Objective:To observe the efficacy and factors influencing sequential or combined tenofovir alafenamide fumarate (TAF) after treatment with entecavir (ETV) in patients with chronic hepatitis B (CHB) with low-level viremia (LLV).Methods:126 CHB cases treated with ETV antiviral therapy in the Department of Infectious Diseases of the First Affiliated Hospital of Nanchang University from January 2020-September 2022 were retrospectively collected. Patients were divided into a complete virologic response (CVR) group ( n = 84) and a low-level viremia (LLV) group ( n = 42) according to the HBV DNA level during treatment. Clinical characteristics and laboratory indicators of the two groups at baseline and 48 weeks were analyzed by univariate analysis. Patients in the LLV group were divided into three groups according to their continued antiviral treatment regimen until 96 weeks: continued use of ETV as a control group; replacement of TAF as a sequential group; and combination of ETV and TAF as a combined group. The data of the three groups of patients were analyzed by one-way analysis of variance for 48 weeks. HBV DNA negative conversion rate, HBeAg negative conversion rate, alanine aminotransferase (ALT), creatinine (Cr), and liver stiffness test (LSM) were compared among the three groups after 96 weeks of antiviral treatment. Multivariate logistic regression was used to analyze the independent factors influencing the occurrence of HBV DNA non-negative conversion in LLV patients at 96 weeks. Receiver operating characteristic curve (ROC) was used to evaluate the effectiveness of predicting the occurrence of HBV DNA non-negative conversion in LLV patients at 96 weeks. Kaplan-Meier was used to analyze the cumulative negative rate of DNA in LLV patients, and the Log-Rank test was used for comparison. HBV DNA and HBV DNA negative conversion rates during treatment were observed dynamically. Results:Univariate analysis showed statistically significant differences in age, BMI, HBeAg positivity rate, HBV DNA, HBsAg, ALT, AST, and LSM at baseline between the CVR group and the LLV group ( P < 0.05). Univariate analysis of variance revealed no statistically significant difference among the three groups of LLV patients at 48 weeks ( P > 0.05). HBV-DNA negative conversion rate in the sequential group and the combination group was significantly higher than that in the control group after 96 weeks of treatment (88.89% vs. 41.18%, 85.71% vs. 41.18%, χ2 = 10.404, P = 0.006). HBeAg negative conversion rate was higher than that of the control group, with no statistically significant difference ( P > 0.05).Compared with the control group, ALT, Cr, and LSM in the sequential group and the combined group were equally improved to varying degrees, with a statistically significant difference ( P < 0.05). Subsequent use of ETV and HBV DNA at 48 weeks were independent risk factors for HBV DNA positivity at 96 weeks in LLV patients ( P < 0.05). The AUC of HBV DNA at 48 weeks was 0.735 (95% CI: 0.578 ~ 0.891), the cut-off value was 2.63 log 10 IU/ml, and the sensitivity and specificity were 76.90% and 72.40%, respectively. DNA conversion rate was significantly lower in LLV patients receiving 48-week ETV and 48-week HBV DNA≥2.63 log10 IU/mL than in patients receiving sequential or combined TAF and 48-week HBV DNA < 2.63 log 10 IU/mL. HBV DNA negative conversion rates in the sequential group and combined group at 72 weeks, 84 weeks, and 96 weeks were higher than those in the control group during the period from 48 weeks to 96 weeks of continuous treatment, and the differences were statistically significant ( P < 0.05). Conclusion:Sequential or combined TAF antiviral therapy could more effectively improve the 96-week CVR rate, as well as hepatic and renal function, and alleviate the degree of hepatic fibrosis in CHB patients with LLV following ETV treatment. Subsequent use of ETV and HBV DNA load at 48 weeks were independent predictors of HBV DNA positivity at 96 weeks in LLV patients.

Objective To investigate the influencing factors for low-level viremia (LLV) and their dynamic changes in chronic hepatitis B (CHB) patients treated with nucleos(t)ide analogues (NAs) for the first time. Methods A retrospective analysis was performed for 78 CHB patients who attended Department of Infectious Diseases, The First Affiliated Hospital of Nanchang University, from November 2020 to March 2022 and received antiviral therapy with NAs for at least 12 months, and according to HBV DNA level during treatment, they were divided into sustained virologic response (SVR) group with 58 patients and LLV group with 20 patients. The independent samples t -test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups. The multivariate Logistic regression analysis was used to investigate the independent influencing factors for LLV and establish a predictive model, and the receiver operating characteristic (ROC) curve was used to evaluate the predictive value of this model. The Kaplan-Meier method was used to analyze cumulative HBV DNA negative conversion rate, and the Log-rank test was used for comparison. The analysis of variance with repeated measures was used to analyze the differences in HBV DNA and HBsAg between the two groups or within each group at weeks 0, 12, 24, 36, and 48. Results Compare with the SVR group, the LLV group had significantly higher HBeAg positive rate (90.0% vs 48.3%, χ 2 =10.701, P =0.001), log(HBV DNA) value (7.26±1.46 vs 5.65±1.70, t =-4.178, P < 0.001), and log(HBsAg) value (4.53±0.86 vs 3.44±0.93, t =-4.813, P < 0.001) and significantly lower age [29 (26-34) vs 33 (30-43), Z =-2.751, P =0.009], alanine aminotransferase (ALT) [67.0 (54.0-122.0)U/L vs 111.0 (47.0-406.0)U/L, Z =-2.203, P =0.028], aspartate aminotransferase [43.5 (32.8-62.8) U/L vs 77.5 (35.0-213.0)U/L, Z =-2.466, P =0.014], and liver stiffness measurement [7.7 (6.3-8.5)kPa vs 8.9 (7.2-11.4)kPa, Z =-2.022, P =0.043]. The multivariate logistic regression analysis showed that baseline HBV DNA (odds ratio [ OR ]=2.365, 95% confidence interval [ CI ]: 1.220-4.587, P =0.011), HBsAg ( OR =4.229, 95% CI : 1.098-16.287, P =0.036), and ALT ( OR =0.965, 95% CI : 0.937-0.994, P =0.018) were independent influencing factors for LLV in CHB patients, and the predictive model of Logit(MLLV)=-8.668+1.441×lgHBsAg+0.598×lgHBV DNA-0.016×ALT was established based on these factors, which had a larger area under the ROC curve than HBV DNA, HBsAg, and ALT (0.931 vs 0.774/0.856/0.666), with a sensitivity of 85.00% and a specificity of 93.10% at the optimal cut-off value of 0.44. The CHB patients with baseline HBV DNA > 7.29 lgIU/mL or HBsAg > 4.38 lgIU/mL had a significantly lower DNA negative conversion rate than those with DNA ≤7.29 lgIU/mL or HBsAg ≤4.38 lgIU/mL ( χ 2 =22.52 and 26.35, both P < 0.001). In the CHB patients, the highest reduction rates of HBV DNA and HBsAg were observed at weeks 12 and 24, respectively, and the LLV group had significantly higher levels of HBV DNA and HBsAg than the SVR group at weeks 0, 12, 24, 36, and 48 (HBV DNA: t =-4.084, -4.526, -5.688, -7.123, and -6.266, all P < 0.001; HBsAg: t =-4.652, -4.691, -4.952, -4.804, and -4.407, all P < 0.001). Conclusion For the CHB patients treated with NAs for the first time, those with high HBV DNA load, high HBsAg quantification, and low ALT level at baseline are more likely to develop LLV, and dynamic monitoring of these indices is of great significance to observe the onset of LLV.