The role of quantitative hepatitis B surface antigen revisited
Markus Cornberg
, Vincent Wai-Sun Wong
, Stephen Locarnini
, Maurizia Brunetto
, Harry L.A. Janssen
, Henry Lik-Yuen Chan correspondencePress enter key for correspondence informationemailPress enter key to Email the author
Article has an altmetric score of 8
DOI: http://dx.doi.org/10.1016/j.jhep.2016.08.009
Summary
In the past 10 years, there has been a lot of enthusiasm surrounding the use of serum hepatitis B surface antigen (HBsAg) quantification to predict disease activity and monitor treatment response in chronic hepatitis B. The measurement of HBsAg levels have been standardized in IU/ml, and nowadays it is almost a mandatory measurement due to the development of new antiviral treatments aiming at HBsAg seroclearance, i.e., functional cure of hepatitis B. Recently, there has been an improved understanding of the molecular virology of HBsAg, and particularly the relative roles of covalently closed circular DNA and integrated hepatitis B virus (HBV) DNA. This has shed new light on the interpretation of HBsAg levels in different phases of chronic hepatitis B. HBsAg level can assist the differentiation of immune tolerance and immune clearance in hepatitis B e antigen (HBeAg)-positive patients, and it can predict inactive disease and spontaneous HBsAg seroclearance in HBeAg-negative patients. The determination of HBsAg level is pivotal to individualize pegylated interferon (PegIFN) treatment; it is the key investigation to decide early termination of PegIFN among non-responders. Among patients treated by nucleos(t)ide analogues, responders tend to have dramatic reduction of HBsAg to low levels, which may be followed by HBsAg seroclearance. With newer data on combination treatment of PegIFN and nucleos(t)ide analogues as well as emerging new antiviral agents, HBsAg quantification is expected to become increasingly important to monitor and guide antiviral therapy for chronic hepatitis B.
Keywords:
Hepatitis B, HBsAg, Pegylated interferon, Entecavir, Tenofovir, Antiviral treatment 作者: StephenW 时间: 2017-1-20 21:27
Productive replication of HBV, a DNA virus that replicates via reverse transcription, is driven from its transcriptional template, the cccDNA, which is found in the nucleus as a viral minichromosome [[10], [11]]. Transcription from this minichromosome generates all the mRNAs needed for HBV replication including SVP production. HBsAg may also be produced from HBV DNA integrated into the host genome (Fig. 2). Although viral integration is not required for normal productive replication, integration of HBV DNA occurs illegitimately through recombination mechanisms using host enzymes acting on the double-stranded linear (DSL) DNA form of HBV [12]. The DSL DNA replicative intermediate is generated as a consequence of the failure to translocate the RNA primer needed to prime plus-stranded DNA synthesis of the HBV genome [13]. The DR-1/DR-2 regions of the viral genome are preferential sites for integration [14], but integrated sequences cannot provide a template for productive viral replication since the complete genome is not present. However, the open reading frame (ORF) of the S gene with its regulatory elements are often still present in integrated sequences, are intact and so, HBsAg can be produced. Thus, two sources of HBsAg can be identified: cccDNA derived and integrated DNA derived (Fig. 2). This has significance, not only in defining cure end-points such as functional or complete [15] but also in attempting to correlate HBsAg levels in serum to particular replicative markers in the liver.
The aim of NA treatment is maintained viral suppression during treatment [66]. The optimal endpoint and the only situation where NA treatment can be safely discontinued is HBsAg loss, which is a rare event [74]. In HBeAg-positive patients, discontinuation of NA treatment 12 months after HBeAg seroconversion can be recommended [66] but relapse is not infrequently observed [75]. HBsAg levels may help to predict who may achieve HBsAg loss in the long-term and HBsAg may also be an interesting marker to predict HBV rebound after stopping NA treatment.
General trend of HBsAg decline during nucleos(t)ide analogue therapy
HBsAg decline during NA therapy is much slower and less pronounced compared to PegIFN treatment, although NA are much more potent on HBV DNA suppression [[69], [76], [77]]. NAs inhibit only the reverse transcription of the pgRNA but do not target the cccDNA directly. Thus, changes at transcriptional levels, particularly in the HBsAg secretory pathway, are not expected. On the other hand, IFN has both direct antiviral and immune mediated effects. It is likely that the immune modulation by IFN leads to a more dramatic decline in HBsAg production and secretion. Based on HBsAg kinetics, some authors estimated that the median time to HBsAg loss in NA treated patients could be far more than 30 years [[78], [79]]. The rate of HBsAg decline is higher in HBeAg-positive patients vs. HBeAg-negative patients [[79], [80], [81]]. The faster decline in HBeAg-positive patients, especially in the first year of NA therapy [[80], [82]], may be explained by the NA effect on HBV DNA containing virions. In addition, HBeAg-negative patients may have higher amounts of integrated HBV DNA, which can still lead to HBsAg production, as discussed above. Although HBsAg decline is very slow, there are individual differences [83]. Stronger HBsAg decline during NA therapy was associated with higher pre-treatment ALT [79] or IP-10 (CXCL-10) level [[83], [84]] confirming that immune responses are required for HBsAg decline and HBV clearance. So far there is no evidence that different NA or even combinations of NA have different effects on HBsAg kinetics [[81], [83]]. It may be more likely that inter-current events such as infections which may induce cytokines leading to HBsAg decline. Just recently, it has been shown that IFN gamma or tumor necrosis factor alfa can reduce cccDNA without cytolysis [85]
In HBeAg-positive patients it would be interesting if HBsAg level could predict HBsAg loss or sustained immune control after HBeAg seroconversion. Wursthorn et al. showed that a rapid HBsAg decline of more than 1 log after 1 year of treatment with telbivudine was predictive for HBsAg loss [86]. Supporting the aforementioned hypothesis, HBsAg decline was associated with markedly enhanced antiviral T cell reactivity. Similar data have been documented in patients treated with tenofovir or entecavir. In patients treated with tenofovir, a reduction in HBsAg level of at least 1 log by week 12 or 24 were predictive for HBsAg loss with a positive predictive value of up to 45% and a NPV of up to 97% [87]. It appears that HBeAg-positive patients with stronger HBsAg decline are more likely to achieve HBeAg seroconversion [[81], [88]] but this was not observed in all studies [[89], [90]]. There is less data if HBsAg level can predict off-treatment response after HBeAg seroconversion. For example, in a small study with 11 HBeAg-positive patients who were treated with telbivudine for 2 years, HBsAg <100 IU/ml at the end of treatment predicted for sustained response (defined as undetectable HBV DNA, normal ALT and HBeAg seroconversion) for 2 years after stopping treatment [91].
HBeAg阳性患者
在HBeAg阳性患者中,如果HBsAg水平可以预测HBeAg血清学转换后HBsAg丢失或持续的免疫控制,将是有趣的。 Wursthorn et al。显示在使用替比夫定1年的治疗后,HBsAg的快速下降超过1 log是HBsAg缺失的预测[86]。支持上述假说,HBsAg下降与显着增强的抗病毒T细胞反应性相关。已经在用替诺福韦或恩替卡韦治疗的患者中记录了类似的数据。在用替诺福韦治疗的患者中,在第12或24周时HBsAg水平降低至少1个log是HBsAg丧失的预测,阳性预测值高达45%,NPV高达97%[87]。似乎HBeAg阴性的HBeAg阳性患者更有可能实现HBeAg血清学转换[[81],[88]但这没有在所有的研究中观察到[[89],[90]]。如果HBsAg水平可以预测HBeAg血清转化后的治疗反应,则有较少的数据。例如,在11名HBeAg阳性患者接受telbivudine治疗2年的小型研究中,治疗结束时HBsAg <100 IU / ml,预测持续反应(定义为不可检测的HBV DNA,正常ALT和HBeAg血清转换)停止治疗后2年[91]。作者: StephenW 时间: 2017-1-20 21:43
HBeAg-negative patients
The predictive value of HBsAg levels and interpretation of HBsAg kinetics is more difficult in HBeAg-negative patients [[88], [92]]. HBsAg negative patients may have higher amounts of integrated HBV DNA, which can be a source of HBsAg as discussed above. Thus, the relative effect of NA on the replenishment of cccDNA is lower. In addition, non-cytolytic immune responses may have effect on cccDNA degradation [85] but not on the cell and integrated DNA. Thus, HBeAg-negative patients may have different HBsAg kinetics to cytokines (i.e., IFN treatment) or non-cytolytic immune responses during the natural course of HBV infection or NA therapy compared with HBeAg-positive patients.
Another important fact for the interpretation of HBsAg levels is that some HBeAg-negative patients with early HBsAg decline during NA therapy might have just changed the phase of HBV infection (i.e., transition from immune clearance phase to HBeAg-negative hepatitis) [83], which is associated with lower HBsAg levels [[34], [35]]. Thus, it may represent an already ongoing natural HBsAg decline in some patients.
HBsAg levels in HBeAg-negative patients may be useful for the decision if treatment cessation is an option. Because of the aforementioned long-term treatment with NAs, efforts have been made to identify possible stop points for NA treatment. Hadziyannis et al. showed in HBeAg-negative infection with normalized ALT and suppressed HBV DNA after treatment with adefovir for 4–5 years, the withdrawal of antiviral therapy led to a sustained off-treatment HBV DNA suppression in 55% of patients and even subsequent HBsAg loss in 39%. Lower HBsAg levels at end of treatment were predictive for later HBsAg loss [93]. Again, this supports the idea that immune responses are important for the long-term control of HBV infection. A systematic review of several studies, most retrospective suggest that some patients with decreasing HBsAg levels or lower HBsAg levels (<100 IU/ml) are able to maintain control of HBV after discontinuation of long-term NA therapy [94]. In addition, a consolidation therapy of >3 years before stopping NA seem to be important as well [94]. However, stopping NA might be more complex than anticipated. Some studies suggest that HBV DNA rebounds shortly after NA cessation in most cases [[93], [95]]. This may induce ALT flares [[93], [95]] indicating immune responses, which may be the key for subsequent immune control and HBsAg loss [96]. Therefore, stopping NA is not at all recommended in patients with cirrhosis.
HBeAg阴性患者中的HBsAg水平可能有助于决定是否可以选择治疗。由于上述用NA的长期治疗,已经做出努力来鉴定NA治疗的可能停止点。 Hadziyannis et al。在用阿德福韦治疗4-5年后的HBeAg阴性感染中显示出标准化的ALT和抑制的HBV DNA,在55%的患者中撤出抗病毒治疗导致持续的脱离HBV DNA抑制,甚至在39天后的HBsAg消失%。在治疗结束时较低的HBsAg水平预示着后来的HBsAg缺失[93]。同样,这支持免疫反应对于HBV感染的长期控制很重要的观点。几项研究的系统综述,大多数回顾性研究表明,一些具有降低的HBsAg水平或更低的HBsAg水平(<100 IU / ml)的患者能够在停止长期NA治疗后维持对HBV的控制[94]。此外,在停止NA之前≥3年的巩固治疗同样重要[94]。然而,停止NA可能比预期更复杂。一些研究表明,HBV DNA在大多数情况下在NA停止后不久就会反弹[[93],[95]]。这可能诱导ALT耀斑[[93],[95]]表明免疫反应,这可能是后续免疫控制和HBsAg消失的关键[96]。因此,在肝硬化患者中完全不推荐停止NA。作者: StephenW 时间: 2017-1-20 21:46
Table 1
Quantitative HBsAg in the management of different settings of chronic HBV-infections.
Natural course
HBeAg positive
HBsAg >100,000 IU/ml associated with high replicative HBsAg carrier (“immune tolerance”)
HBsAg >25,000 IU/ml >90% PPV for minimal liver fibrosis <F1
HBeAg negative
HBsAg <1000 IU/ml and HBV-DNA <2000 IU/ml is associated with lower risk for HCC
HBsAg <1000 IU/ml and HBV DNA <2000 IU/ml corresponds to 90% PPV for inactive carrier phase (genotype D)
HBsAg <100 IU/ml is probably associated with spontaneous HBsAg clearance
Treatment with PegIFN
HBeAg positive
HBsAg <1500 IU/ml at week 12 corresponds to 57% PPV for HBeAg seroconversion and 17.6% HBsAg clearance
No decline (any decline) of HBsAg at week 12 has a high NP for response (HBeAg loss and HBV DNA <2000 IU/ml at 24 weeks post-treatment). Response <5% (genotypes A and D)
HBsAg >20,000 IU/ml at week 12 and 24 associated with 100% NPV for response (HBeAg loss and HBV DNA <2000 IU/ml at 24 weeks post-treatment) (genotypes B and C)
HBeAg negative
No HBsAg decline (any decline) and <2 log decline of HBV DNA showed a NPV of 100% for non-response in genotype D patients
Treatment with NA
HBeAg positive
HBsAg decline >1 log after 12–48 weeks has been associated with HBsAg loss
HBeAg negative
Very slow decline of HBsAg.
Low HBsAg levels (<100 IU/ml) may predict off-treatment response after cessation of NA (after consolidation therapy ⩾3 years)
Treatment with PegIFN and NA
HBsAg decline of <1 log from baseline to week 12 is associated with high NPV for HBsAg loss
Co-infections
HBV/HCV: Lower HBsAg in HCV dominant patients
HBV/HIV: Higher HBsAg levels compared to monoinfection. Association with CD4 T-cell count. HBsAg decline during ART is associated with CD4 T-cell count
HBV/HDV: Relative high HBsAg level. HBsAg level may be useful to guide IFN therapy