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Keywords:

  • hepatitis B virus;
  • HBeAg;
  • lamivudine;
  • relapse

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. METHODS
  6. RESULTS
  7. DISCUSSION
  8. REFERENCES

Background and Aim:  Studies from hepatitis B virus endemic areas have shown less durable lamivudine-induced responses and have raised issues about the management of a post-treatment relapse.

Methods:  From January 2000 to June 2004, all 51 patients (43 HBeAg-positive and eight HBeAg-negative) were retreated with lamivudine for at least 12 months. All had a post-treatment relapse after HBeAg responses (HBeAg loss/seroconversion) during the first therapy.

Results:  During retreatment, HBeAg seroconversion occurred more frequently in those patients with HBeAg seroconversion than in those with HBeAg loss alone during prior lamivudine therapy (= 0.001). On multivariate analysis, prior HBeAg seroconversion and early virological response (EVR) (≤ 2 months of retreatment) independently predicted HBeAg seroconversion (= 0.012 and P = 0.004, respectively). With regard to virological breakthrough, only the time to virological response (> 2 months of retreatment) remained significant (= 0.048). Among the HBeAg-negative patients, virological breakthrough occurred in only one patient with a late virological response.

Conclusions:  EVR is a major predictor in determining a favorable response to lamivudine retreatment. Our observations suggest that lamivudine retreatment will provide more therapeutic gains in those patients with a prior HBeAg seroconversion than in those with HBeAg loss alone.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. METHODS
  6. RESULTS
  7. DISCUSSION
  8. REFERENCES

Chronic hepatitis B virus (HBV) is a major public health problem that affects more than 350 million people worldwide.1 Lamivudine was the first nucleoside analog licensed for the treatment of chronic hepatitis B, and it is accepted as an initial therapeutic option for patients. Although lamivudine produces an initial virological response, the emergence of viral resistance with extended treatment and the lower post-treatment durability remain the major drawbacks of lamivudine monotherapy. In a Western study, hepatitis B e antigen (HBeAg) responses, such as HBeAg seroconversion or HBeAg loss, were durable in most patients with chronic hepatitis B during the post-treatment period, and HBeAg responses were considered to be a stopping point for therapy.2 However, a series of studies from HBV endemic areas have provided disappointing clinical results in which HBeAg responses were not durable and additional treatment was needed to achieve a sustained post-treatment response after HBeAg seroconversion.3–5 In our unpublished data, post-treatment relapse was observed in more than half of patients with HBeAg responses. As a result, managing patients with a post-treatment relapse has become an issue of medical concern.

To date, there have been limited data on the readministration of lamivudine to patients who relapse after HBeAg responses,6,7 in which detailed long-term outcome of lamivudine retreatment is lacking. The data have also not consistently established when, and to whom lamivudine retreatment should be given. In this study, we evaluated the clinical outcomes of extended lamivudine retreatment in patients who relapsed after stopping lamivudine therapy following HBeAg responses. We also examined virological and serological responses and predictive factors for HBeAg re-seroconversion or viral resistance during lamivudine retreatment.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. METHODS
  6. RESULTS
  7. DISCUSSION
  8. REFERENCES

Patients

From January 2000 to June 2004, 107 patients stopped lamivudine therapy after achieving HBeAg responses without developing viral resistance. Of these 107 patients, 65 relapsed during follow up. These relapsed patients had been all seropositive for hepatitis B surface antigen (HBsAg), HBeAg and HBV DNA for at least 6 months before the initial lamivudine therapy. However, 52 of the 65 patients were HBeAg positive and the remaining 13 were HBeAg negative at the time of post-treatment relapse. Lamivudine retreatment for relapsed hepatitis B was started when serum alanine aminotransferase (ALT) levels increased to ≥ 2 × the upper limit of normal (ULN). From the 65 relapsers, 51 patients who received extended lamivudine retreatment (for at least 12 months) were entered into the study. Four patients with a minimal elevation of serum ALT levels below 2 × ULN did not receive lamivudine retreatment. Patients with short-term retreatment or non-compliance were excluded from the study. Patients with clinical evidence of hepatic decompensation, such as ascites, variceal bleeding or hepatic encephalopathy, were also excluded. The schematization of the patient enrollment is shown in Figure 1.

image

Figure 1. Schematization of the patient enrollment.

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METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. METHODS
  6. RESULTS
  7. DISCUSSION
  8. REFERENCES

Fifty-one patients received lamivudine 100 mg per day during the study period. Serum HBeAg and anti-HBe as assessed by radioimmunoassay (Abbott Laboratories, Chicago, IL, USA), HBV DNA, and serum ALT levels (ULN: 36 IU/L) were measured at intervals of 2–8 weeks (mean follow-up interval: 4.7 ± 3.0 weeks) until HBeAg seroconversion, and then tested every 4–12 weeks after HBeAg seroconversion (defined as loss of HBeAg and appearance of anti-HBe in serum). Serum HBV DNA was measured by Quantiplex branched-DNA assay (Bayer Diagnostics, Berkeley, CA, USA; sensitivity > 7 × 105 copies/mL). Virological response was defined as a reduction in serum HBV DNA to undetectable levels. Early virological response (EVR) was defined as an achievement of virological response within 2 months of starting lamivudine retreatment. Relapse was defined as the reappearance of HBV DNA in serum after discontinuing lamivudine treatment. The genotyping of HBV was performed by enzyme-linked immunosorbent assay (ELISA) (Institute of Immunology, Tokyo, Japan) using monoclonal antibodies to the pre-S2 region, as previously described.8 Virological breakthrough was considered as the reappearance of HBV DNA after an initial virological response during retreatment. HBV variants at YMDD motif were detected by restriction fragment length polymorphism (RFLP) analysis, as previously described.9 In brief, primers used to amplify the sequence surrounding the M552 site (YMDD region) were F1 at nt 720 (sense; 5′-CACTGTTTG GCTTTCAGTCAT-3′) and B2 at nt 839 (antisense; 5′-GTTCAAATGTATACCCAAAG-3′). Primers used to amplify the region surrounding the L528 variant were F3 at nt 648 (sense; 5′-GTGGGCCTCAGTC CGTTTCTC-3′) and B2. After amplification, the PCR products were digested with NdeI to detect rtM204V/I (M552V/I) or NlaIII to detect rtL180M (L528M), according to the manufacturer's protocol (New England BioLabs, Beverly, MA, USA). Digested products were electrophoresed on precast 6% non-denaturing polyacrylamide gel. The primary endpoint of the study was HBeAg seroconversion, and additional endpoints included virological response, normalization of serum ALT and virological breakthrough.

Statistical analysis

Data were analyzed using the Statistical Package for Social Science version 11.5 (SPSS, Chicago, IL, USA). Variables between groups were compared using Student's t-test, Mann–Whitney U-test, chi-squared test and Fisher's exact test, while the comparison of variables within the same group was performed using Wilcoxon rank test. The Kaplan–Meier method was used to estimate the cumulative rates of virological breakthrough and HBeAg seroconversion, and the difference was determined by the log rank test. Factors that showed some evidence (< 0.25) of an association with HBeAg seroconversion or virological breakthrough during retreatment were then categorized as appropriate and analyzed in a multivariate analysis using Cox's proportional hazard model. A P-value < 0.05 was considered to be statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. METHODS
  6. RESULTS
  7. DISCUSSION
  8. REFERENCES

Study population

All 51 relapsed patients who showed HBeAg responses, including HBeAg seroconversion or HBeAg loss alone, in the prior lamivudine therapy were enrolled in this study. All were positive for serum HBsAg and HBV DNA before retreatment; 43 were HBeAg positive and eight were HBeAg negative. The 51 patients included 39 men and 12 women aged 27–65 years. All 51 relapsed patients were infected with HBV genotype C. At the time of starting lamivudine retreatment, all patients enrolled had serum ALT levels of ≥ 2 × ULN, which were 2–5 × ULN in 11 patients, 5–10 × ULN in 19 patients, and ≥ 10 × ULN in 21 patients, respectively. None had decompensated liver diseases at that time. For the 51 enrolled patients, overall duration of the prior lamivudine therapy was 19.9 ± 14.2 months, and the mean time to relapse after stopping the prior therapy was 5.0 ± 3.6 months (range: 1–17 months). The median interval between relapse and initiating retreatment was 1 month (range: 0–28 months). The mean duration of lamivudine retreatment was 20.2 ± 8.6 months, and the mean follow-up period was 25.8 ± 13.9 months. Table 1 summarizes demographic features of the HBeAg-positive and -negative patients at the time of lamivudine retreatment.

Table 1.  Demographic features of all 51 patients at the time of starting lamivudine retreatment
 HBeAg-positive patients (n = 43)HBeAg-negative patients (n = 8)
  • Median and range are further provided. ALT, alanine aminotransferase; HBV, hepatitis B virus; ULN, the upper limit of normal (reference range: ≤ 36 IU/L).

Age (years)43.3 ± 13.141.5 ± 8.9
Sex (male : female)32:117:1
ALT (IU/L)369.9 ± 345.4217.1 ± 111.7
2–5 × ULN 83
5–10 × ULN163
≥ 10 × ULN192
Total bilirubin (mg/dL)1.41 ± 1.021.36 ± 0.64
HBV DNA (× 106 copies/mL)101 (1.4–5457.7)96.5 (6.7–805.7)
HBV genotypeC (43/43, 100%)C (8/8, 100%)
Duration of previous lamivudine treatment (months)20.0 ± 10.119.6 ± 10.2
Time to relapse after stopping previous lamivudine therapy (months)4.9 ± 3.4 4 (1–18)5.6 ± 3.5 5 (2–12)
Achievement of HBeAg seroconversion during previous lamivudine therapy27/43 (62.8%)6/8 (75%)

Achievement of HBeAg seroconversion in all 43 HBeAg-positive patients

Of the 43 patients who were HBeAg positive, all had a virological response and ALT normalization was observed in 39 (90.7%) during up to 1 year of retreatment. Overall, 28 (65.1%) of the 43 HBeAg-positive patients achieved HBeAg seroconversion during retreatment. The cumulative rates of HBeAg seroconversion at 6, 12 and up to 36 months of retreatment were 50.6, 63.9 and 71.1%, respectively. Among the 10 variables listed in Table 2, HBeAg seroconversion during the prior therapy and the time to virological response after the initiation of retreatment were correlated with HBeAg seroconversion during retreatment (= 0.001 and P = 0.011, respectively). The time to HBeAg loss during the prior therapy was marginally associated with the achievement of HBeAg seroconversion (= 0.095). Multivariate analysis demonstrated that previous HBeAg seroconversion (odds ratio [OR], 3.61; 95% confidence interval [CI]: 1.33–9.75, P = 0.012) and an EVR after initiating retreatment (OR, 3.42; 95% CI: 1.49–7.82, P = 0.004) were the two independent predictors of HBeAg seroconversion during retreatment (Table 3). Figures 2 and 3 show the differences in the cumulative rates of HBeAg seroconversion according to its previous achievement (log rank test, P < 0.001) and time to virological response during retreatment (log rank test, P < 0.001), respectively.

Table 2.  Comparison of clinical characteristics of patients with and without the acquisition of HBeAg seroconversion during lamivudine retreatment
 Patients with acquisition of HBeAg seroconversion (n = 28)Patients without acquisition of HBeAg seroconversion (n = 15)P-value
  • Median and range are further provided. ALT, alanine aminotransferase; HBV, hepatitis B virus.

Age (years)41.9 ± 13.446.1 ± 12.60.327
Sex (male : female)21:711:41.000
ALT (IU/L)412.7 ± 399.9290.6 ± 199.20.292
Total bilirubin (mg/dL)1.41 ± 0.971.40 ± 1.130.978
HBV DNA (× 106 copies/mL)29.4 (1.4–5457.7)110.7 (2.7–5000.0)0.336
Achievement of HBeAg seroconversion during previous lamivudine therapy23/28 (82.1%)4/15 (26.7%)0.001
Time to HBeAg loss during previous lamivudine therapy (months)7.7 ± 5.7 6 (2–26)11.3 ± 7.8  9 (3–31)0.095
Time to relapse after stopping previous lamivudine therapy (months)5.0 ± 3.1 4 (1–13)5.0 ± 4.0 3 (2–18)0.972
Time interval between relapse and initiation of retreatment (weeks)1 (0–19)  1 (0.3–28)0.989
Time to virological response during retreatment (months)2.0 ± 1.2 1.8 (0.5–2.5)3.2 ± 1.1 3.3 (1.8–6)0.011
Table 3.  Multivariate analysis of predictable factors for acquisition of HBeAg seroconversion during lamivudine retreatment
 HBeAg seroconversion during lamivudine retreatmentOR (95% CI)P-value
Presence (n = 28) (%)Absence (n = 15) (%)
  1. CI, confidence interval; OR, odds ratio.

HBeAg response during previous lamivudine therapy
 HBeAg seroconversion23 (82.1) 4 (26.7)3.61 (1.33–9.75)0.012
 HBeAg loss alone 5 (17.9)11 (73.3)1 
Time to virological response during retreatment
 ≤ 2 months18 (64.3) 2 (13.3)3.42 (1.49–7.82)0.004
 > 2 months10 (35.7)13 (86.7)1 
Time to HBeAg loss during previous lamivudine therapy
 ≤ 9 months20 (71.4) 8 (53.3)1.65 (0.68–4.04)0.269
 > 9 months 8 (28.6) 7 (46.7)1 
image

Figure 2. Difference in HBeAg seroconversion rates during lamivudine retreatment between patients with and without a prior HBeAg seroconversion (log rank test, P < 0.001).

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image

Figure 3. Difference in HBeAg seroconversion rates between patients with and without a virological response (VR) within 2 months of starting retreatment with lamivudine (log rank test, P < 0.001).

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Reacquisition of HBeAg seroconversion in the prior HBeAg seroconversion group only

A total of 27 patients had initially achieved HBeAg seroconversion during prior therapy. Of these, with retreatment, 25 (92.6%) attained normalization in serum ALT levels at least once and 23 (85.2%) reacquired HBeAg seroconversion during the study period. The remaining four patients who did not achieve HBeAg seroconversion during retreatment ultimately developed viral resistance. The time to HBeAg seroconversion was significantly shorter during retreatment than during the first course of lamivudine therapy (6.27 ± 6.14, range: 1–24 versus 11.46 ± 10.6, range: 2–47 months; P = 0.04). All but one patient achieved HBeAg seroconversion within 12 months of retreatment. Age, sex, baseline ALT, total bilirubin, HBV DNA levels, time to HBeAg loss in serum, time to relapse and the interval between relapse and retreatment did not predict seroconversion during retreatment. Only an EVR within 2 months of retreatment remained significant on multivariate analysis (OR, 3.61; 95% CI: 1.31–9.90, P = 0.013) (data not shown). Patients with an EVR within 2 months of starting retreatment showed a significantly higher rate of HBeAg seroconversion than those without an EVR (log rank test, P = 0.006).

Occurrence of virological breakthrough during retreatment in HBeAg-positive patients

Of the 43 patients, 12 (27.9%) developed virological breakthrough during the retreatment period. However, no hepatic decompensation was observed during retreatment. Genotypic assay for the YMDD motif mutations using RFLP showed rtM204V in two patients, rtM204I in five patients, and rtM204I/V + rtL180M in five patients, respectively. The mean time to virological breakthrough was 12.8 ± 5.9 months. The cumulative virological breakthrough rates at 6, 12, 18 and 24 months were 4.9, 18.2, 28.1 and 32.4%, respectively. During virological breakthrough, peak ALT levels increased to less than twice the ULN in two patients, 2–5 times the ULN in four patients, and over five times the ULN in six patients. Among the 12 variables listed in Table 4, previous HBeAg seroconversion and the time to virological response during retreatment were correlated with virological breakthrough during retreatment (= 0.032 and P = 0.018, respectively). On multivariate analysis, only the time to virological response after starting retreatment remained significant (OR, 7.84; 95% CI: 1.02–61.98, P = 0.048) (Table 5). Patients with an EVR also showed a significantly lower rate of virological breakthrough than those without an EVR (log rank test, P = 0.02) (Fig. 4).

Table 4.  Comparison of clinical characteristics of patients with and without development of virological breakthrough during lamivudine retreatment
 Patients with breakthrough (n = 12)Patients without breakthrough (n = 31)P-value
  • Median and range are further provided. ALT, alanine aminotransferase; HBV, hepatitis B virus.

Age (years)41.5 ± 11.544.1 ± 14.20.588
Sex (male : female)11:121:100.139
ALT (IU/L)338.7 ± 211.3389.1 ± 297.90.683
Total bilirubin (mg/dL)1.41 ± 1.191.44 ± 0.970.935
HBV DNA (× 106 copies/mL)137.8 (3.7–5457.7)39.7 (1.4–3633.8)0.783
Achievement of HBeAg seroconversion during previous lamivudine therapy4/12 (33.3%)23/31 (74.2%)0.032
Time to HBeAg loss during previous lamivudine therapy (months)9.3 ± 6.6 8 (2–21)8.1 ± 5.4 7 (3–31)0.553
Time to relapse after stopping previous5.1 ± 4.74.9 ± 2.80.922
lamivudine therapy (months)3 (2–18)4 (1–13) 
Time interval between relapse and initiation of retreatment (weeks)  1.25 (0–6) 0.9 (0–28)0.828
Time to virological response during retreatment (months)3.2 ± 1.3 3 (1.8–6)2.1 ± 1.1 2 (0.5–4)0.018
Duration of previous lamivudine treatment (months)18.2 ± 7.220.1 ± 10.90.598
Total duration of lamivudine treatment (months)44.0 ± 14.745.1 ± 15.30.823
Table 5.  Multivariate analysis of predictable factors for the occurrence of virological breakthrough during lamivudine retreatment
 Virological breakthrough during lamivudine retreatmentOR (95% CI)P-value
Presence (n = 12) (%)Absence (n = 31) (%)
  1. CI, confidence interval; OR, odds ratio.

Sex
 Male11 (91.7)21 (67.7)1.23 (0.13–11.97)0.856
 Female1 (8.3)10 (32.3)1 
HBeAg response during previous lamivudine therapy
 HBeAg loss alone 8 (66.7) 8 (25.8)2.44 (0.66–8.99)0.181
 HBeAg seroconversion 4 (33.3)23 (74.2)1 
Time to virological response during retreatment
 > 2 months11 (91.7)12 (38.7)7.84 (1.02–61.98)0.048
 ≤ 2 months1 (8.3)19 (61.3)1 
image

Figure 4. Difference in virological breakthrough rates between patients with and without a virological response (VR) within 2 months of starting retreatment with lamivudine (log rank test, P = 0.02).

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Outcomes of lamivudine retreatment in the eight HBeAg-negative patients

All eight patients showed an initial virological response at the mean time of 3.4 ± 3.2 months (range: 1–8 months) after initiating retreatment, but one patient (12.5%) ultimately developed virological breakthrough at 12 months. A normalization of serum ALT levels was observed in all patients during a period of up to 8 months. The time intervals between the initiation of retreatment and virological response were a median 1.8 months (range: 1–4.8 months) in the seven patients without virological breakthrough and 8 months in the one patient with virological breakthrough during the study period.

Durability in the responders to lamivudine retreatment

During up to the end of follow-up, 12 of 28 patients with HBeAg seroconversion stopped lamivudine retreatment. All the eight HBeAg-negative patients maintained lamivudine retreatment. Of the 12 patients who stopped lamivudine retreatment, five (41.7%) had a relapse 2, 6, 7, 9 and 12 months after stopping lamivudine retreatment, respectively. The estimated relapse rates at 6 and 12 months of stopping lamivudine retreatment were 18.5 and 49.1%, respectively. We did not conduct statistical analysis for the predictors of durability of response to lamivudine retreatment because the sample size was too small.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. METHODS
  6. RESULTS
  7. DISCUSSION
  8. REFERENCES

Both spontaneous and therapeutically induced HBeAg responses are associated with improved clinical outcomes and prolonged survival in chronic HBV carriers.10,11 Early studies from Western countries have also shown that HBeAg responses to lamivudine therapy are well maintained, with a durability of approximately 80–90%.2,6 Therefore, it has been assumed that HBeAg responses remain an endpoint of lamivudine therapy for chronic HBeAg-positive hepatitis.2,6 However, Korean studies have raised questions about the durability of HBeAg seroconversion during lamivudine monotherapy and suggested both the presence of ethnic differences in response to the drug and that it has relatively poor efficacy in an endemic area.3,4 To date, there is no established strategy to manage relapsed hepatitis after the discontinuation of lamivudine therapy and, until recently, lamivudine was the only oral antiviral agent available to Korean patients who had a post-treatment relapse.

The data in this study have identified the patients who are most likely to respond to lamivudine retreatment. This study showed that, unlike patients with HBeAg loss alone, those who experienced HBeAg seroconversion in the previous lamivudine course generally reacquire HBeAg seroconversion during retreatment, with the exception of a small number of patients. Conversely, a considerable proportion of patients who previously had HBeAg loss alone developed viral resistance on retreatment, despite having initial gains in virological and biochemical tests. It might be inferred from this finding that prior HBeAg loss alone with lamivudine therapy does not necessarily guarantee a repeated responsiveness during retreatment. Our results suggest that patients with a prior HBeAg seroconversion might be one of the more favorable groups for lamivudine retreatment rather than those with prior HBeAg loss alone.

In addition to a prior HBeAg seroconversion, EVR was also identified as a favorable factor during retreatment in both univariate and multivariate analysis. Our data showed that an EVR during retreatment was associated with a higher rate of HBeAg seroconversion and lower occurrence of virological breakthrough. In contrast to previous studies which indicated pretreatment virological or biochemical characteristics as predictive factors during the first course of lamivudine therapy,12–14 this study found no baseline factor that remained significant as a predictor of outcomes during retreatment.

It is currently assumed that the selection of drug-resistant mutants is increased with longer duration of therapy. In this regard, our patients might have been at high risk for developing viral resistance, given that overall treatment durations including the first and second courses in our patients, reached almost 40 months. However, our data revealed that virological breakthrough did not significantly increase after approximately 2 years of retreatment. Multivariate analysis also demonstrated that instead of treatment duration, the time to virological response is independently predictive of the occurrence of virological breakthrough in the course of retreatment. These findings suggest again that early virological suppression is pivotal in achieving a favorable response to retreatment.

As observed earlier, some patients (8/51) developed HBeAg-negative hepatitis at the time of relapse although they had been HBeAg positive previously. All had suppressed and undetectable levels of HBV DNA in serum during retreatment with lamivudine, but one patient developed viral resistance during the extended period of retreatment. In contrast to the remaining seven patients who had a virological response within a median of 1.8 months of retreatment, the patient with virological breakthrough did not have a virological response until 8 months of therapy and ultimately developed virological breakthrough 4 months after having a virological response. In accordance with results in HBeAg-positive patients, this observation might also support the concept that EVR is a major determinant of favorable response to lamivudine retreatment.

In our study, the endpoints including HBeAg seroconversion and virological breakthrough were observed early in the course of retreatment, usually during the first year; nearly 90% of the patients reached the endpoints during this period. In addition, patients who achieved an EVR showed a significantly higher rate of HBeAg seroconversion, indicating that the time to virological response predicted the final outcome of retreatment. In contrast, the majority of late virological responses were associated with emerging viral resistance on further therapy. Thus, it might be advisable to monitor patients more closely in the initial period of lamivudine retreatment.

One of the goals of this study was to determine the appropriate time to retreat. However, the data from this study have demonstrated that the timing of retreatment was not significant as a prognostic factor, and neither the time to post-treatment relapse or the time-gap from relapse to retreatment was correlated with retreatment outcomes. Only the time to virological response was found to be independently predictive of HBeAg seroconversion. This suggests that, rather than the timing of retreatment, individual characteristics in susceptibility to antiviral therapy may act, at least in part, as a key determinant of retreatment response. However, because the timing of therapy was not controlled in this study, further studies are needed to clarify this issue.

The retrospective nature of this study introduced some limitations in terms of study design. Our study did not include a control group without lamivudine retreatment. This study also did not examine viral mutations in precore or core promoter region in the HBV, and although the efficacy of initial lamivudine therapy is similar in mutant and wild type virus,15 there is no data on its efficacy during retreatment. In addition, the relatively insensitive method of detecting HBV DNA used in this study did not provide detailed data on the changes in HBV DNA levels below our detection limit.

In conclusion, our data showed that EVR is a major predictor of a favorable response to lamivudine retreatment. Most patients with a history of HBeAg seroconversion in a previous course of lamivudine will reacquire HBeAg seroconversion during lamivudine retreatment, although patients with HBeAg loss alone during the first therapy should be closely followed up to detect emerging viral resistance during retreatment. The results of this study suggest that therapeutic gains from retreatment with lamivudine might be obtained in those patients with a prior HBeAg seroconversion rather than in those with prior HBeAg loss alone. To determine the best candidate for retreatment with lamivudine, more prospective studies are needed.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. METHODS
  6. RESULTS
  7. DISCUSSION
  8. REFERENCES