Abstract
Lamivudine, telbivudine, and entecavir are the first‐line drugs covered by the Taiwan National Health Insurance as 3‐year treatments for patients with chronic hepatitis B virus (HBV), but the optimal treatment duration of each remains unclear. We aimed to detect HBV treatment‐cessation durability, and compare the predictors in patients with and without clinical relapse. In this retrospective cohort study, 210 patients with chronic HBV who tested hepatitis B e‐antigen positive or hepatitis B e‐antigen negative were treated for 3 years with a nucleos(t)ide analogue. Of these, 102 patients continued therapy after 3 years, while 88 patients stopped treatment and were followed for 1 year due to financial difficulties. Efficacy was assessed in terms of alanine aminotransferase (ALT) level normalization, HBV DNA clearance, virus breakthrough, clinical relapse, and liver decompensation. The durability predictors were evaluated by host factors, HBV DNA, and drug differences. Eighty patients (14 on lamivudine, 19 on telbivudine, and 47 on entecavir) were recruited. There was no difference in clinical‐relapse rate among lamivudine, telbivudine, and entecavir (35.7% vs. 36.8% vs. 31.9%, respectively; p = 0.916), and liver decompensated hepatitis was absent. In baseline clinical characteristics, there were no differences between the clinical‐relapse and nonrelapse groups in age, sex, cirrhosis, prior treatment, HBV DNA, pretreatment ALT, or hepatitis B e‐antigen (HBeAg). The mean 3rd year serum ALT level differed significantly between clinical‐relapse and nonrelapse patients (37.5 U/L vs. 27.7 U/L, respectively; p = 0.044). The 3‐year nucleos(t)ide analogue off‐treatment in patients with chronic HBV delivered according to the Taiwan National Health Insurance guidelines had an overall 33.8% 1‐year clinical‐relapse rate without any decompensated hepatitis flare‐ups.
Keywords: Alanine aminotransferase, Entecavir, Hepatitis B virus, Lamivudine, Telbivudine
Introduction
Chronic hepatitis B virus (HBV) infection is an important clinical problem worldwide due to its adverse outcomes, including liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. According to the Asian‐Pacific consensus statement on the management of HBV, lamivudine (LAM), adefovir (ADV), entecavir 0.5 mg (ETV), telbivudine (LdT), and tenofovir (TDF) can all be considered initial therapy options for patients with HBV [1]. In Taiwan, LAM, ETV, LdT, and TDF are the popular first‐line nucleos(t)ide analogues covered by the National Health Insurance (NHI) as 3‐year treatments for patients with chronic HBV, while ADV and ETV 1 mg are reserved as second‐line drugs for virus breakthrough. These recommendations in Taiwan differ somewhat from the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases guidelines because of insurance budget problems [[2], [3]].
ETV and TDF are more effective in suppressing viral levels and in improving biochemical and histological disease features, but the ideal therapy duration, which criteria should be stopped, and the long‐term safety and efficacy data are lacking [4]. Based on the guidelines of Asian Pacific Association for the Study of the Liver, stop nucleos(t)ide analogue therapy can be considered if undetectable HBV DNA on three separate occasions at least 6 months apart in HBeAg‐negative patients, or serum HBeAg seroconversion in HBeAg‐positive patients. According to previous studies, HBeAg seroconversion is an imperfect end point in antiviral treatment because of the high cumulative virological recurrence rate after its discontinuation [[5], [6]]. In Taiwan, some patients with HBV had to stop antiviral drug treatment due to economic problems, while decompensated hepatitis flare‐up is a continuous concern of patients and doctors.
In this retrospective cohort study from our clinical practice, we provided patients with chronic HBV with 3 years of nucleos(t)ide analogue off‐treatment, and followed them for 1 year to evaluate its efficacy. Our aim was to investigate the differences between the clinical‐relapse and nonrelapse groups.
Methods
Patients and study procedure
This retrospective cohort study was approved by the Institutional Review Board of Mackay Memorial Hospital, Taipei, Taiwan (15MMHIS014). We recruited patients from the hepatology clinics of Taipei Mackay Memorial Hospital who had chronic HBV treated according to the Taiwan NHI clinical practice guideline [HBsAg‐positive and all HBeAg‐negative patients with an HBV DNA level > 2000 IU/mL and a serum alanine transaminase (ALT) level > 80 IU/L for 3 months, all HBeAg‐positive patients with an HBV DNA level > 20,000 IU/mL and serum ALT > 80 IU/L, and all HBeAg‐positive patients with an ALT > 5× the upper limit of normal (ULN)] from January 2009 to December 2010. Patients were eligible for recruitment in this study if they were aged ≥ 20 years and had chronic HBV that was treated with LAM, ETV, or LdT for 3 years. Patients with a coexisting hepatitis C virus infection, liver decompensation, or autoimmune disease; change in nucleos(t)ide; or malignancy, and those who were lost during follow‐up were excluded. The definition of liver decompensation is cirrhosis complicated with splenomegaly, esophageal varices, gastric varices, jaundice (total bilirubin ≥ 2 mg/dL), or coagulopathy (prolonged prothrombin time ≥ 3 seconds). The recruited HBV patients in this study were divided into those who continued treatment beyond 3 years and those who stopped by patients' willingness after 3 years of treatment; all patients submitted to a follow‐up exam every 3 months for 1 year. Clinical relapse was defined as an increase in serum HBV DNA level > 2000 IU/mL and a serum ALT level > 2× the ULN [1].
Age, sex, prior treatment, presence of cirrhosis, baseline biochemical data, and serum HBV viral load were recorded. Treatment was provided according to the Taiwan NHI clinical practice that dictates a regular follow‐up abdominal echo and serum HBV DNA every 6 months during treatment, checking of serum HBV DNA, aspartate aminotransferase (normal range, 15–41 IU/L), and ALT (normal range, 14–40 IU/L) levels every 3–6 months for 1 year after the 3‐year mark. The patients were treated with add‐on ADV or switched to ETV 1 mg for 3 years if clinical viral breakthrough occurred. The definition of viral breakthrough was a serum HBV DNA level that increased > 1 log (IU/mL) over the previous serum level. The consolidation duration was calculated from the first demonstration of undetectable HBV DNA to the end of treatment.
Biochemical and efficacy analysis
The serum ALT and aspartate‐aminotransferase ULN was set by the laboratory at 40 U/L and 41 U/L (UniCel DxC 800, Beckman Coulter, Inc., CA, USA), respectively, for men and women; HBV DNA was measured by a Roche AMPLICOR polymerase‐chain‐reaction assay (COBAS‐AM test; Roche Molecular Systems, Pleasanton, California, USA) with a lower limit of detection and quantitation of 20 IU/mL. Serum hepatitis markers, including HBsAg, hepatitis B surface antibody, HBeAg, hepatitis B e‐antibody (chemiluminescent microparticle immunoassay, ARCHITECT; Abbott, Abbott Laboratories, Abbott Park, Illinois, U.S.A.), and anti‐hepatitis C virus were tested. Patients who completed 3 years of oral nucleos(t)ide analogue treatment with a consolidation duration > 1 year in the clinical‐relapse group were included in the analysis. The end points were real‐world efficacy and virus‐breakthrough rates of LAM, ETV, and LdT, and we compared the clinical data between the clinical‐relapse and nonrelapse groups.
Statistical analysis
Categorical variables were compared using the Chi‐square test or Fisher's exact test for each patient characteristic category, while continuous variables were compared with Student t test. The statistical analyses were performed using the SPSS version 12.0 statistical package (SPSS Inc., Chicago, IL, USA). Missing data were treated using the SPSS Missing Values option. All of the statistical analyses were based on two‐sided hypothesis tests with a significance level of p < 0.05.
Consent
A written informed consent was obtained from the patients for publication of this article and any accompanying images.
Results
A total of 266 adult patients with chronic HBV were treated with a nucleos(t)ide analogue (ETV, LAM, LdT) in this study; of them, 210 patients completed the full 3‐year course. The patients were divided into those who continued treatment (n = 102) and those who stopped the drug with 1 year of follow‐up (n = 88), and then further divided into the clinical‐relapse (n = 27) and nonrelapse (n = 53) groups (Figure 1). The clinical‐relapse rate of the 3‐year treatment course with 1 year of follow‐up under the Taiwan NHI clinical practice guideline was 31.9% (15/47) in the ETV group, 35.7% (5/14) in the LAM group, and 36.8% (7/19) in the LdT group. The average clinical‐relapse rate was 33.8%. If we analyzed the clinical‐relapse rate in these 80 patients between HBeAg positive and HBeAg negative, there was no significant difference (12/33 vs. 15/47; p = 0.679).
Figure 1.
Clinical flow diagram of the 266 enrolled patients with chronic hepatitis B virus. Of the 210 patients who completed 3 years of treatment, 102 continued treatment and 88 stopped treatment and were followed up for 1 year. E = entecavir; HBV = hepatitis B virus; HIV = human immunodeficiency virus; L = lamivudine; T = telbivudine.
The baseline demographic and clinical characteristics of the patients with chronic HBV in the clinical‐relapse group (n = 27) and nonrelapse group (n = 53) were similar in sex proportion, mean age, baseline HBV DNA, and baseline ALT. There was no significant difference between these two groups in baseline HBeAg‐positive rate, prior treatment rate, liver‐cirrhosis percentage, or treatment drugs (Table 1). The diagnostic criteria of liver cirrhosis are by abdominal sonography, and we have excluded the decompensated liver, including splenomegaly, esophageal varices, and gastric varices who need long‐term nucleoside‐analogue therapy without the limitation of 3 years by the Taiwan NHI. The distribution of 1‐year off‐therapy clinical‐relapse percentages among these three nucleos(t)ide analogues showed that 40% of ETV relapses occurred in Months 6–9, 60% of LAM relapses occurred in Months 1–3, and 43% of LdT relapses occurred in Months 1–3 (Figure 2). No cases of liver decompensation occurred during the 1‐year follow‐up period.
Table 1.
Comparisons of baseline and end‐of‐therapy parameters between relapsers and nonrelapsers.
| Nonrelapsers (n = 53) | Relapsers (n = 27) | p | |
|---|---|---|---|
| Male | 42 (79.2) | 23 (85.2) | 0.520 |
| Age (y) | 43.5 ± 12.5 | 48.6 ± 13.7 | 0.098 |
| HBV DNA (base, 105 IU/mL) | 150 ± 230 | 170 ± 240 | 0.753 |
| ALT (base, IU/L) | 246.7 ± 272.4 | 231.3 ± 174.9 | 0.790 |
| HBeAg (positive) | 21 (39.6) | 12 (44.4) | 0.679 |
| Prior treatment | 9 (17.0) | 3 (11.1) | 0.487 |
| Drug (E/L/T) | 32/9/12 | 15/5/7 | 0.916 |
| Liver cirrhosis | 7 (13.2) | 4 (14.8) | 0.844 |
| ALT (end, IU/L) | 26.3 ± 12.3 | 28.9 ± 18.3 | 0.450 |
| AST (end, IU/L) | 23.5 ± 10.3 | 28.9 ± 14.1 | 0.059 |
Data are presented as n (%) or mean ± standard deviation, unless otherwise indicated.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; base = baseline; E = entecavir; end = end of therapy; HBV = hepatitis B virus; L = lamivudine; T = telbivudine.
Figure 2.
Off‐therapy 1‐year clinical‐relapse percentage distribution of different nucleos(t)ide analogues.
In this study, there were 88 patients who completed three‐year treatment and then stopped the drug for 1 year, the serum ALT level during the 3 years of antiviral treatment, there was significant difference in the 3rd year ALT serum level between clinical‐relapse and clinical nonrelapse patients (37.5 U/L vs. 27.7 U/L; p = 0.044, Figure 3A). Upon the division of all patients into consolidation duration > 1 year group (n = 80) and < 1 year (n = 8) group, there was a trend of normal ALT since the 6th month of treatment in the consolidation duration > 1 year group (Figure 3B).
Figure 3.
Serum alanine‐aminotransferase level during the 3 years of antiviral treatment between clinical‐relapse and nonrelapse patients. [C: consolidation duration > 1 year group (n = 80); U: consolidation duration < 1 year group (n = 8)]. (A) The serum alanine‐aminotransferase level between relapse patients and nonrelapse patients during 3 years antivirus treatment; and (B) there was a trend of normal alanine aminotransferase since the 6th month treatment in consolidation duration > 1 year group. ALT = alanine aminotransferase.
Discussion
The oral nucleos(t)ide analogues have good antiviral effects during the treatment period, but tend to have poor durability after therapy discontinuation. According to previous studies, in HBeAg‐negative patients, the durability of 30 months of LAM treatment had a 1‐year off‐therapy hepatitis flare rate of 43.6% [7]. Wang et al. [8] stated that the durability of 3‐year LAM treatment in HBeAg‐positive patients had a 1‐year off‐therapy virological relapse rate of 35%. For LdT, the 60‐month durability after off‐treatment had a clinical‐relapse rate of 16.3%, and no difference was found between HBeAg‐positive and HBeAg‐negative patients [9]. Concerning ETV therapy, HBeAg‐negative patients treated for > 2 years still had a 74.2% virological relapse rate after stopping the drug for 1 year [10]. Dai et al. [11] reported that consolidation therapy for more than 18 months significantly improved the outcome of LAM therapy, particularly for patients who achieved a combined response after 6 months. Jeng et al. [12] also reported that the off‐therapy 1‐year durability of ETV in HBeAg‐negative patients had a 45% clinical‐relapse rate. In our study, we found that 3‐year ETV (31.96%), LAM (35.7%), and LdT (36.8%) had similar 1‐year off‐therapy clinical‐relapse rates that might be due to the Taiwan NHI clinical practice guideline that covered ADV or ETV 1 mg to keep continuing treatment when viral breakthrough occurred.
Concerning chronic HBV treatment efficacy, Yao et al. [13] stated that 74% of ETV‐treated and 41% of LAM‐treated patients had HBV DNA clearance at the end of 2 years of treatment, and that 96% of ETV‐treated patients and 82% of LAM‐treated patients had normalized ALT. This result is like ours, and showed that ETV had the best antiviral efficacy, but not in ALT normalization among the three drugs. Concerning LAM and LdT resistances, the strategy of ADV add‐on therapy (22.6%) or a switch to ETV 1 mg (19.5%) was not satisfied in HBeAg‐positive hepatitis B patients because a low virological response was observed at Month 12 [14].
Patients with chronic HBV treated with a low‐genetic‐barrier nucleos(t)ide analogue may experience drug resistance even in the 1st year of therapy. According to a previous study, the incidence of LAM resistance increased from 24% in 1 year to 70% in 5 years [15]. The risk of LdT resistance was lower than that with LAM in the international (GLOBE) and China Phase III studies; the 2‐year risk of resistance was 25.1% in HBeAg‐positive patients and 10.8% in HBeAg‐negative patients [16]. ETV resistance is very rare; the cumulative probability of ETV resistance was only 1.2% after 5 years of ETV treatment [17]. In this study, the viral breakthrough data are similar to those of previous studies. Concerning the time of clinical‐relapse onset after off‐therapy, it most frequently occurred for LAM and LdT in the 1st–3rd months, and for ETV in the 6th–9th months. This result reconfirmed the previously reported data [11].
Some factors are associated with chronic HBV disease progression, including age, sex, HBV genotype, HBV DNA serum viral load, treatment duration, and HBeAg, but which factors are correlated with off‐therapy clinical relapse remain unknown. In one recent study of LdT off‐treatment durability, no significant difference was found in baseline or on‐treatment factors between cumulative clinical‐relapse rates of HBeAg positive and HBeAg negative [9]. Kim et al. [18] reported that age, especially > 40 years, was a significant predictor of both early and delayed relapse in HBeAg‐positive patients with chronic HBV treated with LAM. In this study, we found that the mean age in the clinical‐relapse group (49 years) was higher than that of the nonrelapse group (44 years), although the difference was not statistically significant (p = 0.098), but it might be considered a risk factor of clinical relapse (Table 1).
The opinions concerning when to stop nucleos(t)ide analogue treatment differ between Eastern and Western countries. In the West, the goal of chronic HBV treatment is to achieve seroclearance of HBsAg, so HBeAg‐positive patients could discontinue nucleos(t)ide analogue treatment if they achieved HBeAg seroclearance and maintain undetectable HBV DNA levels. For HBeAg‐negative patients, stopping nucleos(t)ide analogue therapy is not recommended [19]. In the Asian‐Pacific area, the rule in HBeAg‐positive patients is similar to that in the West, but HBeAg‐negative patients need to demonstrate undetectable HBV DNA levels for > 1 year, because cost is an important factor in the selection of treatment strategy [1].
Here, we demonstrated that the patients with consolidation duration > 1 year had early normal serum ALT 6 months after the initiation of treatment, but careful consideration is needed before antiviral therapy is modified with early suboptimal virological response to ETV due to the majority of them achieving HBV DNA clearance [20]. By contrast, the 88 off‐therapy chronic hepatitis B patients who experienced clinical relapse had a relatively high normal average ALT (37.5 U/L) than the nonrelapse patients (ALT 27.7 U/L, p < 0.05), but whether the 3rd year serum ALT level could be a predictor of clinical relapse warrants further evaluation.
Our study had numerous limitations. First, it was a retrospective cohort study and included only a small sample of HBV off‐therapy patients. Second, tests for HBV genotype and mutation are not currently available under the Taiwanese NHI budget. In conclusion, this study showed that patients with chronic HBV in Taiwan, whether HBeAg positive or HBeAg negative, who completed 3 years of oral nucleos(t)ide analogue treatment with an HBV DNA consolidation duration > 1 year had a mean 33.8% 1‐year clinical‐relapse rate without any liver decompensated hepatitis flare‐ups.
Acknowledgments
The authors thank the project staff of the Division of Gastroenterology of Mackay Memorial Hospital who collected and interpreted the data, or revised the manuscript for important intellectual content.
Conflicts of interest: All authors declare no conflicts of interest.
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