柳叶刀子刊：低病毒载量慢乙肝不建议这样用药！

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对于低病毒载量的慢乙肝病毒感染者目前并不建议进行抗病毒治疗。然而，也有认为他们或将从获得功能性治愈（HBsAg消失伴随anti-HBs的出现或anti-HBs没有出现）中获益。为此，荷兰学者在低病毒载量的慢乙肝患者中进行了一项旨在评估聚乙二醇干扰素a-2a (peg-IFN)和核苷酸类似物联合治疗对于该类患者HBsAg消失情况的研究。该项研究发表在柳叶刀子刊（ The Lancet Gastroenterology & Heptaology）上。

该项研究为一项随机对照、开放标签研究，受试对象来自荷兰阿姆斯特丹医学中心（the Academic Medical Center (AMC), Amsterdam, Netherlands）。纳入的对象为HBsAg阳性、HBeAg阴性至少6个月的患者，可能是未经治的或者是经治的，转氨酶（ALT）水平为低于5倍正常值上限(ULN)。

参与者被使用计算机随机分配系统按照1:1:1的比例随机分配接受 peg-IFN 180 μg/周+ 阿德福韦 10 mg/天组、peg-IFN 180 μg/周 +替诺福韦（TDF）245 mg/天组和不治疗组，用药疗程均为48周。

研究的首要研究终点为至少用药一次或有过一次研究随访（校正的意向性治疗人群 [mITT]）患者的血清学HBsAg消失比例。所有的患者均已完成72周的初始研究并将进入长达5年的随访期。该研究在 ClinicalTrials.gov进行了登记，编号为：NCT00973219。

该项研究总共在2009年8月至2013年10月中筛查纳入了167名患者，其中151名被随机标记，52名使用peg-IFN +阿德福韦, 51名使用 peg-IFN +替诺福韦, 48名没有用药。46名使用peg-IFN +阿德福韦, 45名使用 peg-IFN +替诺福韦, 43名没有用药的患者开始用药或观察并被包含进了mITT人群。

在第72周，2(4%) 名使用peg-IFN +阿德福韦, 2(4%)名使用 peg-IFN +替诺福韦的患者实现 HBsAg 血清学消失，而没有用药的患者没有一例出现 HBsAg 血清学消失 (p=0·377)。

最常见 (>30%) 的不良反应为疲劳、头痛、发热和肌痛，这些都跟peg-IFN 的使用有关。

Peg-IFN +阿德福韦组报道了2(4%)例严重不良反应事件（因酒精相关性胰腺炎和怀孕入院治疗[第6周; n = 1]，其被选择性地中止[第9周; n = 1]）；

Peg-IFN + 替诺福韦组报道有3名（7％）出现严重不良反应事件（因出现严重抑郁症有自杀倾向（第23周; n = 1），腹部疼痛入院治疗（第2周; n = 1）和选择性椎板切除术（40周; n = 1）；

没有用药组有3名（7％）患者出现严重不良反应事件（因脓毒性关节炎入院（72周，n = 1），心内膜炎[第5周，n = 1]和甲状腺机能亢进[第20周; n = 1]）。

在该研究最后，研究人员写道，在低病毒载量的慢乙肝患者中，peg-IFN + 阿德福韦或 peg-IFN + 替诺福韦的联合治疗跟没用药的患者相比并没能使 HBsAg 出现显著的消失，因此，不支持给此类患者群体进行联合用药治疗。



参考文献：de Niet A, Jansen L, Stelma F, et al. Peg-interferon plus nucleotide analogue treatment versus no treatment in patients with chronic hepatitis B with a low viral load: a randomised controlled, open-label trial.Lancet Gastroenterol Hepatol. 2017 Aug;2(8):576-584.  doi: 10.1016/S2468-1253(17)30083-3.


Abstract
BACKGROUND: Antiviral treatment is currently not recommended for patients with chronic hepatitis B with a low viral load. However, they might benefit from acquiring a functional cure (hepatitis B surface antigen [HBsAg] loss with or without formation of antibodies against hepatitis B surface antigen [anti-HBs]). We assessed HBsAg loss during peg-interferon-alfa-2a (peg-IFN) and nucleotide analogue combination therapy in patients with chronic hepatitis B with a low viral load.

METHODS: In this randomised controlled, open-label trial, patients were enrolled from the Academic Medical Center (AMC), Amsterdam, Netherlands. Eligible patients were HBsAg positive and hepatitis B e antigen (HBeAg) negative for more than 6 months, could be treatment naive or treatment experienced, and had alanine aminotransferase (ALT) concentrations less than 5 × upper limit of normal (ULN). Participants were randomly assigned (1:1:1) by a computerised randomisation programme (ALEA Randomisation Service) to receive peg-IFN 180 μg/week plus adefovir 10 mg/day, peg-IFN 180 μg/week plus tenofovir disoproxil fumarate 245 mg/day, or no treatment for 48 weeks. The primary endpoint was the proportion of patients with serum HBsAg loss among those who received at least one dose of study drug or had at least one study visit (modified intention-to-treat population [mITT]). All patients have finished the initial study of 72 weeks and will be observed for up to 5 years of follow-up. This study is registered with ClinicalTrials.gov, number NCT00973219.



FINDINGS: Between Aug 4, 2009, and Oct 17, 2013, 167 patients were screened for enrolment, of whom 151 were randomly assigned (52 to peg-IFN plus adefovir, 51 to peg-IFN plus tenofovir, and 48 to no treatment). 46 participants in the peg-IFN plus adefovir group, 45 in the peg-IFN plus tenofovir group, and 43 in the no treatment group began treatment or observation and were included in the mITT population. At week 72, two (4%) patients in the peg-IFN plus adefovir group and two (4%) patients in the peg-IFN plus tenofovir group had achieved HBsAg loss, compared with none of the patients in the no treatment group (p=0·377). The most frequent adverse events (>30%) were fatigue, headache, fever, and myalgia, which were attributed to peg-IFN dosing. Two (4%) serious adverse events were reported in the peg-IFN plus adefovir group (admission to hospital for alcohol-related pancreatitis [week 6; n=1] and pregnancy, which was electively aborted [week 9; n=1]), three (7%) in the peg-IFN plus tenofovir group (admission to hospital after a suicide attempt during a severe depression [week 23; n=1], admission to hospital for abdominal pain [week 2; n=1], and an elective laminectomy [week 40; n=1]), and three (7%) in the no treatment group (admission to hospital for septic arthritis [week 72; n=1], endocarditis [week 5; n=1], and hyperthyroidism [week 20; n=1]).



INTERPRETATION: In patients with chronic hepatitis B with a low viral load, combination treatment (peg-IFN plus adefovir and peg-IFN plus tenofovir) did not result in significant HBsAg loss compared with no treatment, which does not support the use of combination treatment in this population of patients.

作者：略晓薛  来源：  HeparSpace

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