引用本文

庄辉. 慢性乙型肝炎部分治愈是功能性治愈的中间终点，不是理想终点[J]. 中华肝脏病杂志,2025, 33(10):950-954. DOI:10.3760/cma.j.cn501113-20250804-00309.

摘 要

慢性乙型肝炎部分治愈的定义是停药后24周持续HBsAg水平<100 IU/mL和乙型肝炎病毒（HBV）DNA低于定量下限，即<10 IU/mL，它是功能性治愈的中间终点，不是理想的终点。达到部分治愈的慢性乙型肝炎患者，其临床预后良好。定量HBsAg联合新标志物，如HBV RNA、乙型肝炎核心相关抗原、大表面蛋白、中表面蛋白和定量抗-HBc，可预测部分治愈患者停药后病毒学复发和临床复发。部分治愈患者应确保停药后密切监测，停药后发生病毒主导的肝炎发作患者需要再治疗，而宿主主导的肝炎发作患者可不治疗。

一、部分治愈与功能性治愈的区别

部分治愈是指停药后24周，HBsAg阳性，定量<100 IU/mL；抗-HBs阴性（<10 IU/mL）；HBeAg阴性，抗-HBe阳性；乙型肝炎病毒（hepatitis B virus，HBV）DNA<定量下限（lower limit of quantification，LLOQ）（即<10 IU/mL）；丙氨酸转氨酶（alanine transaminase，ALT）正常；cccDNA和整合HBV DNA存在；临床预后改善，但不及功能性治愈；再活动或复发及肝细胞癌风险降低，但高于功能性治愈；应答的持久性低于功能性治愈；有传染性和乙型肝炎歧视［1-10］。因此，部分治愈有别于功能性治愈，是功能性治愈的中间终点，不是理想的终点（ 表1 ）。

由 表1 可见，无论是功能性治愈还是部分治愈，均不是以单独HBsAg一项指标来区分，而是要符合该两个治愈定义的多项标准［1-2］。

二、部分治愈患者的预后

部分治愈可自发或经抗HBV治疗获得。Wang等［11］对138例初治HBsAg阳性但定量<100 IU/mL、HBV DNA未检测到和ALT正常的患者（即自发获得的部分治愈），随访中位数时间25.7个月，13.0%（18/138）患者获得HBsAg自发清除，有显著肝纤维化的发生率为2.2%（3/138），HBV DNA>2 000 IU/mL的发生率为2.9%（4/138），与171例HBsAg>100 IU/mL患者（分别为0、9.9%和7.0%）比较，差异有统计学意义。最近，该团队［12］对521例初治HBsAg阳性、定量<100 IU/mL、HBV DNA未检测到和ALT正常患者（即自发获得的部分治愈），随访中位数时间25.3个月，10.0%（52/521）患者获得HBsAg自发清除。

Hirode等［13］对1 546例经核苷（酸）类似物［nucleos（t）ide analogue，NA］治疗获得病毒学抑制、HBeAg阴性慢性乙型肝炎患者进行了队列探究，停药后随访4年，停药时HBsAg<100 IU/mL患者（部分治愈）的累计HBsAg消失率为43.0%，显著高于停药时HBsAg100～1 000 IU/mL患者（7.4%），以及停药时HBsAg>1 000 IU/mL患者（1.1%）。Liu等［14］系统分析了11项研究，共计1 716例经NA治疗的亚洲慢性乙型肝炎患者（包括HBeAg阳性和阴性），随访至停药后≥12个月，停药时HBsAg<100 IU/mL患者的病毒学复发率和临床复发率范围分别为9.1%～19.6%和15.4%～29.4%，显著低于停药时HBsAg>100 IU/mL患者（范围分别为31.4%～86.8%和48.1%～63.6%）；停药后≥39个月，停药时HBsAg<100 IU/mL患者的HBsAg消失率范围为21.1%～58.8%，显著高于停药时HBsAg>100 IU/mL患者（范围为3.3%～7.4%）。Lim等［15］对24项（16项停药时HBsAg<100 IU/mL和8项停药时HBsAg≥100 IU/mL），共计3 732例经NA治疗、HBeAg阴性慢性乙型肝炎患者进行荟萃和荟萃回归分析，停药时HBsAg<100 IU/mL患者的HBsAg消失率、病毒学复发率和生物化学（临床）复发率分别为41.8%、33.4%和17.3%，与停药时HBsAg≥100 IU/mL患者（分别为4.6%、72.1%和34.6%）比较，差异有统计学意义。

上述研究表明，自发或经抗HBV治疗获得的部分治愈患者，随访期间HBsAg消失率、病毒学复发率、临床复发率如 表2 所示，该3项指标发生率的高低与抗病毒治疗持续时间、NA类型、随访时间、人种、年龄、性别、HBV基因型、治疗前HBeAg情况、HBV DNA水平和HBV准种多样性等因素有关［13-20］。

由于各队列研究的影响因素不同，报告的HBsAg消失率、病毒学复发率和临床复发率差异较大。慢性乙型肝炎患者在获得部分治愈后，与功能性治愈患者不同，停药后，虽有一定比例患者可获得HBsAg消失，但相当比例患者可发生病毒学复发或临床复发，说明部分治愈是功能性治愈的中间终点，不是理想的终点。

三、部分治愈患者的管理

（一）定量HBsAg联合新标志物检测，评价部分治愈患者的停药

对功能性治愈患者随访5～12.4年，HBsAg持续消失率高达90.3%～95.0%［21-25］。因此，只要达到功能性治愈定义各项标准的患者，可以停药，但要定期随访。而部分治愈患者，因停药后复发风险较高，因此，在停药前应进行评估。定量HBsAg联合新生物标志物检测有可能提高HBsAg消失率，降低病毒学复发率和临床复发率。Xie等［26］报告，停药时HBsAg<100 IU/mL且HBV RNA阴性患者，随访24个月的累计病毒学复发率（5%），显著低于停药时HBsAg<100 IU/mL但HBV RNA阳性患者（58%）。Hsu等［27］报告，停药时HBsAg<100 IU/mL且HBcrAg<4 log₁₀ U/mL患者，随访24个月的累计病毒学复发率（10.5%）显著低于停药时HBsAg<100 IU/mL但HBcrAg≥4 log₁₀ U/mL患者（56.7%）。Suzuki等［28］报告，对停药时HBsAg<100 IU/mL且HBcrAg <3 log₁₀ U/ml患者，随访1年，无病毒学复发。上述研究表明，HBsAg联合HBV RNA和/或HBcrAg可能对评价部分治愈患者停药有意义。 图1 为部分治愈患者停药后监测示意图［29］。

Pfefferkorn等［30］报告，接受NA治疗的慢性乙型肝炎患者，其血清HBV大、中表面蛋白消失早于HBsAg。Bae等［31］报告，定量抗-HBc水平（qAnti-HBc）与肝内共价闭合环状DNA呈正相关；慢性乙型肝炎患者接受抗病毒治疗，HBsAg消失患者的抗-HBc 水平较低［32-34］。定量HBsAg联合上述新标志物能否作为部分治愈患者停药的评价指标，值得进一步研究。

（二）部分治愈患者停药后监测和复发后再治疗

达到HBsAg<100 IU/mL、HBV DNA<10 IU/mL、HBeAg转换和ALT恢复正常的患者只有在确保停药后密切监测12个月以上，方可停药［9，13］。停药后头3个月每月检测1次ALT、HBsAg和HBV DNA；尔后每2～3个月检测1次ALT、HBsAg和HBV DNA；1年后每3～6个月检测1次ALT、HBsAg和HBV DNA（图1）。

Liaw等［35-36］指出（如 图2 ），慢性乙型肝炎患者停药后肝炎发作（hepatic flare）分为2类：一类为宿主主导（好的）的肝炎发作，通过有效免疫可清除HBV；另一类为病毒主导（坏的）的肝炎发作，免疫应答失败，不能有效清除病毒。

病毒主导的肝炎发作需要再治疗，而宿主主导的肝炎发作可暂缓再治疗［35-37］，因此，正确区分该两类肝炎发作极为重要。肝炎发作后再治疗不能太晚，也不能太早［35-41］。目前，复发或肝炎发作的再治疗至少有8种方案［42］，但最佳再治疗时机是基于病毒载量、病毒动力学还是ALT水平，至今尚未定论，仍需进一步研究。

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