The long‐term clinical impact of low‐level viremia (LLV; <2,000 IU/mL) is not well understood. As a result, it is unclear whether the development of LLV during entecavir monotherapy requires a change in therapy. A retrospective cohort of 875 treatment‐naive chronic hepatitis B virus (HBV) monoinfected patients (mean age 47.7 years, male = 564 [65.5%], cirrhosis = 443 [50.6%]) who received entecavir monotherapy were analyzed for the development of hepatocellular carcinoma (HCC). The HCC risk was compared between patients who maintained virological response (MVR), defined by persistently undetectable HBV DNA (<12 IU/mL), and patients who experienced LLV, defined by either persistent or intermittent episodes of <2,000 IU/mL detectable HBV DNA. During a median 4.5 years of follow‐up (range 1.0‐8.7 years), HCC was diagnosed in 85 patients (9.7%). HCC developed more frequently in patients who experienced LLV than MVR (14.3% versus 7.5% at 5 years, P = 0.015). The hazard ratio comparing those with LLV to MVR was 1.98 (95% confidence interval = 1.28‐3.06, P = 0.002, adjusted for age, sex, hepatitis B e antigen, baseline HBV DNA levels, and cirrhosis). Among patients with cirrhosis, those with LLV exhibited a significantly higher HCC risk than those with MVR (HCC incidence rate at 5 years 23.4% versus 10.3%, adjusted hazard ratio = 2.20, 95% confidence interval 1.34‐3.60; P = 0.002). However, for patients without cirrhosis, there was no significant difference in the HCC risk between LLV and MVR. Conclusion: LLV observed during entecavir monotherapy was associated with a higher risk of HCC, especially for those with cirrhosis, indicating that LLV during potent antiviral therapy is consequential. (Hepatology 2017;66:335–343).

Controversy exists about whether antiviral therapy (AVT) should be recommended for compensated cirrhosis patients with chronic hepatitis B virus (HBV) infection and detectable, but low, serum HBV‐DNA levels. A retrospective cohort of 385 treatment‐naïve, HBV‐related compensated cirrhosis patients (mean age: 51.1 ± 9.7 years; 66% male) with low HBV‐DNA levels (<2,000 IU/mL) was assessed for the development of hepatocellular carcinoma (HCC). During a median of 5.6 years of follow‐up, HCC had developed in 37 (9.6%) patients. The 5‐year cumulative HCC incidence rate was 2.2%, 8.0%, and 14.0% for patients with undetectable HBV DNA (<12 IU/mL), low HBV‐DNA levels plus normal alanine aminotransferase (ALT) levels, and low HBV‐DNA levels plus elevated ALT levels at baseline (P = 0.011). During follow‐up, 71 patients maintained undetectable HBV‐DNA levels, and 126 experienced HBV‐DNA elevation over 2,000 IU/mL. AVT was initiated in 77 patients. In patients without AVT, the 5‐year cumulative HCC incidence rates were 13.3%, 8.8%, and 1.4% for those who experienced HBV‐DNA elevation, those who maintained detectable, but low, HBV‐DNA levels, and those who maintained undetectable HBV‐DNA levels, respectively. The 5‐year cumulative HCC incidence rate was 5.9% for patients who started AVT; longer AVT duration and longer complete virological response (<12 IU/mL) duration was associated with lower HCC risk. Conclusion: Compensated cirrhosis patients with detectable, but low, viral load were not at low risk for HCC, and AVT was associated with lower HCC risk, suggesting that prompt AVT should be considered for these patients. (Hepatology 2015;62:694–701)

We assessed the association among ultrasonographically detected non-alcoholic fatty liver disease (US-NAFLD), metabolic syndrome (MetS), and insulin resistance (IR) in non-obese, non-diabetic middle-aged adults, to find out whether US-NAFLD is independently associated with IR in this population. A total of 5,878 non-obese (body mass index, ≥18.5 and <25), non-diabetic individuals were analyzed. IR was estimated with the homeostasis model assessment index (HOMA2–IR) and defined when HOMA2–IR ≥1.5. MetS was defined by the Adult Treatment Panel III (ATP III) criteria. MetS was present in 381 (6.5%) participants, IR was present in 801 (13.6%) participants, and US-NAFLD was present in 1,611 (27.4%) participants. The increase in the prevalence of US-NAFLD closely followed the increase in the number of metabolic components diagnosed according to the ATP III criteria (15.2%, 28.5%, 48.0%, 65.7%, 71.4%, and 100% for 0, 1, 2, 3, 4, and 5 metabolic components, respectively, P<0.001). US-NAFLD showed a significantly higher odds ratio (OR) for IR, regardless of the number of metabolic components (OR (95% confidence interval) of 3.48 (2.45–4.94), 3.63 (2.74–4.82), 3.19 (2.29–4.44), and 2.43 (1.43–3.81) for 0, 1, 2, and ≥3 metabolic components, respectively, P<0.001 for all values). MetS showed a low sensitivity (0.22) for the identification of individuals with IR, and either US-NAFLD alone (0.60) or US-NAFLD with MetS (0.66) improved sensitivity with acceptable trade-off in specificity. US-NAFLD was an independent predictor for IR, irrespective of the number of metabolic components of MetS in the non-obese, non-diabetic middle-aged Asian adults. US-NAFLD could identify individuals with IR that cannot be identified by MetS in this population.

Background/Aims: Although hepatocellular carcinoma (HCC) is notorious for its high recurrence rate, some patients do not experience recurrence for more than 5 years after resection or radiofrequency ablation for early-stage HCC. For those with five recurrence-free period, the risk of HCC recurrence within the next 5 years remains unknown.Methods: A total of 1,451 consecutive patients (median, 55 years old; males, 79.0%; hepatitis B virus-related, 79.3%) with good liver function (Child-Pugh class A) diagnosed with early-stage HCC by Barcelona Clinic Liver Cancer Staging and received radiofrequency ablation or resection as an initial treatment between 2005 and 2010 were analyzed.Results: During a median follow-up period of 8.1 years, 961 patients (66.2%) experienced HCC recurrence. The cumulative recurrence rates increased to 39.7%, 60.3%, and 71.0% at 2, 5, and 10 years, respectively, and did not reach a plateau. Five years after HCC diagnosis, 487 patients were alive without experiencing a recurrence. Among them, during a median of 3.9 additional years of follow-up (range, 0.1–9.0 years), 127 patients (26.1%) experienced recurrence. The next 5-year cumulative recurrence rate (5–10 years from initial diagnosis) was 27.0%. Male sex, higher fibrosis-4 scores, and alpha-fetoprotein levels at 5 years were associated with later HCC recurrence among patients who did not experience recurrence for more than 5 years.Conclusions: The HCC recurrence rate following 5 recurrence-free years after HCC treatment was high, indicating that HCC patients warrant continued HCC surveillance, even after 5 recurrence-free years.