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Ayoub et al. Nucleos(t)ide therapy for hepatitis B impacts HCC incidence

with NAs. A total of 322 patients were followed for estimated by the REACH-B risk calculator. Starting
a median of 3.2 years; median treatment duration at 3.3 years, divergence emerged and progressively
with NAs was 3.4 years (interquartile range 1.6-5.9) widened between the predicted and observed
and 80% of the patients were treated with tenofovir incidence of HCC between the 2 groups. Furthermore,
or entecavir. During the study period, 11 patients, at latest follow-up (median of 5.52 years), the SIR
3.2%, developed HCC; 9 of these were Asian men. between observed and predicted supporting that
Cirrhosis was the strongest risk factor for HCC treatment with tenofovir is beneficial. A recent study
development (unadjusted risk 22-fold); patients with conducted in Taiwan examined the efficacy and safety
cirrhosis had an annual HCC incidence rate of 4.3% of treatment in NA-naive and NA-experienced patients
vs. 0.2% in patients without cirrhosis. Use of NAs with CHB; after 3 years of therapy, cumulative HCC
reduced the risk of HCC development; based on the incidence at 12, 24 and 36 months were 0%, 1.2%,
REACH-B model, there was a 50% relative reduction and 4.8%, respectively, and no significant differences
in HCC incidence with NA use, noted as early as were found between NA-naive and NA-experienced
4 years after initiation of treatment [25] . The Chronic patients in regards to HCC development [29] .
Hepatitis Cohort Study, a longitudinal study in the
United States, recently evaluated the relationship IMPACT OF NA CHOICE ON HCC
between CHB therapy and HCC incidence in 2,671 INCIDENCE
patients. Patients were diagnosed with CHB between
1992 to 2011 and data were analyzed and collected
over a 5-year period; 49% of the sample was Asian. In a study conducted in Korea, patients with
Using propensity score matching and Cox regression compensated cirrhosis secondary to CHB, hepatitis
analysis, the authors found that patients treated with B DNA < 2,000 IU/mL, and normal ALT had HCC
antivirals had a lower risk of HCC than those who incidence of nearly 10% over 5 years, but NA therapy
were not treated with antivirals (adjusted HR 0.39; reduced incidence to 5.9% for HBV patients treated
95%CI 0.27-0.56; P < 0.001), after adjusting for with NAs; longer duration of treatment and virological
[30]
abnormal level of alanine aminotransferase (ALT). response were associated with lower risk of HCC .
Like the Canadian study above, the observational, A recent multicenter study demonstrated a reduction
retrospective, multicenter cohort study ENUMERATE of 77% in HCC incidence in those treated with NAs
conducted in the United States used the REACH-B treatment compared to those who were untreated; this
system to assess HCC risk in NA-treated patients. was adjusted for age, gender, ALT, and HBV DNA and
[31]
The study included 841 treatment-naïve CHB patients was independent of the presence of cirrhosis .
over an 8-year period who had received > 12 months
of entacavir with a median follow-up of 4 years. Several studies have also evaluated whether the
Overall, HCC was diagnosed in 17 patients (2.6%): 8 choice of NA affects risk reduction of HCC. In a
patients had cirrhosis (13.1%) and developed HCC and retrospective study of CHB patients with cirrhosis (n
9 patients without cirrhosis (1.5%) developed HCC. In = 227, 104 with decompensated cirrhosis) who were
[32]
comparison to those who did not develop HCC, the followed over 21-36 months, Koklu et al. showed the
patients with HCC were more likely to have cirrhosis incidence of HCC to be 3%, 5%, and 8%, respectively,
(47.1% vs. 8.4%) and to be older (53 years vs. 47 in the tenofovir, entacavir, and lamivudine groups.
years). Among patients who did not have cirrhosis, the There was no significant difference found between
observed HCC incidence was lower than the predicted the NA in the prevention of HCC. In a study of 355
incidence by the fourth year [standardized incidence treatment-naïve patients with CHB, 39.2% of whom
ratio (SIR) 0.37; 95%CI 0.166-0.82]. By 8.2 years, had cirrhosis, who received entecavir or tenofovir,
[33]
the maximum follow-up time, the observed incidence Idilman et al. found that the cumulative incidence
of HCC was significantly lower than predicted for all of HCC at 1 year was 3.3% and at 4 years was 7.3%.
patients (SIR 0.56; 95%CI 0.35-0.905) [26] . No significant difference was found between the 2
groups. A multicenter European study evaluated 1,756
In addition to reversing fibrosis, tenofovir therapy has Caucasian patients in an attempt to evaluate the
been shown to decrease HCC risk. In the seminal impact of treatment with entecavir and/or tenofovir for
study by Marcellin et al. [27] , treatment with tenofovir for 39 months on HCC occurrence. Overall, the 5-year
5 years led to improvement in histology and regression cumulative probability of HCC was 8.7%. In patients
of fibrosis regression (≥ 1 point decrease by Ishak without cirrhosis, the cumulative 5-year HCC rate was
scoring system) in 87% and 51% of the patients, 3.7% compared to 17.5% in patients with cirrhosis and
respectively. Kim et al. [28] compared the observed 36.3% in patients with decompensated cirrhosis [34] . In
HCC incidence among the 641 patients enrolled in 2 a recent review of NAs including lamivudine, tenofovir,
tenofovir registration trials to the incidence of HCC and entecavir, Papatheodoridis et al. [35] concluded
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