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

that no significant difference exists between agents in (RR 0.46; 95%CI 0.32-0.68; P < 0.001) in these
preventing HCC even in patients who were rescued patients [41] . Clearly, surgical and medical treatment of
after development of lamivudine resistance. CHB improves mortality due to HCC and reduces its
recurrence.
A recent Greek analysis compared a cohort of patients
treated with entecavir (n = 321), for a median duration LIMITATIONS OF THE HCC PREDICTOR
of 40 months to a matched cohort of patients (n = 818), MODELS
initially treated with lamivudine for a median duration
of 60 months. Using multivariable Cox regression
analysis, risk of HCC was independently associated Several HCC risk calculators have been proposed
with male gender (P = 0.011), older age (P < 0.001), including the REACH-B based on a Taiwanese
and cirrhosis (P = 0.025); HCC risk was not associated population, the Chinese-University-Hepatocellular
[42]
with the choice of agent used, at least for the first 5 carcinoma score (CU-HCC) score , and the GAG-
years [36] . In a Taiwanese population-based cohort HCC score, which incorporates age, gender, HBV
study, 1,544 patients with active hepatitis due to HBV DNA, presence of core promoter mutations and
[43]
taking lamivudine, entecavir, tenofovir, or telbivudine cirrhosis . These models were developed in Asians
over an 8-year period were evaluated for HCC risk and and the application to other populations is unclear,
risk of mortality. For the propensity score matching, though one study showed good performance in
[44]
patients not treated with NAs (n = 1,544), were selected non-Asians . The platelet, age, gender (PAGE-B
as the comparison group. As mentioned previously, score is based on platelet, age and gender and was
the treated cohort had a significantly lower rate of HCC developed to assess risk of HCC in Caucasians.
occurrence (6.0%; 95%CI 4.4%-7.9%) compared to the Another limitation of these models is that they do not
cohort not treated with NAs (8.5%; 95%CI 6.6%-10.6%; include a liver fibrosis assessment such as transient
P = 0.0025). Overall mortality rate for the treated elastography. In addition, some models like the CU-
cohort was 6.9% (95%CI 5.3%-8.7%) compared to HCC included 15% of HBV treated patients rather
9.4% for the untreated cohort (95%CI 7.7%-11.3%) (P than all treatment naïve patients. It is questionable
= 0.0003). Cox regression analyses demonstrated that whether the HCC risk predictor models can be used
use of NAs use significantly reduced the risk of HCC in patients on HBV therapy, as therapy leads to viral
(HR 0.64; 95%CI 0.45-0.93; P = 0.017) and overall suppression and may lead to fibrosis regression.
mortality (HR 0.58; 95%CI 0.43-0.79; P < 0.001) [37] . In addition, the absence of the degree of HBV viral
suppression in some models is a major limitation of
Finally, there is new evidence that treatment of CHB the risk calculators [35] .
reduces mortality related to HCC and HCC recurrence
in patients undergoing curative treatments [38] . CONCLUSION
Huang et al. [38] demonstrated antiviral therapy after
liver resection to be an independent protective In patients with CHB, successful treatment can
factor of late tumor recurrence (HR 0.348). Similar reduce but not eliminate the risk of developing
results were reported by Yin et al. [39] In a randomized HCC, regardless of the presence or absence of
controlled trial, antiviral therapy reduced both tumor cirrhosis. Treatment of CHB can reverse fibrosis as
recurrence (HR 0.48) and HCC-related death (0.26). demonstrated by studies involving the third-generation
In a study of Taiwanese patients undergoing resection NAs tenofovir and entecavir, which have a high genetic
(n = 4,569), those who received NA had significantly barrier to resistance. Additionally, growing evidence
lower recurrence rate at 6 years compared to patients supports that treatment of CHB reduces recurrence
not treated with NAs (45.6% vs. 54.6% respectively) (P rates of HCC and HCC-related mortality in CHB
< 0.001). Additionally, the NA-treated group had lower patients who received curative treatments for HCC.
mortality overall at 6 years (29% vs. 42.4%) (P < 0.001) [40] .
In a recent meta-analysis including 8,204 patients Most data regarding chemoprevention is derived
status-post curative resection of HCC, high viral load from studies using lamivudine and this significantly
was significantly associated with increased risk of limits interpretation of the data. It is possible that the
recurrence, poorer disease-free survival and overall chemopreventative effect is more pronounced with the
survival of HBV-related HCC after surgical resection. long term use of entecavir and tenofovir, which have a
However, NA therapy significantly decreased the much lower risk of resistance with prolonged use when
recurrence risk (RR 0.69; 95%CI 0.59-0.80; P < compared to lamivudine. Most of the studies evaluating
0.001) and improved both disease-free (RR 0.70; the effect of chemoprevention are retrospective in
95%CI 0.58-0.83; P < 0.001) and overall survival nature, which is another major limitation. In other

306 Hepatoma Research ¦ Volume 3 ¦ December 20, 2017