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The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy - HBV Therapy Reduced HCC Risk by 50%, Patients with Cirrhosis Had Increased Risk: increased the unadjusted risk 22-fold
 
 
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"We found that underlying cirrhosis, as determined by FibroScan®, US imaging or other biochemical markers, was the most important risk factor for HCC development......As noted, most patients were on highly potent NA (i.e. entecavir and tenofovir) with suppressed HBV DNA and normal ALT, which is expected to have an even greater effect on reducing the incidence of HCC. A recent analysis of the REVEAL data has shown that long-term changes in HBV DNA and ALT are independent risk factors for HCC."
 
"In this large North American retrospective cohort study, we observed that long-term therapy with oral NAs reduces the incidence of HBV-related HCC likely via potent and persistent suppression of viral replication. Despite NA therapy, cirrhotic patients with CHB are still at risk and warrant ongoing surveillance."
 
"The observed annual incidence of HCC in the study cohort was 0.9% per year (95% CI 0.5-1.7). This risk was greatest in patients with cirrhosis [annual incidence 4.3% (95% CI 2.2-8.3) vs. 0.2% (95% CI 0.05-0.8) per year in patients without cirrhosis; P < 0.00005; Figure 2].......the observed to expected number of HCC cases was significantly reduced by year 4, when there were 7 observed vs. 14 expected HCC cases (SIR 0.49; 95% CI 0.20-1.00; Figure 3). By the end of 9 years of follow-up, the SIR was 0.46 (95% CI 0.23-0.82) based on 11 observed cases vs. 24 predicted by the REACH-B model.....In this study, in 11 patients who developed HCC on NA, two patients died due to metastatic disease and nine had no recurrence at last follow-up after receiving potentially curative HCC therapy (i.e. radiofrequency ablation, surgical resection and/or liver transplant). Thus, it is possible that potent NA therapy also prevented HCC recurrence but cannot be definitively proven in this study.
 
"There is limited literature evaluating the chemopreventive effect of NA therapy on the incidence of HCC among the North American CHB population. The objective of this study was to utilise the REACH-B scoring system to calculate the expected risk of HBV-related HCC in Canadian patients treated with NAs. We hypothesised that the observed risk of HCC would be lower than that expected in the absence of treatment, supporting a chemopreventive effect of NAs on HCC development."
 
"A combination of host and viral factors exert synergistic effects on the risk of HBV-related HCC including older age, male gender, cirrhosis, hepatitis B-e antigen (HBeAg) positivity, higher serum alanine aminotransferase (ALT) and HBV DNA concentrations, and HBV genotype (i.e. genotype C > B and D > A). Several risk prediction models including these and other factors have been developed and validated to predict the risk of HBV-associated HCC.[21-24] For example, based on data from the REVEAL (Risk Evaluation of Viral Load and Associated Liver Disease/Cancer - Hepatitis B Virus) study, a population-based study that included 3584 untreated Taiwanese individuals followed up for over 10 years,[25] the REACH-B risk score (Risk estimation for HCC in CHB) was developed. The REACH-B model (which includes age, gender, ALT, HBeAg and serum HBV DNA concentration) has been validated in both untreated and NA-treated patients to accurately predict the risk of HCC[22, 23]; was used to calculate an empirical HCC risk score,[22, 26] and has also been used to accurately classify anti-viral treatment eligibility.[27]"
 
"Over a median follow-up period of 3.2 years (IQR 1.9-4.6 years), 11 patients (3.2%) developed HCC. The median duration of anti-viral treatment before the diagnosis of HCC was 3.4 years (IQR 1.6-5.9; range 1.1-9.0). ......Five patients with HCC had been treated with lamivudine (45%), three with tenofovir (27%), two with adefovir (18%) and one with entecavir (9%).
 
........The majority of patients [82% (9/11)] with HCC had underlying cirrhosis, all of whom were HBeAg negative, compared with those who remained tumour-free only 17% (54/311) had cirrhosis (P < 0.00005; Table 1). Patients with HCC were older than non-HCC cases (median age 57 vs. 46 years; P = 0.03) and 10 of the 11 patients with HCC were Asian males. However, median baseline serum ALT (90 vs. 71 U/L; P = 0.69) and HBV DNA (6.50 vs. 6.38 log10 copies/mL; P = 0.99) did not differ between HCC and non-HCC cases. By univariate Cox regression analysis, older age [hazard ratio (HR) 1.07; 95% CI 1.01-1.14] and cirrhosis (HR 21.8; 95% CI 4.7-101.1) were associated with HCC development. Male gender (P = 0.10), HBeAg positivity (P = 0.22), and baseline serum ALT (P = 0.38) and HBV DNA (P = 0.96) were not significant."
 
"The observed annual incidence of HCC in the study cohort was 0.9% per year (95% CI 0.5-1.7). This risk was greatest in patients with cirrhosis [annual incidence 4.3% (95% CI 2.2-8.3) vs. 0.2% (95% CI 0.05-0.8) per year in patients without cirrhosis; P < 0.00005; Figure 2]. Based on the REACH-B model, the observed to expected number of HCC cases was significantly reduced by year 4, when there were 7 observed vs. 14 expected HCC cases (SIR 0.49; 95% CI 0.20-1.00; Figure 3). By the end of 9 years of follow-up, the SIR was 0.46 (95% CI 0.23-0.82) based on 11 observed cases vs. 24 predicted by the REACH-B model.
 
.......The median age was 46 years [interquartile range (IQR) 38-56], 65% of patients were male, 32% were HBeAg positive and 20% had cirrhosis. The median pre-treatment serum HBV DNA concentration was 6.48 log10 copies/mL (IQR 4.95-8.04) and the median serum alanine aminotransferase (ALT) was 71 U/L (IQR 41-127). More than 80% of the cohort initiated treatment with either tenofovir (41%) or entecavir (39%), 14% received lamivudine, and 6% were treated with either telbivudine or adefovir."
 
"Due to the small number of HCC cases in our study, we could not conduct subgroup analyses in this regard. This study also confirms that anti-viral therapy with newer NAs reduces, but does not eliminate, the probability of HBV-associated HCC despite very effective suppression of viral replication. This is likely due to the early integration of HBV genomic fragments into the host genome, even before the initiation of anti-viral therapy, which could lead to genomic alterations and/or chromosomal instability. Furthermore, the presence of established cirrhosis is an additional independent risk factor for HCC development due to the induction of liver inflammation, cell turnover and regeneration.[43, 44] Although the risk of HBV-related HCC was reduced after 4 years on therapy, cirrhosis is a pre-neoplastic state and the concomitant oncogenic impact of HBV-host genome integration events, warrants ongoing surveillance in all patients with advanced liver disease. However, it remains unknown if the degree of risk reduction would justify changing our current screening guidelines in noncirrhotic patients that have been on potent anti-viral therapy."
 
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The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy Alimentary Pharmacology and Therapeutics
 
13 October 2014
 
C. S. Coffin, M. Rezaeeaval, J. X. Pang, L. Alcantara, P. Klein, K. W. Burak & R. P. Myers
 
Summary
 
Background

 
North American data are lacking on the effect of nucleos(t)ide analogues (NA) in preventing chronic hepatitis B (CHB)-related hepatocellular carcinoma (HCC).
 
Aim
 
To determine the incidence of HCC in NA-treated patients and compare this risk with that predicted without treatment based on the REACH-B model.
 
Methods
 
In this retrospective study, the incidence of HCC was determined in CHB patients initiated on NA from 1999 to 2012. Pre-treatment data utilised in the REACH-B model were used to predict the annual HCC risk. The standardised incidence ratio (SIR) for HCC was calculated by comparing the observed to expected number of cases, and HCC risk factors determined by Cox proportional hazards regression.
 
Results
 
Five hundred and forty nine initiated NA (14% lamivudine, 5% adefovir, 1.5% telbivudine, 39% entecavir, 41% tenofovir). Over a median follow-up of 3.2 years (IQR 1.9-4.6), 11 (3.2%) were diagnosed with HCC. Among 322 with data to calculate the REACH-B model, the median age at treatment initiation was 46 years (IQR 38-55), 65% were male, 32% HBeAg positive and 20% had cirrhosis. The median pre-treatment ALT was 71 U/L (IQR 41-127) and HBV DNA was 6.48 log10 copies/mL (4.95-8.04). The observed annual HCC incidence (0.9%; 95% CI 0.5-1.7) was significantly lower than predicted without treatment by the REACH-B model (SIR 0.46; 95% CI 0.23-0.82); this risk was reduced after 4 years of therapy (SIR 0.49; 95% CI 0.2-1.00).
 
Conclusions
 
In this Canadian study of nucleos(t)ide analogues-treated patients with chronic hepatitis B, the incidence of HCC was lower than expected, suggesting that NA reduce the risk of chronic hepatitis B-related HCC.
 
Introduction
 
Approximately, 350-400 million individuals globally are chronically infected with the hepatitis B virus (HBV), of which up to 40% may develop complications including cirrhosis and hepatocellular carcinoma (HCC).[1] Although Canada is a low HBV prevalence region, chronic hepatitis B (CHB) remains important due to the impact of immigration.[2-4] Overall, the annual incidence of HCC in Canada is low (6.9/100 000 in males and 1.9/100 000 in females),[4, 5] but there is little Canadian data describing the incidence of HBV-related HCC. In one long-term study of 317 inactive CHB carriers of mainly French Caucasian origin, no cases of HCC were identified after 16 years of follow-up.[6] However, a recent study in a major Canadian tertiary referral centre reported that 46% (181/386) of all liver resections for HCC were related to HBV.[7]
 
Several studies have demonstrated that treatment with nucleo(s)tide analogues (NAs) reduces the risk of HBV-related HCC.[8-16] In a recent meta-analysis of 49 studies of >10 000 CHB patients treated with oral NA (in both the Western and Eastern hemispheres), NA therapy significantly reduced HCC incidence compared to no treatment.[17] The most robust study was a randomised, placebo-controlled trial that included 651 Asian patients with advanced hepatic fibrosis.[15] Compared to patients who received placebo, Liaw and colleagues reported an approximately 50% reduction in the risk of disease progression and the incidence of HCC in lamivudine recipients. Although most studies evaluated the effect of earlier generation NAs (e.g. lamivudine and adefovir), recent data suggest that newer agents (e.g. tenofovir and entecavir), with higher potencies and genetic barriers to resistance, have a similar beneficial effect.[18-20] In the study of Liaw et al.,[15] patients with lamivudine-associated resistance mutations (YMDD) were more likely to experience disease progression than patients without these mutations; however, their outcomes were still superior to those of placebo recipients.
 
A combination of host and viral factors exert synergistic effects on the risk of HBV-related HCC including older age, male gender, cirrhosis, hepatitis B-e antigen (HBeAg) positivity, higher serum alanine aminotransferase (ALT) and HBV DNA concentrations, and HBV genotype (i.e. genotype C > B and D > A). Several risk prediction models including these and other factors have been developed and validated to predict the risk of HBV-associated HCC.[21-24] For example, based on data from the REVEAL (Risk Evaluation of Viral Load and Associated Liver Disease/Cancer - Hepatitis B Virus) study, a population-based study that included 3584 untreated Taiwanese individuals followed up for over 10 years,[25] the REACH-B risk score (Risk estimation for HCC in CHB) was developed. The REACH-B model (which includes age, gender, ALT, HBeAg and serum HBV DNA concentration) has been validated in both untreated and NA-treated patients to accurately predict the risk of HCC[22, 23]; was used to calculate an empirical HCC risk score,[22, 26] and has also been used to accurately classify anti-viral treatment eligibility.[27]
 
The incidence of HCC varies significantly by geographical origin and ethnic group due to differences in the age at infection (e.g. perinatal vs.
 
adult-acquired infection), genetic background, HBV genotype, and exposures to HCC risk factors including alcohol and aflatoxin.[28, 29] There is limited literature evaluating the chemopreventive effect of NA therapy on the incidence of HCC among the North American CHB population. The objective of this study was to utilise the REACH-B scoring system to calculate the expected risk of HBV-related HCC in Canadian patients treated with NAs. We hypothesised that the observed risk of HCC would be lower than that expected in the absence of treatment, supporting a chemopreventive effect of NAs on HCC development.
 
Methods
 
Study design and study population

 
This retrospective study was conducted at the Calgary Liver Unit, a tertiary referral clinic that serves the majority of patients with liver disease residing in southern Alberta and southeastern British Columbia, Canada (catchment population ~1.5 million individuals). The study cohort included all adult patients (18 years) with CHB (HBsAg positive for at least 6 months) treated with NAs (i.e. lamivudine, telbivudine, adefovir, entecavir or tenofovir) between November 1999 and December 2012 (n = 549). Patients were excluded if the duration of follow-up was less than 1 year (n = 77), HCC was diagnosed before NA initiation (n = 44) or within the first year of therapy (n = 2), if they were coinfected with the hepatitis C virus or the human immunodeficiency virus (n = 9), or if insufficient data were available to calculate the REACH-B score (n = 95) (see Figure 1 for flow of study participants). Study patients provided signed informed consent to participate, and a waiver of consent was obtained if this was not possible under section 50, Health Information Act of Alberta. The Conjoint Health Research Ethics Board at the University of Calgary approved the study (Ethics ID 16636 and 140609).
 
Clinical and laboratory data were collected via a retrospective review of medical records including pre-treatment liver biochemistry, HBeAg, antibody to HBeAg (anti-HBe) (detected by commercial immunoassays; Abbott Architect, Chicago, IL, USA), and serum HBV DNA concentration by polymerase chain reaction assay (lower limit of detection, <20 to <55 IU/mL; TaqMan, Roche Molecular Systems, Inc., Branchburg, NJ, USA or <10 IU/mL; Abbott v 2.0, Mississauga, ON, Canada). A conversion factor of 5.26 copies/IU was used for conversion of copies/mL to IU/mL.[30] Underlying cirrhosis was diagnosed based on liver biopsy, liver stiffness (LS) measured by transient elastography (TE; FibroScan®; Echosens, Paris, France) >11.0 kPa,[31] or conventional imaging criteria (e.g. shrunken, nodular liver, or evidence of portal hypertension on ultrasound, computed tomography or magnetic resonance imaging). FibroScan® or TE was not routinely available until ~2008 in our clinic. However, in cases tested, TE did correlate with liver biopsy, biochemical and other imaging tests suggestive of cirrhosis.
 
Outcomes and follow-up
 
Patients were managed at the discretion of their treating hepatologist as per relevant consensus guidelines (i.e. Canadian Association for the Study of the Liver and American Association for the Study of the Liver Diseases).[32-34] Clinic visits occurred at 6-12-monthly intervals and the response to anti-viral therapy was based on 3-6-monthly monitoring of liver biochemistry, HBeAg, anti-HBe and serum HBV DNA concentrations. In patients with viral breakthrough and/or biochemical flares indicative of anti-viral resistance development, alternative anti-virals with complementary resistance profiles were added or substituted (e.g. the addition of adefovir or substitution with tenofovir in cases of lamivudine resistance). Genotypic confirmation of resistance was not routinely available. Appropriate salvage therapy was initiated in patients with confirmed evidence of a virological and/or biochemical flare within the 3-6-month monitoring period. Patients underwent HCC surveillance at 6-monthly intervals using abdominal ultrasound as per relevant consensus guidelines.[32, 35, 36] The primary outcome measure was HCC as confirmed according to the AASLD diagnostic algorithm.[37]
 
Statistical analyses
 
Comparisons between groups were made using Fisher's exact tests for categorical variables and Mann-Whitney tests for continuous variables. The impact of patient demographics (age and gender), HBeAg status, serum ALT and HBV DNA concentration, and the presence of underlying cirrhosis on the risk of HCC were determined using Cox proportional hazards regression. A multivariate analysis could not be conducted due to the low number of events. The primary analysis consisted of a comparison of the observed to expected (O/E) number of HCC cases among CHB patients treated with NAs. The interval between the initiation of NA treatment and the date of HCC diagnosis was used for all analyses. Patients were followed from the start of NA therapy to the time of death, liver transplantation or the last documented clinic evaluation. The expected number of HCC cases was calculated using the REACH-B model[22] annually up to 9 years of therapy and compared with the observed number of cases using O/E ratios and standardised incidence ratios (SIR) with 95% confidence intervals (CI).[38] All statistical analyses were performed using STATA v11.0 (StataCorp, College Station, TX, USA). P-values less than 0.05 were considered statistically significant.
 
Results
 
Characteristics of the study cohort and participant flow

 
Among 549 patients who initiated NA therapy between November 1999 and December 2012, 322 participants were eligible for study inclusion (Figure 1). The clinical characteristics of the included patients are summarised in Table 1. The median age was 46 years [interquartile range (IQR) 38-56], 65% of patients were male, 32% were HBeAg positive and 20% had cirrhosis. The median pre-treatment serum HBV DNA concentration was 6.48 log10 copies/mL (IQR 4.95-8.04) and the median serum alanine aminotransferase (ALT) was 71 U/L (IQR 41-127). More than 80% of the cohort initiated treatment with either tenofovir (41%) or entecavir (39%), 14% received lamivudine, and 6% were treated with either telbivudine or adefovir.
 
Incidence and predictors of HCC development
 
Over a median follow-up period of 3.2 years (IQR 1.9-4.6 years), 11 patients (3.2%) developed HCC. The median duration of anti-viral treatment before the diagnosis of HCC was 3.4 years (IQR 1.6-5.9; range 1.1-9.0). The majority of patients [82% (9/11)] with HCC had underlying cirrhosis, all of whom were HBeAg negative, compared with those who remained tumour-free only 17% (54/311) had cirrhosis (P < 0.00005; Table 1). Patients with HCC were older than non-HCC cases (median age 57 vs. 46 years; P = 0.03) and 10 of the 11 patients with HCC were Asian males. However, median baseline serum ALT (90 vs. 71 U/L; P = 0.69) and HBV DNA (6.50 vs. 6.38 log10 copies/mL; P = 0.99) did not differ between HCC and non-HCC cases. By univariate Cox regression analysis, older age [hazard ratio (HR) 1.07; 95% CI 1.01-1.14] and cirrhosis (HR 21.8; 95% CI 4.7-101.1) were associated with HCC development. Male gender (P = 0.10), HBeAg positivity (P = 0.22), and baseline serum ALT (P = 0.38) and HBV DNA (P = 0.96) were not significant.
 
Five patients with HCC had been treated with lamivudine (45%), three with tenofovir (27%), two with adefovir (18%) and one with entecavir (9%). The majority of non-HCC cases (82%) had been treated with entecavir or tenofovir (Table 1; P = 0.004). All five lamivudine-treated patients with HCC had evidence of phenotypic lamivudine resistance, yet all were successfully rescued with a more potent agent within 3 months of confirmed virological breakthrough. At the time of HCC development, 5 of 11 cases had undetectable serum HBV DNA; the others had low-level viraemia (<100 copies/mL). Two patients with HCC died and two underwent liver transplantation (Table S1).
 
Impact of anti-viral treatment on the incidence of HCC and HCC recurrence The observed annual incidence of HCC in the study cohort was 0.9% per year (95% CI 0.5-1.7). This risk was greatest in patients with cirrhosis [annual incidence 4.3% (95% CI 2.2-8.3) vs. 0.2% (95% CI 0.05-0.8) per year in patients without cirrhosis; P < 0.00005; Figure 2]. Based on the REACH-B model, the observed to expected number of HCC cases was significantly reduced by year 4, when there were 7 observed vs. 14 expected HCC cases (SIR 0.49; 95% CI 0.20-1.00; Figure 3). By the end of 9 years of follow-up, the SIR was 0.46 (95% CI 0.23-0.82) based on 11 observed cases vs. 24 predicted by the REACH-B model.
 
The HCC treatment and outcomes of 11 patients who developed HCC despite suppressive NA therapy is summarised in Table S1. Several patients received multiple HCC therapies, including radiofrequency ablation, surgical resection, liver transplant, sorafenib, transarterial chemoembolisation and percutaneous ethanol injection. In total, two patients died from metastatic HCC and 9/11 had no recurrence at last follow-up.
 
Discussion
 
In this retrospective Canadian cohort study, long-term NA therapy appeared to reduce the incidence of HBV-related HCC. Specifically, the observed incidence of HCC was 0.9% per year; significantly lower than predicted in untreated patients based on the REACH-B predictive model. The effect of NA treatment - an approximately 50% relative reduction in the incidence of HCC - was significant as early as 4 years after treatment initiation and remained significant through 9 years of follow-up. This risk reduction is similar to that observed in the randomised trial comparing lamivudine with placebo in patients with advanced hepatic fibrosis reported by Liaw et al., showing that continuous treatment with lamivudine significantly reduced the incidence of hepatic decompensation and HCC.[15] A recently published meta-analysis of over 10 000 treated CHB patients[17] and a retrospective study using propensity score matched cohorts also showed that NA therapy is associated with a reduced risk of HCC, especially in young noncirrhotic subjects,[39] and provides further evidence for the need to inhibit viral replication to avert the risk of HCC. Anti-viral therapy also has potential beneficial effects in terms of recurrence after curative treatment of HBV-related HCC as well as overall survival.[40] In this study, in 11 patients who developed HCC on NA, two patients died due to metastatic disease and nine had no recurrence at last follow-up after receiving potentially curative HCC therapy (i.e. radiofrequency ablation, surgical resection and/or liver transplant). Thus, it is possible that potent NA therapy also prevented HCC recurrence but cannot be definitively proven in this study.
 
In our study, the most important risk factor for HCC development despite NA therapy was the presence of underlying cirrhosis, which increased the unadjusted risk 22-fold. As previously described,[22, 25] patients with HCC were more often male and older than non-HCC cases. However, pre-treatment ALT and HBV DNA concentrations were not statistically significant likely due to the highly effective nature of NA therapy. Interestingly, patients with HCC often had a history of lamivudine resistance, a factor associated with an increased risk of HCC in the study by Liaw and colleagues.[15] However, this characteristic is confounded by patient age and the duration that patients were at risk for HCC. Specifically, as lamivudine was the first oral anti-viral approved to treat CHB in Canada, many patients who developed HCC had been treated with lamivudine for prolonged periods, and therefore, more likely to develop resistance.
 
Several recent nonrandomised studies have evaluated the preventive effect of first-line potent NA therapy on the incidence of HBV-related HCC.[17] In a retrospective study from Japan, patients treated with entecavir had a lower cumulative incidence of HCC at 5 years compared to an untreated control group (3.7% vs. 13.7%; P < 0.001).[19] In a 5-year open-label study, Marcellin et al. reported that treatment with tenofovir leads to regression of HBV-related fibrosis, including cirrhosis.[41] In the same cohort, Kim et al. used methodology as described in our study to compare the number of observed to expected cases of HCC among cirrhotic and noncirrhotic CHB patients using the REACH-B risk prediction model.[42] The authors reported that tenofovir was associated with a 55% reduction in the risk of HCC as early as 3.5 years after treatment initiation. These results are remarkably similar to our own findings. However, the effect of tenofovir was less pronounced in cirrhotic patients. Due to the small number of HCC cases in our study, we could not conduct subgroup analyses in this regard. This study also confirms that anti-viral therapy with newer NAs reduces, but does not eliminate, the probability of HBV-associated HCC despite very effective suppression of viral replication. This is likely due to the early integration of HBV genomic fragments into the host genome, even before the initiation of anti-viral therapy, which could lead to genomic alterations and/or chromosomal instability. Furthermore, the presence of established cirrhosis is an additional independent risk factor for HCC development due to the induction of liver inflammation, cell turnover and regeneration.[43, 44] Although the risk of HBV-related HCC was reduced after 4 years on therapy, cirrhosis is a pre-neoplastic state and the concomitant oncogenic impact of HBV-host genome integration events, warrants ongoing surveillance in all patients with advanced liver disease. However, it remains unknown if the degree of risk reduction would justify changing our current screening guidelines in noncirrhotic patients that have been on potent anti-viral therapy.
 
Our study is a retrospective study with inherent limitations, but to date it is one of the largest North American cohort studies of HBV natural history in patients treated with NAs. Similar to the cohort enrolled in the study by Yang et al.[21] that was used to validate the REACH-B prediction model, our study participants were mainly Asian men with HBeAg-negative CHB of a similar median age (46 vs. 45.7 respectively). In contrast to the Yang study, which included mostly noncirrhotic patients, 20% of our cohort had underlying cirrhosis. Therefore, the REACH-B risk prediction model may not be applicable to this patient subset. Further, it is unknown if the REACH-B model can be applied to Caucasian patients as it was developed and validated in mostly Asian patient cohorts. Most patients included in our study were likely infected prior to immigration from their country of origin; hence it is expected that the model can be applied to persons of Asian descent living in Western countries. We found that underlying cirrhosis, as determined by FibroScan®, US imaging or other biochemical markers, was the most important risk factor for HCC development. Not all patients had TE done at baseline, as this test was not routinely available until 2008 in our clinic. However, in a related study in our clinic, of 2052 consecutive adults who underwent LS measurement by TE between July 2008 and June 2011, we found an independent association between LS and death or hepatic complications (decompensation, HCC and liver transplantation).[45] We also lack data on other factors associated with HCC development including exposure to environmental factors, family history, viral genomic changes as well as HBV genotype.[46, 47] This latter is of interest as HBV genotype C is especially known to be associated with HCC development compared to other genotypes.[48] Although HBV genotyping was not routinely available in our clinic, most patients of Asian descent are likely infected with HBV genotype B or C, as was found in our recent prospective study of HBV genotype epidemiology in Canada.[49] As noted, most patients were on highly potent NA (i.e. entecavir and tenofovir) with suppressed HBV DNA and normal ALT, which is expected to have an even greater effect on reducing the incidence of HCC. A recent analysis of the REVEAL data has shown that long-term changes in HBV DNA and ALT are independent risk factors for HCC.[50] The REACH-B model was initially developed and validated for untreated CHB patients. However, it would not be ethically justifiable to perform placebo-controlled trials with an untreated control group, or comparison studies with less potent NA therapy.
 
Hepatocellular carcinoma is a dreaded complication of chronic HBV infection. The ability to accurately risk-stratify patients with HBV who are treated with NAs in predicting HCC is important from a public health, health economic and an individual patient care perspective. In this large North American retrospective cohort study, we observed that long-term therapy with oral NAs reduces the incidence of HBV-related HCC likely via potent and persistent suppression of viral replication. Despite NA therapy, cirrhotic patients with CHB are still at risk and warrant ongoing surveillance.

 
 
 
 
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