BACKGROUND. It is unclear whether the level of serum hepatitis B virus (HBV) DNA at baseline affects the on-treatment risk of hepatocellular carcinoma (HCC) in hepatitis B e antigen–positive (HBeAg-positive), noncirrhotic patients with chronic hepatitis B (CHB). METHODS. We conducted a multicenter cohort study including 2073 entecavir- or tenofovir-treated, HBeAg-positive, noncirrhotic adult CHB patients with baseline HBV DNA levels of 5.00 log₁₀ IU/mL or higher at 3 centers in South Korea between January 2007 and December 2016. We evaluated the on-treatment incidence rate of HCC according to baseline HBV DNA levels. RESULTS. During a median 5.7 years of continuous antiviral treatment, 47 patients developed HCC (0.39 per 100 person-years). By Kaplan-Meier analysis, the risk of HCC was lowest in patients with baseline HBV DNA levels of 8.00 log₁₀ IU/mL or higher, increased incrementally with decreasing viral load, and was highest in those with HBV DNA levels of 5.00–5.99 log₁₀ IU/mL (P < 0.001). By multivariable analysis, the baseline HBV DNA level was an independent factor that was inversely associated with HCC risk. Compared with HBV DNA levels of 8.00 log₁₀ IU/mL or higher, the adjusted HRs for HCC risk with HBV DNA levels of 7.00–7.99 log₁₀ IU/mL, 6.00–6.99 log₁₀ IU/mL, or 5.00–5.99 log₁₀ IU/mL were 2.48 (P = 0.03), 3.69 (P = 0.002), and 6.10 (P < 0.001), respectively. CONCLUSION. On-treatment HCC risk increased incrementally with decreasing baseline HBV DNA levels in the range of 5.00 log₁₀ IU/mL or higher in HBeAg-positive, noncirrhotic adult patients with CHB. Early initiation of antiviral treatment when the viral load is high (≥8.00 log₁₀ IU/mL) may maintain the lowest risk of HCC for those patients. FUNDING. Patient-Centered Clinical Research Coordinating Center (PACEN) (grant no. HC20C0062) of the National Evidence-based Healthcare Collaborating Agency; National R&D Program for Cancer Control through the National Cancer Center (grant no. HA21C0110), Ministry of Health and Welfare, South Korea.

Telbivudine has been suggested to induce hepatitis B surface antigen (HBsAg) decline to the similar degree as pegylated interferon. We aimed to investigate whether telbivudine could further decrease HBsAg titer in patients who maintain undetectable serum hepatitis B virus (HBV) DNA after initial entecavir treatment. In this open-label trial, patients who had serum HBsAg and HBV DNA levels ≥1,000 IU/mL and 0.5 log₁₀ IU/mL. Eleven patients (23.4%) in the telbivudine group, but none in the entecavir group, experienced virologic breakthrough (P < 0.001). Seven patients (14.9%) exhibited genotypic resistance mutations (M204I +/− L180M) during the virologic breakthrough. Sequential therapy with entecavir followed by telbivudine resulted in a high rate of virologic breakthrough and drug-resistance without any beneficial effect on HBsAg decline. These results do not support the use of low genetic barrier drugs as a switch treatment strategy in patients who achieve virologic response with high genetic barrier drugs. NCT01595685 (date of trial registration: May 8, 2012)

Aim and Objectives: Direct-acting antiviral (DAA) therapy can cure chronic hepatitis C (CHC), and daclatasvir (DCV)/asunaprevir (ASV) was the first interferon-free DAA therapy introduced in Korea. Patients who achieve sustained virologic response (SVR) after DAA treatment are expected to have good prognoses. Therefore, in this study, we aimed to investigate the prognosis of these patients. Materials and Methods: This multicenter prospective observational study included patients with CHC who achieved SVR after DCV/ASV treatment. The primary endpoint was hepatocellular carcinoma (HCC) occurrence, which was reviewed annually. Results: We included 302 patients (median follow-up duration: 38 [16.5–60.0] months; median age: 58 [49–67] years) in the study. Cirrhosis was observed in 103 patients (34.1%), and the median Child–Pugh score was 5.0. HCC occurred in 16 patients (5.3%) within six years post-SVR; these patients were older and had higher cirrhosis prevalence, alpha-fetoprotein levels, and fibrosis-4 index scores than did those without HCC development. Cox proportional hazards analysis revealed that age > 71 years (p = 0.005) and cirrhosis (p = 0.035) were significant risk factors for HCC occurrence. Conclusions: Although the prognoses of patients who achieved SVR with DCV/ASV therapy were generally good, the risk for HCC was present, especially in older patients and in those with cirrhosis. Hence, early treatment at younger ages and regular follow-up surveillance after achieving SVR are warranted.

Background and Objectives: Chronic hepatitis C (CHC) can be cured with direct-acting antiviral (DAA) therapy. In Korea, sofosbuvir (SOF) and ledipasvir (LDV)/SOF were launched in 2016. Patients who achieve a sustained virologic response (SVR) following DAA treatment are predicted to have a favorable prognosis. Nevertheless, little is known regarding the prognosis of Korean CHC patients who receive SOF-based treatment and achieve SVR. Therefore, the purpose of this study was to look into the long-term outcomes for these patients. Materials and Methods: This was a prospective, multicenter observational study. CHC patients were enrolled who, following SOF or LDV/SOF treatment, had achieved SVR. The last day for follow-up was December 2023. The primary endpoint was HCC occurrence, which was checked at least once per year. Results: A total of 516 patients were included in this analysis, with a median follow-up duration of 39.0 months. Among them, 231 were male patients (44.8%), with a median age of 62.0 years. Genotypes were 1 (90, 17.4%), 2 (423, 82.0%), and 3 (3, 0.6%). The combination of SOF plus ribavirin was the most common treatment (394, 76.4%). In total, 160 patients were cirrhotic (31.0%), and the mean Child–Pugh score was 5.1. Within a maximum of 7 years, 21 patients (4.1%) developed HCC. Patients with HCC were older (69 vs. 61 years, p = 0.013) and had a higher cirrhosis incidence (81.0 vs. 28.9%, p < 0.001), higher AFP (6.0 vs. 3.3, p = 0.003) and higher APRI (0.8 vs. 0.5, p = 0.005). Age over 65 (p = 0.016) and cirrhosis (p = 0.005) were found to be significant risk factors for HCC by Cox regression analysis. Conclusions: Patients who achieved SVR with SOF-based treatment had a relatively favorable prognosis. However, the risk of HCC was not eliminated, especially in older and cirrhotic patients. Therefore, routine follow-up, surveillance, and early treatment are required.

Background and Aims: Glecaprevir/pibrentasvir achieves sustained virologic response (SVR) rates above 95% in chronic hepatitis C (CHC). Nevertheless, the residual risk of hepatocellular carcinoma (HCC) after SVR, especially in patients with advanced liver disease, has not been fully defined. We prospectively evaluated longitudinal changes in liver function and fibrosis and sought predictors of post-SVR HCC in a real-world multicenter cohort. Methods: A total of 395 CHC patients who attained SVR with glecaprevir/pibrentasvir were followed prospectively. Liver function tests, noninvasive fibrosis indices, and clinical outcomes were recorded at predefined intervals. Cox proportional hazards regression identified factors associated with incident HCC. Results: Over a median follow-up of 31.1 months, HCC occurred in 16 patients (4.1%). From univariate analysis, baseline FIB-4 > 3.25, APRI > 1.5, MELD ≥ 10, Child–Pugh score ≥ 6, and clinically significant portal hypertension were associated with HCC. Multivariate analysis retained FIB-4 > 3.25 (p = 0.003) and MELD ≥ 10 (p = 0.032) as independent predictors. Cumulative incidence rose stepwise with the number of risk factors. Conclusions: Despite a virologic cure, patients with advanced fibrosis or impaired liver function remain susceptible to HCC. Risk stratification using FIB-4 and MELD and continued surveillance are therefore warranted.