OBJECTIVES It was suggested that normalization of serum alanine aminotransferase (ALT) levels at 1 year of antiviral treatment is associated with a lower risk of hepatic events in patients with chronic hepatitis B (CHB). However, it remains unclear whether earlier ALT normalization is associated with lower hepatocellular carcinoma (HCC) risk, independent of fatty liver or cirrhosis and on-treatment virological response (VR), in patients with CHB. METHODS We analyzed 4,639 patients with CHB who initiated treatment with entecavir or tenofovir using landmark analysis and time-dependent Cox analysis. We defined normal ALT as ≤35 U/L (men) and ≤25 U/L (women) and VR as serum hepatitis B virus DNA <15 IU/mL. RESULTS During a median 5.6 years of treatment, 509 (11.0%) patients developed HCC. ALT normalization occurred in 65.6% at 1 year and 81.9% at 2 years and was associated with a significantly lower HCC risk in landmark (P < 0.001) and time-dependent Cox analyses (adjusted hazard ratio [AHR] 0.57; P < 0.001). Compared with ALT normalization within 6 months, delayed ALT normalization at 6-12, 12-24, and >24 months was associated with incrementally increasing HCC risk (AHR 1.40, 1.74, and 2.45, respectively; P < 0.001), regardless of fatty liver or cirrhosis at baseline and VR during treatment. By contrast, neither earlier VR (AHR 0.93; P = 0.53) nor earlier hepatitis B e antigen seroclearance (AHR 0.91; P = 0.31) was associated with a significantly lower HCC risk. DISCUSSION In patients with CHB treated with entecavir or tenofovir, earlier ALT normalization was independently associated with proportionally lower HCC risk, regardless of fatty liver or cirrhosis at baseline and on-treatment VR.

中文翻译：

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抗病毒治疗期间早期丙氨酸氨基转移酶正常化与慢性乙型肝炎肝细胞癌风险降低独立相关

目的 有人提出，抗病毒治疗 1 年时血清丙氨酸转氨酶 (ALT) 水平正常化与慢性乙型肝炎 (CHB) 患者发生肝脏事件的风险降低有关。然而，尚不清楚在 CHB 患者中，较早的 ALT 正常化是否与较低的肝细胞癌 (HCC) 风险相关，而与脂肪肝或肝硬化和治疗中病毒学反应 (VR) 无关。方法 我们使用标志性分析和时间依赖性 Cox 分析分析了 4,639 名开始使用恩替卡韦或替诺福韦治疗的 CHB 患者。我们将正常 ALT 定义为≤35 U/L（男性）和≤25 U/L（女性），VR 定义为血清乙型肝炎病毒 DNA <15 IU/mL。结果 在中位 5.6 年的治疗期间，509 名 (11.0%) 患者发展为 HCC。1 年和 81 年时 65.6% 的 ALT 正常化。2 年时为 9%，并且在地标 (P < 0.001) 和时间依赖性 Cox 分析（调整后的风险比 [AHR] 0.57；P < 0.001）中与显着降低的 HCC 风险相关。与 6 个月内 ALT 正常化相比，延迟 6-12、12-24 和 >24 个月的 ALT 正常化与逐渐增加的 HCC 风险相关（AHR 分别为 1.40、1.74 和 2.45；P < 0.001），与脂肪无关基线时的肝脏或肝硬化和治疗期间的 VR。相比之下，早期 VR（AHR 0.93；P = 0.53）和早期乙型肝炎 e 抗原血清清除（AHR 0.91；P = 0.31）均与显着降低 HCC 风险相关。讨论 在接受恩替卡韦或替诺福韦治疗的 CHB 患者中，早期 ALT 正常化与成比例地降低 HCC 风险独立相关，