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 ~  Abstract
 ~ Introduction
 ~  Materials and Me...
 ~ Results
 ~ Discussion
 ~ Conclusions
 ~ Acknowledgement
 ~  References
 ~  Article Figures
 ~  Article Tables

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  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 33  |  Issue : 5  |  Page : 20-25
 

The predictive value of early indicators for HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients with Telbivudine treatment for 104 weeks


Center of Infectious Diseases,West China Hospital of Sichuan University; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, China

Date of Submission14-Jul-2013
Date of Acceptance02-Apr-2014
Date of Web Publication6-Feb-2015

Correspondence Address:
Hong Tang
Center of Infectious Diseases,West China Hospital of Sichuan University; Division of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan
China
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Source of Support: National Science and Technology Major Project of China (No. 2012ZX10002007.001.003), Conflict of Interest: None


DOI: 10.4103/0255-0857.148827

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 ~ Abstract 

Purpose: Through an observation on HBeAg-positive chronic hepatits B (CHB) patients in Telbivudine (LDT) treatment for 104 weeks, we tried to explore valuable early predictors for HBeAg seroconversion during the treatment. Materials and Methods: A prospective study lasting for 104 weeks was conducted, and the patients enrolled were administered with LDT 600 mg daily. The medical evaluation went every 12 weeks, then the age distribution, baseline ALT level, early HBVDNA, HBsAg and HBeAg levels at baseline, week 12 and 24 as well as the decrease of the three indicators at week 12 and 24 were analyzed for their predictive values for HBeAg seroconversion at week 104. Result: Thirty-three patients finished the observation. All patients got ALT normalisation and 28 patients (84.84%) got complete virological response (HBV DNA < 291 copies/ml) at week 104. Poor virological response and virologic breakthrough was observed in two (6.06%) and three patients (9.09%), respectively. Nine patients (27.27%) got HBeAg seroconversion. HBeAg levels and its decrease levels at week 12 and 24 showed significant differences between patients with and without HBeAg seroconversion. And the HBsAg levels at week 12 and 24 showed tendencies of significant differences in two groups. HBeAg level at week 24 was confirmed related to its longer term seroconversion in regression analysis. The patients with HBeAg level < 2.1 S/CO at week 24 would be more possible to get HBeAg seroconversion at week 104, with sensitivity, specificity, positive and negative predictive value of 95.83%, 88.89%, 95.8% and 88.9%, respectively. Conclusion: Good efficacy of long-term LDT treatment in biological and virological response and its advantage in serological response was confirmed again in our study. The HBeAg level at week 24 showed significant value in prediction for HBeAg seroconversion at week 104 compared to other serological markers in the early period.


Keywords: Chronic hepatitis B, prediction, serological markers ,telbivudine


How to cite this article:
Wang J, Du Ly, Zhu X, Chen Eq, Tang H. The predictive value of early indicators for HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients with Telbivudine treatment for 104 weeks . Indian J Med Microbiol 2015;33, Suppl S1:20-5

How to cite this URL:
Wang J, Du Ly, Zhu X, Chen Eq, Tang H. The predictive value of early indicators for HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients with Telbivudine treatment for 104 weeks . Indian J Med Microbiol [serial online] 2015 [cited 2019 Aug 20];33, Suppl S1:20-5. Available from: http://www.ijmm.org/text.asp?2015/33/5/20/148827



 ~ Introduction Top


The antiviral therapy is the key to the treatment of CHB. However, the efficacy is affected by many elements such as drug, virus and host. Some patients receiving standard therapy would hardly achieve ideal therapeutic response and the duration is indefinite. The rebound is also common after drug discontinuance even if the complete virological response or HBeAg seroconversion has been achieved. As a result, it is necessary to find some early predictive indicators before and during the treatment in order to forecast the long-term efficacy and drug resistance, adjust the treatment, judge the therapeutic terminal and improve the compliance. [1],[2],[3]

The ALT and HBV-DNA levels at baseline and the virological response at week 24 are recognised predictive indicators for efficacy during the antiviral treatment of CHB. [4],[5],[6],[7] In recent studies on interferon, the quantitative changes of HBeAg and HBsAg in early period could be better predictive indicators for their superiority in prediction of long-term virologic and serologic responses. [2],[4],[8] However, when it comes to treatments with kinds of nucleoside analogs (NAs), Consensus is needed about whether early levels of sero-markers remain the same in predictive values. A Korean study indicated that the HBV DNA and HBsAg levels at week 12 were independent predictors of HBeAg seroconversion in HBeAg-positive patients after 1 year's treatment with entecavir (ETV). [9] Zhang X et al., found in 65 CHB patients in treatment with ETV that more than 65% decrease of HBeAg level at week 24 showed significant predictive effect on HBeAg seroconversion at week 92 (OR = 70.578, P < 0.0001). [10] In another study about 42 HBeAg-negative patients treated with lamivudine for an average duration of 66 months, patients with HBsAg decrease less than 0.9log10 at month 6 would encounter virological breakthrough (PPV, 90%; NPV, 100%). [11] These studies had limited period less than 2 years under observation which was far shorter than the average duration of treatment with NAs, and did not concern the NA agent LDT which had an advantage in HBeAg seroconversion.

As a result, our study focused on the long-term therapeutic effect of 104 weeks' LDT treatment in HBeAg-positive CHB patients, and the variation in serological markers besides HBV-DNA in early period of the treatment were analyzed to explore valuable early predictors for HBeAg seroconversion during the treatment.


 ~ Materials and Methods Top


Study subjects

The subjects were selected from the patients who visited the Hepatitis Clinic of West China Hospital, Sichuan University between 2008 and 2009. They were diagnosed as CHB patients according to "Guideline on prevention and treatment of chronic hepatitis B in China" established jointly by Chinese Society of Hepatology, Chinese Medical Association (CMA) and Society of Infectious Diseases, CMA in 2005. Following criteria should be meet when one patient was enrolled: Age from 16-65 years old; ALT ≥ 2 ULN; HBV-DNA ≥ 10 5 copies/mL; positive in HBeAg; antiviral treatment naïve; and free of immunoregulation drugs in last 12 months. Patients who encountered one of the following situations should be excluded: Coinfection with other hepatitis viruses; advanced liver diseases such as liver cirrhosis or hepatocellular carcinoma; presence of complications such as metabolic liver disease, autoimmune hepatitis, myositis or myopathy; in pregnancy or lactation; alcohol and/or drug abuse in last 12 months; and serious diseases such as malignancy, severe cardiopulmonary disease, renal insufficiency, etc.

Study design

This was a prospective observation study aim to explore whether the early variation of serologic makers contribute to the prediction of long-term efficacy. All patients enrolled were administered with LDT 600 mg daily. The optimal observing duration was 104 weeks. And the medical assessments were carried out every 12 weeks during the treatment. For ethical principles, in patients with primary treatment failure, the therapy would be adjusted with more effective NAs or combined with NAs without cross-resistance. In patients with virological breakthrough, the therapy would be combined with NAs without cross resistance. Only the patients continuing LDT monotherapy would be kept under observation for full period. The assessments included inquiry, physical and laboratory examinations.

This study was conducted for observation only and intervened less into patients' ordinary medical procedure. Written informed consents were acquired. All procedures were in accordance with the 1975 Declaration of Helsinki.

Serum assay

The serum samples were collected every 12 weeks during the treatment for tests of biochemical, virological and serological indicators. ALT which represented the liver function most was detected by automatic biochemical analyzer according to standard procedures. Biochemical response (BR) was defined as the normalisation of serum ALT.

Serum HBV-DNA was quantified via real-time polymerase chain reaction (RT-PCR) assay with a lower limit of 291copies/mL (COBAS Tagman TM HBV Test Kit, Roche Molecular Systems, Inc., USA). Primary treatment failure was defined as a decrease of HBV DNA < 1log (10) IU/ml at week 12 or <2log (10) IU/ml at week 24 compared to baseline. Complete virological response (CVR) was defined as the HBV-DNA descended below the detection limit. Partial virological response (PVR) was defined as the decrease of HBV DNA > 2 log (10) IU/ml, but still above the detection limit at week 24 compared to baseline. Virological breakthrough (VB) was defined as the elevation of HBV-DNA > 1log (10) IU/ml compared to the lowest level ever achieved during the treatment.

Serum HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc) were tested by electrochemiluminescence immunoassay (MOUDULAR E170; Roche Diagnostics, IN, USA). The HBsAg level <1 IU/ml, the HBeAg level <1 S/CO and the HBeAb level <1 S/CO were defined as negative ones, respectively. HBsAg serological response (SR) would be achieved when the loss/conversion of HBsAg occurred and the definition of HBeAg SR was similar.

Statistical analysis

The indicators under observation in early period were analyzed for correlation with efficacy. Continuous data were expressed as mean and standard deviation or median and interquartile range after One-Sample Kolmogorov-Smirnov Test for normality. Categorical data were expressed by frequency and proportion. The baseline and on-treatment indicators were analyzed by logistic regression for their association with HBeAg seroconversion at the endpoint. The area under the receiver operating characteristic (ROC) curve (AUC) as well as sensitivity, specificity, positive predictive value and negative predictive value were calculated for evaluating the discriminatory ability. All statistical analyses were performed in SPSS18.0 and a P value < 0.05 was considered as statistical significance.


 ~ Results Top


Clinical characteristics at baseline

There were 33 patients who had completed the 104 weeks' monotherapy, including 24 men and 9 women with a median age of 23 ± 13 years (distributing from 19 to 48 years). The mean serum ALT level was 223.12 ± 136.20 IU/L. The mean HBV-DNA level was 8.67 ± 1.01 log (10) copies/mL. The mean HBsAg level was 4.25 ± 0.81 IU/ml and the median HBeAg level was 2.49 ± 0.35 log (10) S/CO.

Therapeutic efficacy of LDT treatment at week 104

After 104 weeks' treatment, ALT normalisation was achieved in all 33 patients. CVR was achieved in 28 patients (28/33, 84.84%). VB was observed in three patients (3/33, 9.09%) and two patients (2/33, 6.06%) with poor virological response but good BR (i.e., HBVDNA > 10 4 copies/mL along with normal ALT level during all the period under observation). It needed to be indicated that in these five patients with VB or poor virological response, the treatment was supposed to be modified with more effective agents or combined with drugs without cross resistance. However, they could not afford it because of financial reasons. So they had to keep LDT monotherapy on. At the end point of observation, there were nine patients achieved HBeAg seroconversion (9/33, 27.27%).

The decline patterns of HBeAg levels in the first 52 weeks on treatment

As we tried to find out whether there was an HBeAg decline pattern in the first year on treatment help for HBeAg seroconversion afterwards, the HBeAg levels form each patients in the first 52 weeks were collected for analysis. Five HBeAg decline patterns were found [Figure 1]. Early decline, HBeAg decline > 1log (10) S/CO at week 12, appeared in 17 patients (17/33, 51.52%). Delayed decline, HBeAg decline > 1log (10) S/CO at week 24, appeared in three patients (3/33, 9.09%). Late decline, HBeAg decline > 1log (10) S/CO at week 36, appeared in two patients (2/33, 6.06%). Terminal decline, HBeAg decline > 1log (10) S/CO at week 52, was found in two patients (2/33, 6.6%). And insignificant decline, HBeAg decline < 1log (10) S/CO at week 52, appeared in nine patients (9/33, 27.27%). The patients with HBeAg seroconversion at the end point belonged to in Pattern A, B and E. Most of them belonged to Pattern A (6/9, 66.67%). A less proportion belonged to Pattern B (1/9, 11.11%). And the rest belonged to Pattern E (2/9, 22.22%). What should be emphasised is the two patients with insignificant HBeAg decline achieved HBeAg seroconversion might reason for their extremely low HBeAg values at baseline (<5 S/CO).
Figure 1: Five HBeAg decline patterns in the first 52 weeks on treatment

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The predictive values of baseline and early on-treatment indicators for HBeAg seroconversion

We selected 17 possibly involved indicators to test their potentials as predictor for HBeAg seroconversion, including the age distribution, ALT level, HBV-DNA, HBsAg and HBeAg at baseline, the HBV-DNA, HBsAg and HBeAg at week 12 and week 24, the differences of HBV-DNA, HBsAg and HBeAg at week 12 and week 24 compared to baseline. These indicators were analyzed by independent sample test first to identify if they would show significant differences between patients with and without HBeAg seroconversion [details in [Table 1]. We could figure out from the result that there were significant differences in the HBeAg levels at week 12 (P < 0.001) and HBeAg level at week 24 (P < 0.001) between patients with and without HBeAg seroconversion. Consequently, the decrease of HBeAg levels at week 12 and 24 showed significant differences in the two groups with P = 0.009 and 0.002, respectively. Moreover, although the HBsAg levels at week 12 (P = 0.062) and week 24 (P = 0.057) did not show significant differences in the two groups, we should still enrolled them into the next step for regression analysis because the differences would most likely happen if the sample size would be expanded.
Table 1: The single factor analysis for the seventeen possible involved indicators

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Then the six indicators with P < 0.05 or close to 0.05 were chosen for logistic regression to analyze their correlation with HBeAg seroconversion at week 104. When the variables were analyzed separately in the equation in the beginning block, the equation would be changed with statistical significance as HBeAg levels at week 12 or 24 were enrolled (P < 0.001). It implied the HBeAg levels at week 12 or 24 might impact the HBeAg seroconversion at week 104. Unfortunately, after the conditional forward stepwise block, most indicators seemed to be less relative to the seroconversion and the HBeAg level at week 24 was only indicator left in the equation with limited statistical significance [Table 2].
Table 2: Result of logistic regression for correlation between indicators and seroconversion

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Although in this analysis, the result (P = 0.059) seemed to be statistical insignificant. But we should still accept it in the equation because when this indicator was removed from the equation, a change with statistical significance would occur (P < 0.001). And we did observe such relationship between the HBeAg level and seroconversion in our clinical trial and the tendency in [Figure 1]. It might result from the limited number of patients enrolled. A correlation with statistical significance would be probably observed if the sample size was expanded.

The analysis for ROC curve of HBeAg level at week 24 was then processed for the cutoff value, AUC, sensitivity, specificity, PPV and NPV [Table 3].
Table 3: Result of ROC curve analysis for HBeAg level at week 24

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From the result we could learn that the HBeAg level at week 24 impacted HBeAg seroconversion at week 104 with AUC = 0.097 (P < 0.001). HBeAg seroconversion would not occur at week 104 in patients with Log (10) HBeAg level ≥ 0.3230. In another word, HBeAg seroconversion at week 104 would be observed in patients with Log (10) HBeAg < 0.3230 (i. e. approximately HBeAg < 2.1S/CO) at week 24 with sensitivity, specificity, PPV and NPV of 95.83%, 88.89%, 95.8%, 88.9%, respectively.


 ~ Discussion Top


In the REVEAL study from Taiwan and other large studies on the natural history of chronic hepatitis B, persistent high level of HBV replication was associated with increased risk of cirrhosis, liver cancer and liver-related mortality. [12],[13] As a result, Asian and Pacific Association for the Study of the Liver (APASL) revised the primary goal of antiviral treatment for chronic hepatitis B as "permanently HBV suppression'' in the Guideline in 2005. [14] It meant to keep HBV viral load beneath the lower detection limit as long as an antiviral therapy could do was valid for efficacy judging. Long-term LDT treatment did offer effective viral suppression to CHB patients with certain baseline characteristics and on-treatment virological response in our study. Most patients achieved CVR as expected. Even in patients with poor virological response or VB, LDT monotherapy maintenance could still provide long-term ALT normalisation.

For patients with positive serum HBeAg, the HBeAg seroconversion was considered as a satisfactory therapeutic goal prior to CVR. Because in such patients, the earlier the HBeAg seroconversion achieved, the better the long-term prognosis would be. [15],[16] It had been a consensus that patients in LDT treatment showed a noteworthy rate of HBeAg seroconversion. [17] And in our study, a relative high rate of HBeAg seroconversion with a ratio of 27.27% was observed. As a result, it was worth exploring which kind of the patients in LDT treatment were more possible to get HBeAg seroconversion. In GLOBE trials, Wursthorn et al. found 43% of patients with HBeAg < 10PEI U/ml at week 24 could achieve HBeAg seroconversion at the end point of observation. [18] It implied that the serum HBeAg level itself, especially in the early period, would be considered as an important predictive indicator for HBeAg seroconversion in long term. So we analyzed the serum HBeAg level in the first 52 weeks to find out whether the decline pattern of HBeAg level in the early period impact HBeAg seroconversion in this trial. Five patterns of HBeAg decline were found according to the variation of average logarithmic HBeAg levels in the first 52 weeks during the treatment. Most patients with HBeAg seroconversion at week 104 showed early decline in their HBeAg levels, then delayed decline. Similar result was found in Zhang's trial as we mentioned before which was consistent with our outcome. [10] Two patients got the insignificant decline with a ratio of 22.22% (2/9). But the average HBeAg values in these two patients at baseline were very low (<5 S/CO). So we could infer that patients with extremely low HBeAg levels at baseline were more possible to get serologic response in LDT treatment.

The correlation between indicators on the early period of the treatment and HBeAg seroconversion at week 104 was studied with data from our trial. Seventeen indicators including the age distribution, baseline ALT level, early HBVDNA, HBsAg and HBeAg levels at baseline, week 12 and 24 as well as the decrease of the three indicators at week 12 and 24 were enrolled for analysis. It turned out the HBeAg levels and its decrease levels at week 12 and 24 showed significant differences between patients with and without HBeAg seroconversion and the HBsAg levels at week 12 and 24 showed tendencies of significant differences in two groups. It implied these indicators would be possibly involved in the prediction of long-term HBeAg seroconversion. However, after logistic regression analysis, most indicators seemed to be less relative to the seroconversion. The HBeAg level at week 24 was the only indicator shows limited correlation with the seroconversion (P = 0.059). We still consider this correlation acceptable as the relationship between the HBeAg level and seroconversion was actually observed in our clinical trial and the tendency in [Figure 1] was obvious. Moreover, as our sample size was only 33 subjects, a correlation with statistical significance would be probably observed if the sample size was expanded. As a result, the HBeAg level at week 24 was a valuable indicator for HBeAg seroconversion prediction. ROC curve analysis was also performed to confirm its predictive value. It turned out to be a good predictor with a AUC of 0.977 (P < 0.001) according to the cutoff value of Log (10) HBeAg level = 0.3230. In another word, HBeAg seroconversion at week 104 would be observed in patients with Log (10) HBeAg < 0.3230 (i. e., approximately HBeAg < 2.1S/CO) at week 24 with sensitivity, specificity, PPV and NPV of 95.83%, 88.89%, 95.8%, 88.9%, respectively. For the timing of week 24, we could find consistent result from other studies. For example, in a clinical trial of 30 HBeAg-positive CHB patients treated with pegylated interferon for 48 weeks carried out by Tangkijvanich et al., a decreased HBeAg level of 2.0 log (10) at week 24 provided the best prediction for sustained virological response, with sensitivity (Sen) and negative predictive value (NPV) of 85% and 92%, respectively. [19] Therefore, the HBeAg at week 24 was a better predictor with more predictive value, although the HBeAg at week 12 or even earlier took advantage of timeliness.

In LAM monotherapy trial, HBeAg seroconversion was closely correlated with levels of serum HBV DNA at week 12 (P = 0.000, OR = 0.394) and 24 (P = 0.019, OR = 0.442). [20] Moreover, it was already demonstrated by multiple stepwise regression analysis in GLOBE trial, that efficacy at week 104 was significantly associated with the situation whether serum HBV-DNA level was <300 copies/ml at week 24. [21] And in other studies, it seemed that lower 24-week serum HBV-DNA levels after lamivudine, telbivudine or entecavir administered were associated with higher rates of maintained ALT normalisation, HBV DNA non-detectability, HBeAg seroconversion and lack of resistance. [7],[20],[22] All these studies contributed to the strategy that HBV-DNA week 24 was a more appropriate predictor. However, the HBV-DNA at this time point showed little value to be a predictor in our study which might result from the sample size.

Serum HBsAg seemed to be an excellent on-treatment indicator for predicting sustained off-treatment response and identifying in the early phase of PEG-IFN therapy patients who would most likely benefit from this treatment. [23] However, as the decline in HBsAg level was much slower during NA therapy and the data on its predictive value were very preliminary, it remained to be determined on the wide application. [11],[15] We could only find a possible tendency of involvement between early HBsAg levels and HBeAg seroconversion. Further studies are needed about the effect of quantitative HBsAg changes in the prediction for long-term efficacy.


 ~ Conclusions Top


Good efficacy of long-term LDT treatment in biological and virological response and its advantage in serological response was confirmed again in our study. In all indicators in the early period of LDT treatment, the HBeAg levels and its decrease levels at week 12 and 24 showed significant differences between patients with and without HBeAg seroconversion. And the HBsAg levels at week 12 and 24 showed tendencies of significant differences in two groups. It implied these indicators would be possibly involved in the prediction of long-term HBeAg seroconversion. Among these possible predicators, HBeAg level at week 24 was the confirmed one. As the most probable potential predictor of HBeAg seroconversion, it could allow the most appropriate treatments to the most suitable patients. We should also notice that the number of subjects was limited, only the patients with HBeAg positive were enrolled and the observation lasted for 104 weeks, as a result the prediction value of other five possible predictors should be studied in other clinical trials with expanded sample size or longer observation.


 ~ Acknowledgement Top


This work was supported by National Science and Technology Major Project of China (No. 2012ZX10002007-001-003).

 
 ~ References Top

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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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