Objective: To investigate the demographic characteristics and clinical influencing factors which associates with the occurrence probability of persistent or intermittent hypoviremia (LLV) in patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogues (NAs). Methods: A single-center retrospective analysis was performed on patients with CHB who received outpatient NAs therapy for≥48 ± 2 weeks. According to the serum hepatitis B virus (HBV) DNA load at 48±2 weeks treatment, the study groups were divided into LLV (HBV DNA < 20 IU/ml and < 2 000 IU/ml) and MVR group (sustained virological response, HBV DNA < 20 IU/ml). Demographic characteristics and clinical data at the start of NAs treatment (considered as baseline) were retrospectively collected for both patient groups. The differences in the reduction of HBV DNA load during treatment was compared between the two groups. Correlation and multivariate analysis were further conducted to analyze the associated factors influencing the LLV occurrence. Statistical analysis was performed using the independent samples t-test, c2 test, Spearman analysis, multivariate logistic regression analysis, or area under the receiver operating characteristic curve. Results: A total of 509 cases were enrolled, with 189 and 320 in the LLV and MVR groups, respectively. Compared to patients with MVR group at baseline: (1) the demographics characteristics of patients showed that LLV group was younger in age (39.1 years, P = 0.027), had a stronger family history (60.3%, P = 0.001), 61.9% received ETV treatment, and higher proportion of compensated cirrhosis (20.6%, P = 0.025) at baseline; (2) the serum virological characteristics of patients showed that LLV group had higher HBV DNA load, qHBsAg level, qHBeAg level, HBeAg positive rate, and the proportion of genotype C HBV infection but decreased HBV DNA during treatment (P < 0.001) at baseline; (3) the biochemical characteristics of patients showed that LLV group had lower serum ALT levels (P = 0.007) at baseline; (4) the noninvasive fibrosis markers of patients showed that LLV group were characterized by high aspartate aminotransferase platelet ratio index (APRI) (P = 0.02) and FIB-4 (P = 0.027) at baseline. HBV DNA, qHBsAg and qHBeAg were positively correlated with LLV occurrence (r = 0.559, 0.344, 0.435, respectively), while age and HBV DNA reduction were negatively correlated (r = -0.098, -0.876, respectively). Logistic regression analysis showed that ETV treatment history, high HBV DNA load at baseline, high qHBsAg level, high qHBeAg level, HBeAg positive, low ALT and HBV DNA level were independent risk factors for patients with CHB who developed LLV with NAs treatment. Multivariate prediction model had a good predictive value for LLV occurrence [AUC 0.922 (95%CI: 0.897 ~ 0.946)]. Conclusion: In this study, 37.1% of CHB patients treated with first-line NAs has LLV. The formation of LLV is influenced by various factors. HBeAg positivity, genotype C HBV infection, high baseline HBV DNA load, high qHBsAg level, high qHBeAg level, high APRI or FIB-4 value, low baseline ALT level, reduced HBV DNA during treatment, concomitant family history, metabolic liver disease history, and age < 40 years old are potential risk factors for developing LLV in patients with CHB during the therapeutic process.
目的： 探讨慢性乙型肝炎(CHB)患者核苷（酸）类似物（NAs）经治发生持续或间歇性低病毒血症（LLV）可能的相关人群特征及其临床影响因素。 方法： 单中心对接受NAs治疗≥（48±2）周的门诊CHB患者进行回顾性分析。依据治疗（48±2）周血清乙型肝炎病毒（HBV）DNA载量进行研究分组：LLV组（20 IU/ml<HBV DNA<2 000 IU/ml）和持续性病毒学应答组（MVR，HBV DNA<20 IU/ml）；回溯收集2组患者在开始接受NAs治疗当时的人口学特征、临床资料作为基线及治疗中HBV DNA载量下降幅度进行组间差异性比较，进一步行相关性及多因素分析影响患者发生LLV的相关因素。采用独立样本t检验、Mann-Whitney U检验、c检验、Spearman分析、logistic多因素回归分析或受试者操作特征曲线下面积进行统计学分析。 结果： 共纳入509例CHB患者，其中LLV组189例、MVR组320例。与MVR组患者基线比较：(1)LLV组患者呈现年龄偏小(39.1岁，P = 0.027)、多有家族史(60.3%，P = 0.001)、61.9%的患者接受恩替卡韦治疗，代偿期肝硬化占比偏高(20.6%，P = 0.025)等人口学基线特征；(2)LLV组患者呈现HBV DNA载量、qHBsAg水平、qHBeAg水平、HBeAg阳性率、C基因型HBV感染比例均在较高水平状态以及治疗中HBV DNA下降幅度低(P<0.001)等血清病毒学基线特征；(3)LLV组患者呈现丙氨酸转氨酶（ALT）水平低（P = 0.007）等血清生化学基线特征；（4）LLV组患者呈现为天冬氨基酸转移酶和血小板比率指数（APRI）(P = 0.02)、FIB-4（P = 0.027）偏高的无创肝纤维化指标基线特征。其中HBV DNA、qHBsAg及qHBeAg与LLV的发生呈正相关（r值分别为0.559、0.344、0.435），而年龄、HBV DNA下降幅度呈负相关（r值分别为-0.098、-0.876）；logistic回归分析提示恩替卡韦治疗史、基线高HBV DNA载量、高qHBsAg水平、高qHBeAg水平、HBeAg阳性、低ALT水平及低HBV DNA下降幅度均为影响NAs经治CHB患者发生LLV的独立风险因素；多因素预测模型对LLV发生有较好的预测价值[AUC 0.922（95%CI：0.897~0.946）]。 结论： 研究中有37.1%经一线NAs治疗的CHB患者存在LLV。LLV的形成是多因素影响所致。HBeAg阳性、C基因型HBV感染、基线高HBV DNA载量、高qHBsAg水平、高qHBeAg水平、高APRI或FIB-4值、基线低水平ALT、治疗中HBV DNA下降幅度低、同时合并有家族史、代谢性肝病史、年龄<40岁的CHB患者存在治疗过程发生LLV的潜在风险。.
Keywords: Chronic hepatitis B; Low-level viremia; Nucleos(t)ide analogues; Risk factors.