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%, χ (2) = 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.
目的： 观察恩替卡韦（ETV）经治后低病毒血症（LLV）的慢性乙型肝炎患者序贯或联合富马酸丙酚替诺福韦（TAF）的疗效及影响因素。 方法： 回顾性收集2020年1月至2022年9月于南昌大学第一附属医院感染科的经ETV抗病毒治疗的慢性乙型肝炎患者126例，根据治疗期间的HBV DNA水平，将患者分为完全病毒学应答组（n = 84）和LLV组（n = 42），对两组患者基线及48周的临床特征和实验室指标进行单因素分析。根据LLV组患者继续抗病毒治疗方案分为3组：续用ETV为对照组、换用TAF为序贯组、ETV联合TAF为联合组，并持续抗病毒治疗至96周。对3组患者48周的资料进行单因素方差分析，比较3组患者96周抗病毒治疗后HBV DNA转阴率、HBeAg转阴率、丙氨酸转氨酶、肌酐和肝硬度测定值。用多因素logistic回归分析LLV患者96周HBV DNA未转阴发生的独立影响因素，用受试者操作特征曲线评估预测LLV患者96周HBV DNA未转阴发生的效能。运用KaPlan-Meier分析LLV患者的DNA累积转阴率，用Log-Rank检验进行比较；动态观察治疗期间HBV DNA和HBV DNA转阴率。 结果： 完全病毒学应答组与LLV组单因素分析结果显示基线时年龄、人体质量指数、HBeAg阳性率、HBV DNA、HBsAg、丙氨酸转氨酶、天冬氨酸转氨酶、肝硬度测定值差异均有统计学意义（P值均<0.05）。3组LLV患者48周单因素方差分析结果显示差异均无统计学意义（P值均> 0.05）；96周治疗后序贯组及联合组HBV DNA转阴率明显高于对照组（88.89%比41.18%、85.71%比41.18%，χ(2) = 10.404，P = 0.006），HBeAg转阴率高于对照组，差异无统计学意义（P值> 0.05）；序贯组及联合组的丙氨酸转氨酶、肌酐、肝硬度测定值与对照组相比均有不同程度改善，差异均具有统计学意义（P值均< 0.05）。48周后续用ETV和48周HBV DNA是LLV患者96周HBV DNA未转阴的独立危险因素（P值均<0.05）。48周HBV DNA的受试者操作特征曲线下面积为0.735（95%CI：0.578~0.891），cut-off值为2.63 log(10) IU/ml，灵敏度、特异度分别为76.90%、72.40%。48周续用ETV和48周HBV DNA≥2.63 log(10) IU/ml LLV患者HBV DNA转阴率明显低于序贯或联合TAF和48周HBV DNA < 2.63 log(10) IU/ml的患者。继续治疗48周至96周期间，序贯组和联合组72、84、96周的HBV DNA转阴率均高于对照组，差异均具有统计学意义（P值均< 0.05）。 结论： 序贯或联合TAF抗病毒治疗可以更有效地提高ETV经治后发生LLV的慢性乙型肝炎患者96周完全病毒学应答率，且可以改善患者肝肾功能和减轻肝纤维化程度。48周后续用ETV和48周时HBV DNA载量是LLV患者96周HBV DNA未转阴的独立预测因素。.
Keywords: Chronic hepatitis B; Dynamic changes; Low-level viremia; Tenofovir alafenamide fumarate tablets; sequential combination therapy.