirrhosis and/or with active hepatitis (high alanine amino-
transferase levels, high-level HBV DNA) are candidates for NA
treatment, since clinical benefits have not been demon-
strated for patients without active hepatitis (alanine amino-
transferase levels within the reference range). Even for treat-
ment candidates, additional barriers to receipt of NAs include
expense and disparities in access to care. Because 248 mil-
lion people with chronic HBV exist worldwide,3 other, less
costly chemoprevention strategies are being examined, in-
cluding nonpharmacologic (coffee, tea, fruits, vegetables) and
pharmacologic (statins, metformin, and aspirin) agents.
Aspirin has been shown to reduce the incidence of colorec-
tal cancer in large population studies, possibly owing to its an-
tioncogenic effects, such as induction of apoptosis and inhibi-
tion of cyclooxygenase. Data on the effect of aspirin on HCC have
only started to emerge. A large, population-based study in the
National Institutes of Health–AARP Diet and Health Study cohort
showed that aspirin use was associated with a 41% lower risk of
HCC compared with nonuse.4 Two prospective US cohort stud-
ies including 133 371 persons found that regular use of standard-
dose aspirin at least 2 or more times per week was associated with
a 49% reduced risk of HCC. Benefits appeared with aspirin use
for 5 years or more in patients with and without cirrhosis.5 A pro-
spective trial showed that daily low-dose aspirin therapy was as-
sociated with a significantly reduced HCC risk (hazard ratio, 0.39;
95% CI, 0.17-0.91), but neither a dose-response nor duration-
response relationship was observed.6 These existing studies are
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Invited Commentary
encouraging but problematic owing to the variable dosage of as-
pirin, variable duration of aspirin, variable causes of liver disease,
variable patient populations, confounding by indication, and in-
complete adjustment for multiple confounders, such as age, sex,
cirrhosis status, alcohol use, and current or previous use of HBV
antiviral therapy.
In this issue of JAMA Internal Medicine, Lee and colleagues7
aim to examine the use of aspirin and HCC risk, but without
some of the limitations of the previous studies.8 The authors
take advantage of a national medical database in Taiwan with
approximately 23 million people. The retrospective cohort de-
sign always introduces biases, such as selection and observa-
tional bias, but studies from a database this large with well-
validated data on prescription history and disease diagnoses
can illuminate clinically important associations. Unlike the
prior studies, the investigators were able to identify a rela-
tively homogeneous cohort of patients with a single liver dis-
ease (chronic HBV) and further identify those who were re-
ceiving consecutive aspirin therapy. These patients were
propensity matched to similar patients with chronic HBV who
were not receiving aspirin therapy, including matching for im-
portant factors known to influence HCC risk, such as use of NA
treatment and presence of cirrhosis. Results confirmed sev-
eral established associations in the field: the strongest inde-
pendent predictor of HCC was cirrhosis, and the strongest in-
dependent factor to reduce the risk of HCC was the use of NAs.
The aspirin findings are promising. Most importantly, aspirin
was associated with a reduced HCC risk, specifically for pa-
tients with HBV who were not receiving NA therapy. The study
highlights that at least 2 years of aspirin therapy were needed
to lower the 5-year incidence of HCC. However, for patients al-
ready receiving NA therapy or those with cirrhosis, aspirin was
not significantly associated with any further reduced HCC risk.
While intriguing and improving upon the presently avail-
able literature, there are still certain limitations of the cohort
and the study methods that merit deeper scrutiny First, of the
HBV cohort of 204 507 patients identified between 2003 and
2012, only 1.0% (2123) were aspirin users, as opposed to ap-
proximately one-third of US adults 40 years or older who re-
ported taking preventive aspirin in the 2011-2012 National
Health and Nutrition Examination Survey study.8 Such a low
frequency appears conspicuous given that the majority of the
cohort consisted of men with a mean age of 58.7 years. These
data suggest that either prescribing patterns for aspirin strongly
differ in Taiwan compared with the United States or there is
bias in ascertainment or selection. The authors report the fre-
quency of some of the possible conditions that may warrant
aspirin therapy in the aspirin users from this cohort, but do not
report the frequency of these conditions in the nonusers. In
the United States, a major reason for daily low-dose aspirin
(Reprinted) JAMA Internal Medicine Published online March 18, 2019 E1
 Invited Commentary Aspirin Use and Risk of Hepatocellular Carcinoma in Hepatitis B

therapy is primary and secondary prevention of atheroscle-
rotic disease. In this aspirin cohort, 98.0% were using a low
dose (<100 mg/d) and most (82.2%) had 1 or more risk factors
for cardiovascular disease, but a significant plurality had al-
ready been diagnosed with coronary artery disease (41.2%) or
cerebrovascular disease (37.6%). This finding raises the con-
cern that cardiovascular disease–associated death could have
been a significant competing risk for HCC in the population.
In addition, for patients with chronic liver disease, higher se-
rum cholesterol levels are associated with less advanced stages
of hepatic fibrosis, and therefore hyperlipidemia as an indi-
cation for aspirin use could be a sign that the aspirin users had
less severe liver disease than the non-aspirin users. This po-
tential for confounding by indication could predefine the as-
pirin users as having a lower risk for liver morbidity and HCC,
independent of aspirin prescription.
Similarly, factors determining why the untreated group was
not prescribed aspirin are incompletely explored; unlike for
the aspirin cohort, the authors did not report the frequency
of some of the possible conditions that may be cause for aspi-
rin use in the non-aspirin cohort. Could concerns over risk of
aspirin-induced bleeding in patients with more advanced liver
disease have altered prescribing patterns, despite the similar
rates of diabetes, hypertension, and hyperlipidemia? Such con-
founders in indication and selection biases are challenging to
eliminate in retrospective administrative studies, and thus,
while provocative and hopeful, these results should be vali-
dated using randomized clinical trials.
With the rising incidence and deaths due to HCC across the
globe, there is a need for uncomplicated, inexpensive, and ef-
fective interventions to reduce HCC incidence. Patients with
HBV are particularly at risk of HCC, and although there is a ben-
eficial role of NA therapy, because so many patients are not can-
didates for or lack access to antivirals, an agent such as aspi-
rin holds promise. The potential role for aspirin to be used as
chemoprevention for HCC would be relevant to patients world-
wide and would bring a change in practice for primary care cli-
nicians and specialists, including gastroenterology, hepatol-
ogy, infectious diseases, and oncology. In particular, the ease
of use and affordability of aspirin would mean hundreds of
millions of patients would potentially benefit. There is opti-
mism in the current research, but a recommendation for wide-
spread use of aspirin across the HBV population is prema-
ture, as important questions remain, including duration of
therapy, age at initiation, degree of benefit for patients taking
NAs, and risk for gastroduodenal toxic effects. Given the global
burden of HBV, especially in resource-limited regions, the
World Health Organization could consider conducting fur-
ther investigation. In the meantime, physicians can individu-
ally counsel patients who have an indication for aspirin about
the potential for HCC risk reduction, especially if they are not
candidates for NA therapy.

ARTICLE INFORMATION REFERENCES 5. Simon TG, Ma Y, Ludvigsson JF, et al. Association

Author Affiliations: Division of General Internal
Medicine, School of Medicine, University of
California, San Francisco (Fox); Department of
Medicine, Veterans Affairs Connecticut Healthcare
System, West Haven (Taddei); Division of Digestive
Diseases, Yale University School of Medicine,
New Haven, Connecticut (Taddei); Division of
Gastroenterology, School of Medicine, University of
Pennsylvania Philadelphia (Kaplan); Department of
Medicine, Corporal Michael J. Crescenz Veterans
Affairs Medical Center, Philadelphia, Pennsylvania
(Kaplan).
Corresponding Author: Rena K. Fox, MD, Division of
General Internal Medicine, School of Medicine,
University of California, San Francisco, 1545
Divisadero St, Ste 307, PO Box 0320, San Francisco,
CA 94143 (rena.fox@ucsf.edu).
Published Online: March 18, 2019.
doi:10.1001/jamainternmed.2018.8314
Conflict of Interest Disclosures: None reported.
1. Ryerson AB, Eheman CR, Altekruse SF, et al.
Annual report to the nation on the status of cancer,
1975-2012, featuring the increasing incidence of
liver cancer. Cancer. 2016;122(9):1312-1337. doi:10.
1002/cncr.29936
2. Papatheodoridis GV, Idilman R, Dalekos GN, et al.
The risk of hepatocellular carcinoma decreases
after the first 5 years of entecavir or tenofovir in
Caucasians with chronic hepatitis B. Hepatology.
2017;66(5):1444-1453. doi:10.1002/hep.29320
3. Schweitzer A, Horn J, Mikolajczyk RT, Krause G,
Ott JJ. Estimations of worldwide prevalence of
chronic hepatitis B virus infection: a systematic
review of data published between 1965 and 2013.
Lancet. 2015;386(10003):1546-1555.
4. Sahasrabuddhe VV, Gunja MZ, Graubard BI, et al.
Nonsteroidal anti-inflammatory drug use, chronic
liver disease, and hepatocellular carcinoma. J Natl
Cancer Inst. 2012;104(23):1808-1814. doi:10.1093/
jnci/djs452
between aspirin use and risk of hepatocellular
carcinoma. JAMA Oncol. 2018;4(12):1683-1690.
6. Petrick JL, Sahasrabuddhe VV, Chan AT, et al.
NSAID use and risk of hepatocellular carcinoma and
intrahepatic cholangiocarcinoma: the Liver Cancer
Pooling Project. Cancer Prev Res (Phila). 2015;8(12):
1156-1162. doi:10.1158/1940-6207.CAPR-15-0126
7. Lee TY, Hsu YC, Tseng HC, et al. Association of
daily aspirin therapy with risk of hepatocellular
carcinoma in patients with chronic hepatitis B
[published online March 18, 2019]. JAMA Intern Med.
doi:10.1001/jamainternmed.2018.8342
8. Gu Q, Dillon CF, Eberhardt MS, Wright JD, Burt VL.
Preventive aspirin and other antiplatelet medication
use among US adults aged ⱖ40 years: data from the
National Health and Nutrition Examination Survey,
2011-2012. Public Health Rep. 2015;130(6):643-654.
doi:10.1177/003335491513000614

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