慢性B型肝炎患者的乙肝表面抗原定量的临床意义

肝胆速递

Clinical implications of HBsAg quantification in patients with chronic hepatitis B
慢性B型肝炎患者的乙肝表面抗原定量的临床意义

肝胆速递：有助于检测病情，但需要更多临床数据的研究

The Saudi Journal of Gasteroenterology

REVIEW ARTICLE      
Year : 2012  |  Volume : 18  |  Issue : 2  |  Page : 81-86
Clinical implications of HBsAg quantification in patients with chronic hepatitis B

Mauro Viganò1, Pietro Lampertico2
1 Hepatology Unit, Ospedale San Giuseppe, Università degli Studi di Milano, Milano, Italy
2 1st Division of Gastroenterology, Fondazione Cà Granda IRCCS Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, Italy


Date of Submission    16-Jan-2012
Date of Acceptance    16-Jan-2012
Date of Web Publication    14-Mar-2012

Abstract
Quantification of serum hepatitis B surface antigen (HBsAg) helps the management of patients with chronic hepatitis B virus (HBV) infection. Median HBsAg levels differ significantly during the natural history of HBV infection, progressively declining from immune tolerance to inactive phase. The combination of an HBsAg <1000 IU/mL and HBV DNA <2000 IU/mL at a single time point accurately identifies true inactive carriers. During antiviral treatment, HBsAg levels decline more rapidly in patients under peg-interferon (Peg-IFN) than in those under nucleos(t)ide analogues (NUC), and in responders to peg-IFN compared to non responders suggesting that a response-guided therapy in both HBeAg-positive and -negative patients treated with Peg-IFN could improve to cost-effectiveness of this therapeutic approach. Given the low rates of HBsAg clearance on NUC therapy, new studies to test whether Peg-IFN and NUC combination fosters HBsAg decline in long-term responders to NUC, are being explored.

HBsAg Quantification in Untreated Patients     


Chronic HBV infection runs through four chronologic phases: an initial "immune tolerance phase" characterized by serum HBeAg and high viremia accompanied by null or minimal histologic damage. The second phase is the "immune clearance phase," whereby the immune system recognizing HBV as a foreign invader causes extensive liver cell inflammation, that is, the HBeAg-positive chronic hepatitis. The third phase is the "inactive phase" in anti-HBe-positive patients showing persistently normal alanine aminotransferase (ALT) and low HBV DNA levels (<2000 IU/mL). The fourth phase is characterized by late reactivation of infection with persistently or intermittently increased HBV DNA and ALT levels accompanied by progressive liver damage, the so-called HBeAg-negative chronic hepatitis. While in most patients these phases occur in sequence, there are patients who apparently do not experience all phases like those persistently positive for HBeAg and those who remain persistently inactive carriers of HBsAg.

While the median HBsAg levels differ significantly during the 4 phases of infection, serum HBsAg progressively declines from immune tolerance to inactive phase. [9],[10],[11],[12] A longitudinal study of 68 HBeAg-negative untreated patients followed up for 99±16 months showed that a >1 log 10 IU/mL HBsAg decline between the initial and last visits was associated with a higher HBsAg seroclearance rate and stronger viral suppression. [11] Two other studies in inactive carriers confirmed that HBsAg seroclearance was preceded by a greater HBsAg decline than in patients who remained HBsAg-seropositive. [13],[14] Serum HBsAg level at 1 year after spontaneous HBeAg seroconversion may also be a harbinger of HBsAg clearance as shown by patients with HBsAg levels <100 IU/mL and between 100 and 999 IU/mL having higher hazard ratios of HBsAg loss (24.3 and 4.4, respectively) than patients with higher HBsAg levels. [15] Combining serum HBsAg with HBV DNA may provide stronger prediction of HBsAg seroclearance. This was the case in the study by Brunetto et al, who reported the combination of an HBsAg <1000 IU/mL and HBV DNA <2000 IU/mL at a single timepoint to accurately identify inactive carriers with a 88% positive (PPV) and a 97% negative predictive value (NPV). [13] In a longitudinal study in China, levels of HBsAg <1000 IU/mL and HBV DNA <2000 IU/mL were proved to predict the likelihood of HBsAg seroclearance, too, with a cumulative probability of HBsAg seroclearance at 5 years of 10%, which rose to 23% at 8 years. [16] In another study of 102 HBeAg-negative patients a cutoff of 2040 IU/mL of HBsAg had high sensitivity (87%) and high specificity (75%) to diagnose the inactive carrier state. [17] All these data need to be prospectively validated in larger sample size studies, including patients infected with all the major genotypes to establish reasonable intervals of surveillance in patients with chronic hepatitis B with respect to the risk of reactivation and seroclearance.
沙特的Gasteroenterology

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年份：2012卷：18期：2页：81-86
慢性B型肝炎患者的乙肝表面抗原定量的临床意义

毛罗Viganò1，彼得Lampertico2
1个的肝病单位，如UniversitàOspedale圣朱塞佩教堂STUDI米兰，米兰，意大利
2月1日胃肠科，中基金会Cà格兰达IRCCS Ospedale马焦雷Policlinico大学留学教堂STUDI米兰，米兰，意大利


日期提交的16-1-2012
接受16 2012年01月2012年
网络出版日期2012年3月14日

摘要
慢性乙型肝炎病毒（HBV）感染患者的血清乙肝表面抗原（HBsAg），有助于量化管理。不同HBsAg水平中位数显着HBV感染的自然史的过程中，逐步下降，从免疫耐受不活跃的阶段。相结合的乙型肝炎表面抗原（HBsAg）<1000 IU / mL和HBV DNA <2000 IU / mL的在一个单一的时间点准确地识别真正的非活动性携带者。抗病毒治疗期间，HBsAg水平更迅速地下降的患者下销钉-干扰素（PEG-IFN）的比那些在核苷（酸）类似物（NUC）中，并在反应，以聚乙二醇化IFN相比，无应答，表明响应制导与PEG-IFN治疗的HBeAg阳性和阴性患者的治疗，可以改善这种治疗方法的成本效益。 NUC治疗HBsAg清除率很低，新的研究，以测试是否PEG-IFN和国统会的结合，促进乙肝表面抗原长期反应下降到国统会，目前正在探讨。

未经治疗的患者中乙型肝炎表面抗原的定量前


慢性HBV感染贯穿四个年代学阶段：最初的“免疫耐受期”的特点是血清HBeAg和高病毒血症的陪同下空或最小的病理损害。第二阶段是“免疫清除期，HBV的免疫系统识别为外国侵略者”，引起了广泛的肝细胞炎症，也就是e抗原阳性慢性乙型肝炎。第三阶段是“非活动期”的持续正常的谷丙转氨酶（ALT）和低HBV DNA水平（<2000 IU / mL）的抗-HBe阳性的患者。第四阶段的特征在于伴随着逐行肝损害，所谓的HBeAg阴性慢性肝炎感染后期重新与持续或间歇地增大HBV DNA和ALT水平。虽然大多数患者的这些阶段按顺序发生，也有患者显然不经历的各个阶段，如对于HBeAg持续阳性者和那些保持持续非活动性携带者，乙肝表面抗原。

虽然HBsAg水平中位数在4个阶段的感染显着差异，血清HBsAg逐步下跌从免疫耐受到非活动期。 [9]，[10]，[11]，[12] 68例HBeAg阴性未经治疗的患者随访99±16个月的纵向研究表明，1日志> 10 IU / mL的乙肝表面抗原下降的最初和最后的访问伴随着较高的乙肝表面抗原转阴率和更强的病毒抑制。 [11]另外两项研究证实，在非活动性携带者的乙肝表面抗原转阴之前受到了较大的乙肝表面抗原保持HBsAg血清学阳性的患者比下降。 [13]，[14]在1年后自发性HBeAg血清转换的血清HBsAg水平也可能是一个预兆的HBsAg清除的患者HBsAg水平<100 IU / mL和100至999 IU / mL的具有较高的风险比HBsAg消失（24.3和4.4），分别比HBsAg水平较高的患者。 [15]结合血清HBsAg，HBV DNA与乙肝表面抗原转阴提供更强大的预测。这是情况的研究布鲁涅托等人，谁报告相结合的乙型肝炎表面抗原（HBsAg）<1000 IU / mL和HBV DNA <2000 IU / mL的在一个单一的时间点准确地识别非活动性携带者的88％为阳性（PPV） 97％的阴性预测值（NPV）。 [13]在一项纵向研究，在中国的乙型肝炎表面抗原（HBsAg）<1000 IU / mL和HBV DNA <2000 IU / mL的水平，证明了预测乙肝表面抗原转阴的可能性，也与乙肝表面抗原转阴的累积概率在5年以上10 ％，在8年上升到23％。 [16]在另一项研究中，102例HBeAg阴性患者，截止2040 IU / mL的乙肝表面抗原具有较高的灵敏度（87％）和高特异性（75％），诊断惰性载体状态。 [17]所有这些数据需要在更大样本量的研究，包括所有主要的基因型，建立合理的时间间隔的监控方面的风险激活和转阴的慢性乙型肝炎患者感染的患者进行前瞻性验证。

肝胆速递

HBsAg Quantification During Antiviral Therapy    


Peg-IFN therapy of HBeAg-positive patients

Reports of HBsAg decline in HBeAg-negative and -positive patients undergoing interferon-based therapy suggested the potential role of this marker for prediction of a treatment response. [7],[18] HBsAg levels at the end of Peg-interferon (Peg-IFN) treatment has been shown to be significantly lower both in HBeAg-positive and negative patients with a sustained virologic response. [6],[7],[19] Owing to the fact that a rapid on-treatment decline of HBsAg levels predicts a sustained response, HBsAg levels at 12 or 24 weeks after the beginning of treatment have been associated with the identification of nonresponders or for tailoring treatment duration in responders. The lack of a significant decline of HBsAg at week 12 of Peg-IFN is a strong negative predictor of response in HBeAg-positive patients. This was demonstrated by Sonneveld et al, who showed that no decline in HBsAg levels at week 12 of Peg-IFNa-2b±lamivudine had a 3% chance of achieving a response, that is, HBeAg loss with HBV DNA <10,000 copies/mL 26 weeks after treatment, only (97% NPV). [20] The retrospective analysis of the Peg-IFNa-2a registration trial was less conclusive, as it demonstrated 18% of patients lacking a HBsAg decline at week 12 could achieve HBeAg loss and HBV DNA <2000 IU/mL 6 months posttreatment (82% NPV). [21] Whether these differences are explained by differences in HBV genotypes prevalence between studies, needs confirmation.

Piratvisuth et al demonstrated that patients with low HBsAg levels (<1500 IU/mL) at weeks 12 and 24 of Peg-IFNa-2a treatment had 57% and 54% chances of HBeAg seroconversion 6 months after completing treatment. Response rates were significantly lower in patients with intermediate HBsAg levels, that is, 1500-20,000 IU/mL (32 and 26%, respectively) or HBsAg levels >20,000 IU/mL (16% and 15%, respectively) (P<0.0001 for <1500 IU/mL vs higher levels). [22] The association of on-treatment HBsAg levels and sustained posttreatment response was confirmed by the NEPTUNE study, [23] where HBeAg seroconversion rates 6 months after treatment were significantly higher in patients with HBsAg <1500 IU/mL at weeks 12 and 24 (58% and 57%, respectively) compared with patients with HBsAg 1500-20000 IU/mL (42% and 35%, respectively) or patients with HBsAg >20,000 IU/mL that did not achieve sustained response and may therefore be considered for discontinuation of therapy.

In general, the serum cutoff of HBsAg predicts the intensity of a virologic response, too. Chan et al, reported a sustained response, that is, HBeAg seroconversion and HBV DNA ≤2000 IU/mL, occurring 12 months post-Peg-IFN treatment, being more frequently observed in patients with HBsAg ≤ 300 IU/mL at month 6 of treatment (62% vs 11%, P<0.001). The highest rates of response (75%) were in patients having both >1 log HBsAg decline and serum HBsAg level ≤300 IU/mL at month 6 of treatment compared with 15% in patients lacking such a combined response (P<0.001). The PPV and NPV for a sustained response by the combination of HBsAg and HBV DNA levels were 75% and 85%, respectively. [24] The association between on-therapy HBsAg levels and HBeAg seroconversion was observed in Asian patients as well.

Peg-IFN therapy of HBeAg-negative patients

In a landmark study of 48 HBeAg-negative patients receiving Peg-IFNa-2a, a decrease of 0.5 and 1 log 10 IU/mL of serum HBsAg levels at weeks 12 and 24 of therapy had a 90% NPV and a 89% PPV for week 12 and 97% NPV and a 92% PPV for week 24 sustained response, respectively. [7] This was the first study to suggest early kinetics (week 12) of HBsAg to differentiate sustained responders from relapsers to Peg-IFN, although the limited sample size, the retrospective design, the heterogeneous genotype distribution, and the very strict definition of virologic response, caution against generalizability of the results. This notwithstanding, this information helps to identify early on-treatment (weeks 12 or 24) patients who are more likely to achieve a sustained response, and therefore should continue therapy up to week 48. In a retrospective analysis of HBsAg levels in the Peg-IFNa-2a registration study, patients who achieved a ≥10% decline in serum HBsAg at week 12 of treatment had a higher probability of sustained response compared with those with a lesser decline (47% vs 16%, P<0.01). [25] The association between on-treatment HBsAg decline ≥10% and sustained response in genotype D patients was analyzed in the PegBeLiver study that enrolled 96% of genotype D patients, a subgroup of patients being treated for 96 weeks. This study showed that a ≥10% decline of HBsAg at week 24 (not at week 12) of treatment, was significantly associated with a sustained response to Peg-IFN in patients treated for 96 weeks, only. [26] Early kinetics of serum HBsAg might help tailoring duration of Peg-IFN therapy to spare costs and unnecessary morbidity in nonresponders.

Among 102 HBeAg-negative patients, predominantly infected with genotype D who were treated with Peg-IFNa-2a±ribavirin for 12 months, the week 12 level of serum HBsAg and HBV DNA predicted a nonresponse. None of the 20 patients with unmodified HBsAg levels and a <2 log 10 copies/mL HBV DNA decline, had a long-term response defined as serum HBV DNA <10,000 copies/mL and normal ALT 6 months posttreatment (100% NPV). [27] This was the first study to suggest a week 12 stopping rule for Peg-IFN treated HBeAg-negative patients, and was recently confirmed by the pooled analysis of 160 HBeAg-negative patients who received either Peg-IFN for 48/96 weeks in the phase III registration trial (n=85) or in the PegBeLiver study (n=75). The "week 12 stopping rule" performed well across these studies identifying patients who have no or a very low chance of a response, defined as HBV DNA <2000 IU/mL combined with normal ALT at 24 weeks of posttreatment followup, to either 48 or 96 weeks of Peg-IFN. However, the performance of this score was best among the 91 genotype D infected patients with 19% of patients that would be allowed to discontinue therapy, while maintaining all sustained responders on treatment. Among the 34 patients treated for 96 weeks with Peg-IFN, none of the 7 (21%) patients fulfilling the criteria the "week 12 stopping rule" achieved a response. [28]

Given the low PPV of these scores, other scores have been proposed to optimize prediction of outcome of Peg-IFN treatment. Recently, a week 24 rule has been proposed: patients with HBsAg >7500 IU/mL at week 24 had very low chance of achieving a sustained response defined as HBV DNA <2000 IU/mL 1 year posttreatment (NPV: 93% and 100% for 48 and 96 weeks treatment, respectively). If externally validated, the 24-week cutoff might be a second stopping rule for Peg-IFNα-2a treated patients, however, restricted to those infected with genotype D of HBV. [29] Indeed, there are data indicating that HBV genotype may influence the on-treatment HBsAg kinetics, thus making the identification of genotype-specific thresholds for HBsAg levels, necessary. In genotype A and B, 100% of responders to Peg-IFN (HBV DNA <2000 IU/mL 5 years posttreatment) had HBsAg ≤400 IU/mL and ≤50 IU/mL, respectively. In genotype C 41% of responders had HBsAg ≤50 IU/mL, whereas in genotype D 60% of responders had HBsAg ≤1000 IU/mL. [30]

These studies provide a rationale for stopping Peg-IFN at week 12 in approximately 20% of HBeAg-negative patients with a <2 log HBV DNA decrease and no change in HBsAg levels, since these patients would have no chances of a response even after extended therapy beyond week 48. Since this stopping-rule has not been validated for HBeAg-negative patients infected with non-D genotypes, [27],[28],[29],[30],[31] there is a need for genotype-specific prediction rules.

在抗病毒治疗前HBsAg的定量分析


PEG-IFN治疗的HBeAg阳性患者

乙肝表面抗原下降，HBeAg阴性和阳性的患者接受干扰素为基础的治疗建议报告预测治疗反应的潜在作用，这个标记。 [7]，[18] PEG-干扰素（PEG-IFN）治疗结束时HBsAg水平已被证明是显着降低，在HBeAg阳性和阴性患者的持续病毒学应答。 [6]，[7]，[19]由于快速的治疗上的HBsAg水平下降的事实，预测持续反应，治疗开始后，在第12周或24周HBsAg水平识别已与无反应者或剪裁治疗有反应的持续时间。在第12周的PEG-IFN对HBsAg的显着下降的缺乏是一个强大的负向预测，在HBeAg阳性患者的反应。这是证明等，Sonneveld显示，PEG-IFNa的-2B±拉米夫定12周时HBsAg水平没有下降，实现了响应有3％的几率，这是与HBV DNA <10,000拷贝/ ml，HBeAg转阴治疗26周后，只有97％（NPV）。 [20] PEG-IFNa的-2A登记试验的回顾性分析少确凿的患者缺乏乙肝表面抗原在第12周下降了18％，因为它可以实现HBeAg消失，HBV DNA <2000 IU / mL的6个月的治疗后（82 ％NPV）。 [21]这些差异是否都说明了不同的HBV基因型与肥胖的关系的研究中，需要确认。

Piratvisuth等表明，患者的HBsAg水平低（<1500 IU / mL）的PEG-IFNa的-2a治疗12周和24有57％和54％，HBeAg血清学转换完成治疗后6个月的机会。响应率显着降低，患者中间HBsAg水平，也就是1500-20,000 IU /毫升（分别为32％和26％）或HBsAg水平> 20,000 IU /毫升（分别为16％和15％）（P <0.0001 <1500 IU / ml和更高级别）。该协会对治疗的HBsAg水平和持续治疗后的反应也证实了NEPTUNE研究，[22] [23]治疗6个月后HBeAg血清转换率显着较高的患者的乙型肝炎表面抗原（HBsAg）<1500 IU / mL的12周和24周（分别为58％和57％）相比，与HBsAg 1500-20000 IU / mL的（分别为42％和35％），或与HBsAg患者与患者> 20000 IU / mL的，没有实现持续响应，因此，可以考虑停止治疗。

在一般情况下，血清的HBsAg截止预测的病毒学反应的强度，也陈等人，报告了持续的反应，也就是发生HBeAg血清转换和HBV DNA≤2000 IU /毫升，12个月后的PEG-IFN治疗，更频繁地观察到患者的乙型肝炎表面抗原（HBsAg）≤300 IU / mL的6个月治疗（62％对11％，P <0.001）。响应率最高的（75％）> 1日志乙肝表面抗原下降，血清HBsAg水平≤300 IU / mL的15％的患者缺乏这样的综合反应（P <0.001）相比，在6个月的治疗的患者。 PPV和NPV的持续反应相结合的HBsAg和HBV DNA水平分别为75％和85％，分别为。 [24]治疗HBsAg水平和HBeAg血清学转换之间的关联，以及在亚洲患者中观察到。

PEG-IFN治疗的HBeAg阴性患者

在一个具有里程碑意义的研究，48例HBeAg阴性患者接受PEG-IFNa的-2A，下降了0.5和1日志10 IU / mL的血清HBsAg水平在12和24周的治疗有90％的NPV和PPV为89％ 12周和97％，NPV和92％，PPV为每周24个持续的反应，分别。 [7]这是首次有研究表明早期的动力学（12周），乙肝表面抗原区分复发患者对PEG-IFN的持续应答，虽然样本量有限，追溯设计，异质性的基因型分布，以及非常严格的定义，病毒学应答，注意防止一般化的结果。尽管如此，这个信息可以帮助识别早期治疗（12周或24周），患者谁更有可能实现持续的反应，因此，应继续治疗到48周。 HBsAg水平在PEG-IFNa的-2A注册研究的回顾性分析，谁取得了在治疗12周时血清HBsAg下降≥10％的患者有较高的持续反应的概率比一个较小的跌幅（47％比16％，P <0.01）。 [25]之间的关联，对治疗乙肝表面抗原下降≥10％，持续在D基因型患者的反应进行了分析研究，招收的96％的D型患者，一个亚组的患者正在接受治疗96周的P​​egBeLiver。这项研究表明，在第12周）的治疗24周时，乙肝表面抗原（≥10％的跌幅，显著与持续PEG-IFN治疗的患者96周，只有。 [26]早期血清HBsAg动力学，可能有助于剪裁的PEG-IFN治疗的持续时间，腾出成本和不必要的发病率无反应。

在102例HBeAg阴性患者，主要感染D型，分别用PEG-IFNa的-2A±利巴韦林为12个月，12周时血清HBsAg和HBV DNA水平预测无反应。没有20例患者与未改性的HBsAg水平<2 log10拷贝/ mL的HBV DNA下降，有一个长期的响应定义为血清HBV DNA <10,000拷贝/ ml和ALT正常的6个月的治疗后（100％NPV）。 [27]这是第一次研究，建议一个星期，12停止规则的PEG-IFN治疗HBeAg阴性患者，并于近日确认的汇总分析160例HBeAg阴性患者接受PEG-IFN 48/96周III期注册临床试验（n = 85）或在PegBeLiver研究组（n = 75）。 “12周停止规则”的执行以及在这些研究确定病人没有或非常低的机会的响应，定义为HBV DNA <2000 IU / mL时ALT正常，在24周的治疗后随访，48或PEG-IFN 96周。然而，这个分数的性能是最好的91个基因型D感染的病人有19％的患者将被允许停止治疗，同时保持了持续应答者的治疗。在PEG-IFN治疗96周，34例符合标准的“12周停止规则”的7例（21％），实现了响应。 [28]

鉴于这些分数低的PPV，以及其他分数已经被提出来优化穿心-干扰素治​​疗的结果的预测。最近，一个24周的规则已被提出：患者的乙型肝炎表面抗原（HBsAg）> 7500 IU / mL的24周实现持续应答定义为HBV DNA <2000 IU / mL的1年的治疗后（NPV：93％和100％的几率很低48和96周治疗后，分别）。然而，如果外部验证，在24周的截止可能是第二个停止规则的PEG-IFNα-2a干扰素治疗的患者，感染者的HBV基因型D的限制。 [29]事实上，有数据表明，HBV基因型可能影响治疗上的HBsAg的动力学，从而基因型HBsAg水平的特定的阈值，必要的识别。在基因型A和B，100％（HBV DNA <2000 IU / mL的5年治疗后的反应，以PEG-IFN）乙肝表面抗原≤400 IU / ml和≤50 IU /毫升，分别为。在基因型C 41％的被调查者乙肝表面抗原≤50 IU / mL的，而基因型D 60％的被调查者乙肝表面抗原≤1000 IU / mL的。 [30]

这些研究提供了理论基础，停止PEG-IFN 12周时，在约20％的HBeAg阴性患者<2日志HBV DNA下降并没有改变HBsAg水平，因为这些病人没有机会的响应即使长时间超过48周的治疗。由于停止规则并没有得到证实HBeAg阴性感染患者与非D型，[27]，[28]，[29]，[30]，[31]有需要特定基因型的预测规则。

肝胆速递

Nucleos(t)ide analogues therapy of naïve patients

Lamivudine

Patients with chronic hepatitis B treated with lamivudine (LMV) show a gradual decrease of serum HBsAg concentrations. [32] This happens, however, without obtaining HBsAg clearance, whereas an increase of HBsAg titers precedes the emergence of drug resistance. In 21 HBeAg-negative patients who were followed up for a median of 46 months, Manesis et al. reported a median decrease of HBsAg of 470 IU/mL (range: −64 to 2354) with a monthly rate of HBsAg decrease of 7.7 UI. [8] This was also the experience in Italy where Brunetto et al confirmed a modest decline of HBsAg during 48 weeks of LMV treatment of 122 HBeAg-negative patients (−0.02 log 10 IU/mL). [6]

Telbivudine

In HBeAg-positive patients, effective therapy with telbivudine (LdT) caused progressive serum HBsAg levels decline from a baseline value of 3.8±0.6 log 10 IU/mL to week 24 value of 3.4±0.7 log 10 IU/mL, year 1 value of 3.3±0.8 log 10 IU/mL and year 3 value of 3.0±1.4 log 10 IU/mL (P<0.0001). During the first year, 3 patterns of HBsAg decline associated with different rates of HBsAg loss in the long-term treatment were observed: rapid (≥1 log 10 IU/mL, mostly in genotype A) in 20% of patients, slow (0-1 log 10 IU/mL) in 45% of patients and steady in the remaining patients. Twenty-five percent of patients with a rapid HBsAg decline achieved undetectable serum HBsAg at year 3 compared with none of the patients with steady HBsAg levels (P=0.0024). [33] The power of LdT was confirmed by a small study in 17 HBeAg-positive patients where serum HBsAg levels <2 log 10 IU/mL at year 2 were highly predictive of sustained response, that is, HBV DNA <300 copies/mL, HBeAg seroconversion, and ALT normalization at 2 years off-treatment followup, with a 93% PPV and 100% NPV. Moreover, HBsAg decline >0.8 and >1 log 10 IU/mL from baseline to weeks 24 and 52 of treatment were more predictive of sustained response than HBV DNA decline, having a 75% and 86% PPV and NPV, respectively, for both weeks 24 and 52 assessment. [34]

Entecavir

There is limited data on HBsAg quantification in entecavir (ETV)-treated patients. In one study, HBsAg was quantified at baseline and during ETV therapy in 33 HBeAg-positive and 37 HBeAg-negative patients, only. HBeAg-positive patients showed a mean decline of 0.38 log 10 IU/mL at week 48, the higher decrease being observed in those who cleared HBeAg and in patients with elevated baseline ALT levels. Conversely, the HBsAg decline was negligible in HBeAg-negative patients (−0.10 log 10 IU/mL). [35] In another small study, where 28 HBeAg-positive patients received ETV for 21 months (range: 18-24), HBsAg declined from a mean baseline value of 4.0 log 10 IU/mL to 3.7 and 3.6 log 10 IU/mL at months 6 and 12, respectively (P<0.001). The 5 patients with a >1 log 10 IU/mL decline of HBsAg level from baseline to month 12 of treatment, showed a 80% cumulative incidence of HBeAg loss at 1 year compared with 30% in those with less HBsAg decline. [36]

Tenofovir

Data on HBsAg kinetics in tenofovir (TDF)-treated patients are scanty as well. In a 3-year study, HBeAg-positive patients who cleared HBsAg were those with a greater median change from baseline in HBsAg levels at week 24 compared with patients who did not (−2.41 vs −0.20 log 10 IU/mL). [37] HBeAg-negative patients showed a negligible HBsAg levels decline of −0.20 log 10 IU/mL mean reduction from baseline to year 3. HBsAg decline was quicker in patients who lost HBsAg than in those who failed to clear HBsAg at 4-year treatment. [38]

核苷（酸）类似物初治患者的治疗

拉米夫定

治疗慢性乙型肝炎的拉米夫定（LMV）的患者血清HBsAg浓度逐渐下降。 [32]然而，出现这种情况，未取得HBsAg清除，乙肝表面抗原滴度增加而之前出现的耐药性。在21的HBeAg阴性患者随访中位数为46个月，Manesis等。 470 IU / mL的乙肝表面抗原（范围：-64〜2354）报道了平均下降与每月的HBsAg下降7.7 UI。 [8]这也是在意大利布鲁涅托等人证实了轻微下跌乙肝表面抗原在48周的LMV治疗122例HBeAg阴性患者（-0.02日志10 IU / mL）的经验。 [6]

替比夫定

在HBeAg阳性患者中，替比夫定（LDT）引起的有效的治疗方法进行血清HBsAg水平下降，从基线值3.8±0.6日志10 IU / mL的24周值3.4±0.7日志10 IU / mL时，今年1值3.3±0.8日志10 IU / mL和3值3.0±1.4日志10 IU /毫升（P <0.0001）。在第一年，3种模式以不同的速率在长期治疗的HBsAg转阴的乙肝表面抗原下降观察：快速（≥1日志10 IU / mL时，大多是在基因型A）在20％的患者，慢（0 -1日志10 IU / mL）的45％的患者和稳定，其余患者。乙肝表面抗原的快速下降百分之二十五的患者血清乙肝表面抗原检测不到，第3年的相比，没有稳定的HBsAg水平的患者（P = 0.0024）。 [33] LDT的力量是由一个小的研究证实，在17例HBeAg阳性患者血清HBsAg水平<2个10年2 IU / mL的高度持续应答的预测，那就是，HBV DNA <300拷贝/ ml ，e抗原血清学转换，ALT复常场外治疗随访2年时，一个93％的PPV和100％NPV。此外，乙肝表面抗原下降> 0.8> 1日志10 IU /毫升，从基线到24和52周的治疗，有75％和86％，PPV和NPV分别为周持续HBV DNA下降的反应比预测24和52的评估。 [34]

恩替卡韦

对HBsAg定量的数据是有限的，在恩替卡韦（ETV）治疗的患者。在一项研究中，乙肝表面抗原进行定量在基线和在ETV治疗33例HBeAg阳性和37例HBeAg阴性患者中，只有。 HBeAg阳性患者表现为平均下降幅度为0.38日志10 IU / mL的48周时，减少被观察到在清除HBeAg阳性的人，在基线ALT水平升高的患者中。相反，HBsAg的下降是可以忽略不计的HBeAg阴性患者（-0.10日志10 IU /毫升）。 [35]在另一项小研究，其中28例HBeAg阳性患者接受ETV为21个月（范围：18至24个月），乙肝表面抗原4.0日志中，平均基线值下降到10 IU / mL至3.7％和3.6日志10 IU / mL的6和12个月时，分别为（P <0.001）。 1日志> 10 IU / mL的下降HBsAg水平从基线到12个月的治疗，5例表现相比，用更少的乙肝表面抗原下降30％，HBeAg转阴，1年累积发病率的80％。 [36]

替诺福韦

对HBsAg动力学的数据，替诺福韦（TDF）治疗的患者是很少的为好。在3年的研究中，HBeAg阳性患者的HBsAg清除是那些具有更大的中位数从基线的变化在第24周时HBsAg水平的患者相比，谁没有（-2.41和-0.20日志10 IU /毫升）。 [37] HBeAg阴性患者表现为一个可以忽略不计的乙肝表面抗原水平下降-0.20日志10 IU / mL的平均减少从基线到第3年。乙肝表面抗原的患者谁失去了在4年的治疗未能清除乙肝表面抗原乙肝表面抗原比下降快。 [38]

肝胆速递

Therapy of nucleos(t)ide analogs resistant patients

Interestingly, the HBsAg decline in LMV-resistant patients in whom HBV DNA was successfully suppressed by LMV+ adefovir dipivoxil (ADV) combo therapy, is suboptimal. The log decline of HBsAg levels from baseline to last observation in 39 LMV-resistant patients on LMV+ADV for 40 months (range: 24-84) was in fact <0.5 log and none of the patients cleared HBsAg. [39] More encouraging were the results of a study in Italy in 88 patients with persistently undetectable serum HBV DNA (<35 copies/mL) for at least 3 years of either LMV monotherapy (n=23) or ADV+LMV combination therapy (n=65), in whom HBsAg titers progressively declined over time with a few patients achieving HBsAg loss. The median HBsAg log titers were in fact 3.2 at year 1, 3.1 at years 2 and 3, 2.9 at year 4, and 2.8 at year 5, with an overall median decline of 0.8 log 10 UI/mL. Twenty-one patients (27%) at 4-year and 19 (41%) at 5-year had a >1 log reduction compared with baseline and 24 (29%) patients had HBsAg levels below 250 UI/mL after 4 years of therapy. Seven (30%) long-term responders to LMV monotherapy had reduced HBsAg titers below the limit of detection (0.05 UI/mL). [40]

Overall, despite a greater suppressive effect on HBV DNA, patients on nucleos(t)ide analogs (NUC) had a slower and less pronounced HBsAg decline, even in those who later cleared HBsAg. [6],[8],[35] As a general rule, the HBsAg decline was less pronounced in HBeAg-negative than in HBeAg-positive patients. [35],[37],[38] Based on HBsAg kinetics, we estimated the time to HBsAg loss to be >10 years in LMV responders, [8] which however was extended >30 years by others. [41],[42]


   Conclusion  


HBsAg is an important test that not only marks active infection with HBV, but may also predict the clinical outcome of the infection. Detection of low HBsAg and HBV DNA levels may accurately identify true inactive carriers who need neither strict followup nor antiviral treatment. Based on HBsAg quantification, a response-guided therapy in both HBeAg-positive and -negative patients treated with Peg-IFN has been developed. According to the data, therapy can be stopped at week 12 in primary nonresponders, who become candidate to alternative therapies, such as unlimited suppressive therapy with NUC. Decline of serum HBsAg may also assist NUC-treated patients, mainly the HBeAg-positive ones, however, according to slower kinetics than those related to Peg-IFN therapy. Because progressive decline of HBsAg heralds clearance of HBsAg in all instances, this may help increasing cost-effectiveness ratio of NUC therapy. New approaches to test whether Peg-IFN and NUC combination fosters HBsAg decline in long-term responders to NUC, are being explored.

核苷（酸）类似物耐药患者的治疗

有趣的是，LMV耐药患者HBV DNA LMV +阿德福韦酯（ADV）组合疗法，成功地抑制乙肝病毒表面抗原下降是最理想的。 LMV耐药患者中，39 LMV + ADV为40个月（范围：24-84）HBsAg水平从基线到最后的观察，其实是下降的日志<0.5日志，并没有患者HBsAg清除。 [39]更令人鼓舞的是意大利的一项研究结果，在88例患者中，血清HBV DNA持续检测不到（<35拷贝/毫升）至少3年的LMV单药治疗组（n = 23）或ADV +的LMV结合治疗（ N = 65），其中乙肝表面抗原滴度逐渐下降随着时间的推移，少数患者达到HBsAg消失。滴度的乙肝表面抗原日志中位数3.2其实在第1年，3.1年2，3，4年的2.9和2.8的5年中，与整体平均下降0.8日志10 UI /毫升的。 a> 1时数减少21例（27％），4年和19（41％），5年相比，基线和24（29％）患者HBsAg水平低于250 UI /毫升，经过4年的治疗。七（30％）长期LMV单药治疗的反应，以减少乙肝表面抗原滴度检测（0.05 UI /毫升）以下的限制。 [40]

总体而言，尽管更大的抑制HBV DNA的影响，患者对核苷（酸）类似物（NUC）有乙肝表面抗原下降速度较慢，不太明显的，即使是在那些谁后HBsAg清除。 [6]，[8]，[35]作为一般规则，是不太明显比HBeAg阳性患者HBeAg阴性乙肝表面抗原下降。 [35]，[37]，[38]基于对HBsAg动力学，我们估计HBsAg消失的时间是10年的LMV反应，[8]，但延长30年的人。 [41]，[42]


   结论


乙型肝炎表面抗原（HBsAg）是一个重要的测试，不仅标志着乙肝病毒活动性感染，但也可以预测感染的临床效果。低HBsAg和HBV DNA水平的检测可以准确地找出真正的非活动性携带者，他们既不需要严格的随访，也没有抗病毒治疗。在乙肝表面抗原定量分析的基础上，响应制导与PEG-IFN治疗的HBeAg阳性和阴性患者的治疗中得到了发展。据有关资料显示，治疗可以停止在小学成为候选替代疗法，如与国统会的无限抑制治疗无反应，在第12周。血清HBsAg下降也有助于NUC治疗的患者，主要是HBeAg阳性的，但是，根据慢动力学相关的PEG-IFN治疗。因为乙肝表面抗原逐渐下降预示着在所有情况下，乙肝表面抗原的清除，这可能有助于提高成本效益比的NUC治疗。新的方法来测试是否PEG-IFN和国统会的组合促进长期反应的乙肝病毒表面抗原下降到国统会，正在探索。

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