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HBV DNA阴性、HBsAg阳性的乙型肝炎肝硬化代偿期患者需要抗病毒治疗吗？
DOI: 10.3969/j.issn.1001-5256.2023.01.006
Do HBV DNA-negative HBsAg-positive patients with compensated hepatitis B cirrhosis need antiviral therapy?
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摘要: HBV感染为我国肝病的常见病因，随着慢性乙型肝炎(CHB)抗病毒治疗相关研究的不断进展，抗病毒适应证也在不断扩大。然而，CHB患者抗病毒治疗的适应证仍存在很多争议，尤其对于HBV阴性的患者。本文通过对HBV DNA检测的局限性、HBV阴性CHB患者病毒再激活风险、DNA阴性的乙型肝炎肝硬化代偿期人群病情进展风险、抗病毒疗效及抗病毒治疗经济效益五方面进行分析，提出对HBV阴性、HBsAg阳性的乙型肝炎肝硬化代偿期患者抗病毒治疗的必要性。Abstract: Hepatitis B virus (HBV) infection is a common cause of liver disease in China, and with the continuous progress in the research on antiviral therapy for chronic hepatitis B, the indications for antiviral therapy are constantly expanding. However, there are still controversies over the indications for antiviral therapy in patients with chronic hepatitis B (CHB), especially those with negative HBV. By analyzing the limitations of HBV DNA detection, the risk of HBV reactivation in HBV-negative CHB patients, the risk of disease progression in the DNA-negative population with compensated hepatitis B cirrhosis, antiviral response, and the economic benefits of antiviral therapy, this article proposes the necessity of antiviral therapy for HBV-negative HBsAg-positive patients with compensated hepatitis B cirrhosis.
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Key words:
- Hepatitis B virus /
- Liver Cirrhosis /
- Therapeutics
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HBV感染目前已成为全球性公共健康危害，我国是世界上HBV感染人数最多的国家[1]。但我国乙型肝炎的诊断和治疗覆盖率仍较低[2]，这导致大量慢性乙型肝炎(CHB)患者进展为肝硬化、肝癌。如何最大程度抑制HBV复制，减少肝硬化、肝癌的发生成为目前亟待解决的问题。我国《慢性乙型肝炎防治指南(2019年版)》[3]指出，存在肝硬化的客观依据，不论ALT和HBeAg状态，只要可检测到HBV DNA，均应进行积极的抗病毒治疗。对于失代偿期肝硬化者，只要HBsAg阳性，即建议抗病毒治疗，而尚未对HBV DNA阴性乙型肝炎肝硬化代偿期患者有抗病毒建议。2022年《扩大慢性乙型肝炎抗病毒治疗的专家意见》[4]扩大了HBV阳性CHB患者抗病毒的适应证，但亦未对HBV DNA阴性的乙型肝炎肝硬化代偿期患者提出抗病毒治疗建议。对于这部分人群，缺乏抗HBV的病因学治疗很可能成为肝硬化进展的重要因素之一，也成为进展为失代偿期肝硬化、肝癌的重要危险因素。
1. HBV DNA检测的局限性
HBV DNA定量是评估HBV感染者病毒复制水平的重要指标。CHB患者在抗病毒治疗过程中，持续性的病毒学应答(maintained virological response，MVR)可显著控制HBV相关肝脏疾病进展(HR=0.09，95%CI：0.038~0.221，P=0.000 1)，降低肝细胞癌(HCC)风险(HR=0.03，95%CI：0.009~0.113，P < 0.000 1)[5]。在肝硬化患者中低病毒血症患者的HCC风险显著高于MVR患者(5年HCC发病率分别为23.4%和10.3%，调整后的HR=2.20，95%CI：1.34~3.60，P=0.002)[6]。目前认为HBV DNA检测不到即为阴性，然而HBV DNA检测采用实时定量PCR检测技术，检测下限值因不同的检测仪器及不同的生产厂商试剂而异。国内HBV DNA定量检测下限多为500 IU/mL，我国《慢性乙型肝炎防治指南(2019年版)》未明确提出HBV DNA定量检测下限问题，而国外多项CHB防治指南[7-10]均推荐采用10~15 IU/mL为HBV DNA的检测下限。张小曼等[11]对427例HBV DNA < 500 IU/mL的患者进行高敏HBV DNA(检测下限 < 20 IU/mL)检测时发现结果为阳性的患者高达40.98%。卢建华等[12]对49例CHB患者141份血标本采用普通PCR检测结果为阴性(< 500 IU/mL)的标本采用高敏PCR试剂(检测下限 < 10 IU/mL)进行复查，发现63.8%的患者结果为阳性，其中甚至有13.5%的患者HBV DNA定量 > 500 IU/mL。这提示我国有相当一部分患者被误判为HBV DNA阴性，由此引起的肝损伤、肝硬化进展及肝癌的风险也常被忽略。国际上对于高灵敏HBV DNA检测下限通常采用最低为10 IU/mL，而在0~10 IU/mL，仍可能存在极低量的病毒复制，但因为检测技术的局限性，尚无法检测出该范围的HBV DNA定量指标，故即使应用高灵敏HBV DNA检测方法仍无法完全确定HBV DNA真实水平为阴性。2019年《非一线核苷(酸)类似物经治慢性乙型肝炎患者治疗策略调整专家共识》[13]指出，CHB患者抗病毒治疗的主要目的是持续抑制HBV DNA水平，越低越好，最大限度的减少纤维化进展、肝硬化及肝癌风险。现阶段，临床通过检测血清HBV DNA水平来评估HBV复制的情况，然而血清HBV DNA定量就真的能完全反应肝组织学HBV的真实情况吗？有研究[14]证实，血清中检测HBV DNA阴性时，所有患者肝组织均可检测到HBV，且HBeAg阴性的患者肝内HBV DNA水平与血清HBsAg定量之间呈显著正相关(r=0.52，P=0.006)。这提示血清HBV DNA定量不能完全反应组织学病毒复制水平，HBsAg水平对组织学病毒可能更具有预测价值。
2. HBV阴性CHB患者病毒再激活风险
乙型肝炎肝硬化患者病因为HBV感染，HBV在肝细胞内已经引起机体发生相应的免疫反应，造成肝损伤、肝硬化，患者已不再属于乙型肝炎免疫耐受期，虽血液中HBV DNA阴性，然肝组织中存在共价闭合环状DNA (cccDNA)，cccDNA可导致慢性HBV再激活(HBV reactivation，HBVr)[15-18]，同时表达病毒抗原，激活免疫导致肝损伤。多项研究[19-20]表明，肝硬化、HBsAg阳性为HBVr的危险因素，这提示HBsAg阳性的肝硬化患者HBVr风险明显增高。这类患者肝功能虽为代偿期，但存在肝细胞过度负荷，当受到疲劳、酒精、药物及其他加重肝脏负担情况影响时，HBV随时面临再激活可能，如果HBV再激活没有得到及时识别和治疗，可导致HBV再激活相关的肝衰竭和乙型肝炎相关病死率的风险增加[21]。一项高质量低异质性的CHB患者远期结局荟萃分析[22]纳入了188 316例CHB患者，随访时间为1486 091人年，发现HBsAg血清清除与长期不良临床事件(肝癌、失代偿肝硬化、肝移植和/或死亡)风险显著降低密切相关(RR=0.31，P < 0.001)。故对于HBV DNA阴性的乙型肝炎肝硬化代偿期患者抗病毒治疗，不仅可以减少HBV再激活风险，同时如进一步降低HBsAg水平，甚至清除HBsAg，将可进一步改善患者的远期结局(肝癌、失代偿肝硬化、肝移植和/或死亡)，尤其对于不能规律复诊病毒被激活而不自知的患者受益更大。
3. DNA阴性的乙型肝炎肝硬化代偿期人群病情进展风险
既往研究[6, 23-24]表明HBV DNA是慢性HBV感染者疾病进展的主要驱动因素。特别是血清HBV DNA水平≥2000 IU/mL的患者患HCC的风险明显增加[23]。然而，有关纵向研究[23, 25]的数据表明，对于病毒载量低于2000 IU/mL的患者HCC的年发生率仍为0.06%，对于乙型肝炎人口众多的我国，这个发生率仍不容小觑。一项2688例初治患者的大型队列研究[26]显示，在低病毒载量(< 2000 IU/mL)的HBeAg阴性患者中，多变量分析显示，HBsAg水平≥1000 IU/mL与 < 1000 IU/mL患者的HCC校正HR为13.7(95%CI: 4.8~39.3)，而HBV DNA水平不是决定HCC的风险因素，这提示患者HBV DNA即使阴性，HBsAg阳性的患者仍有明确进展为HCC的风险，且HBsAg水平越高，其发生HCC风险也会随之增加。我国一项对481例低病毒载量HBV相关肝硬化患者进行的临床特征分析[27]中显示，HBV DNA阴性患者(HBV DNA < 100 IU/mL)占多数(阴性70.89% vs阳性29.11%)，为341例，其并发症(脾功能亢进、食管胃底静脉曲张、食管胃底静脉曲张破裂出血、腹水、肝性脑病、肝癌)发生率高达82.7%(HBV阳性者为73.6%)，研究中甚至有95例患者HBsAg呈阴性，其并发症的发生率较HBsAg阳性患者无统计学差异(阴性85.3% vs阳性78.8%)。这提示对于低病毒载量患者来说，HBV DNA水平并不能完全反应HBV相关肝硬化患者的病情严重程度并作为抗病毒治疗的主要依据，HBV DNA阴性，甚至HBsAg阴性，肝硬化仍可能继续进展，甚至失代偿或发生肝癌。
4. HBV阴性CHB患者抗病毒疗效
一些学者担心，患者血液中HBV DNA阴性，抗病毒是否能取得预期的效果。目前已有多项研究[28-31]表明，HBV DNA阴性CHB患者继续口服抗病毒治疗，会出现HBsAg定量下降，cccDNA水平的降低，进而减少肝硬化进展及HCC风险。对于血清HBV DNA阴性患者抗病毒治疗可减少再激活因素所致肝损伤风险(治疗组27.8% vs对照组3.0%，P < 0.001)[32]。亦有学者[33-34]对HBV DNA阴性(< 20 IU/mL)HBsAg水平较低的CHB患者进行干扰素治疗，结果显示高达83.3%~92.9%的患者均得到了HBsAg的清除，较对照组0~7.7%的HBsAg转阴率明显增高(P < 0.05)。个别HBV DNA阴性的乙型肝炎肝硬化代偿期患者使用聚乙二醇干扰素α-2b治疗实现了纤维化逆转，HBsAg转阴的效果[35]。这说明对于HBV DNA阴性的患者进行抗病毒治疗，不仅可以减少病毒再激活，同时亦减少了乙型肝炎相关肝病进展，部分优势人群甚至可以清除HBsAg，获得临床治愈。
5. 抗病毒治疗经济效益分析
全球每年有超过88万人死于HBV感染相关疾病，其中肝硬化占30%，HCC占45%[1, 36]。在不进行治疗的情况下，每年有2%~5%的肝硬化患者发展为肝癌[37]。2016年世界卫生组织(WHO)启动的全球消除乙型肝炎规划[38]明确提出，到2030年，将肝炎相关病死率降低65%[39]。我国由HBV感染所致的肝硬化及HCC者分别高达77%和84%[3]，要达到相关规划要求任重而道远。众所周知，乙型肝炎疾病发展程度越晚，对患者及其家属造成的经济负担也越重[40-42]。据浙江省乙型肝炎相关疾病经济负担统计结果分析，失代偿期肝硬化和原发性肝癌患者平均每人每年经济负担分别高达4.28万元和4.35万元，较代偿期肝硬化患者人年经济负担2.37万元明显增多[42]。随着我国抗病毒药物医保报销政策及乙型肝炎抗病毒药品带量采购政策的实施，抗病毒药物价格大幅度下降，明显减少了患者的个人经济负担[43]，抗病毒治疗本身已不是乙型肝炎相关疾病患者经济负担的影响因素，同时抗病毒口服药物，如恩替卡韦、替诺福韦具有强效低耐药的特点，且可有效降低HBsAg水平，持续抑制HBV DNA复制，不仅减少肝硬化进展，降低肝癌风险，同时还进一步减轻了患者家庭乃至整个社会沉重的经济负担。
6. 小结
综上，HBV DNA定量结果不应作为乙型肝炎肝硬化代偿期患者抗病毒的限制条件，疾病处于肝硬化阶段，虽为代偿期，但随着病情的进展，患者逐渐发展为失代偿期、甚至出现肝癌，给患者及家庭带来巨大的痛苦及经济负担。要采取有效措施对肝硬化代偿期患者早期干预，早期病因治疗，减少肝硬化进展及肝癌的风险。因此笔者建议HBsAg阳性的乙型肝炎肝硬化代偿期患者有条件均行HBV DNA高精度检测，更确切了解病毒情况；同时应追求更高临床治愈的目标，清除乙型肝炎HBsAg，即使HBV DNA定量阴性，仍需要抗病毒治疗。患者已然出现乙型肝炎肝硬化，抗病毒刻不容缓，只有争取最大限度的病因治疗，才能改善患者远期预后，减轻家庭及社会的经济负担。
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