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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Aliment Pharmacol Ther 2011; 34: 424–431

Summary

Background  Previous studies suggested that a finite course of peginterferon alfa-2a may offer an alternative rescue therapy for patients with lamivudine resistance. However, because of the limitation of study design and small sample size, it is difficult to make definitive conclusion.

Aim  To explore the role of peginterferon alfa-2a, in the rescue treatment of HBeAg-positive chronic hepatitis B patients with lamivudine resistance.

Methods  In this randomised study, chronic hepatitis B patients with lamivudine resistance were treated with peginterferon alfa-2a for 48 weeks (= 155) or adefovir for 72 weeks (= 80). All enrolled patients were treated with lamivudine for the first 12 weeks.

Results  At 6 months posttreatment, 14.6% (18/123) of peginterferon alfa-2a-treated patients achieved HBeAg seroconversion, in contrast to 3.8% (3/80) of adefovir-treated patients after 72 weeks continuous therapy (= 0.01). For peginterferon alfa-2a-treated patients, the rate of HBeAg seroconversion at week 72 was significantly higher in patients who had HBsAg decline >0.5 Log10 IU/mL from baseline at week 24, compared with patients with HBsAg decline ≤0.5 Log10 IU/mL from baseline at week 24 (25.5% vs. 7.7%, = 0.01). After 72 weeks continuous adefovir treatment, 22.5% of patients achieved HBV DNA <80 IU/mL, compared with 10.6% in peginterferon alfa-2a-treated patients at 6 months off-treatment (= 0.02).

Conclusions  Overall, the response to peginterferon alfa-2a among patients with lamivudine resistance was suboptimal. HBeAg seroconversion rate at week 72 by 48 weeks peginterferon alfa-2a treatment was higher than continuous adefovir therapy. Monitoring HBsAg levels can help to predict response to peginterferon alfa-2a.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Lamivudine was first approved for the treatment of chronic hepatitis B (CHB) in 1998 and have been widely used around the world because of its ability to significantly reduce HBV replication, its favourable safety profile and its relatively low cost.1 Clinical data have clearly shown that resistance to lamivudine increased with treatment duration, approaching 70% after 4–5 years continuous drug exposure.2 Given the high incidence of lamivudine resistance and the possibility of the development of subsequent resistance to other nucleot(s)ide analogues (NAs), it is not surprising that lamivudine is not recommended as first-line therapy in AASLD and EASL guidelines.3, 4 However, it is still used around the world, particularly in some parts of Asia, where the prevalence of CHB is high and generics are available at a low cost. In some Asian countries, there is a need to further investigate management strategies to treat the increasing number of patients with lamivudine resistance as well as to prevent the emergence of resistance in the first instance.

Although patients with lamivudine resistance can be switched to an alternative NA, such antiviral rescue therapy is limited by cross-resistance development.5–9 Combination therapy using noncross-resistant antivirals may reduce the incidence of resistance development.10, 11 The addition of adefovir to lamivudine when viral resistance emerges results in a pronounced viral load reduction and significantly decreases the risk of resistance to adefovir compared with switching from lamivudine to adefovir.10 Consequently, most guidelines focused on the use of NAs to rescue patients with lamivudine resistance using an add-on strategy.3, 4 However, such strategies have to be given to patients for many years and have the potential to lead to multi-drug resistance.

In contrast with the need for extended treatment with NAs to ensure constant viral suppression, a finite course of interferon-based therapy is not associated with resistance development and can induce a sustained immunological response, as illustrated by hepatitis B e antigen (HBeAg) seroconversion and hepatitis B surface antigen (HBsAg) seroconversion, in a proportion of patients. Initial data suggested that it may provide a novel therapeutic option for management of patients carrying lamivudine resistant virus.12–16 However, because of the limitation of study design and small sample size, it is difficult to make definitive conclusion.

We, therefore, set out to conduct a multi-centre, randomised study to determine if a finite course of peginterferon can lead to long-term viral suppression and HBeAg seroconversion in HBeAg-positive CHB patients with lamivudine resistance.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study design

This randomised, open-label study, for which all patients gave written informed consent before entry, was carried out in 13 centres across China, including Hong Kong from 2005 to 2008. The study received prior Ethics Committee/Institutional Review Board approval and was conducted in accordance with the Declaration of Helsinki and guidelines for Good Clinical Practice.

Patients and treatments

Patient population.  Male or female patients, aged 18–65 years, with lamivudine-resistant [tyrosine-methionine-aspartate-aspartate (YMDD) mutant as determined by the INNO-LipA method] HBeAg-positive CHB who had received lamivudine for at least 6 months and were still receiving lamivudine at the start of the trial were eligible for inclusion. Patients were HBsAg-positive, HBeAg-positive for at least 6 months, with ALT levels greater than the upper limit of normal (ULN) but ≤10 × ULN on at least two occasions taken ≥14 days apart in the previous 6 months. To exclude any patient with advanced fibrosis (Ishak score ≥5), liver biopsy samples were obtained within 6 months prior to randomisation for all patients.

Patients with Child-Pugh score >5 or co-infected with hepatitis C, D or the human immunodeficiency virus were excluded, as were patients with hepatocellular carcinoma and other malignancies or a history of significant hepatic (other than hepatitis), pulmonary or cardiac disease, immunologically mediated disorders, thyroid dysfunction, ophthalmological disorders, seizure disorders and serious psychiatric illness. Other exclusion criteria included a history of drug or alcohol abuse, previous treatment with other antivirals for HBV infection except lamivudine, previous treatment with antineoplastic or immunomodulatory agents, evidence of anaemia (haemogloblin < 11.5 g/dL for females and <12.5 g/dL for males), neutrophils < 1500 cells/mm3, platelets < 90 000 cells/mm3, phosphate < 0.65 mmol/L and serum creatinine > 1.5 × ULN at screening.

Treatments.  Patients were randomised (2:1) to weekly subcutaneous injections of peginterferon alfa-2a 180 μg for 48 weeks and followed up for 24 weeks or once-daily oral adefovir 10 mg for 72 weeks. Patients in both treatment groups continued lamivudine 100 mg/day for the first 12 weeks of the study to decrease the chance of hepatitis flare during the switching period. As the study was designed in 2004, at that time, tenofovir was not available in China and in most practice guidelines, the standard of care for patients developing lamivudine resistance was switching to adefovir rather than adding-on adefovir. So these two arms were included in this study to compare the efficacy of switching to adefovir (standard of care in 2004) vs. peginterferon, which was usually assessed 6 months posttreatment.

Efficacy outcome measures

The primary efficacy endpoint was the rate of HBeAg seroconversion at week 72. Secondary efficacy endpoints at week 48 and 72 included HBeAg clearance, HBV DNA <80 IU/mL, ALT normalisation and HBsAg seroconversion. Changes in quantitative HBsAg levels from baseline to week 24, 48 and 72 were also determined.

Qualitative hepatitis B serological tests were performed by MDS Pharma Services, Beijing, China, using the Abbott chemiluminescence immunoassay (Abbott Laboratories, Abbott Park, IL, USA). Quantitative test for HBsAg was performed by ADICON Clinical Laboratories (Shanghai, China) using the Abbott Architect I2000 platform. HBV DNA, measured using polymerase chain reaction (Cobas Amplicor HBV Monitor V2.0) and ALT tests were performed by MDS Pharma Services.

Safety outcome measures

The frequency, nature and severity of adverse events together with changes from baseline in clinical laboratory parameters and vital signs were assessed. All events considered to be serious had to be reported to study organisers within 1 working day.

Statistical methods

Assuming 2:1 randomisation, the sample size was calculated for the primary efficacy variable, HBeAg seroconversion. Assuming a response rate of 30% for peginterferon alfa-2a-treated patients and 12% for adefovir-treated patients, 140 and 70 patients, respectively, were required to yield an 85% chance of detecting such a difference when a two-tailed test was employed at the 0.05 significance level. Assuming a 10% drop-out rate, 154 and 77 patients, respectively, were required.

All randomised patients who had received at least one dose of study medication and had at least one subsequent safety assessment were included in the safety analysis [intent-to-treat (ITT)]. Efficacy analyses were based on the modified ITT population – patients in the ITT analysis with efficacy assessments available at baseline and at least one visit post-baseline and with no significant baseline violations.

Independent two-sample t-tests, the Wilcoxon rank-sum test, the Chi-square or Fisher’s exact test (for expected cell value less than 5) were used to determine baseline comparability between the two treatment groups and to analyse primary and secondary efficacy endpoints.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patient population

Patient disposition is shown in Figure 1. A total of 255 patients with documented lamivudine-resistant CHB (confirmed by the existence of YMDD mutant with INNO-LipA) were randomised. Of these, 167 and 84 patients, respectively, received at least one dose of study medication. A total of 235 patients were included in the efficacy analysis (modified ITT). The eleven patients not included in the efficacy analysis had significant baseline protocol violations: HBeAg-negative (= 9), bilirubin > 34 μmol/L (= 2). The other excluded five patients had no postdose efficacy assessments (= 5). Baseline characteristics were similar for the two groups (Table 1).

image

Figure 1.  Flow chart.

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Table 1.   Baseline patient characteristics (modified ITT population)
 Peginterferon alfa-2a (= 155)Adefovir (= 80)
Mean age ± s.d. (years)34.4 ± 9.233.9 ± 8.8
Males, n (%)130 (83.9)67 (83.8)
Genotype, n (%)
 Genotype B23 (14.8)9 (11.3)
 Genotype C103 (66.5)58 (72.5)
 Genotypes B/C29 (18.7)13 (16.3)
Anti-HBe negative, n (%)149 (96.1)79 (98.8)
Anti-HBs negative, n (%)154 (99.4)79 (98.8)
Mean HBV DNA (log10 IU/mL) ± s.d.7.35 ± 0.977.39 ± 1.17
Mean HBsAg (log10 IU/mL) ± s.d.4.07 ± 0.563.97 ± 0.74
Median (min, max) ALT (U/L)74.0 (9.0, 1776)61.5 (7.0, 698)
ALT > 1 ULN, n (%)115 (74.2)57 (71.3)
Pattern of YMDD mutant, n (%)
 rtM204I59 (38.1)31 (38.8)
 rtM204V55 (35.5)25 (31.3)
 rtM204I + rtM204V41 (26.5)24 (30.0)

Primary efficacy analysis

At 6 months post-treatment, 14.6% (18/123) patients in the peginterferon alfa-2a treatment arm achieved HBeAg seroconversion, compared with only 3.8% (3/80) patients achieved this endpoint after 72 weeks continuous adefovir treatment (= 0.01, Table 2). Rates of HBeAg seroconversion were similar for both treatments at week 24, but increased progressively in the peginterferon alfa-2a treatment arm between week 24 and 72, however, not in the adefovir group.

Table 2.   Efficacy over 72 weeks (modified ITT population)
EndpointTime pointPeginterferon alfa-2a (= 155)Adefovir (= 80)P-value
HBeAg seroconversion (%, n)Week 243.2 (5/155)3.8 (3/80)1.00
Week 489.3 (14/151)2.5 (2/80)0.05
Week 7214.6 (18/123)3.8 (3/80)0.01
HBeAg loss (%, n)Week 243.9 (6/155)3.8 (3/80)1.00
Week 4814.6 (22/151)5.0 (4/80)0.03
Week 7217.1 (21/123)8.8 (7/80)0.09
HBV DNA < 80 IU/mL (%, n)Week 4823.8 (36/151)16.3 (13/80)0.18
Week 7210.6 (13/123)22.5 (18/80)0.02
ALT normalisation (%, n)Week 4854.5 (61/112)71.9 (41/57)0.03
Week 7251.1 (46/90)66.7 (38/57)0.06
HBsAg lossWeek 724.1 (5/123)0.0 (0/80)0.16
HBsAg seroconversionWeek 722.4 (3/123)0.0 (0/80)0.28

Secondary efficacy analysis

A higher proportion of peginterferon alfa-2a-treated patients compared with adefovir-treated patients achieved HBeAg clearance at week 72 (Table 2). However, the difference was not statistically significant.

Five patients in the peginterferon alfa-2a treatment arm achieved HBsAg clearance 6 months post-treatment and three patients underwent HBsAg seroconversion; none of the adefovir-treated patients achieved these endpoints.

After 72 weeks continuous adefovir treatment, 22.5% of patients achieved HBV DNA <80 IU/mL, compared with 10.6% in peginterferon alfa-2a-treated patients at 6 months off-treatment (= 0.02). Along with the suppression of HBV replication, for patients with elevated ALT at baseline, at week 72, ALT normalised in over one half and two-third of peginterferon and adefovir-treated patients respectively.

HBsAg quantification during treatment with peginterferon alfa-2a

For peginterferon alfa-2a-treated patients, the HBsAg decline was more pronounced in patients who had achieved HBeAg clearance 6 months post-treatment (responders) than in nonresponders (Figure 2). Rate of HBeAg seroconversion at week 72 was significantly higher in patients who had HBsAg decline >0.5 Log10 IU/mL from baseline at week 24, compared with patients with HBsAg decline ≤0.5 Log10 IU/mL from baseline at week 24 [25.5% (13/51) vs. 7.7% (5/65), = 0.01].

image

Figure 2.  HBsAg decline from baseline in peginterferon alfa-2a-treated patients who achieved HBeAg clearance at week 72 (responders) and in those without HBeAg clearance at week 72 (nonresponders).

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Safety and tolerability

Adverse events were consistent with the known profiles of the two study medications (Table 3). Overall, 13/167 (7.8%) of peginterferon alfa-2a-treated patients and 2/84 (2.4%) adefovir-treated patients experienced serious adverse events (SAEs) during treatment, all of which had resolved by the end of the study. Despite discontinuation of lamivudine at week 12, only 1% of patients in each treatment arm experienced a serious hepatobiliary disorder (abnormal hepatic function/hepatitis in peginterferon alfa-2a patients and a case of cholestatic jaundice in the adefovir-treated patients).

Table 3.   Frequency of adverse events in the safety population
 Peginterferon alfa-2a (= 167)Adefovir (= 84)
  1. Values are expressed as n (%).

All adverse events114 (68.3)2 (2.4)
Fatigue32 (19.2)0
Pyrexia84 (50.3)0
Increase in ALT10 (6.0)2 (2.4)
Myalgia20 (12.0)0
Headache23 (13.8)0
Skin and subcutaneous tissue disorders27 (16.2)0

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Although most guidelines propose the use of NAs to rescue patients with lamivudine resistance, there is still debate about the use of IFN to rescue patients with lamivudine resistance. In our clinical practice, some doctors and patients prefer to choose IFN to rescue patients with NAs resistance because both of doctors and patients worried about indefinite duration of treatment and the development of multi-drug resistance.

This is the first randomised, multi-centre study to investigate the efficacy of peginterferon alfa-2a in patients harbouring lamivudine-resistant virus and it showed that response to peginterferon alfa-2a were suboptimal for these patients, compared with treatment-naïve patients.

The viral suppression in both treatment arms was suboptimal. For peginterferon-treated patients, 23.8% of patients achieved HBV DNA <80 IU/mL after 48 weeks of treatment, however, at the end of 24 weeks off-treatment follow-up, only 10.6% of patients sustained the effect. For adefovir-treated patients, the proportion of patients who achieved HBV DNA <80 IU/mL increased steadily from 16.3% at week 48 to 22.5% at week 72 and more patients are supposed to achieve this endpoint if treated even longer. At the end of this study, all patients in adefovir group have the option of continuing adefovir or receiving other treatments based on the recommendation of investigators. So the off-treatment response for adefovir-treated patients is not available.

The HBeAg seroconversion rate 6 months post-treatment seen in peginterferon alfa-2a group was lower than expected. For the 18 patients who achieved HBeAg seroconversion, 10 of them achieved HBV DNA less than 2000 IU/mL which may indicate inactive chronic hepatitis B. We tried to find any predictor of response to peginterferon including the pattern of YMDD mutant, genotype, ALT and HBV DNA level. We performed a sub-group analysis to determine which, if any, could explain the lack of response to peginterferon. None of these predictors were found to influence treatment outcome (data not shown). However, in this study, around two-thirds of patients were genotype C. In addition, as the allowed time interval from screening visit to baseline was within 4 weeks, at baseline, only 72.9% and 67.5% of patients fit the intended cohort at baseline (ALT within the range of 1–10 times ULN) in peginterferon group and adefovir group, respectively. These unfavourable prediction parameters still contributed to the lower response rate in peginterferon-treated patients. Although lower than expected, five patients achieved HBsAg clearance at 24 weeks post-treatment in peginterferon group, in contrast to none in adefovir group. As HBsAg clearance is closest to cure of hepatitis B and may indicate favourable long-term outcome for these patients, the response to peginterferon alfa-2a in the current study is still encouraging.

The suboptimal response of peginterferon alfa in patients harbouring YMDD mutant virus has been reported in other preliminary studies with limited sample size. In 2006, Leemans et al. reported 16 HBeAg positive CHB patients with YMDD mutations treated with peginterferon for a median of 52 weeks and followed up for 26 weeks. Only 2 of 16 (12.5%) patients seroconverted to HBeAg negative and achieved sustained virological and biological response.12 Another study included 20 anti-HBe positive patients with lamivudine resistance treated with combination of peginterferon alpha-2b and lamivudine. Only 5% patients showed sustained virological response after 1-year follow-up.13 As the development of lamivudine resistance has a negative impact on the efficacy of rescue therapy (peginterferon, adefovir or entecavir) in CHB patients, the importance of preventing the development of lamivudine resistance should be highlighted.

Apart from the above-mentioned studies, there are some confounding results concerning the efficacy of peginterferon in patients with previous exposure to lamivudine. In a large retrospective cohort study (PEGaLAM), treatment with peginterferon alpha-2a was found to be as effective in both HBeAg positive and HBeAg negative patients who had received prior NA therapy as in NA-naïve patients.17 Two independent studies from China also analysed the efficacy of 48 weeks peginterferon alpha-2a in HBeAg positive patients who failed prior lamivudine treatment (nonresponders or relapsers).18, 19 Both of these two studies reported that around one-third of patients achieved HBeAg seroconversion 24 weeks post-treatment. However, the three above-mentioned studies shared the same feature that the enrolled patients were not homogeneous population which included patients with or without resistance, patients who have stopped treatment for different intervals and patients with different duration of previous NAs treatment. On the contrary, all the patients enrolled in our study were proved to carry lamivudine resistant virus as detected by Inno-LiPA and all patients were still on lamivudine treatment before study entry. Based on the limited information from these abstracts, we need to be cautious about the conclusion that the efficacy of peginterferon in patients with lamivudine resistance was similar to that in treatment-naïve patients.20

Recently, a study in HBeAg-positive patients investigated the potential of a decline in HBsAg from baseline to predict response post-treatment and showed that patients who experienced no decline in HBsAg levels from baseline at week 12 had little chance of achieving a sustained response post-treatment.21 Our study showed that patients with a rapid decline of HBsAg from baseline to week 24 had a better post-treatment response compared with patients without the rapid decline (25.5% vs. 7.7%, < 0.01). So the monitoring of HBsAg level during treatment is helpful to indicate the subgroup of patients most likely to respond to peginterferon alfa-2a treatment.

The safety profile of peginterferon alfa-2a in the treatment of CHB with lamivudine resistance was similar to that in previous studies in treatment-naïve patients.22 Despite withdrawal of lamivudine at week 12, the frequency of serious hepatobiliary disorders was low in both treatment groups and there was also an absence of hepatic decompensation.

The important limitation of this study is the design of controlled arm–adefovir monotherapy. We clearly understand that this strategy has already been replaced by the combination of lamivudine with adefovir or tenofovir in the updated guidelines after 2004. However, as the objective of this study was to explore the role of peginterferon in the rescue treatment of patients with lamivudine resistance, this randomised study still provided very important information to us.

In conclusion, this study demonstrated that the response to peginterferon alfa-2a was suboptimal among patients with lamivudine resistance. Week 72 HBeAg seroconversion rate by 48 weeks peginterferon alfa-2a was higher than continuous adefovir therapy. However, the off-treatment viral suppression after 48 weeks peginterferon alfa-2a treatment was not as strong as 72 weeks continuous adefovir treatment. Rapid decline of HBsAg levels from baseline at week 24 may be helpful to indicate the subgroup of patients most likely to respond to peginterferon alfa-2a treatment.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The authors thank Professor Anna S. F. Lok (Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, MI) for critical revision of the manuscript. Declaration of personal interests: Michael Jiang and Matei Popescu are employees of F. Hoffmann-La Roche. The other authors have received research grants from Roche to carry out this research. Jin-Lin Hou has acted as a consultant for Novartis, Bristol-Myers Squibb and GSK. Ji-Dong Jia has acted as a consultant for Novartis, Bristol-Myers Squibb, GSK, Roche and MSD. Jak-Yiu Lai has received an honorarium and travel expenses from F.Hoffmann-La Roche. Henry LY Chan has acted as an advisory board member for Roche, Novartis Pharmaceutical, Merck, Bristol-Myers Squibb and Abbott Diagnostics, and has received speaker’s honoraria from Roche, Novartis Pharmaceutical, GSK, Merck and Bristol-Myers Squibb. Jian Sun, Qing Xie, Xiu-Hui Li, Ji-Ming Zhang, Yu-Ming Wang, Hao Wang, Shi-Jun Chen, Ji-Fang Sheng, Jie-Fei Wang, Michael KK Li and Joseph JY Sung have no conflict of interest to declare. Declaration of funding interests: This study was sponsored by Shanghai Roche Pharmaceuticals. The sponsors were involved in the study design and analysis of data. The funders had no role in data interpretation, decision to publish or preparation of the manuscript. They provided financial support for editorial assistance. Jian Sun was supported by Major Science and Technology Special Project of China Eleventh Five-year Plan (2008ZX10002-004, 2009ZX10004-314). Liesje Thomas from Elements Communications provided writing assistance which was sponsored by Shanghai Roche Pharmaceuticals.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References