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Aspirin Use and Risk of Hepatocellular Carcinoma in Hepatitis B Invited Commentary

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

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Invited Commentary Aspirin Use and Risk of Hepatocellular Carcinoma in Hepatitis B

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

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

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Conflict of Interest Disclosures: None reported. jnci/djs452

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