B,C基因型的HBeAg阴性慢性乙型肝炎患者乙肝表面抗原转阴的预测评分系统
A Predictive Scoring System for the Seroclearance of HBsAg in HBeAg-seronegative Chronic Hepatitis B Patients with Genotype B or C Infection
Jessica Liu a, b,
Mei-Hsuan Lee b, c,
Richard Batrla-Utermann d,
Chin-Lan Jen b,
Uchenna H. Iloeje e,
Sheng-Nan Lu f,
Li-Yu Wang g,
San-Lin You b,
Chuhsing K. Hsiao a,
Hwai-I. Yang b, h, i,
Chien-Jen Chen a, b, Corresponding author contact information, E-mail the corresponding author
a Graduate Institute of Epidemiology and Preventative Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
b The Genomics Research Center, Academia Sinica, Taipei, Taiwan
c Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan
d Roche Diagnostics, Ltd., Switzerland
e Global Health Economics and Outcomes Research, Bristol-Myers Squibb Co., USA
f Department of Gastroenterology, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan
g MacKay College of Medicine, Taipei, Taiwan
h Molecular and Genomic Epidemiology Center, China Medical University Hospital
i Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
Seroclearance of hepatitis B surface antigen (HBsAg) is the most ideal endpoint in the treatment of chronic hepatitis B. This study develops a predictive scoring system to assess whether the addition of serum levels HBsAg may improve the predictability of HBsAg loss.
Methods
This study included 2491 untreated participants with genotype B or C HBV infection, who were HBsAg-seropositive, HBeAg-seronegative, anti-HCV-seronegative, and cirrhosis free at study entry. Regression coefficients of predictors in Cox Regression models were converted into integer scores for predicting HBsAg seroclearance. Predictive accuracy was assessed with area under the receiver operating characteristic curves (AUROC), and predictive accuracies of models with and without serum HBsAg levels were compared. [Results]
Low serum levels of both HBsAg and HBV DNA were the strongest predictors of spontaneous HBsAg seroclearance. Compared to baseline serum HBsAg levels ⩾1000 IU/mL, the multivariate adjusted rate ratio of spontaneous HBsAg seroclearance was 10.96 (7.92-15.16) for those with baseline serum HBsAg levels <100 IU/mL. The predictive ability of HBsAg levels was modified by HBV viral load, showing a weaker effect in those with higher viral loads, and the strongest effect among those with undetectable viral loads. The inclusion of serum HBsAg levels greatly improved the AUROC for predicting HBsAg seroclearance at the fifth (from 0.79 [0.787-0.792] to 0.89 [0.889-0.891]) and tenth year (from 0.73 [0.728-0.732] to 0.84 [0.839-0.841]) after study entry.
Conclusion
Incorporated into an easy-to-use scoring system, HBV viral load and quantitative serum HBsAg levels can accurately predict HBsAg seroclearance. 作者: StephenW 时间: 2012-12-28 13:48
A list of 5-year and 10-year probabilities of spontaneous HBsAg seroclearance by serum
HBsAg level and the total score of other predictors is shown in Table 4. In order to
emphasize the difference in spontaneous HBsAg seroclearance probabilities among different
serum HBsAg levels, the listed probabilities are stratified, using serum HBsAg levels as a
base score. Scores of age, BMI, and serum levels of HBV DNA in Model 2 of Table 3 were
summed to derive the total score of other predictors. For example, a 45-year-old male with
BMI <30 kg/m2 and undetectable serum HBV DNA has a total score of the other predictors
of 8 (1+0+7). If he has a serum HBsAg level of 100-999 IU/mL, his 5-year and 10-year
probability of spontaneous HBV seroclearance are 9.35% and 23.47%, respectively.
Chronic hepatitis B is a global public health threat due to its widespread distribution and potential to cause adverse clinical outcomes such as cirrhosis, hepatocellular carcinoma (HCC) and even death [1, 2]. The natural history of chronic hepatitis B is typically defined by several phases, which are characterized by changes and interactions among several key seromarkers including alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), anti-HBe, and hepatitis B virus (HBV) DNA [3, 4].
Previous studies have shown that HBeAg-seropositive patients are at increased risk for hepatocellular carcinoma, and HBeAg seroconversion is an important milestone for clinical management of these patients [5]. For HBeAg-seronegative patients, HBsAg seroclearance has been well-documented as the most important clinical and treatment endpoint, as it signals immunity to HBV, leads to an improved prognosis, and confers lower rates of HCC [6, 7].
Our previous study from the R.E.V.E.A.L.-HBV cohort found that lowering HBV DNA
levels was the most significant predictor of spontaneous HBsAg seroclearance, with 95.8% of individuals reaching undetectable HBV DNA levels prior to spontaneous HBsAg seroclearance [8].
Recent technological advances enabled the rapid and inexpensive quantification of HBsAg levels in serum, stimulating interest in the role of quantitative HBsAg in the natural history of chronic hepatitis B [9]. Quantitative HBsAg has been suggested as a promising new seromarker for the immunological response to therapy for chronic hepatitis B as well as a potential predictor of liver disease progression [9-13]. Recently, the rapid on-treatment decline in serum HBsAg levels, as well as combination of HBsAg and HBV DNA decline has been found to predict sustained virological response to interferon therapy, as well asHBsAg loss after treatment [14-16]. Quantitative serum HBsAg levels have also been shown to successfully distinguish inactive from active carriers in genotype C and D patients [17, 18].
A few recent studies examined the predictability of quantitative HBsAg levels for HBsAg seroclearance, and showed a reverse association between serum HBsAg levels and HBsAg seroclearance in clinical patients [19-22]. However, these studies emphasized HBsAg levels as the most important predictor of seroclearance without placing enough emphasis on the role of HBV DNA levels, which has been established as an important long-term predictor of HBsAg seroclearance [19-22]. These studies were limited by small sample sizes, clinic-based enrollment of treated patients, and no direct comparison between models with and without the inclusion of serum HBsAg levels. Furthermore, they did not develop a prediction scoring system for HBsAg seroclearance.
Therefore, this study aims to develop a predictive scoring system for spontaneous HBsAg seroclearance in a natural history cohort of treatment naïve HBeAg-seronegative patients affected with genotype B or C chronic hepatitis B, to assess whether the addition of serum HBsAg levels into currently available models may improve the predictability of spontaneous HBsAg seroclearance.
慢性乙型肝炎是一个全球性的公共健康威胁，由于其广泛的分布及潜在造成不良的临床结果，如肝硬化，肝细胞癌（HCC），甚至死亡[1，2]。慢性乙型肝炎的自然史通常是由几个阶段的变化和相互作用之间的几个关键seromarkers包括丙氨酸氨基转移酶（ALT），乙型肝炎表面抗原（HBsAg），乙型肝炎e抗原（HBeAg）阳性，其特点是，反HBe阳性，B型肝炎病毒（HBV）DNA [3，4]。
以前的研究已经表明，HBeAg血清学阳性的患者是肝癌的风险增加，HBeAg血清学转换是一个重要的里程碑，对这些患者的临床管理[5]。对于e抗原阴性的患者，乙肝表面抗原转阴记载的最重要的临床治疗终点，因为它标志着对HBV的免疫力，改善预后，并赋予较低的利率HCC [6,7]。
我们以前发现的REVEAL-HBV队列的研究从降低HBV DNA
水平是最重要的预测自发乙肝表面抗原转阴，有95.8％的人达到检测不到HBV DNA水平之前，自发的乙肝表面抗原转阴[8]。
最近的技术进步，使快速和廉价的定量乙肝表面抗原血清中HBsAg定量的作用，刺激兴趣的自然史的慢性肝炎B [9]。被认为是HBsAg定量的免疫反应治疗慢性乙型肝炎，以及作为一个潜在的预测肝脏疾病的进展[9-13]一个前途的新seromarker的。最近，快速治疗血清HBsAg水平下降，以及HBsAg和HBV DNA下降的组合已经发现预测持续病毒学应答对干扰素治疗，以及asHBsAg了损失后处理[14〜16]。定量血清HBsAg水平也被证明
成功地分辨从积极的运营商处于非活动状态C和D基因型患者[17，18]。
最近的一些研究分析了对乙肝表面抗原HBsAg定量水平的可预测性
转阴，并呈现出反向之间的关联和HBsAg血清HBsAg水平
在临床上患者的血清清除[19-22]。然而，这些研究强调HBsAg水平
作为最重要的预测指标转阴的作用不够重视，没有将
HBV DNA的水平，这已被确立为一个重要的长期预测
乙肝表面抗原转阴[19-22]。这些研究仅限于小样本，临床为基础的
入学接受治疗的病人，并没有直接的比较模型和
血清HBsAg水平列入。此外，他们还没有发展预测得分
系统为乙肝表面抗原转阴。
因此，本研究的目的是开发一个自发乙肝表面抗原的预测评分系统
初次接受治疗的HBeAg阴性患者的自然史队列转阴
与B型或C慢性乙型肝炎的影响，以评估是否加入血清
HBsAg水平可能会提高到目前现有的模型的可预测性自发
乙肝表面抗原转阴。 作者: StephenW 时间: 2013-1-3 19:08
DISCUSSION
Fully elucidating the determinants of HBsAg seroclearance and predicting its occurrence is
important for the prevention of liver disease progression [7, 29, 30]. Our previous study
found that decreasing serum HBV DNA level was the most important predictor of HBsAg
seroclearance [8]. However, recent studies have shown an association between serum HBsAg levels and HBsAg seroclearance [17, 19]. This study is the first to examine whether the addition of quantitative serum HBsAg levels into current models may increase the
predictability of spontaneous HBsAg seroclearance in a large community-based natural
history study of previously untreated individuals.
In accordance with recent studies which reported serum HBsAg levels as the most important
predictor of HBsAg seroclearance among HBeAg-seronegative individuals,[19-22] our study
also found the importance of serum HBsAg levels in predicting HBsAg seroclearance.
Previous studies emphasized serum HBsAg levels alone as an independent predictor [19-22].
However, our study further emphasizes the important role of HBV viral loads in predicting
HBsAg seroclearance in addition to serum HBsAg levels.
We found a significant biological gradient between decreasing serum HBsAg levels and
increasing rates of HBsAg seroclearance, even after adjustment for serum HBV DNA level.
The cumulative lifetime incidence of HBsAg seroclearance was significantly higher among
individuals with undetectable HBV DNA levels. Although the effect of serum HBsAg levels
was extremely high for those with undetectable serum HBV DNA levels, its effect decreased
strikingly, among those with baseline serum HBV DNA levels ≥2,000 IU/mL.
The predictive ability of serum HBsAg levels varies according to different phases of disease
and is, most importantly, HBV DNA dependent. Thus, serum HBV DNA levels continue to
play a crucial role in spontaneous HBsAg seroclearance. It is also important to lower serum
levels of HBsAg in order to maximize the probability of HBsAg seroclearance, especially in
those with undetectable HBV DNA levels.
Based on results from the R.E.V.E.A.L.-HBV study, in Asian chronic hepatitis B patients
with genotypes B or C infection who were HBeAg- seropositive, serum HBV DNA levels
were the most significant predictor of HBsAg seroclearance, while serum HBsAg levels did
not play a significant role [31]. In this study, among HBeAg-seronegative Asian patients
infected with genotypes B or C with predominantly normal ALT levels and viral loads
≥2,000 IU/mL, serum HBV DNA and HBsAg levels were equivalently important for the
prediction of HBsAg seroclearance. Among those who were HBeAg-seronegative with viral
loads <2,000 IU/mL, serum HBsAg levels became the most important predictor, while HBV
DNA levels were less important (Table 2). Thus, the study by Tseng et al. may not have
found HBV DNA levels to predict HBsAg seroclearance because the study was limited to
individuals with low viral loads [19]. We did not find ALT levels to be significant, perhaps
due to the low frequency of ALT elevation in this cohort. However, this finding is in
agreement with previous studies in genotype B and C patients [8, 19-21].
Current treatment guidelines use HBV DNA levels as the main tool for monitoring chronic
hepatitis B, but have begun to incorporate serum HBsAg levels,[7] and suggest that the use of serum HBsAg levels in addition to serum HBV DNA levels may further refine clinical
management of patients with chronic hepatitis B. Studies have shown a positive correlation
between serum HBsAg and liver cccDNA levels, although this positive correlation was not
always found in HBeAg-seronegative patients [6, 11, 12, 32]. Serum HBsAg levels may
reflect the translation of mRNA’s produced from cccDNA, although the association between
HBsAg and HBV replication seems to break down in HBeAg-negative disease [9, 12, 32].
Serum HBsAg may reflect the balance between the virus and host immune response rather
than viral replication alone, although its exact role is still unclear.
Previous studies have proposed cutoff points of serum HBsAg levels for the prediction of
HBsAg seroclearance. However, it is important to note that probability of HBsAg
seroclearance is a continuum, which varies with the unique clinical profile of each patient
instead of being defined by HBsAg levels alone. In this cohort study, two separate scorebased
prediction models were developed that were able to accurately estimate the probability
of HBsAg seroclearance for different clinical profiles. While the first model containing only
serum HBV DNA levels provided moderate predictive accuracy of the 5-year and 10-year
probability of HBsAg seroclearance, the addition of serum HBsAg levels provided a
significant improvement in both 5-year and 10-year predictive accuracy. The model
containing both HBV DNA and serum HBsAg levels showed excellent calibration correlation
coefficients greater than 0.95.
The score-based prediction model has been widely used by the Framingham Heart Study to
estimate the risk of coronary heart disease [25]. In the case of chronic hepatitis B, this
methodology has been successfully applied in predicting the long-term risk of HCC [26, 27].
The predictive score system in this study not only incorporates other well-known predictors
of HBsAg seroclearance, but captures a profile-based probability distribution for spontaneous HBsAg seroclearance that can be used to further stratify risk groups and refine clinical
management of patients with chronic hepatitis B. A simple score-based prediction model can
potentially eliminate the need for complicated calculations in clinical settings, allowing
clinicians to easily make clinical decisions in patient treatment while helping clinicians to
provide a personalized consultation to each patient.
There are some limitations to be noted. This study only included baseline serum HBsAg
levels, thus the long-term change in serum HBsAg levels must be further elucidated. An
ongoing study from the R.E.V.E.A.L. group will perform long-term repeated measurements
of HBsAg levels to examine HBsAg kinetics and its association with seroclearance and
clinical outcomes. In addition, participants in this study were treatment naïve chronic HBV
carriers. Therefore, the applicability of these results to patients undergoing treatment needs to be explored. Lastly, this study was limited to participants between 30 and 65 years old mostly infected at birth through perinatal infection with HBV genotype B and/or C. Therefore, rates of seroclearance in this study may differ from other genotypes. In addition, the predictive score needs to be clarified in younger carriers, those infected in adulthood, or in individuals infected with other HBV genotypes. 作者: StephenW 时间: 2013-1-3 19:09